Historique accès ARV Génériques Recommandations OMS Discussions Cours IMEA/Fournier 19/11/2006Dr Roland Landman

Access to ARV in developing countries: pieces of History (1) 1981: First AIDS cases reported 1984: HIV discovery 1987: AZT licensed 1990: 80 % reduction of MTC transmission with AZT during pregnancy + labor (IV) + 6-week newborn regimen 1992: Superiority of Double Therapy vs Monotherapy 1996: First HAART regimen (triple therapy including protase inhibitor) : Major impact of HAART on AIDS morbidity & mortality

Access to ARV in developing countries: pieces of History (2) 1993: Thailand starts producing AZT generics without publicizing 1996: First mobilization for drug access to developing countries. Gay community claims for ARV in Brazil. 1997: African AIDS conference (Abidjan), « Patients are in South, Drugs are in North » 1998: « Bridging the Gap » (International AIDS Conf, Geneva) 1998: Brazil starts producing generics 1998: Sénégal launches National Access to Antiretrovirals; WHO creates with 5 companies the « Access program » with cut prices. 1999: Activists and NGO claim access to ARV at WTO meeting (Seattle)

Access to ARV in developing countries: pieces of History (3) 1999: Activists and NGO claim access to ARV at WTO meeting (Seattle). GSK cuts AZT prices for MTC prevention. 2000: G8 commits to facilitate ARV access to developing countries : Major decrease of drug prices Brazil offers to sell generics (« mandatory license ») Cipla (India) offers triple therapy for $ 600/year instead of $ 600/month Accelerated Initiaitive Access (UNAIDS) 2001: Pretoria trails: 39 Drug Companies withdraw prosecution against developing countries govt 2001: UN launches « Global Fund against AIDS, malaria & TB » 2003: US pdt announces $ 15 billions against AIDS, malaria, TB

TB/MALARIA/HIV Global Fund

Why we want to introduce ARV in developing countries : a biosocial analysis (P. Farmer, 2002) VBecause they are effective and will reduce suffering, mortality, HIV transmission ? VBecause the transnational « outcome gap » is growing VBecause HIV prevention may be re-enforced by attending to each of the above VBecause they are demanded by those most affected by HIV

Reasons to treat AIDS in Africa (1) Important component of a strategy to support people living with HIV and AIDS as well as preventing transmission of infection People may be more willing to undergo voluntary counselling and testing People may be more willing to disclose their HIV status if there is a possibility of getting effective treatment

Reasons to treat AIDS in Africa (2) By reducing viral load, ARVs might also reduce the risk of sexual transmission Sick people will be able to return to work. Parents will stay alive longer, thus delaying the time when children become orphans The rate of mother-to-child-transmission will be reduced

POPULATION OBJECTIVES OF ARV DRUG THERAPY PROGRAMS Objective 1: Maintaining Economic Stability Objective 2: Achieving Distributive Justice Objective 3: Curbing the HIV Epidemic Objective 4: Reducing Morbidity and Mortality Desvarieux et al. July 2005, Vol 95, No. 7 | American Journal of Public Health

Basic minimum package for HIV in endemic settings Agressive AIDS prevention programmes, including barrier methods Social assistance to HIV-affected families, including orphans Maternal-child transmission package (including milk supplements) Diagnosis, treatment and prevention of opportunistic infections and sexually transmitted diseases Post-exposure prophylaxis for rape and professional accidents HAART

Five key-elements for antiretroviral policy package Harries AD et al Lancet 358, August Government commitment 2-Case detection through passive case finding 3-Standardized antiretroviral regimens 4-Establishment of a regular drug supply 5-Establishment and maintenance of a monitoring system

Aim: scaling up Integration with the national tuberculosis control programme Package of care -Voluntary conselling and testing -Psychological support -Palliative care -Home based care -Essential drugs for the treatment and prevention of opportunistic infections and STD -Nutritional support Government commitment

ARV in developing countries: main issues Comprehensive programme re-enforcing prevention & VCT MTCT prevention programme Define eligibility criteria in the context of limited ressources Ensure drug supplying and quality control Define monitoring criteria: tolerance/efficacy

Estimated Number of HIV Infected Adults in Brazil in the Year 2000 Word Bank Projection (1992) Brazilian MOH Estimate (2000) Thousands 1,200, ,000 MOH, %

Historique accès ARV Génériques Recommandations OMS Discussions

Historique accès ARV Génériques Recommandations OMS Discussions

years 4 8 HIV RNA / ml Immune responses against HIV Ab, HIV killer cellsCD4 anti-VIH HAART HAART limitations: lack of immune restoration against HIV HIV rebound when stopping HAART Total CD4 Stop HIV RNA

Presenting diagnoses in 200 patients with HIV disease, clinique Bon Sauveur (Haïti),

