A Study to Determine the Best Dose of Antivirals in Patients With Both TB and HIV

Study Overview
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Brief Summary
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Because drugs used to treat TB can reduce the amount of the anti-HIV drugs that reach the sites where the virus is located, this study is designed to see whether it is necessary to use higher doses of antiviral (anti-HIV) drugs while patients are receiving therapy with rifampin, one of the drugs commonly used to treat TB. Participants will be assigned to one of 4 arms (see below) and will be followed during the time when they are receiving both treatments.

Detailed Description
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This is an open label, randomized study with 4 arms: 1.) Standard dose and 2.) high dose nevirapine; and 3.) standard dose and 4.) high dose efavirenz. Subjects in all 4 arms will also receive 2 nucleoside analog drugs. Patients will have routine monitoring for the treatment of TB and HIV, as well as some additional blood samples to follow the virus in the blood and to determine the effect of the TB therapy on the amounts of anti-HIV drugs that are in the body.

Conditions
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HIV Infections, Tuberculosis

Intervention / Treatment
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* Drug: efavirenz or nevirapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ARV naïve subjects Documented HIV infection Documented TB infection Platelet count 40,000/mm3 Hemoglobin ≥8.0 g/dL Absolute neutrophil count (ANC) >500/mm3 AST (SGOT), ALT (SGPT), and alkaline phosphatase <3 X ULN Total bilirubin <2.5 x ULN Calculated creatinine clearance ≥60 mL/min For women of reproductive potential, negative urine pregnancy test Exclusion Criteria: Unable to provide informed consent. History drug abuse that the investigators suspect will interfere with compliance to study medications and visits. Patients on hemodialysis. Tuberculosis meningitis. Women with CD4 > 250 and men with CD4 > 400 due to higher risk of hepatotoxicity related to use of NVP. Positive serology for hepatitis C. Evidence for active hepatitis B including positive serologies for HBsAg, HBeAg, or HBV-DNA. Note: If anti-HBs is positive, patient is eligible for study if liver enzymes are within the parameters indicated in the inclusion criteria Women who are breast-feeding Known allergy/sensitivity to study drug(s) or their formulations Patients with other OIs or intercurrent illness that could affect their ability to take study drugs

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>Standard dose nevirapine (200 mg 2x daily) in combination with 2 nucleoside analogs | Drug: efavirenz or nevirapine<br>* Patients co-infected with HIV and TB will receive either standard doses of nevirapine (200 mg 2x daily) or efavirenz (600 mg daily) or high doses of nevirapine (400 mg and 200 mg daily) or efavirenz (800 mg daily) that are chosen to compensate for the change in pharmacokinetics shown to occur when co-infected patients are treated with the antituberculous drug, rifampin.<br>* Other names: Viramune (nevirapine);|
| Experimental: 2<br>High dose nevirapine (400 mg in the morning, 200 mg in the evening) in combination with 2 nucleoside analogs | Drug: efavirenz or nevirapine<br>* Patients co-infected with HIV and TB will receive either standard doses of nevirapine (200 mg 2x daily) or efavirenz (600 mg daily) or high doses of nevirapine (400 mg and 200 mg daily) or efavirenz (800 mg daily) that are chosen to compensate for the change in pharmacokinetics shown to occur when co-infected patients are treated with the antituberculous drug, rifampin.<br>* Other names: Viramune (nevirapine);|
| Active Comparator: 3<br>Standard dose efavirenz (600 mg at bedtime) in combination with 2 nucleoside analogs | Drug: efavirenz or nevirapine<br>* Patients co-infected with HIV and TB will receive either standard doses of nevirapine (200 mg 2x daily) or efavirenz (600 mg daily) or high doses of nevirapine (400 mg and 200 mg daily) or efavirenz (800 mg daily) that are chosen to compensate for the change in pharmacokinetics shown to occur when co-infected patients are treated with the antituberculous drug, rifampin.<br>* Other names: Viramune (nevirapine);|
| Experimental: 4<br>High dose efavirenz (800 mg at bedtime) in combination with 2 nucleoside analogs | Drug: efavirenz or nevirapine<br>* Patients co-infected with HIV and TB will receive either standard doses of nevirapine (200 mg 2x daily) or efavirenz (600 mg daily) or high doses of nevirapine (400 mg and 200 mg daily) or efavirenz (800 mg daily) that are chosen to compensate for the change in pharmacokinetics shown to occur when co-infected patients are treated with the antituberculous drug, rifampin.<br>* Other names: Viramune (nevirapine);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decline in HIV RNA in plasma Rise in CD4 cell count | These laboratory measures would be used to determine if there was a difference in the ARV failure rate between patients receiving standard dose vs high dose treatment with NNRTIs | Baseline, and Weeks 8, 20 and 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Co-infection, Tuberculosis, HIV, Drug interactions, Non nucleoside reverse transcriptase inhibitors, Therapy, Treatment Naive