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

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 when they start TB treatment. All the enrolled patients will immediately be switched to rifabutin and randomized, to one of the RBT doses that will be then adapted to the allocated RBT regimen according to a cross over scheme. Three full pharmacokinetics profile will be performed at different time point : before initiation of ARV, after three weeks of the first RBT dosage and after three weeks of the secondRBT dosage. Patients will then be referred to the national program for further treatment. A follow-up visit will be planned at the end of the antiTB treatment.

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

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

Intervention / Treatment
-----------------
* Drug: rifabutin in combination with lopinavir boosted by ritonavir - dosing schedule 1
* Drug: rifabutin in combination with lopinavir boosted by ritonavir - dosing schedule 2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pulmonary tuberculosis defined as either at least 2 sputum smears positive for AFB 1 sputum smear positive for AFB and a chest radiograph compatible with active tuberculosis 1 sputum culture positive and and a chest radiograph compatible with active tuberculosis a clinical history and chest radiograph compatible with active tuberculosis and 2 sputum smear negative for AFB Positive HIV antibody and CD4 count <=250 /mm3 Weight > 40 kg No history of ART 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 or MDR TB treatment 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 (150 mg TPW during 3 weeks switch to 150mg OD for the following 3 weeks) associated with LPV/r based ART | Drug: rifabutin in combination with lopinavir boosted by ritonavir - dosing schedule 1<br>* 3TC(300mg)/D4t(60mg)/LPV/r(800mg/200mg)+INH/PZA/EMT/Rifabutin(150 mg TPW 3 wks switch to 150 mg OD 4 wks);<br>|
| Experimental: 2<br>RBT (150 mg OD during 3 weeks switch to 150mg TPW for the following 3 weeks) associated with LPV/r based ART | Drug: rifabutin in combination with lopinavir boosted by ritonavir - dosing schedule 2<br>* 3TC(300mg)/D4t(60mg)/LPV/r(800mg/200mg)+INH/PZA/EMT/Rifabutin(150 mg OD 3 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 lopinavir/ritonavir) |  | 2, 5 and 8 weeks after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of lopinavir/ritonavir in combination with two doses of rifabutine |  | 5 and 8 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, Vietnam