Pharmacokinetics of Emtricitabine/Tenofovir/Efavirenz in HIV-infected Patients With Tuberculosis (PETE)

The Pharmacokinetics of Co-formulated Emtricitabine/Tenofovir/Efavirenz in HIV-infected Patients With Smear-positive Pulmonary Tuberculosis in the Kilimanjaro Region, Tanzania

In this pilot study the pharmacokinetics and safety of the antiretroviral combination of co-formulated emtricitabine/tenofovir/efavirenz will be studied in HIV-positive patients with pulmonary tuberculosis (TB) who are concomitantly treated with a standard rifampin-containing tuberculostatic regimen. It is expected that this antiretroviral combination causes minimal drug interactions with the rifampin-containing anti-tuberculosis medication.

Study Overview

• Status: Unknown
• Conditions: HIV Infections; Tuberculosis
• Intervention / Treatment: Drug: Emtricitabine/tenofovir/efavirenz

Detailed Description

The primary objectives of this pilot study in 30 patients are:

1. To determine the effect of rifampin-containing tuberculostatic treatment on the pharmacokinetic profile of emtricitabine+tenofovir+efavirenz, when co-formulated in one tablet, in HIV-infected patients with smear-positive pulmonary tuberculosis in Tanzania.
2. To determine the effect of the emtricitabine+tenofovir+efavirenz regimen on the pharmacokinetics of tuberculostatics in the same population.

The secondary objectives are:

1. To determine the safety of co-administration of emtricitabine+tenofovir+efavirenz with treatment for smear-positive pulmonary tuberculosis.
2. To determine the short-term (24 weeks) virological efficacy on HIV of an emtricitabine+tenofovir+efavirenz regimen in patients with smear-positive pulmonary tuberculosis.
3. To determine the short-term bacteriological efficacy on smear-positive tuberculosis of the co-administration of a standard regimen for tuberculosis and an emtricitabine+tenofovir+efavirenz regimen.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Tanzania
  • Kilimanjaro Region
    • Moshi, Kilimanjaro Region, Tanzania, P.O. Box 12
      • Recruiting
      • Kibong'oto National Tuberculosis Hospital
      • Contact: Liberate Mleoh, MD; Phone Number: 027 2756194; Email: lmleoh@yahoo.com
      • Principal Investigator: Gibson Kibiki, MMed, PhD
      • Sub-Investigator: Elton Kisanga, B-Pharm, PhD
      • Sub-Investigator: Liberate Mleoh, MD
      • Sub-Investigator: Jossy van den Boogaard, MD
      • Sub-Investigator: Hadija Semvua, B-Pharm, MPH
      • Sub-Investigator: Charles Mtabho, MD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A smear-positive pulmonary tuberculosis, based on positive smear of at least two sputum samples with Ziehl-Neelsen (ZN) staining.
• HIV-infected as documented by positive HIV antibody test.
• Subject is at least 18 years of age at the day of the first dosing of study medication.
• Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
• CD4 cell count > 50 copies/mm3.
• Karnofsky score > 40.
• Willing and able to regularly attend the Kibung'oto National Tuberculosis Hospital (KNTH) clinic.

Exclusion Criteria:

• History of sensitivity/idiosyncrasy to the drug or chemically related compounds or excipients, which may be employed in the trial.
• Previously treated for HIV infection with antiretroviral agents.
• Pregnant or breastfeeding.
• Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
• A history of severe psychiatric disease such as psychosis, schizophrenia, etc.
• Inability to understand the nature and extent of the trial and the procedures required.
• Abnormal serum transaminases or creatinine, determined as levels being > 5 times upper limit of normal.
• Active hepatobiliary or hepatic disease (Non B Chronic Hepatitis B/C co-infection is allowed).
• CD4 cell count > 350 cells/mm3.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic parameters of emtricitabine, tenofovir and efavirenz	Two 24 hour pharmacokinetic (PK) curves (week 8 and 28)
Pharmacokinetic parameters of the tuberculostatic agents	Pharmacokinetic (PK) samples at 2 hours and 6 hours postdose (week 2 and 8)

Secondary Outcome Measures

Outcome Measure	Time Frame
Biochemistry and haematology samples for safety	Samples at screening, baseline, week 2, 4, 6, 8, 12, 16, 24, 28
Questioning about occurrence of adverse events	At baseline, week 2, 4, 6, 8, 12, 16, 24, 28
CD4 count and HIV-1 RNA	At screening, week 4, week 16 and week 28
Sputum staining and culture	At screening, week 4, 8, and 28

