The PARTNERS Report on MDR-TB Treatment

Half of his family died from TB but Joel has survived the disease because of an affordable new treatment.

The PARTNERS Report on

MDR-TBTreatment

The message is hope.

Special PrintingSpecial Printing

ANNIVERSARYANNIVERSARYANNIVERSARY

As the coordinating body for the PARTNERS Project,

The Task Force for Global Health was responsible for production of this report.

It was written in 2006–2007, and printed by

The Task Force for Global Health in October 2015.

©The Task Force for Global Health 2015.

Contributors included:

Writers: Pranay Ranjan, Alan Hinman, Margaret McIntyre

Editors: Katie Baer, Debbie Horvitz, Julie Rosenberg

Photographers: Mark Rosenberg, Margaret McIntyre, Chip Simone

Graphic Designer: Cathey Oldroyd

Creative Director: Mark Rosenberg

325 Swanton Way | Decatur, Georgia, USA 30030

+1 404.371.0466 www.taskforce.org

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National TB Control Program

Ministry of Health, Lima, Peru

Partners in Health and Socios en Salud

Boston, Massachusetts, USA and Lima, Peru

The Task Force for Global Health

Decatur, Georgia, USA

US Centers for Disease Control and Prevention

Atlanta, Georgia, USA

World Health Organization

Geneva, Switzerland

AcknowledgementsOur deepest, heartfelt thanks go to the patients and their families who shared their stories

of struggle and strength with us and whose experiences inform and shape this work. None of the work would have been possible without the devoted community health workers and the dedicated staff who delivered care on the front lines.

Thank you to the Peruvian Ministry of Health for the invaluable human and material resources and for believing in and supporting a new approach to MDR-TB. Partners in Health and Socios en Salud staff, including nurses and physicians, were there supporting the project and the patients throughout. The US Centers for Disease Control and Prevention and the World Health Organization provided valuable technical and scientific support and a voice for patients in the global policy arena. The Bill & Melinda Gates Foundation trusted in this work and the goal of social justice enough to provide unprecedented levels of financial support.

A special thank you to: Roberto Accinelli, Jaime Bayona, Katie Baer, Mercedes Becerra, César Bonilla, Roberto Canales, Ken Castro, Peter Cegielski, Nicholas DeLuca, Marcos Espinal, Paul Farmer, William Foege, Hamish Fraser, Jennifer Furin, Howard Hiatt, Alan Hinman, Debbie Horvitz, Keith Joseph, Salmaan Keshavjee, Kayla Laserson, Evan Lyons, Jim Kim, Edward Nardell, Margaret McIntyre, Carol Mitnick, Joia Mukherjee, Cathey Oldroyd, Pranay Ranjan, Mario Raviglione, Lee Reichman, Michael Rich, Julie Rosenberg, Rocio Sapag, KJ Seung, Sonya Shin, Chip Simone, Peter Small, Sally Stansfield, Pedro Suarez, Eduardo Ticona, Luis Zavala, Paul Zintl and countless others who helped and remained committed to this project through-out as well as those who continue to build on the work that was done. Don Berwick, Llyod Provost, Judy Provost and the staff the the Institute for Healthcare Improvement provided valu-able guidance on management systems and project planning and continuous improvement.

Partners

T h e R e p o r t o n M D R - T B T r e a t m e n t |

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Preface 3

Thoughts 4

Foreword 5

Introduction 7

Chapter One: The Ever-Growing Threat of MDR-TB 13

Chapter Two: Global Efforts 23

Chapter Three: Peru and The PARTNERS Project 31

Chapter Four: Controlling MDR-TB in Other Countries 53

Joel — A Photodocumentary 60

Chapter Five: Research 91

Chapter Six: Challenges 99

Chapter Seven: Recommendations 111

Afterword 116

Abbreviations Used 117

References 118

Table of Contents

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| P r e f a c e

PrefaceThe PARTNERS TB Control Program accomplished

perhaps the most important thing we can hope to accom-

plish in global health: it won a victory for humanity and

made the world a better place for everyone. The effort

began simply enough, with a vision and the visionar-

ies. These two things were the most critical elements,

the vision — treating drug-resistant TB in resource-poor

areas — and getting the right people, working together and

independently, in locations all around the world. Then, as

I’ve seen so many times in such earthshaking, convention-

breaking efforts, the rest of us must just get out of the way.

The PARTNERS project has seen learning continue

to occur and strategy develop over time. The trick was

in choosing the objective and then recognizing that you

would be changing strategy as you went forward. As a

result — a wonderful result — instead of exporting a

simple model, they exported an attitude that the desired

results can be achieved.

The PARTNERS project also served to unite many dif-

ferent threads. It was serendipitous that so many things

started happening in multiple locations. Usually they

don’t get connected. But the partners in this project were

smart enough to link all these pieces together.

We know we can do better together than we can do

separately. We help our own peoples, our own countries

by being globalists, by learning from and with others.

Einstein reminded us that Nationalism is an infantile

disease. He called it the measles of mankind. We have

learned that strengthening our ability to solve disease

problems involves the paradox involved in strengthen-

ing ourselves… that is, our independence as both people

and countries is achieved through consenting to interde-

pendence. As Gandhi said, if we understand that, we will

pursue interdependence with the same zeal that we show

when pursuing self-reliance.

Having worked on treating MDR-TB should make us

a lot more humble in our approach to other diseases. The

time and energy that people have wasted in arguing over

the right approach could have gone into saving so many

lives. There is a lesson here. In talking about TB or AIDS,

you have to do treatment in order to prevent disease. But

what frequently happens is that treatment absorbs all the

emotional energy of both patients and healthcare person-

nel. This MDR-TB project helped people to stand back

and look at various approaches, to use unique resources

and to adapt. We have to be very careful that we are not so

successful in treatment that we fall behind on prevention.

One secret to successful coalitions is to make the last

mile absolutely clear. For some things, this is easy. For

disease eradication — smallpox and polio — or if you’re

running the International AIDS Vaccine Initiative (IAVI)

program, you know the last mile has to do with develop-

ing a vaccine. For political campaigns, people see the

election of a person as the last mile. But after defining the

last mile, one has to figure out the first mile. How do we

get started? You can’t figure out that first mile until you’ve

identified the last mile.

We seek social justice in health. It is our work foun-

dation, our professional creed, our reason for holding

the positions we hold. There will be a moment when the

phrase, “The world cannot be allowed to exist half healthy

and half sick,” goes from being a nice statement to an

actual commitment. A moment when there is no turning

back and the world, in the words of Toynbee, “dares to

think of the health of the whole human race as a practical

objective.” That moment could come at any time in the

future, but it might just as well come today. It will require

us to give new attention to accumulating data, identifying

gaps, evaluating interventions, and always emphasizing

outcomes.

There are pioneers helping to blaze this trail. The

Bill and Melinda Gates Foundation, along with Rotary

International, has totally changed the paradigm for

global health. We’ve gone from “what can we do with

what we have” to “what will it take to do what needs to be

done” — as partners with government, the private sector,

and NGOs. When Bill Gates was asked how it matters to

an American what happens to someone else in another

country, he said that you do something because this is the

right thing to do.

There is something better than just global health.

Global health is not our last mile. It is not just how do we

improve global health, but how do we enhance civiliza-

tion? How do we enhance the way we treat each other?

We have much left to do.

William H. Foege, MD, MPH

The Task Force for Global Health, Founder

Bill & Melinda Gates Foundation, Senior Adviser


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Thoughts from Project Leaders (2007)

“The valuable financial and technical support we

received through the PARTNERS project helped us

accomplish what many would have considered a mission

impossible in the fight against MDR-TB.

Additionally, I must acknowledge the extraordinary

contributions made by the health promoters, the mem-

bers of the community. Their genuine commitment and

solidarity towards their neighbors affected by this terrible

disease have formed a key weapon in this fight. They are

pioneers, accompanying patients day to day, encouraging

them to not abandon treatment, and identifying and help-

ing satisfy their most urgent needs. Their tireless patience

and cleverness, working to overcome the obstacles, has

been an unforgettable lesson to me.”

Jaime Bayona, MD, MPP

Socios En Salud (SES), Lima, Peru

“The PARTNERS project was truly a labor of love for

all of us who were lucky enough to have participated. A

commitment to treating MDR-TB is by necessity a com-

mitment to the poorest and most marginalized people on

the planet. Now, as MDR-TB emerges as a major threat

to the millions living with HIV in Africa and elsewhere,

the global community can take some comfort in know-

ing that the PARTNERS project has helped to identify

the most effective treatment regimens, designed com-

munity based delivery models, helped shape policy and

prepared the way for a much more aggressive assault on

drug-resistant tuberculosis. We will be forever grateful to

the Bill and Melinda Gates Foundation for giving us this

opportunity.”

Jim Yong Kim, MD, PhD

Brigham and Women’s Hospital

François-Xavier Bagnoud Center for Health and Human

Rights, Department of Social Medicine,

Harvard Medical School, Boston, Massachusetts, USA

“This was not an easy project, and we encountered

strong opposition from outside forces and intense

debates among ourselves, but what ultimately kept us

together and provided the driving and sustaining force

for our success was our common goal: to make avail-

able to even the poorest people in the poorest countries

the treatment that could save their lives and cure their

MDR-TB, because it was a treatment that the rich coun-

tries had and a treatment that the world could well afford.

This goal — of global health equity — inspired us as

individuals, mobilized our organizations, and helped to

change the policies of the most important health bureau-

cracies in the world. We are grateful to all those who had

faith in us and shared our goal.”

Mark L. Rosenberg, MD, MPP

The Task Force for Child Survival and Development

Decatur, Georgia, USA

“The MDR TB projects have provided a powerful

‘proof of principle’ and thus enabled us to collectively

overcome the impoverished will and resignation that

plagued tuberculosis control in resource-limited settings.

Both caretakers and affected persons now feel empow-

ered to think boldly and expansively and to demand the

resources necessary to benefit the individual and their

communities. This win-win situation seeks optimal indi-

vidual outcomes while simultaneously protecting effective

tuberculosis treatment regimens for future generations.”

Ken Castro, MD

National Center for HIV, STD and TB Prevention

Centers for Disease Control and Prevention,

Atlanta, Georgia, USA

“Never was a project more timely and with such

an extraordinary historical importance. [The PARTNERS

project] was timely, as it allowed a rapid transformation

of a dream into reality: the Green Light Committee, just

established with minimum finances by a group of friends,

got the funding needed resulting in a true model in pub-

lic health. It was historically important, as it proved that

modern MDR-TB treatment in resource-limited settings

was feasible. Today this is clear, but it was not at all five

or six years ago. I truly loved this project, for it challenged

the status quo: as a result, thousands of lives were, and

will be, saved.”

Mario Raviglione, MD, FRCP

The Stop TB Department, World Health Organization

Geneva, Switzerland

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| F o r e w o r d

ForewordThe lessons learned in the fight against multidrug-

resistant tuberculosis (MDR-TB) are more relevant

today than ever before. The emergence of a newly identi-

fied threat to tuberculosis control — extensively drug-

resistant or XDR-TB — has been reported in countries

in every region of the world. Data from a rural com-

munity hospital in KwaZulu-Natal province in South

Africa appears to confirm the worst fears: of 53 patients

affected by XDR-TB, only one person survived, all others

died within an average of 25 days. All those who were

tested were HIV-infected, confirming the much feared

convergence of the HIV epidemic with that of highly

drug-resistant TB. The findings have prompted unprece-

dented media attention in Africa and globally. Journalists

refer to the fear and awakening of a “preantibiotic era”

in TB control.

While most of the news reporting on XDR-TB has

been accurate, some of it has been exaggerated by head-

line grabbing hyperbole. In spite of this, the international

TB community must maintain a strategic and technically

sound approach to identifying and treating this disease.

Public health seeks to understand more and to explore

emergency interventions that can save lives. As always

in TB control, the efficacy of the approach to combat

XDR-TB will be measured not by reactions to front-page

headlines but by the intensity of the response and the

cure rates. Our mandate at the international level is to

seek to provide countries with the best recommenda-

tions and to support them in their attempts to imple-

ment complex interventions in the field. The experiences

with MDR-TB of the PARTNERS TB Control Program and

other DOTS-Plus projects have been invaluable and so

can guide the global response to XDR-TB.

The challenges around prevention, diagnosis, and

treatment of drug-resistant TB are enormous, and in

the case of XDR-TB even more so. Although our knowl-

edge of the extent of XDR-TB is still limited, it is likely

to be a global phenomenon with foci in many settings.

Therefore, we must fight this disease globally using a

combination of prevention, diagnosis, and treatment

to control it, and using country-led campaigns to raise

awareness, resources and responses. The main target

is to strengthen TB control in general, for this is the

best way to prevent the onset of drug resistance, be it

multi-drug or extensive drug resistance. At the same

time, case management is fundamental for those who

are already infected.

We believe XDR-TB can still be cured, though in most

cases it will be extremely difficult. Thus, we need to put in

place the best practices for treatment success. We must

examine closely where there have been positive results in

the management of MDR-TB, such as in Latvia, Estonia,

the Philippines, and Peru, countries whose experiences

are profiled in this report.

We also need to address the risks associated with

poor infection control to prevent XDR-TB gaining ground

in congregate settings. Good practices of infection con-

trol are ignored in most settings around the world. We

need to guarantee protection through prevention to

those most vulnerable, especially people living with HIV/

AIDS. This must be done without delay, everywhere.

Further, we must fight not only the disease, but also

the stigma associated with it. As pointed out in this

report, we will not combat MDR-TB and XDR-TB (and

tuberculosis in general, for that matter) successfully

unless we also tackle stigma, ignorance, and fear. This

must be done through information-sharing, public edu-

cation, and effective communication strategies that have

the right outcomes at all levels.

We must also intensify resource mobilization, as

MDR-TB and XDR-TB require additional resources often

not foreseen in the modest national TB control budgets.

We have then to revise (where necessary) the compelling

argument for Stop TB stakeholders to implement and

fund the Global Plan to Stop TB 2006-2015. This is an

absolute necessity if we are to prevent and cure drug-

resistant TB. The Global Plan is ambitious, with a target

to treat more than 50 million TB patients and save mil-

lions of lives, but achievable. And the revised MDR-TB

section of the Plan must be fully implemented to man-

age 1.6 million patients by 2015, given the additional,

urgent threat of XDR-TB.

Finally, we need to take a hard look at the agenda

of TB research and development. We cannot afford fail-

ure and slow progress in this area. The emergence of

XDR-TB has exposed us to the limits of current tools. We

must have new rapid diagnostics, new drugs and new

vaccines, and we must have them as soon as possible.

When available they must quickly be made accessible to

all, no matter who TB patients are or where they live.


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All of these challenges are summarized in this report

and also prominently featured in a document that has

become the cornerstone of our work — the new Stop TB

Strategy, which calls for integration of activities relating

to MDR-TB (and XDR-TB) and TB/HIV into all TB control

programs. The Stop TB Strategy was launched with The

Lancet in its World TB Day 2006 edition. The Strategy

was developed over a two-year period alongside other key

initiatives in public health such as universal access to HIV

care and prevention. One approach cannot be complete

without the other.

Through the strengthening of TB control every-

where, through the full and high quality expansion and

enhancement of DOTS as outlined in the 2006 Stop TB

Strategy, we can strike a serious blow against one of the

world’s leading infectious killers and we can prevent fur-

ther misery caused by the manmade failures that unleash

TB drug resistance. This is the responsibility of everyone

working in TB control today.

Mario Raviglione, MD

Director, Stop TB Department

World Health Organization

Geneva, Switzerland

November 2006

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| I n t r o d u c t i o n

Introduction

health. Furthermore, many in the healthcare community

believed that “failed” patients who developed MDR-TB

did so because they did not adhere to their prescribed

regimen. Treating a small number of patients who may

have brought the disease upon themselves, they argued,

was worth neither the resources nor the difficulties inher-

ent in such a complex treatment. At this point, the sci-

ence behind the development of the disease was not fully

understood and, hence, it was determined that MDR-TB

would not be treated in resource-poor countries.

Patricia watched friends and neighbors die. When the

doctors at the National Tuberculosis Program suggested

A New Twist on an Old DiseaseTuberculosis (TB) had killed millions of people for

thousands of years until treatments finally became avail-

able in the middle of the 20th century. (See Box 1 for an

overview of TB.) No treatment had been accepted as

the universal standard of care until the World Health

Organization (WHO) endorsed the Directly Observed

Treatment — Shortcourse (DOTS) strategy in 1994. (See

Box 2 for components of DOTS.) DOTS, a strategy in

which healthcare workers supervise patients while they

undergo a standard six-month treatment, brought hope

to caretakers and patients alike.

Patricia received DOTS treatment in Peru the same

year that WHO endorsed the DOTS strategy. Two years

later, at the time WHO recognized Peru for having one

of the best national tuberculosis programs in the world,

Patricia gave birth to her third child and relapsed with TB.

Returning to her local health center, she received DOTS

again but reacted differently to the medicines and suf-

fered debilitating side effects. So that she could physi-

cally care for her three small children, Patricia temporarily

stopped her treatment. Growing sicker by the day, she

later returned to the health center and resumed her treat-

ment. She stopped only when told that she had exhausted

all of her treatment options and could not be cured.

Patricia’s strain of tuberculosis was resistant to the

two primary drugs used in DOTS treatment, isoniazid

and rifampicin, and so was identified as multi-drug resis-

tant tuberculosis (MDR-TB). Although cases of MDR-TB

were recorded around the globe, it was considered rare in

the early 1990s. (Box 3 gives an overview of MDR-TB.)

Healthcare professionals continued to recommend

the standard DOTS treatment — short-course chemo-

therapy with first-line drugs — for all TB patients. The

treatment “failed” for some patients, but treating these

“failures” on a programmatic level would have required

an enormous investment of money and supplies, as well

as the development of a treatment protocol far more

complex than DOTS. Realizing that DOTS was not a

“magic bullet” for all patients was extremely difficult; its

broad success had been an enormous victory in public

Tuberculosis (TB) is a bacterial infection caused by the organism, Mycobacterium tubercu-losis. Globally, 2 million people die from TB every year. Most commonly this bacterium infects the lung, giving rise to pulmonary tuberculosis (PTB). Infection with the organism does not always prog-ress to disease. In the vast majority of cases, the infection is successfully countered by the body’s immune response and does not progress to dis-ease. In some cases however, the infection can lie dormant for several years before causing illness. Usually such a dormant infection surfaces when the immune system is weakened, either due to ill-ness or old age. Infection with HIV is a common

reason for activation of dormant TB infection.

What are first-line drugs (FLDs)?The 5 main drugs used to treat drug susceptible tuberculosis are called first-line drugs (FLDs):

• Rifampicin• Isoniazid• Ethambutol• Pyrazinamide• Streptomycin

Box 1

What is TB?


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she invest in a coffin rather than in further health interven-

tions, she worried that the end was in sight for her too.

A Cure to Treat All IndividualsAmong those refusing to dismiss MDR-TB as

untreatable in resource-poor countries were Paul Farmer

and Jim Kim, two doctors from Harvard Medical School

in Boston who were committed to making the highest

quality of medical care available to the poor around the

globe through the work of their non-profit organization,

Partners in Health (PIH), established in 1987. Recognizing

that WHO’s DOTS “solution” was not the ultimate in TB

control and disagreeing with a decision that, in essence,

decreed that the poor did not merit expensive and dif-

ficult medical treatments, Farmer and Kim expanded their

vision of a “preferential option for the poor.” Noting that

people in the poor shantytown of Carabayllo, Peru, were

not responding to TB treatment and dying from a treatable

disease, the two PIH physicians joined with a doctor from

Lima, Jaime Bayona, to establish Socios en Salud (SES),

a community-based health clinic located in Carabayllo.

They found that most of the patients who did not respond

to DOTS treatment were infected with resistant strains of

the disease, sometimes resistant to as many as 9 or more

drugs. While some patients had strains that developed

resistance over time as a result of multiple treatments,

others had been directly infected with resistant strains.

SES developed a system for treating Carabayllo’s

MDR-TB patients. Sputum samples from patients

considered “treatment failures” were shipped to the

Massachusetts State Laboratory Institute (MSLI), where

experts identified which drugs would work on the micro-

organisms infecting each patient. SES then procured the

drugs from Harvard Medical School (HMS) and estab-

lished individualized treatment plans. Since many of the

very powerful medications used to treat MDR-TB caused

severe side effects, patients often felt worse once they

began their new, individualized treatment. Furthermore,

because they had been told by their local doctors that there

was no cure for their disease, some patients did not believe

in the new treatments that the foreign organization was

offering. Aware of these concerns, the trained community

health workers who were administering the medication,

patient by patient, also provided psychological support.

SES made financial and nutritional support available to

patients to ensure that they were equipped with at least the

minimal resources necessary for recovery and health.

By 1998, only three years after SES was established,

several patients were cured. SES had proven that this indi-

vidualized treatment for MDR-TB was, indeed, feasible

in a resource-poor setting. WHO named this treatment

DOTS-Plus and organized a DOTS-Plus working group.

(Box 4 explains the basics of the DOTS-Plus strategy.)

The movement for change envisioned by Farmer and Kim

was in motion. Beginning in 2000, several DOTS-Plus

projects were established around the world.

That same year, the still-small SES opened a clinic in

Patricia’s district of Lima. She was living in her parents’

home with her husband, three children, four siblings, and

extremely damaged lungs after six years of TB. Hopeful

that her illness would come to an end, she began the

new treatment targeted specifically at her strain of TB.

However treatment had come too late and, at 28 years

In 1995, WHO officially named Directly Observed Therapy Short-Course (DOTS) as the strategy for global TB elimination. Initially ap-plied in 1991, DOTS was based on the short course chemotherapy that had long been used in vari-ous settings around the world. DOTS involves 5 components:

• Sustained political commitment to increase hu-man and financial resources and make TB con-trol a nation-wide activity and an integral part of the national health system.

• Access to quality-assured TB sputum microsco-py for case detection among persons presenting with symptoms of TB, screening of individuals with prolonged cough by sputum microscopy and special attention to case detection among HIV-infected people and other high-risk groups, e.g. people in institutions.

• Standardized short-course chemotherapy to all cases of TB including direct observation of treat-ment; and proper case management conditions with technically sound and socially supportive treatment.

• Uninterrupted supply of quality-assured drugs with reliable drug procurement and distribution systems.

• Recording and reporting system enabling out-come assessment of each patient and assess-ment of the overall program performance.

Box 2

What is DOTS?

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old, Patricia died. She had fought the disease, the drug

side effects, the heavy stigma of carrying a “deadly” infec-

tious disease, and the burden of poverty. By the time she

died, the infection had spread to four of her siblings. Their

awareness of DOTS-Plus and timely search for individual-

ized treatment saved their lives.

Reconsidering the ParadigmJoel‘s siblings were not as lucky as Patricia’s. In

2000, the year Patricia began and ended individualized

treatment, Joel’s 17-year-old sister, Jonni, died suddenly

from MDR-TB. His brothers, Moses and Marcos, were ill

by the next year. At the time of their deaths, Moses was

27 and Marco, 32. Each had received DOTS, but none was

cured. They did not know about drug-resistant strains and

their disease advanced quickly. Living too far from SES

or arriving for help too late, people in shantytowns like

Carabayllo were continuing to die.

As PIH and SES doctors shared their experiences,

proving that poverty did not prevent MDR-TB from being

cured, the global burden of the disease came to be rec-

ognized. Several groups joined together to advocate for

immediate action against MDR-TB and to combat the

threat it posed to future generations. In August 2000, the

Partnership Against Resistant Tuberculosis: A Network

for Equity and Resource Strengthening (PARTNERS) was

established. PARTNERS members were the Peruvian

National TB Control Program (PNCT), SES, PIH, WHO,

the Centers for Disease Control and Prevention (CDC), and

The Task Force for Child Survival and Development (Task

Force). Funded by the Bill and Melinda Gates Foundation

(Gates Foundation), PARTNERS aimed to develop a

model for treating MDR-TB in a resource-poor country

(Peru) and in an MDR-TB hot-spot (Tomsk, Russia). A fur-

ther goal was to create global policies for MDR-TB based

on research and programmatic findings. The project was

funded for five years. WHO shifted its TB control strate-

gies and became part of a team with a powerful philoso-

phy about MDR-TB treatment to share and spread.

Other alliances and committees formed as well. The

Green Light Committee (GLC), for example, negotiated

significant discounts in the prices of second-line drugs.

The GLC also provided expertise for DOTS-Plus projects

seeking technical assistance. Some drugs were reduced

in cost by up to 99%, thanks to the GLC. Not only had

MDR-TB treatment become feasible, it could be affordable.

Joel and his sister, Marlene, were among the esti-

mated 273,000 MDR-TB cases in 2002; the number of

cases was growing quickly. They started DOTS-Plus treat-

ment with SES. Unfortunately, Marlene started too late

and she died soon after. Having watched Marlene as

well as three other siblings die within two years, Joel was

depressed. Taking every dose of his medication, he tried

to believe in a cure, but it was hard. The drugs exacerbated

his depression and caused psychosis, nausea, and skin

discoloration. His relationship with his girlfriend fell apart,

as did his health. Despite his new college degree, Joel had

to stop working, as did his father who became mentally

ill after losing four children. Joel’s mother supported the

household, including her orphaned grandchildren, work-

ing every day in the market. The health promoters reas-

sured Joel that the treatment would work if he stayed with

his drug regimen, and he attended an SES patient support

group. With lots of help, Joel pulled through.

Multi drug-resistant tuberculosis (MDR-TB) is a form of tuberculosis in which the TB bacteria are resistant to the two main first-line drugs used to treat TB, Rifampicin and Isoniazid. It typically arises as a result of incomplete or inadequate treat-ment of drug sensitive TB (acquired resistance) but a person can also be infected with multiply-resistant bacteria (primary resistance).

What are second-line drugs?

Because of resistance to FLDs, MDR-TB re-quires a second set of drugs also known as second-line drugs (SLDs). The TB bacteria are much less likely to have resistance against these drugs.

• Amikacin• Capreomycin• Ciprofloxcacin• Cycloserine• Ethionamide• Kanamycin• Levofloxacin• Ofloxacin• Para-aminosalycylic acid • Prothionamide

Box 3

What is MDR-TB?


10 |

As Joel began to recover, his mother fell ill, revealing

the unyielding resilience of the TB bacilli. He risked rein-

fection in order to help her, even as he completed his own

treatment. They survived together no longer infectious

and able to move ahead with life and work. As people gain

access to treatment earlier, the outcome improves. Over

time the disease becomes more familiar to doctors and

the stigma lessens.

Esperanza and her husband represent two additional

MDR-TB cases. When Esperanza’s husband relapsed

after completing DOTS treatment in 2001, doctors knew

to prescribe DOTS-Plus treatment for him. Esperanza

took a second job to provide food for the family while

her husband was treated. A 29-year-old mother of four,

Esperanza lived in a small, two-room house with a dirt

floor, but she trusted the treatment and believed her hus-

band would recover. Before long, however, she became ill

with TB. After three months of first-line treatment with no

improvement, Esperanza began DOTS-Plus. She stopped

working while she was contagious and received some

financial help from SES. Her primary worry was her chil-

dren. Esperanza and her husband gained strength and

grew closer by sharing their experiences. They believed

in the treatment and the SES health workers who visited

daily as the couple struggled through the disease that

exacerbated the hardships of poverty. After two years of

treatment, both were cured and able to raise their children

in a stronger, happier family.

The Paradigm Change in TB Control

Until the late 1990s, virtually nothing was known

about MDR-TB. No initiatives or guide-lines for its pre-

vention and treatment in resource-poor countries were

in sight; there were no public health programs or poli-

cies; only a few parts of the world had been surveyed;

scarcely any research existed. In fact, experts doubted the

transmissibility and resiliency of MDR-TB and questioned

whether it was a threat at all.

The research and clinical work performed by the

PARTNERS TB Control Program and other DOTS-Plus

projects have erased that doubt. Over 100 DOTS-Plus

programs around the world are now treating families and

saving lives in small shantytowns like Esperanza’s that

a few years ago would have left children, like Patricia’s,

orphaned. In 2002, the year after WHO first published

guidelines on the programmatic management of

MDR-TB, the disease’s global incidence was estimated

to be 273,000. Four years later, that estimate was revised

upwards to 423,000, showing that the disease was a big-

ger problem than previously acknowledged. The explod-

ing HIV epidemic also has brought attention to MDR-TB

because concurrent infection increases its spread.

Publicity also surrounds recent information about the

potentially lethal co-existence of HIV/AIDS and exten-

sively drug-resistant TB (XDR-TB).

WHO revised its MDR-TB management guidelines

in 2006 and now recommends that programs to control

MDR-TB be integrated within all TB programs around the

world. WHO set specific objectives in the second Global

Plan to Stop TB and brought this enormous public health

The term DOTS-Plus was adopted by WHO in 1998 at a conference in Cambridge, Massachusetts, as a case management approach for MDR-TB. Since then DOTS-Plus pilot projects have been initiated in several countries and DOTS-Plus has come to encompass the following five principles slightly adapted from the principle of DOTS.

• Sustained political commitment that assures: long term investment of staff and resources; co-ordination of efforts between community, local governments, and international agencies; a well-functioning DOTS program; and prevention of the emergence of MDR-TB

• Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing; prop-er triage of patients into DST testing and the DOTS-Plus program; and relationship with Supra-National Laboratory

• Appropriate treatment strategies that utilize SLDs under proper management conditions; rational treatment design (evidence-based); di-rectly observed therapy (DOT); monitoring and management of side effects; and adequate hu-man resources

• Uninterrupted supply of quality-assured second-line anti-tuberculosis drugs

• Recording and reporting system designed for DOTS-Plus programs that enables program per-formance monitoring and evaluation of treat-ment outcome.

Box 4

What is DOTS-Plus?

| 11


problem into the world’s consciousness. This sea change

regarding drug-resistant strains of TB is a result of the

dedication of so many people who, in addition to saving

lives, have helped bring attention to the disease, which, in

turn has enhanced funding to control and prevent it.

PARTNERS TB Control Program’s Role in the Change

While numerous people around the world deserve

credit for the successes achieved thus far in controlling

MDR-TB in resource-poor countries, this report focuses

on the work of the PARTNERS TB Control Program. This

report documents the stages and phases of the major

paradigm change in TB control over the last decade and

especially between 2000 and 2005, when the PARTNERS

group was active. It is the story of the group that gal-

vanized efforts and helped prove to the world that

MDR-TB is curable, even in resource-poor nations. Its

members’ commitment to bringing first rate medical

care to impoverished patients has inspired the initially

reluctant public health world to change its view and save

lives everywhere.

Challenges remain for future leaders, and we hope

that this report also helps policy and healthcare fund-

ing leaders understand the threat that MDR-TB poses

to the world and can build upon these past successes.

Furthermore, this report can be a tool for those with

visions like Farmer and Kim; we hope it serves as a road

map for those who are inspired to organize their own

project or to take action with people locally to bring about

a higher quality of life. Above all, the report aims to show

that we can bring to poor places and poor people the

same opportunities for good health that we bring to peo-

ple in richer countries. Demonstrating the feasibility of

global health equity was as central to this project as dem-

onstrating the effectiveness of DOTS-Plus as a treatment

for MDR-TB.

This report records the evolution of the struggle that

motivated WHO, among other organizations, to reverse

its strategic position on MDR-TB and agree to treat the

disease in resource-poor countries. The Task Force, as

a member of the PARTNERS Project, has accepted the

responsibility and challenge of documenting this power-

ful story that summarizes what was accomplished with

the support of the Gates Foundation. While this report

addresses global policy makers on TB control, funding

organizations, leaders of national tuberculosis programs,

and other institutions directly concerned with TB, it will,

we hope, be instructional and inspirational to those unfa-

miliar with tuberculosis who will, we think, be interested

in its broader aspects, such as working within a coali-

tion that is forging a new path, establishing effective pro-

grams, contending with adversity, and accommodating

to enormous cultural differences. If this report engages

anyone in the movement for social change and universal

MDR-TB treatment, it will have proven successful.

The PARTNERS ReportThe chapters that follow will explain what the global

community needs to do to meet the goals of the second

Global Plan for TB control. Chapter 2 discusses how the

threat of MDR-TB has increased over the past few years

and Chapter 3 traces the global efforts to tackle it. Chapter

4 describes how DOTS-Plus has been implemented in

several countries and how each pilot project has influ-

enced global policy. Since Peru was the initial site for

DOTS-Plus, as well as a primary focus for the PARTNERS

Project, Chapter 5 is dedicated to the experience there.

Chapter 6 discusses what has been gleaned from targeted

research, including the tremendous advances in science

resulting from investigations and studies conducted in

Peru and elsewhere. And, the report closes with a compi-

lation of the challenges we face along with recommenda-

tions for immediate and long-term action.

Throughout the report, we have included photographs

and quotations from three Peruvian patients — Patricia,

Esperanza, and Joel, already introduced. We got to know

them well over the years as they shared their stories with

us. They volunteered to participate in this photo docu-

mentary to give voice to all patients affected by MDR-TB–

those who are undergoing treatment now, feeling sick

from the medication every day, and those who continue

to suffer without access to care. The patient’s family

members speak for families that can no longer speak for

themselves, some still struggling with the disease and

others that have been cut in half. The photos of the chil-

dren represent our hope that future generations will know

about this disease only as a piece of past history if we all

continue to do our parts to bring about change.

“My biggest fear is that my children will come down with TB.

We have to take care of them, lots of care.”

–Esparanza, MDR-TB patient

Chapter One

| 13

| T h e E v e r - G r o w i n g T h r e a t o f M D R - T B

Through the efforts of many organizations and

dedicated individuals over the past seven years, we have

learned much about the origin, distribution, diagnosis,

treatment, and prevention of MDR-TB. The most signifi-

cant finding is that it is a far more serious and pervasive

threat than previously realized. Already wide-spread and

increasingly recognized are even more highly resistant

strains, called Extensively Drug Resistant TB (MDR-TB),

resistant not only to the two most important first-line

anti-TB drugs but also to any fluoroquinolone and at least

one of three injectable second-line drugs (capreomycin,

kanamycin, and amikacin). Furthermore, MDR-TB poses

a grave threat when it occurs in persons with HIV/AIDS.

