Body Compartment PK for New HIV Pre-exposure Prophylaxis Modalities

Study Overview
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Brief Summary
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The purpose of this study is to determine the ability of new anti-HIV agents to penetrate different body compartments in HIV negative men who have sex with men and transgender women. These new agents might be considered for pre-exposure prophylaxis regimens in the future. This study will include 90 healthy, HIV-negative men who have sex with men and transgender women who are not taking hormones aged 18-49 years. Participant must be willing to participate in 1 of the 3 study phases, be willing to take Truvada® (PrEP) or Genvoya®, and willing to undergo blood draws, urethral swabs, and rectal biopsy procedures.

Detailed Description
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Men who have sex with men (MSM) and Transgender women (TGW) who have sex with men continue to be disproportionately affected by HIV. Over 60% of new HIV infections in the US occur among MSM. The majority of HIV infections among MSM and TGW occur through exposure to the rectal mucosa during receptive anal intercourse (RAI). Pre-exposure prophylaxis (PrEP) is a new HIV prevention method that is recommended by CDC and WHO for MSM at risk of HIV infection. PrEP entails taking an anti-HIV medication (Truvada®; tenofovir/emtricitabine) on a daily basis to prevent HIV infection. However, current tenofovir- based regimens have shown to have side effects that researchers are hoping to reduce in newly developed anti-HIV agents. This study is designed to examine the ability of these new agents to penetrate mucosal tissues and potentially prevent HIV infection during RAI exposure for MSM and TGW.

Official Title
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Body Compartment PK for New HIV Pre-exposure Prophylaxis Modalities

