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

Sponsored by:	French National Agency for Research on AIDS and Viral Hepatitis
Information provided by:	French National Agency for Research on AIDS and Viral Hepatitis
ClinicalTrials.gov Identifier:	NCT00640887

Purpose

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.

Condition	Intervention	Phase
HIV Infections Tuberculosis	Drug: rifabutin in combination with efavirenz Drug: rifabutin in combination with nevirapine Drug: rifabutin in combination with lopinavir/ritonavir	Phase II

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

Resource links provided by NLM:

MedlinePlus related topics: AIDS Tuberculosis

Drug Information available for: Rifabutin Nevirapine Efavirenz Ritonavir Lopinavir

U.S. FDA Resources

Further study details as provided by French National Agency for Research on AIDS and Viral Hepatitis:

Primary Outcome 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 ] [ Designated as safety issue: No ]

Secondary Outcome 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 ] [ Designated as safety issue: No ]
Safety : proportion of patients with grade 3 and grade 4 adverse events [ Time Frame: through out the trial ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	48
Study Start Date:	February 2009
Estimated Study Completion Date:	February 2010
Estimated Primary Completion Date:	November 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental 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);
2: Experimental 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);
3: Experimental 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).

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

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00640887

Contacts

Contact: Anthony D Harries, MD	+33 1 44 32 03 60	adharries@theunion.org
Contact: Philippe Clevenbergh, MD	+33 1 44 32 03 60	pclevenbergh@iuatld.org

Locations

South Africa
Unit for Clinical and Biomedical TB Research (Medical Research Council)	Recruiting
Durban, South Africa, 4067
Contact: Alexander Pym, MD +27 31 203 47 45 alexander.pym@mrc.ac.za

Sponsors and Collaborators

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

More Information

No publications provided

Responsible Party:	French National Agency for Research on AIDS and Viral Hepatitis ( Claire Rekacewicz )
Study ID Numbers:	ANRS12150a
Study First Received:	February 6, 2008
Last Updated:	August 17, 2009
ClinicalTrials.gov Identifier:	NCT00640887 History of Changes
Health Authority:	South Africa: Medicines Control Council

Keywords provided by French National Agency for Research on AIDS and Viral Hepatitis:

HIV
Tuberculosis
Rifabutin
Pharmacokinetics
South Africa

Study placed in the following topic categories:

Bacterial Infections
Anti-Infective Agents
Efavirenz
Sexually Transmitted Diseases, Viral
Stavudine
Rifabutin
Acquired Immunodeficiency Syndrome
Lamivudine
Immunologic Deficiency Syndromes
Virus Diseases
Anti-Bacterial Agents

Nevirapine
Gram-Positive Bacterial Infections
Lopinavir
Ritonavir
HIV Infections
Sexually Transmitted Diseases
Mycobacterium Infections
Tuberculosis
Antitubercular Agents
Retroviridae Infections

Additional relevant MeSH terms:

Bacterial Infections
Communicable Diseases
Anti-Infective Agents
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Rifabutin
Infection
Anti-Bacterial Agents
Gram-Positive Bacterial Infections
Therapeutic Uses
Tuberculosis
Retroviridae Infections
RNA Virus Infections

Immune System Diseases
Acquired Immunodeficiency Syndrome
Immunologic Deficiency Syndromes
Actinomycetales Infections
Pharmacologic Actions
Antibiotics, Antitubercular
Virus Diseases
HIV Infections
Sexually Transmitted Diseases
Lentivirus Infections
Mycobacterium Infections
Antitubercular Agents

ClinicalTrials.gov processed this record on September 10, 2009