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

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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

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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

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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

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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)

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METHODS

• 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

• 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

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Trial design

ARV

2NRTI

+

NNRTI

TB drugs

with

RMPEFV group NVP group

Viral load & pharmacology

Viral load & pharmacology

Evaluation at 24 weeksViral load & pharmacology

Evaluation at 48 weeksViral load & pharmacology

W12

W24

W36

W48

W0

TB-HIV co-infection naïve of ARTCD4<250 cells/mm3

4-6 weeks antiTB treatment

ARV

2NRTI

+

NNRTI

TB drugs

with

RMPEFV group NVP group

Viral load & pharmacology

Viral load & pharmacology

Evaluation at 24 weeksViral load & pharmacology

Evaluation at 48 weeksViral load & pharmacology

W12

W24

W36

W48

W0

TB-HIV co-infection naïve of ARTCD4<250 cells/mm3

4-6 weeks antiTB treatment

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)

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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

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Baseline characteristics

N (%), median (interquartile range)

NVP (n=285) EFV (n=285)

Female 125 (43.9) 114 (40)

Age (yrs) 33 (29-41) 33 (28-40)

Weight (Kg) 51.7 (46.6-57.2) 52.5 (47.5-58.8)

Pulmonary TB 226 (79.3) 217 (76.1)

Time to ART initiation (w) 4.9 (4.4-5.1) 4.9 (4.4-5.1)

ALAT (U/l) 24.2 (15-39) 23.7 (16.3-37.8)

CD4 (cell/mm3) 92 (44-148) 86 (44-140)

Plasma HIV-RNA (log) 5.7 (5.1-6.1) 5.5 (5.2-6.1)

HBV surface antigen 58 (20.4) 63 (22.1)

HBC antibody 5/270 (1.8) 6/266 (2.2)

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Efficacy

0 5 10 15 20 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= failurePer 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%

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Probability to have HIV-RNA<50cp/mL

Kaplan Meier estimates

225 177 97 73 54

224 140 73 47 29

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

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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%

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Main safety results

n (%) NVP (n=285) EFV (n=288)

At least one Serious AE 54 (18.9) 52 (18.1)

Treatment discontinuation due to AE 14 (4.9) 3 (1)

Deaths 17 (6) 16 (5.6)

Pregnancies 11 (3.9) 12 (4.2)

Specific AE of interest

Hepatitis (grade > 2) 59 (20.7) 54 (18.8)

Severe hepatitis (grade > 3) 20 (7) 17 (5.9)

Rash (grade > 2) 22 (7.7) 24 (8.3)

Severe rash (grade > 3) 3 (1.1) 1 (0.3)

Safety population: all included patients exposed to NVP or EFV

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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

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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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