Evaluation of the Cellular Pharmacology of Tenofovir and Emtricitabine According to HIV Infection Status

NCT01040091 | Completed Phase 1

• 2 other identifiers: U01 Anderson10817
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are two antiretroviral medications used for the treatment and prevention of HIV/AIDS. This study will examine how these medications are processed in the body of people who are HIV-infected, as well as in people who are HIV-uninfected.

Conditions

HIV Infections

Keywords

HIV Seronegativity; Treatment Experienced

Outcome Measures

Primary Outcomes (4)

• Comparison of the first dose tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) area under the concentration-time curve (AUC) in HIV-uninfected adults versus HIV-infected adults

  Measured at the time of the first dose

• Comparison of average steady-state plasma deoxyguanosine concentrations before therapy and after 30 days of TDF/FTC therapy

  Measured through Day 30

• Comparison of TFV-DP and FTC-TP in HIV-seroconverters versus matched non-seroconverters from the iPrEx study

  Measured throughout the 4-year study

• Modeling describing intracellular pharmacokinetics of TFV-DP and FTC-TP in PBMCs so dosing strategies can be tested on the model to identify the optimal dosing that most rapidly achieves and sustains the desired prophylactic threshold for HIV prevention

  Measured throughout the 4-year study

Secondary Outcomes (13)

• Definition of the terminal elimination phase of TFV-DP and FTC-TP in HIV-uninfected adults

  Measured from Day 30 to 60

• Characterization of TFV-DP and FTC-TP according to cell types: PBMCs, CD4-purified PBMCs (as well as erythrocytes-to include dried blood spot analyses, CD8 cells, B-cells, and monocytes), genital mononuclear cells, and rectal mucosal mononuclear cells

  Measured through Day 30

• Comparison of TFV-DP and FTC-TP between male and female participants

  Measured through Day 30

• Characterization of intracellular TFV, tenofovir-monophosphate (TFV-MP), emtricitabine-monophosphate (FTC-MP), and emtricitabine-diphosphate (FTC-DP)

  Measured through Day 30

• Evaluation of markers of cell activation (HLA-DR and CD38 expression) and the relationship to TFV-DP and FTC-TP concentrations

  Measured through Day 30

Study Arms (2)

HIV-Infected Participants

ACTIVE COMPARATOR

HIV-infected participants will receive FTC, TDF, and EFV for 60 days by prescription from their physicians. Participants will receive Truvada (FTC/TDF) and EFV for the first 30 days. After Day 30, participants may switch to the TDF/FTC/EFV co-formulation through Day 60 as directed by their physician.

Drug: Emtricitabine (FTC); Drug: Tenofovir disoproxil fumarate (TDF); Drug: Efavirenz (EFV); Drug: Truvada

HIV-Uninfected Participants

ACTIVE COMPARATOR

HIV-uninfected participants will receive Truvada (FTC/TDF) for 30 days.

Drug: Truvada

Interventions

Emtricitabine (FTC) DRUG

200 mg once a day

HIV-Infected Participants

Tenofovir disoproxil fumarate (TDF) DRUG

300 mg once a day

HIV-Infected Participants

Efavirenz (EFV) DRUG

600 mg once a day

HIV-Infected Participants

Truvada DRUG

200 mg emtricitabine + 300 mg TDF once a day

HIV-Infected Participants; HIV-Uninfected Participants

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Ability to provide informed consent
• Ability to comply with the study procedures

You may not qualify if:

• Positive screening test for HIV infection
• Positive screening test for hepatitis B (HBV) infection
• Pregnant or planning to become pregnant in the 3 months after study entry
• Breastfeeding
• If sexually active and fertile (no tubal ligation or hysterectomy), refusal to use two forms of birth control (e.g., condom and hormonal birth control) during the 60-day study
• Estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m\^2 by the Modification of Diet in Renal Disease (MDRD) method
• Albuminuria (greater than 30 mg urine albumin per g of urine creatinine)
• Blood donation within 56 days of the screening visit
• Any grade I or higher abnormality in hemoglobin, platelets, serum phosphorous, and lipase on the screening visit; grade I abnormalities in other labs will be evaluated on a case by case basis (using DAIDS criteria)
• Any greater than grade I abnormality in screening laboratory tests (using DAIDS grading criteria)
• Medical history of chronic uncontrolled high blood pressure equal to or above 140/90 mm Hg
• Use of any investigational medication in the 30 days before study entry
• Daily anticoagulant therapy (daily aspirin or non-steroidal anti-inflammatory drugs \[NSAIDs\] will be allowed if discontinued for 1 week prior to the rectal biopsy)
• Any nephrotoxic concomitant medication (e.g., aminoglycosides, cyclosporine, cidofovir, foscarnet, amphotericin B)
• Active recreational drug or alcohol abuse

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

University of Colorado CTRC CRS

Aurora, Colorado, 80045, United States

Location

Related Publications (3)

• Castillo-Mancilla J, Seifert S, Campbell K, Coleman S, McAllister K, Zheng JH, Gardner EM, Liu A, Glidden DV, Grant R, Hosek S, Wilson CM, Bushman LR, MaWhinney S, Anderson PL. Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6692-6697. doi: 10.1128/AAC.01017-16. Print 2016 Nov.

  PMID: 27572401 DERIVED

• Chen X, Castillo-Mancilla JR, Seifert SM, McAllister KB, Zheng JH, Bushman LR, MaWhinney S, Anderson PL. Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5387-92. doi: 10.1128/AAC.01019-16. Print 2016 Sep.

  PMID: 27353267 DERIVED

• Castillo-Mancilla JR, Meditz A, Wilson C, Zheng JH, Palmer BE, Lee EJ, Gardner EM, Seifert S, Kerr B, Bushman LR, MaWhinney S, Anderson PL. Reduced immune activation during tenofovir-emtricitabine therapy in HIV-negative individuals. J Acquir Immune Defic Syndr. 2015 Apr 15;68(5):495-501. doi: 10.1097/QAI.0000000000000529.

  PMID: 25763783 DERIVED

Related Links

• Click here for the "Chemoprophylaxis for HIV Prevention in Men (iPrEx)" ClinicalTrials.gov study record.

MeSH Terms

Conditions

HIV Infections

Interventions

Emtricitabine; Racivir; Tenofovir; efavirenz; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Peter L. Anderson, PharmD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 23, 2009
• First Posted: December 25, 2009
• Study Start: December 1, 2009
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: December 16, 2016

Record last verified: 2014-04

Locations

US (1)