Which tools to monitor HIV

treatment in resource-limited

settings?

Pierre-Marie Girard

Hôpital St Antoine

Institut de Médecine et d’Epidémiologie Appliquée,

Fondation Internationale Léon Mba

Paris, France

« ARV therapy in sub saharan Africa : • Complicated combination regimens• Expensive and dangerous• Severe side effects• Rapid development of drug resistance in the

community»

Lancet, 2002

There is no excuse for There is no excuse for delay !!!!delay !!!!

IAS Conference, Paris,2003IAS Conference, Paris,2003

Where are we ?

• Anti retroviral therapy has become a reality in

developing countries

• With SUCCESS, CONSTRAINTS, LIMITATIONS,

and MANY HOT QUESTIONS FOR THE FUTURE

• We have moved from « proof of concept » to

« public health approach »

• Is Universal therapy » for HIV patients (WHO)

in 2010 a realistic target ?

Figure

2008 Report on the global AIDS epidemic

Selected events related to the treatment of AIDS

2000 2005 2006 2010

Accelerating Access Initiative launched by UN/industry partnership

3 million people on treatment in developing countries

UN General Assembly Political Declaration on Universal Access to Prevention, Treatment care and support

1996

Introduction of HAART

World Bank MAP II includes ART in developing countries

G8 Declaration for Universal Access to treatment

First Global Fund Grants awarded for treatment

20032002

WHO launches 3 x 5 initiative

Universal Universal AccessAccessTargetsTargets

MillenniumMillenniumDevelopmentDevelopment

GoalsGoals

Midway toMillennium Development Goals

UN General Assembly Special Session on HIV/AIDS June 2001/189 Member States signed the Declaration of Commitment

2001 2008 2015

5.1

Comparison of 2005 and 2007 percentage coverage of antiretroviral therapy for people with advanced HIV and

percentage coverage of antiretroviral drugs for HIV positive pregnant w omen by

region

7.2 Source: UNAIDS/UNICEF/WHO.

GLOBALEasternEuropeand

Central Asia

Latin Americaand the

Caribbean

North Africaand the

Middle East

East, South and

South-East Asia

Sub-SaharanAfrica

0

20

40

60

80

100

Per

cent

(%

)�

2005 2007 2005 2007

Antiretroviral Therapy Prevention of Mother to Child Transmission

Figure

2008 Report on the global AIDS epidemic

Total annual resources available for AIDS 1986–2007

[i] 1996-2005 data: Extracted from 2006 Report on the Global AIDS Epidemic (UNAIDS, 2006); [ii] 1986-1993 data: Mann.&. Tarantola, 1996

Notes: [1] 1986-2000 figures are for international funds only; [2] Domestic funds are included from 2001 onwards

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

US

$ m

illio

n

2921623

8.3 billion

Signing of Declaration of Commitment on HIV/AIDS,

UNGASS

1996 1997 1998 19992000 20012002 2003 2004 200519861987 1990 19911992 1993

Less than US$ 1 million

59 212

World BankMAP

launch

Global Fund

PEPFAR

257

UNAIDS

Gates Foundation

2006 2007

10 000 8.9 billion

10 billion

7.1 Source: UNAIDS & WHO unpublished estimates, 2007

Huge international fundings are

critical

but are not enough…

Critical Actions to improve access and success of ARV programs

• Diagnose HIV infection at much larger scale• Better utilization of scarce human resources• Make available the best drugs (not only the

cheaper ones)• Extend access to Lab facilities• In the meantime, revisit and adapt to local

settings the monitoring of therapy• Monitor (population level) the positive impact or

ARVs and their risks• Ensure durability of the programs.

Critical Actions to improve access and success of ARV programs

• Diagnose HIV infection at much larger scale• Better utilization of scarce human resources• Make available the best drugs (not only the

cheaper ones)• Extend access to Lab facilities• Meantime revisit and adapt to local settings

the monitoring of therapy• Monitor (population level) the positive impact or

ARVs and their risks• Ensure durability of the programs.

Diagnose HIV infection at much larger scale

• Performance and availability of tests are no more an issue

• Issue N°1: POLICY of HIV tests proposal• We must get out of the « HIV exceptionalism »

(Ron Bayer) • We must do it with respect of ethics,

confidentiality, and incorporating preventionissues.

