This study is comparing rectal and oral Tenofavir-based prep. The rectal study product is a rectal douche, or enema, that contains the anti-HIV drug tenofovir (TFV). The other study product is taken by mouth and is a combination of two drugs, called emtricitabine (FTC or F) and tenofovir disoproxil fumarate (TDF).

Tenofovir (TFV) rectal douche is considered investigational because it is not approved by the U.S. Food and Drug Administration (FDA). Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) is FDA-approved and used according to FDA labeling.

Participants are randomized to one of two groups. Randomization is like flipping a coin and there is a 50/50 chance of being assigned to either group.

 One group will use a Tenofovir (TFV) douche then take oral F/TDF. The other group will take oral F/TDF then TFV douche. Both groups will last for 8 weeks with a 2 to 4-week washout period in between.

Total study participation will be for about 19 weeks, including the treatment period and approximately 8 visits in the study clinic.