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Quand faut-il débuter les antirétroviraux au cours d’une tuberculose ? F.Xavier BLANC, M.D., Ph.D. CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre. xavier.blanc@bct.aphp.fr.

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Présentation au sujet: "Quand faut-il débuter les antirétroviraux au cours d’une tuberculose ? F.Xavier BLANC, M.D., Ph.D. CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre. xavier.blanc@bct.aphp.fr."— Transcription de la présentation:

1 Quand faut-il débuter les antirétroviraux au cours d’une tuberculose ? F.Xavier BLANC, M.D., Ph.D. CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre. Rencontres Nord-Sud IMEA / IRD 25 novembre 2008, Palais de l’UNESCO, Paris.

2 HAART AND TB TREATMENT MANAGT
High pill burden, overlapping drug toxicities, IRIS / PR, adherence challenge… Strategy trials needed+++. Three strategy questions in adult patients: Which HAART regimen? High pill burden Overlapping drug toxicities IRIS When to start HAART? How to (better) diagnose/manage IRIS?

3 HAART AND TB TREATMENT MANAGT
High pill burden, overlapping drug toxicities, IRIS / PR, adherence challenge… Strategy trials needed+++. Three strategy questions in adult patients: Which HAART regimen? High pill burden Overlapping drug toxicities IRIS When to start HAART? How to (better) diagnose/manage IRIS?

4 TB: QUAND DÉBUTER LES ARV ?
ÉTAT DES LIEUX : quelles recommandations ? GRANDES ÉTUDES EN COURS

5 QUELLES RECOMMANDATIONS ?
ÉTAT DES LIEUX : QUELLES RECOMMANDATIONS ? CD4 > 350/mm3 200 < CD4 ≤ 350/mm3 CD4 ≤ 200/mm3

6 TB and HIV: Immediate vs. Delayed HAART
Arguments for delaying potent HIV therapy until TB is treated: 1. HIV is a chronic disease. 2. Adherence may be compromised. 3. Toxicity management is more complex. 4. Immune restoration may produce “paradoxical reactions.” Pozniak A. May 2003

7 TB and HIV: Immediate vs. Delayed HAART
Arguments for initiating potent HIV therapy at the onset of TB: 1. TB is associated with immune activation, increased HIV replication, and HIV disease progression. 2. Potent antiretroviral therapy can reduce HIV RNA levels, improve immune function and slow HIV disease progression. 3. HIV therapy reduces risk of developing other opportunistic infections Pozniak A. May 2003

8 « Even among patients who have low CD4 cell counts, we recommend that antiretroviral (ARV) therapy be delayed until the first 2 months of TB therapy has been completed ».

9 Don’t Wait till it’s too late Further AIDS
Dean et al.: AIDS 2002 Observational study ( ) 27/188 TB/HIV patients developed further AIDS On HAART =3 Not on HAART= 24 median CD4 in this group was 70 cells 90% had median CD4 < months post TB 16 died; only 4 on HAART (3 short term) Dean et al AIDS 2001 Pozniak A. May 2003

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15 BHIVA February 2005 TB treatment must be given urgently.
The urgency of HIV treatment depends on predictors of HIV disease progression especially the CD4 cell count. <100 cells/mm HAART ASAP (some delay up to 2 mo) cells/mm3 - HAART after 2 months >200 cells/mm HAART after TB treatment finished

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18 NIH / CDC / HIVMA / IDSA June 2008
<100 cells/mm HAART after 2 weeks cells/mm3 - HAART after 2 months cells/mm3 - HAART during anti-TB maintenance phase >350 cells/mm HAART after TB treatment finished

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20 DHHS / OARAC November 2008 <100 cells/mm3 - HAART after 2 weeks
cells/mm3 - HAART after 8 weeks (on case-by-case basis) >350 cells/mm HAART after 8 to 24 weeks or after end of TB treatment

