MDR – TB

Jaime C. Montoya MD, MSc

Definitions of MDRTB and XDRTB

Historical background of the problem

Global and Philippine Data on MDRTB

Risk Factors

Diagnosis

Treatment

Research Gaps

Guidelines for the programmatic management of drug-resistant tuberculosis, WHO, 2006, 2008, 2011 update

Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015, WHO Progress Report 2011

Management of MDRTB: A Field Guide, WHO and Partners in Health, 2009

Multidrug-resistant tuberculosis (MDRTB) indicators, WHO, 2010

Discussions and recommendations apply only to MDR-TB

Findings may not be generalizeable to all populations in settings with high or low prevalences of drug resistance or different levels of resources

Problems, however, in resource poor settings considered

Results represent best available evidence to date for recommendations

Multidrug resistant tuberculosis (MDRTB)

- TB caused by strains of Mycobacterium tuberculosis that are resistant to at least isoniazid and rifampicin

Extensively drug resistant tuberculosis (XDRTB)

- MDRTB plus resistance to a fluoroquinolone and at least one second line injectable agent: amikacin, kanamycin and/or capreomycin

In 2006, first reports of XDR-TB (Extensively Drug Resistant TB)

Within the same year, cases of TB resistant to all first line and second line drugs reported in Italy (Extremely Drug Resistant TB or XXDRTB?)

In 2009, cohort of 15 patients in Iran resistant to all anti-TB drugs reported (Totally Drug Resistant TB or TDRTB?)

In 2009, the Beijing Call for Action and the passage of World Health Assembly Resolution 62.15 signaled a major step forward in coordinated planning for the treatment and control of MDRTB and commitment to achieve universal access to diagnosis and treatment by 2015

• Mainstream PMDT to NTP – With implementing guidelines for PMDT

implementation – DOH AO 2008-0018 “Guidelines for the Implementation of PMDT”

– With the development of 2010–2016 Philippine Plan of Action to Control TB (PhilPACT) The vision is a TB-free Philippines. - # 5 strategy:Address MDR-5. TB, TB/HIV, and needs of vulnerable populations

– Training for different health staff involved in the management of DR/MDR cases (TOT, TC/STC/

TS, Volunteers)

In the Philippines……

Stop TB department of WHO convened technical consultation in Geneva March 2012 back to back with expert group meeting

Objectives included overview of current information on XDRTB with additional drug resistance and feasibility and implications of new definitions

A new definition or category beyond XDRTB not recommended given technical difficulties of DST

Insufficient evidence for linking DST results to treatment outcomes of patients

Lack of standardised DST methods for several anti-TB drugs including investigational drugs

DST for drugs used to define MDR and XDRTB are standardised, accurate and reproducible

All injectables and fluoroquinolones should routinely be tested in specimens from confirmed MDRTB to screen for XDRTB

DST for all other drugs remains problematic for technical reasons

Countries not advised to invest resources for developing capacity for DST of new drugs

Need for research to develop standardized DST methods

Estimated % of New TB cases with MDR – TB

Estimated % of Retreatment TB cases with MDR – TB

Global 3.4 20

Western Pacific Region (WPR)

4.9 23

High MDR – TB Burden Countries

3.8 21

Philippines 4.0 21

Estimated Proportion of TB Cases that Have MDR - TB

Global tuberculosis control: WHO report 2011

As of January 2012, a total of:

12 regions are engaged in PMDT

18 PMDT treatment centers (12 public and 6 private facilities)

13 PMDT Satellite treatment centers (12 public facilities and 1 private facility)

Total of 2, 303 patients currently ongoing Category IV Treatment

2003 2008 2009 2010 2011

NCR Reg. 7 Reg. 10 CAR CARAGA

Reg. 11 Reg. 6

Reg. 1 Reg. 9

Reg. 5 Reg. 12

Reg. 4A 1) NCR

2) Reg. 7

7) Reg. 4A

6) Reg. 5

9) Reg. 6

11) Reg. 12

10) Reg. 9

3) Reg. 10

4) Reg. 11

5) Reg. 1

8) CAR

15) CARAGA

• Regions to be engaged in 2012 – 2013: • Reg. 2 • Reg. 3 • Reg. 4B • Reg. 8 • ARMM

Region Treatment Center Satellite Treatment Center NCR KASAKA – QI

LCP – PHDU DJNRMH PTSI – Tayuman San Lazaro Hospital

Lagrosa HC Gat Andres MMH Tondo foreshore Moonwalk Super Batasan Grace Park Lacson HC

7 Eversley Child’s Vicente Sotto MC 1 ITRMC Region 1 MC

4A DLSHSI and Batangas Reg. Hosp

Cainta PPMD, Gumaca and Laguna

5 SMMGHHSC BMC 10 German Doctors ISI PPMD 11 SPMC DRH 6 WVMC and DPOTMH Roxas CHO 9 ZCMC Dr. Jose Rizal Mem Hosp

12 Koronadal CHO CAR BGHMC

CARAGA CARAGA Reg. Hosp. OVERALL 18 TCs 13 (4 incomingSTC)

