Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146 CARINEMO)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the use of Nevirapine in HIV patients already treated against tuberculosis by Rifampicin is as efficient and as well tolerated as Efavirenz.

Detailed Description
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Anti Retroviral Therapy (ART) reduces tuberculosis (TB) incidence in HIV-infected patients and reduces mortality among TB patients with deep immune suppression. The Fixed Drug Combination (FDC) nevirapine (NVP)-lamivudine-stavudine is the first line ART available for low-income countries. Rifampicin (RMP), due to its liver induction effect, reduces significantly NVP plasma concentration, raising concerns regarding the risk of resistance and subsequent treatment failure. Therefore, in co-infected patients, WHO recommends delaying ART or using efavirenz (EFV)-based ART. Although EFV is also reduced at lower level, longitudinal studies report good efficacy and safety when given concomitantly with RMP. In low-income countries, poor access to EFV, contradiction during pregnancy and absence of FDC containing EFV lead to difficulties in HIV-TB treatment. Despite 2 limited retrospective studies and a non-randomised prospective study, which report good virological response at 6 months in co-infected patients receiving NVP and RMP co-administration, existing data are too limited to change the recommendation. The aim of the study is to compare, in terms of therapeutic efficacy and clinical safety, the nevirapine-based HAART to the standard efavirenz-based HAART, in HIV/TB co-infected patients receiving a rifampicin-based TB treatment. The study will evaluate one year after TB treatment initiation, whether the HAART efficacy (virological outcome, death or lost of follow-up) induced by NVP-based HAART is non-inferior to those induced by EFV based HAART, in patients receiving concomitantly HAART and RMP-based TB treatment.

Official Title
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Randomized Non-inferiority Trial Comparing the Nevirapine-based Antiretroviral Therapy Versus the Standard Efavirenz-based ART for the Treatment of HIV-TB Co-infected Patients on Rifampicin-based Therapy (ANRS 12146 CARINEMO)

Conditions
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Tuberculosis, Aids, Hiv Infections

Intervention / Treatment
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* Drug: Nevirapine based therapy
* Drug: Efavirenz based therapy
* Drug: Rifampicin (RMP) Ethambutol (E) Isoniazid (H) Pyrazinamid (Z)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Person HIV infected Aged of 18 years or more Signed informed consent New case of tuberculosis: patient who never received TB treatment or for less than 1 month Patients receiving rifampicin based TB regimen since 4 to 6 weeks CD4 cell count < 250 cell/mm3 in the 4 weeks following the TB diagnosis Naïve of HAART For women of childbearing age, to have a negative plasmatic test for pregnancy and to accept to take a contraception or declare no wish of pregnancy in the coming year. Exclusion Criteria: To have a positive plasmatic test for pregnancy Karnofsky score <60% ALAT > 4N (Hepatitis grade 3 or 4) Ongoing psychiatric pathology Refuse to participate in the study Amendment : bilirubin > grade 3 any grade 4 clinical sign or biological result at time of inclusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Nevirapine-based ART | Drug: Nevirapine based therapy<br>* Patients below 60 kg: 1 tablet twice a day of Triomune30®, including NVP 200 mg, 3TC 150 mg and D4T 30mg Patients above 60kg: 1 tablet twice a day of Triomune40®, including NVP 200 mg, 3TC 150 mg and D4T 40 mg)<br>* Other names: Triomune;Drug: Rifampicin (RMP) Ethambutol (E) Isoniazid (H) Pyrazinamid (Z)<br>* Intensive phase: 2 months daily E(RMP)HZ. PTB smear positive patients at month 2 will receive 1 more month intensive phase. Continuation phase: 4 months daily H(RMP). Patients with meningitis will receive Streptomycin instead of E during intensive phase.<br>|
| Active Comparator: 2<br>Efavirenz-based ART | Drug: Efavirenz based therapy<br>* Efavirenz EFV 200 mg (3 tablets/d) Lamivudine 3TC 300mg (2 tablets of 150mg/d) D4T generic 30mg or 40mg (2 tablets/d)<br>* Other names: Cipla drugs;Drug: Rifampicin (RMP) Ethambutol (E) Isoniazid (H) Pyrazinamid (Z)<br>* Intensive phase: 2 months daily E(RMP)HZ. PTB smear positive patients at month 2 will receive 1 more month intensive phase. Continuation phase: 4 months daily H(RMP). Patients with meningitis will receive Streptomycin instead of E during intensive phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral load measure (Virological failure will be defined after 2 consecutive measures as : More than 1 log10 increase in plasma HIV-1 RNA concentration for patients with detectable viral load (> 50 copies/mL) at the previous dosage.) |  | 3, 6 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New or recurrent stage 3 or 4 HIV/AIDS related events |  | 12 months | 
| Deaths after one year |  | 12 months | 
| Severe drugs side effects |  | 12 months | 
| Immune Reconstitution Syndrome(IRIS) |  | 12 months | 
| Increase of CD4 cell count induced by HAART |  | at 6 months and 1 year | 
| Pharmacokinetic profile of nevirapine when combined with rifampicin |  | 2 months | 
| Rifampicin plasma concentration dosage |  | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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drug interactions, Treatment Naive