The Compartmental Biology of HIV in the Male Genital Tract

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Human Immunodeficiency Virus, Virus Shedding

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HIV positive TDF/FTC<br>8 HIV positive men taking TDF/FTC as treatment | |
| HIV negative<br>8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis | |
| HIV Positive TAF<br>8 HIV positive men taking TAF as treatment | |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, tenofovir-emtricitabine, antiretroviral therapy, Prevention, tenofovir alafenamide