Our research affirms that controlling MDR-TB

demands a still greater investment of time, resources,

and dedicated effort. Today we are treating less than 2%a

of the cases that occur each year. The Global Plan to Stop

TB 2006–2016 calls for immediate and considerable

expansion of programs over the 10-year period. However

it is likely that at the end of the period too few new inci-

dent cases will have been treated.

MDR-TB Is More Widespread than Previously ThoughtLatest Estimates of Incidence Are

Significantly Larger than Previous Estimates

In 1994, the World Health Organization (WHO),

the International Union Against Tuberculosis and Lung

Diseases (IUATLD), and other partners began the

Global Project on Anti-Tuberculosis Drug Resistance

Surveillance, which has published three reports over

the last 10 years, including one in March 2004. Based

on the collected data, estimates of the global burden of

MDR-TB have regularly been revised upwards. In 2002,

the estimate of new cases was 273,000, while in 2006

the total estimated number grew to 424,000.1 One

explanation for the increase is the fact that the 2006

estimate is the first to include patients with MDR-TB

patients who had been previously treated at least once

in addition to those who had received no prior treat-

ment. Before this, all reports counted only patients in

the latter group.

The Ever-Growing Threat of MDR-TB

a Annual incidence was 489,000. One percent was 4,890. We treated 30,000 in the years 2000-2005 or approximately 6,000 per year.

14 |

Prevalence

� 0.9%

1.0%-2.9%

3.0%-6.4%

� 6.5%

Prevalence

� 9.9%

10.0%-19.9%

20.0%-29.9%

� 30.0%

Highest MDR-TB rates >10% among new cases | >50% among previously treated cases

Estonia

Kazakhstan

Russia (Tomsk)

New cases

14.2

14.2

13.7

Uzbekistan

Russia (Ivabovo)

13.2

12.3

Russia (Ivabovo)

Kazakhstan

Lithuania

Previously treated cases

58.1

66.4

63.3

Figure 1:

MDR-TB prevalence among

new (never treated before)

cases has been estimated for

several countries between

1994 and 2002.

(Source: World Health

Organization)

Figure 2:

MDR-TB prevalence

among previously treated

cases has been estimated

for several countries

between 1994 and 2002.


Organization)

Figure 3:

Highest MDR-TB rates

were found in the Eastern

European Region and

the Russian Federation.


Organization)

Chapter One

| 15


Figure 1 shows the estimated prevalence of MDR-TB

among patients around the globe who were not previously

treated for TB. It is believed that a substantial proportion

of these patients have primary MDR-TB; that is, their ini-

tial infection was with multidrug-resistant organisms.

Figure 2 plots the prevalence of MDR-TB among

patients who have been treated previously. These patients

may have acquired MDR-TB as a result of inappropriate

treatment or they may have primary MDR-TB.

MDR-TB rates in the areas studied in the Russian

Federation and the Eastern European region are among

the highest in the world (Figure 3), where inadequate

treatment of TB underlies the vast majority of cases.

Confinement in close quarters combined with inap-

propriate treatment of drug-resistant cases led to high

rates of MDR-TB among prisoners in Russia and Eastern

Europe. Many infections that originated in prison are

believed to have spread into the civilian sector as pris-

oners were released, often with incomplete follow-up.

Figure 3 reflects the highest MDR-TB rates from the sites

that have reported incidence; it is possible that there are

sites with higher rates that have neither measured nor

reported them.

Current Surveillance Incomplete

Despite considerable progress in the number of coun-

tries it has covered since 1994, the Global Project’s most

recent report acknowledges enormous gaps in surveil-

lance. No data are available for more than 100 countries.

And, in China, India, and the Russian Federation — three

countries that combined are estimated to account for two-

thirds of the global burden of MDR-TB — we still do not

have countrywide data. Figure 4 shows the parameters of

our data procurement efforts around the world. The rates

of MDR-TB for these countries have been extrapolated

from subnational surveys — surveys that cover only por-

tions of the country. Because estimates have been made

on the basis of incomplete data, it is possible that MDR-TB

is even more extensive than the current surveys predict.

One reason why surveillance is incomplete at this

time is because early surveys were designed to assess

MDR-TB incidence in new, untreated patients. More

recent studies, however, include the previously treated

cases as well. Another reason we lack data for so many

regions is the difficulty of diagnosing MDR-TB, which

involves complex and expensive procedures. (See Box 5,

p 16 for more on MDR-TB diagnosis.) While in the long

term, surveillance data can reveal trends in the disease as

well as its prevalence, MDR-TB has not been monitored

long enough to establish the necessary data points.

Unaccounted Patients Treated

in the Private Sector

Persons with TB who are diagnosed and treated in

the public sector (National TB Programs) are reported

and treated with standardized regimens. By contrast,

those who are diagnosed and treated in the private sector

may not be reported and may be treated with regimens

that do not follow guidelines.

Thus far, no adequate strategy has been implemented

for monitoring the vast number of MDR-TB patients who

are treated by private practitioners. In India, for example,

Data source

no data

estimates

sub-nationalsurveys

countrywidesurveys

Figure 4:

China, India, and the

Russian Federation,

responsible for two-thirds

of the global cases of

MDR-TB, have had only

sub-national surveys.


Organization)


16 |

as many as half of the approximately 2 million newly diag-

nosed TB patients per year visit private physicians, alter-

native healers, or pharmacies for their care.2 And since, in

general, the private sector remains insufficiently informed

about TB, the likelihood that these patients will develop

MDR-TB is higher, as a result of inadequate or improper

treatment. Poor reporting combined with poor treatment

means that an enormous number of MDR-TB cases are

probably being missed. Given that India’s private sec-

tor treats one-sixth of TB cases worldwide,3 it is impera-

tive that accurate methods of surveying privately-treated

patients are developed. The lack of information from

the private sector is certainly not a problem restricted

to India; many other countries with large populations of

TB patients treated outside of national government pro-

grams have similar difficulties estimating MDR-TB’s true

danger. If knowing the adversary is crucial to defeating it,

we are duty-bound to learn the full extent of MDR-TB’s

global burden. Only then can we extinguish its threat to

the world’s health.

MDR-TB Cases Continue to Be Generated in Many Ways

Current estimates suggest that around the world,

approximately 489,000 cases of MDR-TB are generated

annually, creating a global pool (or prevalence) of 1.0 to

1.5 million.4 Among the flowing spigots adding to this

global pool of infection5 are unavoidable treatment fail-

ures, inadequate treatment, amplification of resistance,

transmission of drug-resistant strains, and the activation

of latent infection.

The difficulty of diagnosing MDR-TB is a major obstacle to conducting good surveillance on the disease.

This is not the case when diagnosing TB in general. That diagnosis is made by confirming whether or not

the TB bacteria are present in a patient’s sputum, which is determined with a simple microscopic examina-

tion by preparing and staining specimens, then detecting bacteria appearing in red (i.e. acid fast bacilli) on

the slide.

But diagnosing MDR-TB is a far more intricate procedure. First, the organisms must be cultured in ap-

propriate media followed by complex and quantitatively precise measurement of how the cultured mycobac-

teria grow when exposed to the antibiotics used to treat TB. Using traditional techniques, this can take weeks

to perform and many factors can interfere with accurate results, such as the culture becoming contaminated

by cross-infection with other mycobacteria. Spurious results can also occur if good quality control is not

maintained, which is much more likely if personnel are insufficiently trained in the handling of specimens

and laboratory equipment. Furthermore, susceptibility testing for second-line drugs is more complex and

less standardized than that for first-line drugs.

In the field, numerous other factors can affect an accurate diagnosis. For example, in order for a labora-

tory to function properly, it must be well equipped, with appropriate equipment, reagents, and a continuous

supply of electricity and water. Scrupulous attention must be paid to several operational aspects including

specimen labeling, recordkeeping, and reporting. Good management and sustained funding by the health

ministry of each country are mandatory to maintain the equipment, supplies, and the building itself. And,

importantly, personnel must be specifically trained and supervised in the correct testing technique for MDR-

TB. When laboratories that do not regularly perform these tests are asked to do so for a survey, the results

are less likely to be accurate.

Countries that lack the laboratory capacity to diagnose MDR-TB also lack the capacity to count cases,

both new and existing and thereby contribute significantly to the uncertainties of global estimates. This is

why the parameters of this global epidemic remain uncertain.

Box 5

Diagnosing MDR-TB

Chapter One

| 17


Even Good DOTS Programs Cannot Completely Prevent MDR-TB Cases

Even in countries with excellent DOTS programs,

some patients’ treatments are unsuccessful. A country

with a cure rate as high as 90% still has a 10% failure

rate. It’s likely that these patients’ diseases may progress

to a stage where the bacteria become resistant to first-line

drugs. It’s not know what fraction of “unsuccessful” treat-

ments will be cured by repeating DOTS treatment. Peter

Small and colleagues did a study6 in Mexico and found

that repeating DOS treatment and doing it better cured

a large portion of previous failures, even those thought

to have MDR-TB. However retreatment may lead to the

development of further resistance and lower cure rates;

the issue requires additional consideration.

Inadequate Treatment Causes Drug Resistance

Patients who are not prescribed the right drugs or

dosages, those who receive poor-quality drugs, and those

who either don’t take all their drugs or don’t complete

the regimen often develop mutant strains of TB bacilli

that are resistant to the medicines most commonly used

to treat TB. While inadequate treatment may occur more

often in the private sector, even committed DOTS cam-

paigns cannot always guarantee success. While trying to

assure that every patient is adequately supervised and

completes his or her treatment, DOTS cannot eliminate

development of resistance in individual strains of M.

tuberculosis or the operational problems suffered by many

facilities, including drug shortages and/or too few work-

ers to assure patient follow-up. As a result of poor com-

pliance, resistant strains of TB may emerge. Moreover, as

we mentioned earlier, many TB patients seek care from

the private sector or from alternative health providers

where inadequate treatment is much more likely. Varying

greatly in the type, dosage, and duration of treatment

they prescribe for TB, these providers seldom supervise

or educate their patients adequately, which explains a

great deal of patient non-compliance and, in turn, leads

to acquired resistance to the TB drugs.

When a person with active TB is treated more than

once with the same regimen to which the TB bacilli have

already developed resistance to one or more of the drugs,

a progressive increase in the number of drugs to which

the TB bacteria become resistant often occurs. This phe-

nomenon, called “amplification of resistance,” has been

well documented in many countries, including Peru and

the countries of the former Soviet Union. Several settings

have reported a disturbing trend: patients with strains

that are resistant to many first-line drugs in addition to

isoniazid and rifampicin, the two most important first-

line drugs. Some are even resistant to all five first-line

drugs. When these patients are treated with first-line

drugs repeatedly and repeatedly fail to be cured, they

may be labeled ‘chronic’ cases. The problem, however,

is not that they are incurable; rather it is that they are

being treated over and again with drugs that are ineffec-

tive against their resistant strains of bacteria, treatment

which only exacerbates the problem of resistance. In addi-

tion, repeated treatment regimens that add only a single

new drug to a failing combination can amplify resistance,

which can develop to both first- and second-line drugs.

Unfortunately, some patients have strains resistant to as

many as 7 or 8 second-line drugs.

Infectious Cases Spread Disease through Primary Transmission

Whether or not MDR-TB is as infectious as drug-sus-

ceptible TB continues to be debated. While some believe

that the MDR-TB bacteria are neither as robust nor as eas-

ily transmitted as drug-susceptible TB bacteria, epidem-

ics of MDR-TB suggest otherwise. The outbreaks in New

York in the late 1980s and early 1990s, those in Russian

prisons, and nosocomial infections in other places5 have

shown that the bacteria can be readily transmitted.


18 |

Previously, epidemiologists thought that one per-

son with drug-susceptible TB would infect 7 additional

people each year,7 but more recent estimates lower this

figure to between 4 and 5.8 That MDR-TB may have simi-

lar transmission dynamics bodes poorly for the health

of the world, especially in the context of ever-increasing

globalization. With growing trade and tourism, this is

potentially a worldwide epidemic.

In hospitals where MDR-TB patients are being

treated, the disease may spread readily when proper steps

to prevent airborne transmission have not been taken.

Poor ventilation designs and not separating MDR-TB

patients from others are just two examples. In some

facilities, inadequate understanding of the dynamics of

airborne transmission contributes to the disease’s esca-

lation. Studies in Tomsk have shown that patients who

began treatment for non-resistant TB in hospitals were

12.7 times more likely to develop MDR-TB as compared

with those who were treated as outpatients only; those

who were later hospitalized were 9.6 times more likely to

develop MDR-TB than the outpatients.9 A study in South

Africa designed to measure airborne infection of MDR-TB

has shown that 82% of guinea pigs exposed to air from

MDR-TB patients’ rooms developed positive skin tests.10

Certainly these figures highlight the need to imple-

ment stricter measures of infection control in hospitals,

clinics, labs, and other settings where MDR-TB can be

transmitted easily. Personnel in many facilities still need

to be educated to the fact that sub-standard measures for

controlling infection can lead directly to airborne spread.

And, among those who are aware of this and are trying to

promote higher standards of infection control, procuring

necessary training and expertise is happening too slowly.

Latent Infection with MDR-TB May Progress to Active Disease

Persons who are infected with TB bacilli but are not

clinically ill are considered to have latent infections. While

these individuals are not contagious, their infections may

manifest clinically at a later stage through endogenous

reactivation. In a life-time, the risk for an infected individ-

ual to develop TB is on the order of 10%. If he or she has

already been infected with HIV, the risk jumps to 8-10%

per year.11

Although latent infection with TB can be identified

in many settings, it is not currently possible to differenti-

ate latent infection with susceptible strains from latent

infection with MDR strains. And, if we could, there are as

yet no chemoprophylactic regimens shown to be effective

in preventing future manifestation of MDR disease. Even

a properly run DOTS program would be unable to cure

latent MDR-TB infections.

Programmatic Control of MDR-TB is Difficult

In the last few years, projects around the world have

demonstrated that MDR-TB can be controlled within

existing national tuberculosis programs. Yet, program-

matic issues — diagnostic, clinical, and logistical — inter-

fere with the successful management of MDR-TB more

so than they do with drug-susceptible TB:

• Diagnosing MDR-TB requires expensive, tech-nologically advanced equipment, and well-trained personnel.

• Treatment has to be tailored according to the specific resistance pattern of the microbes.

• Treatment requires between 18-24 months, during which patients need to be closely monitored the entire time for side effects, which in themselves can be difficult to manage.

• Medicines are expensive and may not be easily available.

• Recordkeeping is complicated considering the long treatment with numerous drugs, and the variety of possible side effects.

Chapter One

| 19


Program managers have a host of other, equally com-

plex issues to tackle when dealing with MDR-TB, such

as the patients’ economic, social, and psychological

circumstances. As with HIV/AIDS, a prevailing stigma

is attached to MDR-TB, which may prevent some suf-

ferers from seeking help or following through with the

lengthy treatment. Many feel hopelessness and despair.

Programs have to provide social, psychological, and

nutritional support. Routinely, program staff has to act

as advocates and mobilize resources to educate families,

as well as communities, dispel erroneous information,

raise awareness about the disease, and procure funding.

DOTS-Plus projects face these obstacles every day and it

is only because of the dedicated determination of many

committed people that they are frequently overcome.

However, if we do not continue to confront and deal with

these aspects of patients’ lives, we may never be able to

successfully control MDR-TB.

MDR-TB Coupled with HIV/AIDS Has Become a Dangerous Threat

The HIV/AIDS epidemic is responsible for a tremen-

dous increase in the number of TB cases, particularly in

sub-Saharan Africa. Not only does HIV make a person

more susceptible to contracting TB, it also increases the

likelihood that latent infection will be activated. Yet, many

programs focused on providing anti-retroviral drugs to

HIV/AIDS patients are not also treating them for TB.

Likewise, some TB programs are unwilling or unable to

provide appropriate therapy to those infected with HIV.

Because more than 80% of MDR-TB patients in Africa

live in countries with a high incidence of HIV, it is imper-

ative that, as treatment programs are expanded, the

governments ensure that patients in whom HIV/AIDS

and MDR-TB co-exist are treated for both conditions.

Otherwise, those patients will not be fully helped by the

health programs whose mandate is to help them.

The data on coexisting HIV and MDR-TB cases,

most of which come from South Africa, are alarming. In

KwaZulu Natal, South Africa, about 67% of TB cases are

coinfected with HIV. Sadly, MDR-TB is emerging as the

primary cause of death in these patients. With about 6000

MDR-TB cases a year and a nationwide HIV prevalence of

55% in TB patients, this problem has reached frightening

proportions. As further surveillance is conducted, similar

pictures may emerge in other places where TB and HIV

infections are both common.

Disproportionately affecting the poor, both HIV/

AIDS and MDR-TB are expensive to treat and require fre-

quent interactions with the health care system. As we said

earlier, sufferers of both diseases are often stigmatized

by their communities and experience feelings of depres-

sion. This, combined with the large number of different

drugs that are required, the frequency of side effects,

and the complexities of obtaining treatment in the first

place, explains why many do not seek or do not complete

treatment.

Clearly, co-infection of MDR-TB and HIV is particu-

larly dangerous. Even though patients with HIV infec-

tion may be receiving anti-retroviral therapy to prolong

their lives, if they also have MDR-TB and do not receive

proper treatment for it, they will continue to harbor the

disease, spread the infection to others, and often die of

it. This is especially tragic because it is unnecessary. TB

in persons with HIV/AIDS can be treated very effectively;

nonetheless, it remains the leading killer of most people

with AIDS in developing countries.

Although HIV/AIDS has drawn substantial public

attention and money, worldwide, in the last few years, it

continues to spread like wildfire through affected areas.

The threat of MDR-TB grows as HIV/AIDS remains out

of control.

Clearly, co-infection of MDR-TB and HIV is

particularly dangerous. Even though patients

with HIV infection may be receiving anti-ret-

roviral therapy to prolong their lives, if they

also have MDR-TB and do not receive proper

treatment for it, they will continue to harbor

the disease, spread the infection to others, and

often die of it. This is especially tragic because

it is unnecessary. TB in persons with HIV/

AIDS can be treated very effectively; none-

theless, it remains the leading killer of most

people with AIDS in developing countries.


20 |

Poverty Conditions Heighten the Threat of MDR-TB

More than 1 billion of the world’s population survives

on less than US $1/day, including 46% of the population

of sub-Saharan Africa. Another 1.5 billion live on US $1

to 3 per day.12 One billion people live in urban slums and

this number is projected to reach 2 billion in the next

30 years.13 Since MDR-TB, like drug-susceptible TB, is

primarily a disease of the poor, these statistics represent

a potentially devastating threat to controlling its spread.

With scant resources, the poor tend to have unhealthy

nutrition, which lowers their immune systems, and sub-

sist in unhygienic, badly ventilated and overcrowded con-

ditions that facilitate transmission of MDR-TB.

Not only are these settings conducive to widespread

transmission; in addition, the diagnosis and manage-

ment of the disease are also more difficult. The poor are

often uneducated regarding their health and less likely to

seek medical care as long as they can manage without it.

They often have to travel long distances to a health center,

then wait in long lines to be seen. For this group, trans-

portation fares can be an insurmountable hurdle.

It is significant that indigent patients are frequently

not offered the privacy everyone needs and deserves

when seeking health care, making them less inclined

to seek treatment. This, in turn, increases transmission

and makes detecting the disease more difficult. It is not

unusual for these patients to be examined and diagnosed

in an open area where other patients can see and hear the

interaction between clinician and patient. Once some-

one’s diagnosis becomes public, he or she may be humili-

ated, rejected, and shunned by both health workers and

other members of the community.

There is a direct link between how well a treatment

facility is functioning — its infrastructure, support staff,

and programs — and how consistent the patients will be

in their treatment. If the facility cannot reliably support

the patient during the 18-24 months of treatment, which

commonly includes side effects of nausea and depres-

sion, there is a high likelihood that treatment will be inter-

rupted or terminated.

Furthermore, poor patients find it hard to accom-

modate the need for daily clinic visits. Time spent at the

health center and away from a job may translate into the

loss of a partial or full day’s wage. Those who work at

home find it difficult to take significant time away from

household chores or child care. Additionally, the treat-

ment fees and transportation costs impose even bigger

barriers for the poor.

These findings emphasize the need for compassion-

ate care that must include social, emotional, and financial

support for TB patients, particularly for those who are

poor. And, for MDR-TB patients, the needs are, in general,

even greater because they have probably been sick lon-

ger, hence potentially unable to work, and their treatment

requires much more time.

Improper Treatment is Creating XDR-TB,

the Next Major ThreatExtensively drug-resistant TB (XDR-TB) is defined as

an infection with strains of bacteria that are resistant not

only to isoniazid and rifampin, but to any fluoroquino-

lone and at least one of three injectable second-line drugs

(capreomycin, kanamycin, and amikacin), in addition to

MDR-TB.

In 2000, there were several anecdotal reports of

XDR-TB cases that were resistant to virtually all second line

drugs. Supra National Research Laboratory (SNRL) direc-

tors confirmed similar findings. In 2005, a collaborative

project between the CDC, WHO, and the SNRL network,

consisting of 25 mycobacteriology laboratories from across

the world, began to assess the degree to which second-

line drug resistance had begun to appear among MDR-TB

strains. The SNRL network analyzed the isolates tested

between 2000 and 2004. Of the 3520 MDR-TB isolates

analyzed, 347 (10%) were found to be XDR-TB cases.14

These findings emphasize the need for com-

passionate care that must include social, emo-

tional, and financial support for TB patients,

particularly for those who are poor. And, for

MDR-TB patients, the needs are, in general,

even greater because they have probably been

sick longer, hence potentially unable to work,

and their treatment requires much more time.

Chapter One

| 21


XDR-TB is not a threat to the future, it is here now. In

many former Soviet Union countries (Estonia, for exam-

ple), patients with primary TB are proving to have infec-

tions that are resistant to numerous drugs, both first and

second-line Already present in countries and regions with

high rates of MDR-TB, XDR-TB could hamper efforts at

global TB control. It is important to conduct prospective

population-based surveys in order to describe the mag-

nitude of XDR-TB, follow its trends, and study high-risk

groups. In addition, it is crucial to develop standardized

methods for drug sensitivity testing (DST) for second-line

drugs to assure that results will be comparable around

the world.

The combination of XDR-TB and AIDS creates an

enormous threat. In one study from South Africa, approxi-

mately 37% of all culture-positive TB cases were found

to be MDR-TB, and XDR-TB constitutes approximately

37% of the MDR-TB cases.15 All of the XDR-TB patients in

this study were coinfected with HIV/AIDS. Furthermore,

these cases seem to have been transmitted recently and

became fatal rapidly.15 The substantial gains made by the

use of antiretroviral drugs (ARV) and the DOTS program

in lowering morbidity and mortality rates are now being

threatened by MDR-TB and XDR-TB.

“Are the side effects of the medicine so bad that I would rather not get the

treatment? Look at me, look at my kids. I am being treated for MDR-TB,

my husband is being treated for MDR-TB, and all my kids have been treated

for TB. Look at all of us in your pictures. Without this treatment, we would

all be dead.”

–Esperanza, MDR-TB patient

| 23

| G l o b a l E f f o r t s

Chapter Two

Global EffortsAs policies and practices on MDR-TB were evolving,

the achievements of the DOTS-Plus projects around

the world were dispelling doubts that MDR-TB could

be controlled. Attempts to address the problem pro-

grammatically in resource-poor countries were finding

success; in turn, global efforts to combat the disease

were gaining momentum. This chapter is the story of

how the world’s health community joined together to

confront MDR-TB.

Earlier Efforts at TB Elimination Through history, TB has been one of the world’s

deadliest diseases. Every year, it continues to infect 100

million people, 8 million of whom develop TB. A quarter

of these, 2 million, die from it. Yet, until very recently,

there was no systematic, widely applicable treatment plan

that could be expanded quickly.

In 1991, the World Health Assembly set the goal of

controlling TB by the year 2000. In 1995, WHO imple-

mented a strategy — a hugely successful treatment

strategy — called Directly Observed Treatment Short-

course (DOTS): a short-course chemotherapy with five

different drugs administered to the patient under direct

observation for six to eight months. Although earlier treat-

ment with only one or two drugs had led to the growth

of bacterial strains resistant to a particular drug, experts

believed that the combination therapy would not produce

multidrug resistance in TB bacteria.

Excited about DOTS’ resounding success and anx-

ious to broaden its application, the health community

identified 22 low- and middle-income countries that car-

ried 80% of the world’s TB — the “high burden countries”

(HBC). These were the areas where application of DOTS

could make a difference in disease control. But expanding

DOTS to all of these countries demanded a global collab-

oration among both developed and developing countries

and no coordinating mechanism was in place.

To address this need, WHO and others introduced

several initiatives in the late 1990s and early 2000s,

including the Stop TB Initiative, out of which grew the

Stop TB Partnership and the Global Drug Facility. The Stop

TB Partnership, in turn, led to The Global Plan to Stop TB,

which became a guiding force for TB control worldwide.

Another initiative was the Global Fund to Fight AIDS,

Tuberculosis, and Malaria (the Global Fund), developed

to subsidize initiatives focused on three deadly diseases

in resource-poor countries — AIDS, TB, and Malaria.


24 |

The Stop TB Initiative

In 1998, the new Stop TB Initiative laid the founda-

tion for numerous strategic efforts aimed at treating and

preventing TB. It was a global effort involving, though

not limited to, governmental, private, non-profit, and

educational institutions, and agencies. One of its early

accomplishments was the Amsterdam Declaration, a

conference in March 2000 where ministers of 20 of the

22 HBCs gathered to support a declaration demanding

urgent action against TB. Notably, they acknowledged for

the first time that effective treatment for TB was a human

right. Calling for accelerated research for effective drugs,

diagnostics, and vaccines, the Amsterdam Declaration

members formed a new group, the Stop TB Partnership,

which would coordinate TB control at the global level.

The Stop TB Partnership

The Stop TB Partnership, launched in Bangkok in

November 1998, set the ambitious goal of eliminating TB

as a public health concern. The Partnership is a network

of international, governmental, and non-governmental

organizations, public and private donors, and academic

institutions. The Secretariat, headed by an Executive

Secretary, is housed at WHO with a small staff.

One of its first major steps was the development

in 2001 of the Global Plan to Stop TB. The Global Plan

set objectives to reduce the epidemiological, economi-

cal and social burden of TB and drafted the action steps

that would achieve them. This plan was based on the

Global Investment Plan, which was developed earlier by

Partners in Health (PIH) with support from the Open

Society Institute (OSI). In identifying a hierarchy of priori-

ties for the allocation of funds and resources, the Global

Investment Plan provided a framework for the Global

Plan, which became the guiding document for all global

efforts to control TB from 2001 to 2006.

The Global Drug Facility

The Global Drug Facility (GDF), established in March

2001, was created as a response to the problems that

several countries faced in securing a continuous sup-

ply of drugs for their national TB control programs. In

addition to providing procurement services and techni-

cal assistance to countries, the GDF offers emergency

and bridge financing, as well as funding for operational

research aimed at improving, and streamlining the drug

supply. Thus far, it has concentrated only on first-line

medications.

The Global Fund to Fight AIDS, Tuberculosis, and Malaria

The mandate of the Global Fund to Fight AIDS, TB,

and Malaria (The Global Fund), formed in 2002, is to

combat these three diseases that together kill about 6

million people every year. In fact, because of the colossal

economic and health burdens on several resource-poor

countries, the need for such a fund had been expressed

at the Amsterdam meeting two years earlier. Financed by

a partnership of governments and private agencies, the

Global Fund has given momentum to TB control efforts

worldwide. It stands as the major funding source in the

fight against TB.

The Magnitude of MDR-TB Is Discovered

While these crucial initiatives were successfully

addressing drug-susceptible TB, awareness of MDR-TB

was increasing. In 1994, WHO and the International

Union Against Tuberculosis and Lung Disease (IUATLD)

initiated the Global Project on Anti-TB Drug Resistance

Surveillance to estimate the extent of MDR-TB worldwide.

Its findings, announced in its first report in 1997, were

shocking: MDR-TB had been found in all major regions

of the world. That the scope of the disease had been

In 1994, WHO and the International Union

Against Tuberculosis and Lung

Disease (IUATLD) initiated the Global Proj-

ect on Anti-TB Drug Resistance Surveillance

to estimate the extent of MDR-TB worldwide.

Its findings, announced in its first report in

1997, were shocking: MDR-TB had been

found in all major regions of the world. That

the scope of the disease had been underesti-

mated was unmistakable and no clear

strategy for dealing with it existed.

| 25


Chapter Two

underestimated was unmistakable and no clear strategy

for dealing with it existed. The underestimation and shock

can be partially explained by the earlier, unrealistic hope

many held that full implementation of DOTS would pre-

vent development of MDR-TB. Additionally, many policy

makers felt that available resources would best serve the

TB problem by treating the much larger number of per-

sons with drug-sensitive TB, since treatment for MDR-TB

required prolonged therapy with expensive second-line

drugs (SLD).

Later, with the advantage of further surveillance,

the threat MDR-TB posed was evident and undeniable.

By 2004, the Global Project published its third report

with information on new (not previously treated) cases

from 90 countries and on previously treated cases from

77 countries. Fourteen of the 22 high burden countries

(HBC) had been surveyed and drug resistance was pres-

ent or had occurred in all fourteen. High levels of MDR-TB

were found in several areas, particularly in some countries

of the former Soviet Union. In 2004, the estimated num-

ber of MDR-TB cases, including both new and previously

treated, was 424,203,16 which represents a 55% increase

over the 272,906 cases estimated in 2000.17 While DOTS

revolutionized the treatment of drug-susceptible TB, the

increase in drug-resistant cases confirmed that DOTS

alone was not the complete answer to MDR-TB. Still, rea-

sons for optimism remained. The ingenious efforts of the

GLC and other health care pioneers resulted in unprec-

edented advances: not only were they responsible for a

significant reduction in the costs of SLDs; they were able

to demonstrate that managing MDR-TB at a program-

matic level, though complex, was possible.

Initiatives to Treat MDR-TBThus, various public health partners launched a

number of initiatives designed to treat drug-resistant TB

in low- and middle-income countries. Originally not a

part of DOTS, these efforts have now joined with it under

one umbrella that encompasses any and all forms of TB

control. DOTS-Plus as Catch-Phrase

In the 1990s, Paul Farmer along with colleagues from

PIH was working in Haiti with MDR-TB patients, many of

whom also had HIV/AIDS. Labeling the treatment strat-

egy needed for this population, Farmer and his colleagues

used the term “DOTS-Plus,” indicating that they required

a program like DOTS, but “more.” Little did they know

that this term would become the catch-phrase for naming

programmatic management of MDR-TB.

In April 1998, Partners in Health (PIH) hosted in

Cambridge, Massachusetts, a meeting attended by rep-

resentatives from WHO, PIH, Harvard Medical School,

Medecins Sans Frontieres, and CDC. At this signal event,

WHO officially adopted the name DOTS-Plus for the

MDR-TB case-management initiative that was about to

enter the testing phase. What followed was a series of

events and developments that led to the creation of sev-

eral DOTS-Plus pilot projects. These pilots, in turn, gen-

erated rapid advances in our knowledge of the problems

MDR-TB posed as well as effective approaches to deal

with them.

DOTS-Plus Working Group

As attention to developing DOTS-Plus efforts grew,

so did the need for a central coordinating body at WHO.

The solution was the “DOTS-Plus for MDR-TB” Working

Group, created in 1999; the group became a part of the

Stop TB Partnership in 2001. In its first few years, this

group organized the projects, determined and issued a

set of guidelines for DOTS-Plus pilot projects, and set

up the Green Light Committee (GLC), which is described

below. (Note: see Chapter 6, Challenges, for additional

discussion of the GLC.) Later, a second set of guidelines

for the programmatic management of drug-resistant TB

were issued.

First Guidelines

One of the Working Group’s first tasks was design-

ing what were to become the First Guidelines on DOTS-

Plus pilot projects. The guidelines had to include a num-

ber of management issues that had not been previously

addressed and were far more complicated than those

posed by drug-susceptible TB. They also had to include

criteria for monitoring and evaluating the newly formed

DOTS-Plus projects. In October 2000, the Scientific Panel

of the DOTS-Plus Working Group produced these guide-

lines, which remained in effect until the Second Guidelines

were published in early 2006.

Second Guidelines

Issued in early 2006, the Second Guidelines, based

primarily on the evidence and experience of the DOTS-


26 |

Plus projects, expanded and provided more detailed rec-

ommendations for managing MDR-TB. They noted that

“the framework for the management of drug-resistant TB

… can be adapted to all national TB control programmes

and integrated within the basic DOTS strategy.”

The Second Guidelines outline the five components

of DOTS-Plus (slightly expanded from the five compo-

nents of DOTS):

1. Sustained political commitment

2. Diagnosis of MDR-TB through quality-assured cul-ture and drug susceptibility testing

3. Appropriate treatment strategies that utilize second-line drugs under proper management conditions

4. Uninterrupted supply of quality assured second-line anti-tuberculosis drugs

5. Recording and reporting system designed for DOTS-Plus programs

An important advance in these guidelines is the cat-

egorization of anti-TB drugs into a hierarchy, as shown in

Table 1.

Table 1. Hierarchy of Anti-TB Drugs

1 First-line bactericidal agents

2 Injectable agents

3 Fluoroquinolones

4 Second-line bacteriostatic agents

5 Agents of unclear efficacy

Numerous revisions in the 2006 (second) guidelines

reflect the knowledge gleaned from the DOTS-PLUS pilot

projects. For example, the 2000 guidelines called for the

“use of regimens including at least three drugs to which

the strain is known or likely to be susceptible;”18 In 2006,

the guidelines state that “treatment regimens should con-

sist of at least four [not three] drugs with either certain or

highly likely effectiveness.” The new guidelines also add

that the injectable agent should be given for a period not

less than 6 months and continued for at least 4 months

after the patient is sputum smear or culture negative.

