1 Challenges in HIV Treatment and Care in a Resource Constrained Environnement Serge Paul Eholié...

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Challenges in HIV Treatment and Care in a Resource

Constrained Environnement

Serge Paul Eholié

Xavier Anglaret

Affiliation:•ANRS research site in Côte d’Ivoire•Infectious Disease Department, Treichville University Hospital, Abidjan•Inserm U897, ISPED, Bordeaux University

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INTRODUCTION• In 1998-2001, pilot programs gave evidence that ART could

be feasible and effective in resource limited settings: – UNAIDS Initiative (Uganda, Côte d’Ivoire, Chile, Vietnam)– Countries (Senegal) or NGOS (MSF) initiatives

• From 2000 to 2010, large programs confirmed that ART was feasible and effective in resource limited settings: – As of june 2010, approx 6.6 million people on ART in low- and

middle-income countries (4.5 millions in sub-Saharan Africa); – With success in Scaling program and decentralization, almost

19 000 health facilities implemented;– With extensive evidence that ART reduces morbidity and

mortality in routine conditions.

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Successes of ART in low and middle income settings

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SUCCESSES

However, challenges remain!!!!

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Challenges to ensure the successof ART programs in low- and middle-income countries

* Increase coverage

* Ensure financing sustainability

* Reduce AIDS and HIV non-AIDS morbidity, and mortality

* Implement 2010 WHO guidelines

* Improve assessment of programs efficacy

* Improve prevention, diagnosis, and management of adverse events

* Improve retention

* Ensure comprehensive HIV care

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CHALLENGE 1

Coverage

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Number of people receiving ART in december 2009

ART coverage in 2009, based on 2006 guidelines

ART coverage in 2009, based on 2010 guidelines

South Africa 971 556 56% 37%

Kenya 336 980 65% 48%

Nigeria 320 024 31% 21%

Zambia 283 863 85% 64%

Thailand 216 118 76% 67%

Uganda 200 413 57% 39%

Botswana 145 190 >95% 83%

Cameroon 76 228 41% 29%

Côte d’Ivoire 72 011 39% 28%

COVERAGE, December 2009: 36% in LMICIntraregional differences

Towards universal access: Scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010

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Challenge 2:Financing sustainability

80-95% of funds are from international donors

Achilles’ heel of ART programs

Source Hecht R, Lancet 2010Courtesy of PM Girard

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CHALLENGE 3

REDUCE MORBIDITY AND MORTALITY

ART Mortality

Countries

* Zambia, Stringer JSA, JAMA 2006

* Senegal, Etard JF, AIDS 2006

* Zimbabwe, Erisktrup C, JAIDS 2007

* Haiti, Tuboi H, JAIDS 2009

* Honduras, Tuboi H, JAIDS 2009

Mortality rate

7%

23.1%

29.5%

12.4%

10.1%

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Risk factors for mortality

• Male sex• Clinical stage, WHO 3-4, CDC C• Body Mass Index <18-19 Kg/m2

• Haemoglobin<10g/dl• CD4 <200 cells/mm3

• Viral load >5 log10 copies/ml

Stringer JF JAMA 2006, Etard JF AIDS 2006, Erisktrup C JAIDS 2007, Moh R AIDS 2007, Tuboi SH JAIDS 2009, Mills EJ AIDS 2011,

Toure AIDS 2008, Lawn AIDS 2009

12Severe P, N Engl J Med 2010

200-350 CD4/mL

< 200 CD4/mL

Mortality reduction 75%

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Challenge 3: REDUCE MORBIDITY AND MORTALITY

1) Certainly start ART earlier… but how much earlier ?

< 350 CD4 : minimal threshold worldwide1

< 500 CD4 : minimal threshold in increasing number of rich countries2,3

> 500 CD4 : ongoing randomized trials (START, Temprano4…)

2) Improve access to care, diagnosis and treatment of comon morbity (TB, bacterial diseases…)

1-WHO, Antiretroviral Therapy for HIV infections in adults and adolescents, Recommandations, 2010, h http://www.who.int ttp://www.who.int2- Prise en Charge Me´dicale des Personnes Infecte´es par le VIH Ministry of Health France, 2008. http://www.sante-sports.gouv.fr/3- Panel on Antiretroviral Guidelines for Adults, and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS, USA,20094- Temprano study ANRS 12 136, clinicaltrials.govNCT00495651

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Challenges 4

IMPLEMENT 2010 WHO GUIDELINES

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Main changes in WHO 2010 Guidelines

* Start earlier: CD4 < 350/mm3 or WHO stage 3,4

(vs. 200 CD4 or WHO stage 4 or WHO stage 3 & 200-350)

* First line regimen:

* Include viral load in routine monitoring

* Second line regimen:

WHO, Antiretroviral Therapy for HIV infections in adults and adolescents, Recommandations, 2010, h http://www.who.int ttp://www.who.int

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1) Start earlier: CD4 < 350/mm3 or WHO stage 3,4


* First line regimen:

* Include viral load in routine monitoring

* Second line regimen:


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ART at 350 CD4 vs. 200 CD4

Where to find patients at earlier stage of HIV disease ?

