Comparison of NRTI combinations

1. Comparison of NRTI combinations • ZDV/3TC vs TDF + FTC • Study 934 • ABC/3TC vs TDF/FTC • HEAT Study • ACTG A5202 Study • ASSERT Study • FTC/TDF vsFTC/TAF • Studies GS-US-292-0104 and GS-US-292-0111

2. ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV • Design Randomisation* 1 : 1 Open-label W48 W96 N = 195 > 18 years ARV-naïve HIV RNA > 1,000 c/mL Any CD4 cell count HLA-B*5701 allele negative N = 197 * Randomisation was stratified by screening eGFR (MDRD), race (black or non black), and BMI • Primary analysis • Intention to treat, exposed analysis : 2-sided significance level of 5%, with 90% power to detect a difference of 10 mL/min in eGFR (MDRD) change from baseline between arms Post FA. JAIDS 2010;55:149-57 ASSERT

3. ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV Baseline characteristics and patient disposition Post FA. JAIDS 2010;55:149-57 ASSERT

4. ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV Adjusted mean change from baseline in eGFR by MDRD (ml/min/1.73 m2), ITT-e population ABC/3TC + EFV 8 8 TDF/FTC + EFV TDF/FTC EFV QD Better 4 4 P = 0.435 Change from BL in GFR by MDRD (ml/min/1.73 m²) Treatment difference(ml/min/1.73 m²) 0 0 ABC/3TC EFV QD Better -4 -4 -8 -8 0 4 12 24 36 48 Treatment Difference at week 48 Week Mean change in eGFR at week 96 : + 1.48 (ABC/3TC) - 1.15 (TDF/FTC) Subjects at visit ABC/3TC + EFV TDF/FTC + EFV 192 193 172 181 158 176 155 173 144 167 135 159 Repeated measures mixed model analysis Post FA. JAIDS 2010;55:149-57 ; Moyle GJ, Antiviral Therapy 2013;18:905-13 ASSERT

5. ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV • Secondary renal endpoints • No differences between arms in proportion with significant declines in eGFRor with renal failure • Percentage change from baseline at week 48 • Urinary retinol-binding protein/creatinine ratio : TDF/FTC = + 50% vs ABC/3TC = 0% (p < 0.0001) • Urinary b2-microglobulin/creatinine ratio : TDF/FTC = + 24% vs ABC/3TC = - 47% (p < 0.0001) Changes in bone density (DXA) at week 48 • Bone turnover markers : increased in both groups over the first 24 weeks (significantly greater with TDF/FTC), stabilizing or decreasing thereafter ASSERT Post FA. JAIDS 2010;55:149-57 ; Moyle GJ, Antiviral Therapy 2013;18:905-13 ; Stellbrink HJ. CID 2010;51:963-72

6. ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV Efficacy at week 48 HIV RNA < 50 c/mL ABC/3TC + EFV % TDF/FTC + EFV 100 71.0 • Protocol-defined virologic failure (< 1 log10 c/mL reduction in HIV RNA by W4, confirmed rebound ≥ 400 c/mL after confirmed HIV RNA < 400 c/mL by W24 or confirmed HIV RNA > 400 c/mL after W24) • 6 on ABC/3TC + EFV • Emergence of resistance : 3/6 • 2 patients with NNRTI mutations • 1 patient with NNRTI mutation and K65R + D67N • 2 on TDF/FTC + EFV = no resistance emergence 75 59.4 50 25 0 ITT, TLOVR Adjusted difference 95% CI = 11.6% (2.2 ; 21.1) Median CD4/mm3 increase at W48 : + 150 in both groups Post FA. JAIDS 2010;55:149-57 ASSERT

7. ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV • Safety at W48 Post FA. JAIDS 2010; 55:149-57 ASSERT

8. Conclusion No difference in estimated glomerular filtration rate between ABC/3TC + EFV and TDF/FTC + EFV However, increases in markers of tubular dysfunction in the TDF/FTC arm No differences in markers of glomerular dysfunction over 96 weeks Significant higher virologic efficacy for TDF/FTC + EFV Emergence of resistance to NNRTI and NRTI on virological failure with ABC/3TC + EFV but not with TDF/FTC + EFV Incidence of grade 4 adverse events and serious adverse events was higher in the ABC/3TC arm, mainly because of drug hypersensitivity or hypersensitivity Smaller increases in serum lipids with TDF/FTC Greater increases in bone turnover and decreases in hip and vertebral bone mineral density with TDF/FTC + EFV compared to ABC/3TC + EFV ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV Post FA. JAIDS 2010; 55:149-57 ; Moyle GJ, Antiviral Therapy 2013;18:905-13 ASSERT