Then, treatment with an oral agent should last for at least

18 months after culture conversion.

Green Light Committee (GLC)

In 2000, two major concerns impeded efforts to con-

trol MDR-TB in resource-poor settings. First was the cost

of second-line drugs. At that time, poor countries faced a

horrible choice. They could offer treatment to many more

patients with drug-sensitive TB; expensive regimens for

MDR-TB consumed resources that could support treat-

ment for many times that number of people with drug-

sensitive TB. Yet not treating MDR-TB patients meant

allowing the spread of multi-drug-resistant disease in

families and communities as the disease progressed and

leaving those people to die. The other obstacle was the

complexity of MDR-TB control, requiring expert technical

assistance and oversight to insure the appropriate man-

agement of therapy. The Green Light Committee (GLC),

funded primarily by the PARTNERS project and formed

at the WHO in 2000, was formed to address these prob-

lems. Since there was little agreement on how to best

manage MDR-TB, the GLC provided a critical crucible for

debate and discussion.

Inspired by similar successful initiatives, the GLC

introduced a pooled-procurement mechanism to pur-

chase drugs from suppliers. This allowed the group to

negotiate price discounts of up to 90% for SLDs with

the assurance of strict supervision of the drugs’ use.

Indeed, WHO estimates that in 2005 the average cost of

the medications on the open-market cost was US$14,628

in low-income countries and US$29,779 in high-income

countries but only approximately US$3,000 when pro-

cured through a GLC-approved program. Clearly this was

a substantial victory in the struggle against MDR-TB.

Ensuring the rigorous drug monitoring standards

was the GLC’s next responsibility. The GLC membersb

met six times per year to review applications, share new

information, and discuss how to proceed. Their meetings,

which led to consensus, were intense and focused. They

also provided invaluable technical assistance to countries

that were applying, or considering applying, to the GLC.

With affordable medications, five countries—Peru,

Philippines, Latvia, Estonia and Russia (Tomsk)—initi-

ated demonstration projects that resulted in dramatic

cure ratesc for a disease widely believed to be untreatable

b When it started, the members of the GLC included Jim Kim (Harvard/PIH), Chair; Marcos Espinal (WHO); Kitty Lambregts (KNCV TB Foundation); Myriam Henkens (MSF); Peter Cegielski (CDC); and Raj Gupta (WHO/Secretariat).

c For some of the countries included here, it was felt that the term “success rate” was more appropriate because the definition of cure was evolv-ing over the years and the exact criteria for cure may not have been followed consistently for all cases considered as cured, cases which could be a combination of cured and completed.

| 27


Chapter Two

in developing countries. Initial cure rates, excluding

chronically ill patients, were between 61-82%. Cure rates

for patients whose diseases were identified earlier (before

they experienced extensive lung damage) were even

more promising.

Contributing their experience with the DOTS-Plus

projects worldwide, GLC members helped develop guide-

lines for implementing new DOTS-Plus programs. The

guidelines are tested in the field by consultants who pro-

vide technical assistance and will be improved as relevant

information is gathered.

The GLC Today

Currently, the GLC’s responsibilities include training

local public health representatives in SLD management

and in sound practices for MDR-TB treatment programs.

In addition to increasing patients’ access to high-quality

and low-priced drugs, it develops policies that address

the problems inherent in drug-resistant TB and provides

technical assistance at the local level. Its technical review

panel evaluates project proposals to determine if the prin-

ciples stipulated in the Guidelines for Establishing DOTS-

Plus Projects are being followed. GLC members assess

applications from interested countries and they conduct

monitoring visits to confirm that already-existing projects

are adhering to their protocols. Managing logistics as

well, the GLC assures proper ordering, stocking, and dis-

tributing of drugs and advises on facilities and personnel

management.

While its primary foci are technical, operational, and

policy issues, the GLC also acts as an advocate to encour-

age more countries to undertake the complex health

intervention of DOTS-Plus. Toward that end, it works to

share information and knowledge in this rapidly develop-

ing field.

Looking Back, Looking AheadAs of June 2007, 56 GLC-approved DOTS-Plus proj-

ects had been, or were in the process of being, imple-

mented in 45 countries around the world.19 This means

that more than 14,000 MDR-TB patients in resource-lim-

ited areas had already been treated or were scheduled to

receive treatment. Nearly forty percent of this population

was either in Peru or Tomsk. [Note that more than 20,000

MDR-TB patients have been treated in South Africa with

second-line drugs purchased directly from manufactur-

ers rather than through the GLC.] And the cure rates

have been as high as 75-80%. Twenty-five sites have been

approved for SLD through the Global Fund to fight AIDS,

Tuberculosis, and Malaria.

A major challenge for the future will be to preserve

the GLC’s superb level of technical expertise and assis-

tance as more and more countries begin addressing the

problem of drug-resistant tuberculosis. The group must

continue to maintain high-quality DOTS-Plus care in

already-approved projects and expand it to include the

many countries that will be integrating DOTS-Plus into

their DOTS programs (either nationwide or in pilot prov-

inces) over the next few years.

When, the GLC was formed in 2000, the number

of projects and involved countries was small enough to

allow group members to review and oversee them easily.

After thoroughly evaluating and discussing the proposals,

a volunteer staff offered detailed feedback to the applicant

countries, allowing them to understand and correct the

deficiencies in their original applications. But this process

cannot keep pace with the rapid proliferation of sites and

participating countries that are expected over the next few

years, To conceptualize the most effective and efficient

approaches for the submission, review, approval, and

follow-up phases, the GLC has developed a Business Plan

and a Plan for Resource Mobilization to obtain the funds

to support its activities in the future.

GLC’s Effect on the Global Fund’s Fight against AIDS, TB, and Malaria

Although the Global Fund originally did not recog-

nize a role for the GLC in reviewing DOTS-Plus projects, it


28 |

has since recognized the GLC’s critical role in the crusade

against MDR-TB and has become an important source

of financing for many programs. The Globol Fund now

requires projects receiving Global Fund financing must

secure GLC approval of SLDs.

At its third board meeting, in October, 2002, the

Board resolved:

…to help contain resistance to second-line anti-

TB drugs and consistent with the policies of

other international funding sources, all procure-

ment of medications to treat MDR-TB must be

conducted through the Green Light Committee.”

By pooling drug procurement and negotiating with

pharmaceutical companies, the GLC is able to secure

major price reductions. The International Dispensary

Association serves as the drug procurement agent for

GLC-approved programs.

The GLC’s Effect on the Global Drug Facility

The Global Drug Facility (GDF), another group that

did not originally manage SLDs, is engaged in the process

of converging with the GLC in order to increase countries’

access to and rational use of anti-TB drugs. Planning for

coordinated drug procurement began in 2006 but con-

vergence is incomplete. If the GDF is able to accurately

predict and meet demand for SLDs, it will be in a better

position to help integrate efforts to control both drug-

susceptible and drug-resistant TB.

Second Global Plan to Stop TB The First Global Plan to Stop TB, launched in October

2001, had clearly pointed out the challenges for TB con-

trol overall and laid out steps to address these challenges.

It acknowledged the growing threat of MDR-TB and the

small window in which it could be managed before it grew

into an out-of-control global epidemic.

By 2006, when the Global Plan to Stop TB 2006-

2015 was released, the world had learned much more

both about the extent of MDR-TB and about ways to

address it. The global community had acknowledged the

need for the conceptual and programmatic integration

of approaches to address both drug-susceptible TB and

MDR-TB, primarily as a result of the GLC’s and the DOTS-

Plus Working Group’s achievements in pilot countries.

In response, WHO expanded its policy and combined

DOTS and DOTS-Plus. This enhanced strategy, referred

to as “DOTS.2” to emphasize the important integration,

declares the rights of all people to appropriate care and

treatment for TB, TB-HIV, and MDR-TB. Stipulated in the

Second Global Plan, the new DOTS.2 protocol requires

quality laboratory services, specialized medical expertise,

effective infection control, and access to necessary sec-

ond-line drugs, thus integrating the DOTS-Plus frame-

work into the overall global effort.

While the First Global Plan covered the years 2001-

2006, the Second extends from 2006-2015 and contains

the new strategy to deal with TB over those years. It also

lays out the vision of the DOTS-Plus Working Group,

which calls not only for enhancing MDR-TB surveillance

and effectively managing the disease based on those find-

ings, but guaranteeing that those simultaneous processes

are “routine components of TB control.” The vision also

includes “access to diagnosis and treatment for all TB

patients” and the capacity of “all health care providers”

to offer it.

The new Global Plan’s MDR-TB objectives are to:

1. Expand drug resistance surveillance

2. Monitor trends and regularly update the global MDR-TB estimates

3. Strengthen capacity to perform quality-assured cul-ture and drug susceptibility testing

In contrast to the inchoate approaches to

MDR-TB in 2000, we are now armed with

the knowledge, strategies, and mechanisms

that can effect change throughout the world

on a condition which, until recently, was

considered hopeless. Our challenges now are

finding the human and financial resources

to apply the effective tools we have and to

develop newer, even more effective approaches

to wiping out tuberculosis.

| 29


Chapter One

4. Scale-up MDR-TB treatment according to WHO guidelines

5. Create a healthy and competitive market of quality-assured second-line drugs

6. Provide technical and global coordination to accom-plish the goals.

According to the Plan, drug susceptibility testing (DST)

will be expanded so that by 2015, all patients previously

treated for TB will have DST as will all new cases of TB in

Eastern Europe and 20% of targeted new cases in the Latin

America, Southeast Asia, and Western Pacific Regions.

With the expansion of DOTS-Plus, the Global Plan

called for 800,000 MDR-TB patients to be treated

between 2006-2015 — approximately 20% of the total

number of cases expected to occur during that period.

However, Global Task Force members urged implemen-

tation of additional measures to scale-up control of TB

to prevent emergence of new MDR-TB and XDR-TB

cases. The Global MDR-TB and XDR-TB Response Plan

2007-2008 calls for treatment of 1.6 million MDR-TB and

XDR-TB patients by 2015.20

The Response Plan, aiming to increase access to drugs

and diagnostic tests, aims to meet the original goal of sav-

ing the lives of up to 1.2 million patients. The Global Plan

projects that by 2015 a new safe, effective, and licensed vac-

cine to prevent TB will be available and seven new drugs

will be registered for TB treatment. Also expected by 2015

are a revolutionized treatment regimen lasting only 1-2

months (for drug-sensitive TB) and a diagnostic test that

can be carried out at the point of patient care.

In contrast to the inchoate approaches to MDR-TB in

2000, we are now armed with the knowledge, strategies,

and mechanisms that can effect change throughout the

world on a condition which, until recently, was considered

hopeless. Our challenges now are finding the human and

financial resources to apply the effective tools we have

and to develop newer, even more effective approaches to

wiping out tuberculosis.

| 31

Chapter Three| P e r u a n d t h e P A R T N E R S P r o j e c t

Peru and the PARTNERS Project

...many experts believed it was not

cost-effective to treat MDR-TB

patients in resource-poor countries.

But Farmer and Kim believed

otherwise. For them, access to

healthcare was not an economic

matter; it was an issue of basic

human rights.

The PARTNERS Project has its roots in the belief

that the poor should have access to health care that is

every bit as good as the health care that the rich can get.

Inspired by a priest’s relentless struggle in Carabayllo,

Lima, to provide hope and relief to poor TB patients

who were not cured even after repeated treatments, two

physicians from Partners in Health (PIH), Paul Farmer

and Jim Kim, began to explore the reasons why these

patients were not getting better and find out what could

be done for them. At that time, there was a prevailing

notion that MDR-TB control in resource-poor countries

was not feasible, and that scarce resources would be

better put to use in treating drug-susceptible TB. The

drugs used to treat MDR-TB were very expensive (up to

200 times the cost of drugs used to treat drug-suscep-

tible TB), and the laboratory sophistication required to

reliably diagnose MDR-TB and monitor its treatment

required laboratory tools, materials, and personnel who

would not be found in developing nations. Consequently,

many experts believed it was not cost-effective to treat

MDR-TB patients in resource-poor countries. But Farmer

and Kim believed otherwise. For them, access to health-

care was not an economic matter; it was an issue of

basic human rights. With Dr. Jaime Bayona, they set up

Socios en Salud (SES), a sister organization of PIH, as

a way to bring world-class medical treatment — some-

thing they called “preferential options for the poor” — to

the patients of Carabayllo and Lima.

The Work of SES in CarabaylloIn 1996, SES began working in the poor shantytowns

of Carabayllo, to diagnose and treat the poor TB patients

who were being turned away from government clinics as

untreatable or “chronic” patients. These patients were

being told that nothing could be done to treat them

any further. PIH/SES partnered with the Massachusetts

State Laboratory Institute (MSLI) to carry out drug sen-

sitivity testing (DST) on sputum samples from these

patients. SES began sending sputum samples from the

“chronic” patients in Carabayllo to MSLI, where DST

results allowed SES to find out which drugs would

work for these patients, and which drugs were useless

because the infecting strain of TB had developed resis-

tance to them. The results showed that many of these

patients were infected with strains of TB bacilli that were

resistant to rifampicin and isoniazid (MDR-TB), point-

ing to an epidemic of MDR-TB in Carabayllo. In fact,

DST on some of these samples showed strains that

were resistant to all first-line drugs (FLDs); others were

also resistant to some second-line drugs (SLDs). Thus,


32 |

extremely drug-resistant-TB (DR-TB), which is now being

recognized as a dangerous development worldwide, was

present even then.

Based on DST results, PIH/SES began tailoring drug

regimens for each patient, including in the regimen only

those drugs that would be effective in combating the

particular strain of bacteria infecting the patient — an

individualized treatment regimen (ITR). This strategy of

using ITR was highly successful with cure rates of up to

70%. The data from the first cohort are summarized in

Chapter 5 (Mitnick study). While PHI/SES workers were

finding and treating MDR-TB patients, they also started

to advocate for the cause of MDR-TB patients, engaging

the Peruvian government and other local organizations

to recognize the problem of MDR-TB in Carabayllo and

urging their participation in finding and treating more

cases of MDR-TB throughout Lima using ITR.

Birth of the PARTNERS ProjectFor the first few years, PIH/SES was able to carry

out its activities using financial support from Thomas

J. White, a benefactor in Boston. But, soon they began

running out of money. It was at this time that Jim Kim

and Paul Farmer approached The Task Force for Child

Survival and Development (TFCSD) for help in procur-

ing additional funds. The Task Force suggested widen-

ing the scope of the effort in Peru and including WHO,

CDC, and the Peruvian government in a partnership with

PIH/SES and The Task Force to help drive global policy

changes around MDR-TB control. Having international

partners like these was crucial for developing policies

that would ultimately be widely accepted.

As a result of these discussions, the five organiza-

tions came together and applied to the Gates Foundation

for funds. The remarkable success that PIH/SES had

already achieved on a small scale for people in Carabayllo,

showed how much more might be done if this approach

could be scaled up, shown to be effective, and then used

to develop models for MDR-TB treatment in other low-

and middle-income countries. The Gates Foundation

was convinced about the potential of the idea that these

organizations presented, and awarded them a grant of

US $44.7 million, the primary recipients of which were

the Harvard Medical School and Partners in Health. The

Partnership Against Resistant Tuberculosis: A Network

for Equity and Resource Strengthening (PARTNERS TB

Control Program, as it was called) began in August 2000.

PARTNERS included PIH/SES, CDC, WHO, TFCSD, and

the Peruvian National TB Control Program (PNCT)/

Ministry of Health (MINSA).

Hitting the Ground Running

The PARTNERS grant gave a fresh lease of life to the

work that SES had been doing in the preceding years. Not

only did it bring in strong financial support, but it also

gave SES some very strong partners — MINSA with its

ability to make local decisions and provide the support

necessary for country-wide scale up of MDR-TB control;

CDC with its researchers, research capabilities, and lead-

ership; WHO with its policy-making power; and The Task

Force with its experience in managing large-scale, multi-

partner international projects.

Project Objectives and Overall Goals

The PARTNERS project had four specific objectives.

1. Demonstrate the success of an integrated DOTS and DOTS-Plus program that can contain drug-resistant TB in Peru.

2. Develop the necessary infrastructure in Peru to sup-port the Peruvian DOTS-Plus program model and make it “exportable” to other settings where drug-resistant TB is a problem.

3. Export this program model and evaluate its effective-ness in at least one other hot spot of drug-resistant TB (Tomsk).

4. Help develop an integrated TB-control program model that can support a WHO/CDC-led strategy for global TB elimination.

The main goal of the PARTNERS Project was to

show feasibility of MDR-TB control in resource-poor set-

tings and use the scientific evidence this demonstration

provided to drive policy formation for global control of

MDR-TB. Peru was chosen as the site where an attempt

would be made to incorporate MDR-TB treatment into

the National TB Control Program and spread MDR-TB

treatment throughout the country. A basic document

underpinning the Project was the Proyecto Collaborativo

(Collaborative Project), an agreement between PIH/

SES and MINSA signed in 1999. This allowed PIH/SES

to treat up to 1,450 MDR-TB patients in northern Lima

using ITR.

| 33

| P e r u a n d t h e P A R T N E R S P r o j e c t

Chapter Three

There were two aspects of showing feasibility: the

clinical and the programmatic. Clinical feasibility would

be demonstrated by acceptable cure rates in treatment

of the 1450 patients. Programmatic feasibility would be

shown by successful integration of MDR-TB control into

the National TB Control Program and the handover of

MDR-TB program management to the Peruvian govern-

ment at the end of the PARTNERS Project.

Proving Clinical FeasibilityThe PARTNERS Project continued the model that was

being implemented by PIH/SES. For accurate diagnosis,

sputum specimens were sent to the Massachusetts State

Laboratory Institute (MSLI). Drugs were procured in Peru

and also outside Peru from the Brigham and Women’s

Hospital (BWH) and other external sources. Physicians

from BWH continued to diagnose and supervise treatment

of the poor patients of Carabayllo. Community health work-

ers well-trained in patient support were heavily used to

ensure that MDR-TB patients not only received their proper

medicines, but that they had proper nutrition as well as

the social and psychological support needed to endure

a lengthy course of treatment with many side effects.

Infection control procedures were put in place. Along with

these measures, the Partners (i.e., the principle partners in

the Project) continued to educate the public and worked

to remove the stigma associated with MDR-TB. The plan

was to continue using all the mechanisms available to get

the best cure rates possible. What the principle Partners

attempted was to institutionalize an experiment by PIH/

SES that had been successful in achieving a cure rate of

70% in the first set of 75 MDR-TB patients enrolled from 1

August 1996 to 31 January 1999.

Diagnosis by Sending Specimens to MSLI

The principle Partners continued the collaboration

that had existed between PIH/SES and MSLI. The high-

quality results of first- and second-line DSTs conducted

by the MSLI gave the BWH and Peruvian doctors an

accurate understanding of which drugs would work and

which would not. While a transfer of skills and capacity

from MSLI to Peruvian laboratories was part of the infra-

structure improvement over the five years, the first few

years, when all sputum samples were sent to MSLI, were

very important in helping to get off to a rapid start. With

MSLI’s fast turn-around of laboratory results, PIH/SES

physicians were able to obtain the most accurate diagno-

sis possible for the patients in Lima.

Procurement of Drugs

From 1996 to 1999, PIH/SES had been procuring

drugs from BWH, Eli Lilly, Farmaindustria, Ethionamida,

and PASER. PIH/SES was responsible for making sure

each patient had his/her complete treatment available.

When the Partners started the Project, SES continued to

play this vital role and managed it very well. Each patient

had a box with his/her name labeled on it. The box con-

tained all of the medications that were needed to com-

plete the course of therapy. When the patient came to the

health center, he/she could see the entire set of medica-

tions in the box. Thus, the patients were assured that

they would get their treatment and not be turned away

because they did not have money or because the drugs

were in short supply. They could also see that, as time

went on, there were visibly fewer medications remaining

to be taken.

Medical Treatment

Quality Clinical Care by BWH Doctors

Doctors from BWH, a teaching affiliate of Harvard

Medical School, continued to play a major role in the

treatment of MDR-TB patients in Carabayllo. They trav-

eled to Peru every month and evaluated the condition of

patients. They also provided training to Peruvian health

workers so that they could use standardized algorithms

for treating patients while waiting for DST results and

design ITR after the results became available. These doc-

tors also stayed in constant touch with their Peruvian

counterparts through email. Later when the Electronic

Medical Records (EMR) system was working and inte-

grated into a web-based module, communication became

much easier. The EMR allowed BHW doctors to track of

the conditions of hundreds of patients, view their records,

and provide the appropriate advice. The doctors moni-

tored the side effects that the patients suffered and tried

to minimize them while helping patients adhere to their

treatment. As a result of these measures, PARTNERS

achieved an 85% cure rate.

This was in sharp contrast to the results achieved

by the standardized treatment being offered by PNCT. In

1997, PNCT, which was recognized as having one of the

best DOTS programs in the world, had recognized the


34 |

presence of MDR-TB cases. With the help of WHO, PNCT

had prepared treatment regimens for such patients. Under

this regimen, when a patient “failed” a DOTS course,

which was also called Esquema uno (Scheme one), he/she

was put on Esquema dos (Scheme two), which was essen-

tially the same treatment regimen as DOTS, but given

for 12 months instead of 6 months. Those who failed

Esquema dos were called “chronic” cases and treated by

adding one second-line drug to Esquema dos (standard-

ized treatment regimen, STR). However, this achieved

very low cure rates of 48%.

This contrast was to be expected. The standardized

regimen was designed to treat patients whose sputum

samples could not be tested. It was not known which

drugs the patients’ bacilli are sensitive to. The addition of

just one drug to a failing regimen could not be expected

to achieve the results similar to the individualized regi-

men that was adjusted according to the DST profile.

Little Use of Hospitalization, Surgery in Extreme Cases

PARTNERS adopted a strategy to use minimal hos-

pitalization. This kept the costs of treatment very low.

Most of the patients were treated on an ambulatory

basis. Some were treated at health centers; for others, the

health workers visited their homes. Drugs were given to

the patients under supervision, twice a day. Community

health workers (CHW) were an integral part of super-

vising therapy and monitoring adverse effects. In some

cases, hospitalization was necessary and, rarely, surgery

was done to resect a part of the lung that was damaged to

such an extent that it was not possible to kill the bacteria

that resided there or to bring it back to normal function.

Monitoring/Managing Side Effects

SES workers deserve credit for a large part of the suc-

cess achieved by PIH/SES doctors because they encour-

aged patients to complete the full 18- to 36-month course of

treatment. One of the key factors in assuring patient adher-

ence for the entire course duration was the management

of side effects of second-line drugs, which could be very

severe. Many patients felt very sick after taking the medica-

tions and it took persistent encouragement from the health

workers, as well as drugs to manage the side effects, for the

patients to continue treatment. The side effects included

nausea, vomiting, gastritis, headaches, joint pains, and

darkening skin color. One particular drug, cycloserine,

given to most patients, is most strongly associated with

psychiatric symptoms. An analysis21 of the first cohort of

75 patients treated by SES from 1996 to 1999 found that 10

patients had suffered from depression, 9 from anxiety, and

9 from psychosis. At 13.3%, 12%, and 12%, these figures

show the large extent to which patients suffered from psy-

chological side effects of the anti-MDR-TB drugs.

Patient Support

Support for Patients/Nutrition

Apart from the psychiatric symptoms caused by TB

drugs, patients also suffered from depression because

their community rejected them. Several of them had been

turned away earlier by government health workers. Having

failed many treatments before, these patients were known

as “chronic” cases and it was assumed they had very

little chance, if any, to be cured. Indeed, so entrenched

was this perception that some health workers advised

them to stop wasting their money on more drugs and

invest in purchasing a coffin instead. This rejection had

spread from health workers to the community, and many

patients also faced rejection from family and community

members.

SES health workers addressed this problem by provid-

ing psychosocial and nutritional support to the patients,

helping them adhere to the prolonged treatment and

heal faster. One of the key strategies was to form support

groups. Led a psychiatrist and a social worker or nurse,

each support group consisted of 8 to 12 patients. Those

considered infectious or too psychologically disturbed to

be able to contribute effectively to group dynamics were

not included.

Initially it was difficult to establish the support

groups. The challenges included finding low-cost facilities

to conduct meetings, facilitators who would be willing

to conduct meetings in the face of a generally prevailing

fear of getting infected with MDR-TB, and resources to

conduct excursions and subsidize transportation costs

for patients. Despite these challenges, persistence and

dedication from PIH/SES paid off.

The support groups offered a forum for current

patients, cured patients, and health workers to share

stories, information, and support. Patients related sto-

ries of rejection by community members, family, and

health workers. They talked about feelings of shame and

guilt, explaining that they felt they were being punished

for something they had done. They had suspicions that

the new individualized treatment was nothing but an

| 35


Chapter Three

experiment being tried on them, that they were being used

as guinea pigs. They felt isolated, helpless, and hopeless

about the possibility of ever regaining their health.

The support groups managed to sustain patients’

morale, giving them hope and reducing their stigma,

while helping to ensure adherence to treatment despite

serious drug side effects. The groups celebrated special

occasions like festivals and birthdays and attended recre-

ational events. Patients who felt rejected by others began

to find a renewed sense of community and belonging in

these support groups.

PIH/SES and PNCT also began educating family

members and the community about MDR-TB, the way it

is transmitted, and spreading the message that it is treat-

able. Posters were put up at health centers that conveyed

these messages in a succinct way. Perhaps, the most

effective means of conveying these messages, however,

was transforming the behavior of health workers. When

the patients with drug-susceptible TB saw that health

workers were not afraid of MDR-TB patients anymore,

they began to believe that there was nothing to fear about

MDR-TB patients.

Apart from the psychosocial support, the patients

were also given food packets. Good nutrition was essen-

tial for their recovery. Many of the patients were too poor

to purchase their own food, especially as many of them

had lost their livelihoods as a result of being severely sick.

Giving these patients drugs without giving them food

to survive would have made no sense. So PARTNERS

ensured that they received nutritious food that included

essential vitamins, proteins, and carbohydrates.

Infection Control

Protecting Patients, Family, and Healthcare Workers

From the beginning, infection control was stressed as

a very important part of controlling the disease. Hospitals,

laboratories, and homes were all very likely places where

infection could spread easily. Much depended on the

proximity of MDR-TB patients to others and the environ-

mental conditions that might spread their infections; the

safety precautions being used by health workers, other

patients, and family members; and on ventilation mecha-

nisms that channeled the airflow in the buildings that

housed the patients with MDR-TB.

In the hospitals and clinics, PARTNERS studied the

airflow patterns in the patients’ rooms; whether they were

mixed with other patients, in separate wards, or in pri-

vate/semi-private rooms. They also studied ventilation

mechanisms, and airflow from bronchoscopy rooms.

They found to their dismay that many MDR-TB patients

shared rooms with susceptible patients with other dis-

eases. Particularly distressing was the fact that on many

occasions HIV patients were housed in the same room

as MDR-TB patients. They also found in one hospital that

the air from the bronchoscopy room flowed into the cor-

ridor where many people passed by each day. Findings

such as these were cause for alarm. PARTNERS made

several recommendations to the hospital administrators

and to MINSA, provided training, and suggested design

changes to prevent hospital transmission; many of these

recommendations were subsequently implemented over

the course of the PARTNERS Project.

In laboratories, infection control experts suggested

design changes and recommended the use of biosafety

cabinets — laminar flow systems with negative pres-

sure — that made it much safer for laboratory technicians

who worked with MDR-TB cultures. Because the cabinets

require maintenance and there were no certified techni-

cians in Peru, PARTNERS also arranged for training and

certification.

Infection control was also practiced in the clinics and

at homes. Health workers were advised to wear masks

and were given proper training in dealing with MDR-TB

patients in such a way that they protected themselves

without giving the impression that they were treating

MDR-TB patients as pariahs. Family members were given

Having failed many treatments before, these

patients were known as “chronic” cases and

it was assumed they had very little chance,

if any, to be cured. Indeed, so entrenched

was this perception that some health work-

ers advised them to stop wasting their money

on more drugs and invest in purchasing a

coffin instead. This rejection had spread from

health workers to the community, and many

patients also faced rejection from family and

community members.


36 |

training on how to take care of MDR-TB patients and

make sure that they did not end up getting infected in the

process.

Tackling Stigma

When SES had started working with MDR-TB patients

in 1996, they found that the common perception was

that MDR-TB was an “incurable” disease. The patients

who came to SES had failed the treatments offered by the

government and were called desahuciados, the hopeless,

released from treatment and left to die. Such was the

fear of the disease that family members, health workers,

and many other members of the community shunned

MDR-TB patients and treated them like social pariahs.

As a result, MDR-TB patients tried to hide their disease

as much as they could. Health workers were reluctant to

come near them, and the community refused to accept

them as productive members of society. In order to show

feasibility of treatment, it was important for PARTNERS to

win the trust of the people in the new treatment regimen

and decrease the stigma which had become attached to

this disease.

PIH/SES doctors led by example and showed no hes-

itation in touching and interacting with MDR-TB patients.

This emboldened the community health workers and they

followed suit. PIH/SES doctors also facilitated discus-

sions among the health workers and made them under-

stand that the best way to get rid of the disease in the

community was to tackle it. Not all the health workers

were comfortable, despite the training and the approach

taken by these doctors. Some of them left, but most

stayed. The renewed energy and faith that the community

health workers brought to their work was infectious. It

started to trickle down to the patients and the commu-

nity. Besides, when patients started to get cured and they

spoke in group sessions, it made a huge impact.

These achievements did not come easily, however.

There were many rumors flying around that SES was a

“foreign” organization that was conducting an “experi-

ment” for its own advantage. The side effects of the sec-

ond-line drugs also made things difficult. Many patients

felt worse than before and this made it difficult for them

to believe that their disease was indeed curable. The dark

skin coloration caused by one of the second-line drugs,

clofazamine, also marked the MDR-TB patients and

made them uneasy about taking the second-line drugs.

But seeing patients get cured opened up new possibilities

for health workers and patients alike and did a tremen-

dous amount to lessen the suspicions of new patients

and diminish stigma. The continued caring attitude and

dedication of the community health workers was also a

major help.

Proving Programmatic FeasibilityThe programmatic aspect of proving feasibility was

more difficult because there was no model for delivering

complex health interventions in resource-poor settings.

Despite preliminary planning, many aspects of the pro-

gram had to be improvised and developed on a learn-as-

you-go basis, using information gathered from ongoing

operational research. In order to plan and monitor the

programmatic scale-up in Peru, PARTNERS formed an

operational planning committee. The idea was to develop

local laboratory infrastructure, assure quality diagnosis,

train all workers involved in the program, assure proper

drug ordering and management, and apply MDR-TB treat-

ment on a much broader scale than had been previously

implemented. To support these activities, PARTNERS had

to also develop a strong information system that could

help in the collection, analysis, and communication of

data. Further, they had to pay attention to getting the right

people on board and providing incentives to make sure

they stayed with the program.

Developing Lab Capacity

The scale-up of lab capacity in Peru was one of the

most essential elements for the programmatic success

of MDR-TB control. PARTNERS set about developing lab

capacity at both the central laboratory and five regional

labs. The Massachusetts State Laboratory Institute

(MSLI) played a key role in this effort and was supported

by the CDC. Together with the Peruvian National Institute

of Health (INS), they not only helped develop capacity for

doing culture and sensitivity testing, they also ensured

proper equipment and facilities, improved biosafety,

assured that quality control and assurance procedures

were in place, and conducted extensive training for lab

technicians and administrators.

The Laboratory Set-Up

Peru has three levels of laboratories. Level I labo-

ratories are the most decentralized, integrated into the

general health services and represented by 1,334 Level

| 37


Chapter Three

I laboratories throughout Peru. These are supported by

67 Level II laboratories, of which 23 are considered to be

“Regional Reference Laboratories.” Finally, the National

Mycobacterial Reference Laboratory of the INS in Lima

provides overall direction to all the laboratories and also

serves as the reference lab for any tests that are referred

to it from the regional or peripheral labs. This is depicted

in Figure 5.

The Plan for Lab Capacity Development

At the first PARTNERS meeting, in November 2000,

a workgroup for “introduction of new tools” was formed.

Later that year, it was renamed as the ‘diagnostics’ work-

group. This workgroup focused on intermediate labora-

tory capacity development. This workgroup made an initial

assessment of the overall infrastructure of the Peruvian

laboratory system, its testing capabilities, and the needs

of the National Reference Laboratory for Mycobacteria

(NRLM) at the INS, in January 2001. In the second year,

a more comprehensive needs assessment was performed

for the regional laboratories in Peru.

The analysis of the laboratory network in Peru

showed that many different issues had to be addressed.

Drug sensitivity testing (DST) was central to MDR-TB

control, so both first-line and second-line drug testing

capabilities needed to be built. Although first-line drug

sensitivity testing (FLDST) did exist at the central lab in

Peru, the procedure was old; newer methods needed to

be established. Besides, having just one lab do the test-

ing for the whole country was impractical. More Level II

labs were needed to perform FLDST. This capacity had to

be built from scratch at these labs. Apart from extending

FLDST, the capability and capacity for second-line drug

sensitivity testing (SLDST) also needed to be built in

Lima. This would be much more expensive and difficult.

The goals of the workgroup were to develop the

capacity of the labs and conduct research on the rela-

tive utility and cost-effectiveness of various diagnostic

techniques. The Peru National Laboratory needed to be

able to meet all program needs, including second- and

third-line drug sensitivity testing. Four to six regional labs

would have the capacity to conduct first-line DST by 2005,

and some local laboratories would be able to carry out

cultures. The research would focus on studying the use

of different diagnostic tests to determine the relative util-

ity and cost-effectiveness and improvement in diagnos-

tic turn-around-time (TAT). Other studies would focus

on costs of scaling up (including cost-

ing variables in timing of DST, cost of

repeat failures, etc.). All the labs were

to be linked by a management informa-

tion system (MIS). Major laboratories

would be equipped for all types of diag-

nostic tests, with rapid tests for identi-

fying resistance and for basic research

(i.e., molecular biology for gene iden-

tification). The INS would receive ISO

certification as a regional reference lab-

oratory by 2005. The aim was to build

capacity in such a way that all these

laboratories would endure beyond the

life of the grant.