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• Find patients with higher CD4 counts??• Increase Voluntary Counseling and Testing (VCT)• Facilitate or strenghten the link between

VCT centers and ART clinics• Anticipate and face an increase in the number of

patients on ART• Demonstrate cost effectiveness/acceptability to

governments and donors

19Nash D, AIDS 2011

8 countries:3 Eastern Africa, 3 Southern Africa, 1 Western Africa,

1 Central Africa267 sites (ICAP centers)

121 404 patients

Median CD4136 cells/l

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• Find patients wiht higher CD4 counts– Change the paradigm – Target HIV negative patients

• Increase Voluntary Counseling and Testing (VCT)• Facilitate or strenghten the link between

VCT centers and ART clinics• Anticipate and face an increase in the number of patients on

ART• Demonstrate cost effectiveness/acceptability to governments

and donors

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• Find asymptomatic patients– Change the paradigm – Target HIV negative patients

• Increase Voluntary Counseling and Testing (VCT)• Facilitate or strenghten the link between



and donors

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Insufficient time

Consent process

Lack of knowledge/training

Language

Lack of patient acceptance

Pre-test counselling requirements

Competing priorities

Inadequate reimbursement

Prenatal

24 barriersOther medical

settings

23 barriers

Why don’t physicians test for HIV? A review of the US littérature. Burke RC, AIDS 2007

Much of the failure to expand HIV Testing guidelines are related to physicians

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Standard of Care and Intervention periods in a routine HIV Testing Cohort in an out patient department, Durban, SA

Standard of Care(14 weeks)

Intervention(12 weeks)

Patients tested/offered, N (%)

HIV-infected patients, N (%)

HIV infection identified,

average N per week

137/435 (31.5%)

102/137 (74.5%)

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1414/2912 (48.6%)

463/1414 (32.8%)

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Bassett IV, JAIDS 2007

We need a pro-active approach!!!!

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• Increase Voluntary Counseling and Testing (VCT)– HIV testing is general medicine (« it’s all HCW business »)– Make rapid tests available

• Facilitate or strenghten the link between



and donors

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• Increase Voluntary Counseling and Testing (VCT)– HIV testing is general medicine (« it’s all care workers business »)– Make rapid tests available


VCT centers, Ante Natal Clinic and ART clinics• Anticipate and face an increase in the number of patients on


and donors

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VCT centers and ART clinics• Anticipate and face an increase in the number of patients

on ART• Demonstrate cost effectiveness/acceptability to governments

and donors

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<200

% ELIGIBLE<250 (2008 criteria)

%ELIGIBLE<350

%ELIGIBLE

Age 15-24 25+

22.4%41.5%

25.9% (1,15 increase)51.1% (1,24 increase)


Sex Female Male

35.2%37.5%


57.2%(1,63 increase)55.0%(1,47 increase)

Overall 35.7% 43.7% (1,23 increase) 56.8% (1.59 increase)

Source: Konde-Lule J, AIDS Care 2010

< 350 vs <200 = 59% increase in demand of services

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Adjusted HR(95% CI)

p

Patient volume Low (reference) Medium High

-1.40 (1.03-1.92)

1.34 (0.95-1.89) 0.47

Clinical Staff Burden Low (reference) Medium High

-1.01 (0.78-1.32)

1.02 (0.69-1.52) 0.91

Pharmacy Staff Burden Low (reference) Medium High

-1.68 (1.29-2.19)

2.63 (1.70-4.06) < 0.001

Patients Volume, Human Resources Levels and Attrition from HIV Treatment Programs in Central Mozambique

Lambdin BH, JAIDS 2011

Staff burden : do not forget those who deliver the pills !(200-300 patients/day or more !!!!)

