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INS-MISAU

Results of the CARINEMO ANRS 12146 randomized trial comparing the efficacy and safety of nevirapine vs efavirenz for treatment of HIV-TB co-infected patients in Mozambique.

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INS-MISAU

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  1. Results of the CARINEMO ANRS 12146 randomized trial comparing the efficacy and safety of nevirapine vs efavirenz for treatment of HIV-TB co-infected patients in Mozambique Bonnet M, Bhatt N, Baudin E, Silva C, Michon C, Taburet AM, Ciaffi L, Sobry A, Bastos R, Nunes E, Barreto A, Rouzioux C, Jani I, Calmy A, on behalf of the CARINEMO study group INS-MISAU

  2. BACKGROUND • Tuberculosis (TB): leading opportunistic infection in high HIV prevalence countries • 1st line nevirapine (NVP)-based antiretroviral therapy (ART) raises concerns in patients receiving rifampicin (RMP) • Reduction of NVP concentration with potential loss of efficacy • Risk on increased toxicity: hepatitis and rash • Limitations of the use of efavirenz (EFV) • Contraindicated during 1st trimester of pregnancy • More expensive than NVP in Fixed Dose Combination

  3. Existing data • One small randomized trial in Thailand (N=140) • No difference in virological response at 48 weeks • Few data on toxicity • Discordant results between cohort studies • Good virological response in Bostwana and Thailand • Increased virological failure in South Africa Shipton LK, et al. IJTLD 2009; Boulle A, et al. Jama 2008; Manosuthi W et al. CID 2009

  4. Hypothesis • NVP with no lead-in dose (200 mg BID) in HIV-TB co-infected patients receiving RMP will be non inferior in terms of efficacy (HIV-RNA<50cp/mL) as compared to an EFV-based regimen • If confirmed, it will allow for HIV-TB co-infected patients to use a safe alternative to an EFV-based regimen

  5. OBJECTIVES • Primary: to compare the 48 weeks virological efficacy of a NVP-based ART initiated at full dose with an EFV-based ART when given concomitantly with RMP • Secondary: to measure • Probability of HIV-RNA <50cp/mL • Proportion of deaths • Incidence of adverse events (AE) • TB treatment outcomes • Proportion of paradoxical TB Immune Reconstitution Inflammatory Syndrome (IRIS)

  6. Inclusion criteria HIV infected & ART naive New TB adults with RMP since 4 to 6 weeks CD4 <250 cell/mm3 Exclusion criteria Positive pregnancy test ALAT > 5 x ULN Grade 4 clinical or biological AE Karnovski < 60% Unable or refused to consent METHODS • Multicenter randomised open-label non-inferiority trial • 3 sites in Maputo (Mozambique) • 570 patients • 70% efficacy of the EFV arm • Non-inferiority margin (Δ = EFV-NVP efficacy) of 10% • 1-sided α level of 0.05, 80% power and 10% dropout • Primary endpoint: HIV-RNA<50cp/mL at 48 weeks • Lost to follow-up (LFU) or deaths as failures

  7. Trial design Drugs nevirapine-lamivudine-stavudine, Cipla Ltd. (India) efavirenz, Aurobindo Pharma Ltd (India) + lamivudine-stavudine, Cipla Ltd. (India) stavudine replaced by zidovudine as of August 2010 rifampicin-isoniazid-ethambutol-pirazinamide and rifampicin-isoniazid, Lupin LTd. (India)

  8. Assessed for eligibility (n=702) Decline to participate (n=20) Not meeting inclusion criteria (n=101) Other (n=8) Enrolled (n=573) 3 started on EFV without randomization Randomized (n=570) Allocated to NVP (n=285) Allocated to EFV (n=285) Lost to follow-up (n=4) Death (n=18) Withdrawals due to MDR (n=3) Voluntary withdrawals (n=15) Other (n=3) Lost to follow-up (n=8) Death (n=16) Withdrawals due to MDR (n=1) Voluntary withdrawals (n=27) Completed follow-up (n=233) Completed follow-up (n=242) RESULTS Trial profile: Nov 2007-Feb 2011

  9. Baseline characteristics N (%), median (interquartile range)

  10. Efficacy Virological success: 48 weeks HIV-RNA<50cp/mL EFV - NVP = Δ 68.4% - 60% = 8.4% ITT (195/285) (171/285) 78.9% - 70% = 8.9% PP (194/246) (170/243) 15% 15.4% Δ Non inferiority margin Δ = 10% Intention to treat population (ITT):randomized patients who received at least one dose of study medication to which they were randomly allocated. Switch= failure Per protocol population: ITT population excluding patients with major protocol deviations, treatment switch and patients who did not reach a trial primary endpoint

  11. Probability to have HIV-RNA<50cp/mL ART + RMP ART alone Patients at risk NVP: 67% of patients with HIV-RNA>50 cp/mL at week 48 had HIV-RNA<400 cp/mL Kaplan Meier estimates

  12. Tuberculosis outcomes • TB treatment success • NVP: 261/285, 91.7% • EFV: 260/288, 90.3% • Paradoxical TB IRIS (Lancet Infect Dis 2010) • NVP: 33/285, 11.6% • EFV: 21/288, 7.3%

  13. Main safety results Safety population: all included patients exposed to NVP or EFV

  14. CONCLUSIONS • Non inferiority of NVP as compared to EFV is not shown  No recommendation for systematic use of NVP in TB-HIV co-infected patients even if started at full dose • Although there was lower virological response in the NVP arm, most patients had HIV-RNA<400cp/mL • Absence of lead-in dose does not jeopardize safety of NVP in TB-HIV co-infected patients  For patients who can not receive EFV, NVP without lead-in dose remains a safe alternative • On-going work • To assess resistance mutations in patients failing ART • To assess the NVP and EFV pharmacokinetics • To assess long term clinical outcome in 200 consecutive patients

  15. ACKNOWLEDGMENT • ANRS, Paris • Médecins Sans Frontières, Geneva • National Health Institute, Maputo • Alto Mae HC, José Macamo and Mavalane hospitals, Maputo • National TB control program, Maputo • International Center for AIDS Care and Treatment Program, Maputo • Virology laboratory of Necker hospital, Paris • Pharmacology laboratory of Bicêtre hospital, Paris • Institute of Tropical Medicine, Antwerp • Data Monitoring Committee • Study participants

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