GGrading of recommendations and levels of evidence Strength of recommendation, Level of evidence to make for recommendation A. A Recommended - should be followed B. B Consider - applicable in most situations C. C Optional I. I At least one randomized controlled trial with clinical, laboratory or programmatic endpoints II. II At least one high quality study or several adequate studies with clinical, laboratory or programmatic endpoints III. III Observational cohort data, one or more case controlled or analytic studies adequately conducted ExIV Expert opinion based on evaluation of other evidence

Table 2 WHO classification of HIV-associated clinical disease a Classification of HIV-associated clinical disease WHO Clinical Stage Asymptomatic 1 Mild 2 Advanced 3 Severe 4 a Annexes 1 and 2 provides further details on staging events and criteria for recognising them

Table 3 CD4 criteria for initiation of ART in Adults and Adolescents CD4 (cell /mm3) a Treatment recommendation b < 200 Treat irrespective of clinical stage c [A-III] Consider treatment [B-III] and initiate ART before drop below 200 cell/mm3 c [A-III] >350 Defer treatment in asymptomatic persons [A-III] a CD4 cell count should be measured after stabilization of any intercurrent condition b CD4 cell count supplement clinical assessment and should therefore be used in combination with clinical staging in decision making c A drop of CD4 cell count below 200 cells/mm 3 is associated with a significant increase of opportunistic infections and death

Table 4 Recommendations for initiating ART in adults and adolescents based on clinical stage and availability of immunological markers WHO Clinical Staging CD4 testing not available CD4 testing available 1Do not treat [A-III] Treat if CD4 cell count < 200/mm3 a [A-III] 2Do not treat c [B-III] 3Treat [A-III] Treat irrespective of CD4 cell count, with consideration of CD4< 350/mm3 in some situations b [A-III] 4Treat [A-III] Treat irrespective of CD4 cell count [A-III] a The precise CD4 cell level above 200/mm 3 at which ARV treatment should be started has not been established. b CD4 cell count advisable to assist with determining need for immediate therapy for situations as pulmonary TB and severe bacterial infections, which may occur at any CD4 level. c A total lymphocyte count of 1200/mm 3 can be substituted for the CD4 count when the latter is unavailable and mild HIV disease exist. It is not useful in the asymptomatic patients. Thus, in the absence of CD4 cell count and TLC, patients with WHO Adult Clinical Stage 2 should not be treated.

Table 8 Clinical, CD4 Cell Count, and Virological Definitions of Treatment Failure for Patients on a First-Line Antiretroviral Regimen for at Least Six Months Clinical failureOccurrence of new or recurrent WHO stage 3 or 4 condition a b CD4 cell failure c · 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/mm 3 d Virological failurePlasma HIV-1 RNA level >10,000 copies/ml e a. This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS) b. Pulmonary TB and some types of extra pulmonary TB (simple glandular TB or pleural effusion) should not be automatically considered treatment failure unless there are other clinical signs of HIV disease progression. (See section 11) c. Without concomitant infection to cause transient CD4 cell decrease d. Certain experts consider that patients with persistent CD4 cell count <50/mm 3 after 12 months on ART may be more appropriate e. The optimal viral load value at which ART should be switched has not been defined. However, the value of more than 10,000 copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline

WHO Stage 1WHO Stage 2WHO Stage 3WHO Stage 4 CD4 failure b (Viral load testing not available) Do not switch regimen. Follow patient for development of clinical signs or symptoms. Repeat CD4 in 3 months. Do not switch regimen. Follow patient for evidence of further clinical progression. Repeat CD4 in 3 months. Consider switch a to second- line regimen. Recommend switch a to second- line regimen. CD4 failure b and viral load failure c Consider switch to second-line regimen. Switch to second- line regimen. a Switching from first- to second-line regimen for treatment failure should not be done until the first regimen has been given sufficient time to succeed. This should be a minimum 6 month period. With only one second-line regimen available in most circumstances, premature switching should be avoided. b 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/mm 3 c Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy.

ABC or AZT± 3TC # TDF or ddI EFV or NVP NRTI sparing option if simplified triple NRTI approach were used in 1 st line Standard 2 nd line option if NRTI/NNRTI approach were used in 1st line PI/r*

First Line Regimen Second Line Regimen RTI ComponentPI Component b Standard Strategy AZT or d4T + 3TC a + NVP or EFV ddI + ABC or TDF + ABC or TDF + AZT ± 3TC c PI/r d TDF + 3TC a + NVP or EFV ddI + ABC or ddI + AZT ± 3TC c ABC + 3TC a + NVP or EFV ddI + AZT ± 3TC c or TDF + AZT ± 3TC c Alternative Strategy AZT or d4T + 3TC a + TDF or ABC EFV or NVP ± ddI or EFV or NVP ± 3TC c