The scale-up was planned in four

phases. The plan was for MSLI to pro-

vide the immediate diagnostic needs

while gradually transferring capacity to

Peruvian laboratories through training,

building of local lab capacity, and assuring quality through

validation testing.

Activities

According to the plan, the MSLI initially tested the

sputum samples, and provided consultation and training

to the INS. It also initiated all the needed research at first.

This allowed patients to be treated while capacity in Peru

USC5,300

LL1,334

IL44

Level IIINational Reference Laboratory for Mycobacteria (NRLM) DST of FLDs and SLDs

Level IIRegional Reference Laboratory for Mycobacteria (RRLM)

Intermediate Laboratories(National Hospitals) Cultures

Level ILocal Laboratories(Medical Post) AFB

Unities for Samples Collection (USC) National Strategy

RRL23

NLR1

Figure 5. National Institute of Health of Perú

Organization of the Public Health Laboratory Network


38 |

was developed. MSLI increased its capacity to perform

necessary reference testing for the Peruvian labs and pro-

vided lab support for all 1450 of the Gates grant-funded

patients in Peru. Original sputum specimens were pro-

cessed by MSLI, where they were plated for growth and iso-

lation, and tested for identification and drug susceptibility.

When necessary, additional laboratory and DST was per-

formed at the National Jewish Medical Center in Denver.

In order to build capacity in the labs of Peru,

PARTNERS had to provide new technologies, procure

supplies and equipment, train the lab workers, ensure

quality control, and put infection control measures in

place. They also continued to conduct research at the

same time.

The Peru National TB Reference Laboratory already

had the capacity to do first-line DST, but the methods

used were old. MSLI helped them develop newer tech-

nologies,22 validate the processes, and train the tech-

nicians. Teams of consultants went down to Peru and

stayed there for months as these processes were put

in place. The capacity to do second-line DST was also

developed. MSLI also put in place advanced molecular

identification methods and conducted research along

with the CDC and the INS.

Although new facilities were not required, the INS

needed to purchase supplies and equipment for the new

technologies, many of which had to be ordered from out-

side Peru because the companies manufacturing these

supplies and equipment did not distribute them in Peru.

So MSLI had to get these for the INS. This involved elabo-

rate customs procedures and bureaucratic hurdles which

took substantial time.

Experts from MSLI and CDC provided comprehen-

sive training to the lab workers in Peru. While MSLI

focused mainly on the national reference labs, the CDC

took on the task of strengthening laboratory service at

the regional level. However, there was a great degree of

overlap between their tasks. Around the end of year three,

the responsibility for training moved from MSLI to rest

entirely with CDC and PIH. Once the workers at the INS

were trained, they joined the Partners in providing train-

ing to workers in peripheral labs.

Along with developing the capacity, MSLI also put

quality assurance and quality control (QA/QC) methods

in place. DST is a complicated process where results in the

laboratory may not accurately predict clinical results, par-

ticularly if the tests are not done properly. So, criteria for

determining resistance need to be carefully defined, and

the tests standardized in such a way that reliable results

are produced. This validation process had to be done for

both FLD and SLD and took a long time. Duplicate testing

for many cultures was done at the MSLI to ensure reli-

ability. Site visits were made to different laboratories, QA/

QC protocols laid out, and training was provided. This

ensured prevention of contamination, viability of cultures,

and clinically relevant DST results.

Safety of lab workers was a key concern while scaling

up the lab facilities. In 2002, PARTNERS began intro-

ducing measures for infection control. MSLI procured

biosafety cabinets for the labs. These cabinets allowed

an inward airflow that would prevent the workers from

being exposed to the MDR-TB bacilli. But, existence of

these cabinets by themselves was not sufficient to pro-

tect the workers. They needed to know how to use and

maintain the equipment, know the risks involved, and

take additional precautionary measures. For this, MSLI

implemented an extensive Biosafety Cabinet Certification

Program through which workers were trained in taking

appropriate safety measures while testing the specimens

and handling lab equipment. Courses were held not only

in Lima, but also in Maine, where advanced concepts

were taught to health workers from Lima. This program

was very involved and took a long time.

One of the most challenging tasks in show-

ing programmatic feasibility of MDR-TB

control was ensuring proper documentation

and handling of information. Healthcare

personnel in all clinics needed to commu-

nicate health information about patients

using terms and data that had uniform

meaning. Proper collection and recording

of data, fast processing, and needs-based

reporting helped to ascertain the big picture

and to quickly understand any problems at

the peripheral levels.

| 39


Chapter Three

While the PARTNERS were building local capac-

ity, they also conducted important research work.

Sometimes, there was a competition for resources

between the research and clinical work that slowed the

labs’ capacity to handle increased loads of patients.

However, for the most part, the labs were able to han-

dle these dual tasks efficiently. One of the important

research findings showed that the turn-around time for

DSTs could be reduced substantially by operational effi-

ciencies alone. At that time, while culturing a specimen

took 3–8 weeks, performing DSTs took an additional 6–8

weeks. The overall turn-around time (TAT), defined as

the time taken between when a physician requests an

analysis of a sputum sample and when he/she gets the

lab results back, took as much as 6 months or more.

Experts from the CDC conducted extensive studies on

how to decrease this TAT. Apart from focusing on rapid

diagnostic methods, they also concentrated on logis-

tics, efficient handling of samples, and rapid reporting.

The findings showed that the process of transporting

the specimens and conveying the results alone took as

much as a month. Frequently, the specimens were dried

up by the time they reached the lab and had to be sub-

cultured, adding in an additional delay of 4–6 weeks.

These pointed to flaws in administration of the sputum

samples and overall management as key contributors

to the TAT. Accordingly, recommendations were made

that helped to accelerate the handling of samples and

improve administrative efficiency, cutting TAT by as much

as a month.

Developing an Information System

The Need for EMR System in Peru

One of the most challenging tasks in showing pro-

grammatic feasibility of MDR-TB control was ensuring

proper documentation and handling of information.

Healthcare personnel in all clinics needed to commu-

nicate health information about patients using terms

and data that had uniform meaning. Proper collection

and recording of data, fast processing, and needs-based

reporting helped to ascertain the big picture and to quickly

understand any problems at the peripheral levels.

The complexity of MDR-TB management, where

many more data are required on each patient, made it

even more difficult. These pieces of information included

not only patient history, clinical exam findings, and spu-

tum smears, but also cultures, done every month; DST

results for each patient; different drug regimens for each

patient; identification of patients as a ‘culture conversion’,

a ‘reconversion’, a ‘cure’, or a ‘failure;’ documenting the

many side effects, each of which might need a different

drug; and many more.

When the PARTNERS started working in Peru, most

information was collected in paper records. While some

electronic records did exist, they were scattered in dif-

ferent Microsoft (MS) Excel or MS Word files with dif-

ferent clinics maintaining records differently. There was

one centralized database that was maintained using

information from the separate paper and electronic files

and there were many errors. The paper records created

many opportunities for errors of recording, interpret-

ing, and collating information. Additionally, paper files

could easily be destroyed or lost. The separate electronic

files had issues including data duplication, lack of secu-

rity measures, and lack of uniformity. The distributed

files made it difficult to analyze the data in an integrated

fashion. The data could only be used in a retrospective

sense to analyze patterns and trends. They could not be

used to monitor the conditions of patients in an ongoing

manner, track drug management, or provide real-time

information to help improve the quality of healthcare

programs.

At the beginning of the Project, PIH physicians had

been exchanging emails with physicians in Lima and

discussing the ways to manage individual patients. This

was telemedicine in its most basic form. With growing

numbers of patients, it was quickly becoming a night-

mare to track the histories of patients through emails

and provide responses. The answer seemed to be a

web-based integrated electronic medical record (EMR)

system that could serve not only as an electronic medi-

cal record solution, but also help meet the telemedi-

cine needs that were coming up in the management

of MDR-TB patients in Lima. A search for solutions in

existing EMRs proved to be disappointing. There was no

system that could deal with the peculiarities of MDR-TB

and support different languages. Peru did have a central-

ized analytical system (SYSTB), but it was useful only for

aggregate data and could not provide information for

individual patients. So the PARTNERS set about to build

a system from scratch.

A workgroup on information technology was set up

at the second PARTNERS meeting in January, 2001. It

discussed plans to implement a web-based information


40 |

system that could serve not only as an electronic medical

record system, but also become a portal for telemedi-

cine, provide decision support for physicians, and help

manage drug supply/inventory databases efficiently.

Videoconferencing as a mechanism for training and com-

munication between remote sites was also to be used.

The EMR in Peru

The electronic medical record (EMR) system that

PARTNERS built is a web-based application that allows

secure and reliable, real-time access to patient records

from anywhere that an internet connection is available.

It took 8–9 months to develop a working model of the

system that could support basic patient records in both

English and Spanish. Begun in September 2000 and

piloted in August 2001, the system was fully imple-

mented in 2003. The complete system included bac-

teriology results, other lab data, and drug regimens. It

also allowed for bacteriology results to be transferred

from personal digital assistants (PDAs), thus eliminat-

ing the need for duplicate data entry, first in paper based

records, and later transferring the data into electronic

form. The system was designed keeping in mind that

most clinics in Peru would have a slow dial-up connec-

tion. In this sense, this system could be used in other

developing country settings where fast internet access

may not be a reality.

There were several problems that had to be dealt

with in achieving complete implementation of the EMR.

Initial attempts using a Microsoft Access©-like system

to facilitate easy entry and retrieval of data had to be

shelved because of the rapidly increasing complexity of

data and the need to connect many different places. A

web-based solution was identified as the best approach.

The process of data entry had also to be resolved. The

right kinds of forms had to be designed and people

trained to use them. Another difficulty arose when the

system, designed to manage patient records, had to be

redesigned to also function as drug-management soft-

ware. These problems caused unanticipated delays in

implementation.

The EMR had to link into a central place that could

coordinate the collection, processing, analysis, and

reporting of all the data. This function was served by

the Unidad Tecnica (Technical Unit) which was created

in 1999. In October 1997 Peru had begun STR follow-

ing recommendations of WHO as part of a DOTS-Plus

Strategy. The Unidad Tecnica was planned as a mecha-

nism at the national level to maintain and monitor a

registry of patients who were undergoing treatment

under the DOTS-Plus program and help achieve a bet-

ter application of the DOTS-Plus strategy. This body

reports directly to PNCT, with support and ongoing con-

sultation from WHO/PAHO. It coordinates and super-

vises the information and technical evaluation of cases

who receive treatment for MDR-TB, whether STR or

ITR. It staffs the National Committee on Evaluation of

Retreatment (CERN), which makes decisions on which

patients need to be treated by an ITR. When there is a

treatment failure at the local level, an intermediate level

committee on evaluation of retreatment in each DISA

(health district) reviews the information and decides if

the person should be put on STR. The information is

then sent to the national level. At the national level, the

committee reviews that information and makes a deci-

sion on who would get first and second-line drug sensi-

tivity testing and who should get an individualized treat-

ment regimen. Each of these bodies needs to be able to

see the data and preferably have access to it as and when

required. The web-based system that was developed in

Peru, allowed them to do this easily.

The PARTNERS maintained extensive documenta-

tion of all that they did. They also conducted studies to

assess the effect of the drug regimen recording system

on data quality and drug supply management. These

studies ensured not only appropriate research on oper-

ationalizing an EMR system in developing countries,

but also improved patient care substantially through the

highly improved quality of data management.

Initiating a new paradigm of organizing and moni-

toring information is always difficult. It requires exten-

sive analysis and evaluation, the acceptance of a new

technology by people, intensive training, and continuing

modification to fit the needs of the program. This system

could not have been as successful as it is without the

support of various partners. While the Gates grant was

instrumental in financing this Project, support from the

Peruvian government and other PARTNERS right from

the start was crucial to overcoming the skepticism of

many people.

| 41


Chapter Three

Building Up the Human Resources

Rapid Scale-Up Required

Managing the human resources required for the

scale-up in Peru was a major part of proving the pro-

grammatic feasibility of MDR-TB control. People had

to be hired, trained, and adequately supported in their

tasks. A system of supportive supervision that demanded

accountability while providing continued encouragement

had to be put in place. The PARTNERS had to manage

routine issues of human resource management such as

opportunities for career growth, minimizing turnover,

and countering attrition. In addition, they had to face

other issues that were peculiar to MDR-TB, such as coun-

tering the fear that health workers had of getting infected,

and developing the faith of health workers in the possibil-

ity of effective treatment when in the past they had seen

MDR-TB patients as untreatable.

Although treatment for MDR-TB had begun in Peru

in 1997 as part of a DOTS-Plus effort, it gained substan-

tial momentum with the PARTNERS Project. There was

a tremendous need for scaling up human resources to

handle the rapid scale-up that was being done. The 1,450

patients that the PARTNERS had intended to enroll in

the program over five years were registered and put on

treatment by the third year. An increasing number of phy-

sicians, nurses, community health workers, laboratory

technicians, and other staff were needed to handle this

load and the program required smooth coordination of

different areas of work.

The PARTNERS also needed people who could main-

tain effective communication with local and international

partners and work with them to ensure sustainability once

the PARTNERS Project was over. SES developed institu-

tional links with other local NGOs such as PROVIDA

(with expertise in maintaining pharmacy stocks),

CARITAS (a non-profit Catholic organization that pro-

vides social support), and Vaso de Leche (a program pro-

viding nutritional support to needy children). PARTNERS

worked with MINSA to develop an application to the

Global Fund against AIDS, TB, and Malaria (GFATM) for

continuing support in treating MDR-TB patients. PIH/

SES also worked together with CARE to manage drug

warehousing and distribution once the GFATM money

was being used to make drug purchases. Meanwhile, the

PARTNERS maintained constant communication with

international organizations, including PAHO, IUATLD,

MSF, IDA, and several others.

Strategies Used

In order to handle the complex task of human

resource management, the PARTNERS began intensive

training of physicians, nurses, laboratory technicians and

managers, and DOTS workers. Perhaps one of the most

significant steps was the enlisting of community health

workers and making them one of the strongest pillars

of success for the program. In addition, the PARTNERS

teamed up with the Institute for Healthcare Improvement

(IHI) to start a collaborative project in Peru to implement

high quality procedures and help the spread of these

techniques for improved program outcome.

In 2002 the PARTNERS, in collaboration with IHI,

launched a TB Control Improvement Collaborative in

which 41 teams from different MINSA health centers

across Lima were brought together to improve TB care

outcomes throughout Peru. It was designed as a way

of spreading the knowledge and principles of MDR-TB

control in such a way that it could be integrated into the

existing NTP program. These teams participated in dis-

cussions and prepared a change package that was then

implemented in different health centers through regular

execution of Plan-Do-Study-Act (PDSA) cycles. Although,

the IHI was initially designed to focus on MDR-TB, it

later shifted its goals to address TB overall. Because of

the success of this collaboration, MINSA launched a sec-

ond collaboration to improve maternal and child health.

The first cohort of MDR-TB patients had been

treated under supervision of experts from Harvard. This

was in keeping with the intention of providing the best

possible treatment to the poor patients of Lima. But as

the treatment was scaled up, these skills needed to be

transferred to workers in Peru, including government

workers, workers for non-profit organizations, and vol-

unteers. Most of the training that the PARTNERS pro-

vided was in individualized treatment regimens (ITR),

although it also included standardized treatment regi-

mens (STR).

A training needs assessment in 2001 showed a

number of weaknesses in the program. Health workers

had limited training for MDR-TB; there was insufficient

educational material for them; the content of training

that was being given had to be expanded and include


42 |

items such as management of adverse reactions and

co-morbid conditions, infection control, patient support,

and health worker- patient communication; and educa-

tional material needed to be developed for patients and

their families as well.

The PARTNERS began training programs in earnest.

They started to institute two kinds of training, “Crash”

and “Exploratory.” While “Crash” training was meant as

a short-cut method to bring physicians, nurses, and lab

technicians to a level where they could perform the mini-

mum functions of MDR-TB control, “Exploratory” train-

ing took that one step further and provided the detailed

knowledge and skills necessary to implement all aspects

of the program. The differences between these trainings

are outlined in Table 2.

The detailed training was based on an in-depth

analysis of previous training experience. In 2003, a team

comprising experts from the CDC, PIH, and MINSA

developed a survey for health workers that examined

their knowledge, attitudes, and practices for TB care.

The survey was carried out throughout metropolitan

Lima. This helped set the training objectives and con-

tent. Soon, participatory and other novel teaching aids

were created and validated. Evaluation instruments were

created and different training teams were also trained.

Training programs were then initiated for different

groups of health workers — physicians, nurses, labora-

tory technicians, and community health workers.

Several factors were important for success. Since the

target for the training was an adult audience comprising

people from different geographical and cultural regions,

the learning materials had to be appropriately designed.

Training had to be done in small groups or individu-

ally, include substantial interactive components, and

use site visits and field experiences to show a particular

point. A system of certificates was instituted to maintain

quality. Initially the training for individualized treatment

regimen (ITR) began in the areas of metropolitan Lima.

Soon, it spread to several other regions including Ica,

La Libertad, Ancash, Arequipa, Lambayeque, Piura, and

Junin.

PARTNERS faced many challenges in ensuring

appropriate and qualified human resources for the scale-

up. The primary challenge was ensuring that the staff

was competent and had the skills and knowledge to han-

dle all the issues about MDR-TB relevant to their field.

Apart from that, it was important to ensure a sufficient

number of people, keep their morale and motivation

high, assure safe working conditions, have encouraging

policies and practices in place (career structures, pay),

provide supportive supervision, and minimize attrition

due to death and migration.

While many of the challenges of human resource

development are not uncommon in other programs,

there were a few problems that were unique to MDR-TB

control in Peru. Before the PARTNERS Project, the

health workers had been accustomed to watching

MDR-TB patients fail repeated treatment. This perpetu-

ated the fear that if one were to contract this disease,

there was no cure. This fear was palpable in the begin-

ning and it was difficult to recruit CHWs to work with

the PARTNERS. It took much reassurance and showing

by example before health workers started to gain trust

in the efforts of the physicians from PIH to treat this

deadly disease. Apart from the fear, there also was skep-

ticism about whether this disease could really be cured.

Since it takes about two years to assure that patients are

cured, the PARTNERS had to persevere to win the trust

of these workers and instill faith that this disease was

indeed curable.

Table 2. “Crash” and “Exploratory” Training

Crash (yr 2000) Exploratory (since yr 2001 )

Target group Physicians, nurses, technicians CHWs, nurses, technicians/physicians

Responsible team SES nurses SES nurses

Core contentsIndividualized treatment

(IT) deliveryMDR-TB and

IT delivery

Methodology Lecture Course-workshops (participatory)

Duration 1-2 hours 7-12 hours

Evaluation None Process and outcome

Training Plan None Yes (short-term)

| 43


Chapter Three

Unanticipated ChallengesDespite having a good plan, committed people, and

working in Peru — with one of the best DOTS programs

in the world — the Project ran into many obstacles. As a

result of health sector reform (HSR) and many political

changes, the NTP suffered from a lack of sustained lead-

ership, financial difficulties, and a disruption of program

activities. This caused delays in the PARTNERS Project

that were not anticipated.

Strength of Peruvian NTPOne of the important reasons why Peru was chosen

as the country to develop a model of integrated drug-

susceptible and drug-resistant TB control was because

of its strong DOTS infrastructure built under the strong

leadership of Pedro Guillermo Suarez.

Peru had been one of the 20 highest burden TB

countries (HBCs) in the 1980s and the program was

weak. Leading up to 1990, the incidence of TB in Peru

had been 230 per 100,000 for 15 years. Only 50% of TB

patients received treatment. Health workers were not

trained, clear protocols of treatment were missing, there

was a shortage of drugs and supplies, and systems of

recording and monitoring had not been established.

Over the course of the 1990s, through the efforts of

Pedro Guillermo Suarez, Peru dramatically improved its

National TB Program, which became recognized as one

of the best in the world — a global model for DOTS. The

TB budget was increased from US $600,000 to US $5

million per year. While in 1991 there were only 997 health

centers providing TB treatment, the number rose to 6,351

in 1999. Similarly the number of laboratories performing

sputum smear microscopy increased from 307 to 1,200

by year 2000. These numbers were indicative of the rapid

strides that the DOTS program had taken in Peru. As a

result, by 2000 Peru was taken off the list of HBCs and

the Peruvian DOTS program, with cure rates of more

than 90%, was lauded as one of the best in the world.

When the PARTNERS Project began in Lima, the

Peruvian government was already addressing MDR-TB

in the country, using then-recommended standardized

therapy regimens and working with PIH/SES to allow

individualized treatment for a small section of the popu-

lation in Carabayllo. Given this background, it seemed as

if the PARTNERS Project would be able to leverage the

strong infrastructure and have little difficulty in getting

full support from the Peruvian government in achieving

its goals.

Negative Impact of Health Sector Reform and Political ChangeSoon after the Project began, there was a nearly com-

plete breakdown of the NTP structure because of HSR and

the many political changes that happened over the next

few years. HSR has been promoted by the World Bank to

improve the delivery of health care services in resource-

poor countries by decentralizing the governance of the

health system and integrating disease- or area-specific

programs. However, experience in a number of countries

has shown that it can result in declines in outcomes in TB

programs. During his tenure as NTP Director, Dr. Suarez

had been able to maintain the strength of the vertical pro-

gram. However, when he left in July 2001 when there was

a change in government, the leadership and management

of NTP deteriorated rapidly.

Peru’s health system had been organized into several

vertical programs that made it difficult to offer integrated

healthcare to people. HSR was intended to be an answer

to this problem. However, implementing HSR caused a

radical change in the system, distributing the key activi-

ties that had been centralized as part of the NTP. Instead

of organizing by vertical disease areas, HSR organized

the health system by age groups. It replaced vertical pro-

grams like HIV and TB with age-based clinics such as

child, adult, and geriatric clinics that offered comprehen-

sive health care in each category. Key functions such as

training and purchasing were handled by other depart-

ments. Although there was merit in integrating health-

care delivery, it caused people who had been trained

extensively in one area to adapt to offering other forms

of healthcare also. Likewise, it meant that some patients

of TB were being treated by health workers who did not

necessarily have specialized knowledge of TB.

The next few years also witnessed a frequent change

in leadership that did not allow the sustained commitment

needed to manage the NTP and address the disruptions

caused by HSR. Almost every year saw a change of leader-

ship within the Ministry of Health. Each change at the top

of the ministry had ripple effects throughout the agency,

including the NTP. From 2000 to 2005, six different leaders


44 |

headed the NTP, some of them remaining in place only for

a few months. This made it very difficult for any govern-

ment commitment to be carried out effectively. Table 3

shows the leadership changes in Peru’s NTP.

The changes in political appointments were happen-

ing not only at the NTP, but at higher levels of the govern-

ment as well. Between 2003 and 2004, for example, three

ministers and three general directors were changed in

just one year. This rate of change proved to be seriously

damaging to both the TB and MDR-TB control efforts in

the country.

Each time the leadership changed, the TB and

MDR-TB programs lost ground due to the delays from

the changes and the need to educate the next group of

officials while they oriented themselves to the challenges

Peru was facing in a number of diseases.

The Consequences

These unanticipated challenges caused the break-

down of several planned activities for scale-up soon after

the PARTNERS Project began. HSR led to several chal-

lenges in the proper functioning of the NTP. It caused

difficulties in reorganizing technical responsibilities to

fit an integrated approach, dilution of expertise that had

been concentrated within the TB program, and lack of

targeting of high risk groups for TB, as programs were

re-grouped and reorganized. It also led to inadequate

financing at the regional level, lack of absorptive capacity

of national delivery systems for drug and supply procure-

ment, and changes in donor and government relation-

ships. It created managerial and policy challenges leading

to lack of capacity of regional organizations to manage

disease issues as well as the vertical organization did,

poor prioritization of disease issues at regional level, lack

of advocacy, lack of attention, and lack of follow-through

on program commitments.

The leadership of the NTP passed through many

hands, some of whom were not capable managers and

others who, having inherited a host of problems and

working without the protection of a stable government,

were unable to steer the NTP out of trouble until a few

years later.

In mid-2001, after Dr. Suarez’s departure, unilateral

changes were made in programmatic activities, caus-

ing disruption and confusion in the field. In early 2002,

PAHO brought together a team of global TB experts to

conduct an external evaluation of Peru’s NTP. The team

found that TB continued to be a major health problem in

Peru and that data from the field accurately reflected the

TB situation. At the field level, program activities contin-

ued with well-trained and motivated staff. However, there

were a number of very serious concerns, including:

• Drug supply — no drug purchases in 2001 and some districts only had supplies through March 2002.

• Directives from national level changing definitions (e.g., cure, failure, relapse) made comparisons dif-ficult, were not in accord with international organiza-tions, and were creating confusion in the field.

• New directives, mainly implemented in Lima/Callao, called for massive use of X-rays and house-to-house search for cases, both of which were low yield and high cost and not internationally recognized as proper methods.

• Deterioration in management, as manifested by loss of communication with DISAs (districts), little partic-ipation of DISAs in preparing directives, and reduced training/supervision from central level to DISAs.

• Lab network deterioration, with insufficient coverage with cultures and lack of biosafety threatening staff.

• Health sector reform could negatively affect the dynamics of TB control.

• Two new proposed standardized regimens for MDR-TB were not science-based and could cre-ate chaos in management as well as increase

Table 3. Leadership Changes

Director of the NTP (MINSA) Start End

Dr. Pedro Guillermo Suárez Late-90 July-01

Dr. Roberto Accinelli Jul-01 Mar-02

Dr. Eduardo Ticona Mar-02 Apr-03

Dr. Roberto Canales Apr-03 May-04

Dr. Luis Zavala May-04 Sep-04

Dr. César Bonilla Sep-04 beyond 2006

| 45


Chapter Three

resistance to second-line drugs. A proposal to pur-chase second-line drugs (US $20m) was not fea-sible, justified, or in agreement with international recommendations.

As a result of this alarming evaluation, a number

of changes were made. The NTP program director was

replaced in March 2002. The new director made an

official response in July 2002, reaffirming Peru’s com-

mitment to DOTS, consistent with WHO’s guidelines.

He asserted that HSR should not interfere with the TB

Control Program and declared that standardized treat-

ment for MDR-TB patients would be analyzed for effec-

tiveness and then enhanced as necessary and that the

program of retreatment for MDR-TB would be reviewed.

He also assured that MINSA would continue to col-

laborate in the PARTNERS Project for individualized

MDR-TB care.

Despite these renewed commitments, it took time

for things to become stable and start improving.

Shortage of Drugs and Supplies

One of the most difficult problems the NTP encoun-

tered was the lack of the regular first-line drug order

needed to ensure a proper supply. Perhaps due to the

change in administration or perhaps due to health sec-

tor reform, those in charge were not aware of the needs

of the NTP or were not aware of the new procedures for

purchasing drugs. For whatever reason, first-line drugs

were not ordered in the normal window for such pur-

chases; neither were sputum cups. Both are a necessity

for diagnosing and treating TB. MINSA’s system would

not allow an order to make up for this serious error. As a

result, the entire country and its many health centers were

in jeopardy of running out of first-line drugs. This had its

effect on MDR-TB efforts as well. The GLC declared that it

would not endorse Peru’s purchase of second-line drugs

if first-line drugs were not available.

The Peru program was saved during this crisis by the

network of TB specialists in the DISAs and health centers

in the field. They had been well-trained under Dr. Suarez

and began to look out for each other and the TB patients

by sharing drugs and supplies in their warehouses,

making sure they went to the health centers where they

were most needed. This cooperative effort averted the

looming drug crisis and, after months and months of

struggling with the political system, first-line drugs finally

were obtained.

Personnel Changes

As part of HSR, the NTP was demoted from being

a program to being a strategy within the system of inte-

grated care. Much of the MINSA TB staff, who had been

working in TB for years, was transferred to new positions

unrelated to TB or left. The changes in organizational

lines of responsibility created tremendous confusion

with regards to planning and management of the DOTS

program. Untrained workers ended up having to tackle

issues of TB, and many of those trained in caring for TB

patients were being put to work on managing other dis-

ease areas.

Funding Cuts

In addition, continuing budget cuts had begun to

severely affect the NTP. With communication and coordi-

nation problems, TB became neglected. The systems for

calculating, ordering, and distributing supplies were bro-

ken. When health issues were analyzed by age groups, TB

did not rank as a primary concern because it affected peo-

ple in all of them. Because there was no separate budget

for TB and no budgetary allocation of NTP to reimburse

any DISA health center that attempted to continue treat-

ment on its own, the health centers no longer had money

for case finding or to order sputum cups. TB health work-

ers at all levels were demoralized. With the TB program in

such a state, it was nearly impossible to tackle MDR-TB.

In order for MDR-TB scale-up to continue as envisioned,

the neumologos (pulmonary specialists) needed to work

more than they were at that time and they needed to be

paid for those extra hours. Yet, there was not enough

money to pay them. The budget cuts had also begun to

affect the operations of health clinics in the DISAs with no

funding for health care worker incentives such as nutri-

tion or for transportation for case finding.

Other Program Disruptions

The program suffered greatly during this time with

so much effort focused on the first-line drug problem

and the confusion arising from rapid and sweeping

personnel changes. With these critical functions of the

NTP compromised and funding shortages, MINSA’s


46 |

commitment to MDR-TB control also suffered. The

planned scale-up, as envisioned by the PARTNERS

Project when it began, suffered a big setback. All aspects

of the program, including surveillance, training, and

infection control, were delayed.

Other Setbacks

Besides the deterioration of the NTP, there were other

setbacks for the PARTNERS. While most of the changes in

leadership happened due to political reasons, in 2003, an

injury suffered by the Director of the Instituto Nacional de

Salud (INS) left him unable to work for several months.

This caused further delays in the planned activities.

The many changes in personnel and breakdown of

existing organizational structures led to confusion and lack

of communication between various groups — including

infectious disease physicians, pulmonary physicians, and

the leaders of the NTP. This made it difficult for trust to be

established and hampered the progress of MDR-TB control

despite the fact that people recognized the problems that

needed to be addressed. In 2004, for example, the NTP

leadership and the neumologos acknowledged that the

existing standardized regimen to treat MDR-TB was inef-

fective and wanted to replace it with a seven-drug regimen.

After several discussions, the neumologos agreed to sign an

agreement that would change the failing drug regimen. It

was another year, however, before the new, more effectivej

regimen took effect in 2005.

This lack of trust and proper communication was a

problem not only between health workers, but also between

the NTP and the public. In 2003, a public interest litiga-

tion group filed a lawsuit against the government, alleging

that its intention to start treating MDR-TB patients with

ITR only in Lima, while ignoring the rest of the country,

was a violation of the rights of those other patients to be

treated. The public interest group also protested the use

of an ineffective regimen (the STR) by the NTP.

The NTP has been re-established as a separate pro-

gram and is now functioning more efficiently than it did

in years 2002–2004.

Goals Surpassed Despite Challenges

Despite these challenges, in many ways, the Project

ended up achieving more than it had set out to achieve.

Not only did it create a successful model for integrated

drug-susceptible and drug-resistant TB, it also yielded

valuable lessons for managing other complex health

interventions in resource-poor countries.

Clinical Treatment and Patient Support

By 2005, Peru had integrated DOTS-Plus into its TB

control program. MDR-TB patients were being treated

with ITR throughout the country. This was a big change

from only five years before, when the Peruvian govern-

ment was using STR and ITR was only available in Lima.

The PARTNERS Project had a huge role in this change.

On a more international scale, perhaps the most signifi-

cant contribution of the PARTNERS Project, in terms of

clinical treatment, was the successful demonstration of

individualized treatment regimens (ITR) as a strategy to

treat MDR-TB cases in developing countries. The Project

showed that ITR could be very effective and efficient, and

that it could be used along with standardized approaches

to suit the needs of different countries with different epi-

demiological profiles.

Initially the PARTNERS Project intended to treat only

1,450 patients over the five years of the Project. However,

that number of patients was enrolled within the first three

years and patients continued to enroll. By October 2004,

the GLC had given its approval for MINSA to treat an

additional 2,000 MDR-TB patients with support from the

GFATM. At this time, MINSA had completely assumed

the responsibility for patient care. When the Project

ended in 2005, MINSA had enrolled the additional 2,000

patients, as well as 570 more. In total, more than 4,000

patients were treated under the PARTNERS Project. This

number was radically different from the estimate of 300

MDR-TB patients made by the Peruvian government

when the Project had started. This difference not only

showed that MDR-TB was much more of a problem than

originally estimated, it also showed that, despite a chal-

lenging political environment, a dedicated team could

exceed targets and scale up rapidly.

Of the 1,450 patients enrolled by the Project in the first

three years, 1,304 had completed treatment in September

2005. Although more than two-thirds of these patients

will likely have good treatment outcomes, the remaining

third are unlikely to be cured. Yet, they have not been for-

saken: MINSA pays the continued treatment and medica-

tion costs for these patients. Recent data from the newer

patients enrolled with support from GFATM showed that

| 47


Chapter Three

over 90% of patients enrolled became culture negative

within four months of treatment initiation. This indicates

that the backlog of patients with many previous treat-

ments has been cleared and that patients are now being

diagnosed and treated earlier.

Of the 1,304 initial patients who completed treat-

ment, 858 (66%) were cured. The most important pre-

dictor of cure is the number of previous treatment regi-

mens the patient has undergone. In its first two years, the

Project encountered its sickest patients, with the highest

numbers of previous treatments. As shown in Table 4,

cure rates were far better for patients who had 2 or fewer

than 2 previous treatment courses (71% and 77%), than

for patients with more previous treatments (60%).

One of the key factors in the success of the ITR that

the Project provided was the patient support groups they

had created. By 2004, the PARTNERS established seven

support groups throughout metropolitan Lima and in two

other provinces of Peru. Of the 285 patients who partici-

pated over 3 years, only 3.2% defaulted from treatment.

