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

NCT ID: NCT00640887

Last Updated: 2011-06-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-28
• Study Completion Date: 2010-10-31

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.

Conditions

HIV Infections; Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

RBT associated with EFV based ART

Group Type: EXPERIMENTAL

rifabutin in combination with efavirenz

Intervention Type: DRUG

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);

2

RBT associated with NVP based ART

Group Type: EXPERIMENTAL

rifabutin in combination with nevirapine

Intervention Type: DRUG

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);

3

RBT associated with LPV/r based ART

Group Type: EXPERIMENTAL

rifabutin in combination with lopinavir/ritonavir

Intervention Type: DRUG

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).

Interventions

rifabutin in combination with efavirenz

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);

Intervention Type: DRUG

rifabutin in combination with nevirapine

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);

Intervention Type: DRUG

rifabutin in combination with lopinavir/ritonavir

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).

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

French National Agency for Research on AIDS and Viral Hepatitis

OTHER_GOV

Sponsor Role: lead

Responsible Party

French National Agency for Research on AIDS and Viral Hepatitis

Principal Investigators

Anthony D Harries, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

The international Union Against Tuberculosis and Lung Diseases (IUATLD), Paris, France

Alexander PYM, MD

Role: PRINCIPAL_INVESTIGATOR

Medical Research Council, South Africa

Locations

Unit for Clinical and Biomedical TB Research (Medical Research Council)

Durban, , South Africa

Countries

South Africa

References

Hennig S, Naiker S, Reddy T, Egan D, Kellerman T, Wiesner L, Owen A, McIlleron H, Pym A. Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis. Antimicrob Agents Chemother. 2015 Oct 19;60(1):617-20. doi: 10.1128/AAC.01195-15. Print 2016 Jan.

Reference Type: DERIVED

PMID: 26482301 (View on PubMed)

Naiker S, Connolly C, Wiesner L, Kellerman T, Reddy T, Harries A, McIlleron H, Lienhardt C, Pym A. Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacol Toxicol. 2014 Nov 19;15:61. doi: 10.1186/2050-6511-15-61.

Reference Type: DERIVED

PMID: 25406657 (View on PubMed)

Other Identifiers

ANRS12150a

Identifier Type: -

Identifier Source: org_study_id