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B. Grinsztejn 1 , N. De Castro 2,3 , V. Arnold 4 , V. Veloso 1 , M. Morgado 5 ,

A randomized trial to estimate efficacy and safety of 2 doses of raltegravir and efavirenz for treatment of HIV-TB co-infected patients : ANRS 12 180 REFLATE TB trial. . B. Grinsztejn 1 , N. De Castro 2,3 , V. Arnold 4 , V. Veloso 1 , M. Morgado 5 ,

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B. Grinsztejn 1 , N. De Castro 2,3 , V. Arnold 4 , V. Veloso 1 , M. Morgado 5 ,

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  1. A randomized trial to estimate efficacy and safety of 2 doses of raltegravir and efavirenz for treatment of HIV-TB co-infected patients :ANRS 12 180 REFLATE TB trial. B. Grinsztejn1, N. De Castro2,3, V. Arnold4, V. Veloso1, M. Morgado5, JH. Pilotto6, C. Brites7, JV. Madruga8, N. Barcellos9, BR Santos10, C. Vorsatz1, C. Grondin4, M. Santini-Oliveira1, O. Patey11, C. Delaugerre2,3, G. Chêne4, J-M. Molina2,3 and the ANRS 12 180 Reflate TB study group. 1 Laboratory of Clinical Research on STD/AIDS, IPEC, Fiocruz, Rio de Janeiro, Brazil, 2 University of Paris Diderot, Sorbonne Paris Cité, INSERM U941, 3 Hospital Saint-Louis, AP-HP, France, 4 INSERM U897 and University Bordeaux Segalen, 5 Laboratory of AIDS and Molecular Immunology, Fiocruz, Rio de Janeiro, Brazil, 6 Department of STD/AIDS, Nova Iguacu, Brazil, 7 Laboratory of Research in Infectious Diseases, Salvador de Bahia, Brazil, 8 Research Unit for Treatment of STD/AIDS, Sao Paulo, Brazil, 9 Department of Care and Therapy, Porto Alegre, Brazil, 10 Department of Infectious Diseases, Porto Alegre, Brazil, 11 Department of Internal and Tropical Medicine, Villeneuve St George, France. XIX International AIDS Conference July 26, 2012 Abstract #:THLBB01 CMG-EC ISO 9001:2008 certified for its clinical research activities

  2. ANRS 12 180 Background • WHO guidelines: efavirenz (EFV)-based regimen 1st-line therapy for HIV and Tuberculosis (TB) co-infected patients • Potential limitations to EFV use • Adverse Events : cutaneous rash, central nervous system toxicity • Transmitted drug resistance to NNRTIs • Teratogenicity • Potential interest of Raltegravir (RAL) in HIV-TB co-infection • Favorable safety profile • Not metabolized by CYP450 • Induction by rifampin (RIF): ↓Ctrough 61%, ↓AUC 40% in healthy volunteers partially compensated by ↑ RAL 800 mg bid • Objective of the ANRS 12180 REFLATE TB trial : estimate the antiviral efficacy of two doses of RAL +TDF+ 3TC, in HIV-1 naive patients co-infected with TB

  3. Study design ANRS 12 180 ANRS 12 180 Phase II open label randomized multicenter trial TDF245 mg qd + 3TC 300mg qd + EFV 600 mg qd • HIV RNA>1000 cp/mL • ART naïve • Confirmed or probable TB • RIF containing regimen 1:1:1 TDF245mg qd + 3TC 300mg qd + RAL 400 mg bid TDF245 mg qd + 3TC 300 mg qd + RAL 800 mg bid + RAL 400 mg bid TB drugs RHZE 2mo followed by RH 4mo W 24 W0 W48 Primary endpoint mITT HIV RNA<50copies/mL Sample size : 50 patients/arm, 80% power to show ≥70% success at W24

