# Switch to PIr monotherapy PIVOT Study PIVOT Study

- Slides: 8

Switch to PI/r monotherapy § PIVOT Study

PIVOT Study: switch to PI/r monotherapy § Design HIV-infected patients > 18 years Stable Triple ART (NNRTI or PI/r) HIV RNA < 50 c/m. L > 24 weeks CD 4 > 100/mm 3 Randomisation 1: 1 Open-label Triple therapy * N = 296 PI/r monotherapy ** (selected by investigator) N = 291 Continuation of ongoing triple therapy *** 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 ≥ 1 drug 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; 2 e: 417 -26 Paton N, CROI 2014, Abs. 550 LB

PIVOT Study: switch to PI/r monotherapy Baseline characteristics Triple therapy PI/r monotherapy 43 45 22% 25% 71% / 25% 66% / 30% HCV antibody positive 2% 5% Prior AIDS 20% 19% 512 / 181 516 / 170 36 months 38 months NNRTI at entry EFV NVP ETR 54% 40% 14% 0 53% 39% 13% 1% PI/r at entry ATV/r LPV/r DRV/r SQV/r FPV/r 46% 20% 10% 8% 5% 2% 47% 20% 17% 4% 5% 1% 65%, 27%, 7% 61%, 28%, 11% Median age, years Female White / Black CD 4/mm 3, median (IQR) at baseline / at nadir Median duration of undetectable HIV RNA at baseline NRTI at entry : TDF/FTC, ABC/3 TC, other PIVOT Paton NI. Lancet HIV 2015; 2 e: 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; 2 e: 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) 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) Primary endpoint* N=4 Lost drug options - NVP, EFV - 3 TC, FTC, ATV, SQV, FPV, TPV - 3 TC, FTC, NVP, EFV, ETR, RPV - 3 TC, FTC, ABC, TDF, NVP, EFV, ETR, RPV N=6 - ATV SQV NVP, EFV ZDV * non-inferiority met PIVOT Paton NI. Lancet HIV 2015; 2 e: 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 Without VL resuppression (%) Without VL rebound (%) 100 80 60 40 HR = 13, 9 ; 95 % CI : 6, 8 -28, 6 p < 0, 0001 OT PI-mono 20 0 0 24 48 291 296 96 120 144 168 192 216 240 Weeks from randomisation Number at risk OT PI-mono 72 289 281 287 240 283 220 280 216 279 210 276 208 247 183 10 80 60 median time : 3. 5 weeks 40 20 0 0 Number at risk 133 100 64 53 10 67 12 24 36 Weeks from ART change 11 1 0 § 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 1 st year, 6 per 100 person-years in subsequent years PIVOT Paton NI. Lancet HIV 2015; 2 e: 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 1 (0. 3%) Serious non-AIDS event 7 (2. 4%) 12 (4. 1%) + 93 + 100 Clinical grade 2 or 4 adverse event 16. 8% 22. 0% e. GFR < 60 m. L/min/1. 73 m 2 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 Mean change in CD 4/mm 3 PIVOT Paton NI. Lancet HIV 2015; 2 e: 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 CD 4 change – Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection PIVOT Paton NI. Lancet HIV 2015; 2 e: 417 -26