ADVANCE Design Primary endpoint Proportion of patients with HIV RNA lt 50 cmL at W48 ITTE snapshot analysis noninferiority of TFAFTC if lower margin CI for the difference 10 80 power ID: 1046398
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1. DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTCADVANCE
2. DesignPrimary endpointProportion of patients with HIV RNA < 50 c/mL at W48, ITT-E snapshot analysis ; non-inferiority of TFA/FTC if lower margin CI for the difference = - 10%, 80% powerSecondary endpointsViral load thresholds, CD4 count changes, adverse events, safety, DXA ADVANCERandomisation *1 : 1 : 1Open-labelHIV-1+ ≥ 12 yearsResidents of JohannesburgWeight ≥ 40 kgARV-naïveHIV RNA ≥ 500 c/mLCreatinine clearance (CG) > 60 mL/minNo current treatment for tuberculosisN = 351N = 351 W96ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line* Patients aged 12-19 years randomized separatelyVenter WDF, N Engl J Med. 2019;381:803-15 N = 351DTG + TAF/FTC DTG + TDF/FTC EFV/TDF/FTC
3. DTG + TAF/FTCN = 351DTG + TDF/3TCN = 351EFV/TDF/FTCN = 351Mean age, years333232Female, %615957Mean body weight (kg) : Female / Male68.8 / 67.969.5 / 67.170.2 / 67.3Mean BMI (kg/m2) : Female / Male< 18.5≥ 3025.6 / 21.7121026.1 / 21.6101426.1 / 21.81113HIV RNA ≤ / > 100 000 c/mL, %78 / 2280 / 2077 / 23CD4/mm3, mean349323337Discontinuation or missing data at W48, N (%)For virologic failure, NFor adverse event, NConsent withdrawal / Lost to follow-up, NDeath / Other reasons, N41 (12)018 / 291 / 239 (11)1013 / 211 / 355 (16)21011 / 242 / 6Baseline characteristics and patient dispositionADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15
4. HIV RNA < 50 c/mL 10090704080603050201000122436484WeeksDTG + TDF/FTC = 85%DTG + TAF/FTC = 84%EFV/TDF/FTC = 79%% Adjusted difference, % (98.3% CI)-10-6-20261020-7.75.413.2-0.7-1.912.25.16.3-1.1DTG + TAF/FTC vs EFV/TDF/FTCDTG + TDF/FTC vs EFV/TDF/FTCTAF/FTC vs TDF/FTCADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15
5. HIV RNA < 50 c/mL according to subgroups, ITT-E snapshot768884DTG + TDF/FTCDTG + TAF/FTCEFV/TDF/FTC ≥ 100 000< 100 000> 200≤ 200 HIV RNA, c/mLCD4/mm3080204060801008377878990709086%848486848076768483768278858191FemaleMale Sex82≤ 32> 32 Age, years7388EmployedNoYes70ADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15
6. DTG + TAF/FTCN = 351DTG + TDF/3TCN = 351EFV/TDF/FTCN = 351HIV RNA > 50 c/mL at W48181914 (4.0)HIV RNA < 50 c/mL post W48 with no change in regimen, after interventions to improve adherence15/1714/177/14Virologic failure with resistance testing (2 HIV RNA > 1 000 c/mL), paired baseline-VF samplesEmergence of resistance to NRTIEmergence of resistance to NNRTIEmergence of resistance to INSTI1 (0.3%)0001 (0.3%)1: M184V006 (1.7%)430ADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15 ; Venter WDF, IAS 2019, WEAB0405LB Outcome after HIV RNA > 50 c/mL at W48 and Resistance at virologic failure
7. DTG + TAF/FTCN = 351DTG + TDF/3TCN = 351EFV/TDF/FTCN = 351Adverse event leading to drug discontinuation, NElevated liver enzymesNeuropsychiatric disordersRashRenal disorder110000105122Grade 2-4 adverse event, NHypertensionDizzinessNeutropeniaInsomnia211104619130422641291Most common grade 3-4 laboratory abnormalities, NGamma-GTASTALTCreatinine clearanceLow haemoglobin264106333767611783351814610Adverse eventsADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15
8. DTG + TAF/FTCN = 351DTG + TDF/3TCN = 351EFV/TDF/FTCN = 351New osteopenia, %Whole bodySpineHip1.418.26.62.022.716.20.822.317.8New osteoporosis, %SpineHip4.51.37.00.97.74.6New obesity (BMI ≥ 30 kg/m2), %FemaleMale19.57.110.63.18.73.4DXA results at W48ADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15
9. Mean change in weight (kg) Weight gain ≥ 10% was associated to DTG + TAF/FTC, high baseline HIV RNA, low baseline CD4, female gender and overweight at baselineMenMean BMI at D0: 21.7 kg/m2Women (pregnancy excluded)Mean BMI at D0: 26 kg/m299876543102-10122436484WeeksDTG + TAF/FTC + 4.7 kgDTG + TDF/FTC + 3.0 kgEFV/TDF/FTC+ 0.5 kg*** ns** p < 0.01***p < 0.05****p < 0.001***ADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15 ; Hill A, IAS 2019, MOAX0102LB 876543102-10122436484WeeksEFV/TDF/FTC+ 1.7 kgDTG + TDF/FTC + 3.2 kgDTG + TAF/FTC + 6.4 kg***********
10. WomenBody composition by DXA : mean change from baseline (kg)MenNew obesity at W96 (BMI ≥ 30 kg/m2)Higher rate on DTG + TAF/FTC vs DTG + TDF + FTC vs EFV/TDF/FTC: 19% vs 8% vs 4% (p < 0.01)Regression analysis: emergence of obesity associated to DTG + TAF/FTC, baseline CD4 and HIV RNA, baseline BMI (women predictive factor is BMI omitted)100Limb leanTrunk leanLimb fatTrunk fatW48W96107542863190-1+5.2 kgDTG +TAF/FTC+2.8 kgDTG +TDF/FTC+0.7 kgEFV/TDF/FTC/+5.4 kg+4.3 kg+0.5 kgDTG +TAF/FTCDTG +TDF/FTCEFV/TDF/FTC107542863190-1+6.7 kg+3.4 kg+1.8 kg+9.2 kg+5.4 kg+2.8 kgW48W96DTG +TAF/FTCDTG +TDF/FTCEFV/TDF/FTC/DTG +TAF/FTCDTG +TDF/FTCEFV/TDF/FTC/ADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15 ; Hill A, IAS 2019, MOAX0102LB
11. ConclusionTreatment with DTG combined with FTC and either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen of EFV/TDF/FTCThere was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimenThe concern around the potential teratogenicity of DTG and a dearth of pregnancy safety data with TAF pose complex challenges for practitioners in low- and middle-income countries that rely on health systems with limited options, especially for womenThe increased risk of weight gain with both DTG-containing regimens and the limited knowledge base regarding TAF in pregnancy need to be evaluated against improvements in side effect profile and adherence, slight reductions in time to virologic control, and effect on bone mineral density and renal functionADVANCEADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-lineVenter WDF, N Engl J Med. 2019;381:803-15