The Compartmental Biology of HIV in the Male Genital Tract

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

Status

Completed

Phases

Unknown

Study type

Observational

Source

ClinicalTrials.gov

Registry ID

NCT02638493

Enrollment

Registered

2015-12-23

Start date

2015-12-31

Completion date

2016-10-31

Last updated

2017-07-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Human Immunodeficiency Virus, Virus Shedding

Keywords

HIV, tenofovir-emtricitabine, antiretroviral therapy, Prevention, tenofovir alafenamide

Brief summary

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

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.

Interventions

None listed

Study design

Observational model

CASE_CONTROL

Time perspective

PROSPECTIVE

Eligibility

Sex/Gender

MALE

Age

18 Years to 60 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

Measure	Time frame	Description
Peripheral Blood Mononuclear Cell (PBMC) Clearance (CL) of Emtricitabine Triphosphate	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose	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.
Semen Clearance (CL) of Emtricitabine Triphosphate	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose	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.
Peripheral Blood Mononuclear Cell (PBMC) Clearance (CL) of Tenofovir Diphosphate	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose	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.
Semen Clearance (CL) of Tenofovir	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose	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.
Semen Clearance (CL) of Emtricitabine	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose	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.
Semen Clearance (CL) of Tenofovir Diphosphate	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose	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.

Secondary

Measure	Time frame	Description
Emtricitabine Triphosphate (FTCtp)/Deoxyadenosine Triphosphate (dCTP) Ratio in Seminal Mononuclear Cells	Average concentration in a 24 hour dosing interval	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.
Tenofovir Diphosphate (TFVdp)/Deoxyadenosine Triphosphate (dATP) Ratio in Seminal Mononuclear Cells	Average concentration in a 24 hour dosing interval	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.

Countries

United States

Participant flow

Recruitment details

All participants were recruited at the University of North Carolina at Chapel Hill and surrounding areas, through Institutional Review Board (IRB)-approved advertisements.

Pre-assignment details

Participants interested in the study were pre-screened for eligibility using an IRB-approved questionnaire.

Participants by arm

Arm	Count
HIV Positive TDF/FTC 8 HIV positive men taking TDF/FTC as treatment	8
HIV Negative 8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8
HIV Positive TAF 8 HIV positive men taking TAF as treatment	8
Total	24

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Inability to provide semen samples	2	0	0

Baseline characteristics

Characteristic	HIV Negative	HIV Positive TAF	HIV Positive TDF/FTC	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	8 Participants	8 Participants	8 Participants	24 Participants
Age, Continuous	30.5 years	45.5 years	36.5 years	36.5 years
Region of Enrollment United States	8 participants	8 participants	8 participants	24 participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	8 Participants	8 Participants	8 Participants	24 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 8	0 / 8
other Total, other adverse events	0 / 8	1 / 8	1 / 8
serious Total, serious adverse events	0 / 8	0 / 8	0 / 8

Outcome results

Primary

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.