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Quand faut-il débuter les antirétroviraux au cours dune tuberculose ? F.Xavier BLANC, M.D., Ph.D. CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre. Rencontres Nord-Sud.

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Présentation au sujet: "Quand faut-il débuter les antirétroviraux au cours dune tuberculose ? F.Xavier BLANC, M.D., Ph.D. CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre. Rencontres Nord-Sud."— Transcription de la présentation:

1 Quand faut-il débuter les antirétroviraux au cours dune 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 lUNESCO, Paris. Quand faut-il débuter les antirétroviraux au cours dune 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 lUNESCO, Paris.

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

3 HAART AND TB TREATMENT MANAG T Which HAART regimen? High pill burden, overlapping drug toxicities, IRIS / PR, adherence challenge… Strategy trials needed+++. Three strategy questions in adult patients: 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 ÉTAT DES LIEUX : QUELLES RECOMMANDATIONS ? - CD4 > 350/mm < CD4 350/mm 3 - CD4 200/mm 3

6 TB and HIV: Immediate vs. Delayed HAART delaying 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 Dont Wait till its 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 <100 4 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 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 3 - HAART ASAP (some delay up to 2 mo)<100 cells/mm 3 - HAART ASAP (some delay up to 2 mo) cells/mm 3 - HAART after 2 months cells/mm 3 - HAART after 2 months >200 cells/mm 3 - HAART after TB treatment finished>200 cells/mm 3 - HAART after TB treatment finished BHIVA February 2005

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18 <100 cells/mm 3 - HAART after 2 weeks<100 cells/mm 3 - HAART after 2 weeks cells/mm 3 - HAART after 2 months cells/mm 3 - HAART after 2 months cells/mm 3 - HAART during anti-TB maintenance phase cells/mm 3 - HAART during anti-TB maintenance phase >350 cells/mm 3 - HAART after TB treatment finished>350 cells/mm 3 - HAART after TB treatment finished NIH / CDC / HIVMA / IDSA June 2008

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20 <100 cells/mm 3 - HAART after 2 weeks<100 cells/mm 3 - HAART after 2 weeks cells/mm 3 - HAART after 8 weeks cells/mm 3 - HAART after 8 weeks cells/mm 3 - HAART after 8 weeks (on case-by-case basis) cells/mm 3 - HAART after 8 weeks (on case-by-case basis) >350 cells/mm 3 - HAART after 8 to 24 weeks or after end of TB treatment>350 cells/mm 3 - HAART after 8 to 24 weeks or after end of TB treatment DHHS / OARAC November 2008

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 –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 Questions de recherches : VIH et tuberculoseAETC National Resource Center, 2008

23 GRANDES ÉTUDES EN COURS

24 Août 2007

25 POUR EN SAVOIR PLUS…

26 Blanc FX et al., JID 2007 SAPIT

27 PART STUDY Uganda 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. Started in October Target n=350. More info: Christopher C. Whalen, AZT + 3TC + abacavir

28 TB-HAART STUDY Uganda, Zambia, South Africa and Tanzania 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 Target n=1900. Date of completion: More info: Philip Onyebujoh, AZT + 3TC + efavirenz

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30 TB MENINGITIS STUDY Vietnam 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 Target n=253. Date of completion: Dec. 08 More info: Estee Torok, AZT + 3TC + efavirenz

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32 MEXICAN STUDY Mexique 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. Started in March Target n=160. Date of completion: March 2011 Emtricitabine/Tenofovir disoproxil fumarate + efavirenz More info: Gustavo Reyes-Teran,

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34 AACTG A5221 STUDY 8 countries A strategy study of immediate versus deferred initiation of antiretroviral therapy for HIV-infected persons treated for TB with CD4 less than 200 cells/mm 3 : 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. Started in September Target n=800. Estimated completion date: July 2013 More info: Diane V. Havlir, Emtricitabine/Tenofovir disoproxil fumarate + efavirenz

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36 Etude CAMELIA Quand débuter les ARV chez les patients TB avec CD4 < 200/mm 3 ? ANRS NIH/CIPRA KH001- DAIDS-ESID Investigateurs coordonnateurs : Sok Thim, A.Goldfeld, F.X. Blanc

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

38 - Cambodge : un des 22 pays où lincidence de la TB est la + élevée (506 pour habitants/an) 1 - prévalence de linfection VIH : lune des + élevées dAsie du Sud- Est (1,6% [0,9-2,6%] chez les ans) % des patients nouvellement diagnostiqués VIH+ chez qui lon recherche la TB sont TB Global TB control WHO report UNAIDS report on the global AIDS epidemic MMWR 2005: 54(46); Contexte de létude TB/VIH au Cambodge

39 QUESTION POSÉE PAR LÉTUDE QUESTION POSÉE PAR LÉTUDE Quel est le meilleur moment pour débuter les anti- rétroviraux (ARV) chez les patients adultes naïfs sévèrement immunodéprimés chez qui lon vient de commencer un traitement anti-TB ? OBJECTIF PRINCIPAL introduction précoce des ARV introduction différée des ARV Comparer la survie des patients à la fin de létude (50 semaines après linclusion 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 létude 1.Comparer le taux de survie à 1 an entre les 2 bras ; 2.Évaluer la tolérance de lintroduction précoce des ARV : effets secondaires, réactions paradoxales ou IRIS ; 3.Comparer la survenue dinfections opportunistes entre les 2 bras ; 4.Comparer le taux dhospitalisation entre les 2 bras ; 5.Mesurer lefficacité du traitement antituberculeux ; 6.Évaluer la survenue dune nouvelle TB et déterminer le mécanisme dapparition de ces nouvelles TB (rechute vs. réinfection) ; 7.Mesurer lefficacité du traitement ARV (restauration immunitaire, % de patients avec une charge virale indétectable < 400 copies/ml) 8.Déterminer les facteurs prédictifs de survie, de succès du traitement antituberculeux et ARV, de survenue de réactions paradoxales ; 9.Évaluer lobservance des patients aux traitement antituberculeux et ARV ; 10.Mesurer les concentrations plasmatiques defavirenz, associé à la rifampicine ;

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

42 CAMELIA résumé (600 mg pour tous les patients) 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.).

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44 How should we treat TB-HIV co-infected patients? SAPIT Study: S tarting A ntiretroviral therapy at three P oints i n T B 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 N = 431 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 Baseline CharacteristicIntegrated ArmSequential 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 - % male49.2%51.4% WHO stage 421 (4.9%)10 (4.7%) MDR-TB cases (%)15 (3.5%)7 (3.3%)

51 Interim trial outcome: Mortality rates Integrated Treatment Arm n = 431 Sequential Treatment Arm n = 214 Number of deaths 2426 Person-years of follow-up Mortality rate per 100 person-years % lower mortality in integrated TB-HIV treatment Hazard Rate: (95% CI: 0.26 to 0.79); p = Reduction in mortality in the Integrated arm is statistically significant in both patients with 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.


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