Efficacy Safety Study Comparing 2 Doses of NVP After Initiating Rifampin-containing TB Therapy

Study Overview
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Brief Summary
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A 48 week, randomized, open-label, two arm study to compare the efficacy, safety and tolerability of HAART containing nevirapine 400 mg/day versus nevirapine 600 mg/day in HIV-1 infected patients started at 2-6 weeks after initiating rifampicin containing antituberculosis therapy.

Detailed Description
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Preliminary data from the HIVNAT PK laboratory indicate that out of 5/60 patients treated with nevirapine (200 mg bid) and rifampicin had sub-therapeutic nevirapine levels (<3.0 mg mg/L). In a control group of 38 patients using nevirapine without rifampicin there were no sub-therapeutic levels. A dose increase of nevirapine while patients who are receiving that rifampicin may be required. Both nevirapine and rifampicin are tepatotoxic agents as are other agents used in treatment of HIV or tuberculosis. Using a higher nevirapine may prevent the occurrence of sub-therapeutic nevirapine levels, but may also induce more liver toxicity. To address these issues, we designed a randomized prospective study to evaluate the safety, efficacy and pharmacokinetics of nevirapine 400 mg/day versus 600 mg/day with a two weeks lead-in 200 mg/day and 400 mg/day respectively, in TB-HIV co-infected patients who taking rifampicin and short-term efficacy and toxicity.

Official Title
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A 48 Week, Randomized, Open-label, 2 Arm Study to Compare the Efficacy, Safety and Tolerability of HAART Containing Nevirapine 400mg/Day Versus Nevirapine 600 mg/Day in HIV-1 Infected Patients Started at 2-6 Weeks After Initiating Rifampin Containing Antituberculous Therapy

Conditions
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HIV Infections, Tuberculosis

Intervention / Treatment
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* Drug: HAART containing nevirapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV positive after voluntary counseling and testing Aged 18-60 years of age Antiretroviral treatment naïve. CD4+ cell count of < 200 cells/mm3 at the time of diagnosed TB TB is diagnosed and using treatment with rifampin base therapy for at least 2 weeks but no longer than 4 weeks duration. The requirement for study entry is at least one acid-fast bacillus (AFB) positive smear with a typical syndrome and/or CXR findings consistent with pulmonary TB. Pulmonary TB and / or extra pulmonary TB will be included if AFB or culture for TB is positive. No other active OI (CDC class C event) Negative pregnancy test in females, and willing to use reliable contraception Able to provide written informed consent. Exclusion Criteria: The following laboratory variables, i. absolute neutrophil count (ANC) < 1000 cells/uL ii. hemoglobin < 6.5 g/dL iii. platelet count < 50,000 cells/uL iv. serum AST, ALT > 5 x ULN vi. serum bilirubin > 2 x ULN vii. serum creatinine > 2 x ULN viii. Pregnant or nursing mothers. Current use of steroid and other immunosuppressive agents. Current use of any prohibited medications related to compliance and drug pharmacokinetics (see appendix ) Acute therapy for serious infection or other serious medical illness (in the judgment of the site Principal Investigator) requiring systemic treatment and/or hospitalization. Patients with current alcohol or illicit substance use that in the opinion of the site Principal Investigator would conflict with any aspect of the conduct of the trial. The persons who had been received a mono-therapy of nevirapine Unlikely to be able to remain in follow-up for the protocol defined period. Patients with chronic active liver disease. Patients with proven or suspected acute hepatitis. Patients with chronic viral hepatitis are eligible provided ALT, AST < 5 x ULN. Karnofsky performance score <30%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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>NVP 400 mg | Drug: HAART containing nevirapine<br>* Initially NVP 200 mg BID (400 mg per day) was compared to 400 mg BID and 200 mg OD NVP (600 mg per day). 400 mg/day versus 600 mg/day.<br>|
| Active Comparator: 2<br>NVP 600 mg | Drug: HAART containing nevirapine<br>* Initially NVP 200 mg BID (400 mg per day) was compared to 400 mg BID and 200 mg OD NVP (600 mg per day). 400 mg/day versus 600 mg/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of nevirapine based HAART 400 mg/day versus 600 mg/day on HIV-1 load as measured by HIV-1 RNA quantification in plasma |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of nevirapine based HAART 400 mg/day versus 600 mg/day |  | 48 weeks | 
| Nevirapine level at week 2, 4 and 12 and 12 hour PK at week 4 (only 20 patients) |  | 48 weeks | 
| Immune recovery syndrome, adherence, clinical improvement, incidence of new/recurrent AIDS events (CDC class C) between two group |  | 48 weeks | 
| Time to mortality or new/recurrent AIDS events (CDC class C), 1 year mortality rate of TB/HIV patients, emerging of ARV resistant especially nevirapine, emerging of anti-TB resistance |  | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Naive, HIV-TB, nevirapine based HAART with rifampin treated TB, Compare PK profile, efficacy, safety and tolerability of HAART containing nevirapine 400mg/day versus 600 mg/day in HIV/TB co-infected patients