CD4 Cell Count ART recommendations Timing of ART in relation the start of TB treatment CD4 200 mm 3 Recommend ART a Between 2-8 weeks b CD4 between /mm 3 Recommend ARTAfter 8 weeks CD4 350 mm 3 Delay ART c Re-evaluate patient at 8 weeks and at the end of TB treatment CD4 not availableRecommend ART d Between 2-8 weeks a EFV containing regimen is the preferred first line regimen. Alternative first line treatment regimens to the EFV include NVP, TDF or ABC containing regimens. For NVP containing regimens ALT should be checked at 4, 8 and 12 weeks and symptom directed thereafter b Start ART as soon as TB treatment is tolerated (between 2 and 8 weeks) c If other non-TB Stage 3 or 4 events are present, start ART earlier. d For some TB diagnoses (i.e. Lymph node TB, uncomplicated pleural effusion) consider delaying ART Initiating first line ART in relationship to starting anti-TB therapy

Table 14 ART Recommendations for patients who develop TB within 6 months of starting a first or second line ART regimen First or second line ART ART regimen at the time TB occurs Options First line EFV + 2 NRTIs Continue NVP + 2NRTIs · Switch to EFV a, c or · Continue with NVP+ 2NRTI b or · Switch to triple NRTIs a Triple NRTIs Continue Second linePI + 2NRTI s Switch to or continue( if already being taken) LPV/r or SQV containing regimen and adjust dose of RTV a b, a. Switching back to the original regimens once rifampicin containing regimen is completed can be considered. When switching back from EFZ to NVP no lead-in dose is required b. Careful clinical and laboratory monitoring (liver enzymes) should be ensured where NVP or boosted PIs are administered concurrently with rifampicin c. Switch to EFV-containing regimens is not recommended in women of child bearing potential, if adequate contraception cannot be ensured, and during the first trimester of pregnancy

Table 15 Recommended baseline clinical and laboratory assessments Clinical assessment at baseline · Clinical staging of HIV disease · Determination of concomitant medical conditions (e.g., HBV, HCV, TB, pregnancy, major psychiatric illness) · Concomitant medications (including traditional & herbal medicines) · Weight · Assessment of patient readiness for therapy Laboratory assessment at baseline · Confirmation of HIV infection status · Measurement of CD4, where available · Pregnancy test in women if initiation of EFV is being considered · Screening for TB and malaria (and diagnostic testing where clinically indicated), and for other major treatable HIV co-infections and AIDS-related opportunistic diseases as clinically indicated

Diagnosis and monitoring laboratory tests Pre ART* (at entry into care) At initiation of 1 st or 2 nd line ARV regimen Every 6 months As required (symptom directed) HIV diagnostic testing -- Haemoglobin a - WBC and differential b - - CD4 cell count c Pregnancy testing d -- Full chemistry (including, but not restricted to, ALT e, other liver enzymes, renal function, glucose, lipids, amylase, lipase, and serum electrolytes) f --- HIV-RNA (viral load) measurement g ---

WHO STAGING SYSTEM FOR HIV INFECTION AND DISEASE IN ADULTS AND ADOLESCENTS Clinical stage I 1. Asymptomatic 2. Persistent generalized lymphadenopathy Performance scale 1: asymptomatic, normal activity

Clinical stage II 3. Weight loss, <10% of body weight 4. Minor mucocutaneous manifestations (seborrheic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis) 5. Herpes zoster within the last five years 6. Recurrent upper respiratory tract infections (i.e. bacterial sinusitis) And/or performance scale 2: symptomatic, normal activity

Clinical stage III 7. Weight loss, >10% of body weight 8. Unexplained chronic diarrhoea, >1 month 9. Unexplained prolonged fever (intermittent or consant), >1 month 10. Oral candidiasis (thrush) 11. Oral hairy leukoplakia 12. Pulmonary tuberculosis within the past year 13. Severe bacterial infections (i.e. pneumonia, pyomyositis) And/or performance scale 3: bedridden <50% of the day during the last month

Clinical stage IV (1) 14. HIV wasting syndrome, as defined by the Centers for Disease Control and Prevention 15. Pneumocystis carinii pneumonia 16. Toxoplasmosis of the brain 17. Cryptosporidiosis with diarrhoea >1 month 18. Cryptococcosis, extrapulmonary 19. Cytomegalovirus disease of an organ other than liver, spleen or lymph nodes 20. Herpes simplex virus infection, mucocutaneous >1 month, or visceral any duration 21. Progressive multifocal leukoencephalopathy

22. Any disseminated endemic mycosis (i.e. histoplasmosis, coccidioidomycosis) 23. Candidiasis of the oesophagus, trachea, bronchi or lungs 24. Atypical mycobacteriosis, disseminated 25. Non-typhoid Salmonella septicaemia 26. Extrapulmonary tuberculosis 27. Lymphoma 28. Kaposis sarcoma 29. HIV encephalopathy, as defined by the Centers for Disease Control and Prevention.b And/or performance scale 4: bedridden >50% of the day during the last month Clinical stage IV (2)