Comparison of DTG, TAF/FTC, DTG, TDF/FTC, and EFV/TDF/FTC in ADVANCE Study

ADVANCE Study compared the effectiveness of DTG in combination with TAF/FTC, DTG with TDF/FTC, and EFV/TDF/FTC as first-line treatments for HIV patients. The study involved randomization, primary and secondary endpoints analysis, baseline characteristics evaluation, patient disposition data, and outcomes based on HIV RNA levels. Results showed varying proportions of patients achieving HIV RNA

• HIV treatment
• ADVANCE Study
• DTG
• TAF/FTC
• TDF/FTC

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1. DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC ADVANCE

2. ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line Design Randomisation * 1 : 1 : 1 Open-label W96 N = 351 HIV-1+ 12 years Residents of Johannesburg Weight 40 kg ARV-na ve HIV RNA 500 c/mL Creatinine clearance (CG) > 60 mL/min No current treatment for tuberculosis DTG + TAF/FTC N = 351 DTG + TDF/FTC EFV/TDF/FTC N = 351 * Patients aged 12-19 years randomized separately Primary endpoint Proportion 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% power Secondary endpoints Viral load thresholds, CD4 count changes, adverse events, safety, DXA Venter WDF, N Engl J Med. 2019;381:803-15 ADVANCE

3. ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line Baseline characteristics and patient disposition DTG + TAF/FTC DTG + TDF/3TC EFV/TDF/FTC N = 351 N = 351 N = 351 Mean age, years 33 32 32 Female, % 61 59 57 Mean body weight (kg) : Female / Male 68.8 / 67.9 69.5 / 67.1 70.2 / 67.3 Mean BMI (kg/m2) : Female / Male < 18.5 30 25.6 / 21.7 12 10 26.1 / 21.6 10 14 26.1 / 21.8 11 13 78 / 22 80 / 20 77 / 23 HIV RNA / > 100 000 c/mL, % CD4/mm3, mean 349 323 337 Discontinuation or missing data at W48, N (%) For virologic failure, N For adverse event, N Consent withdrawal / Lost to follow-up, N Death / Other reasons, N 41 (12) 0 1 8 / 29 1 / 2 39 (11) 1 0 13 / 21 1 / 3 55 (16) 2 10 11 / 24 2 / 6 Venter WDF, N Engl J Med. 2019;381:803-15 ADVANCE

4. ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line HIV RNA < 50 c/mL % 100 90 DTG + TDF/FTC = 85% DTG + TAF/FTC = 84% EFV/TDF/FTC = 79% 80 70 Adjusted difference, % (98.3% CI) 60 -1.1 50 5.4 TAF/FTCvs TDF/FTC -7.7 40 6.3 -0.7 DTG + TDF/FTCvs EFV/TDF/FTC 13.2 30 DTG + TAF/FTC vs EFV/TDF/FTC -1.9 12.2 5.1 20 -10 -6 -2 0 2 6 10 20 10 0 0 4 12 24 36 48 Weeks Venter WDF, N Engl J Med. 2019;381:803-15 ADVANCE

5. 76 ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line HIV RNA < 50 c/mL according to subgroups, ITT-E snapshot EFV/TDF/FTC % DTG + TDF/FTC DTG + TAF/FTC 100 91 90 90 8789 88 88 86 86 85 8484 84 84 84 83 83 82 82 81 80 80 80 78 77 76 7676 73 70 70 60 40 20 0 < 100 000 > 200 Female Male > 32 No Yes 100 000 200 32 HIV RNA, c/mL CD4/mm3 Sex Age, years Employed Venter WDF, N Engl J Med. 2019;381:803-15 ADVANCE

6. ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line Outcome after HIV RNA > 50 c/mL at W48 and Resistance at virologic failure DTG + TAF/FTC DTG + TDF/3TC EFV/TDF/FTC N = 351 N = 351 N = 351 HIV RNA > 50 c/mL at W48 18 19 14 (4.0) HIV RNA < 50 c/mL post W48 with no change in regimen, 15/17 14/17 7/14 after interventions to improve adherence Virologic failure with resistance testing (2 HIV RNA > 1 000 c/mL), paired baseline-VF samples 1 (0.3%) 1 (0.3%) 6 (1.7%) Emergence of resistance to NRTI 0 1: M184V 4 Emergence of resistance to NNRTI 0 0 3 Emergence of resistance to INSTI 0 0 0 Venter WDF, N Engl J Med. 2019;381:803-15 ; Venter WDF, IAS 2019, WEAB0405LB ADVANCE

7. ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line Adverse events DTG + TAF/FTC N = 351 DTG + TDF/3TC N = 351 EFV/TDF/FTC N = 351 Adverse event leading to drug discontinuation, N Elevated liver enzymes Neuropsychiatric disorders Rash Renal disorder 1 1 0 0 0 0 10 5 1 2 2 Grade 2-4 adverse event, N Hypertension Dizziness Neutropenia Insomnia 21 11 0 4 6 19 13 0 4 2 26 4 12 9 1 Most common grade 3-4 laboratory abnormalities, N Gamma-GT AST ALT Creatinine clearance Low haemoglobin 26 4 10 6 3 3 37 6 7 6 11 7 83 35 18 14 6 10 Venter WDF, N Engl J Med. 2019;381:803-15 ADVANCE

8. ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line DXA results at W48 DTG + TAF/FTC N = 351 DTG + TDF/3TC N = 351 EFV/TDF/FTC N = 351 New osteopenia, % Whole body Spine Hip 1.4 18.2 6.6 2.0 22.7 16.2 0.8 22.3 17.8 New osteoporosis, % Spine Hip 4.5 1.3 7.0 0.9 7.7 4.6 New obesity (BMI 30 kg/m2), % Female Male 19.5 7.1 10.6 3.1 8.7 3.4 Venter WDF, N Engl J Med. 2019;381:803-15 ADVANCE

9. 99 ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line Mean change in weight (kg) Men Women (pregnancy excluded) Mean BMI at D0: 26 kg/m2 Mean BMI at D0: 21.7 kg/m2 8 8 7 7 DTG + TAF/FTC + 6.4 kg 6 6 **** 5 5 DTG + TAF/FTC + 4.7 kg * **** 4 4 DTG + TDF/FTC + 3.2 kg DTG + TDF/FTC + 3.0 kg ** 3 3 *** EFV/TDF/FTC + 1.7 kg 2 2 ** 1 1 EFV/TDF/FTC + 0.5 kg 0 0 -1 -1 * ns ** p < 0.01 ***p < 0.05 ****p < 0.001 0 4 12 24 36 48 0 4 12 24 36 48 Weeks Weeks Weight gain 10% was associated to DTG + TAF/FTC, high baseline HIV RNA, low baseline CD4, female gender and overweight at baseline Venter WDF, N Engl J Med. 2019;381:803-15 ; Hill A, IAS 2019, MOAX0102LB ADVANCE

10. 100 ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line Body composition by DXA : mean change from baseline (kg) Men Women Trunk fat Limb fat 10 10 +9.2 kg W48 W96 W48 W96 9 9 Trunk lean 8 8 Limb lean +6.7 kg 7 6 7 6 +5.4 kg +5.4 kg +5.2 kg 5 4 3 5 4 3 +4.3 kg +3.4 kg +2.8 kg +2.8 kg +1.8 kg 2 1 0 2 1 0 +0.7 kg +0.5 kg DTG + TAF/FTC DTG + TDF/FTC EFV/ DTG + TAF/FTC DTG + TDF/FTC EFV/ TDF/FTC DTG + TAF/FTC DTG + TDF/FTC EFV/ DTG + TAF/FTC DTG + TDF/FTC EFV/ -1 -1 TDF/FTC/ TDF/FTC/ TDF/FTC/ New 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) Venter WDF, N Engl J Med. 2019;381:803-15 ; Hill A, IAS 2019, MOAX0102LB ADVANCE

11. ADVANCE Study: DTG + TAF/FTC vs DTG + TDF/FTC vs EFV/TDF/FTC in first-line Conclusion Treatment 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/FTC There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen The 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 women The 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 function Venter WDF, N Engl J Med. 2019;381:803-15 ADVANCE