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Truvada
* Drug: Genvoya


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-negative man who reports receptive anal sex with another man in the last 6 months Male to female transgender women who have sex with men who report receptive anal intercourse with another man in the last 6 months and are not currently taking hormonal therapy or plan to take hormonal therapy for the duration of the study Not currently taking PrEP and no plans to initiate during study Able to provide informed consent in English No plans for relocation in the next 3 months Willing to undergo peripheral blood and rectal biopsy sampling Willing to use study products as directed Willing to abstain from receptive anal intercourse 3 days prior to starting study product and for the duration of the study and for 7 days after any rectal biopsy procedure. Exclusion Criteria: History of inflammatory bowel disease or other inflammatory, infiltrative, infectious or vascular condition involving the lower gastrointestinal tract that, in the judgment of the investigators, may be worsened by study procedures or may significantly distort the anatomy of the distal large bowel Significant laboratory abnormalities at baseline visit, including but not limited to: Hgb ≤ 10 g/dL PTT > 1.5x ULN or INR > 1.5x ULN Platelet count <100,000 Creatinine clearance <60 Any known medical condition that, in the judgment of the investigators, increases the risk of local or systemic complications of endoscopic procedures or pelvic examination, including but not limited to: Uncontrolled or severe cardiac arrhythmia Recent major abdominal, cardiothoracic, or neurological surgery History of uncontrolled bleeding diathesis History of colonic, rectal, or vaginal perforation, fistula, or malignancy History or evidence on clinical examination of ulcerative, suppurative, or proliferative lesions of the anorectal or vaginal mucosa, or untreated sexually transmitted disease with mucosal involvement Continued need for, or use during the 14 days prior to enrollment, of the following medications: Aspirin or more than 4 doses of NSAIDs Warfarin, heparin (low-molecular weight or unfractionated), platelet aggregation inhibitors, or fibrinolytic agents Any form of rectally administered agent besides products lubricants or douching used for sexual intercourse Continued need for, or use during the 90 days prior to enrollment, of the following medications: Systemic immunomodulatory agents Supraphysiologic doses of steroids Experimental medications, vaccines, or biologicals Intent to use HIV antiretroviral pre-exposure prophylaxis (PrEP) during the study, outside of the study procedures Symptoms of an untreated rectal sexually transmitted infection (e.g. rectal pain, discharge, bleeding, etc.) Current use of hormonal therapy Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with the study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Phase I/Pre-Drug<br>Ten participants will be asked to complete study phase 1. Participants will be asked to provide blood and urine samples and undergo penile, urethral, and rectal swabs. Up to 12 rectal biopsies will be taken. | |
| Experimental: Phase II/Genvoya<br>Participants will receive one dose Genvoya. Participants will be asked to provide blood and urine samples and undergo penile, urethral, and rectal swabs. Up to 12 rectal biopsies will be taken. | Drug: Genvoya<br>* Genvoya is a 1-pill, once-a-day prescription medicine used to treat HIV-1. Genvoya is a combination of 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamid in one tablet.<br>|
| Experimental: Phase II/Truvada<br>Participants will receive one dose of Truvada. Participants will be asked to provide blood and urine samples and undergo penile, urethral, and rectal swabs. Up to 12 rectal biopsies will be taken. | Drug: Truvada<br>* Truvada is intended for the treatment of HIV-1 infection. Truvada is a combination of emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg in one tablet.<br>|
| Experimental: Phase III/Genvoya<br>Participants will receive Genvoya once daily for ten days. Participants will be asked to provide blood and urine samples and undergo penile, urethral, and rectal swabs. Up to 12 rectal biopsies will be taken. | Drug: Genvoya<br>* Genvoya is a 1-pill, once-a-day prescription medicine used to treat HIV-1. Genvoya is a combination of 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamid in one tablet.<br>|
| Experimental: Phase III/Truvada<br>Participants will receive Truvada once daily for ten days. Participants will be asked to provide blood and urine samples and undergo penile, urethral, and rectal swabs. Up to 12 rectal biopsies will be taken. | Drug: Truvada<br>* Truvada is intended for the treatment of HIV-1 infection. Truvada is a combination of emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg in one tablet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Intracellular Emtricitabine Triphosphate (FTC-TP) | Intracellular emtricitabine triphosphate (FTC-TP) is measured and compared from blood specimen in both arms from baseline to visit 4. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Changes in Intracellular Tenofovir Diphosphate (TFV-DP) | Intracellular tenofovir diphosphate (TFV-DP) is measured and compared from blood specimen in both arms from baseline to visit 4. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Emtricitabine (FTC) Concentration | Plasma emtricitabine (FTC) concentration is measured from blood specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Plasma Tenofovir Disoproxil Fumarate (TDF) Concentration | Plasma tenofovir disoproxil fumarate (TDF) concentration is measured from blood specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Plasma Tenofovir Alafenamide (TAF) Concentration | Plasma tenofovir alafenamide (TAF) concentration is measured from blood specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Plasma Elvitegravir (EVG) Concentration | Plasma elvitegravir (EVG) concentration is measured from blood specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Rectal Emtricitabine (FTC) Concentration | Emtricitabine (FTC) concentration is measured from rectal secretion specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Rectal Tenofovir Disoproxil Fumarate (TDF) Concentration | Tenofovir disoproxil fumarate (TDF), concentration is measured from rectal secretion specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Rectal Tenofovir Alafenamide (TAF) Concentration | Tenofovir alafenamide (TAF) concentration is measured from rectal secretion specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Rectal Elvitegravir (EVG) Concentration | Elvitegravir (EVG) concentration is measured from rectal secretion specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Intracellular Tenofovir Alafenamide (TAF) Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | Intracellular tenofovir alafenamide (TAF) concentration is measured from isolated PBMCs collected via blood draw. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Intracellular Elvitegravir (EVG) Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | Intracellular elvitegravir (EVG) concentration is measured from isolated PBMCs collected via blood draw. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Intracellular Emtricitabine (FTC) Concentration in Rectal Tissue | Tissue emtricitabine (FTC) concentration is measured from rectal biopsies and isolated cells. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Intracellular Tenofovir (TFV) Concentration in Rectal Tissue | Intracellular tenofovir (TFV) Concentration in Rectal Tissue is measured from rectal biopsies and isolated cells. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Tenofovir Alafenamide (TAF) Concentration in Rectal Tissue | Tissue tenofovir alafenamide (TAF) concentration is measured from rectal biopsies and isolated cells. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Elvitegravir (EVG) Concentration in Rectal Tissue | Tissue elvitegravir (EVG) concentration is measured from rectal biopsies and isolated cells. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Emtricitabine (FTC) Concentration in Penile Secretions | Emtricitabine (FTC) concentrations is measured from urethral and penile specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Tenofovir Disoproxil Fumarate (TDF) Concentration in Penile Secretions | Tenofovir disoproxil fumarate (TDF) concentrations is measured from urethral and penile specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Tenofovir Alafenamide (TAF) Concentration in Penile Secretions | Tenofovir alafenamide (TAF) concentrations is measured from urethral and penile specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| Change in Elvitegravir (EVG) Concentration in Penile Secretions | Elvitegravir (EVG) concentrations is measured from urethral and penile specimen. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Baseline, Visit 4 (Up to ten days post drug) | 
| PrEP Efficacy as Measured by Inhibition of in Vitro Infection of Rectal Biopsies to HIV | Rectal biopsies will be subjected to in vitro infection with HIV to test for changes in susceptibility to virus infection. Concentrations of cumulative p24 production in supernatants following in vitro infection of rectal biopsies correlate with viral infection and replication in rectal biopsies. Therefore, lower concentrations of p24 production in biopsies collected from men receiving PrEP compared to controls indicates a potential greater protection from infection and potential increased PrEP efficacy. For the pharmacokinetic analysis, values reported as Below the Limit of Quantification (BLOQ) are assigned a value of zero if it occurs in a profile after dosing at time zero and before the first measurable concentration. | Up to 10 months post-baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preventative Medicine, Infectious Diseases, Sexually Transmitted Diseases