PMDT Indicators 2009 2010 2011 TOTAL

No. of lab confirmed MDR-TB cases detected

Target 1535 2490 3083 7108

Actual

No. of MDR-TB cases enrolled for treatment among those detected

Target 844 1494 1,002 4342

Actual 538 566 2516* 3620

(83.4%)

Interim Outcome

Target 70% 70% 70% 70%

Actual 73% 74%

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

New patients 7 15 86 56 22 99 191 134 313 514 538 566 2516

Cumulative 7 22 108 164 186 285 476 610 923 1437 1975 2541 5057

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

New patients Cumulative

Patient enrolment under Category IV treatment from 1999 to 2011

• An additional 6,981 MDR – TB cases is targeted to be treated under Category IV teatment from 2012 to 2014 • A total of about 15,000 MDR – TB cases is targeted to be treated by 2016 (PhilPACT)

Start of RCC

Cure rate = 48.5%

Success rate = 64%

Cure rate = 38.31%

Success rate = 53.64%

Medium Risk

Migrant worker

Health worker with new TB

Treatment after relapse or default

High Risk

Household contact of known MDRTB patient with new TB

Probable treatment failure

History of treatment with second-line drugs

Mediated exclusively by chromosomal mutations

Affect either the drug itself or bacterial enzymes that activate prodrugs

Well identified in INH and Rifampicin

Local studies being done using spoligotyping and VNTR to identify the common mutations in Philippine isolates

Rapid diagnostic tests

- tests providing diagnosis within two days

of specimen testing

- include test using molecular techniques

(line probe assay and Xpert MDR/RIF)

Rapid DST of isoniazid and rifampicin or rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB subject (very low quality of evidence)

Best strategy for averting deaths and preventing acquired MDR-TB

Most cost-effective strategy for any patient group or setting, even at very low levels of resistance among TB patients

For previously untreated patients, DST at start of treatment was a better strategy than waiting to test only those patients who remained sputum smear-positive later in the course of their first line treatment

High value placed on prevention of death , transmission of MDR-TB as a result of delayed diagnosis and lowered costs to TB control program

Sputum smear microscopy and culture rather than sputum smear microscopy alone recommended for the monitoring of patients with MDR-TB during treatment (very low quality of evidence)

Limit of detection:

smear 10,000 bacilli/ml

culture 10 – 100 bacilli/ml

Concomitant use of sputum smear and culture helps identify patients whose bacteriology remains positive or reverts to positive following initial conversion to negative –

“fall and rise phenomenon”

In the treatment of patients with MDR-TB:

A fluoroquinolone (FQ) should be used (SR)

A later gen FQ rather than earlier gen FQ should be used (SR)

Ethionamide (or prothionamide) should be used (SR)

In the treatment of patients with MDR-TB:

Four second-line anti-TB drugs likely to be effective (including a parenteral agent) as well as PZA should be included in the intensive phase (CR)

Should include at least PZA, a FQ, a parenteral agent, ethionamide (or prothionamide) and either cycloserine or PAS if cycloserine cannot be used (CR)

Recommendations based on three major systematic reviews

Meta-analysis included 32 studies with more than 900 treatment episodes

No superior second line parenteral agent

However, due to lower cost, kanamycin preferred

Use of streptomycin not recommended

Ciprofloxacin, even if with some anti-TB activity should not be used

Cure rates among bacteriostatic drugs:

Ethionamide>cycloserine>PAS

For Group 5 drugs, no significant association with cure due to confounders so not included in recommended standard MDR-TB regimen

In the treatment of patients with MDR-TB:

Intensive phase of at least 8 months duration is recommended (CR)

A total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (CR)

In the treatment of patients with MDR-TB:

Intensive phase of at least 8 months duration is recommended (CR)

A total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (CR)

Patients with MDR-TB should be treated using mainly ambulatory care rather than models of care based principally on hospitalization (CR)

Benefit of reduced transmission can only be expected if proper infection control measures are in place

Persistent or new weight loss

Persistent or new TB symptoms (fever, cough)

Persistently positive sputum smears or culture

Smear or culture positive after being negative for sometime

Lack of high quality evidence from RCT for optimizing treatment regimens in patients with MDR-TB including the best combination of drugs and treatment duration

Lack of evidence for the best drug regimens for treating patients with MDRTB, with XDR-TB and others

Very limited information about treatment of pediatric MDR-TB

Identification of most effective chemoprophylaxis for contacts of MDR-TB cases

Therapy for symptomatic relief from adverse reactions linked to second-line anti-TB drugs

Dr. Rosalyn Vianzon, NTP, DOH

Dr. Celine Garfin, NTP, DOH

Dr. Vivian Lofranco, Lung Center and NTP, DOH

Dr. Charles Yu, DLSU

Dr. Toro Mori, Research Institute of TB, Japan

Dr. Yoshiro Murase, Research Institute of TB, Japan

Dr. Akihiro Ohkado, Research Institute of TB, Japan

So here we are…quite frankly and free

So tell Pasteur and Koch

and whoever they may be

That they have not seen the last

of my comrades and me