Collaborators and Investigators

• Sponsor: African Poverty Related Infection Oriented Research Initiative
• Collaborators: Radboud University Medical Center; Kilimanjaro Christian Medical Centre, Tanzania
• Investigators: Principal Investigator: Martin Boeree, MD, PhD, University Lungcentre Dekkerswald, Groesbeek / University Medical Centre Nijmegen, the Netherlands; Principal Investigator: David Burger, PharmD, PhD, University Medical Centre Nijmegen, the Netherlands; Principal Investigator: Gibson Kibiki, MMed, PhD, Kilimanjaro Christian Medical Centre,Moshi,Tanzania

Publications and helpful links

General Publications

• Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001;40(5):327-41. doi: 10.2165/00003088-200140050-00002.
• Bowen EF, Rice PS, Cooke NT, Whitfield RJ, Rayner CF. HIV seroprevalence by anonymous testing in patients with Mycobacterium tuberculosis and in tuberculosis contacts. Lancet. 2000 Oct 28;356(9240):1488-9. doi: 10.1016/S0140-6736(00)02876-2.
• Msamanga GI, Fawzi WW. The double burden of HIV infection and tuberculosis in sub-Saharan Africa. N Engl J Med. 1997 Sep 18;337(12):849-51. doi: 10.1056/NEJM199709183371210. No abstract available.
• Dean GL, Edwards SG, Ives NJ, Matthews G, Fox EF, Navaratne L, Fisher M, Taylor GP, Miller R, Taylor CB, de Ruiter A, Pozniak AL. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS. 2002 Jan 4;16(1):75-83. doi: 10.1097/00002030-200201040-00010.
• Finch CK, Chrisman CR, Baciewicz AM, Self TH. Rifampin and rifabutin drug interactions: an update. Arch Intern Med. 2002 May 13;162(9):985-92. doi: 10.1001/archinte.162.9.985.
• Lopez-Cortes LF, Ruiz-Valderas R, Viciana P, Alarcon-Gonzalez A, Gomez-Mateos J, Leon-Jimenez E, Sarasanacenta M, Lopez-Pua Y, Pachon J. Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clin Pharmacokinet. 2002;41(9):681-90. doi: 10.2165/00003088-200241090-00004.
• Burger DM, Meenhorst PL, Koks CH, Beijnen JH. Pharmacokinetic interaction between rifampin and zidovudine. Antimicrob Agents Chemother. 1993 Jul;37(7):1426-31. doi: 10.1128/AAC.37.7.1426.
• Gallicano KD, Sahai J, Shukla VK, Seguin I, Pakuts A, Kwok D, Foster BC, Cameron DW. Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Br J Clin Pharmacol. 1999 Aug;48(2):168-79. doi: 10.1046/j.1365-2125.1999.00987.x.
• Friedland G, Abdool Karim S, Abdool Karim Q, Lalloo U, Jack C, Gandhi N, El Sadr W. Utility of tuberculosis directly observed therapy programs as sites for access to and provision of antiretroviral therapy in resource-limited countries. Clin Infect Dis. 2004 Jun 1;38 Suppl 5:S421-8. doi: 10.1086/421407.
• Droste JA, Aarnoutse RE, Koopmans PP, Hekster YA, Burger DM. Evaluation of antiretroviral drug measurements by an interlaboratory quality control program. J Acquir Immune Defic Syndr. 2003 Mar 1;32(3):287-91. doi: 10.1097/00126334-200303010-00007.
• Holland DT, DiFrancesco R, Stone J, Hamzeh F, Connor JD, Morse GD; Adult and Pediatric AIDS Clinical Trials Group Pharmacology Laboratory Committees, Pediatric AIDS Clinical Trials Group. Quality assurance program for clinical measurement of antiretrovirals: AIDS clinical trials group proficiency testing program for pediatric and adult pharmacology laboratories. Antimicrob Agents Chemother. 2004 Mar;48(3):824-31. doi: 10.1128/AAC.48.3.824-831.2004.
• Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001 Jan 5;15(1):71-5. doi: 10.1097/00002030-200101050-00011.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Anticipated): December 1, 2009
• Study Completion (Anticipated): December 1, 2009

Study Registration Dates

• First Submitted: May 16, 2007
• First Submitted That Met QC Criteria: May 16, 2007
• First Posted (Estimate): May 17, 2007

Study Record Updates

• Last Update Posted (Estimate): December 17, 2010
• Last Update Submitted That Met QC Criteria: December 16, 2010
• Last Verified: December 1, 2008

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; Efavirenz; Tuberculosis; Tenofovir; Treatment Naive; Rifampin; Coinfection; Emtricitabine
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Emtricitabine; Efavirenz
• Other Study ID Numbers: UMCN-AKF 04.03