• No testing without free clinical and biologicalevaluation of HIV stage and screening of comorbidities

Projection for HIV care visits in Western Kenya, Cohen et al, AIDS, 2004

Critical Actions to improve access and success of ARV programs

• Diagnose HIV infection at much larger scale• Better utilization of scarce human resources• Make available the best drugs (not only the

cheaper ones)• Extend access to Lab facilities• Meantime revisit and adapt to local settings the

monitoring of therapy• Monitor (population level) the positive impact or

ARVs and their risks• Ensure durability of the programs.

Lyell syndrome : Triomune® D8

Eholié S, Abidjan

Eholié S, Abidjan

Lipodystrophy : Triomune® M12

t

Egger, 2007

Treatment change(any change, including switching,

substitution)

Months after starting ART

0 6 12 18 24

% w

ithtr

eatm

entc

hang

e

0

20

40

60

Switzerland

South Africa

CROI 2007 – response – 26

Switch

Switch

Consider Switch

ConsiderSwitch

Immunologic and Virologic Failure

(CD4 and VL available)

Immunologic Failure(VL not available)

Clinical Failure(CD4 and VL not available)

SwitchConsider Switch3

SwitchSwitch

4

Do Not SwitchN/A2

Do Not SwitchN/A1

WHO Clinical Staging

When to Switch from 1st Line to 2nd Line ARV Regimens for Treatment Failure

Clinical failure is defined as a occurrence of new or recurrent WHO clinical stage 3 or 4 event (excluding IRIS).

CD4 failure is defined as a fall to (or below) the pre-treatment baseline or a 50% drop from the on-treatment peak level or persistent levels < 100 cells/mm3.

Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy.

Plasma HIV-1 RNA level >10,000 copies/ml e

Virologicalfailure

•Fall of CD4 count to pre-therapy baseline (or below) or•50% fall from the on-treatment peak value (if known) or•Persistent CD4 levels < 100 cells/mm3 d

CD4 cell failure c

Occurrence of new or recurrent WHO stage 3 or 4 condition a b

Clinical failure

Clinical, CD4 Cell Count, and Virological Definitions of Treatment Failure for Patients on a First-Line Antiretroviral Regimen for at Least Six Months

Immunological Failure

CD4

Mo 6 Month12

100

Drop > 50 %

Back to baseline

Stay < 100

Messou E, Bull WHO 2008

Messou E, Bull WHO 2008

Second Line ARV in adults and children

96% 99%

4% 1%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Adults Pediatric

% p

atie

nts

Renaud-Théry F, AIDS 2007

Extend access to Lab facilities

• Plasma Viral load measurements are the gold standard for assessing Antiretroviral activity.

• Its value assessed in 90’s firstly as a predictor of HIV clinical course then for early ARV failures

• Sensitivity has improved step-by-step starting from a threshold at 10 000 copies/ml to 40 copies/ml currently.

• Reproducibility is good.• Simplification of techniques less impressive than sensitivity

increase.• Access for PATIENT INDIVIDUAL MONITORING remains

exceptional in most Developing countries settings.

Cumulative proportion of patients needing 2nd Line ARV

Switch to 2d Line: mean 3% per year

5%6%

9%

12%

16%

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

2006 2007 2008 2009 2010

Renaud-Théry F, AIDS 2007

Low performance of WHO criteria for the diagnosis of virological failure

Performance of WHO criteria for Viral failure, Niger ia, « PEPFAR »

40%(34-46)

76%570-82°

59% (48-69)

59%(55-64)

CD4 down 50% from peak value

(n = 219)

42%

537-46°

81%

(74-87)

75%

(66-82)

50%

(46-54)

CD4 < 100 cells/mm3

(n = 233)

59%

(52-65)

64%

(48-78)

80%

(29-48)

39%

(29-48)

CD4 < pre-therapyCD4 (n = 86)

Negativepredictive

value (95% CI)

Positive predictive

value (95% CI)

Specificity(95% CI)

Sensitivity(95% CI)

CD4 criteria(WHO, 2006)

Etiebet MA et al, 16th CROI, 2009

Prices and regimen change in USD

3 000

2 250

Low income Lower Middle income

1 500

750

9191

3 750

132132469469

11391139554554

36203620

X13 X13

X27 X27

D4T/3TC/NVP – 1st line

TDF/FTC/EFV – substitute ABC/ddI/LPVr – 2nd line

Source: WHO HIV Département, AIDS Medicines & Diagno stics Service, Global Price Reporting Mechanism, 2008

