Pharmacokinetics and Safety of Rifabutin 150 mg Once Daily Versus Rifabutin 300 mg Thrice Weekly

Study Overview
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Brief Summary
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To describe the pharmacokinetics of rifabutin 150 mg once daily versus rifabutin 300 mg thrice weekly in combination with LPV/r 400/100mg based HAART in HIV/TB infected patients

Detailed Description
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The overall aim of the project is to evaluate rifabutin as a replacement for rifampicin, for the combined treatment of tuberculosis and HIV infection. Rifabutin represents an alternative to rifampicin for HIV infected patients as its half-life is longer and the enzymatic induction effect appears to be less important on the associated ART drugs. This phase II trial is to determine precisely the pharmacokinetics parameters of rifabutin in combination with LPV/r regimens in Thai HIV/TB infected patients, in order to define optimal doses that will be further tested in a larger phase III trial comparing safety, tolerability and efficacy of rifabutin and rifampicin regimens.

Official Title
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A Pilot Study of the Pharmacokinetics and Safety of Rifabutin 150 mg Once Daily Versus Rifabutin 300 mg Thrice Weekly With Lopinavir/Ritonavir Based HAART in HIV/TB Co-infected Patients

Conditions
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HIV, Tuberculosis

Intervention / Treatment
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* Drug: Lopinavir/r will be supplied by NHSO/GPO
* Drug: Rifabutin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV positive after voluntary counseling and testing Aged >18-60years of age PI-naïve (NNRTI intolerance/failure) or PI experience ( TB developed during on salvage regimen) without prior PI mutation Any CD4 cell count ALT <5 times ULN Serum creatinine <1.4 mg/dl Hemaglobin >7 mg/L TB is diagnosed and planned to receive stable doses of rifabutin containing anti-TB therapy for at least another 4 week period after initiation of ART No other active OI (CDC class C event), except oral candidiasis or disseminated MAC Body weight >40kg Able to provide written informed consent Exclusion Criteria: Current use of steroid (except short course steroid for IRIS) and other immunosuppressive agents. Current use of any prohibited medications related to drug pharmacokinetics. 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. Unlikely to be able to remain in follow-up for the protocol defined period. Patients with proven or suspected acute hepatitis. Patients with chronic viral hepatitis are eligible provided ALT, AST < 5 x ULN. Karnofsky performance score <30% TB meningitis and bone/joints ( due to longer period of anti TB drug) Pregnancy Patient choose to use efavirenz, not LPV/r. However, in ART naïve, EFV is allowed after intensive PK of LPV/r and rifabutin at week 2-4.

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: rifabutin 150<br>rifabutin 150 mg (1 capsule) once daily | Drug: Lopinavir/r will be supplied by NHSO/GPO<br>* 200/50 mg tablet LPV/rtv<br>* Other names: LPV/rtv;Drug: Rifabutin<br> <br> |
| Other: rifabutin 300<br>rifabutin 150 mg (2 capsules) 300 mg 3 times a week | Drug: Lopinavir/r will be supplied by NHSO/GPO<br>* 200/50 mg tablet LPV/rtv<br>* Other names: LPV/rtv;Drug: Rifabutin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pharmacokinetics of rifabutin Cmax | Cmax The peak plasma concentration of rifabutin after administration | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adverse events | number of participants with adverse events | 48 weeks | 
| viral load |  | 48 weeks | 
| CD4 | mean CD4 rise from baseline | 48 weeks | 
| Monodrug resistant TB |  | 48 weeks | 
| death |  | 48 weeks | 
| AIDS event |  | 48 weeks | 
| TB cure |  | 48 weeks | 
| TB relapse |  | 48 weeks | 
| Multidrug-resistant TB (MDR TB) |  | 48 weeks | 
| TB treatment failure |  | 48 weeks | 
| Extensively drug resistant TB (XDR TB) |  | 48 weeks | 
| weight gain | change from baseline in weight gain at 48 weeks | 48 weeks | 
| defervescence | change from baseline in defervescence at 48 weeks | 48 weeks | 
| Karnofsky score | change from baseline in Karnofsky score at 48 weeks | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics of rifabutin, HIV/TB co-infection, resource limited setting, AUC, Cmax, Cmin, Ctrough