HPTN 083

Study Purpose

To evaluate the safety and efficacy of the injectable agent, cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men and transgender women who have sex with men (MSM and TGW)

Study Design

Multi-site, double blind, two-arm, randomized (1:1), controlled non-inferiority trial of the efficacy of CAB LA compared to daily oral tenofovir disoproxyl fumarate (TDF)/emtricitabine (FTC) for HIV prevention

Study Population

HIV-uninfected MSM and TGW at risk for acquiring HIV infection, ages 18 or older.

Study Size

Approximately 4500, 2250 per arm

Study Duration

Approximately 4.5 years total, with individual participants being followed between 1.5 years (for the latest enrolling participants) to 4.5 years (for the earliest enrolling participants). Accrual will require approximately 130 weeks. In Step 1, participants will receive oral tablets for 5 weeks. In Step 2, participants will receive injections (as a single injection at two time points 4 weeks apart and every 8 weeks thereafter) and daily oral tablets. Step 2 will be continued until the required number endpoints is reached, estimated to be approximately when the final participant reaches 60 weeks on Step 2 (week 65 for the final participant). Participants will be all simultaneously unblinded at the conclusion of Step 2. In Step 3, all participants will receive open-label daily oral TDF/FTC for up to 48 weeks. Participants will therefore be followed between 113 weeks to 233 weeks (between 65 and 185 weeks on blinded study medication and up to 48 weeks on open-label daily oral TDF/FTC). All participants will be transitioned to locally-available HIV prevention services, including services for PrEP, if available, at the end of their participation in the study.

Treatment Regime

Once randomized to one of two arms, participants will move through the following steps:

Step 1:
Arm A – Daily oral CAB (30 mg tablets) and oral TDF/FTC placebo for five weeks
Arm B – Daily oral TDF/FTC (300 mg/200 mg fixed-dose combination tablets) and oral CAB placebo for five weeks
A participant that becomes HIV-infected during Step 1 of the study will permanently discontinue study product and will be terminated from the study, and referred for HIV-related care.
Step 2:
Arm A – CAB LA (600 mg as a single intramuscular [IM] injection at two time points 4 weeks apart and every 8 weeks thereafter) and daily oral TDF/FTC placebo.
Arm B – Daily oral TDF/FTC (300/200 mg fixed-dose combination tablets) and IM placebo at two time points 4 weeks apart and every 8 weeks thereafter (matching vehicle, identical volume as active injectable product in Arm A).
This step will continue until the required number of endpoints is reached.
A participant that becomes HIV-infected during Step 2 of the study will permanently discontinue study product, be placed on immediate suppressive ART, and will be followed at quarterly intervals for 52 weeks after their last injection prior to diagnosis of HIV in order to test for safety parameters, as well as CD4 cell count and HIV viral load. After 52 weeks, they will be terminated from the study and transitioned to continued HIV-related care.
Step 3:
Both arms: Open-label daily oral TDF/FTC no later than 8 weeks after the last injection (in order to cover the pharmacokinetic (PK) tail for Arm A participants), for up to 48 weeks. Participants will then transition to locally-available HIV prevention services, including services for PrEP, if available.
A participant with confirmed HIV infection during Step 3 will be followed at least for the duration of Step 3, with possible additional assessments and follow-up to be determined by the Clinical Management Committee (CMC).

Primary Objectives

• To compare HIV incidence among participants randomized to oral CAB/CAB LA (oral lead in and injections) vs. oral TDF/FTC (Steps 1 and 2)
• To compare the safety of oral CAB/CAB LA vs. oral TDF/FTC

Secondary Objectives

• To compare HIV incidence among participants receiving CAB LA injections vs. oral TDF/FTC (each step independently and all steps in aggregate)
• To compare HIV incidence among participants receiving CAB LA injections vs. oral TDF/FTC (Steps 1, 2, and 3 combined)
• To compare HIV incidence among participants randomized to CAB LA injections vs. oral TDF/FTC while taking open label TDF/FTC (Step 3 only, descriptive)
• To compare the change in risk of HIV acquisition between CAB and oral TDF/FTC strategies (Arm A and Arm B) as participants progress from Step 2 to Step 3
• To compare HIV incidence among the subgroups of participants receiving oral CAB/CAB LA vs. oral TDF/FTC by region, age, race, ethnicity, baseline risk, and gender identity
• To compare changes in renal function, liver function, and bone mineral density (BMD) among participants receiving oral CAB/CAB LA vs. oral TDF/FTC
• To evaluate and compare rates of HIV drug resistance among participants who acquire HIV infection during the study among participants receiving oral CAB/CAB LA vs oral TDF/FTC
• To compare the acceptability of and preferences for CAB LA vs. oral TDF/FTC

Other Objectives

• To examine the association between levels of adherence and HIV incidence
• To compare and describe the rates, patterns, and correlates of adherence to CAB LA vs oral TDF/FTC, in aggregate and by psychosocial/demographic variables
• To estimate changes in sexual-risk behavior as measured by self-report and rates of incident gonorrhea, chlamydia, and syphilis in the study population
• To compare the resource utilization and programmatic costs of long-acting injectable PrEP vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW in the US, Brazil, South Africa and India
• To use mathematical simulation to project the short- and long-term clinical impact, cost projections, budgetary impact, and incremental cost-effectiveness of long-acting injectable PrEP vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW in the US, Brazil, South Africa and India