21 Special Issues Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents November 2008 AETC NRC Slide Set

22 HIV and Active TB: Sequencing Treatment
Patients on ART: evaluate ARV regimen for interactions with TB drugs; may need dosage adjustments Patients not on ART: Promptly initiate TB treatment Optimal timing of ART initiation is not known; consider individual factors Consider delay of ART for 2-8 weeks to avoid overlapping adverse reactions and reduce risk of IRIS In patients with CD4 counts of <200 cells/µL, earlier ART initiation may reduce risk of HIV complications November 2008 Questions de recherches : VIH et tuberculoseAETC National Resource Center,

23 GRANDES ÉTUDES EN COURS

24 Août 2007

25 POUR EN SAVOIR PLUS…

26 SAPIT Blanc FX et al., JID 2007

27 PART STUDY Delaying HIV disease progression with punctuated antiretroviral therapy in HIV-associated TB: NCT , Uganda. Designed to determine whether 6 months of anti-HIV drugs given along with TB treatment will delay the onset of AIDS in HIV-infected African patients with CD4 > 350. Primary outcomes: CD4+ decline (slope), time to AIDS. Initial HAART vs. delay HAART until CD4 drop below 250. AZT + 3TC + abacavir Started in October 2004. Target n=350. More info: Christopher C. Whalen,

28 TB-HAART STUDY AZT + 3TC + efavirenz
An evaluation of the impact of early initiation of HAART on TB treatment outcomes for TB patients coinfected with HIV: ISRCTN , Uganda, Zambia, South Africa and Tanzania. 220 < CD4 < 500. Study hypothesis: early concomitant treatment with TB and HIV medications may improve TB outcomes and improve survival. Primary outcome: proportion of subjects reaching the composite endpoint of treatment failure or death at 6 months after the initiation of short-course chemotherapy for TB. Combined HAART with anti-TB vs. delay HAART at 6 months. Started in March 2007. Target n=1900. Date of completion: 2011. AZT + 3TC + efavirenz More info: Philip Onyebujoh,

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30 TB MENINGITIS STUDY Immediate vs. deferred antiretroviral therapy for HIV-associated tuberculous meningitis: NCT Vietnam. Clinical diagnosis of TB meningitis. No CD4 restriction criteria. ART initiated immediately vs. deferred 2 months after initiation of TB treatment. Primary outcome: mortality at 9 months. Secondary endpoints: mortality at 12 months; fever clearance time; coma clearance time; neurological relapse; progression to new or recurrent AIDS defining illness; any grade 3 or 4 adverse event; CD4 count response; plasma HIV-1 RNA response; neurological disability. Started in September 2005. Target n=253. Date of completion: Dec. 08 AZT + 3TC + efavirenz More info: Estee Torok,

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32 MEXICAN STUDY Simultaneous vs. sequential antiretroviral therapy and M. tuberculosis treatment: NCT Mexique. Active pulmonary TB (with or without extrapulm. involvment). CD4 < 200. ART initiated immediately vs. deferred 2 months after initiation of TB treatment. Primary outcome: signs/symptoms of active TB + mycobacterial load in body fluids or affected tissues. Secondary endpoints: CD4 count response; HIV plasma load; HIV genotype; lymphoproliferative response to Mtb specific Ag. Emtricitabine/Tenofovir disoproxil fumarate + efavirenz Started in March 2008. Target n=160. Date of completion: March 2011 More info: Gustavo Reyes-Teran,

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34 AACTG A5221 STUDY A strategy study of immediate versus deferred initiation of antiretroviral therapy for HIV-infected persons treated for TB with CD4 less than 200 cells/mm3: NCT , 8 countries. CD4 < 200; AFB-positive not mandatory. ART initiated within 2 weeks after initiating TB treatment vs. ART deferred until 8 to 12 weeks after initiation of TB treatment. Primary outcome: proportion of participants who have survived without AIDS progression by Week 48. Emtricitabine/Tenofovir disoproxil fumarate + efavirenz Started in September 2006. Target n=800. Estimated completion date: July 2013 More info: Diane V. Havlir,

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36 Etude CAMELIA Quand débuter les ARV chez les patients TB avec CD4 < 200/mm3 ? ANRS NIH/CIPRA KH001- DAIDS-ESID Investigateurs coordonnateurs : Sok Thim, A.Goldfeld, F.X. Blanc

