Quand fautil dbuter les antirtroviraux au cours dune tuberculose F'Xavier BLANC, M'D', Ph'D' CHU Bic

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Quand faut-il débuter les antirétrovirauxau
cours dune tuberculose ? F.Xavier BLANC,
M.D., Ph.D.CHU Bicêtre, AP-HP, Le
Kremlin-Bicêtre.xavier.blanc_at_bct.aphp.frRencon
tres Nord-Sud IMEA / IRD25 novembre 2008, Palais
de lUNESCO, Paris.
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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?
When to start HAART?
How to (better) diagnose/manage IRIS?
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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?
When to start HAART?
How to (better) diagnose/manage IRIS?
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TB QUAND DÉBUTER LES ARV ?

• ÉTAT DES LIEUX quelles recommandations ?
• GRANDES ÉTUDES EN COURS

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ÉTAT DES LIEUX QUELLES RECOMMANDATIONS ?

• CD4 gt 350/mm3
• 200 lt CD4 350/mm3
• CD4 200/mm3

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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
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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
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 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 .
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Dont Wait till its 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 lt100 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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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.
• lt100 cells/mm3 - HAART ASAP (some delay up
  to 2 mo)
• 100-200 cells/mm3 - HAART after 2 months
• gt200 cells/mm3 - HAART after TB treatment
  finished

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NIH / CDC / HIVMA / IDSA June 2008

• lt100 cells/mm3 - HAART after 2 weeks
• 100-200 cells/mm3 - HAART after 2 months
• 200-350 cells/mm3 - HAART during anti-TB
  maintenance phase
• gt350 cells/mm3 - HAART after TB treatment
  finished

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DHHS / OARAC November 2008

• lt100 cells/mm3 - HAART after 2 weeks
• 100-200 cells/mm3 - HAART after 8 weeks
• 200-350 cells/mm3 - HAART after 8 weeks (on
  case-by-case basis)
• gt350 cells/mm3 - HAART after 8 to 24 weeks
  or after end of TB treatment

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Special Issues
Guidelines for the Use of Antiretroviral Agents
in Adults and Adolescents November 2008 AETC
NRC Slide Set
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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 lt200 cells/µL,
  earlier ART initiation may reduce risk of HIV
  complications

Questions de recherches VIH et tuberculoseAETC
National Resource Center, www.aidsetc.org
November 2008
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GRANDES ÉTUDES EN COURS
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Août 2007
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POUR EN SAVOIR PLUS
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SAPIT
Blanc FX et al., JID 2007
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PART STUDY

• Delaying HIV disease progression with punctuated
  antiretroviral therapy in HIV-associated TB NCT
  00078247, 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 gt 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 n350.
More info Christopher C. Whalen, ccw_at_case.edu
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TB-HAART STUDY

• An evaluation of the impact of early initiation
  of HAART on TB treatment outcomes for TB patients
  coinfected with HIV ISRCTN77861053, Uganda,
  Zambia, South Africa and Tanzania. 220 lt CD4 lt
  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 n1900. Date of
completion 2011.
AZT 3TC efavirenz
More info Philip Onyebujoh, onyebujohp_at_who.int
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TB MENINGITIS STUDY

• Immediate vs. deferred antiretroviral therapy for
  HIV-associated tuberculous meningitis NCT
  00433719. 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 n253. Date
of completion Dec. 08
AZT 3TC efavirenz
More info Estee Torok, etorok_at_oucru.org
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MEXICAN STUDY

• Simultaneous vs. sequential antiretroviral
  therapy and M. tuberculosis treatment NCT
  00737724. Mexique.
• Active pulmonary TB (with or without extrapulm.
  involvment). CD4 lt 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 n160. Date of
completion March 2011
More info Gustavo Reyes-Teran,
reyesteran_at_cieni.org.mx
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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 00108862, 8 countries.
• CD4 lt 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 n800.
Estimated completion date July 2013
More info Diane V. Havlir, dhavlir_at_php.ucsf.edu
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Etude CAMELIAQuand débuter les ARV chez les
patients TB avec CD4 lt 200/mm3 ?ANRS 1295 -
12164NIH/CIPRA KH001- DAIDS-ESID 10425
Investigateurs coordonnateurs Sok Thim,
A.Goldfeld, F.X. Blanc
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In CAMbodia, Early vs. Late Introduction of
Antiretroviral therapy in naive HIV-infected
adult patients with newly diagnosed tuberculosis
(TB).
CAMELIA
Essai clinique financé par lANRS (étude 1295) et
le NIH américain via le programme CIPRA (grant 1
U01 AI061736-01, 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.
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Contexte de létude TB/VIH au Cambodge

• Cambodge un des 22 pays où lincidence de la
  TB est la élevée (506 pour 100 000
  habitants/an) 1
• prévalence de linfection VIH lune des
  élevées dAsie du Sud-Est (1,6 0,9-2,6 chez
  les 15-49 ans) 2
• 24 des patients nouvellement diagnostiqués VIH
  chez qui lon 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
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• 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
• 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 lt 200.
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Objectifs secondaires de létude

• Comparer le taux de survie à 1 an entre les 2
  bras
• Évaluer la tolérance de lintroduction précoce
  des ARV effets secondaires, réactions
  paradoxales ou IRIS
• Comparer la survenue dinfections opportunistes
  entre les 2 bras
• Comparer le taux dhospitalisation entre les 2
  bras
• Mesurer lefficacité du traitement
  antituberculeux
• Évaluer la survenue dune nouvelle TB et
  déterminer le mécanisme dapparition de ces
  nouvelles TB (rechute vs. réinfection)
• Mesurer lefficacité du traitement ARV
  (restauration immunitaire, de patients avec une
  charge virale indétectable lt 400 copies/ml)
• Déterminer les facteurs prédictifs de survie, de
  succès du traitement antituberculeux et ARV, de
  survenue de réactions paradoxales
• Évaluer lobservance des patients aux traitement
  antituberculeux et ARV
• Mesurer les concentrations plasmatiques
  defavirenz, associé à la rifampicine

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Schéma de létude
Étude prospective, multicentrique, randomisée,
sans placebo.

• 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 50e semaine du suivi du dernier patient inclus
  dans létude
• 5 sites dinclusion au Cambodge, ouverts
  progressivement

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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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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

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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)?

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Inclusion/Exclusion Criteria

• Inclusion Criteria
• Sputum ve receiving any one of the standard
  anti-TB therapy regimens
• HIV positive
• CD4 count lt 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.

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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

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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
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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

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Results Baseline Characteristics
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Interim trial outcome Mortality rates
55 lower mortality in integrated TB-HIV treatment
Hazard 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 lt 200 and CD4 gt 200
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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 lt500 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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EN FRANCE
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Rapport Yéni 2008
p. 289
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ET POUR COMPLIQUER LES CHOSES
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CONCLUSION
PRIORITÉ ABSOLUE traiter rapidement la
tuberculose ! Si CD4 lt 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
-gt 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.