BACKGROUND: In low- and middle-income countries, most treatment-naïve people living with HIV (PLWH) take tenofovir disoproxil fumarate (TDF) with emtricitabine FTC (or lamivudine (3TC)) and efavirenz (EFV). Dolutegravir (DTG) and tenofovir alafenamide (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 <19 years), and HIV-1 RNA >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 96-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 96-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 96, the percentage of participants with HIV RNA <50 copies/mL was 78.6% for TAF/FTC+DTG, 78.3% for TDF/FTC+DTG and 73.5% for TDF/FTC/EFV. In the on-treatment analysis, 96% of participants on TAF/FTC+DTG, 95.7% on TDF/FTC+DTG and 95.5% on TDF/FTC/EFV had HIV RNA <50 copies/mL at Week 96. Both DTG arms demonstrated non-inferior efficacy versus the EFV arm. Overall, 206/244 (84%) of treatment failures were from discontinuation. Clinical adverse events and laboratory abnormalities were similar between treatment arms.

Table 1, ADVANCE trial results at Week 96

Treatment arm	TAF/FTC+DTG	TDF/FTC+DTG	TDF/FTC/EFV
n	n=351	n=351	n=351
Week 96 Efficacy
HIV RNA <50 copies/mL	276 (78.6%)	275(78.3%)	258 (73.5%)
HIV RNA '¥50 copies/mL	11 (3.1%)	14 (4.0%)	15 (4.3%)
Discontinuation for adverse events	2 (0.6%)	1 (0.3%)	10 (2.8%)
Discontinuation for other reasons	64 (18.2%)	62 (17.7%)	80 (22.8%)
Treatment-emergent drug resistance	0 (0.0%)	2 (0.6%)	14 (4.0%)
Female mean weight change	+8.1kg	+4.8kg	+3.2kg
Male mean weight change	+5.4kg	+3.6kg	+1.1kg
Treatment emergent obesity	47 (18%)	28 (11%)	18 (8%)
Treatment emergent metabolic syndrome	23 (8%)	16 (6%)	10 (4%)

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.