Results of the CARINEMO ANRS 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 1 st 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 1 st 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 METHODS Inclusion criteria – HIV infected & ART naive – New TB adults with RMP since 4 to 6 weeks – CD4 <250 cell/mm 3 Exclusion criteria – Positive pregnancy test – ALAT > 5 x ULN – Grade 4 clinical or biological AE – Karnovski < 60% – Unable or refused to consent 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 Drugsnevirapine-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 RESULTS Assessed for eligibility (n=702) Enrolled (n=573) Decline to participate (n=20) Not meeting inclusion criteria (n=101) Other (n=8) Allocated to NVP (n=285)Allocated to EFV (n=285) Randomized (n=570) 3 started on EFV without randomization Lost to follow-up (n=4) Death (n=18) Withdrawals due to MDR (n=3) Voluntary withdrawals (n=15) Other (n=3) Completed follow-up (n=242) Lost to follow-up (n=8) Death (n=16) Withdrawals due to MDR (n=1) Voluntary withdrawals (n=27) Completed follow-up (n=233) Trial profile: Nov 2007-Feb 2011

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

10 Efficacy 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 EFV - NVP = Δ 68.4%-60% = 8.4% ITT (195/285) (171/285) 78.9%-70% = 8.9%PP (194/246) (170/243) Virological success: 48 weeks HIV-RNA<50cp/mL 15% 15.4%

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

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

16