37 CAMELIA In CAMbodia, Early vs. Late Introduction of Antiretroviral therapy in naive HIV-infected adult patients with newly diagnosed tuberculosis (TB). Essai clinique financé par l’ANRS (étude 1295) et le NIH américain via le programme CIPRA (grant 1 U01 AI , CIPRA KH 001). Collaboration entre plusieurs partenaires : ANRS / NIH-CIPRA / Institut Pasteur du Cambodge / Cambodian Health Committee / Médecins Sans Frontières Belgique / NCHADS / CENAT / ESTHER / OFCP.

38 Contexte de l’étude TB/VIH au Cambodge
Cambodge : un des 22 pays où l’incidence de la TB est la + élevée (506 pour habitants/an) 1 prévalence de l’infection VIH : l’une des + élevées d’Asie du Sud-Est (1,6% [0,9-2,6%] chez les ans) 2 24% des patients nouvellement diagnostiqués VIH+ chez qui l’on recherche la TB sont TB+ 3 1. Global TB control WHO report 2007 2. UNAIDS report on the global AIDS epidemic 2006 3. MMWR 2005: 54(46);

39 QUESTION POSÉE PAR L’ÉTUDE
Quel est le meilleur moment pour débuter les anti-rétroviraux (ARV) chez les patients adultes naïfs sévèrement immunodéprimés chez qui l’on vient de commencer un traitement anti-TB ? OBJECTIF PRINCIPAL Comparer la survie des patients à la fin de l’étude (50 semaines après l’inclusion du dernier patient) selon les 2 bras attribués par randomisation : introduction précoce des ARV (14 jours) vs. introduction différée des ARV (2 mois). Patients naïfs inclus si BAAR+ et CD4 < 200.

40 Objectifs secondaires de l’étude
Comparer le taux de survie à 1 an entre les 2 bras ; Évaluer la tolérance de l’introduction précoce des ARV : effets secondaires, réactions paradoxales ou IRIS ; Comparer la survenue d’infections opportunistes entre les 2 bras ; Comparer le taux d’hospitalisation entre les 2 bras ; Mesurer l’efficacité du traitement antituberculeux ; Évaluer la survenue d’une nouvelle TB et déterminer le mécanisme d’apparition de ces nouvelles TB (rechute vs. réinfection) ; Mesurer l’efficacité du traitement ARV (restauration immunitaire, % de patients avec une charge virale indétectable < 400 copies/ml) Déterminer les facteurs prédictifs de survie, de succès du traitement antituberculeux et ARV, de survenue de réactions paradoxales ; Évaluer l’observance des patients aux traitement antituberculeux et ARV ; Mesurer les concentrations plasmatiques d’efavirenz, associé à la rifampicine ;

41 Bras « précoce» : Introduction ARV après 2 semaines d’antituberculeux
Schéma de l’étude Étude prospective, multicentrique, randomisée, sans placebo. 2 bras : Bras « retardé » : Introduction des ARV après 8 semaines d’antituberculeux Bras « précoce» : Introduction ARV après 2 semaines d’antituberculeux Nombre de patients : 660 (330 dans chaque bras) Durée de l’étude : Durée des inclusions : 3 ans ; Durée du suivi : Chaque patient est suivi jusqu’à la 50e semaine du suivi du dernier patient inclus dans l’étude ; 5 sites d’inclusion au Cambodge, ouverts progressivement

42 CAMELIA résumé Tous les patients reçoivent les mêmes antituberculeux et les mêmes ARV initiaux (D4T + 3TC + efavirenz). Deux bras: introduction des ARV PRÉCOCE (2 semaines après le début des anti-TB) vs. RETARDÉE (8 sem.). (600 mg pour tous les patients)

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44 Salim S. Abdool Karim Director: CAPRISA
How should we treat TB-HIV co-infected patients? SAPIT Study: Starting Antiretroviral therapy at three Points in TB Salim S. Abdool Karim Director: CAPRISA Pro Vice-Chancellor (Research): University of KwaZulu-Natal Professor in Clinical Epidemiology, Columbia University

45 SAPIT: Starting Antiretroviral therapy (ART) in three Points In TB
Primary Objectives: Whether to initiate ART during or after TB treatment? Whether to start ART during TB intensive phase (first 2 months) or during TB continuation phase (months 3 & 4)?

