historique accès arv génériques recommandations oms discussions cours imea/fournier 19/11/2006dr...

•Historique accès ARV

•Génériques

•Recommandations OMS

•Discussions

Cours IMEA/Fournier 19/11/2006 Dr 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)• 1997-1998: Major impact of HAART on AIDS morbidity & mortality



• 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)



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 2000-2001: 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)

Why we want to introduce ARV in developing countries : a biosocial analysis (P. Farmer, 2002)

Because they are effective and will reduce suffering, mortality, HIV transmission ?

Because the transnational « outcome gap » is growing

Because HIV prevention may be re-enforced by attending to each of the above

Because they are demanded by those most affected by HIV

Reasons to treat AIDS in Africa (1)Reasons to treat AIDS in Africa (1)Reasons to treat AIDS in Africa (1)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)Reasons to treat AIDS in Africa (2)Reasons to treat AIDS in Africa (2)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 settingsBasic minimum package for HIV in endemic settingsBasic minimum package for HIV in endemic settingsBasic 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 Five key-elements for antiretroviral policy packagepackage

Five key-elements for antiretroviral policy Five key-elements for antiretroviral policy packagepackage

Harries AD et al Lancet 358, August 2001

1-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 commitmentGovernment commitment

ARV in developing countries: main issuesARV 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)

0

200

400

600

800

1000

1200

1400

Thousands

1,200,000

600,000

MOH, 2002

50%

Historique accès ARV GénériquesRecommandations OMSDiscussions

years4 8

HIV

RN

A /

ml

Imm

un

e re

spo

nse

s ag

ain

st H

IV

Ab, HIV killer cells CD4 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 Presenting diagnoses in 200 patients with HIV disease, clinique Bon Sauveur (Haïti), 1993-95Sauveur (Haïti), 1993-95

Presenting diagnoses in 200 patients with HIV disease, clinique Bon Presenting diagnoses in 200 patients with HIV disease, clinique Bon Sauveur (Haïti), 1993-95Sauveur (Haïti), 1993-95

Tuberculosis

Chronic enteropathies

Partner with HIV or STD

Screening during

pregnancyP. carinii

pneumonia

Herpes zoster

Loeffler's syndrome

Slim disease

Bacterial pneumonia

G Grading of recommendations and levels of evidenceStrength 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

Ex IV 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) aTreatment recommendation b

< 200

Treat irrespective of clinical stage c [A-III]

200 - 350

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 conditionb CD4 cell count supplement clinical assessment and should therefore be used in combination with clinical staging in decision makingc A drop of CD4 cell count below 200 cells/mm3 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]

3 Treat [A-III]Treat irrespective of CD4 cell count, with consideration of CD4< 350/mm3 in some

situations b [A-III]

4 Treat [A-III]Treat irrespective of CD4 cell count

[A-III]

a The precise CD4 cell level above 200/mm3 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/mm3 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 failure Occurrence 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/mm3 d

Virological failure Plasma 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 decreased. Certain experts consider that patients with persistent CD4 cell count <50/mm3 after 12 months on

ART may be more appropriatee. 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 1 WHO Stage 2 WHO Stage 3 WHO Stage 4

CD4 failureb

(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/mm3

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 1st line

Standard 2nd line option if NRTI/NNRTI approach were used in 1st line

PI/r*

First Line Regimen

Second Line Regimen

RTI Component PI Component b

Standard Strategy

AZT or d4T + 3TC a + NVP or EFV

ddI + ABC orTDF + ABC orTDF + AZT ± 3TC c

PI/r d

TDF + 3TC a + NVP or EFV

ddI + ABC orddI + AZT ± 3TC c

ABC + 3TC a+ NVP or EFV

ddI + AZT ± 3TC c orTDF + AZT ± 3TC c

Alternative StrategyAZT or d4T + 3TC a + TDF or ABC

EFV or NVP ± ddI or EFV or NVP ± 3TC c

CD4 Cell Count ART recommendationsTiming of ART in

relation the start of TB treatment

CD4 200 mm3 Recommend ART a Between 2-8 weeks b

CD4 between 200-350/mm3 Recommend ART After 8 weeks

CD4 350 mm3 Delay ART c

Re-evaluate patient at 8 weeks and at the end of

TB treatment

CD4 not available Recommend 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 thereafterb 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 line PI + 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 rifampicinc. 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 1st or 2nd 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 FORHIV INFECTION AND DISEASE IN

ADULTS AND ADOLESCENTS

WHO STAGING SYSTEM FORHIV 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. Kaposi’s 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)

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