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VCT centers and ART clinics• Anticipate and face an increase in the number of patients

on ART– Set up or strenghten task shifting

• Demonstrate cost effectiveness/acceptability to governments and donors

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ART at 350 CD4 vs. 200 CD4• Find asymptomatic patients

– Change the paradigm – Target HIV negative patients




ART– Set up or strenghten task shifting

* Demonstrate benefits and cost effectiveness for acceptability by governments and donors

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CD4<200 CD4<350 Difference

P-Y of ART 40 752 534 61 292 374 + 20 539 839 (+ 50%)

* AIDS/ deaths

8 180 609 6 501 483 - 1 679 126 (- 21%)

* Life years

162 032 903 163 012 351 + 979 448 (+ 1%)

* New HIV infections

11 198 013 9 946 912 - 1 251 101 (- 11%)

Source: Stover J, AIDS Research and Treatment 2011

Benefits on morbidity, mortality and transmission

Cost effectiveness: Walensky R, Ann Intern Med 2009

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1) Start earlier : CD4 < 350/mm3 or WHO stage 3,4


2) First line regimen:* Include viral load in routine monitoring* Switch when VL>5,000 copies/ml (vs. >10,000 copies/ml in

2006 guidelines)* Second line

* Stop ABC+ DDI. * AZT/TDF+XTC+ATVr/LPVr

* Start as soon as possible in case of tuberculosis and HVB

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Challenges for first line regimen

* Costs

* Phase out d4T

* Choice between AZT and TDF- Haematological toxicity, LD (AZT)

- Renal safety, bone mineral toxicity (TDF)

* Choice between efavirenz and nevirapine- Percentage of young women, pregnancy (NVP)

- One pill, once a day, TB co-morbidity (EFV)

* Availabililty of fixed drug combination

* Paediatric formulation

Cost, efficacy, cost-effectiveness and tolerance issues

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Phase out stavudine : issues* Lingering stocks of d4T

- 30 countries have implemented d4T phase out plan (12/2009)

- 60% first line started with d4T (12/2009)

* Finance constraints – TDF or ZDV first line 2-3 times as high as d4T regimen

– … at a time when we still need to scale up the number of

people initiating ART

Need for :

- Further drug price reductions (AZT and TDF)

- Increase funds for ART programme

Renaud-Thery F, AIDS Res and treatment 2011

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Bendavid E, AIDS 2011

WHO MEETING REPORT. Short-Term Priorities for Antiretroviral Drug Optimization, London UK, 18-19 avril 2011.

Prevalence of Renal dysfunction in HIV-seropositive untreated patients in Sub saharan Africa

* Nigeria (n=400)

Emen CP, Nephrol Dial Transplant 2008

* South Africa (n= 1322)

Brennan A, AIDS 2011

* Zambia (n=24 596)

Mulenga BL, AIDS 2008

* Msango L (n=335)

AIDS 2011

38%

35.7%

33.7%

63.6%

36HIV is THE kidney killer (not tenofovir)

Incidence of severe renal dysfunction

DART (n=3316) eGFR < 30ml/mn* Median time to severe renal dysfunction14 weeks IQR [4-52]

* TDF 41/2469 (1.7%)

* NVP (Open-label) 4/247 (1.6%)

* ABC (Nora Study) 3/300 (1.0%)

* NVP (Nora Study) 4/300 (1.3%)

Reid A, Clin Infect Dis. 2008

P=0.94

* Zambia, 30/960 (3.2%), M12 (Chi BH, JAIDS 2010)

* Lesotho, 31/566 (5.5%), M12 (Bygrave H, Plos One 2011)

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Follow WHO guidelines for tenofovir prescription

* Creatinine dosage (creatinine clearance calculation)

* Proteinuria with urines sticks

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1) Start earlier : CD4 < 350/mm3 or WHO stage 3,4

2)°First line:

3) Include viral load in routine monitoring

* Second line


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Case for routine use of viral load

* Best tool to assess adherence

* Maintain first line therapy

* Earlier switch to second line limit NRTI and

NNRTI cumulative resistance;

* Cost effectiveness

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Status at 12 months of ART :

Messou E, JAIDS 2010

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M6N=996

M12N=925

Undectable VL 799 (80.2%) 693 (75%)

Detectable VL

Resistance ≥ 1 mutation

197 (19.8%)

7%

232 (25%)

11%

Messou E, JAIDS 2010

Interest of early viral load (M4-M6) Interventions to reinforce adherence, maintain first line

Half of patients with detectable viral load at 12 months have no resistance mutations

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NNRTI cumulative resistance; Keiser et al, AIDS 2011


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Relative increase in Life Expectancy (vs. only one line

of ART)