46 Inclusion/Exclusion Criteria
Inclusion Criteria Sputum +ve & receiving any one of the standard anti-TB therapy regimens HIV positive CD4 count < 500 Women must agree to use contraception since they will be on efavirenz Exclusion Criterion Should patients not be clinically eligible to maintain a treatment regimen, their entry may be deferred or precluded.

47 Study intervention TB treatment: Standard TB regimen (usually provided thro DOT) All patients provided with cotrimoxazole prophylaxis ART: Once-a-day Didanosine (ddI) + lamivudine (3TC) + Efavirenz Randomized to one of 3 arms: Arm 1: ART initiated during intensive phase of TB treatment Arm 2: ART initiated after intensive phase of TB treatment Arms 1 & 2 combined: Integrated TB-HIV treatment Arm 3: Sequential treatment - ART initiated after TB treatment

48 Status of the trial Screened: N = 1331 Enrolled: N = 645 Integrated
Sequential N = 214 Initiated ARVs N = 349 Initiated ARVs N = 99 Completed trial = 77 Still in follow-up = 219 Completed trial = 32 Still in follow-up = 59

49 SAPIT Trial Milestones
2003: Trial proposed & planning started as ART becoming available in South Africa May 2004: Funding secured from: PEPfAR for all costs of patient care Global Fund for cost of ART drugs NIH for CIPRA research cores – data, pharmacy & laboratory UKZN & CAPRISA for research costs June 2005: First enrollment July 2008: Completed enrollment September 2008: Safety Monitoring Committee review and recommended: - Halt sequential treatment arm & start ART in these patients - Continue the two integrated treatment arms in the trial

50 Results: Baseline Characteristics
Integrated Arm Sequential Arm Age in years (SD) 34.4 (8.36) 33.9 (8.17) CD4 count (SD) 182 (140.6) 168 (126.1) Log viral load (SD) 5.03 (0.92) 5.11 (0.78) Gender - % male 49.2% 51.4% WHO stage 4 21 (4.9%) 10 (4.7%) MDR-TB cases (%) 15 (3.5%) 7 (3.3%)

51 Interim trial outcome: Mortality rates
55% lower mortality in integrated TB-HIV treatment Hazard Rate: (95% CI: 0.26 to 0.79); p = Integrated Treatment Arm n = 431 Sequential Treatment Arm n = 214 Number of deaths 24 26 Person-years of follow-up 469 224 Mortality rate per 100 person-years 5.1 11.6 Reduction in mortality in the Integrated arm is statistically significant in both patients with CD4 <= 200 and CD4 > 200

52 Implications of SAPIT Trial findings
Compelling evidence for changing clinical practice:- integration of TB & HIV care Programmatic implementation involves: All TB patients offered HIV test & CD4 count All TB-HIV patients with CD4 <500 initiated on ART Monitor the proportion of TB-HIV patients on ART Implementation in South Africa: ~150,000 more TB patients initiated on ART annually ~10,000 deaths averted

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54 EN FRANCE

55 Rapport Yéni 2008 p. 289

56 ET POUR COMPLIQUER LES CHOSES…

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58 CONCLUSION PRIORITÉ ABSOLUE : traiter rapidement la tuberculose !
Si CD4 < 500 : ARV à débuter PLUS OU MOINS VITE… Actuellement, le meilleur moment pour débuter les ARV reste à déterminer. Plusieurs études en cours, notamment dans les pays du Sud -> réponse dans 2-3 ans. Plus les CD4 sont bas, plus il faut commencer tôt. Préparation +++ des patients. « Prix à payer » = IRIS. Il est souhaitable de débuter les ARV dans les 2 premiers mois de traitement anti-TB. High pill burden Overlapping drug toxicities IRIS


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