WHO criteria for « virological failure »:poor performance

• Cohort in South Africa :

Sensitivity Specificitypositive

predictivevalue

CD4 21,2 % 95,8 % 36,8 %

ClinicalCriteria 15,2 % 88,1 % 12,8 %

P. Mee et al AIDS 2008,22 17-77

Resistance Profile in Malawi in patients

experiencing 1st line regimen failure

• M184V or M184I 81%• NNRTI mutations 93%

– Median 2 (range 0-3)– 181C 55%, 190A 30%, 103N 28%

• Wild Type Virus 5%• M184 alone 0%• NNRTI mutations alone 2%• M184V & NNRTI mutations alone 16%

M Hosseinipour et al, Mexico 2008

Resistance Profile in Malawi in patients

experiencing 1st line regimen failure

NNRTI mutations +/-184V containing virus + additional mutations

TAM Containing Virus 56%

Tenofovir mutations (K65R or K70E) 23%

Tenofovir & TAM 7%

Q151M Complex 19%

Pan-Nucleoside Mutation Combinations

Q151M Complex & Tenofovir mutations 16%

69 insertion 1%

Pan-Nucleoside

(Q151 & TDF associated mutations or 69 insertion)

17%

M Hosseinipour et al , Mexico 2008

Resistance Profile in Thailand in patients

experiencing 1st line regimen failure

• 98 patients in Thailand failing 1st line ARV (stavudine, lamivudine, nevirapine)

• Median duration of HAART : 20 months• 92% pts > 1 NNRTI associated mutation • 95% pts > 1 NRTI associated mutation:

– M184V: 89%– TAMs: 37% – K65R: 6%– Q151M: 8%

Sungkanuparph S, et al, Clin Inf Dis, 2007

Resistance profile at M12 & M24 ARV in patients with VL >1000 copies/mL , Yaound é, Cameroun,

ESTHERM12

n=249M24

n=178

Viral load > 1000 copies/ml 41(16.4%) 40 (22.5%)

PCR amplification of samples with VL>1000 copies/ml

34/41 38/40

Presence of at least one major drug resistancemutation in amplified samples

11/34 30/38

Genotypic resistance to

– 3TC/FTC only– NVP/EFA only– 3TC/FTC + NVP/EFA– 3TC/FTC + AZT/D4T + NVP/EFA– 3TC/FTC + AZT/D4T + NVP/EFA+ABC+TDF)– 3TC/FTC + AZT/D4T + NVP/EFA+DDI+(ABC/TDF)– 3TC/FTC+ AZT/D4T– 3TC/FTC+AZT/D4T+ IDV

117110

00

0320401

11

DART Trial in Central and East Africa

In failing patients from DART Trial:Prevalence of Thymidine

Analogues Mutations (TAMs) increased from

4 % at Month 12 to 39 % at Month 24

DART study group

Impact of « not-switching » on survival

Risk of death Switching pts vs no Switching = 3.3 [1.6-6.8] Ive P et al, CROI, 2009

AND

The Lancet, Early Online Publication26 November 2008

How can we do better ?

• Have operational centres of reference (country, regions)

• Make biological tools available outside reference centers

– DBS approach

• Antigens quantifications ? • New molecular techniques (semi quantitative) ?

• Assess surrogate markers for virological failure

Any Other Options ?

• CD4 count:– Dynabeats method: Immuoflorescence, good correlation

with FacsCount but not so cheap, and poorly acceptedby technicinas

– Microfluid device for CD4 counting– Portable device for CD4 counting – Total Lymphocyte (only for indication of HAART)

• HIV viral load– The SAMBA project (MRC/MSF)

SAMBA Project

• Semi-quantitative viral load test:– Early diagnosis in newborns– Monitoring of HAART: indication for switching to 2nd line

therapy

• Principles:– Sample preparation– Amplification of DNA (using a small car-battery-

operated heating block about the size of a credit card)– Detection of amplified DNA (via a dipstick)

Closed system

SAMBA Project

Test characteristics:

1. Can detect <1000 virus particles/ml blood 2. Will provide a semi-quantitative or a qualitative resultin < 2 hrs3. Has simple visual readout4.~$6-8/test5.Robust6.Will detect all HIV1 subtypes7.No external water, cold chain or expensive machines need8. No accurate pipetting or centrifugation steps; can be

done by minimally trained staff

PLOS Editorial Comments

Systematic review of 13 publications

Objectives of ARV therapy Programs

• Reducing morbidity and mortality• Curbing the HIV epidemic• Maintaining economic stability• Achieving distributive justice

