Quand faut-il débuter les antirétrovirauxQuand faut-il débuter les antirétroviraux

au cours d’une tuberculose ?au cours d’une tuberculose ?

F.Xavier BLANC, M.D., Ph.D.F.Xavier BLANC, M.D., Ph.D.CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre.CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre.

xavier.blanc@bct.aphp.fr

Rencontres Nord-Sud IMEA / IRDRencontres Nord-Sud IMEA / IRD

25 novembre 2008, Palais de l’UNESCO, Paris.25 novembre 2008, Palais de l’UNESCO, Paris.

HAART AND TB TREATMENT MANAGHAART AND TB TREATMENT MANAGTT

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?

HAART AND TB TREATMENT MANAGHAART AND TB TREATMENT MANAGTT

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?When to start HAART?

How to (better) diagnose/manage IRIS?

TB: QUAND DÉBUTER LES ARV ?TB: QUAND DÉBUTER LES ARV ?

- ÉTAT DES LIEUX : quelles recommandations ?

- GRANDES ÉTUDES EN COURS

ÉTAT DES LIEUX :ÉTAT DES LIEUX :QUELLES RECOMMANDATIONS ?QUELLES RECOMMANDATIONS ?

- CD4 > 350/mm3

- 200 < CD4 ≤ 350/mm3

- CD4 ≤ 200/mm3

TB and HIV: Immediate vs. Delayed HAART

Arguments for delayingdelaying 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

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

« 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 ».

Don’t Wait till it’s too lateFurther AIDS

Dean et al.: AIDS 2002

Observational study (1996-1999)

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 2001Pozniak A. May 2003

• TB treatment must be given urgently.

• The urgency of HIV treatment depends on predictors of HIV

disease progression especially the CD4 cell count.

• <100<100 cells/mmcells/mm3 3 - HAART ASAP (some delay up to 2 mo)- HAART ASAP (some delay up to 2 mo)

• 100-200100-200 cells/mmcells/mm3 3 - HAART after 2 months- HAART after 2 months

• >200>200 cells/mmcells/mm3 3 - - HAART after TB treatment finishedHAART after TB treatment finished

BHIVABHIVAFebruary 2005February 2005

• <100<100 cells/mmcells/mm3 3 - HAART after 2 weeks- HAART after 2 weeks

• 100-200100-200 cells/mmcells/mm3 3 - HAART after 2 months- HAART after 2 months

• 200-350200-350 cells/mmcells/mm3 3 - HAART during anti-TB maintenance phase- HAART during anti-TB maintenance phase

• >350>350 cells/mmcells/mm3 3 - HAART after TB treatment finished- HAART after TB treatment finished

NIH / CDC / HIVMA / IDSANIH / CDC / HIVMA / IDSAJune 2008June 2008

• <100<100 cells/mmcells/mm3 3 - HAART after 2 weeks- HAART after 2 weeks

• 100-200100-200 cells/mmcells/mm3 3 - HAART after 8 weeks- HAART after 8 weeks

• 200-350200-350 cells/mmcells/mm3 3 - HAART after 8 weeks (on case-by-case basis)- HAART after 8 weeks (on case-by-case basis)

• >350>350 cells/mmcells/mm3 3 - HAART after 8 to 24 weeks or after end of TB treatment- HAART after 8 to 24 weeks or after end of TB treatment

DHHS / OARACDHHS / OARACNovember 2008November 2008

Special Issues

Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents

November 2008

AETC NRC Slide Set

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 knownOptimal 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 complicationsQuestions de recherches : VIH et tuberculoseAETC National

Resource Center, www.aidsetc.orgNovember 2008

GRANDES ÉTUDES EN COURSGRANDES ÉTUDES EN COURS

Août 2007

POUR EN SAVOIR PLUS…POUR EN SAVOIR PLUS…

Blanc FX et al., JID 2007

SAPIT

PART STUDY

Delaying HIV disease progression with punctuated antiretroviral

therapy in HIV-associated TB: NCT 00078247, UgandaUganda. 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 2004.

Target n=350.

More info: Christopher C. Whalen, ccw@case.eduMore info: Christopher C. Whalen, ccw@case.edu

AZT + 3TC + abacavir

TB-HAART STUDYAn evaluation of the impact of early initiation of HAART on TB treatment outcomes for

TB patients coinfected with HIV: ISRCTN77861053, Uganda, Zambia, South Africa Uganda, Zambia, South Africa

and Tanzaniaand 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.

More info: Philip Onyebujoh, onyebujohp@who.intMore info: Philip Onyebujoh, onyebujohp@who.int

AZT + 3TC + efavirenz

TB MENINGITIS STUDYImmediate vs. deferred antiretroviral therapy for HIV-associated tuberculous meningitis: NCT 00433719. VietnamVietnam.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 More info: Estee Torok, etorok@oucru.orgMore info: Estee Torok, etorok@oucru.org

AZT + 3TC + efavirenz

MEXICAN STUDYSimultaneous vs. sequential antiretroviral therapy and M. tuberculosis treatment: NCT 00737724. MexiqueMexique.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 2008.

Target n=160.

