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

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ClinicalTrials.gov Identifier: NCT00640887
Recruitment Status : Completed
First Posted : March 21, 2008
Last Update Posted : June 20, 2011
Sponsor:
Information provided by:
French National Agency for Research on AIDS and Viral Hepatitis

Study Description
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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.


Condition or disease Intervention/treatment Phase
HIV Infections Tuberculosis Drug: rifabutin in combination with efavirenz Drug: rifabutin in combination with nevirapine Drug: rifabutin in combination with lopinavir/ritonavir Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : February 2009
Actual Primary Completion Date : October 2010
Actual Study Completion Date : October 2010

Resource links provided by the National Library of Medicine

Drug Information available for: Rifabutin

Arms and Interventions
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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).


Outcome Measures
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Primary Outcome Measures :
  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) [ Time Frame: 2, 6 and 10 weeks after randomisation ]

Secondary Outcome Measures :
  1. 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 ]
  2. Safety : proportion of patients with grade 3 and grade 4 adverse events [ Time Frame: through out the trial ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00640887


Locations
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South Africa
Unit for Clinical and Biomedical TB Research (Medical Research Council)
Durban, South Africa, 4067
Sponsors and Collaborators
French National Agency for Research on AIDS and Viral Hepatitis
Investigators
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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
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Claire Rekacewicz, French National Agency for Research on AIDS and Viral Hepatitis
ClinicalTrials.gov Identifier: NCT00640887    
Other Study ID Numbers: ANRS12150a
First Posted: March 21, 2008    Key Record Dates
Last Update Posted: June 20, 2011
Last Verified: June 2011
Keywords provided by French National Agency for Research on AIDS and Viral Hepatitis:
HIV
Tuberculosis
Rifabutin
Pharmacokinetics
South Africa
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Tuberculosis
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Mycobacterium Infections
 Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Ritonavir
Lopinavir
Nevirapine
Efavirenz
Rifabutin
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents