Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in Patients With TB/HIV Co-infection in South Africa

Study Overview
=================
Brief Summary
-----------------
The overall aim of the project is to evaluate rifabutin (RBT) as a replacement for rifampicin (RMP), for the combined treatment of tuberculosis and HIV infection. RBT represents an alternative to RMP for HIV infected patients as its half-life is longer and the enzymatic induction effect appears to be less important on the associated antiretroviral therapy (ART) drugs. This phase II trial is to determine precisely the pharmacokinetics parameters of RBT in combination with different ART regimens in Vietnamese HIV infected patients with pulmonary tuberculosis, in order to define optimal doses that will be further tested in a larger phase III trial comparing safety, tolerability and efficacy of RBT and RMP regimens.

Detailed Description
-----------------
Patients will be offered to participated in the study after the first 6 weeks of the nationally recommended TB treatment. All the enrolled patients will be switched to rifabutin and randomized, two weeks later, to one of the three study ARV regimens. The RBT doses will be then adapted to the allocated ARV regimen according to a cross over scheme. Three full pharmacokinetics profile will be performed at different time point : before initiation of ARV, after one month of the first RFB dosage and one month after the second RFB dosage.

Official Title
-----------------
Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in the Treatment of Tuberculosis Patient With HIV Infection in South Africa: A Phase II Trial

Conditions
-----------------
HIV Infections, Tuberculosis

Intervention / Treatment
-----------------
* Drug: rifabutin in combination with efavirenz
* Drug: rifabutin in combination with nevirapine
* Drug: rifabutin in combination with lopinavir/ritonavir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pulmonary tuberculosis (proven by AFB positive sputum or culture) Having completed and adhered to 6 wks of intensive phase TB chemotherapy Positive HIV antibody and CD4 count >50 /mm3 and <=200 Weight > 50 kg No ART in the preceding 3 months No more than 2 weeks or ART previously No grade 3 or 4 clinical or laboratory findings Negative pregnancy test and appropriate contraceptive measures during the duration of the trial for female of childbearing age Having a firm home address that is readily accessible Karnofsky score>=80% Exclusion Criteria: History of TB within the 3 years preceding the presenting episode of TB Previous treatment for MDR TB Concomitant OI requiring additional anti-infectious treatment Formal contraindication to any drug used in the trial Diabetes mellitus requiring drug treatment Recreational drug or alcohol abuse History of drug hypersensitivity to TB or related medications Interrupted TB therapy for more than 1 week Less than 90% adherent to first 6 weeks of intensive phase chemotherapy Mental illness that could impair ability to give informed consent or result in poor adherence to trial protocol and therapy Neutropenia <1200 /L, anaemia <6.8 g/dL, liver function test > grade 2 Requiring concomitant medications that may potentially interact with study drugs Pregnant or lactating women Karnofsky score >80% Any condition rendering the patient unable to understand the nature, scope, and possible consequences of thes study and to provide consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>RBT associated with EFV based ART | Drug: rifabutin in combination with efavirenz<br>* Ia. arm 1a: D4T/3TC/EFV(600mg)+INH/Rifabutin(450 mg OD 4 wks switch to 600 mg OD 4 wks); Ib. arm 1b: D4T/3TC/EFV(600mg)+INH/Rifabutin(600 mg OD 4 wks switch to 450 mg OD 4 wks);<br>|
| Experimental: 2<br>RBT associated with NVP based ART | Drug: rifabutin in combination with nevirapine<br>* IIa. arm 2a: D4T/3TC/NVP(200mg)+INH/Rifabutin(300 mg OD 4 wks switch to 450 mg OD 4 wks); IIb. arm 2b : D4T/3TC/NVP(200mg)+INH/Rifabutin(450 mg OD 4 wks switch to 300 mg OD 4 wks);<br>|
| Experimental: 3<br>RBT associated with LPV/r based ART | Drug: rifabutin in combination with lopinavir/ritonavir<br>* IIIa. arm 3a : D4T/3TC/LPV/r(2 tabs BD)+INH/Rifabutin(150 mg TPW 4 wks switch to 150 mg OD 4 wks); IIIb. arm 3b: D4T/3TC/LPV/r(2 tabs BD)+INH/Rifabutin(150 mg OD 4 wks switch to 150 mg TPW 4 wks).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of rifabutine measured (a)before introduction of ART;(b)after ART initiation (two different doses of RBT in combination with efavirenz, nevirapine or lopinavir/ritonavir) |  | 2, 6 and 10 weeks after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of efavirenz, nevirapine and lopinavir/ritonavir in combination with two doses of rifabutine |  | 6 and 10 weeks after randomisation | 
| Safety : proportion of patients with grade 3 and grade 4 adverse events |  | through out the trial | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, Tuberculosis, Rifabutin, Pharmacokinetics, South Africa