These support groups brought together current patients

with those that had been cured. This helped reduce mis-

information and build trust. Many patients who survived

the disease that had earlier killed their near and dear ones

spoke tearfully about the immense gratitude they felt

towards the health workers.

The health workers also conducted information,

education, and counseling sessions with the community.

Slowly, over the years, these efforts have transformed the

community’s perception of MDR-TB. While trust in the

curability of the disease is still tentative, the situation has

changed tremendously from what it used to be.

Infection Control

The PARTNERS Project also achieved significant

successes in infection control, both for patients and for

health workers. Prior to the Project, no training resources

in infection control for TB existed in Peru. Adapting exist-

ing WHO and CDC guidelines, the Project developed a

training manual and pilot tested it at a training course

in Lima. Train-the-trainer courses were conducted in

2004 and 2005. These trainers in turn conducted 16 addi-

tional trainings at their local health centers. The trainings

included a week of classroom instruction and a week of

fieldwork. More than 2,000 copies of the manual were

distributed to health care workers. Infection control suc-

cess was evident: the course of the Project, not one of the

700 health workers engaged in preventing and treating

MDR-TB developed the disease.

Established Capacity for First- and Second-Line Drug Sensitivity Testing

The PARTNERS Project set up first-line and second-

line drug sensitivity testing at the central lab in Peru, as

well as building FLD sensitivity testing at five regional

labs. Establishing high-quality drug sensitivity testing

where this capacity had not existed before turned out to

be much more difficult than anticipated. Although initially

the Project had envisioned the scale-up of diagnostic ser-

vices across the country, eventually it focused on Lima-

Callao and five additional cities for a number of reasons.

The number of MDR-TB patients requiring care in Lima-

Callao, frequent leadership changes within the Ministry of

Health and in the PNCT, and the impact of Peru’s health

Table 4. Treatment outcomes of 1,450 patients analyzed by previous treatment exposure

Previous Treatment Exposure (# of patient-treatments)

Final Outcomes <2 2 >2 Unknown Total %

Abandonment 29 28 87 5 149 11%

Cure/Completion 205 192 437 24 858 66%

Death 30 47 185 6 268 21

Treatment Failure 2 4 23 0 29 2%

Subtotal 266 271 732 35 1,304 100%

Cure Rates 77% 71% 60% 66%

Transfer 1 3 3 2 9

No Outcome as Yet 31 42 72 1 146

Total 298 316 807 38 1,459


48 |

sector reform initiative all made further efforts at geo-

graphical expansion inadvisable. The fact that more than

90% of MDR-TB patients were in the Lima-Callao area

and in five other cities, together with dedicated health

workers eager to participate in the problem, facilitated

the choice of these areas as the primary targets for the

laboratory scale-up.

Despite all the challenges, substantial achievements

were made in terms of the scale-up of diagnostic capacity

in Peru. The central lab was equipped with the capac-

ity to do both first-line and second-line DSTs while five

regional labs were able to do first-line DSTs (see Figure

5). Five regional centers, (three in Lima, one in Arequipa,

and one in Lambayeque) were eventually equipped with

the capacity for first-line DST. Having these additional

labs able to conduct first-line DST apart from the central

one was necessary in order to handle the large burden of

patients. Lambayeque and Arequipa were also developed

to become centers of excellence. Consultants from MSLI

developed algorithms for the use and reporting on the

DST methods at the central and regional labs.

Currently DST is being done for the entire country.

In 2005 alone, a total of 2,596 first-line DSTs, and 2,438

second-line DSTs were performed. Although, these num-

bers still fall short of the needed capacity of 3,500 DSTs a

year for each category, this is a remarkable achievement.

Rapid diagnostic methods have been put in place. While

the Griess method was introduced both at the regional

and central levels, the BACTEC methods required expen-

sive equipment and were implemented at the central lab

only, where three BACTEC machines donated by the CDC

were set up. These technologies reduced DST time to 3-4

weeks. Laboratory technicians have been trained in these

newer techniques as well as in ensuring biosafety. An elec-

tronic information system connects all the labs together

and allows for web-based entry of data.

Extensive Training of Healthcare Workers

The PARTNERS made significant advances in train-

ing health workers. These included workers at the central

and regional labs, physicians, nurses, and community

health workers. Educational materials were created, both

for health workers as well as for patients. There were

two different forms of training — formal, and informal.

Formal training included classroom style teaching of

the issues involved in MDR-TB control and the strate-

gies to deal with them. The informal training was given in

day-to-day practice in the field. Initially the trainers were

from PIH and the CDC. But later, as the Peruvian physi-

cians, nurses, and health workers were trained, they were

used to spread the training further. By 2006, although not

every DISA had health workers trained to deliver ITR to

MDR-TB patients, every DISA in Peru had health workers

who could diagnose, treat and manage MDR-TB patients

using the new standardized treatment regimen (STR)

for MDR-TB. Today the staff working in MDR-TB con-

trol in Peru is motivated and well trained to handle the

challenges of tackling this difficult problem. The training

also helped reassure the health workers that MDR-TB

could be successfully treated, thus reducing their fear of

the disease and helping the Project in tackling the per-

vasive stigma of MDR-TB. These trained workers have

now become important in handling another difficult infec-

tion — HIV— and in treating patients infected with both

MDR-TB and HIV.

Trained Laboratory Technicians

MSLI provided training for a range of different lab

activities. These included laboratory structure, speci-

men reception and processing, media preparation, cul-

ture reading and identification, AFB smear microscopy,

AccuProbe, Mycobacteria Growth Indicator Tube (MGIT),

DST drug dilutions, DST broth and plate inoculation,

BACTEC drug dilutions and inoculation, testing algo-

rithms, biosafety certification program, troubleshooting,

and quality control. Trainings were conducted both in

Peru and in the USA. In Peru, the INS staff joined the con-

sultants from MSLI to reach out to regional labs. Training

manuals and materials were prepared for a number of

these trainings. Recommendations were made for other

areas where training could not be completed.

One of the key training programs for laboratory tech-

nicians was the biosafety cabinet certification course.

Maintaining the safety of laboratory technicians was key

to ensuring the success of the program. As a result, in

2003, the first 8-day training course for Bio-safety Cabinet

Certification was organized. 18 participants from around

Peru underwent this training by the Eagleson Institute,

a non-profit organization in Maine, USA, that provides

training in the principles and practices of laboratory

safety. Training manuals were prepared in Spanish. This

was followed by a 3-day refresher course in 2004. While

the first group underwent a refresher course, a second

group began training in 2004.

| 49


Chapter Three

Trained Physicians and Nurses

The PARTNERS program established a Global Health

Leadership Fellowship at Harvard for training Peruvian

physicians in evidence-based medicine. They were also

trained in both qualitative and quantitative research

methods to help improve health outcomes in impover-

ished regions of the world. In the first year physicians

were brought to Harvard for the training, but later, the

training was moved to the University of Buenos Aires. In

the later years, as more physicians were trained, they were

then enlisted as trainers for other Peruvian physicians. In

Peru, extensive training was provided to nurses as well

as physicians and community health workers. A total of

7,799 staff members were trained from 2000 to 2005

(Figure 6).

Trained Community Health Workers

One of the most important strategies that PARTNERS

adopted was to train community health workers. PIH

had previously been successful in using community

health workers to treat TB and HIV patients in Haiti. The

PARTNERS believed that this model would be appropri-

ate for Peru as well. SES had already enlisted the help of

some community health workers (CHWs) when it started

its work in Peru in 1996. These CHWs had experience

working with the community, but little or no experience

working in health, and certainly no knowledge of TB.

Despite this, these workers were readily trained and they

became critical to the success of the program. Classroom

training used participatory techniques of teaching includ-

ing games, role playing, and group discussions. Although

dealing with ITR is much more complex than STR, which

uses a standardized approach for MDR-TB control, it is a

testimony to the capabilities of the CHWs and the efforts

of PARTNERS that CHWs became very competent in

monitoring the treatment protocols of ITR and watching

out for drug interactions and side effects. The success of

the training of community health workers is shown by the

fact that when MINSA needed workers for rapid scale up

of antiretroviral therapy for HIV, they solicited the services

of these trained CHWs.

Educational Materials

The PARTNERS created several educational materi-

als both for health workers, as well as for patients. Table 5

on page 50 lists some of the materials created in the five

years of the Project.

While educational materials for health workers

became important reference materials to accompany

the training, patient education materials were useful

100%

80%

60%

40%

20%

0%

Others

CHWs

Nurse Tech

Nurses

64

50

242

190

45

207

143

68

109

258

28

67

132

327

119

230

123

430

378

428

342

711

641

834

2000 YEAR2001 2002 2003 2004 2005

Figure 6. Participants According to Type of Health Worker Trained Per Year


50 |

for ensuring the delivery of consistent messages to the

patients. Many of the training materials are now being

used in other countries.

Besides publishing all these educational materials,

the PARTNERS also set up a central repository of informa-

tion in the form of a web-based database that contains

more than 2,000 documents including presentations and

videos; 1,300 journal articles; 500 reports; and 80 books.

90% of the documents are available electronically, with 25%

in Spanish and 75% in English. Members of PARTNERS or

SES wrote 110 of the documents. While these documents

are available only to employees of PIH and SES, efforts

are underway to make the documents available to other

healthcare workers and other institutions.

Electronic Medical Records

The EMR developed in Peru has been another big

accomplishment. This system has not only reduced data

entry errors and speeded up the process of data collec-

tion and analysis; it has also helped address a number

of other constraints that the Project was facing. One of

these was estimating the demand of drugs required. In

treating patients with ITR it is difficult to predict which

patient will require which drug until the DST results have

been obtained. The patients need to be started on medi-

cation as soon as these results arrive, which means that

the drugs for them should have been ordered much ear-

lier — sometimes up to a year and a half in advance — and

available at the clinic. That presents a conundrum as

drugs for MDR-TB are expensive and often have a limited

shelf life. The EMR helped address this issue by tracking

drug usage patterns and predicting drug demand reason-

ably accurately.

Another important issue was to minimize errors

of prescribing the correct drug regimen and streamline

patient management. The EMR helped in this by includ-

ing decision support tools for physicians. These tools

flagged reminders for follow-up investigations, cautioned

against drug interactions, and helped suggest drug regi-

mens based on previous medications and lab DST results.

Patients who had other concurrent illnesses such as HIV

infection could also be managed using this software.

The system also facilitated the storage and retrieval

of digital images of X-rays, which are used frequently in

Table 5. List of educational materials created by the PARTNERS Project

Educational Material Year Target Audience Purpose

DOTS-Plus training modulesCommunity health workers

(CHWs)Contains lectures, printed materials, games and

videos for educating CHWs on MDR-TB

A DOTS-Plus Handbook: Guide to Community-Based Treatment of

MDR- TB2002 CHWs A guide for CHWs to implement treatment of MDR-TB

MDR-TB Clinical Management Pocket Guide

2003 PhysiciansReference in clinical management of MDRTB and co-

morbid conditions, as well as adverse reactions

DOTS-Plus at a Glance 2003 Physicians

Clinical information on MDR-TB treatment, including design of appropriate drug regimens, strategies for side-effect management, and treatment of patients

co-infected with HIV

Patient education flipbook for MDR-TB 2003Health care workers

(HCWs)Educating patients about MDRTB and the treatment

process

Patient education pamphlet 2004 MDR-TB patientsInformation about MDR-TB that can be provided to

the MDR-TB patients

Training module on infection control 2004 HCWs

Posters/brochures/TV spots for Peru World TB Day, plus curriculum for TB

trainings by local Epi Society2005

| 51


Chapter Three

national TB control programs. The software automated

the process of filing the X-rays and linking them to the

right patient. These images could be converted into differ-

ent formats so they can be used by different applications.

The system has been shown to be scalable and can

allow for the management of a large number of patients

on a national scale. Intensive training was provided to

pulmonologists and the system was handed over to the

MINSA in 2005. The facility for continued training was

established at the Unidad Tecnica.

The EMR in Peru was so successful that it is now

being used in many other countries and for other dis-

eases as well. After being piloted in Peru, experts from

PARTNERS installed similar systems in Tomsk and in

Philippines for the DOTS-Plus projects there. Recently,

this system has been adapted to support clinical care of

over 7,000 patients in Haiti, and is being considered for

similar use in Kenya and Rwanda.

Exemption of NTP from Health Sector Reform

The PARTNERS dealt with the difficulties of the initial

years by engaging leaders within the Peruvian govern-

ment and convincing them of the need to exempt the

NTP from HSR. Through careful analysis of the plans for

HSR, they were able to figure out HSR compromises that

allowed for win-win solutions. As a result, the Director

General of Personal Health recognized the risks of allow-

ing the continuation of deterioration of the NTP, and in

2003 modified the health sector reform changes to rein-

state TB as a dedicated program along with HIV/AIDS,

immunizations, and blood supply. This helped the NTP

and the PARTNERS Project get back to stability after a

period of disruption and chaos during the first three years

of the Project.

Global Fund Money Available for DOTS-Plus Program

Because the PARTNERS Project enrolled MDR-TB

patients at a more rapid rate than originally anticipated,

Gates grant funds for supporting individualized treat-

ments were running out before the end of the Project.

As a result, another source of funding was desperately

needed. The PARTNERS turned to the Global Fund for

resources to scale up MDR-TB treatment. PIH and SES

helped MINSA prepare a second proposal to the Global

Fund after its first application had been rejected in 2002.

A country coordinating mechanism with representatives

from 27 different sectors was formed in 2002, and the

next year, it was successful in obtaining a Global Fund

grant of US $28 million.

DOTS-Plus Model Shows How to Tackle Complex Diseases

Using community health workers in Peru to handle

a complex disease like MDR-TB, the PARTNERS created

a novel model, proving that trained staff without the ben-

efit of highly specialized knowledge and skills were able

to handle complex health interventions in resource-poor

countries. This approach was so successful that commu-

nity health workers from the TB program have now been

used to rapidly enroll HIV-infected persons in treatment

programs using anti-retroviral drugs.

Extensive ResearchThe PARTNERS also conducted extensive research,

the findings of which are reported later in this report. (See

Chapter 5.)

| 53

| C o n t r o l l i n g M D R - T B i n O t h e r C o u n t r i e s

Chapter Four

Concurrent efforts in several parts of the world have

succeeded in raising the world’s consciousness about

MDR-TB. Beginning in the mid- to late-1990s, groups in

Eastern Europe, Asia, Africa, and South America were

simultaneously developing new approaches to treating

and controlling this disease. With the help of the Green

Light Committee (GLC) and the Working Group on DOTS-

Plus for MDR-TB, both private, non-governmental agen-

cies, and public institutions in these countries worked

together, sharing information and strategies in an unprec-

edented, focused effort to manage MDR-TB.

This chapter focuses on the process of introduc-

ing DOTS-Plus in six different locations: Estonia, Latvia,

Orel, the Philippines, South Africa, and Tomsk (Russian

Federation). Because every setting had its own method

of diagnosing and treating TB, as well as its own cul-

tural belief system associated with the disease, each area

posed unique challenges, resistances, and obstacles to

be recognized and overcome. Fortunately, what they did

share were successful outcomes, proving that treating

both drug-susceptible tuberculosis and MDR-TB is fea-

sible, affordable, and, most importantly, life saving.

EstoniaDuring the Soviet era, Estonia’s TB management

followed the Soviet model, which lacked standardized

treatment regimens. Cases were identified through

widespread X-ray screening and patients were hospital-

ized for prolonged periods. This approach succeeded in

reducing the incidence of TB from 417 per 100,000 peo-

ple in 1953 to 21 per 100,000 in 1991. However, as a result

of the political and economic changes that followed the

breakup of the Soviet Union and that included deteriora-

tion of the healthcare infrastructure, drug shortages, poor

financial support for, and mismanagement of TB patients,

TB reemerged as a serious health threat.

In 1993 — the year that WHO declared TB a global

emergency — the Estonian Pulmonary Society became

convinced that it was important to intensify the country’s

effort against TB. No TB Baltics, a Scandinavian NGO,

became active in Estonia and advocated for the adoption

of the DOTS strategy. In 1997, the national government

Controlling MDR-TB in Other Countries

ESTONIA

SOUTH AFRICA

LATVIA

TOMASK OBLAST

OREL OBLAST

PHILIPPINES

Baltic Sea

Gulf of Finland

AtlanticOcean

IndianOcean

Gulfof

Riga

DavaoGulf

BalticSea Gulf

ofRiga

SouthChinaSea

Pacific Ocean

SuluSea

Philippine Sea

Muuga

Tartu

LATVIA

BOTSWANANAMIBIA

KHANTY-MANSIYSKY AO

NOVOSIBIRSKAYA OBLAST

TULSKAYA OBLASTKALUZHSKAYA

OBLAST

KURSKAYA OBLAST LIPE

TSK

AYA

OB

LAST

BR

YAN

SKAY

A O

BLA

ST

KR

ASN

OYA

RSK

Y K

RA

I

MOZAMBIQUE

SWAZILAND

LESOTHO

ESTONIA

LITHUANIA

BELARUS

RU

SSIA

MALAYSIA

RU

SSIA Pretoria

Bloemfontein

Cape Town

Manila

Riga

Tomask

Orel

...what they did share were

successful outcomes, proving that

treating both drug-susceptible

tuberculosis and MDR-TB is

feasible, affordable, and, most

importantly, life saving.


54 |

approved a 5-year National Tuberculosis Program (NTP),

which embraced the WHO DOTS plan. Partners in Health

(PIH) and other groups provided technical assistance to

set up the NTP program and the GLC approved its appli-

cation to treat 200 MDR-TB patients in a 2-year program

(2001-2003). In 2004, the GLC approved the NTP’s sec-

ond application for 200 additional patients, and national

legislation has extended the National Tuberculosis

Program through 2007.

What the NTP Accomplished

The NTP reorganized treatment services nationwide

in order to implement DOTS and DOTS-Plus and, in so

doing, managed to reduce the number of TB hospital

beds by 30%. A central TB registry was established and

centralizing the drug procurement process guaranteed

free distribution of all anti-TB drugs, including second-

line drugs, to everyone who needed them.

Before DOTS and DOTS-Plus were introduced in

Estonia, several different laboratories scattered across

the country were processing TB cultures. Quality control

and safety were impossible to insure, evidenced by two

workers in the Tartu laboratory who were diagnosed with

TB in the early 1990s. The solution was to consolidate all

TB lab work, including drug sensitivity testing, into well-

equipped facilities in Tallinn or Tartu, where scrupulous

attention was paid to infection control.

Another indispensable achievement was the NTP’s

effort to educate Soviet-era pulmonary specialists about

new approaches to TB management. If some were under-

standably resistant to change, the treatment’s success

and time have resulted in a unified TB and MDR-TB

healthcare strategy.

DOTS and DOTS-Plus were instituted in Estonia at

nearly the same time and their successes have been unde-

niable. The incidence of TB has declined from 59.1 per

100,000 population in 1998 to 42.7 per 100,000 in 2003.

That 12.0% of all cases reported in 1998 were MDR-TB

made Estonia’s rate of drug-resistant TB one of the high-

est in the world. MDR-TB cases have decreased from a

high of 112 in 1999 to 83 in 2003. However, despite the

fact that cure rates for drug-susceptible TB have increased

from 77% in 1998 to 82% in 2003, the cure rates for

MDR-TB have remained relatively stable at 52–54%. The

default rate (patients who do not complete the treatment

regimen) remains at approximately 20%. Many of these

patients abuse alcohol.

LatviaWith a crumbling public health system, Latvia’s TB

rate, like Estonia’s, escalated following its independence

from the former Soviet Union in 1991. In fact, the republic

had the highest incidence of TB in the European Union

and among the highest rates of MDR-TB in the world. The

Global TB Drug Resistance Survey 1994–1996 reported

that 14% of Latvia’s new TB cases were MDR-TB infec-

tions, the highest level found in the survey. In 1995, the

Ministry of Health established the National Tuberculosis

Control Program (NTCP), which was based on the DOTS

strategy recommended by WHO. Two years later, DOTS-

Plus was implemented to treat MDR-TB patients with

Lessons Learned in Estonia

1. Major socio-political changes may bring oppor-tunities as well as challenges. The breakup of the Soviet Union is a case in point. It allowed physi-cians in former Soviet countries access to non-Soviet medical literature, technical consultation, and pre-viously unavailable collaboration that provided the basis for radical changes in treatment concepts and strategies.

2. External partners can go beyond their usual role of providing technical or financial assistance and influence policy change. As advocates supporting Estonia’s internal efforts, WHO, the GLC, No TB Baltics, IUATLD, CDC, and PIH played a vital role in changing policies on TB treatment and control.

3. Given the right circumstances, DOTS and DOTS-Plus can be implemented simultaneously. Current global policy is that a DOTS program should be in place and well-functioning before a DOTS-Plus pro-gram is initiated. The Estonian experience shows that, with the right infrastructure, the two strategies can be introduced almost simultaneously.

4. Laboratory consolidation may be essential to ensure high-quality testing and safe working conditions. If, as was the case in Estonia, laboratories are scattered throughout the region, consolidating them in a cen-tral location where they can be overseen may be the only way to guarantee the sterile conditions necessary for high quality testing and safe working conditions.

5. Medical providers accustomed to long-standing treat-ment approaches may reject DOTS and DOTS-Plus initially. This is understandable and to be expected. Helping them change their attitudes takes time and training as well as demonstration of the success of the new strategies.

| 55

Lessons Learned in Latvia

1. The experience in Latvia confirmed that Implementation of DOTS-Plus, in the context of a well-functioning DOTS program, can effect a rapid reduction in MDR-TB cases.

2. Well functioning programs can serve as important training centers for programs in other countries.


Chapter Four

individualized treatment regimens (ITR). Patients were

hospitalized until their sputum cultures were negative.

The NTCP obtained its second-line drugs (SLDs) through

the GLC until 2002, and since then through open tenders

on the international market. And several SLDs have been

produced locally under the conditions stipulated by the

good manufacturing process (GMP).

Every year between 1998 and 2002, more than 200

patients with MDR-TB began treatment, with the cure rate

ranging between 66% and 73%. These treatments, along

with the effective DOTS program, reduced the number of

MDR-TB patients by more than half.

In a remarkable collaboration with CDC and the

University of Arkansas for Medical Sciences, the Latvia

NTCP established an International Training Center (ITC)

devoted to the treatment and management of MDR-TB.

With sophisticated clinical and research personnel and

a state-of-the-art laboratory, the Center, which opened

its doors in 2000, functions as both a care facility and a

training center. ITC’s training programs incorporate evi-

dence gained through scientific and operational research

and draw upon the results of extensive field experience

in DOTS and DOTS-Plus implementation. The teaching

modules aim to develop competencies and skills in key

areas, such as the improvement of laboratory diagnos-

tic methods, patient education, and the management of

MDR-TB in prisons. Among those who have attended ITC

training are MDR-TB clinicians, laboratory technicians,

and healthcare workers from Russia, Estonia, Ukraine,

and the Philippines, as well as personnel from the NGO

Medicins sans Frontiers. In November 2004, WHO hon-

ored the training center by awarding it the prestigious sta-

tus of a WHO Collaborating Centre, the first on MDR-TB

in the European region.

Orel

ESTONIA

SOUTH AFRICA

LATVIA

TOMASK OBLAST

OREL OBLAST

PHILIPPINES

Baltic Sea

Gulf of Finland

AtlanticOcean

IndianOcean

Gulfof

Riga

DavaoGulf

BalticSea Gulf

ofRiga

SouthChinaSea

Pacific Ocean

SuluSea

Philippine Sea

Muuga

Tartu

LATVIA

BOTSWANANAMIBIA

KHANTY-MANSIYSKY AO



OBLAST


TSK

AYA

OB

LAST

BR

YAN

SKAY

A O

BLA

ST

KR

ASN

OYA

RSK

Y K

RA

I

MOZAMBIQUE

SWAZILAND

LESOTHO

ESTONIA

LITHUANIA

BELARUS

RU

SSIA

MALAYSIA

RU

SSIA Pretoria

Bloemfontein

Cape Town

Manila

Riga

Tomask

Orel

A rural oblast of the Russian Federation, Orel, located

approximately 380 km southwest of Moscow, was one of

the first administrative units in the Russian Federation to

implement the DOTS strategy in 1999. The Orel project

represents collaboration between the Central Tuberculosis

Research Institute of the Russian Academy of Medical

Sciences, WHO, the United States Agency for International

Development (USAID), the Centers for Disease Control

and Prevention (CDC), and local authorities.

That the Orel TB program had strong leadership

in place accounts, in large part, for the effectiveness of

DOTS implementation. The treatment outcomes were

very good: 81% of newly diagnosed, infectious patients

successfully completed treatment, compared with an esti-

mated pre-project success rate of 65-70%. Furthermore,

coordination between the civilian and prison sectors was

organized from the start.

Compared with other regions in the Russian

Federation, MDR-TB rates were lower in Orel. This may

be explained by the government’s sustained support for

TB control and the region’s relatively stable economy.

Nonetheless, 3.1% of newly diagnosed, infectious TB

ESTONIA

SOUTH AFRICA

LATVIA

TOMASK OBLAST

OREL OBLAST

PHILIPPINES

Baltic Sea

Gulf of Finland

AtlanticOcean

IndianOcean

Gulfof

Riga

DavaoGulf

BalticSea Gulf

ofRiga

SouthChinaSea

Pacific Ocean

SuluSea

Philippine Sea

Muuga

Tartu

LATVIA

BOTSWANANAMIBIA

KHANTY-MANSIYSKY AO



OBLAST


TSK

AYA

OB

LAST

BR

YAN

SKAY

A O

BLA

ST

KR

ASN

OYA

RSK

Y K

RA

I

MOZAMBIQUE

SWAZILAND

LESOTHO

ESTONIA

LITHUANIA

BELARUSR

USS

IA

MALAYSIA

RU

SSIA Pretoria

Bloemfontein

Cape Town

Manila

Riga

Tomask

Orel


56 |

patients had primary MDR-TB. In 2003, the GLC approved

treating MDR-TB patients with individualized (as opposed

to standardized) treatment regimens. The CDC, local and

national Russian authorities, and WHO developed the

protocol upon which these treatments were based. The

protocol subsequently became the model strategy adopted

by the GFATM. Among MDR-TB patients who completed

at least one year of therapy, 74% showed sputum culture

conversion from positive to negative. The Orel project

was the first to receive (in 2001) WHO and GLC approval

to use second-line drugs in treating Category 2 patients

(those who were still sputum smear positive after an ini-

tial round of therapy).

Although CDC’s extensive technical assistance has

led to important improvements in the area of infection

control, Russian national policies have precluded certain

advancements. For example, when ultraviolet germicidal

irradiation (UVGI) is used to sterilize room air in the U.S.,

the bulbs are shielded to avoid contact with the human

eye. This means the air can be exposed to the UV light

continuously. Russian national policy, on the other hand,

requires that the bulbs be unshielded and that no one

can be in the room while the bulbs are illuminated. Thus

UVGI is only available to sterilize the air approximately 30

minutes/day, rather than all the time. Although authori-

ties in Orel were willing to change the sterilization sys-

tem, national polices prevented it.

PhilippinesHalfway around the world from Latvia, the Philippines

was introduced to DOTS in phases beginning in 1996. By

the end of 1999, 43% of its public health clinics were

following DOTS; by mid-2000, 60%; and, at the close

of 2001, 100% of the Philippines’ public health clinics

were adhering to the DOTS protocol. The President of

the Philippines declared TB to be the number one health

problem of the country and, in August 1998, initiated a

“Crush TB” program. Only four years later (2002), WHO

cited the Philippines as a TB success story, noting that

87% of its treated patients were being cured.

While most DOTS activities focus on public clinics,

collaboration between the public and private sectors is

ongoing in the Philippines. Some private facilities receive

free first-line TB drugs from the government in exchange

for following the DOTS strategy. Two such facilities that

have formed a partnership with the Ministry of Health

are the Makati Medical Center (MMC), a private tertiary

medical center in metropolitan Manila, which has been

providing DOTS services since 1999, and its affiliate,

the Tropical Disease Foundation (TDF), a private, non-

profit foundation dedicated to controlling and preventing

tropical infectious diseases through research, training,

and service. With a highly trained staff, a sophisticated

laboratory (capable of performing first- and second-line

drug sensitivity testing [DST]), and an electronic medical

record system (EMR), modeled on the one developed by

PIH, tracking patient care and assisting in data analysis,

TDF/MMC, now treats patients with MDR-TB. A study

conducted by TDF in 1997 examined sputum specimens

from 1,310 individuals from 36 nationwide clusters and

12 urban poor clusters. Among 188 isolates, 4.3% were

MDR (1.5% in specimens from never treated patients [pri-

mary MDR-TB] and 14.3% in previously treated patients

[acquired MDR-TB]).

In 2000, the GLC approved treatment for an initial

cohort of 200 patients with MDR-TB and 3 years later, it

approved an additional cohort of 750 patients. Through

the Global Fund to Fight AIDS, TB and Malaria (GFATM)

support, MDR-TB management expanded to 7 special-

ized treatment centers to treat a total of around 3,200

patients until 2011.

Lessons Learned in Orel

1. With strong yet open-minded leadership, dramatic changes in implementation of TB (and MDR-TB) con-trol can be implemented effectively.

2. National policies can impede progress when they are not modified, even in the face of strong scientific evi-dence and willing local leaders.

ESTONIA

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| 57


Chapter Four

With the experience gained since 2000, a scale-up of

programmatic management of drug-resistant TB (PMDT)

is planned, with full integration of the program into the

NTP and a nationwide scale-up to establish an additional

35 specialized PMDT treatment centers to treat an addi-

tional 13,218 patients, with the aim of attaining universal

access to MDR-TB management by 2015. Of the current

7 treatment centers, 4 are private facilities and only 3 are

public health facilities, demonstrating that the PPMD

concept works well also for DOTS-Plus. Hence, from a

privately initiated program in a PPMD, the program has

now expanded into the public health system.

From a centralized approach in treatment centers

during the sputum-positive phase, MDR-TB services are

being decentralized to community-based DOTS facili-

ties — mostly public health centers and private-public

mix DOTS (PPMD) units — to provide continuing care

to patients in the remaining months of treatment. In the

spirit of private-public collaboration, capacity to manage

MDR-TB programmatically is continuously being main-

streamed from this NGO to the NTP in the country. That

the TDF/MMC facility has grown into a valuable training

center for healthcare workers is being increasingly recog-

nized in and beyond the Philippines.

South AfricaSouth Africa has one of the highest TB rates in the

world, more than double those recorded in other devel-

oping countries. This is complicated by the fact that

more than half of all new TB patients are also infected

with HIV. South Africa encourages public-private col-

laboration. Following elections in 1994, the Department

of Health (DOH) revised its strategy on TB control and

adopted DOTS. After reaching an agreement with the

South African Medical Research Council (MRC) for that

agency to review the scientific evidence and design the

implementation process, the DOH executed a nation-

wide, province-based system to provide the treatment.

Subsequently, the MRC carried out drug resistance

surveillance and confirmed that, although MDR-TB levels

were low overall (≈1% in never treated and 4% in pre-

viously treated cases), there was significant geographi-

cal variation. Furthermore, the high overall TB incidence

meant that there were 2,000–6,000 new cases of MDR-TB

each year.

In 1999, at the DOH’s request, the MRC established

a registration system for MDR-TB patients and developed

policy guidelines for its treatment. A year later, the DOH

revised the South Africa National Tuberculosis Programme

(NTP) policy, adopting elements of DOTS-Plus as the foun-

dation for MDR-TB management. Since little use had been

made of SLDs and no documentation of drug sensitivity on

individual patients existed, a standardized regimen, based

on available surveillance and survey data, was proposed.

Guidelines for the initial treatment were revised to comply

with existing information on DOTS-Plus and policies gov-

erning the diagnosis of MDR-TB were developed according

to NTP diagnostic algorithms.

The next step was to establish MDR-TB referral centers

in each of South Africa’s nine provinces, where healthcare

workers participated in extensive, mandatory training.

Each center was provided with an electronic MDR-TB reg-

istration system, which facilitated patient management

and generated comprehensive reports electronically.

Once the referral facilities were functioning, drug pro-

curement was centralized at the national level. Prescribed

only at the centers by doctors specifically trained in

their use, SLDs were available solely to patients whose

Lessons Learned in the Philippines

1. In conjunction with governmental agencies, non-governmental organizations (NGOs) can play an important role in advancing MDR-TB management.

2. Instead of reinventing the wheel, sometimes it can just be customized, which is what was done in the Philippines with the electronic medical record sys-tem developed in Peru.

3. MDR-TB programs can be implemented, advanced, and scaled-up strategically and effectively.

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Riga

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58 |

names were in the registry. Since South Africa had not yet

approved most of these drugs for use in TB treatment,

arrangements were made with the Medicines Control

Council (MCC), the country’s regulatory organization

(similar to the FDA in the U.S.), to obtain them with spe-

cial exemptions. Establishing extensive recordkeeping

systems and reporting any adverse effects of the drugs to

the MCC were among the administrative tasks required to

accommodate the exemptions. Additionally, an MDR-TB

research agenda was established and pursued through a

5-year noncompetitive cooperative agreement between

the MRC and the US-based CDC.

Starting with 1,000 MDR-TB patients in 2000, the

NTP has advanced rapidly, treating 6,000 patients in 2005

with cure rates of approximately 70%. The strong health-

care infrastructure combined with the relentless effort and

sustained cooperation among groups responsible for dif-

ferent aspects of TB and MDR-TB control account for the

swift progress. Although the MRC oversaw MDR-TB treat-

ment until 2005, the NTP has always funded the activity.

Despite its success, South Africa’s NTP faces a com-

plex challenge: the rising number of patients infected

with both MDR-TB and HIV. The diseases are inextricably

entwined because people with HIV, whose immune sys-

tems are weak, run a greater risk of developing TB, includ-

ing MDR-TB. Yet few of the policies designed to prevent

MDR-TB transmission, especially in institutional settings,

are in place. Tackling combined MDR-TB and HIV infec-

tions is exceedingly difficult in the absence of strong gov-

ernment response against the HIV/AIDS epidemic. That

individuals with both infections can be treated success-

fully for their MDR-TB but remain unable to receive anti-

retroviral therapy at the same time is the tragic reality for

many sufferers in South Africa.