  4. ANRS 12 180 ANRS 12 180 Flow chart Screened n = 179 France n = 8 Brazil n = 171 Not included n = 24 Lab abnormality n=9 HIV RNA < 1000cp/ml n=4 ARV treatment n=2 Death n=2 Other n=7 Randomized n = 155 RAL 800 n = 52 RAL 400 n = 51 EFV n = 52 Not treated n = 1 Not treated n = 0 Not treated n = 1 mITT analysis n = 51 mITT analysis n = 51 mITT analysis n = 51 Disposition at W24 On study drug n = 43 Discontinued study drug n = 8 Adverse event n = 2 Virologic failure n = 4 Lost to follow up n = 0 Withdrawal n = 0 Death n = 2 Disposition at W24 On study drug n = 50 Discontinued study drug n = 1 Adverse event n = 0 Virologic failure n = 0 Lost to follow up n = 0 Withdrawal n = 1 Death n = 0 Disposition at W24 On study drug n = 43 Discontinued study drug n = 8 Adverse event n = 3 Virologic failure n = 1 Lost to follow up n = 1 Withdrawal n = 1 Death n = 2 4

  5. ANRS 12 180 Baseline characteristics

  6. ANRS 12 180 Efficacyoutcomes, W24 Primary endpoint : HIV RNA<50 cp/mL at W20 and W24,mITT (M=F, D/C=F) Secondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F)

  7. ANRS 12 180 % participants with HIV RNA<50 cp/mLateachvisit(M=F, studytreatment discontinuation=F)

  8. ANRS 12 180 Drug resistance by W24 * already present at baseline

  9. Median CD4 cell count ateachvisit(available data) ANRS 12 180

  10. ANRS 12 180 Adverse events (AE) through W24 * Both related to TB drugs: fulminant hepatitis with liver transplant in one patient **Causes of death: EFV arm: 1 TB meningitis W4, 1 sepsis related to TB W6 RAL 800 arm : 1 unknown W2, 1 TB meningitis W12

  11. ANRS 12 180 Laboratory AE (grades 3-4) through W24

  12. ANRS 12 180 Conclusion • In this phase II study, high rates of success were achieved at week 24 with raltegravir 400 mg bid or 800 mg bid and EFV 600 mg qd in combination with TDF and 3TC, in patients receiving a rifampin-containing TB treatment • In the context of HIV and TB co-infection, raltegravir (400 mg bid or 800 mg bid) had a good safety profile • Raltegravir seems to be a suitable alternative to EFV for HIV-TB co-infected patients • Optimal raltegravir dose yet to be defined based on PK sub-study and W48 follow-up data

  13. ANRS 12 180 Aknowledgements The patients for their participation and their commitment during the study and the REFLATE TB Study Group: CLINICAL CENTERS Rio de Janeiro (B. Grinsztejn) Nova Iguaçu (JH.Pilotto) Salvador (C. Brites) Porto Alegre (N. Barcellos) Porto Alegre (B. Rigel Santos) Sao Paulo (J. Valdez Madruga) Saint-Louis, Paris (JM. Molina) Villeneuve Saint- Georges (O. Patey) LABORATORY, PHARMACY Rio de Janeiro (MC. Lourenço) Rio de Janeiro (E. Wreneck Barroso) Rio de Janeiro (T. Torres) Pitié-Salpêtrière, Paris (G. Carcelain) Saint-Louis, Paris (E. Cambau) Saint-Louis, Paris (I. Madelaine) TRIAL STEERING COMMITTEE JM. Molina (Chair) X. Anglaret V. Arnold B. Bazin V. Calvez G. Chêne N. De CastroC. Delaugerre B. GrinsztejnM. Morgado C. Rekacewicz H. Sauvageon AM. Taburet V. Veloso C. Vorsatz COORDINATING CTU INSERM U897/ISPED G. Chêne (head) V. Arnold A. Beuscart C. Fagard C. Grondin N. Stival S. Tabuteau BRAZIL CTU LABORATORY OF CLINICAL RESEARCH ON STD/AIDS - FIOCRUZ B. Grinsztejn (head) R. Millan E. Sampaio M. Santini V. Veloso C. Vorsatz INDEPENDANT DATA & SAFETY MONITORING COMMITTEE F. Raffi (chair) JP. Aboulker D. Descamps B. Durovni MERCK SHARPE & DOHME-CHIBRET (donated raltegravir) F. Durand A. De Jacquelot GILEAD (donated tenofovir) A. Jacob P. Pétour V. Tilliet INSERM-ANRS B. Bazin S. Couffin-Cadiergues A. Diallo C. Rekacewicz B. Larouzé (Chair, Brazil site) BRAZILIAN AIDS PROGRAM C. Possas (co-Chair, Brazil site) EVENTS VALIDATION COMMITTEE G. Breton B. Denis S. Wagner CMG-EC ISO 9001:2008 certified for its clinical research activities

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