Switch to PI/r monotherapy ARV-trial.com Switch to PI/r monotherapy PIVOT Study 1

PIVOT Study: switch to PI/r monotherapy Randomisation 1 : 1 Open-label Design Triple therapy * PI/r monotherapy ** (selected by investigator) HIV-infected patients > 18 years Stable Triple ART (NNRTI or PI/r) HIV RNA < 50 c/mL > 24 weeks CD4 > 100/mm3 N = 296 Continuation of ongoing triple therapy *** N = 291 Randomisation was stratified by centre and baseline ART regimen (NNRTI or PI/r) * Prompt reintroduction of NRTIs (switch PI/r to NNRTI allowed) for protocol-defined viral rebound (3 consecutive HIV RNA > 50 c/ml) ; further management with combination therapy as in the triple therapy group ** PI substitution during follow-up allowed *** Switches for toxic effects, convenience, and viral load failure allowed Objective Primary outcome : non-inferiority of the PI/r-mono group in loss of future drug options, defined as new intermediate-level or high-level resistance to ≥ 1drug in contemporary use to which patient’s virus was considered to be sensitive at trial entry ; 2-sided 95% CI for the difference in maintaining all future drug options during 3 years with upper limit of 10%, 85% power PIVOT Paton NI. Lancet HIV 2015;2e:417-26 Paton N, CROI 2014, Abs. 550LB

PIVOT Study: switch to PI/r monotherapy Baseline characteristics Triple therapy PI/r monotherapy Median age, years 43 45 Female 22% 25% White / Black 71% / 25% 66% / 30% HCV antibody positive 2% 5% Prior AIDS 20% 19% CD4/mm3, median (IQR) at baseline / at nadir 512 / 181 516 / 170 Median duration of undetectable HIV RNA at baseline 36 months 38 months NNRTI at entry EFV NVP ETR 54% 40% 14% 53% 39% 13% 1% PI/r at entry ATV/r LPV/r DRV/r SQV/r FPV/r 46% 10% 8% 47% 17% 4% NRTI at entry : TDF/FTC, ABC/3TC, other 65%, 27%, 7% 61%, 28%, 11% PIVOT Paton NI. Lancet HIV 2015;2e:417-26

PIVOT Study: switch to PI/r monotherapy PI/r monotherapy group DRV/r: 80% LPV/r: 14% ATV/r: 6% Saquinavir/r < 1% 58% still on PI/r monotherapy at trial end (72% of follow-up time on monotherapy) Reasons for reintroduction of combination regimens 23% for protocol-defined confirmed viral rebound 4% for viral rebound not meeting protocol criteria 5% for toxic effects 7% for other or unknown reasons Median duration of follow-up : 44 months PIVOT Paton NI. Lancet HIV 2015;2e:417-26

PIVOT Study: switch to PI/r monotherapy Primary endpoint Definition : Loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient’s virus was deemed sensitive at trial entry (Kaplan-Meier estimate at 3 years) Triple therapy N = 291 PI/r monotherapy N = 296 Difference (95% CI) Primary endpoint* N = 2 (0.7%) N = 6 (2.1%) 1.4% (-0.4 to 3.4) Loss of future options during the full trial period 1.8% 2.1% 0.2% (-2.5 to 2.6) Loss of future options during the full trial period (excluding possible archived mutations) 1.5% 1.0% -0.4% (-2.9 to 1.4) Lost drug options N = 4 NVP, EFV 3TC, FTC, ATV, SQV, FPV, TPV 3TC, FTC, NVP, EFV, ETR, RPV 3TC, FTC, ABC, TDF, NVP, EFV, ETR, RPV N = 6 ATV SQV NVP,EFV ZDV * non-inferiority met PIVOT Paton NI. Lancet HIV 2015;2e:417-26

PIVOT Study: switch to PI/r monotherapy Viral rebound and resuppression Time to viral rebound Time to viral resuppression after change of ART in the PI-mono group 20 40 60 80 100 24 48 72 96 120 144 168 192 216 240 OT PI-mono HR = 13,9 ; 95 % CI : 6,8-28,6 p < 0,0001 Weeks from randomisation 291 296 289 281 287 283 220 280 279 210 276 208 247 183 133 64 53 10 OT PI-mono Number at risk Without VL rebound (%) median time : 3.5 weeks 12 24 36 20 40 60 80 10 67 11 1 Weeks from ART change Number at risk Without VL resuppression (%) Confirmed viral rebound (Kaplan-Meier estimate) during follow-up PI/r monotherapy : 35.0% vs triple therapy : 3.2% (difference : 31.8%) (95% CI : 24.6 to 39.0, p < 0.0001) Rebound on PI/r monotherapy : 24 per 100 person-years during 1st year, 6 per 100 person-years in subsequent years PIVOT Paton NI. Lancet HIV 2015;2e:417-26

PIVOT Study: switch to PI/r monotherapy Secondary outcomes, n (%) Triple therapy N = 291 PI/r monotherapy N = 296 Death 1 (0.3%) 6 (2.0%) AIDS-defining event Serious non-AIDS event 7 (2.4%) 12 (4.1%) Mean change in CD4/mm3 + 93 + 100 Clinical grade 2 or 4 adverse event 16.8% 22.0% eGFR < 60 mL/min/1.73 m2 during follow-up 9.7% 5.1% (p < 0.033) Symptomatic peripheral neuropathy 15.5% 15.9% Facial lipoatrophy 8.2% 12.1% Abdominal fat accumulation 17.2% 20.6% 10 year cardiovascular disease risk, mean change + 1.32 + 1.59 PIVOT Paton NI. Lancet HIV 2015;2e:417-26

PIVOT Study: switch to PI/r monotherapy Conclusion In patients who have achieved viral load suppression with combination treatment, a maintenance strategy of PI/r monotherapy, with reintroduction of combination treatment in the event of viral load rebound, was non-inferior to continuous combination treatment for preservation of future treatment options during 3–5 years Regular viral load monitoring and prompt reintroduction of combination treatment for rebound needed Absolute number of patients who lost future drug options with PI/r monotherapy was very low (only 1 patient with resistance to ATV) No change in overall clinical outcomes or frequency of toxic effects Much higher proportion of patients in the PI/r monotherapy group with viral rebound Rapid resuppression of viral load by reintroduction of combination treatment No adverse effect on CD4 change Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection PIVOT Paton NI. Lancet HIV 2015;2e:417-26