Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

Study Overview
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Brief Summary
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Raltegravir is a potent antiretroviral agent that could be used as an alternative to efavirenz in HIV-1 infected patients with tuberculosis. However due to pharmacokinetic interactions, the optimal dose of raltegravir to be used in combination with rifampin is currently unknown. This phase II open-label randomized multicenter trial is designed to estimate the antiviral efficacy of two doses of raltegravir and one dose of efavirenz at week 24, in HIV-1 naive patients co-infected with active tuberculosis (TB) treated with rifampin.

Official Title
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Phase II Open-label Randomized Multicenter Trial to Compare the Efficacy and Safety of Two Different Doses of Raltegravir and Efavirenz, All in Combination With Tenofovir and Lamivudine, in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

Conditions
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HIV Infections, Tuberculosis

Intervention / Treatment
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* Drug: efavirenz
* Drug: raltegravir
* Drug: raltegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (at least 18 years old) Plasma HIV RNA > 1000 copies/ml HIV-1-infection confirmed by ELISA and Western blot or Immunofluorescence ART naïve patients or ART for less than 3 months and more than 6 months ago ; an HIV resistance genotype at baseline showing no mutation to NNRTI and TDF or 3TC will be required For women of childbearing age, negative urinary test for pregnancy and to accept contraceptive methods: condom use and intra-uterine device when possible or declare no wish of pregnancy in the coming year. Confirmed or probable TB TB treatment including rifampin started since 2 to 8 weeks before randomisation Signed informed consent form For French patients, to be affiliated to the National Health Care System Exclusion Criteria: HIV-2 infection (single or with HIV-1) Woman who is pregnant or likely to become so, is breastfeeding or refuses to use contraception ALT>2.5N, Hb <7g/dl, neutrophils < 750/mm3, platelet<50 000/mm3, bilirubin >5N, lipase >3N Creatinine clearance <60ml/min as assessed by the Cockcroft method Ongoing psychiatric pathology or any condition (including, but not limited to, the consumption of alcohol or drugs) which might, in the investigator's opinion, compromise the safety of treatment and/or patient compliance with the protocol Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1) Prior TB with a Mycobacterium tuberculosis strain resistant to rifampin TB treatment started for more than 8 weeks before randomisation

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 |
| --- | --- |
| Active Comparator: 1<br>efavirenz | Drug: efavirenz<br>* tenofovir 245 mg / lamivudine 300 mg / efavirenz 600 mg<br>|
| Experimental: 2<br>raltegravir 400 mg | Drug: raltegravir<br>* tenofovir 245 mg / lamivudine 300 mg / raltegravir 400 mg<br>|
| Experimental: 3<br>raltegravir 800 mg | Drug: raltegravir<br>* tenofovir 245 mg / lamivudine 300 mg / raltegravir 800 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virologic success, using Time to Loss of Virologic Response (TLOVR) algorithm: -Plasma HIV RNA below 50 copies/ml at week 20, confirmed at week 24 -Absence of permanent treatment discontinuation -Absence of death -Still follow-up at week 24 |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with virologic response with the following definitions: - Plasma HIV RNA <50 copies/ml at week 24 - Rate of strategy discontinuation and treatment changes - Proportion of death - Proportion of patients loss to follow-up |  | 24 weeks | 
| Proportion of patients with virologic response with the following definitions: o Plasma HIV RNA <50 copies/ml o Plasma HIV RNA <400 copies/ml |  | 24 and 48 weeks | 
| Evolution in HIV RNA and HIV DNA (total and 2 LTR circular) from baseline to week 48 |  | 48 weeks | 
| Rate of viral resistance mutations in the plasma at the time of virologic failure and in comparison with HIV-RNA mutations at W0 |  | At the time of virologic failure | 
| Evolution of CD4 cell counts from baseline to week 48 |  | 48 weeks | 
| Frequency, type and time to a new AIDS-defining event or death |  | Through out the trial | 
| Frequency, type, time to grade 3 or 4 adverse event |  | Through out the trial | 
| Rate of success of TB treatment |  | 48 weeks | 
| Anti-TB resistance rate |  | 48 weeks | 
| Evolution of raltegravir and efavirenz trough concentration |  | Through out the trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Tuberculosis, Pharmacokinetics, Raltegravir, France, Brazil, treatment naive