Injectable Cabotegravir Compared to TDF/FTC For PrEP in HIV-Uninfected Men and Transgender Women Who Have Sex With Men

Inclusion Criteria: * MSM and TGW, 18 years or older at the time of screening (male at birth) * Willing to provide informed consent for the study * At high risk for sexually acquiring HIV infection based on self-report of at least one of the following: * Any condomless receptive anal intercourse in the 6 months prior to enrollment (condomless anal intercourse within a monogamous HIV seronegative concordant relationship does not meet this criterion) * More than five partners in the 6 months prior to enrollment (regardless of condom use and HIV serostatus, as reported by the enrollee) * Any stimulant drug use in the 6 months prior to enrollment * Rectal or urethral gonorrhea or chlamydia or incident syphilis in the 6 months prior to enrollment * SexPro score of less than or equal to 16 (U.S. sites only) * In general good health, as evidenced by the following laboratory values, which must be from specimens obtained within 45 days prior to study enrollment: * Non-reactive / negative HIV test results. More information on this criterion can be found in the protocol. * Hemoglobin greater than 11 g/dL, * Absolute neutrophil count greater than 750 cells/mm\^3 * Platelet count greater than or equal to 100,000/mm\^3 * Calculated creatinine clearance greater than or equal to 60 mL/minute using the Cockcroft-Gault equation (use sex at birth for calculation) * Although not protocol exclusionary, sites should carefully consider the advisability of enrolling participants with calculated creatinine clearance between 60-70 mL/min, as limited changes in creatinine clearance during study conduct will lead to protocol-mandated product holds and may alter the risk-benefit considerations of study participation * Alanine aminotransferase (ALT) less than 2 times the upper limit of normal (ULN) * Total bilirubin less than or equal to 2.5 times ULN * Hepatitis B virus (HBV) surface antigen (HBsAg) negative * Hepatitis C virus (HCV) Ab negative * No Grade 3 or higher laboratory abnormalities on any laboratory tests obtained at screening, including tests obtained as part of a panel of tests ordered to obtain the protocol-required laboratory test results. * No medical condition that, in the opinion of the study investigator, would interfere with the conduct of the study (e.g., provided by self-report, or found upon medical history and examination or in available medical records) * Willing to undergo all required study procedures Exclusion Criteria: * One or more reactive or positive HIV test result at Screening or Enrollment, even if HIV infection is not confirmed * Active or recent use of any illicit intravenous drugs ("recent" defined as in the 90 days prior to enrollment) * Co-enrollment in any other interventional research study or other concurrent studies that may interfere with this study (as provided by self-report or other available documentation. Exceptions may be made if appropriate after consultation with the CMC.) * Past or current participation in HIV vaccine trial. An exception will be made for participants that can provide documentation of receipt of placebo (not active arm). Note: Past participation in a monoclonal antibody study is not exclusionary, effective as of Version 1.0 of HPTN 083. * Clinically significant cardiovascular disease, as defined by history/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease * Inflammatory skin conditions that compromise the safety of intramuscular (IM) injections, per the discretion of the Investigator of Record. Mild skin conditions may not be exclusionary at the discretion of the Investigator of Record (IoR) or designee in consultation with the CMC * Has a tattoo or other dermatological condition overlying the buttock region which in the opinion of the IoR or designee, in consultation with the CMC, may interfere with interpretation of injection site reactions * Current or chronic history of liver disease (e.g., non-alcoholic or alcoholic steatohepatitis) or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome, asymptomatic gallstones, or cholecystectomy) * Coagulopathy (primary or iatrogenic) which would contraindicate IM injection (concomitant anticoagulant or anti-platelet therapy use should be discussed with the CMC) * Active or planned use of prohibited medications as described in the Investigator's Brochure or listed in the Study Specific Procedures (SSP) Manual (provided by self-report, or obtained from medical history or medical records). In particular, future use of TDF/FTC at any point during the study. * Known or suspected allergy to study product components (active or placebo), including egg or soy products (egg and soy products are contained in Intralipid) * Surgically-placed or injected buttock implants or fillers, per self-report. Contact the CMC for guidance regarding questions about individual cases. * Alcohol or substance use that, in the opinion of the study investigator, would jeopardize the safety of the participant on study (e.g., provided by self-report, or found upon medical history and examination or in available medical records). * History of seizure disorder, per self-report * QTc interval (B or F) greater than 500 msec