CROSSOVER STUDY OF ON-DEMAND PREP FORMULATIONS COMPARING RECTAL AND ORAL TENOFOVIR

Inclusion Criteria:

1. Assigned male at birth

2.18 years of age or older at the time of screening informed consent

3.Willing and able to provide informed consent to take part in the study

4. Able to read at a level required for the study components (e.g., CASI and SMS)

5. Have access to device and the internet for completion of study procedures

6. Understand and agree to local STI reporting requirements

7.Non-reactive/negative HIV test results at screening and enrollment

8. A history of consensual RAI at least five times in their lifetime and at least oncein the prior 3 months

9. Received or self-administered an enema or rectal douche more than half the timeprior to engaging in RAI in the past year.

10. Willing and able to use condoms for all sexual intercourse for the duration ofparticipation

11. Agrees not to participate in other research studies involving drugs, biologics,medical devices, vaccines, anal products, or genital products for the duration ofthe study

12. Willing and able to provide adequate locator information

13. Agrees not to knowingly engage in receptive or insertive sexual activity withanother study participant for the duration of study participation.

14. Available to return for all study visits and within any site's catchment area

ADDITIONAL INCLUSION FOR THOSE IN THE PK/PD SUB-STUDY

1. Willing to refrain from occasional over-the-counter use of aspirin and NSAID use for 72 hours before and after each study biopsy visit

2. Willing to abstain from insertion of anything (e.g., drug/medication, penis, object,sex toy, or enema including take-home enema) into the anorectum for 72 hours beforestudy drug dose and until 72 hours after each flexible sigmoidoscopy with biopsycollection, or one week after the study drug dose, whichever is later

3. Willing and able to use specific condoms and lubricant provided by the study clinicfor all RAI for the duration of participation

Exclusion Criteria:

1. Any reactive/positive HIV test at screening or at least one reactive/positive testresult at enrollment, even if HIV infection is not confirmed

2. History of active (including chronic) hepatitis B virus (HBV) infection, asdocumented by positive HBV surface antigen (HBsAg) at screening

3. Co-enrollment in any other interventional research study that may interfere withthis study (as provided by self-report or other available documentation). Exceptionsmay be made after consultation with the Clinical Management Committee (CMC).

4. ≥ Grade 2 laboratory abnormality at baseline as defined by The Division of AIDSTable for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1dated July 2017, except for estimated glomerular filtration rate (eGFR), which mustbe >75 mL/ min. (Coagulation (PT/INR) results ≥ Grade 2 are not exclusionary for themain study).

5. Significant colorectal symptom(s) as determined by medical history or by participantself-report (including but not limited to presence of any unresolved injury,infectious or inflammatory condition of the local mucosa, history of inflammatorybowel disease, presence of symptomatic external hemorrhoids, and presence of anypainful anorectal conditions that would be tender to manipulation)

6. At screening, participant-reported symptoms and/or clinical or laboratory diagnosisof active rectal or reproductive tract infection requiring treatment per current CDCguidelines or symptomatic urinary tract infection (UTI) a.Infections requiring treatment include chlamydia (CT), gonorrhea (GC), syphilis,active HSV lesions, chancroid, genital sores or ulcers, and, if clinicallyindicated, genital warts. Note: if an STI apart from HIV is detected, the participant will be referred fortreatment and, upon documented confirmation of definitive treatment, can be retestedin three weeks for evidence of adequate treatment.

7. History of an underlying clinically significant cardiac arrhythmia or renal disease

8. History of severe or recent cardiac or pulmonary event

9. History of significant gastrointestinal bleeding

10. Use of F/TDF or use of F/TAF as HIV PrEP within 8 weeks prior to screening visit oranticipated use throughout study participation

11. Use of injectable PrEP within 8 weeks prior to the screening visit or anticipateduse throughout study participation

12. Use of systemic or anorectal immunomodulatory medications, rectally administeredproducts containing N-9 or corticosteroids, or any investigational products unlessotherwise permitted within 4 weeks of screening or planned use at any time duringstudy participation

13. Known allergic reaction to TFV or other components of the test articles

14. Current known partners with HIV, unless with sustained viral suppression onantiretroviral treatment (ART)

15. History of recurrent urticaria

16. Symptoms suggestive of acute HIV infection at screening or enrollment

17. Any other condition or prior therapy that, in the opinion of the investigator, wouldpreclude informed consent, make study participation unsafe, make the individualunsuitable for the study or unable to comply with the study requirements. Suchconditions may include, but are not limited to, current or recent history of severe,progressive, or uncontrolled substance abuse, or renal, hepatic, hematological,gastrointestinal, endocrine, pulmonary, neurological, or cerebral disease

ADDITIONAL EXCLUSION FOR THOSE IN THE PK/PD SUB-STUDY

1. Current medically-indicated use of warfarin or heparin or other anticoagulantmedications associated with increased risk for bleeding following mucosal biopsy (e.g., daily high dose aspirin [>81 mg], non-steroidal anti-inflammatory drugs [NSAIDs], or Pradaxa®)

2. Previous use of injectable PrEP

3. ≥ Grade 2 laboratory result for coagulation testing (PT/INR) at baseline as definedby The Division of AIDS Table for Grading the Severity of Adult and PediatricAdverse Events, Version 2.1 dated July 2017.