Incremental Cost

Effectiveness Ratio1

($ US/LYS)

Incremental Cost

Effectiveness Ratio2

($ US/LYS)

Switch to 2nd line on :

- WHO stage 3-4 event 24.3 1670 1670

- 50% in peak CD4 46.4 2120 Dominated

- HIV RNA*, 1 log or

return to pretreatment

HIV-RNA

61.3 2280 1990

Source: Kimmel AD,JAIDS 20101 HIV RNA Tests Cost 87 USD2 HIV RNA Tests Cost 25 USD

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Challenges for use of viral load in RLS

* Affordability (once again… costs…) :

- Advocacy (same as before with ARV drugs)

- Generics tests

* Availability in rural settings:

- Point of care

- Dried Blood Spot

- Power (electricity)

- Maintenance Rouet F and Rouzioux C, Expert Rev Mol Diagn 2007Calmy A, AIDS 2008

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1)Start earlier : CD4 < 350/mm3 or WHO stage 3,4

2) First line:

«3) Include viral load in routine monitoring

4) Second line

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Challenges for second line* Costs

* Time to switch to second line in patients failing 1st

line

* Effective NRTI backbone

* Place of drugs already ordered or used (ABC/ddI)

* Fixed Drug Combination or co-blister

* Availability of ritonavir heat stable capsule

* Use in TB co-infected patients

* Forecasting (Renaud-Thery F, AIDS Res and Treatment 2011)

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Regimen Low incomecountries

Middle IncomeCountries

d4T + 3TC + NVP $ 89 $ 88

AZT + 3TC + NVP $ 149 $ 226

AZT + 3TC + EFV $ 220 $ 281

TDF + 3TC + EFV $ 210 $ 268

TDF + FTC + EFV $ 255 $ 325

TDF + 3TC + NVP $ 190 $ 243

AZT + 3TC + LPV/r $ 585 $ 1150

TDF + 3TC + LPV/r $ 590 $ 1070

TDF/AZT + 3TC + ATV/r $ 395/465

ARV cost per patient per year

Sources: WHO/UNAIDS/UNICEF, Clinton Foundation Health Access Iinitiative, MSF

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76.5% LPV/r45% suboptimal NRTI regimen??

1.4% of adults receiving ART

Towards universal access: Scaling up priority HIV/AIDS interventions in the health sector Progress report 2010

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Challenges for second line* Costs

* Time to switch to second line in patients failing 1st

line Keiser et al, AIDS 2011


* Place of drugs already ordered or used (ABC/ddI)




* Forecasting (Renaud-Thery F, AIDS Res and Treatment 2011)

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Second line efficacy in LMIC* South Africa (n= 1648)*

46% failure > 6 months FU

Factors associated

* Cambodgia** (n=70, all LPV/r)

15% VL failure, FU 24 months

* Thailand (n=95)

2nd line based on genotype

test: VL failure

15% (M24), 10% (M36);

Pujades-rodriguez M,

Jama 2010

Low CD4 cells counts

Suboptimal regimen (NRTI +++)

Ferradini L, J Int Aids Soc 2011

May Myat W, J int Assoc Phys

Aids Care 2011

* MSF programs, ** ESTHER

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Challenges for second line* Time to switch to second line in patients failing 1st line

* Costs


* Place of ABC and ddI



* Paediatric formulation


* Forecasting

Renaud-Thery F, AIDS Res and Treatment 2011

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Challenge 5

Third line: Salvage Therapy in LMIC

1-5% or more??

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Challenges for Third Line

* Cost of darunavir, raltegravir, and etravirine

* Use of genotype test: necessary or essential?

* Assessment of real needs

* Pilot studies assessing : resistance patterns in patients

failing 2nd line, place of adherence reinforcement,

adherence efficacy and tolerance of third line drugs…

(ANRS third line trial in 5 west african countries)

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Comparaison of prices for ART regimen according to line of treatment

MSF, Antiretroviral Therapy price reductions, 13th edition, July 2010

X 7

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Challenges for Third Line

* Cost of darunavir, raltegravir, and etravirine

* Place of genotype test: necessary or essential?

