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

Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in the Treatment of Tuberculosis Patient With HIV Infection in South Africa: 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 Overview

• Status: Completed
• Conditions: HIV Infections; Tuberculosis
• Intervention / Treatment: Drug: rifabutin in combination with efavirenz; Drug: rifabutin in combination with nevirapine; Drug: rifabutin in combination with lopinavir/ritonavir

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 Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Durban, South Africa, 4067
    • Unit for Clinical and Biomedical TB Research (Medical Research Council)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 efavirenz, nevirapine or lopinavir/ritonavir)	2, 6 and 10 weeks after randomisation

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety : proportion of patients with grade 3 and grade 4 adverse events	through out the trial
Area under the curve (AUC) of efavirenz, nevirapine and lopinavir/ritonavir in combination with two doses of rifabutine	6 and 10 weeks after randomisation

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: February 6, 2008
• First Submitted That Met QC Criteria: March 17, 2008
• First Posted (Estimate): March 21, 2008

Study Record Updates

• Last Update Posted (Estimate): June 20, 2011
• Last Update Submitted That Met QC Criteria: June 17, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; Tuberculosis; South Africa; Rifabutin
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Tuberculosis; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Nevirapine; Ritonavir; Lopinavir; Rifabutin; Efavirenz
• Other Study ID Numbers: ANRS12150a