1. Switch to low dose ATV/r  LASA Study

2.  Design  Endpoints –Primary: proportion of patients with HIV RNA < 200 c/mL at W48 (ITT-E) ; non-inferiority if lower margin of the two-sided 95% CI for the difference = - 10%, 90% power –Secondary: proportion of patients with HIV RNA < 50 c/mL at W48, CD4 cell count changes, tolerability, adverse events, adherence, quality of life, cardiovascular risk, lipodystrophy Switch to ATV/r 200/100 mg QD + 2 NRTI Switch to ATV/r 300/100 mg QD + 2 NRTI Bunupuradah T. Lancet HIV 2016;3:e343-50 LASA Randomisation * 1 : 1 Open-label Thai adults ≥ 18 years HIV RNA < 50 c/mL ≥ 12 months On 2 NRTI + PI/r ≥ 3 months Creatinine clearance ≥ 60 mL/min N = 280 N = 279 W48 LASA Study: switch to ATV/r 200/100 vs 300/100 mg QD * Randomisation stratified on site, treatment with TDF or with indinavir

3. ATV/r 200/100 mg N = 273 ATV/r 300/100 mg N = 277 Mean age, years4241 Female, %5348 Mean body weight, kg5960 Hepatitis B / hepatitis C coinfection, %8 / 45 / 5 CD4 nadir (cells/mm 3 ), mean120126 CD4/mm 3, mean549528 History of ever used dual NRTI, %1314 Duration of PI/r before screening, mean years3.03.1 PI/r at screening : LPV / IDV / SQV, %85 / 8 / 784 / 9 / 7 NRTI at screening, % 3TC / TDF / ZDV / ddI / d4T82 / 74 / 40 / 6 / 480 / 73 / 45 / 5 / 4 Discontinuation, N (%) For adverse event Died Lost to follow-up / Withdrew consent Protocol deviation 14 (5.1) 5 1 1 / 0 7 33 (11.9) 16 2 1 / 3 11 Baseline characteristics (ITT-e population) and patient disposition LASA Study: switch to ATV/r 200/100 vs 300/100 mg QD Bunupuradah T. Lancet HIV 2016;3:e343-50 LASA

4. Virological success at W48 ATV/r 200/100 (N = 273) ATV/r 300/100 (N = 277) ITT-e 0 97.1 96.4 98.5 99.2 20 40 60 80 100 % 95.0 94.3 92.3 86.6 96.0 91.0 93.4 91.7 Per protocolITT, NC = F ITT-ePer protocolITT, NC = F Difference (95% CI) 0.68 (- 2.29 to 3.65) - 0.72 (- 2.6 to 1.16) 5.00 (0.89 to 9.10) p = 0.02 1.71 (-2.67 to 6.09) 0.72 (-3.23 to 4.67) 5.67 (0.56 to 10.77) p = 0.03 HIV RNA < 50 c/mLHIV RNA < 200 c/mL LASA Study: switch to ATV/r 200/100 vs 300/100 mg QD Bunupuradah T. Lancet HIV 2016;3:e343-50 LASA

5.  Genotype Resistance testing –Done in patients with protocol-defined virologic failure (confirmed HIV RNA ≥ 200 c/mL) and HIV RNA ≥ 1000 c/mL ATV/r 200/100, N = 7 ; emergence of resistance in 1: I50L, V82A, L90M + resistance to all NRTIs ATV/r 300/100, N = 1 ; no emergence of resistance  Study drug discontinuation ATV/r 200/100, N = 7 (3%): 1 death, 2 virologic failures, 2 rashes, 1 jaundice, 1 pregnancy ATV/r 300/100, N = 21 (8%): 1 death, 7 rashes, 6 jaundices, 1 pregnancy, 5 other reasons  Adverse events –Similar proportion in the 2 treatment groups LASA Study: switch to ATV/r 200/100 vs 300/100 mg QD Bunupuradah T. Lancet HIV 2016;3:e343-50 LASA

6. ATV/r 200/100 mg N = 273 ATV/r 300/100 mg N = 277 p Total bilirubin, mg/dL1.051.380.00009 ALT, UI/L10.4912.96ns Serum creatinine, mg/dL0.01- 0.01ns Creatinine clearance (CG formula), mL/min/1.73 m 2 1.303.14ns Fasting total cholesterol, mg/dL- 14.8- 20.20.07 Fasting HDL-cholesterol, mg/dL0.5 ns Fasting triglycerides, mg/dL- 73.1- 59.5ns Fasting glucose, mg/dL- 0.41.1ns Mean change in laboratoty parameters from baseline to W48 ATV/r 200/100 mg N = 273 ATV/r 300/100 mg N = 277 Total bilirubin grade ≥ 317%35% Rash2 (1%)7 (3%) Adverse events of special interest LASA Study: switch to ATV/r 200/100 vs 300/100 mg QD Bunupuradah T. Lancet HIV 2016;3:e343-50 LASA

7.  Pharmacokinetic assessment –Serum samples collected at W12 and W24 for C trough measurements LASA Study: switch to ATV/r 200/100 vs 300/100 mg QD Bunupuradah T. Lancet HIV 2016;3:e343-50 LASA ATV/r 200/100 mgATV/r 300/100 mgp Median (IQR) ATV C trough, mg/L0.31 (0.19-0.47)0.46 (0.26-0.72)< 0.0001 C trough < 0.15 mg/L19%11%0.015 C trough < 0.15 mg/L in patients with HIV RNA ≥ 50 c/mL 10%7%0.63

8.  Conclusion –ATV 200 mg and ritonavir 100 mg when combined with two NRTIs is non-inferior in terms of virological efficacy to ATV 300 mg and ritonavir 100 mg with two NRTIs in virologically suppressed Thai adults with HIV for use as second-line protease inhibitor-based ART –When switches from randomised treatment were imputed as failures, the low-dose group was superior to the standard-dose group because the standard-dose group was associated with increased treatment discontinuation because of adverse events –More patients in the low-dose ATV group than in the standard-dose group had trough concentrations lower than the recommended therapeutic concentration of 0.15 mg/L –Use of the low dose of ATV, with less toxicity than the standard dose, would benefit both patients and health-care systems (significant cost saving) LASA Study: switch to ATV/r 200/100 vs 300/100 mg QD Bunupuradah T. Lancet HIV 2016;3:e343-50 LASA