This is a 48-week, multicenter, multinational, open-label, randomized Phase 3b study to assess whether TDF/FTC/RPV shows noninferior response rates of HIV-1 RNA suppression <400 copies/mL, compared with the control group of TDF/FTC/EFV. Approximately 426 HIV-1 infected subjects, currently with HIV-1 RNA suppression <50 copies/mL on their first-line antiretroviral (ARV) regimen (NNRTI-based), will be randomized to 48 weeks treatment with a FDC regimen of either TDF/FTC/RPV or TDF/FTC/EFV (control group), in a ratio of 1:1. Randomization will be stratified based on the NNRTI the subject is taking at screening (either EFV or nevirapine [NVP]).

The study will include a 6-week (maximum) screening phase, a 48-week (minimum duration) randomized open-label treatment phase, and a follow-up visit 30 to 35 days after the last dose of study drug. During the randomized open-label treatment phase, subjects will return for study visits at Week 4, 12, 24, 36, and 48 during the treatment period, and then every 24 weeks thereafter during the extended treatment period until the last subject has his or her Week 48 (or treatment discontinuation) visit.

Throughout the open-label treatment phase, subjects will return for study visits as specified in the Time and Events Schedule to have procedures performed to assess efficacy (HIV-1 RNA levels, CD4+ cell count; testing performed at a central laboratory; see Efficacy Evaluations/Endpoints) and monitor safety (adverse events including HIV-related events, clinical laboratory analyses [central and local laboratory]; see Safety Evaluations). During the open-label treatment phase, if the HIV-1 RNA level is ≥50 copies/mL at any visit, subjects will have a blood sample collected for retesting at a central laboratory (and will continue to have blood samples collected) at up-to-8 week intervals until the plasma HIV-1 RNA level is <50 copies/mL, or virologic failure is confirmed by 2 consecutive plasma HIV-1 RNA levels ≥400 copies/mL.

The end of the study is defined as the last subject, last follow-up visit in the study. The actual duration of treatment for each subject in the study will vary and will be determined by the length of time it takes to enroll all subjects. Therefore, with an expected enrollment period of 52 weeks, the treatment duration for each subject is expected to be between 48 and 108 weeks.