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

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Dose Comparison, Crossover Assignment, Bio-availability Study

Study Primary Completion Date: September 2010

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.

Intervention(s) in this Clinical Trial

• 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);
• 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);
• 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).

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • RBT associated with EFV based ART
• Experimental: 2
  • RBT associated with NVP based ART
• Experimental: 3
  • RBT associated with LPV/r based ART

Primary 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)
  • Time Frame: 2, 6 and 10 weeks after randomisation
    Safety Issue?: No

Secondary Measures

• Area under the curve (AUC) of efavirenz, nevirapine and lopinavir/ritonavir in combination with two doses of rifabutine
  • Time Frame: 6 and 10 weeks after randomisation
    Safety Issue?: No
• Safety : proportion of patients with grade 3 and grade 4 adverse events
  • Time Frame: through out the trial
    Safety Issue?: Yes

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 > 40 kg
• No history of ART
• 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 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: French National Agency for Research on AIDS and Viral Hepatitis

Overall Clinical Trial Officials and Contacts

Christian Lienhardt, MD Principal Investigator The international Union Against Tuberculosis and Lung Diseases (IUATLD), Paris, France  

Overall Contact: Christian Lienhardt, MD +33 (0)1 44 32 03 60 clienhardt@iuatld.org

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00651066

Study ID Number: ANRS12150b

ClinicalTrials.gov Identifier: NCT00651066

Health Authority: Vietnam: Ministry of Health