Tomsk

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Riga

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ofRiga

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In Tomsk, an oblast (or administrative region) of the

Russian Federation located in the western Siberian plain,

TB control during the Soviet era followed the same model

as Estonia and Latvia. And, like their peers following inde-

pendence, public health officials in Tomsk sought new ways

to control and prevent TB. In conjunction with the British

NGO, MERLIN (Medical Emergency Relief International),

and with support from the European Community

Humanitarian Office (ECHO), the Tomsk Oblast TB Service

(TOTBS) introduced a DOTS-based TB control program in

the civil sector of the region. In 1994–1995, it was the first

DOTS program in the Russian Federation.

In 1997, the Public Health Research Institute (PHRI)

of New York and the Soros Foundation’s Open Society

Institute joined the collaborative effort to control MDR-TB

in Tomsk. In cooperation with the Tomsk Regional

Department of Corrections (UIN), TOTBS also expanded

to include Tomsk’s prisons. In 1999, 18.6% of new cases

of TB in the prison sector were MDR-TB and 12.3% of new

cases in the civil sector were MDR-TB.

Based on their experiences in Peru and Haiti, PIH was

invited to share its expert clinical advice with the Tomsk

group. In 2000, the GLC approved the treatment of 100

patients and subsequently permitted additional cohorts.

A grant from the Bill & Melinda Gates Foundation allowed

PIH to lead the way in providing external technical assis-

tance and Tomsk became the PARTNERS TB Control

Project’s “expansion site,” where lessons learned in Peru

would be applied.

Although more than 900 MDR-TB patients were

enrolled in the program between 2000 and 2005, the

Lessons Learned in South Africa

1. With certain circumstances, MDR-TB control can be implemented nationwide in a short time. In South Africa, where the infrastructure for DOTS was in place and strong, with intensive planning and train-ing, 1,000 patients were treated in the first year.

2. In settings with high HIV populations, the gains of treating MDR-TB are likely to be lost if HIV/AIDS is not simultaneously addressed. The less-than-vigorous implementation of anti-retroviral therapy through-out South Africa is placing in jeopardy some of the progress made with MDR-TB treatment.

| 59


Chapter Four

initial treatments were delayed because three key medi-

cations were temporarily unavailable. Global shortages

of capreomycin and cycloserine and problems obtain-

ing Russian government approval to import and use

PASER® were ultimately resolved. Treatments com-

menced and, in the first cohort of 244 patients, the cure

rate was 77%. If any individual aspect of working with

the prison population could be considered most critical,

it was the coordination between the prison and civilian

sectors. While there was a continuing flow of patients

at different stages of treatment moving from the civil

sector into the prisons, there was, simultaneously, a dif-

ferent group, also still in treatment, being discharged

from prison and moving in the opposite direction. So,

for example, between 1999 and 2005, on average, 41

patients with TB (either drug-susceptible or MDR-TB)

entered the prison sector and 42 reentered the civil sec-

tor. Further complicating this already complex picture

was the fact that only half of the TB patients were resi-

dents of Tomsk city; the others were scattered throughout

the oblast, which has an area of 347,000 km2 and a popu-

lation of 1.1 million. Considering the geographical spread

of Tomsk’s civilian patients, elaborate coordinating sys-

tems were established to insure that patients continued

and completed their treatments, especially those with

MDR-TB, whose therapies lasted 18-24 months. Among

the incentives for follow-up, patients were offered food

assistance as well as their choice of treatment sites where

convenient and flexible hours made it possible to address

any drug side effects quickly. The success of these efforts,

coupled with the patients’ motivation, is reflected in the

fact that only 11.5% of the patients in the first cohort

defaulted on their treatment.

As in all of the settings in the former Soviet Union,

educating clinicians has been a top priority in Tomsk, and

support from the Lilly Foundation is allowing PIH and

TOTBS to expand training across the Russian Federation.

To date, 57 Russian physicians from 15 oblasts have been

expertly trained in DOTS and DOTS-PLUS strategies,

which include follow-up visits to the oblasts by a team

of PIH and TOTBS physicians. PIH and WHO invited the

leadership of the 5 federal level TB Research Institutes with

responsibility for TB training in Russia, to an advanced,

5-day workshop on MDR-TB in St. Petersburg. As a result

of the workshop, all 5 Research Institutes were motivated

to incorporate the MDR-TB training program into their

regional training programs. Doing so represents the

Russian medical establishment’s vital endorsement of

and earnest commitment to the DOTS-Plus protocols

and curriculum.

In 2004, the Global Fund to Fight AIDS, Tuberculosis,

and Malaria approved a 5-year US $10.7 million grant to

continue this training/education project with PIH Russia

serving as the principal recipient for the first two years.

Co-Evolution Continues Coordination, collaboration, and communication

are hallmarks of the projects in Estonia, Latvia, Orel, the

Philippines, South Africa, and Tomsk. Healthcare workers

in each setting have crafted strategies aimed at control-

ling TB and MDR-TB and strive continuously to improve

them. Their innovations in case management and suc-

cesses in clinical care, improvements in laboratories, and

progress in research advance the science of healthcare

and the mission of caring for the public. This multifaceted

“co-evolution” of approaches has yielded vital contribu-

tions to the evolution of global TB strategies and goals.

We hope that other locations and organizations that face

similar challenges — such as projects in India, Honduras,

and Kenya, among others — can take advantage of these

experiences, learn from the efforts of these six sites, and

build on their successes.

Lessons Learned in Tomsk

1. When TB patients are moving in and out of prison, coordi-nation to ensure that therapy is completed must be scrupu-lous, particularly for patients with MDR-TB.

2. Demonstration of effective approaches to MDR-TB in one area can lead, with sufficient communication and training, to changes in national approaches.

| 61

Joel —A Photodocumentary

The PARTNERS TB Control Program began in Carabayllo, a hot, dry, dusty,

and very poor shantytown north of Lima, Peru. In Carabayllo, and, in fact, all

around the world, tuberculosis is very strongly linked to poverty. Crowded

conditions, poor nutrition, and limited access to health care perpetuate

transmission, often from one family member to another. In Carabayllo,

families often live in one-room shacks made of cardboard, tin, and rocks

without stable income for food or medical care.

Many of the people who developed TB in Carabayllo had strains that

were resistant to all of the drugs most commonly used to treat TB. When the

PARTNERS project began, the official policy of the World Health Organization

was to say that it was too difficult and too expensive to treat people in poor

countries with multiple drug resistant TB (MDR-TB). The conclusion was

that these people should just be left to die.

PARTNERS began with the belief that it was not right to treat people with

MDRTB if they were rich and to let them die if they were poor. Made possible

with a grant from the Bill and Melinda Gates Foundation, the project set out

to demonstrate that even in resource-poor settings, people with MDR-TB

could be treated successfully at a cost lower than previously considered

possible.

Joel Panez and his family agreed to tell us their story and let us photograph

them in the hopes that their story might help others understand how MDRTB

affects patients, what it feels like to go through medical treatment, and how

important the treatment is in improving lives.

Mark Rosenberg

physician / photographer

62 |

Joel had been the first one in his family to become ill with TB. He worried he

had passed the disease on to his brothers and sister who had died and felt

guilty. His mother had taken care of all of them when they were sick.

Joel’s sister Nuria: Joel started treatment when my first three brothers

had died already.

| 63

Joel’s Mother: My first son died in the year 2000, on October 21, and he was 17.

My other son, who was 29 years old, also died in the year 2000, on November 21.

And the third one, 34 years old, died almost a year after the first two, on October 1, 2001.

My daughter (28 years old) died on November 1, 2002.

Joel and his sister Nuria in cemetary, Carabayllo, Peru

64 |

Dr. Keith Joseph, (Partners in Health Physician):

We first met [Maleni] the daughter that died in the Panez family in September

or October 2001. Her disease was very localized at the beginning, and she really

wasn’t symptomatic. We didn’t have much to offer her with medicines because

of her high resistance. Had we operated then, we probably could have cut out

the lung that was there and the bacteria level might have been low enough that

the medicines she was taking could have cured her. Patients were not being

operated on a timely basis, though. It’s kind of bordering on hostile towards

MDR patients. It’s not uncommon for hospitals not to want to accept MDR

patients. There is fear of infecting mostly the staff. One hospital, for instance,

had two or three health professionals that became infected with MDR-TB, and

at that point they actually told us, don’t bring your patients here anymore.

For some reason she was one of the patients that was delayed. She eventually

got the surgery. It was probably too late.

| 65

A picture of Maleni, the first Panez child to die of MDR-TB

66 |

Dr. Roberto Canales (Director of Peru’s National TB Control Program):

In the ‘80s and around until 1990, there was no MDR-TB, and so when we

treated TB then, people were cured and there were very few deaths. I did not

see what we just saw, whole families being devastated during those years.

Now we are seeing more cases that are resistant to multiple drugs.

68 |

Joel: I came out of the hospital and then in my neighborhood, they found out

that my first brother died of this disease. All stayed normal, and calm. Then the

second one died, and all remained more or less calm. But, when the third one

died, and next my sister died, then our friends looked at us differently. Then

when I went to church, even the brothers didn’t want to say hello, and when

they did greet you, they turned their faces. It was all from afar, and that hurt

me. It was all because I was sick with TB and they knew my four siblings had

died of TB. For them we were like an infectious pest that they could catch.

Joel’s Mother: In the street, people observe me and our family. They are

afraid. Even my own family, my sister, is afraid. Since my daughter died, my

sister has not come back. They must be afraid that they could get this disease.

Really, I have shame that my children died of this disease. When people ask

how my children died, I make up lies. I don’t want to tell people how they died.

70 |

Joel (at health clinic): I have been coming here every day for 23 months.

Of course, I was coming here before with my brother Marcos. I waited for

him, and I never imagined that one day I would go in myself and have to take

pills. I still think about Marcos when I come here, but I think more about my

sister Maleni, I used to come here with her, and we were in treatment at the

same time.

72 |

Joel: I take 16 pills — 10 in the morning and at night 6 — in total 16 pills daily.

I felt tempted to not take cycloserine because I got in my head that it’s going

to my head. It makes you feel upset, like your eyes are going in different

directions from each other. I feel a lack of concentration, and I feel accelerated

when I walk, when I talk, and it’s difficult. I think this will damage me

permanently so in the future I won’t be able to do anything else.

| 73

Joel: My sadness turns into impotence and I smile because nothing can be

explained. Before, when my brothers and sister were sick, we always asked why,

why, why? Now we have stopped asking. There are no words to explain all that

is coming at us. Really there are no words to explain it. When things seem to

be improving, moving along, then bad things come. I try not to think about

tomorrow. I just live the moment, and I would like my mother to do the same.

It’s difficult because we don’t have any choice but to think of what’s coming.

74 |

Joel met with Ruben, one of the first patients to have been treated by Socios en

Salud for MDR-TB. Ruben told Joel that he had been close to death, depressed,

and even suicidal during his illness and during the two years of treatment that

his disease had required. He told Joel that he was now cured, back at work,

and happy again.

Keith Joseph: Up until November, in one part of the city, we hadn’t had any

patients cured, so a lot of patients were asking whether anyone has ever been

cured from this. That is a common question for patients who live in more

remote areas, and it is important for them to come into contact with patients

who have been cured. I think that it is very important for Joel to see someone

who is leading a normal life after he is cured.

Annika Sweetland (psychosocial support group facilitator):

When Joel first came to the therapy group, about a month ago, he was feeling

suicidal. He brought it up in the group, told everyone about it. He said that

he wished his parents were dead, that the only thing keeping him from killing

himself was that he didn’t want his parents to suffer anymore. Many patients

came forward and expressed how they also felt suicidal at times during

treatment, and they offered him suggestions about how he might overcome it.

In the group he has found a group of people who don’t judge him, who also

have the disease.

76 |

Keith Joseph: It’s kind of hard for you and me to understand how these

families are able to hold things together as much as they do. When we stop,

and step away from the work, and think about it, it makes us want to cry. It

is pretty horrible to think about. It also makes you feel impotent, as much as

this project has changed things here. And fortunately patients are entering

earlier, not passing through so many treatments before they arrive at an

appropriate treatment. But there are still patients that we are not going to be

able to treat, and I imagine it’s similar to what doctors who treat patients with

cancer have to deal with, often. Accepting that there is stuff you just can’t do.

It’s frustrating for us. It is something that we have all talked about, among

the doctors at Socios and the Peruvian doctors, addressing at what point are

we going to say we’re going to stop [trying], because a lot of these patients

we continue pushing, pushing, pushing, giving more medicine, and thinking

about other interventions, when we know there is very little hope. Often, it is

a question of when we are willing to throw in the towel. Yes, it is very hard and

personal. We are going to patients’ houses. We get to know them.

There’s not a lot that can prepare you for this experience.

78 |

Joel’s Mother: We used to have this room and one more, but we were paying

too much, so we decided to move the whole family into this room. Six of us

live here, in this room, including my husband.

My husband has psoriasis and epilepsy. It is very difficult, because before

my children died, he worked. He was never home. Since my children died,

he doesn’t work. We take care of him, and the treatments he follows for the

epilepsy and psoriasis are very expensive. In my house we don’t have money

even for a piece of bread. My daughter Nuria is the only one that works and

receives a monthly salary, but it’s not enough. What can I do? I am obligated

to work. I sell food, I cook, and I get up at 3 AM to cook and be able to go sell

it early.

80 |

Joel’s Mother: When I got the bronchoscopy, I was nervous about how it

would come out. Then, it came out negative, and I was really happy. Shortly

after that I came down with flu symptoms and a cough, so I went to the

hospital and they gave me syrups and pills to take. I took them, and they did

not help at all. I felt worse, and my whole body hurt, so I went to the hospital

again. I did not see Dr. Segura, the TB doctor, but I saw another doctor who

prescribed different medication that didn’t have any effects. And, finally I

went back last week and saw Dr. Segura at the hospital. She said: why didn’t

you come in sooner? You are so sick. I said: what do you mean? I don’t know

what you are talking about. I just have a cough. And the doctor said: no, you

definitely have this disease.

It was a real shock to me. I still can’t accept that I have this disease. It will

consume me like it did my children.

82 |

Joel: The other day when my mother was sick and coughed and coughed, I

thought I was going to die. I thought: this is it. I finished the treatment. I’m

testing negative, but now I will get it again. But it was my mother, so I was in

her room, putting cold compresses on her forehead, and taking care of her.

She is my mother and she gave it all for us, so it is my turn to do for her. If I

die, I will die with her because she’s my mother.

Joel: This disease has taken away a lot from me. I lost people I loved so

much. I’ve lost time, and the possibility of continuing my education, of work,

it has slowed me down some. I have lost my vocabulary. I don’t have words

to express myself, because of all those pills I take. Even though my girlfriend

loves me so much, she does not understand me.

I lost my girlfriend Denise; we are not together anymore. She realized she

didn’t have a future with me. This was crushing — it happened four months

ago. It hurt a lot.

84 |

Mark Rosenberg: Before Socios started treating

people with this very aggressive treatment for

MDR-TB, what would have happened to a family

like this?

Roberto Canales: The same thing that happened

with the first 4 children; there were no other

alternatives.

Joel’s Mother: I’m beginning to accept the

disease. I know I will have to take the medicines.

I don’t have another choice.

86 |

Joel completed 24 months of treatment for MDR-TB and became disease free.

When he no longer had the severe physical and psychological side-effects of

the powerful antibiotics he had been taking, he was able to return to work,

and Denise, his girlfriend, returned to him. Joel’s mother, also diagnosed with

MDR-TB, improved markedly several months after beginning treatment.

88 |

On our last visit Joel gave us this note:

When I think of the lives we live so full of sadness and pain, when I think of a child

without a coat, without bread, sick, my soul hurts. But the one who loses perhaps

wins. If life becomes difficult, I need faith to fight, and think only that after the

anguish peace will come, that after the clouds, the sun will shine. I deeply thank you

for having been part of this battle. Thank you for being with those that by chance

in life are unfortunate, and for fighting along with them to overcome so many great

hurdles. Thank you for helping soothe my damaged emotions and helping me not to

feel alone. Thank you for your patience, for the time spent, and for predicting such a

good outcome, forgive me if my complaints ever hurt you.

Infinite thanks, because even though I was a stranger, you became my friends, and

you held me in high esteem. Thank you for everything,

Joel Panez Chachi

August 2005

“It’s very hard to see my daughter like this. I feel bad there is nothing I can

do to help her get better. I had heard of TB before my daughter got sick, but

I didn’t think it could be so difficult and painful. My daughter has suffered

more than I could ever imagine.”

–Mother of Patricia, MDR-TB patient

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Chapter Five

Research

The sea change in attitudes and approaches to

MDR-TB in the period 2000–2005 has been due, in large

part, to great advances in both our scientific and our

organizational/managerial knowledge about how to deal

with MDR-TB.

The people working on the PARTNERS Project were

driven by a strong desire to improve care — and they were

exposed to patients where they could see how the quality

and availability of good care was a matter of life or death.

The sense of urgency and the direct exposure to patients

and their stories drove research in a way that nothing else

could.

John Seeley Brown, a noted knowledge manage-

ment expert, has defined 4 stages of knowledge develop-

ment: knowledge generation, knowledge dissemination,

knowledge integration, and knowledge application. Each

of these stages of knowledge development was neces-

sary for accelerating the proper treatment of patients with

MDR-TB.

Given that the focus of the PARTNERS grant was

establishing feasibility of treating MDR-TB so that policy

could be changed, the research that was conducted was

largely clinical. In addition to collecting data while patients

were being treated and documenting the outcomes, how-

ever, PARTNERS also prospectively set up research to

answer key questions. The research focus expanded to

include applied and operational research. Research was

driven by a treatment and prevention agenda in both

Peru and Tomsk.

Knowledge GenerationGetting Started

The need to prove the effectiveness of MDR-TB treat-

ment was a strong impetus for organizing a common

approach to MDRTB research. This common approach

could help to accelerate the gathering of critical infor-

mation for refining and spreading this treatment. A first

step was to create a common vocabulary and defini-

tions to enable communication among researchers and

comparisons among studies. An organized approach to

knowledge generation would also accelerate the spread

of appropriate treatments and for this reason a global

research agenda was developed to guide future research.

Creating a Common Language

To accelerate the generation, dissemination, inte-

gration, and application of knowledge, it was necessary

to establish a common language for communicating

results. “Speaking the same language” is one of sev-

eral factors for increasing partnership effectiveness, as

outlined by WHO’s Stop TB Partnership Secretariat in

the “Pocket Guide to Building Partnerships.” Generally,

using simple, standardized language between clinical and

research workgroups assures stronger communication

and smoother operations.

A PARTNERS workgroup, recognizing the need for a

common MDR-TB language, reviewed published litera-

ture and country-specific program experience.


92 |

• Case registration groups

– New

– Previously treated with only first-line drugs

– Previously treated with second-line drugs

– Transfer in

• Interim status definitions

• Treatment outcomes

– Cure

– Treatment completed

– Death

– Treatment default

– Treatment failure

– Transfer out

• Cohort analysis

Box 6

Examples of common language

Previously, individual investigators had developed their

own definitions. With international representation, the

workgroup developed and agreed upon standard defini-

tions, including definitions for case registration patient

groups, interim patient status, patient treatment out-

comes, and cohort analysis of MDR-TB treatment out-

comes. These definitions have been published in the

peer-reviewed literature.23 The use of consistent defini-

tions makes it possible to compare results across studies

among researchers around the globe.

Setting a Research Agenda

A major activity of the PARTNERS was to develop

a research agenda so that they could focus on address-

ing the most critical MDR-TB questions in an organized

and systematic way. At the request of WHO, this effort

expanded to address a global research agenda. This work

was then taken up by the DOTS-Plus Working Group

and through a consensus process a prioritized research

agenda was developed and published and has guided

global research planning.24 The three primary topics on

the agenda were to:

1. Identify the best way to treat MDR-TB (i.e., to gener-ate optimal standardized protocols to treat MDR-TB). Sub-topics include approaches to treatment, clinical efficacy of regimens, prevalence of adverse events,

factors leading to treatment adherence, and eco-nomic analysis.

2. Identify the best way to diagnose MDR-TB (i.e. to generate optimal protocols for diagnostic testing). Sub-topics include identifying ideal time points for identification of patients, minimum and ideal time points for smear/culture/DST, standards and param-eters for DST to second-line drugs, programmatic utility of new tests, in vivo application of in vitro results, and cross resistance in second-line drugs.

3. Identify the best way to organize and spread MDR-TB control programs (i.e., to specify the minimum requirements for constructing and implementing DOTS-Plus Programs). Sub-topics include identify-ing the minimum programmatic infrastructure for a standardized and individualized approach at local, district, and national levels; levels of human and financial resources needed; infection control sys-tems; laboratory capabilities; and clinical expertise/training.

Secondary topics were to identify threshold indica-

tors that would signal the need for implementing DOTS-

Plus (e.g., >5% of new cases are MDR-TB) and other

operational issues, including staff training and increasing

participation of the private sector.

1. Identify optimal standardized protocols to treat MDR-TB.

2. Identify optimal protocols for diagnostic testing.

3. Identify minimum requirements for con-structing and implementing DOTS-Plus.

Box 7

Global research agenda primary goals

Selected Major Scientific Advances

Clinical

Individualized treatment regimens may perform

better than standardized regimens with cure rates that

may be twice as high as standardized regimens. Saravia

and colleagues compared two retreatment strategies in

TB patients in Lima who had failed Category I therapy.

125 patients were enrolled between February 1997 and

October 2001. Of these, 73 received the nationwide

Category II treatment and, if that regimen failed, a stan-

dardized regimen using second-line drugs; 62 received

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Chapter Five

individualized regimens based on drug susceptibility

testing. 79% of those receiving individualized regimens

were cured compared to 38% receiving the standardized

regimen. This dramatic success emphasized the impor-

tance of therapy based on drug susceptibility testing. The

Mitnick and Saravia studies showed that at least ¾ of

patients with MDR-TB could be cured using individual-

ized regimens based on drug susceptibility testing.25

Persons who have had more than two previous

courses of therapy are more likely to have a poor out-

come than those with fewer previous courses. At the May

2006 PARTNERS meeting, Mitnick summarized results

of treating 668 patients with confirmed MDR-TB enrolled

in individualized treatment regimens in Peru between

February 1999 and August 2002. Seventy percent had had

more than two previous treatments. Those with >2 previ-

ous treatments were more likely to have a poor outcome

(37.7% vs 20.7%) or die (24.8% vs 10.9%) than those with

<2 previous treatments. Deaths tended to occur early in

the course of ITR, thus ITR may not mediate the effect of

previous treatment on early deaths.

Results from the first 5 DOTS-Plus pilot projects dem-

onstrated that two-thirds of patients with MDR-TB could

be treated successfully. At the May 2006 PARTNERS meet-

ing, Peter Cegielski presented a retrospective analysis of

treatment and outcomes in the first 5 DOTS-Plus pilot

projects (Estonia, Latvia, Tomsk Oblast, Lima, Makati

Medical Center [Philippines]). These were collaborative

efforts of WHO, CDC, GLC, USAID, and PARTNERS. Of

1,932 cases total, 214 were excluded for various reasons,

leaving 1,718 valid cases for analysis. The 2 PIH projects

contributed 51% of the patients. Overall cure rates were

66.1% and the median duration of treatment was 21

months. The median time from initiation of therapy until

first sputum culture conversion from positive to negative

was in 3 months; 12.4% of patients had more than one

conversion from positive to negative.

Side effects are common and may be quite severe,

but they can be managed. Community health workers

can be trained to recognize adverse effects and provide

important care that is critical to helping patients endure

the side effects and continue treatment. Understanding

and managing patients’ side effects to drug therapy

may increase the likelihood of their continuing medica-

tion throughout the long treatment cycle. Furin and col-

leagues found that adverse effects among 60 patients

being treated with individualized regimens for MDR-TB

in Lima, September 1996 — October 1998, were common

but rarely life threatening. The patients were being treated

in the community with daily contacts with community

health workers. 100% of patients reported mild gastritis,

43.3% had dermatological effects, 16.7% had peripheral

neuropathy, 18.3% had depression, and 11.7% had anxiety.

In no patients did side effects result in discontinuation of

anti-tuberculosis therapy; however, care providers sus-

pended use of a given drug in 11.7% of cases due to side

effects. When side effects can be managed, patients are

more likely to complete the drug course and so experi-

ence improved rates of cure.26

Nathanson summarized the experience with adverse

events in 818 patients in 5 DOTS-Plus projects (Estonia,

Latvia, Peru, Philippines, Tomsk). The five most common

adverse events were nausea/vomiting (32.8%); diarrhea

(21.1%); arthralgia (16.4%); dizziness/vertigo (14.3%);

and hearing disturbances (12.0%). Only 2% of patients

stopped treatment but 30% required removal of suspected

drug(s) from the regimen due to adverse events.27

Failure to convert sputum smear from positive to neg-

ative within the first 3 months of DOTS therapy predicts

treatment failure. This suggests a way to find patients with

MDR-Tb earlier and allow earlier initiation of appropriate

treatment and better treatment results. In a case-control

study of all 38 patients failing Category I therapy in 2000

in central Lima, Chavez Pachas and colleagues found

that sputum smear positivity after 2 months of Category

I therapy was strongly associated with treatment failure

(odds ratio 11.7; 95% confidence interval 2.4−57.5). None

of the 76 controls who were cured with Category I therapy

had positive smears at or after 3 months of therapy. This

indicates that a large proportion of failures on Category I

therapy can be identified early and referred for culture and

drug susceptibility testing to allow prompt initiation of

appropriate therapy and improved outcomes.28

Continued administration of ineffective drug regi-

mens may amplify resistance; using the same treatment

regimen again in patients who have organisms resistant

to some of the drugs is likely to foster emergence of resis-

tance to other drugs in the regimen. The need for DOTS-

Plus was documented by Becerra and colleagues, who

studied 173 patients in Peru between September 1996 and

March 1998 who were persistently sputum smear-positive

at or after 5 months of administration of a DOTS regimen.

They found that 160 (92.5%) had culture-positive TB. Of

the 160, 150 (93.8%) had active, pulmonary MDR-TB as


94 |

shown by cultures in the Massachusetts State Laboratory

Institute. 40% had resistance to all four drugs used in

the primary treatment regimen and 29.3% had isolates

resistant to all five drugs used in the first retreatment regi-

men. This suggested that retreatment regimens in use at

the time were likely to be ineffective and potentially would

result in amplification of resistance patterns.29

Effective treatment of MDR-TB can provide lasting

benefits, both for health and for social well-being. Shin

and colleagues summarized follow-up for a median of

67 months on 86 patients considered cured after com-

pletion of treatment in the PARTNERS Project in Lima.

Only 1 patient had relapsed; 97% remained healthy.

Employment increased from 34% before treatment to

71% at follow-up.30

Epidemiologic

TB transmission in hospitals is a significant problem,

both for patients and staff. At the May 2006 PARTNERS

meeting, Nardell summarized results of a study on PPD

positivity carried out by Accinelli in 488 medical students

at Cayetano Heredia Hospital in Lima. He found that

the positivity increased from 3.5% to 45.9% over 7 years

(average annual increase 6%). He also found that PPD

positivity of students at Cayetano Heredia Hospital was

twice that of students at Loayza hospital, whereas room

volume per bed at Cayetano Heredia was less than half

that of Loayza (16.2 meter3 vs 41.4 meter3). He also sum-

marized overall infection control experience with MDR-TB

as follows:

• Under conditions commonly found in areas with high rates of TB, MDR-TB, and HIV, transmission to staff and patients appears to be common.

• Important variables include:

– Early detection and effective treatment.

– Less hospitalization and more ambulatory care.

– Room volume and crowding.

– Standard infection control practices.

– Infection control may be the most neglected aspect of the new Global Plan to Stop TB.

– A strategic plan (comparable to DOTS expan-sion or new drug or diagnostics development) with measurable objectives is needed to generate political will and to mobilize resources needed to change current practices.

One of the critical questions about MDR-TB was

whether resistant strains of TB could spread as widely

and quickly as non-resistant strains of MDR-TB. Some

thought that resistant strains were less likely to spread as

efficiently as non-resistant strains. Recent studies show

that at least some MDR-TB strains are “fit.” At the May

2006 PARTNERS meeting, Murray summarized studies

on transmission dynamics and fitness of MDR-TB strains

and characterized fitness as a composite trait including

the propensity of the bacteria to be aerosolized, their

ability to withstand environmental stress, their ability

to evade the host’s immune response, growth charac-

teristics of the organisms, and their tissue tropism. As

pointed out by Nardell, if reduced fitness occurs in some

MDR strains, other strains appear to be sufficiently fit

to propagate, especially among immunocompromised

persons.

Diagnostic

Drug susceptibility testing for both first-line drugs

and second-line drugs is essential to design individu-

alized treatment regimens. Timperi and colleagues

assessed the drug susceptibility patterns of TB isolates

from 1,680 patients in Lima referred for suspicion of

MDR-TB between 1996 and 2001. The patients had failed

previous TB treatment regimens administered through

the Peruvian NTP or were known contacts of someone

with documented MDR-TB. 55% of these isolates were

resistant to INH and RMP, two first-line drugs; of these,

40% were resistant to at least five first-line drugs, demon-

strating the broad spectrum of antibiotic resistance that

Effective treatment of MDR-TB can provide

lasting benefits, both for health and for social

well-being. Shin and colleagues summarized

follow-up for a median of 67 months on 86

patients considered cured after completion

of treatment in the PARTNERS Project in

Lima. Only 1 patient had relapsed; 97% re-

mained healthy. Employment increased from

34% before treatment to 71% at follow-up.

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| R e s e a r c h

Chapter Five

had developed. These results demonstrated the impor-

tance of the laboratory capacity for drug sensitivity testing

when designing standardized or individualized treatment

regimens for those who fail first-line therapy for TB.31

Using traditional techniques, TB bacteria grow slowly

and it may take several weeks to identify the organism

and test it for drug susceptibility. This delays initiation of

appropriate therapy and allows patients to continue to

spread their infections to other people. New techniques

offer promise of faster turnaround, allowing earlier ini-

tiation of appropriate therapy and reducing the period in

which patients may transmit their infection. At the May

2006 PARTNERS meeting, Shinnick summarized the

timelines, using traditional solid media, from obtaining

a sputum specimen to detection of acid-fast bacilli by

smear (<24 hours) or culture (3-4 weeks), identification

of M. tuberculosis (5-6 weeks), and completing drug sus-

ceptibility testing (8-9 weeks). By contrast, using liquid

media, these intervals could be reduced to <24 hours, <14

days, <21 days, and <30 days, respectively. Using rapid

direct identification and DST, the overall period could

be reduced to 7-14 days in those who are AFB smear

positive.

At the same meeting, O’Brien presented preliminary

results of an evaluation of the FASTPlaque Response

Test in Peru. FASTPlaque is a phage-based test to detect

rifampin resistance in M. tuberculosis in AFB smear-posi-

tive sputum specimens in 2 days. Compared to the “gold

standard” indirect DST test using Lowenstein-Jensen

solid media, FASTPlaque detected 76%.

Administrative/operational factors can contribute

significantly to delays in diagnosis. Thus, improving turn-

around time in the laboratory without addressing other

factors will not necessarily eliminate delays in diagno-

sis. A study of rapid diagnostic tests in Peru found that

delays in getting viable specimens from regional labora-

tories to the central laboratory for susceptibility testing

and in getting the results back to the clinicians can be

as great, or greater than, the amount of time it takes to

carry out the susceptibility testing (P. Cegielski, personal

communication).

Other

Operational

It is feasible to treat MDR-TB in both adults and chil-

dren on an ambulatory basis using public health nurses

and community health workers to monitor therapy, even

with complex individualized regimens. In one of the first

descriptions of the effectiveness of community-based

outpatient treatment of MDR-TB, Mitnick and colleagues

described the outcomes in the first 75 patients to receive

individualized regimens for chronic MDR-TB in northern

Lima (enrolled August 1996 — February 1999). Among

the 66 patients who completed four or more months

of therapy, 83% were probably cured at the completion

of treatment; 8% died.32 Drobac and colleagues have

reported on outcomes of treatment of 38 children <15

years of age with MDR-TB. The children were monitored

daily by community health workers, weekly by nurses, and

monthly by a physician. One child had treatment failure

and died, one was lost to follow-up, but all of the others

(95%) were either cured or had not yet completed therapy

but were culture-negative. Adverse events were fewer in

the children than in adults with MDR-TB.33

Electronic medical records (EMRs) can successfully

be used in developing countries to guide care and con-

duct research. Health care providers needed a simple

and secure data information system to record and man-

age patient information. PIH consulting physicians were

frequently traveling and needed access to records and to

the care providers to manage treatments. Collaborators

envisioned a communications system that would allow

physicians to review patient history and offer long-dis-

tance consultation with web access to secure patient

care records — in other words, a system to facilitate

telemedicine.

A web-based MDR-TB-specific electronic medical

record (EMR) system was developed and adapted with

some creativity by PARTNERS participants. Currently

clinicians enter data on paper forms and technicians

or administrative assistants record as electronic data;

eventually data will be directly entered into the computer

system by clinicians. The database includes patient care

data, clinical notes, and comprehensive drug data as well

as bacteriological data from the sites. Standard X-rays are

digitally photographed for inclusion. The EMR system

has provided an important underpinning for both clini-

cal care and clinical research involving more than 3,000

patients in Peru, Tomsk, and Haiti. It also has enabled

long-distance consultations. As the tool is improved, it

should help in modeling of future drug requirements and

so will be an important component of expansion and

exportation. 34


96 |

Economic

Treatment of MDR-TB with standardized or individu-

alized regimens is cost-effective and a good investment

compared to other health interventions. Suarez and col-

leagues documented the feasibility and cost-effectiveness

of using a standardized regimen of second-line drugs in

treating patients with chronic tuberculosis. Patients who

remained sputum-smear positive after completing a fully

supervised retreatment regimen were enrolled in a directly

observed standardized 18-month regimen for retreat-

ment. Their chemotherapy included daily injections of

kanamycin and oral doses of ciprofloxacin, ethionamide,

pyrazinamide, and ethambutol. Between October 1997

and March 1999, 466 patients were enrolled in the regi-

men. Even though the cure rate was less than 50%, the

retreatment regimen was cost-effective — approximately

US $211 per disability-adjusted life year (DALY) gained.

