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

French National Agency for Research on AIDS and Viral Hepatitis

Status and phase: Completed; Phase 2

Conditions: Tuberculosis; HIV Infections

Treatments: Drug: rifabutin in combination with nevirapine; Drug: rifabutin in combination with lopinavir/ritonavir; Drug: rifabutin in combination with efavirenz

Study type: Interventional

Funder types: Other

Identifiers

NCT00640887

ANRS12150a

Details and patient eligibility

About

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.

Full 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.

Enrollment: 48 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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48 participants in 3 patient groups

1

Experimental group

Description:

RBT associated with EFV based ART

Treatment:

Drug: rifabutin in combination with efavirenz

2

Experimental group

Description:

RBT associated with NVP based ART

Treatment:

Drug: rifabutin in combination with nevirapine

3

Experimental group

Description:

RBT associated with LPV/r based ART

Treatment:

Drug: rifabutin in combination with lopinavir/ritonavir