The Compartmental Biology of HIV in the Male Genital Tract

IGHID 11526 - The Compartmental Biology of HIV in the Male Genital Tract

Male participants taking tenofovir-emtricitabine (TDF/FTC) will provide semen and blood samples which will be analyzed to better understand the pharmacology of antiretroviral therapy in the male genital tract.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus; Virus Shedding

Detailed Description

8 HIV positive men taking TDF/FTC and 8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis will provide multiple semen and blood samples during a 48-hour inpatient visit. 8 HIV positive men taking TAF (tenofovir alafenamide) will provide multiple semen and blood samples during a 48-hour inpatient visit.

Participants will take part in the study for approximately two months. After the screening visit, there is one 2 day overnight visit for intensive PK/PD (pharmacokinetic/pharmacodynamic) sampling. The investigators will study drug concentrations and intracellular endogenous nucleotide concentrations (dATP and dCTP) in seminal plasma and (where appropriate) seminal cells.

Samples will be analyzed through the use of novel laboratory methods to determine the seminal plasma and seminal cell concentrations of tenofovir and emtricitabine. New technologies will be used to better understand compartmental and intracellular antiretroviral pharmacology of nucleoside/tide reverse transcriptase inhibitors. Pharmacokinetic modeling will be used to estimate the primary outcomes.

• Study Type: Observational
• Enrollment (Actual): 26

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

HIV positive and HIV negative men taking TDF/FTC once daily, HIV positive men taking TAF/FTC once daily

Description

Inclusion Criteria:

• Born male between the ages of 18 and 60
• HIV positive taking TDF/FTC (and a third drug) as treatment; or HIV negative men receiving TDF/FTC as pre-exposure prophylaxis; HIV positive men taking tenofovir alafenamide
• if on routine treatment must have been taking medication for at least 3 months and adherence to medication as assessed by blood plasma HIV RNA less than 50 copies per mL.
• documentation of at least 80% adherence to antiretroviral (ART) regimen, through clinician or self-report, with no missed doses in the 3 days prior to the inpatient visit.
• willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurologic disease that would pose unnecessary risk or interfere with study results.
• unwilling or unable to abstain from sexual activity 72 hours prior to overnight sampling visit
• unlikely to remain on current drug regimen during study period
• anemia that precludes blood donation
• unable to provide semen specimen
• current receipt of other medications that may affect endogenous nucleotide concentrations, such as additional HIV nucleoside reverse transcriptase inhibitors, ribavirin, or adefovir

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
HIV positive TDF/FTC; 8 HIV positive men taking TDF/FTC as treatment
HIV negative; 8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis
HIV Positive TAF; 8 HIV positive men taking TAF as treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Semen Clearance (CL) of Tenofovir	Samples will be analyzed for drug concentrations at the following time points post dose: 3, 6, 9, 12, 18 and 24 hours, and used to estimate clearance from semen from a 300mg dose of tenofovir.	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose
Semen Clearance (CL) of Emtricitabine	Samples will be analyzed for drug concentration at the following time points post dose: 3, 6, 9, 12, 18 and 24 hours, and used to estimate clearance from semen from a 200mg dose of emtricitabine.	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose
Semen Clearance (CL) of Tenofovir Diphosphate	Samples will be analyzed for drug concentration at the following time points post dose: 3, 6, 9, 12, 18 and 24 hours, and used to estimate the clearance of tenofovir diphosphate, an intracellular metabolite of tenofovir, from seminal mononuclear cells, following a 300mg dose of tenofovir.	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose
Semen Clearance (CL) of Emtricitabine Triphosphate	Samples will be analyzed for drug concentration at the following time points post dose: 3, 6, 9, 12, 18 and 24 hours, and used to estimate the clearance of emtricitabine triphosphate, an intracellular metabolite of emtricitabine, from seminal mononuclear cells, following a 200mg dose of emtricitabine.	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose
Peripheral Blood Mononuclear Cell (PBMC) Clearance (CL) of Tenofovir Diphosphate	Samples will be analyzed for drug concentration at the following time points post dose: 3, 6, 9, 12, 18 and 24 hours, and used to estimate the clearance of tenofovir diphosphate, an intracellular metabolite of tenofovir, from peripheral blood mononuclear cells, following a 300mg dose of tenofovir.	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose
Peripheral Blood Mononuclear Cell (PBMC) Clearance (CL) of Emtricitabine Triphosphate	Samples will be analyzed for drug concentration at the following time points post dose: 3, 6, 9, 12, 18 and 24 hours, and used to estimate the clearance of emtricitabine triphosphate, an intracellular metabolite of emtricitabine, from peripheral blood mononuclear cells, following a 200mg dose of emtricitabine.	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tenofovir Diphosphate (TFVdp)/Deoxyadenosine Triphosphate (dATP) Ratio in Seminal Mononuclear Cells	dATP concentrations in seminal mononuclear cells will be measured and compared to tenofovir diphosphate concentrations, using a ratio, and summarized descriptively for each subject, as well as across subjects. As the six seminal cell samples collected per man were pooled for analysis due to low cell recovery, a single ratio value per participant was calculated and summarized by study arm.	Average concentration in a 24 hour dosing interval
Emtricitabine Triphosphate (FTCtp)/Deoxyadenosine Triphosphate (dCTP) Ratio in Seminal Mononuclear Cells	dCTP concentrations in seminal mononuclear cells will be measured and compared to emtricitabine triphosphate concentrations, using a ratio, and summarized descriptively for each subject, as well as across subjects. As the six seminal cell samples collected per man were pooled for analysis due to low cell recovery, a single ratio value per participant was calculated and summarized by study arm.	Average concentration in a 24 hour dosing interval

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Julie Dumond, PharmD, MS, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Galvin SR, Cohen MS. The role of sexually transmitted diseases in HIV transmission. Nat Rev Microbiol. 2004 Jan;2(1):33-42. doi: 10.1038/nrmicro794.
• Cohen MS, Gay C, Kashuba AD, Blower S, Paxton L. Narrative review: antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann Intern Med. 2007 Apr 17;146(8):591-601. doi: 10.7326/0003-4819-146-8-200704170-00010.
• Anderson DJ, Politch JA, Nadolski AM, Blaskewicz CD, Pudney J, Mayer KH. Targeting Trojan Horse leukocytes for HIV prevention. AIDS. 2010 Jan 16;24(2):163-87. doi: 10.1097/QAD.0b013e32833424c8. No abstract available.
• Joseph SB, Swanstrom R, Kashuba AD, Cohen MS. Bottlenecks in HIV-1 transmission: insights from the study of founder viruses. Nat Rev Microbiol. 2015 Jul;13(7):414-25. doi: 10.1038/nrmicro3471. Epub 2015 Jun 8.

Helpful Links

• University of North Carolina website

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: December 10, 2015
• First Submitted That Met QC Criteria: December 18, 2015
• First Posted (Estimate): December 23, 2015

Study Record Updates

• Last Update Posted (Actual): July 24, 2017
• Last Update Submitted That Met QC Criteria: April 24, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: HIV; Prevention; tenofovir alafenamide; antiretroviral therapy; tenofovir-emtricitabine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
• Other Study ID Numbers: 15-2767; R01DK108424-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No