(Interventions are usually considered cost-effective if

the cost per DALY gained is less than the mean annual

gross domestic product/capita [approximately US $3,000

in Peru].)35 A more extensive cost-effectiveness study

including individualized regimens has been carried out

in Peru and data are currently being analyzed. An addi-

tional, follow-up report will incorporate information on

more than 2,000 patients (Mercedes Becerra, May 2006

PARTNERS meeting).

At the 2006 PARTNERS meeting, Floyd summarized

results of studies on cost and cost-effectiveness initi-

ated 2000-2002 and completed 2002-2005 in Peru, the

Philippines, Estonia, and Tomsk. These sites provide a

geographic range of settings in lower and upper-middle

income countries. The cost per patient treated ranged from

~US $2,000 in Peru to >US $10,000 in Tomsk, reflecting

both the difference in the cost of doing business in the dif-

ferent settings and the prominent use of hospitalization in

the European countries. The cost per DALY gained ranged

from US $183 in the Philippines to US $579 in Estonia.

In all countries, these figures are substantially below the

GNI per capita (<25%). These results, with appropriate

adjustments, were used to project the cost/DALY gained

in different regions of the world as part of the assessment

of Disease Control Priorities in Developing Countries.36

Knowledge DisseminationRapid Sharing of Research Findings Accelerated

the Expansion of Knowledge and Action. An important

characteristic of the PARTNERS Project was the major

emphasis on training and exchange of knowledge/

experiences with other DOTS-Plus projects as well as

with countries just beginning to address the MDR-TB

problem. The Project created a systematic approach

to knowledge generation as well as supporting the

dissemination and integration of knowledge, and ulti-

mately, the application of knowledge. This took the

form of site visits/consultations as well as presenta-

tions at scientific forums and formal training sessions

in settings including Lima, Tomsk, Boston, and Riga.

As a result, things were accomplished that could never

have been achieved with a single-faceted, non-compre-

hensive approach.

One indication of the great increase in dissemina-

tion of scientific knowledge is the rapid increase in the

number of articles published in the scientific literature

about MDR-TB — from 40 in the period 1991-1995, to 114

in the period 1996-2000, to 213 in the period 2001-2005.37

Patients who once were doomed to die from MDR-TB now

have hope for life and a cure as a result of this research.

Members of the PARTNERS Project contributed greatly to

the increase in knowledge.

Knowledge IntegrationThe integration of the research findings is seen in

changes in practices and is most notably reflected in the

Global Plan to Stop TB 2006-201538 and the newly revised

WHO guidelines for the management of drug-resistant

tuberculosis.39

The new Global Plan acknowledges that “Multidrug-

resistant TB threatens the potential salutary impact

of DOTS programs. Although progress in widespread

DOTS implementation will help prevent the further

emergence of drug-resistance, expansion of effective

DOTS-Plus programmes is vital to stem the contribu-

tion of drug-resistant cases to the overall TB epidemic.

Too few countries have national policies for the diag-

nosis and treatment of MDR-TB. In some of those that

do, treatment commonly fails to meet acceptable stan-

dards.” The plan calls for “adapting DOTS to prevent

and manage multidrug-resistant TB: DOTS-Plus” and

enunciates the vision of the Stop TB Working group

on DOTS-Plus for MDR-TB — “the integration of drug

resistance surveillance and the management of MDR-TB

as routine components of TB control.” The plan sets a

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| R e s e a r c h

Chapter Five

target that, “overall, the number of people with multi-

drug-resistant TB treated in DOTS-Plus programmes will

rise from 10,000 in the past 10 years to nearly 800,000

in the next ten.”

That these aggressive targets can even be considered

is testament to the knowledge and experience gained dur-

ing the past 5 years.

Another impact of the knowledge gained can be

seen in the change in the guidelines for management

of MDR-TB. In 2000, the guidelines called for the “use

of regimens including at least three drugs to which the

strain is know or likely to be susceptible.40 By contrast, the

2006 guidelines state that “treatment regimens should

consist of at least four drugs with either certain or highly

likely effectiveness.”

The work that has been done has clarified the need

for more work to generate additional knowledge on all

aspects of MDR-TB. Although research conducted to date

has demonstrated feasible and affordable approaches to

prevention and control of MDR-TB, current approaches

are suboptimal. A partial list of new tools that would be

extremely helpful includes:

• Additional effective drugs that are affordable, less toxic and do not have to be administered for as long as current drugs;

• Improved approaches to rapidly and reliably deter-mine drug susceptibility in developing countries;

• Reliable techniques to identify drug resistance in per-sons with latent tuberculosis infection; and

• Improved vaccines to prevent initial infection with M. tuberculosis, whether drug-sensitive or drug-resistant.

Knowledge ApplicationThe major indication of application of the knowledge

gained is in the change in approaches to dealing with

MDR-TB. These changes range from acceptance of the

notion that it is feasible and economical to treat MDR-TB

to specific recommendations for treatment regimens.

The true test of application of the knowledge gener-

ated through this project will be in the implementation of

the Global Plan to Stop TB 2006-2015 and the reduction

in incidence of MDR-TB throughout the world.

“When these doctors tell me I’m not going to get better, it’s very painful and

sad. They look at my x-rays and make faces like there’s nothing they can do,

shaking their heads. I think about abandoning the treatment. But then I

think of my children.”

–Patricia, MDR-TB patient

| 99

Chapter Six| C h a l l e n g e s

ChallengesScaling up DOTS-Plus Programs

at a Global LevelThe success of DOTS-Plus projects in several countries

has proven that MDR-TB can be controlled in resource-

poor countries. In fact, since 2000, these triumphs have

served as a model for how to integrate MDR-TB control

into national TB programs.

But these projects were implemented on a very small

scale compared with what is now required to address

the problem globally. The Global Plan to Stop TB 2006-

2015 (known as the Global Plan), which lays out a 10-year

strategy to combat MDR-TB, sets aggressive targets.

For example, it calls for reducing the annual incidence

of MDR-TB, which was 424,000 in 2006, to 193,000 by

2015. Another goal is to bring the number of detected

cases from the current rate of less than 2% up to 56%

by 2015. Furthermore, the Global Plan proposes treating

100% of the detected cases, with a cure rate of 75% (Table

6), compared with only 17% of detected cases that are

appropriately treated now. The magnitude of this scale-

up becomes apparent when we compare the number of

people treated during the last five years in DOTS-Plus

projects — 12,000 — to those we plan to treat over the

next ten year — 800,000 by 2015.

Until now, the programs have grown incrementally,

but the planned acceleration will be exponential and can-

not be accomplished by merely replicating activities of the

DOTS-Plus projects. The disease is so widespread that

even after 5 years of dedicated effort, the pilot projects

were barely able to diagnose and care for all those who

had MDR-TB or to ensure that a full course of second-

line drugs was available for the relatively small number

of patients who were being treated. These projects had

been served by sophisticated national laboratories, had

a well-developed infrastructure, and had access to noted

Table 6: Target indicators, as outlined in the Global Plan to Stop TB 2006-2015

Global Plan Target Indicator 2005 2006 2010 2015 2006-2015

Estimated incidence of MDR-TB 533,000 193,000

Total number of MDR-TB cases detected* 120,000 140,000 110,000 1,300,000

Total number of detected MDR-TB patients treated

20,000 90,000 110,000 800,000

Total number of MDR-TB patients who are cured

587,000

Percentage of incident cases detected <2% 56%

Percentage of detected MDR-TB cases treated

17% 60% 100% 60%

Percentage of treated MDR-TB patients who are cured

75%

*From 2000–2004, 10,000 cases were detected.


100 |

experts in the field. What can be expected in peripheral

areas? At present, very few countries have the laboratory

capacity, staff, or healthcare infrastructure needed to treat

the MDR-TB populations in their countries.

Further impeding the attainment of the Global Plan’s

goals is Health Sector Reform (HSR), an ongoing pro-

cess in many countries, in which specialized programs,

such as those designed to combat TB, are integrated into

broader primary care approaches. Decision-making is

decentralized, often resulting in the reduction of financial

and technical support to specialized programs. In many

countries, implementation of HSR has resulted in some

slippage in maintaining basic DOTS programs. This trend

will hinder our ability to build the infrastructure necessary

for handling a disease as complex as MDR-TB.

These challenges at both national and global lev-

els complicate the enormously important task of coor-

dinating our common targets and goals for controlling

TB around the world. However, consulting with experts

involved in the PARTNERS Project has helped us to iden-

tify and document the challenges. We group the iden-

tified challenges under two categories: program basics

and supportive actions. Program basics are vital to the

survival of any TB program. They are surveillance, which

is subdivided into programmatic, methodological, logisti-

cal, and ethical concerns; diagnosis, which includes how

the laboratories function; treatment, patient support,

infection control, and program management. Supportive

actions are equally vital though less structured; they are

political will, human resources, GLC oversight, research,

and funding.

Program Basics, Vital ElementsSurveillance

Programmatic Challenges

The Global Project began in 1994 and so far has

gathered data on new (not previously treated) cases from

90 countries (109 settings) and on previously treated

(retreatment) cases from 77 countries. Fourteen of the

22 High Burden Countries (HBCs) have been surveyed.

Of all the countries that have gathered data, only 17 have

not had country-wide surveys. Forty-six settings have

data from at least two time periods, which allows for the

assessment of trends.

Despite these impressive achievements, a huge

amount of work in this area remains. For more than

100 countries, including high-burden countries such as

Afghanistan, Bangladesh, Indonesia, United Republic

of Tanzania, Pakistan and Nigeria,41 we have no data at

all. In Africa, as of 2002, trend data are available only

from Botswana. Many countries that have been sur-

veyed, including the three responsible for two-thirds

of the world’s MDR-TB (China, India, and the Russian

Federation), conducted sub-national surveys, which may

not accurately reflect the burden of the disease through-

out the entire country. Moreover, the majority of the sur-

veillance (56.6%) has been completed through a single

survey, thus not allowing assessment of trends.42 Not

only does having so few data points make it difficult to

interpret trends precisely, but often the first data points

are not very robust, due to sample size or selection.43 In

order to assess epidemiological trends, it is necessary to

repeat surveys and continue surveillance as well as initi-

ate surveillance in many more settings.

Until recently, surveys have been designed to assess

MDR-TB only in cases not formerly treated. However,

information from previously treated (retreatment) cases

is critical to planning the national TB control programs.44

This is because, among other reasons, these infections

tend to have more severe patterns of resistance and often

persist for years.

Although increased surveillance is needed, we must

confront the problematic need of employing more labora-

tories and insuring the quality of the testing conducted in

them. The 25 established supranational reference labora-

tories (SNRLs) and one under consideration, which pro-

vide technical assistance to national and regional labora-

tories as well as monitor the quality of testing, will not be

able to meet the anticipated testing demands.

Additional concerns deserving mention here are the

several methodological, logistical, and ethical challenges

that designing and conducting good surveys pose.

Methodological Concerns of Surveillance

Designing the surveys is complex. First, it is dif-

ficult to identify patients as never treated or as previ-

ously treated because records of earlier treatment may

not be available or accurate. Second, it is difficult to

find representative samples, especially with retreatment

cases. Also, the results are difficult to compare between

countries. At present, three different methods of surveil-

lance are being used: continuous surveillance, sentinel

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Chapter Six

surveillance, and surveys. Continuous surveillance is

the most difficult, as it attempts to detect every case

of MDR-TB that occurs in the country. Sentinel surveil-

lances use specific sites where infection has been identi-

fied to provide ongoing information on a sample of the

population. Surveys are typically one-time efforts. Over

time, however, the systems might need to change, shift-

ing to ongoing diagnostic reporting that would cover an

expanded population.

Logistical Concerns

So far, the national reference laboratories (NRL)

have been conducting drug sensitivity tests (DSTs) and

providing results, which are validated by the suprana-

tional reference laboratories (SRLs). As more samples

are tested, this method cannot keep up with the demand.

Sub-national laboratories need to be equipped with the

ability to conduct the DSTs. The process of identifying

cases, collecting, packaging, and transporting samples

to SRLs and NRLs must become more efficient if these

processes are to serve the increased number of cases.

Ethical Concerns

In many countries, the public sector often experi-

ences a shortage of second-line drugs. In the private sec-

tor, some private physicians provide appropriate treat-

ment for MDR-TB, while others do not. If this situation

does not change, more patients may be identified as

having MDR-TB but not receive appropriate treatment

because appropriate drugs are not available or because

physicians do not prescribe appropriate medications. As

rapid methods of testing and diagnosing are developed,

it is possible that the capacity to treat patients will not be

able to keep up with the process of identifying them. And

that would be a tragedy. The processes of diagnosing and

treating must go hand in hand.

The patients’ lack of privacy and the inadequate

practices in obtaining their consent for treatment are two

other ethical concerns. Many countries do not properly

secure patients’ consent before testing them. Sometimes

test results are not guarded well, so the status of infected

patients can become publicly known. Since the stigma

of MDR-TB can be traumatizing, we need to find a solu-

tion to this dilemma. While some healthcare workers

may find it expedient to relinquish patient privacy dur-

ing this period of rapid escalation, doing so would harm

the program, perhaps irrevocably. And the stigma and

trauma will no doubt intensify for patients with a co-exist-

ing HIV infection.

Diagnosis

Thus far, the diagnostic needs of DOTS-Plus pilot

projects have been handled according to a standard pro-

tocol. As capacity has developed at the national refer-

ence laboratory (NRL), DSTs for both first-line drugs and

SLDs have been carried out by a supranational reference

laboratory (SNRL). A few regional labs also have been

equipped with first-line DST capacity. This process has

been long and expensive and is one reason that building

enough labs is widely viewed as a potential stumbling

block for the planned scale-up of MDR-TB control, espe-

cially given the difficulties that the smaller scale DOTS-

Plus projects have experienced. For example, even after

five years of committed effort in Peru, the demand for

DSTs is surpassing the labs’ capacity to meet it. Currently,

most countries can use the national lab for DST of first-

line drugs. But the question remains: will governments

be able to simultaneously decentralize DST for first-line

drugs and develop capacity for DST of second-line drugs

at the national level?

Lab Infrastructure

In most countries, the NRLs are the only facilities

where DST can be conducted. DOTS strategy stipulates

that sputum smear microscopy is the testing standard in

labs analyzing sputum for the purpose of diagnosing TB.

The fact that many regional and peripheral labs lack the

capacity to conduct cultures, let alone perform DST, means

that the lab infrastructure must be transformed. The labo-

ratories must be enlarged and expanded to accommodate

required infection control procedures as well as obtain the

necessary diagnostic equipment and reagents. Ensuring

that the quality of cultures and DSTs is acceptably main-

tained requires a continuous supply of electricity, gas, and

water. Implementing these changes in hundreds of labs

across numerous countries is a major challenge.

Developing Diagnostic Capacity

The next steps toward conducting first- and second-

line DSTs are training, a system for validating processes,

and a method of continuously monitoring quality. The

training will be intensive since performing cultures and


102 |

DSTs is more complex than performing sputum smear

microscopy. Among numerous other jobs, the workers

will have to know how to operate the machines, maintain

quality of cultures and DSTs, monitor lab reagents and

equipment, watch for potential hazards, and maintain

medical records.

Lab managers will have to be trained on forecasting

lab needs, ordering equipment and reagents on time,

monitoring transportation of sputum samples and lab

supplies, and assuring that diagnostic results are reported

in a timely manner. Ascertaining that labs perform valid

tests requires that a quality-certified lab conduct valida-

tion tests. From our experience in Peru, it is clear that

these are time-consuming procedures. It is daunting to

imagine how they will be enacted in so many labs across

the world. The work does not end when the lab completes

its validation process; quality monitoring of outcomes

must be continuous.

One of the biggest challenges in running an efficient

laboratory diagnosis system is to make it real time — that

is, to ensure it provides results in a timeframe that can

guide clinical decisions. One way to assure this is to have

state-of-the-art diagnostic systems. In many developing

countries, consultants have tried to implement older

technology (solid media cultures) when they could have

been helping develop newer, but more costly, approaches

(e.g., line probe assays or broth media capability).

The other component of the challenge is operational

inefficiencies. Delays in laboratory diagnoses are often

caused, not by the time used to process the test itself, but

by inefficiency in transporting the sample, recording and

reporting systems, and/or delivering the results.

Ensuring Biosafety

Ensuring the lab staff’s safety is the highest priority.

The buildings must be equipped with proper ventilation

pathways, adequate biosafety cabinets, and proper tools

for handling the very specialized equipment. Workers

must be trained to handle cultures safely. If local engi-

neers do not understand the specific requirements of

these lab facilities, the entire construction process must

be monitored. If, due to lapses in biosafety, any lab work-

ers become infected with MDR-TB, the consequences

will be far-reaching. In addition to those workers’ avoid-

able suffering, fear — which may be difficult to man-

age — may occur at other labs where quality procedures

are working well.

Treatment

Drug Regimen

Nothing is more critical to preventing the prolifera-

tion of further drug-resistant strains than selecting the

proper drug regimen for each patient. In pilot sites, where

the number of patients has been relatively small, this has

been a manageable task. However, when the numbers of

patients and health workers increases to the predicted

national and global scale, attention must explicitly be paid

to drug regimen, particularly in the private sector where a

substantial proportion of TB patients are treated.

When determining which drugs to include in a

patient’s regimen, physicians consider, in addition to

DSTs, the patient’s age, previous medical conditions,

alcohol or drug abuse, pregnancy, and his or her other

medications. In some countries, it may not be feasible to

design individual treatment regimens (ITRs) because of

limitations in capacity to perform DSTs or in the number of

trained specialists. In such circumstances, epidemiologi-

cal profiles and standardized treatment regimens (STRs)

will be created for the particular community. As in the

DOTS-Plus programs, health workers must be trained in

the recommended protocol as well as in how to recognize

and manage drug side effects, which are often severe.

Drug Supply

Of course, sustaining a supply of second-line drugs

is fundamental to treating MDR-TB. This has been dif-

ficult in the small projects, so it is sobering to consider

the challenges we must overcome as we orchestrate drug

supplies at national and global levels.

Poor Forecasting Creates Limited Incentive to Produce

Insufficient knowledge about trends of MDR-TB and

patterns of drug-resistance makes it difficult to predict

what specific drugs are most needed. While, to some

extent, there is an opportunity to identify the trends and

patterns by sharing information among projects, this sort

of communication is not yet well developed. Vague infor-

mation surrounding the demand for particular SLDs pro-

vides little incentive for drug manufacturers to undertake

production since manufacturers cannot be assured they

will even recover the costs of making the drugs.

Likewise, lack of knowledge regarding the quanti-

ties of needed drugs creates problems for projects. The

lead time for production for some of the drugs, like

Table 7. Drug Suppliers for Second-Line Drugs

Drugs Manufacturer

Capreomycin, powder for injection Eli Lilly

Kanamycin, powder for injection Panpharma

Cycloserine Macleods, Eli Lilly

Ethionamide Macleods

Prothionamide Fatol

Ofloxacin Brown Burke, Macleods

PASER Jacobus

PAS Macleods

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Chapter Six

capreomycin, is as much as 6 months. This, combined

with the delays in transportation of drugs and delays

introduced by drug registration issues, makes it impracti-

cal to order drugs after obtaining DST results. The drugs

may arrive too late for the patients. So drugs are ordered

in advance, based on a particular community’s drug

usage patterns. Needless to say, these orders are far from

exact and, if drugs are not used in time, they may go to

waste. The short shelf-lives of some drugs (18 months for

cycloserine and 24 months for capreomycin) provide little

margin for error in estimating demand.

Fortunately, the GLC’s procurement staff is devel-

oping a matrix for forecasting need. While in Peru, the

electronic medical record (EMR) system has been used

successfully to predict demand. How this system and

other instruments will be applied to estimating need on a

global scale remains to be seen.

Regulatory Complexity

Drugs must be registered in a country before they

can be sold or distributed; minimizing the delays in this

process is crucial. The protocols for approving drugs

obtained from abroad are different in each country. Long

regulatory delays discourage manufacturers from selling

their drugs in other countries. Minimizing these delays

will not only ensure that patients get drugs on time but

will act as a much-needed incentive for the manufacturers

to distribute in many countries.

Few Suppliers of Second-Line Drugs

Currently, the market for MDR-TB medications is

not very big and demand is erratic. Table 7 shows the

few manufacturers who produce some of the second-line

drugs and supply them to the GLC. But, even these com-

panies’ manufacturing capacity is limited.

Expensive Drugs Constrain Health Budgets

Although the drugs cost much less as a result of

the GLC’s pooled procurement policies, they are still

expensive (US $2500–US $3000 for a course regimen).

National treatment programs typically provide drugs at

no cost to financially-strapped patients. Unfortunately,

this may happen less in the future since the NTPs operate

with strained resources.

Quality of Drugs

Thus far, the few manufacturers that, based on qual-

ity assessment of their drugs, have received international

approval have been able to provide for the patients treated

in pilot projects. However, unsurprisingly, the complicated

process of pre-qualifying manufacturers for international

supply is slow and needs to be speeded up now more

than ever. A number of generic manufacturers are plan-

ning to produce and distribute drugs within individual

countries, such as India and China. The concern is that

manufacturers, unfamiliar with the limitations imposed by

the qualification process, will find it intolerably frustrating.

Organizing and expediting this qualification process at the

global level is crucial. Nothing looms larger than the fear

that drugs that do not meet international standards will

somehow be introduced. Not only would their use lead to

ineffective treatment, it could create further TB resistance.

This major threat must be addressed immediately.

Lack of Buffer Stock

Since the time between ordering and receiving the

drugs is 2–6 months, buffer stocks would ensure that

treatments are not interrupted. Establishing such a mech-

anism is a goal in many countries. Another mechanism

would be to maintain a central buffer stock through the

GLC, but this is not yet in place.

Patient Support

Clinical treatment alone is not sufficient. Experience

in Peru and other countries shows that constant sup-

port provided by healthcare workers is one of the primary

reasons patients adhere to their treatments, despite

severe drug side effects, for as long as two years. MDR-TB

patients, most of whom are poor, respond to psycho-

logical support, social rehabilitation, and nutritional guid-

ance. We must do whatever it takes to make sure these

services are available on a mass scale.

Table 7. Drug Suppliers for Second-Line Drugs

Drugs Manufacturer

Capreomycin, powder for injection Eli Lilly

Kanamycin, powder for injection Panpharma

Cycloserine Macleods, Eli Lilly

Ethionamide Macleods

Prothionamide Fatol

Ofloxacin Brown Burke, Macleods

PASER Jacobus

PAS Macleods


104 |

Infection Control

Controlling the transmission of MDR-TB in labs, hos-

pitals, and clinics represents another challenge. Any set-

ting in which infected patients are in close proximity to

others (particularly those with HIV) is a potential site of

contagion. Procedures for keeping patients separate from

each other, as well as assuring proper ventilation, will help

prevent transmission. This will be all the more important

considering the increasing incidence of XDR-TB.

Research studies in South Africa reveal that MDR-TB

is frequently transmitted to staff and other patients in

healthcare settings. In response, researchers recommend

early detection and treatment, less hospitalization and

more ambulatory care, less crowding, and the implemen-

tation of standard infection control practices.45

Administratively, executing these recommendations

on a large scale requires new policies and guidelines in

hospitals, placing MDR-TB patients in separate rooms.

Even if such policies are adopted, implementing them will

be difficult. In resource-poor countries with too few hospi-

tal beds, patients must share the same bed, let alone the

same room.

In fact, several hospitals will need to be redesigned to

accommodate the effective ventilation systems that con-

tain, rather than spread, infection. This will disrupt exist-

ing facilities, interrupt routine work, and require training

hospital staff.

Unfortunately, it is likely that, when establishing and/

or scaling up MDR-TB prevention and treatment, diagno-

sis and treatment issues will get more priority than infec-

tion control issues. An attitudinal change on the part of

health workers, administrators, and policy makers will be

necessary. This, again, will be difficult.

Program Management

MDR-TB control is complex. Managing an MDR-TB

control program requires sophisticated skills to coordi-

nate a number of components successfully. When coupled

with health sector reform and changing political environ-

ments, the managerial task becomes extremely challeng-

ing. Issues of budgeting, procuring of funds, mobilizing

human resources, planning and developing the infrastruc-

ture — all are critical components for a successful scale-up.

Many programs are being led by health workers who have

not been trained to address such issues. A shortage of

managerial capacity is one of the NTP’s biggest concerns.

Highlighting the importance of managerial compe-

tency, PARTNERS made training in managerial issues a

high priority for leaders of NTPs, directors of labs and

clinical facilities, and those who oversee procuring, ware-

housing, and distributing drugs. Training for the planned

expansion will require experts in the field; monitoring

teams will assist NTP managers as they integrate MDR-TB

control into their ongoing activities. While there are many

experts in the clinical treatment of MDR-TB and in devel-

opment of diagnostic capacity, trainers who can impart

competencies in management are in short supply. This

will be another challenge in achieving the time bound and

resource-limited targets of the second Global Plan.

Challenges in Providing Support to Programs

Leadership, Coordination, and Political Will

Without coordinated, sustained, and committed lead-

ership at both global and national levels, it will be impossi-

ble to achieve our goals for the rapid expansion of MDR-TB

control. At the global level, sustained and committed

leadership is required to guide activities toward achiev-

ing the Global Plan targets. Commitments from govern-

ments are necessary for program success at the national

level. It is unrealistic to anticipate success — national or

global — without the help of stable governments.

While the leadership of the WHO understands the

importance of taking risks in order bring about change,

the Ministers of Health of individual countries may be

averse to risk. This makes it impractical for the WHO

to set breakthrough policies by itself. Robust leadership

from multi-disciplinary international teams, including

private, non-profit, and governmental agencies com-

mitted to MDR-TB programs in each country, will be

crucial to making efficient, informed, and bold policy

decisions.

Procuring funding, assuring the cooperation of all

required parties, negotiating communication and part-

nerships, and committing resources to action demands

aggressive steps at the global level. The importance of

identifying key opinion leaders cannot be overempha-

sized, particularly now that health sector reform has been

introduced in many countries. As Jim Kim of PIH has

noted, “Global health is all about political will. Without it,

everything else fails.”

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Chapter Six

GLC Oversight

As the main body coordinating DOTS-Plus activi-

ties at the global level, including solicitation and review

of applications, technical assistance, drug-procurement,

policy development, and partnership coordination, the

Green Light Committee (GLC) has been indispens-

able to MDR-TB control. However, it is now facing

major constraints in all areas — financial, human, and

organizational.

Structure

When the GLC was created in June 2000, it consisted

of six volunteer members from participating agencies and

was designed to review and oversee MDR-TB projects in

a few countries. It discussed the proposals in detail and,

when their original applications were deficient, helped

applicant countries understand the problems so that they

could reapply. However, in the last five years, the number

of applicants has increased tremendously. As of 2006,

the GLC had reviewed applications from 52 projects in 41

countries.Staff has increased to thirteen, but is stretched

beyond capacity. And certainly the demand will intensify

with new programs. Right now, the GLC team functions

as one unit that works on every task, but it has drafted

a business plan proposing a reorganization in which

work is distributed among four units: GLC Secretariat,

Technical Review Panel, Monitoring and Evaluation, and

Procurement Unit. This plan, released in 2006, uses two

models of growth — steady and rapid — to forecast its

targets. In the rapid growth scenario, the GLC would have

40 staff members at the global, country, and regional

levels by 2008 with the aim of decentralizing the GLC’s

functions.46

Function

Increasing the GLC staff, while an enormous help, is

not sufficient. Organizational processes must be stream-

lined. For example, there is typically a lag time of three

months and longer between GLC approval of a project

and receipt by the project of the approved drugs. A doc-

ument published by Medecins Sans Frontieres (MSF)

shows that 14.5 months elapsed after one country received

GLC approval before it obtained the drugs.47 Such unac-

ceptable delays will create serious backlogs when the vol-

ume of applications to the GLC multiplies. The prepara-

tion, submission, review, approval, and follow-up phases

must be managed efficiently and effectively in light of the

increased volume.

Another knotty problem has arisen that has caused

the GLC to reconsider its mandate to help procure appro-

priate drugs at vastly reduced prices. Some countries,

including India and China, are looking into manufacturing

generic second-line drugs themselves. Doing so would

give these countries access to second-line drugs at prices

even lower than what they would pay through the GLC

and so may remove their incentive to accept the organiza-

tion’s supervision. Hence, the issue of how to evaluate

and monitor the drugs themselves and their appropriate

use in programs may necessitate reinvention of the GLC.

This approval and monitoring process must be closely

linked to estimates of drug demand and development of

drug supply capacity. These must be timed to meet the

financial allocation periods of governments in order to

enable timely procurement of the drugs. Currently, WHO

and the GLC are considering synergies to work out a part-

nership between the GLC and the Global Drug Facility so

that these issues can be better addressed.

Financing the GLC

Finally, the GLC needs substantial funding — about

US $30 million10 — if it is to meet the goals of the Global

Plan in the three years from 2006 to 2008. At present,

sources for only about US $5 million48 have been identi-

fied. They include the Gates Foundation, USAID, Eli Lilly,

WHO, the UK government, and the US Government.

While it remains unclear from where the remaining US $25

million49 will come, the hope is that the Global Fund and

individual governments will fill the gap, although no com-

mitments exist right now. If this funding does not come

through, then the best of plans will go unimplemented.

Human Resources

Most of the MDR-TB patients in each project have

been managed by a small number of health workers,

managers, researchers, and technical assistants. A tre-

mendous increase in human resources is needed to meet

the future demand.

Ensuring There Is Enough Staff Available

At the country level, more doctors, nurses, village

health workers, patient advocacy leaders, drug supply

managers, and laboratory specialists are needed and


106 |

must be hired to perform specific functions of MDR-TB

control, including surveillance, diagnosis, clinical treat-

ment, patient support, infection control, and program-

matic management. Globally, additional staff will be

needed to enhance efforts to produce more and over-

see existing high-quality drugs. Expert committees that

include technical, clinical, and laboratory specialists,

researchers, management consultants, and other person-

nel will be sorely needed to guide countries implementing

integrated programs. For example, new programs often

require a great deal of technical support; new partici-

pants, funded through the Global Fund, will constitute an

increasing percentage of projects.

Ensuring that Existing Staff Is Well-Trained

Of course, we need to ensure that new staff mem-

bers are trained and that their skills are regularly updated

as newer techniques and paradigms of MDR-TB control

evolve. Not only should training take place at all profes-

sional levels, but healthcare workers must know how to

identify, refer, and diagnose possible cases of TB as well

as individuals at high risk. Furthermore, they must be

familiar with TB/HIV, XDR-TB, and well-versed in how to

protect patients’ rights.

An important component of training is to create

mechanisms of communication that ensure standardized

knowledge and information delivery across different sec-

tors. Because misinformation spreads readily, continuous

training on how to implement the solutions that result

from ongoing research is imperative. Multi-disciplinary

teams should be organized and meet regularly to discuss

diagnosis, standard treatment guidelines, and practices

for the management of MDR-TB patients. The discus-

sions’ content should be revised regularly as new relevant

data emerge. For example, information flows, indicators

for monitoring, and standardized reporting all need to be

clearly defined.

Unfortunately, inappropriate or inadequate training is

currently being provided in many places. Many healthcare

workers have limited access to current information or new

knowledge and they often lack supportive supervision.

While training is often performed by international teams

in international courses, it must be offered locally as well.

If MDR-TB control is to be successfully integrated into

national TB control programs, then MDR-TB training on it

must be integrated into the overall TB training.

Considering the Staff’s Well-Being

Attrition of healthcare workers is a big problem in

MDR-TB control programs — perhaps a greater problem

than in other health programs. One reason is that work-

ing with so many patients who are not cured may cause

workers to feel demoralized, undervalued, or hopeless

and, once they lose morale, they usually and understand-

ably leave.

The lack of safety in the workplace is another cause of

the high attrition. Health workers may not feel certain that

they will be cared for and treated if they develop MDR-TB.

If they do not feel secure, they will not stay.

The staff also needs to know that their viewpoints

matter and that they have a voice in the decision-making

processes. Neither the programs nor the health workers

will succeed if their opinions on nearly all aspects of the

expansion are not heard. Underlying each program must

be a system in which everyone involved feels trust, sup-

port, respect, and mutual responsibility.

Research

Despite the enormous advances in MDR-TB control,

further research to improve prevention, diagnosis and

treatment and to reduce costs is needed. Equally neces-

sary is study on two issues that are central to the pro-

grammatic management of MDR-TB: cost effectiveness

and transmission dynamics. Further research challenges

are the fact that current data is, for the most part, based

on small projects and is lacking in many regions of the

world, especially low-income and less-developed areas.

Expanding studies to include multi-cohort and random-

ized trials will increase the validity of research findings.

And, as always, new diagnostic tools, vaccines, and more

effective drugs are urgently needed.

Research on Cost Effectiveness

That MDR-TB treatment is cost-effective has been

established. What we do not know is the true cost of

not treating it. Calculating this is important because the

results will allow us to assess accurately the threat that the

disease poses. Specific data needed include patients’ out-

of-pocket expenses, the cost of their reduced productivity,

the cost of damage to their lungs sustained in the course

of multiple treatment regimens, the price incurred when

staff loses morale, and the cost if patients lose faith in the

system. In addition to the quantitative methods used to

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Chapter Six

put an actual dollar value on the disability adjusted life

years (DALYs), we must assess these costs with qualita-

tive methods as well. Moreover, our data on the costs and

treatment outcomes of chronic cases of MDR-TB in the

absence of DOTS-Plus treatment are limited and it will be

important to conduct these studies.

