A Study to Determine the Best Dose of Antivirals in Patients With Both TB and HIV (OPTI-NNRTI)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV Infections; Tuberculosis	Drug: efavirenz or nevirapine	Phase 4

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	5 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Study Start Date :	July 2007
Actual Primary Completion Date :	March 2008
Actual Study Completion Date :	March 2008

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: 1; Standard dose nevirapine (200 mg 2x daily) in combination with 2 nucleoside analogs	Drug: efavirenz or nevirapine; 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.; Other Names: Sustiva (efavirenz); Viramune (nevirapine)
Experimental: 2; High dose nevirapine (400 mg in the morning, 200 mg in the evening) in combination with 2 nucleoside analogs	Drug: efavirenz or nevirapine; 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.; Other Names: Sustiva (efavirenz); Viramune (nevirapine)
Active Comparator: 3; Standard dose efavirenz (600 mg at bedtime) in combination with 2 nucleoside analogs	Drug: efavirenz or nevirapine; 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.; Other Names: Sustiva (efavirenz); Viramune (nevirapine)
Experimental: 4; High dose efavirenz (800 mg at bedtime) in combination with 2 nucleoside analogs	Drug: efavirenz or nevirapine; 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.; Other Names: Sustiva (efavirenz); Viramune (nevirapine)

Outcome Measures

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Primary Outcome Measures :

1. Decline in HIV RNA in plasma Rise in CD4 cell count [ Time Frame: Baseline, and Weeks 8, 20 and 32 ]
   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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

Brazil
Hospital Universitario Prof. Edgard Santos/Universidade Federal da Bahia
Salvador, Bahia, Brazil, 40110-160

Sponsors and Collaborators

Stanford University

Investigators

Principal Investigator:	Terrence F Blaschke, M.D.	Stanford University

More Information

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Responsible Party:	Terrence F Blaschke, Principle Investigator, Stanford University School of Medicine
ClinicalTrials.gov Identifier:	NCT00523458 History of Changes
Other Study ID Numbers:	Stanford Protocol ID: 95564
First Posted:	August 31, 2007
Last Update Posted:	July 22, 2011
Last Verified:	July 2011

Keywords provided by Stanford University:

Co-infection; Tuberculosis; HIV; Drug interactions	Non nucleoside reverse transcriptase inhibitors; Therapy; Treatment Naive

Additional relevant MeSH terms:

HIV Infections; Tuberculosis; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Efavirenz

Nevirapine; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Anti-HIV Agents