Date of completion: March 2011

Emtricitabine/Tenofovir disoproxil fumarate + efavirenz

More info: Gustavo Reyes-Teran, More info: Gustavo Reyes-Teran,

reyesteran@cieni.org.mxreyesteran@cieni.org.mx

AACTG A5221 STUDYA 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 00108862, 8 countries8 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 2006.

Target n=800.

Estimated completion date: July 2013

More info: Diane V. Havlir, dhavlir@php.ucsf.eduMore info: Diane V. Havlir, dhavlir@php.ucsf.edu

Emtricitabine/Tenofovir

disoproxil fumarate + efavirenz

Etude CAMELIA

Quand débuter les ARV chez les patients TB avec CD4 < 200/mm3 ?

ANRS 1295 - 12164NIH/CIPRA KH001- DAIDS-ESID 10425

Investigateurs coordonnateurs : Sok Thim, A.Goldfeld, F.X. Blanc

In CAMCAMbodia, EEarly vs. LLate IIntroduction of AAntiretroviral 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 l’ANRS (étude 1295) et le NIH américain via le programme CIPRA (grant 1 U01 AI061736-01, CIPRA KH 001).

CAMELIA

- Cambodge : un des 22 pays où l’incidence de la TB est la + élevée (506 pour 100 000 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 15-49 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); 1177-1180

Contexte de l’étude TB/VIH au Cambodge

QUESTION POSÉE PAR L’ÉTUDEQUESTION 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 PRINCIPALOBJECTIF 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 ARVintroduction précoce des ARV (14 jours) vs. introduction différée des ARVintroduction différée des ARV (2 mois).

Patients naïfs inclus si BAAR+ et CD4 < 200.Patients naïfs inclus si BAAR+ et CD4 < 200.

Objectifs secondaires de l’étude1. Comparer le taux de survie à 1 an entre les 2 bras ;2. Évaluer la tolérance de l’introduction précoce des ARV : effets

secondaires, réactions paradoxales ou IRIS ; 3. Comparer la survenue d’infections opportunistes entre les 2 bras ;4. Comparer le taux d’hospitalisation entre les 2 bras ;5. Mesurer l’efficacité du traitement antituberculeux ;6. Évaluer la survenue d’une nouvelle TB et déterminer le mécanisme

d’apparition de ces nouvelles TB (rechute vs. réinfection) ;7. Mesurer l’efficacité 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 l’observance des patients aux traitement antituberculeux et

ARV ;10. Mesurer les concentrations plasmatiques d’efavirenz, associé à la

rifampicine ;

Schéma de l’étude

• 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

Étude prospective, multicentrique, randomisée, sans placebo.Étude prospective, multicentrique, randomisée, sans placebo.

CAMELIA résumé

Day 0

Rd : Randomization H : isoniazid Z : pyrazinamide R : rifampicin E : ethambutol D4T : stavudine 3TC : lamivudine EFV : efavirenz

TB treatment

2EHRZ/4HR

Week 26 (6 months)

Week 8 (2 months)

Week 2

Rd

TB treatment Late

ARV D4T-3TC-EFV

Early

Week 50 (12 months)

Week 58 Week 78 (18 months)

=

End of Trial

Consider ARV switch

Follow-up (every 6 months after week 78)

ARV D4T-3TC-EFV

(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.).

Questions de recherches : VIH et tuberculose

How should we treat TB-HIV co-infected patients?

SAPIT Study: Starting Antiretroviral therapy at three Points in TB

Salim S. Abdool Karim

Director: CAPRISAPro Vice-Chancellor (Research): University of KwaZulu-Natal

Professor in Clinical Epidemiology, Columbia University

SAPIT: Starting Antiretroviral therapy (ART) in three Points In TB

Primary Objectives: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)?

Inclusion/Exclusion Criteria

Inclusion CriteriaInclusion 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 CriterionExclusion Criterion • Should patients not be clinically eligible to maintain a

treatment regimen, their entry may be deferred or precluded.

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

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 = 77Still in follow-up = 219

Completed trial = 32Still in follow-up = 59

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

Results: Baseline Characteristics

Baseline Characteristic 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%)

Interim trial outcome: Mortality rates

Integrated Treatment Arm

n = 431

SequentialTreatment 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

55% lower mortality in integrated TB-HIV treatmentHazard Rate: 0.451 (95% CI: 0.26 to 0.79); p = 0.0049

Reduction in mortality in the Integrated arm is statistically significant in both

patients with CD4 <= 200 and CD4 > 200

Implications of SAPIT Trial findingsImplications 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 ARTAll 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

EN FRANCEEN FRANCE

Rapport Yéni 2008Rapport Yéni 2008

p. 289

ET POUR COMPLIQUER LES CHOSES…ET POUR COMPLIQUER LES CHOSES…

CONCLUSIONCONCLUSION

PRIORITÉ ABSOLUE : traiter rapidement la tuberculose !

Si CD4 < 500 : ARV à débuter PLUS OU MOINS VITE…

Actuellement, le meilleur moment pour débuter les ARV Actuellement, le meilleur moment pour débuter les ARV

reste à déterminer.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 Il est souhaitable de débuter les ARV dans les 2 premiers

mois de traitement anti-TB.mois de traitement anti-TB.