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Background: In low- and middle-income countries, most treatment-naïve people living with HIV (PLWH) take tenofovir disoproxil fumarate (TDF) with FTC (or 3TC) and efavirenz (EFV). Dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF) are recommended in international guidelines, but clinical experience with these ARVs in sub-Saharan Africa is limited. In South Africa, over 10% of patients have transmitted NNRTI drug resistance. Methods: We conducted a 96-week, open-label randomised trial in South Africa, comparing TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV. Inclusion criteria included age ≥12 years, no prior ART >30 days, creatinine clearance >60 mL/min (>80 mL/min if 500 copies/mL. Pregnancy and tuberculosis (TB) were exclusion criteria. There was no screening for baseline drug resistance, consistent with South African treatment guidelines. The primary treatment failure endpoint was 48-week HIV-1 RNA >50 copies/mL, discontinuation or missing data (Intent-to-treat population, non-inferiority margin -10%, significance level p=0.017, adjusted for multiple comparisons). We report 48-week efficacy and safety data. Results: We randomised 1053 PLWH between February 2017 and May 2018: 99% black, 59% female, mean age 32 years, with mean CD4 336 cells/uL. At week 48, the percentage of participants with HIV RNA < 50 copies/mL was 83.8% for TAF/FTC/DTG, 84.9% for TDF/FTC/DTG and 78.6% for TDF/FTC/EFV. In the on-treatment analysis, 96% of participants on TAF/FTC/DTG, 94% on TDF/FTC/DTG and 95% on TDF/FTC/EFV had HIV RNA < 50 copies/mL at Week 48. Both DTG arms demonstrated non-inferior efficacy versus the EFV arm. Over 70% of participants with HIV RNA >50 copies/mL re-supressed after adherence counselling and re-testing. Overall, 136/185 (74%) of treatment failures were from discontinuation. Clinical adverse events and laboratory abnormalities were similar between treatment arms. Conclusions: In the ADVANCE study, TAF/FTC/DTG and TDF/FTC/DTG demonstrated non-inferior efficacy versus TDF/FTC/EFV, with low rates of virologic failure in all three arms despite country-level background NRTI/NNRTI resistance. There were more discontinuations for adverse events in the TDF/FTC/EFV arm.