Research on Transmission Dynamics

Debates about the transmission dynamics of

MDR-TB strains continue in the absence of sufficient sci-

entific data. Which strains, in particular, are transmitted

and how they progress remains unclear. We need more

data on how transmission is affected by coexisting dis-

eases, such as HIV, and more information about environ-

mental/social factors, such as congregate living.

Different Research Designs

To date most studies have been conducted on cohorts

of patients from a single site in a country. Cohort studies

from multiple sites will shed light on several issues, includ-

ing duration of therapy, required number of “active” drugs,

the role of lung resection (surgery), the effects of therapeu-

tic drug monitoring (TDM), the significance of new drugs,

and how to treat latent TB in those exposed to MDR-TB.

New Drugs

Despite the fact that 2 million people die from TB

each year, all of the first-line drugs currently used were

developed 40 to 50 years ago. Despite the desperate need

for new drugs, only recently has there been much activity

on this front. In February 2000, the Global Alliance for

TB Drug Development, a public-private partnership, was

established to develop new drugs that would reduce both

the time and costs of TB treatment. As a result, we now

have moxifloxacin, a drug designed to cut the primary TB

treatment regimen from 6 to 3 months. At present, it is

undergoing clinical trial.

Moxifloxacin’s effectiveness for MDR-TB is unknown.

And, although this new drug is a promising start, one drug

is not enough. A combination that will replace the current

regimen is needed. Our hope is that new drugs will act

faster than existing FLDs and replace them completely, so

that the strains of MDR-TB currently resistant to rifampi-

cin and isoniazid can be effectively killed. But until such

a regimen is designed, new medication that can relieve

some of difficulties of treating this disease is urgently

needed. It is imperative to world health that we have SLDs

that are less toxic, faster acting, and less expensive than

the current ones, which cause a multitude of side effects,

take between 18-36 months to cure MDR-TB, and cost

more than some countries feel they can afford.

New Diagnostics

Current diagnostics, which have served us well on

a small scale, are too slow, expensive, or complicated

to be used on a broad scale. As yet, we have no tool for

diagnosing latent MDR-TB infections. And, as PARTNERS

and other DOTS-Plus projects have pointed out, late diag-

nosis increases the chances of treatment failure. New

diagnostics that allow for early treatment are desperately

needed; they must be inexpensive and easy to use so that

they can be implemented widely in resource-poor coun-

tries. In May 2003, the Foundation for Innovative New

Diagnostics (FIND), funded by the Bill & Melinda Gates

Foundation, was formed to address this precise need.

Hopefully, FIND will develop better diagnostic technolo-

gies soon so that the planned expansion will not have to

begin with the expensive, complicated ones currently in

place. Additional resources and greater commitment to

this goal are needed to find a solution soon.

New Vaccines

Although we have vaccines for many diseases, a

major effort to develop one for TB had not been exerted

until recently. Bacille Calmette-Guerin (BCG), developed

in the early 20th century, provides protection against dis-

seminated TB in newborns and young children but does

not significantly affect transmission dynamics; hence, its

impact is very limited. Leading efforts to develop a TB vac-

cine, the Gates Foundation provided funds for the estab-

lishment of the Aeras Global TB Vaccine Foundation in

1997. In 2004, Aeras conducted Phase 1 trials of a recom-

binant BCG vaccine that looks promising. A vaccine

would enormously improve the Global Plan’s chances for

success. But, this cannot happen without commitments

of even greater political will and funding.

Funding for MDR-TB Control

Though we have said this before, it can not be over-

emphasized: in order to achieve the Global Plan’s tar-

gets and address the challenges of controlling MDR-TB

throughout the world, it is paramount that we procure


108 |

the required funds. In this context, it is important to

understand the questions regarding funding that we now

confront, such as which countries require the majority

of the funding and what strategies work best to mobilize

domestic and donor sources?

The Global Plan needs US $56 billion overall for the

period 2006-2015; available funds total only US $25 bil-

lion. Figure 7 shows the resources sorted by category of

TB control activities.

28.5

5.8

6.7

2.9

2.9

.5

4.8

3.6

DOTS Expansion

DOTS-Plus

Funding Gap of US $31 billion

TB/HIV

ACSM

Technical Cooperation

Diagnostics

Drugs

Vaccines

The Global Plan projects the total cost of treat-

ing 800,000 MDR-TB patients over the next 10 years

(2006 — 2015) is US $5.8 billion. Since the expansion will

not occur all at once, most of the funds will not be needed

until the later stages. Presently, US $55 million is available

for second-line drugs for 73 countries (these countries

accounted for 90% of new global TB cases in 2006). At

current drug prices through the Global Plan, this money

could buy enough drugs for 16,000 MDR-TB patients to

be treated annually, which is only about 20% of those

who will require treatment annually. 50 And, as a main-stay

in the planned expansion of MDR-TB activities, the GLC

must have a steady source of funding. As stated in our

“Financing the GLC” section, the projected need for GLC

activities until 2008 is US $25 million.51

Two distinct challenges of funding MDR-TB control

activities confront us as we plan for the future. The first

is the complex issue of analyzing how much money is

required where. The second is who or which organiza-

tions will provide it. To determine the answers, detailed

analyses are being conducted for different areas of the

world.

Funding Requirements in

Different Regions of the World

Figure 8 above shows the per-patient costs of treat-

ment in several areas of the world, categorized by differ-

ent aspects of MDR-TB control.

Figure 9 shows the resources needed by different

regions of the world. Drugs form the major component of

MDR-TB control in all regions. Interestingly, treatment is

most ex-pensive in the Eastern European region, primarily

because of the extensive use of hospitalization there.

The analyses reflected in these figures have impor-

tant implications for determining resources to fund the

expansion. First, they show that reducing drug costs

would significantly enhance our chances of meeting

the Global Plan’s targets. This could happen by nego-

tiating lower prices for existing SLDs or by developing

new, cheaper SLDs that also reduce the treatment time.

Second, because Eastern Europe’s long standing tradition

of hospitalizing TB patients serves myriad social func-

tions in addition to offering medical treatment, replacing

hospitalization with outpatient care in that region may

be impractical. And third, given the comparatively much

higher costs in Eastern Europe, it may make sense to

identify funding agencies that are uniquely invested in

that region to fund MDR-TB control activities there.

Procuring the Required Funds

The Global Plan estimates US $5.8 billion over the

next ten years52 to be the sum required to fund the expan-

sion and acceleration of MDR-TB control. Assuming the

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

KEY

Africa, high HIV prevalence (AFR high)Africa, low HIV prevalence (AFR low)Eastern Europe (EEUR)

Eastern Mediterranean (EMR)Latin America (LAC)

South-East Asia (SEAR)Western Pacific (WPR)

US

$ (2

006

pric

es)

EEUR WPR LAC SEAR EMR AFRhigh

AFRlow

OtherTrainingLaboratory tests and X-raysProgramme/data managementDOT visitsHospitalizationDrugs

Figure 8. Cost per patient treated by region, GP2

Figure 7. Total Resource Needs for Global Plan— US $56 billion

| 109


Chapter Six

funding gap for DOTS-Plus efforts is the same as for

overall TB activities (estimated requirement US $56.1 bil-

lion; available funds US $25.3 billion; funding gap 55%),

the available funds will have to be more than doubled

to achieve the DOTS-Plus scale-up targets of the Global

Plan. Some analyses have been done with regards to

probable sources of funding the global scale up.53

Full implementation of the Global Plan in its entirety

depends upon planning meticulously, mobilizing

resources, and implementing programs in eight countries

in particular: India, China, and six countries in Eastern

Europe (Russian Federation, Ukraine, Uzbekistan,

Kyrgyzstan, Kazakhstan, and Moldova). Most of these

(excluding India) are middle income indicating that they

may be in positions to raise domestically a large percent-

age of the needed funds.

Table 8 depicts estimates released by The

Commission on Macroeconomics and Health (2001) on

how much healthcare funding can be raised domestically.

Ninety-five percent of the Eastern Europe funds are

needed in the six middle-income countries previously

identified: the Russian Federation, Ukraine, Uzbekistan,

Kyrgyzstan, Kazakhstan, and Moldova. In the Western

Pacific, the majority is needed by China, a lower middle-

income country; and in South East Asia, India, which is

the only low-income country, is the neediest. The fact

that both India and China have recently allocated large

increases toward TB control is very encouraging.

While research indicates that these countries should

be able to raise a high proportion of funding for the

MDR-TB control scale-up, convincing them of this may be

difficult. Currently, China and the Philippines are covering

about 40% of total costs of their programs. This propor-

tion must increase so countries share much more of the

burden. Until this occurs, it remains unclear how we will

secure sufficient funds to control MDR-TB throughout

the world.

It is important that funding uncertainty be addressed

as soon as possible. Though we have recently seen an

encouraging surge of interest in global health from both

private and government funding agencies, many health

needs are competing for these funds. We must advo-

cate for MDR-TB funds with renewed strength, especially

when it comes to financing the GLC, which remains a cor-

nerstone for achieving success. While domestic funding

holds promise, other options, both through the Global

Fund and from private agencies, need also to be explored.

In 2006 The Global Fund provided US $57 million to the

fight against MDR-TB, but its continuation, as well as that

of the GLC, will depend upon serious commitments from

the involved countries.

We need strategic plans for donor and domestic

resource mobilization as well as contingency plans in case

the Global Fund runs into difficulties. Donors must be

educated about the strategic importance of the GLC, the

threat of MDR-TB, and the possibility that XDR-TB could

become more prevalent. The challenges we confront while

working to procure appropriate funds are immense and

demand sustained collaboration among all of the agen-

cies concerned with the threat of drug-resistant TB.

9000

3000

2500

2000

1500

1000

500

0

US

$ (2

00

6 pr

ices

)

EEUR WPR LAC SEAR EMR AFRhigh

AFRlow

Table 8. Percentage of health care funding that can be raised domestically

Country income category

Percentage of required funding that can be

raised domestically for health care*

Least developed countries 43-44%

Other low-income 91%

Lower middle-income 96-97%

Upper middle-income 100%

* Assuming health spending as % GNI increases by 1 percentage point over 5 years and by 2 percentage points over 10 years

Figure 9. DOTS-Plus resources needed at country level, 2006-2015, almost US $6 billion

| 111

| R e c o m m e n d a t i o n s

Chapter Seven

RecommendationsThese recommendations for successfully dealing with

the challenges of scaling up to address MDR-TB around

the world are targeted toward different groups of people,

including global policy making bodies, funding organiza-

tions, ministries of health, national tuberculosis programs,

research and academic institutions, nonprofit organiza-

tions and private agencies. We organized these recom-

mendations into five broad groups: (1) mobilize politi-

cal commitment at the highest levels (wake up); (2) take

programs to scale (scale up); (3) develop new and bet-

ter diagnostic tools, treatments, and vaccines (tool up);

(4) develop effective collaborations and coalitions (team

up); (5) and improve the quality of patient-centered care

(care). In compiling these recommendations, we have

interpreted and summarized suggestions from interviews

with those involved in the PARTNERS Project in Peru and

DOTS-Plus projects in other countries, as well as sugges-

tions made at the DOTS-Plus Working Group meeting

(Atlanta, May 2006).

Wake UpMobilize Political Commitment

at the Highest Levels

The threat of MDR-TB is very real; the world must

take notice of this threat. The alarming discovery of

XDR-TB has added urgency to this call. Without a mark-

edly increased commitment to solving this problem now,

it will soon become overwhelming and impossible to con-

trol without paying an extremely high price in terms of

human lives lost and resources spent to tackle it.

When tuberculosis was a major problem in indus-

trialized countries, there was great interest in tackling

it. However, after TB ceased to be a major public health

problem, interest waned. As a result, there have been no

new drugs developed in the last 50 years, few new diag-

nostic tests developed, and limited attempts made to

develop a better vaccine. Currently, TB is a major problem

only in resource-poor countries. However, with increased

globalization, it poses a threat to all countries, rich and

poor. While resource-rich countries may be able to treat

their current TB burden within existing programs, most

are ill equipped to handle the drug-resistant forms of

TB. The rise of MDR-TB and XDR-TB could become a

nightmare for all countries, partly because of high treat-

ment costs and partly because, with increased resistance,

available drugs may become unable to treat the disease.

Global leaders need to wake up to this threat and prevent

an impending disaster, rather than let the problem get

out of hand and then face spending billions on damage

control.

Scale UpTake Programs to Scale

Scaling up involves taking different program com-

ponents to more locations and to more people and mak-

ing sure that the necessary support to implement these

activities is in place. To reach the Global Plan targets, the

rate of scale up must increase dramatically.

“We tell him she is sleeping,

and we try to help him

not miss her as much,

but he remembers his mother.”

– Sister of Patricia, deceased MDR-TB patient


112 |

Program Components

Broad Surveillance

Increased, broader and better surveillance is nec-

essary in order to properly assess the magnitude of the

MDR-TB problem and monitor its course over time. The

Global Plan efforts to survey more parts of the world need

to be stepped up and more resources invested so that

surveillance can be expanded as soon as possible. Larger

sample sizes are needed in areas where surveys are con-

ducted. Current estimates of incidence are often based

on sub-national surveys that may not accurately reflect

the true burden throughout the country. Countries need

to prioritize this task and assist the Global Plan in this

effort. Newer survey approaches should be designed so

that new and previously treated patients can be accurately

counted.

Diagnostic Capacity

The capacity to rapidly diagnose MDR-TB is essential

so that resistant strains do not spread and build up in

the community. Programs need to invest resources in

setting up laboratories and training lab personnel. The

Supranational TB Reference Laboratory Network (SNRL)

must be expanded and strengthened so that more assis-

tance can be provided to National Reference Laboratories

(NRL). Each country developing its lab capacity should

first conduct a thorough needs assessment and then draft

a plan detailing how to proceed. A resource-poor country

should thoroughly explore the degree to which new tech-

nologies can be used and, where applicable, how to inte-

grate those technologies in various lab and field settings.

Guidelines on drug susceptibility testing for second-line

drugs and on the use of rapid diagnostic tests for screen-

ing must be developed. Consultants from the SNRL and

GLC should assist the countries in planning for expanded

lab capacity and in executing such plans. These consul-

tants must receive proper training so they can provide

appropriate technical assistance; proper curricula and

workshops should be designed for this purpose.

Treatment

Countries need to ensure that proper treatment regi-

mens are used within their national treatment programs

as well as by private practitioners. The decision to follow

individualized treatment regimens (ITR) or standardized

treatment regimens (STR) must be tailored to local needs

and local capacity, and proper training must be given

to health workers in each program. A complete course

of quality assured drugs needs to be available for each

patient and, whenever possible, ancillary drugs should be

procured to help manage patient side effects caused by

second-line drugs (SLD).

Drug Supply and Management

Many programs lack experience in forecasting and

managing drug inventories. Proper training and technical

assistance provided to programs should help address

this issue and should be a priority. Accurate estimates

of global drug demand could provide a strong incentive

for more manufacturers to produce second-line drugs.

Currently, a single source manufactures most of the SLDs

used; a problem with or interruption of the drug sup-

ply could be catastrophic for a program and its patients.

The availability of more manufacturers could help pro-

tect against such catastrophes and possibly reduce drug

prices through healthy competition.

Drug-supply lag time — the gap between when the

drugs are needed and when they are delivered — is a

major problem for some programs. Advance purchase

orders based on estimated needs can eliminate the lag

time. Delay is sometimes the result of a lack of coordina-

tion between recipients of GFATM grants and the pro-

curement agency contracted by the GLC. This could be

solved with direct payment from the GFATM to the drug

procurement agency. A buffer supply at the global level

It is easy to lose momentum when fighting

diseases that take a long time and concerted

effort to prevent and control. Leaders at both

global and country levels need to remain

committed, consistent, and focused. They

must realize that MDR and XDR-TB are no

longer the problems of just one country. These

diseases are not bound by political boundar-

ies. Unless all countries work together, it will

be difficult to address this global epidemic.

| 113


Chapter Seven

needs to be created to hedge against temporary short-

ages of drugs in any program.

WHO has established a prequalification project for

drug manufacturers to assure quality and help prevent

development of further resistance; however, by mid-2006

only one manufacturer had been approved. In the 2007-

2008 Response Plan, WHO commits to accelerating

prequalification and has recommended the Global Drug

Facility (GDF) create and manage a buffer stock of SLDs

for GLC-approved programs. More manufacturers must

be pre-qualified. WHO must determine how to assure the

quality of drugs when and if drug manufacturers, such

as those in China and India, start production of generic

second-line drugs.

Recording and Information Management

Accurate recording of and timely access to informa-

tion are essential. Electronic medical records (EMRs)

should be used wherever possible, to facilitate faster and

more reliable collection of data. This will require a good

information technology infrastructure to be in place and

trained personnel to support the system. The EMR sys-

tem developed and used in Peru has been successfully

adapted for use in the Philippines. Other countries can

customize this record system to suit their needs, rather

than reinvent the wheel. With the development of a

proper communications protocol, different EMR systems

can exchange data. Additionally, development of a stan-

dardized recording and reporting system based on an

international consensus process and instituted globally

would simplify collection and sharing of information and

dramatically improve communication. This will not be an

easy task but will be worth the effort.

Management

Effective management is essential for ensuring

increased surveillance, building diagnostic capacity, ensur-

ing drugs and supplies for programs, managing human

resources, and implementing good record and informa-

tion systems. Yet, this is one of the most neglected com-

ponents of public health programs. Each country needs

to establish training programs that teach management

skills to program leaders and heads of departments that

handle crucial program components, such as lab capac-

ity and drug management. The GLC needs to coordinate

the availability of consultants who can provide technical

assistance to these leaders and the Stop TB Partnership

must provide further training in management as and

when necessary. While the focus has been on delivering

complex health interventions in resource poor settings, it

is equally important to focus on delivering these complex

health interventions in management-poor settings. Public

health can learn a great deal about how to do a better job

at the business of public health from the business sector.

Supporting Activities

Leadership and Policy

It is easy to lose momentum when fighting diseases

that take a long time and concerted effort to prevent and

control. Leaders at both global and country levels need to

remain committed, consistent, and focused. They must

realize that MDR and XDR-TB are no longer the prob-

lems of just one country. These diseases are not bound by

political boundaries. Unless all countries work together, it

will be difficult to address this global epidemic.

Continued support and guidance from the GLC will

be especially important in this work. To date, the GLC

has been instrumental in reducing drug prices, provid-

ing technical assistance to DOTS-Plus pilot projects, and

monitoring the proper use of drugs in these projects. The

GLC has played a major role in developing guidelines on

managing drug-resistant TB. It has negotiated an agree-

ment with GFATM to fund projects that agree to GLC

oversight. From 2000 to 2005, the GLC has approved

12,805 MDR-TB patients for treatment; in 2006 alone it

has approved treatment for 9,000 patients. Now the GLC

must expand to handle the increasing number of applica-

tions. The GLC also needs to adjust the way it functions

so it can continue to be integral to MDR-TB control even

when programs procure SLDs outside its purchasing

mechanism.

Human Resources

A major increase in human resources is required.

Appropriately trained healthcare workers are needed to

handle the additional tasks required in treating MDR-TB.

The first step will be to identify the number and catego-

ries of staff needed. This should go hand-in-hand with

an analysis of current turnover and the reasons for loss

and retention of staff. Factors responsible for discourage-

ment or apathy in staff and the loss of healthcare workers

from programs should be addressed as possible. Workers

should have opportunities of career advancement, ben-

efits, and job security. Working conditions should be such


114 |

that workers feel their safety is properly addressed. The

role of the private sector in MDR-TB management should

also be analyzed.

While many workers receive training before they start

work, on-the-job training is also very important and must

be pursued aggressively. For this, proper training mod-

ules need to be created in different languages. Curricula

and evaluation procedures should be charted out clearly.

Advocacy and Resource Mobilization

The threat of MDR-TB must be communicated to

people around the globe to raise awareness about the

suffering it causes and the fact that it can be addressed,

even in resource-poor countries. Achieving the targets

in the Global Plan requires major increases in contribu-

tions from different sources. Funding organizations need

to understand the stakes involved and commit to fund-

ing and proper monitoring of funds. Programs in need

of funds have to become more inventive in generating

money for their activities. As previously explained, there

are not enough funds to achieve the targets of the second

Global Plan to Stop TB. To procure sufficient funds, a

major push is required for increased resource mobiliza-

tion, both within countries and internationally. Advocacy

efforts should be started in each country. These efforts

should be targeted to both domestic and external donors,

including non-traditional donors and the corporate sec-

tor. Further discussions should be undertaken with the

GFATM on its role in funding GLC services. It is also nec-

essary to highlight the threat of MDR and XDR-TB (par-

ticularly in conjunction with HIV) at international confer-

ences and meetings.

More financial resources — government, educational,

charitable, and private funds — will be needed. Current

budgeting will not accommodate the management of pre-

vention and treatment programs.

Tool UpDevelop New and Better Diagnostic Tools,

Treatments, and Vaccines

Increased support must be given by policy mak-

ers, funding organizations, and research institutions

to develop better, faster, and cheaper diagnostic tools;

newer drugs that cut down the treatment time, have fewer

side effects, and are cheaper; and new vaccines that will

prevent transmission of TB. New diagnostic tools are

needed to provide the fast, accurate results of the current

diagnostics but with the lower costs and ease of use of

older, slower tools. Current second-line drugs can treat

MDR-TB, but the long duration of treatment and the addi-

tional medications required to ease side effects of these

drugs create huge problems for program management.

Much of the expenses currently projected to achieve the

targets of the Global Plan could be avoided if newer drugs

with shorter duration of treatment are developed. Costs

can be further cut if vaccines are in place to prevent dis-

ease transmission. Potential cost-savings should be an

incentive for funding organizations to put more money

into research programs dedicated to finding better tools

for MDR-TB.

Team UpDevelop Effective Collaborations

and Coalitions

The mammoth task of scaling up cannot be achieved

without continued and strengthened collaboration

between different agencies and organizations at global,

national, and sub-national levels. The Stop TB Partnership

should help such collaborations avoid mistakes that can

result in a failed partnership. At the country level, different

communities and organizations need to collaborate as

they fight a common enemy.

Negotiating partnerships and collaborations can be

messy. There can be differences about who provides the

leadership, how the funding is allocated, how the respon-

sibilities are apportioned, and what kinds of evaluation

mechanisms are in place. Where possible, the pres-

ence of a neutral convening party to negotiate some of

these sticky situations can help. However, partnerships

can succeed without external help when there is a clear

and shared goal, mutual trust and open communication

between all parties concerned.

Clear communication and coordination will also be

needed between different levels of the NTP as the DOTS-

Plus programs are integrated with DOTS and as inte-

grated delivery of TB treatment is provided irrespective

of the form of TB the patient has. Similarly, cooperation

and communication will also be important between dif-

ferent components of the ministries of health as health

sector reform unfolds in many countries. WHO should

provide continuous assistance to countries during these

transitions.

| 115


Chapter Seven

CareImprove the Quality of Patient-Centered Care

Human Rights

While some people were arguing that it was not

cost-effective to treat MDR-TB patients in poor coun-

tries, PARTNERS and other DOTS-Plus projects began

with the idea of health as a fundamental human right. It

was incomprehensible to the pioneers of these projects

that some patients would be allowed to die just because

they could not afford treatment and that their local and

national governments lacked healthcare policies or fund-

ing to treat them. When policy and funding are discussed

and debated, the lives and deaths of poor people, unfortu-

nately, are often undervalued. These projects both made

the case that patients with MDR-TB (or with TB/HIV) have

the same human right to treatment as those with drug-

sensitive TB and that treatment was cost-effective. This

human right to equal access to care must be respected,

protected, and fulfilled.

Dealing with Stigma

The stigma of MDR-TB is very real and very disem-

powering. It cuts off patients from the community and

increases their suffering manifold. When people start

suffering from symptoms of TB, they need support and

caring the most. Yet, in cases of MDR-TB patients, it is

unfortunately at this very time, that they may be deserted

by health workers, employers, friends, and even their

families. NTPs need to recognize this and deal with it.

They should ensure that accurate information is provided

to health workers as well as the general population, so

that myths are dispelled, and unnecessary suffering

is avoided. It has been seen that stigma spreads sig-

nificantly from the behavior of health workers toward

MDR-TB patients. If health workers don’t show fear in

communicating with the patients that they treat, the

community sees this as a sign that they also have noth-

ing to fear. NTPs need to undertake programs targeted

toward making the health workers feel safe in dealing

with MDR-TB patients.

Patient Support

Treatment alone is not likely to succeed if it is not

accompanied by adequate patient support. Program

managers and staff need to provide respect and support

to patients with MDR-TB, who are often marginalized by

the stigma associated with the disease. Programs need

to assure adequate nutrition of patients who, owing to

the stigma of MDR-TB, often end up losing jobs that pro-

vided them daily subsistence. As a result, they may suffer

from malnutrition, which makes it much more difficult for

them to recover from the disease. Apart from nutritional

support, patients also need psychological support to deal

with the depression that may be a side-effect of some of

the second-line drugs. They also need to feel a part of a

community since they may be alienated from friends and

family who fear they will contract a deadly disease. Finally,

providing economic incentives such as bus passes helps

patients overcome common hurdles that prevent them

from seeking care at clinics that might be remote from

their homes.


116 |

We have learned a lot about MDR-TB. We have

learned that successfully controlling tuberculosis

requires addressing MDR-TB and TB/HIV as well as

drug-sensitive TB. Standardized treatment regimens (as

an alternative to individualized treatment regimens) can

work if they are based on data evaluating local patterns

of drug sensitivity/resistance, but that data must be

obtained, documented, and made available. We’ve dem-

onstrated that the human rights approach to TB control

does not necessarily conflict with the financial approach.

Most importantly, we have learned that MDR-TB can be

addressed successfully in developing countries.

The PARTNERS Project successfully brought

together different partners with different perceptions

and experiences; separately and together they devel-

oped and implemented approaches to treat and control

MDR-TB in resource-poor settings. Their work comple-

mented efforts of other DOTS-Plus projects, improving

the science of healthcare and advancing the mission of

caring for the public.

Afterword

The PARTNERS Project experiences significantly

advanced global TB knowledge and, we believe, will influ-

ence global objectives and strategy. Lessons learned from

these projects can be applied in the care of the estimated

1.4 million persons who will need treatment for MDR-TB

through 2015. These lessons are also applicable in dealing

with other complex health problems.

A substantial financial investment in fighting

MDR-TB has yielded substantial results and brought

about a sea change in attitudes toward addressing

MDR-TB

Now, a focus on action is needed. Existing tools

and knowledge are beneficial only when implemented.

We need to apply what we now know. While we can do

a lot with the tools we have, we will be able to do so

much more when we have better tools. Development

of new tools for prevention, diagnosis, and treatment is

essential.

| 117

| A b b r e v i a t i o n s U s e d

ARD Antiretroviral drugs

BWH Brigham and Women’s Hospital

CDC United States Centers for Disease Control and Prevention

CHW Community Health Worker

DISA District (in Peru)

DST Drug susceptibility testing

EMR Electronic medical record

FLD First-line drugs

FLDST First-line drug sensitivity testing

GDF Global Drug Facility

GLC Green Light Committee

HSR Health sector reform

HBC High burden countries

HIV Human immunodeficiency virus

HSR Health Sector Reform

INS Peruvian National Institute of Health

ITR Individualized treatment regimen

IUATLD International Union Against Tuberculosis and Lung Diseases

MDR-TB Multidrug-resistant tuberculosis

MINSA Ministry of Health, Peru

MIS Management information system

MSLI Massachusetts State Laboratory Institute

Abbreviations Used

NACP National AIDS Control Programme

NRL National TB Reference Laboratory

NRLM National Reference Laboratory for Mycobacteria

NTCP National Tuberculosis Control Program (Latvia)

NTP National Tuberculosis Control Program (Peru)

OSI Open Society Institute

PARTNERS Partnership Against Resistant Tuberculosis: a Network for Equity and Re-source Strengthening

PDA Personal digital assistant

PMDT Programmatic management of drug-resistant TB

PNCT Peruvian National TB Control Program

SLD Second-line drugs

SLDST Second-line drug sensitivity testing

SRL Supranational TB reference laboratory

STR Standardized treatment regimen

TAT Turn-around time

TB Tuberculosis

TFCSD The Task Force for Child Survival and

Development 1

WHO World Health Organization

XDR-TB Extensively drug-resistant tuberculosis

a In 2008, The Task Force for Child Survival and Development changed its name to The Task Force for Global Health.


118 |

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11 Chaisson RE, Benson CA. Tuberculosis and HIV infection. In Rossman MD, MacGregor RR, eds. Tuberculosis Clinical Management and New Challenges. New York; McGraw-Hill, Inc. 1995. pp 223-238.

12 United Nations Development Program. Human Development Report. 2005. New York, UNDP. p3.

13 Stop TB Partnership. Global Plan to Stop TB 2006-2015. 2006. Geneva, WHO. p45.

14 Shah NS. Extensively Drug-Resistant Tuberculosis (XDR TB): First Global Survey of Supranational Reference Laboratories for Mycobacterium tuberculosis with Resistance to Second-Line Drugs. Presentation at the MDR-TB Summit, PARTNERS Meeting for MDR-TB Control. Atlanta, Georgia, May 10-11, 2006.

15 Gandhi NR. XDR TB as Cause of Death in TB/HIV Coinfected Patients in Rural South Africa. Presentation at the MDR-TB Summit, PARTNERS Meeting for MDR-TB Control. Atlanta, Georgia, May 10-11, 2006.

16 Zignol M, Hosseini MS, Wright A, Weezenbeek CL, Nunn P, Watt CJ, Williams BG, Dye C. Global incidence of multidrug-resistant tuberculosis. J Infect Dis. 2006 Aug 15;194(4):479-85. Epub 2006 Jul 12.

17 Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG. Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis. 2002 Apr 15;185(8):1197-202. Epub 2002 Apr 1.

18 World Health Organization. Guidelines for establishing DOTS-Plus projects. 2000

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21 Furin JJ, Mitnick CD, Shin SS, Bayona J, Becerra MC, et al. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2001;5(7):648-55.

22 Griess and Bactec

23 Laserson KF, Thorpe LE, Leimane V, et al. Speaking the same language : treatment outcome definitions for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2005;9:640-645.

24 Stop TB Working Group on DOTS-Plus for MDR-TB. A prioritized research agenda for DOTS-Plus for multidrug-resistant tuberculosis (MDR-TB). Int J Tuberc Lung Dis. 2003;7:410-414

25 Saravia JC, Appleton SC, Rich ML, Sarria M, Bayona J, et al. Retreatment management strategies when first-line tuberculosis therapy fails. Int J Tuberc Lung Dis. 2005;9:421-429.

26 Furin JJ, Mitnick CD, Shin SS, Bayona J, Becerra MC, et al. Occurrence of serous adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2001;5:648-55.

27 Nathanson E, Gupta R, Huamani P, Leimane V, Pasechnikov AD, et al. Adverse events in the treatment of multidrug-resistant tuberculosis: results from the DOTS-Plus initiative. Int J Tuberc Lung Dis. 2004;8:1382-1384.

28 Chavez Pachas AM, Bland R, Smith Fawzi MC, Bayona J, Becerra MC, et al. Identifying early treatment failure on Category I therapy for pulmonary tuberculosis in Lima Ciudad, Peru. Int J Tuberc Lung Dis 2004;8:52-8.

29 Becerra MC, Freeman J, Bayona J, Shin SS, Kim JY, et al. Using treatment failure under effective directly observed short-course chemotherapy programs to identify patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2000;4:108-14.

30 Shin SS, Furin JJ, Alcántara F, Bayona J, Sánchez E, Mitnick CD. Long-term follow-up for multidrug-resistant tuberculosis. Emerg Inf Dis. 2006;12:687-688.

31 Timperi R, Han LL, Sloutsky A, Becerra MC, Nardell EA, et al. Drug resistance profiles of Mycobacterium tuberculosis isolates: five years’ experience and insight into treatment strategies for MDR-TB in Lima, Peru. Int J Tuberc Lung Dis 2005;9:175-80.

32 Mitnick C, Bayona J, Palacios E, Shin S, Furin J, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. NEJM. 2003;348:119-28.

33 Drobac PC, Mukherjee JS, Joseph JK, Mitnick C, Furin JJ, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics. 2006;117:2022-2029.

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35 Suarez PG, Floyd K, Portocarrero J, Alarcon E, Rapiti E, et al. Feasibility and cost-effectiveness of standardized second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002;359:1980-9.

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37 Medlars search on articles published 1990-2005 on MDR-TB, February 21, 2006.

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41 Anti-tuberculosis drug resistance surveillance – Third Global Report.

42 Abigail Wright presentation May 06 PARTNERS meeting: Global Surveillance of Anti-TB Drug Resistance.

43 Presentation: Anti-TB Drug Resistance Surveillance History, Coverage, Issues, Future. Joint Working Group meeting; HIV and drug resistance surveillance and testing. Versailles, France 16 Oct 2005.

44 Abigail Wright presentation May 06 PARTNERS meeting: Global Surveillance of Anti-TB Drug Resistance.

45 MDR-TB transmission: New data from the Airborne Infections Research (AIR) Facility, S. Africa Presentation by Ed Nardell at PARTNERS meeting in Atlanta, 2006.

46 Peter Cegielski presentation, “GLC History, Function, and Structure,” May 2006.

47 MSF. Difficulties in procurement of second-line anti-tuberculosis drugs: The experience of MSF in Abkhazia. 2005. available at http://www.msf.fr/documents/base/2005-10-20-MSF.pdf.

48 Eva Nathanson presentation, “GLC Business Plan,” May 2006.

49 Resource Mobilization and the Global Plan (MDR TB) – Presentation by Marcos Espinal at the PARTNERS meeting in Atlanta, 2006.

50 Presentation by Katherine Floyd at PARTNERS meeting in Atlanta, 2006.

51 Resource Mobilization and the Global Plan (MDR

TB) — Presentation by Marcos Espinal at the PARTNERS meeting in Atlanta, 2006.

52 Global Plan to Stop TB.

53 Presentation by Katherine Floyd at the PARTNERS meeting in Atlanta, 2006.

References (Continued)

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