* Set up pilot studies assessing resistance patterns

in patients failing 2nd line, place of adherence

reinforcement, efficacy and tolerance of third line

drugs… (ANRS third line trial in 5 West African

countries, 1 South East Asian country)

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Challenge 6

Long term issues :

• Improve monitoring• Ensure long term adherence• Prevent and take care of long-term toxicity• Diagnose and treat HIV non-AIDS morbidity

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ART laboratory monitoring (WHO 2010)

Phase of HIV Management

Recommended Test

Desirable Test

At HIV diagnosis CD4 HBs Ag, anti-HCV?Pre ART CD4

At start of ART CD4 Hb for AZT1

Creatinine clearance for TDF2

ALT for NVP3

On ART CD4Hb for AZT1

Creatinine clearance for TDF2

ALT for NVP3 At clinical failure CD4 Viral loadAt immunological failure Viral load

1 Recommended test in patients with high risk of adverse events associated with AZT (low CD4 or low BMI).

2 Recommended test in patients with high risk of adverse events associated with TDF (underlying renal disease, older age group, low BMI, diabetes, hypertension and concomitant use of a boosted PI or nephrotoxic drugs).

3 Recommended test in patients with high risk of adverse events associated with NVP ( ART naive HIV+ women with CD4 > 250 cells/mm3, HCV co-infection)

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Long term monitoring issues We need tests for :

• Metabolic syndrom…

• Renal function …

• Bone Mineral density …

• Cardio-vascular assessment …

• Malignancies diagnosis …

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Challenges for long term follow-up

• HIV and ageing: 3 millions HIV individuals >50 years in sub-Saharan Africa (14% of overall HIV adults)

• Access to treatment for: malignancies, cardiovascular diseases/neurological diseases, diabetis, dyslipidemia, renal insufficiency …

Mills EJ, Lancet Infect Dis 2010Negin J, JAIDS 2010Nakimuli-Mpungu E, Neurobehavioral HIV Medicine 2011

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Challenges 7

ENSURE COMPREHENSIVE HIV CARE

Percentage of household expendituresNon ARVs and non CD4 costs among patients receiving ART

Cameroun1 Côte d’Ivoire2

Health expenditures

Medical visits and others

Transportation

20 USD/month

44%

12%

24.3 USD/month

50%

25%

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1- Boyer S, Bull WHO 2010

2- Beaulière A, PLoS ONE 2010

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Challenges 8

IMPROVE RETENTION

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Towards universal access: Scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010

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* Serious barriers

- Transport costs

- Time needed for treatment

- Logistical challenges

* Less influencal factors

- Stigma around HIV/AIDS

- Side effects

Patients’ perception

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1) Set up and maintain simple standardized monitoring systems

2) Reliably ascertain true treatments outcomes

3) Reduce death rates

4) Ensure uninterrupted drugs supplies

5) Use simple, non toxic and free ART-regimens

6) Decentralized ART clinics and reduce frequency of visits

7) Reduce indirect patients costs

8) Strenghten ART-links within and between health services and the community

9) Use ART-services to deliver other useful interventions

10) Innovative (tining out of the box intervention)

Harries AD, Trop Med Intern Health 2010

Challenge 9: Human resources

* Motivation: Increase salary

* Struggle the brain draining of health care workers to national

or international NGOs (disparities)

* Cure an emerging disease, « the perdiemitis »

(Ridde V, Trop Med Int Health 2010)

* Set up the task shifting

(monitoring ART: nurses vs doctor, 1.09 (95% CI 0.89–1.33)

(Sanne I, CIPRA Study-South Africa, Lancet 2010)

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Challenges 10

Earthquake (Haiti)Floads

Dryness and Food crisis (eg; East Africa)Socio-political crisis (Eg:Côte d’Ivoire)

Out-of-controlHumanitarian crisis

Jeopardize 10-15 years of successes! !

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http://www.lemonde.fr/idees/article/2011/04/05/l-attention-aux-malades-du-sida-barometrede-l-humanite_1502634_3232.html

“Justice must prevail against those who exploit patients as political weapons and thereby undermine years of human rights progress. Much has been said and written about the need to treat as war crimes all failures to protect civilians during conflict. Obstructing access to needed medical care should rank high among these.”

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Conclusion

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« A perpetual challenge will be living up with the commitment and courage of those who went before- health care workers, scientists, and affected persons- who faced the unknown and took risks. In general 30 years of AIDS confirm that there is indeed « more to admire in men than to despise »

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Courtesy of S Matheron

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Acknowledgements* E Bissagnéné

* A Calmy

* JF Delfraissy

* DK Ekouevi

* PM Girard

* C Kouanfack

* PS Sow

* M Vitoria

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Grazie Merci

ChoukranThank you

Obrigado

Mo

Dieureudieuf Djaraman

Asanti

I ni tché

M"pussda barka

Bondodi

AkpéNgiyabonga

Mo Pi Wo

Amesegnalehu

Gracias

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