Am. J Public Am. J Public HealthHealth, 2005, 7, 1117, 2005, 7, 1117--11221122

Proposal for a New Program based Strategy

• Immediate planning of First and Second Line ARV drug supply

• Program Evaluation: principles of Mass therapy• Simple schemes for community level HIV

treatment• A plan for adherence monitoring• ARV therapy deliverers as primary care

deliverers

Am. J Public Am. J Public HealthHealth, 2005, 7, 1117, 2005, 7, 1117--11221122

HIV GFATM (R 1 – 8): Funds available

Total WCAR: US$ 1.7 BillionSource: GFATM �

Benin 42.4

Burkina Faso 48.2

Central African Republic 50.5

Côte d’Ivoire 4.3

Cameroon 22.1

Congo Dem. Rep. 359.3

Congo 32

Cape Verde 12.6

Gabon 21.9

Ghana 147.7

Guinea 24.2

Gambia The 48.1

Guinea-Bissau 43.1

Equatorial Guinea 5.3

Liberia 100.9

Mali 179.3

Mauritania 12.9

Niger 32.4

Nigeria 295.4

Senegal 19.3

Sierra Leone 28.7

Sao Tome and Principe 0.8

Chad 90

Togo 113.5

US$ mill ion US$ mill ion US$ mill ion US$ mill ion

Less than 30

30 - 60

60 - 120

More than 120

Note: The boundaries and the names shown and the designations used on these maps do not imply official endorsement or acceptance by the United Nations.

$1,734,813,655$646,565,408$2,381,379,063WCAR

$113,477,136 $36,783,867 $150,261,003 Togo (2,4,8)

$28,726,643 $15,576,275 $44,302,918 Sierra Leone (R4,6)

$19,315,563 $21,503,185 $40,818,748 Senegal (R1,6)

$761,824 $645,628 $1,407,452 Sao Tome and Principe (R5)

$295,368,508 $91,278,915 $386,647,423 Nigeria (R1,5,8)

$32,449,207 $14,733,061 $47,182,268 Niger (R3,7)

$12,868,844 $6,184,934 $19,053,778 Mauritania (5,8)

$179,336,394 $35,298,749 $214,635,143 Mali (R4,8)

$100,851,547 $18,671,704 $119,523,251 Liberia (R2,6,8)

$43,076,489 $3,325,547 $46,402,036 Guinea-Bissau (R4,7)

$24,192,710 $5,877,738 $30,070,448 Guinea (R2,6)

$147,738,493 $63,389,207 $211,127,700 Ghana (R1,5,8)

$48,055,967 $13,397,229 $61,453,196 Gambia R3,8)

$21,921,892 $6,890,482 $28,812,374 Gabon (R3,8)

$5,269,881 $4,554,955 $9,824,836 Equatorial Guinea (R4)

$4,307,760 $46,884,732 $51,192,492 Côte d'Ivoire (R2,3,5)

$359,290,475 $88,670,284 $447,960,759 DRC (R3,7,8)

$32,002,024 $10,586,465 $42,588,489 Congo (R5)

$90,022,154 $8,815,312 $98,837,466 Chad (R3,8)

$50,541,040 $33,397,822 $83,938,862 Central African Republic (R2,4,7)

$12,578,727 $12,578,727 Cape Verde(R8)

$22,069,480 $61,440,887 $83,510,367 Cameroon (R3,4,5)

$48,229,771 $28,626,376 $76,856,147 Burkina Faso (R2,6)

$42,361,126 $30,032,054 $72,393,180 Benin (R2,5)

All Rounds included BalanceTotal Funds DisbursedTotal Lifetime Budget

Source GFATM

Which strategy ?

ClinicalApproach(ie CD4 count, pVL)

WHO « public healthapproach

A mixed model that needs:New simple, cheap, easy-to-do, techniquesRevisiting our standard for monitoring

Much more commitment of all partners in this operationalresearch

Acknowledgements:To my colleagues at the IMEA & Hôpital St Antoine in Paris,

and, in West Africa,With special thanks

today and daily to Karine Lacombe, Paris, and Serge

Eholié, Abidjan

Françoise in Fann Hospital, Dakar, 2008

Thank you………………