Clinical trial NCT00640887: Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in Patients With TB/HIV Co-infection in South Africa
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Tuberculosis
Keywords: HIV
Tuberculosis
Rifabutin
Pharmacokinetics
South Africa
Lead sponsor: French National Agency for Research on AIDS and Viral Hepatitis
Sponsor class: OTHER_GOV
First posted: 2008-03-21
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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)
timeFrame: 2, 6 and 10 weeks after randomisation
Secondary outcomes:
measure: Area under the curve (AUC) of efavirenz, nevirapine and lopinavir/ritonavir in combination with two doses of rifabutine
timeFrame: 6 and 10 weeks after randomisation
measure: Safety : proportion of patients with grade 3 and grade 4 adverse events
timeFrame: through out the trial
Other outcomes:
Locations:
city: Durban
country: South Africa
facility: Unit for Clinical and Biomedical TB Research (Medical Research Council)
Study officials:
affiliation: The international Union Against Tuberculosis and Lung Diseases (IUATLD), Paris, France
name: Anthony D Harries, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Research Council, South Africa
name: Alexander PYM, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.