Clinical trial NCT00651066: Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in Patients With TB/HIV Co-infection in Vietnam
Official title: Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in the Treatment of Tuberculosis Patient With HIV Infection in Vietnam : A Phase II Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Tuberculosis
Keywords: HIV
Tuberculosis
Rifabutin
Pharmacokinetics
Vietnam
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
First posted: 2008-04-02
Enrollment: 47
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 when they start TB treatment. All the enrolled patients will immediately be switched to rifabutin and randomized, to one of the RBT doses that will be then adapted to the allocated RBT regimen according to a cross over scheme. Three full pharmacokinetics profile will be performed at different time point : before initiation of ARV, after three weeks of the first RBT dosage and after three weeks of the secondRBT dosage. Patients will then be referred to the national program for further treatment. A follow-up visit will be planned at the end of the antiTB treatment.

Eligibility criteria: Inclusion Criteria:

* Pulmonary tuberculosis defined as either

  * at least 2 sputum smears positive for AFB
  * 1 sputum smear positive for AFB and a chest radiograph compatible with active tuberculosis
  * 1 sputum culture positive and and a chest radiograph compatible with active tuberculosis
  * a clinical history and chest radiograph compatible with active tuberculosis and 2 sputum smear negative for AFB
* Positive HIV antibody and CD4 count \<=250 /mm3
* Weight \> 40 kg
* No history of ART
* 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

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 lopinavir/ritonavir)
timeFrame: 2, 5 and 8 weeks after randomisation
Secondary outcomes:
measure: Area under the curve (AUC) of lopinavir/ritonavir in combination with two doses of rifabutine
timeFrame: 5 and 8 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: Ho Chi Minh City
country: Vietnam
facility: Pham Ngoc Tach Hospital
Study officials:
affiliation: The international Union Against Tuberculosis and Lung Diseases (IUATLD), Paris, France
name: Anthony D. Harries, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam
name: Huy Dung Nguyen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lan NT, Thu NT, Barrail-Tran A, Duc NH, Lan NN, Laureillard D, Lien TT, Borand L, Quillet C, Connolly C, Lagarde D, Pym A, Lienhardt C, Dung NH, Taburet AM, Harries AD. Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam. PLoS One. 2014 Jan 22;9(1):e84866. doi: 10.1371/journal.pone.0084866. eCollection 2014.