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

NCT00640887 | Completed Phase 2 DMC

• 1 other identifier: ANRS12150a
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV Infections; Tuberculosis

Keywords

HIV; Tuberculosis; Rifabutin; Pharmacokinetics; South Africa

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• 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

Study Arms (3)

1

EXPERIMENTAL

RBT associated with EFV based ART

Drug: rifabutin in combination with efavirenz

2

EXPERIMENTAL

RBT associated with NVP based ART

Drug: rifabutin in combination with nevirapine

3

EXPERIMENTAL

RBT associated with LPV/r based ART

Drug: rifabutin in combination with lopinavir/ritonavir

Interventions

rifabutin in combination with efavirenz 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);

1

rifabutin in combination with nevirapine 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);

2

rifabutin in combination with lopinavir/ritonavir 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).

3

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%

You may not qualify if:

• 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

Sponsors & Collaborators

• French National Agency for Research on AIDS and Viral Hepatitis: lead

Study Sites (1)

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

Durban, 4067, South Africa

Location

Related Publications (2)

• 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.

  PMID: 26482301 DERIVED

• 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.

  PMID: 25406657 DERIVED

MeSH Terms

Conditions

HIV Infections; Tuberculosis

Interventions

Rifabutin; efavirenz; Nevirapine; Lopinavir; Ritonavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrimidinones; Pyrimidines; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER GOV

Study Record Dates

• First Submitted: February 6, 2008
• First Posted: March 21, 2008
• Study Start: February 1, 2009
• Primary Completion: October 1, 2010
• Study Completion: October 1, 2010
• Last Updated: June 20, 2011

Record last verified: 2011-06

Locations

ZA (1)