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

Sponsor

French National Agency for Research on AIDS and Viral Hepatitis (Other)

Overall Status

Completed

CT.gov ID

NCT00640887

Collaborator

(none)

Enrollment

Location

Arms

19.9

Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections Tuberculosis	Drug: rifabutin in combination with efavirenz Drug: rifabutin in combination with nevirapine Drug: rifabutin in combination with lopinavir/ritonavir	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Study Start Date :

Feb 1, 2009

Actual Primary Completion Date :

Oct 1, 2010

Actual Study Completion Date :

Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 RBT associated with EFV based ART	Drug: 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);
Experimental: 2 RBT associated with NVP based ART	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);
Experimental: 3 RBT associated with LPV/r based ART	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).

Arm

Intervention/Treatment

Experimental: 1

RBT associated with EFV based ART

Drug: 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);

Experimental: 2

RBT associated with NVP based ART

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);

Experimental: 3

RBT associated with LPV/r based ART

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).

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Unit for Clinical and Biomedical TB Research (Medical Research Council)	Durban		South Africa	4067

Sponsors and Collaborators

French National Agency for Research on AIDS and Viral Hepatitis

Investigators

Principal Investigator: Anthony D Harries, MD, PhD, The international Union Against Tuberculosis and Lung Diseases (IUATLD), Paris, France
Principal Investigator: Alexander PYM, MD, Medical Research Council, South Africa