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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Tuberculosis; HIV Infections	Drug: Emtricitabine/tenofovir/efavirenz	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	30 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	The Pharmacokinetics of Co-formulated Emtricitabine/Tenofovir/Efavirenz in HIV-infected Patients With Smear-positive Pulmonary Tuberculosis in the Kilimanjaro Region, Tanzania
Study Start Date :	November 2008
Estimated Primary Completion Date :	December 2009
Estimated Study Completion Date :	December 2009

Arms and Interventions

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Intervention Details:

Drug: Emtricitabine/tenofovir/efavirenz

Co-formulated in one tablet (taken once daily by oral administration):

• emtricitabine 200 mg
• tenofovir DF 300 mg
• efavirenz 600 mg

Outcome Measures

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Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Contacts

Contact: Gibson Kibiki, MMed, PhD	+255 754 572767	gkibiki@gmail.com
Contact: Jossy van den Boogaard, MD	+255 787 148431	jossyvandenboogaard@gmail.com

Locations

Tanzania
Kibong'oto National Tuberculosis Hospital	Recruiting
Moshi, Kilimanjaro Region, Tanzania, P.O. Box 12
Contact: Liberate Mleoh, MD 027 2756194 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

Sponsors and Collaborators

African Poverty Related Infection Oriented Research Initiative

Radboud University

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

More Information

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Publications:

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.

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.

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.

Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001;40(5):327-41. Review.

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. Review.

López-Cortés LF, Ruiz-Valderas R, Viciana P, Alarcón-González A, Gómez-Mateos J, León-Jimenez E, Sarasanacenta M, López-Pua Y, Pachón J. Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clin Pharmacokinet. 2002;41(9):681-90.

Burger DM, Meenhorst PL, Koks CH, Beijnen JH. Pharmacokinetic interaction between rifampin and zidovudine. Antimicrob Agents Chemother. 1993 Jul;37(7):1426-31.

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.

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.

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.

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.

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.

Responsible Party:	Martin Boeree, University Lungcentre Dekkerswald, Groesbeek, the Netherlands
ClinicalTrials.gov Identifier:	NCT00474435 History of Changes
Other Study ID Numbers:	UMCN-AKF 04.03
First Posted:	May 17, 2007
Last Update Posted:	December 17, 2010
Last Verified:	December 2008

Keywords provided by African Poverty Related Infection Oriented Research Initiative:

Tuberculosis; HIV; Coinfection; Pharmacokinetics; Emtricitabine	Tenofovir; Rifampin; Efavirenz; Treatment Naive

Additional relevant MeSH terms:

HIV Infections; Tuberculosis; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Tenofovir

Emtricitabine; Efavirenz; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Anti-HIV Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP2B6 Inducers