The Compartmental Biology of HIV in the Male Genital Tract

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT02638493
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 26
• Location: 1
• Actual Duration (Months): 10
• Patients Per Site Per Month: 2.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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 Design

• Study Type: Observational
• Actual Enrollment: 26 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: IGHID 11526 - The Compartmental Biology of HIV in the Male Genital Tract
• Actual Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Secondary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: Male
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• National Institutes of Health (NIH)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Julie Dumond, PharmD, MS, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of North Carolina website

Publications

• 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. Review.
• 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. Review.
• Galvin SR, Cohen MS. The role of sexually transmitted diseases in HIV transmission. Nat Rev Microbiol. 2004 Jan;2(1):33-42. Review.
• 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. Review.

• Responsible Party: Julie Dumond, PharmD, Assistant Professor, University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT02638493
• Other Study ID Numbers: 15-2767; R01DK108424-01
• First Posted: Dec 23, 2015
• Last Update Posted: Jul 24, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Julie Dumond, PharmD, Assistant Professor, University of North Carolina, Chapel Hill: HIV; tenofovir-emtricitabine; antiretroviral therapy; Prevention; tenofovir alafenamide
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections

Study Results

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

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC (Tenofovir Disoproxil Fumarate/Emtricitabine) as treatment	8 HIV negative men taking TDF/FTC (Tenofovir Disoproxil Fumarate/Emtricitabine) as pre-exposure prophylaxis	8 HIV positive men taking TAF (Tenofovir Alafenamide) as treatment
Period Title: Overall Study
STARTED	10	8	8
COMPLETED	8	8	8
NOT COMPLETED	2	0	0

Baseline Characteristics

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF	Total
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment	Total of all reporting groups
Overall Participants	8	8	8	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 100%	8 100%	8 100%	24 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	36.5	30.5	45.5	36.5
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	8 100%	8 100%	8 100%	24 100%
Region of Enrollment (participants) [Number]
United States	8 100%	8 100%	8 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	Semen Clearance (CL) of Tenofovir
Description	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.
Time Frame	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [L/hr]	33.88	51.21	5.65

2. Primary Outcome

Title	Semen Clearance (CL) of Emtricitabine
Description	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.
Time Frame	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [L/hr]	5.91	8.72	7.12

3. Primary Outcome

Title	Semen Clearance (CL) of Tenofovir Diphosphate
Description	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.
Time Frame	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [fmol/10x6 cells]	21	21	35

4. Primary Outcome

Title	Semen Clearance (CL) of Emtricitabine Triphosphate
Description	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.
Time Frame	Samples collected at 3, 6, 9, 12, 18 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Semen (SMC) Steady State Concentrations (Css,ave) of Emtricitabine Triphosphate

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [fmol/10 E6 cells]	59	90	179

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [fmol/10 E6 cells]	174	119	935

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [fmol/10 E6 cells]	6038	6135	8242

7. Secondary Outcome

Title	Tenofovir Diphosphate (TFVdp)/Deoxyadenosine Triphosphate (dATP) Ratio in Seminal Mononuclear Cells
Description	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.
Time Frame	Average concentration in a 24 hour dosing interval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [TFVdp:dATP ratio]	0.99	0.66	1.10

8. Secondary Outcome

Title	Emtricitabine Triphosphate (FTCtp)/Deoxyadenosine Triphosphate (dCTP) Ratio in Seminal Mononuclear Cells
Description	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.
Time Frame	Average concentration in a 24 hour dosing interval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV Positive TDF/FTC	HIV Negative	HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment	8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis	8 HIV positive men taking TAF as treatment
Measure Participants	8	8	8
Median (Inter-Quartile Range) [FTCtp:dCTP ratio]	0.52	0.96	3.81

Adverse Events

Time Frame	Adverse events were collected from the time of informed consent, until end of study enrollment.
Adverse Event Reporting Description	does not differ
Arm/Group Title	HIV Positive TDF/FTC		HIV Negative		HIV Positive TAF
Arm/Group Description	8 HIV positive men taking TDF/FTC as treatment		8 HIV negative men taking TDF/FTC as pre-exposure prophylaxis		8 HIV positive men taking TAF as treatment
All Cause Mortality
	HIV Positive TDF/FTC		HIV Negative		HIV Positive TAF
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)
Serious Adverse Events
	HIV Positive TDF/FTC		HIV Negative		HIV Positive TAF
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	HIV Positive TDF/FTC		HIV Negative		HIV Positive TAF
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		1/8 (12.5%)		1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Viral Pharyngitis	0/8 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Penile skin irritation	0/8 (0%)	0	0/8 (0%)	0	1/8 (12.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.