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Published byTracy Stephens Modified over 9 years ago
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Switch to DRV/r monotherapy MONOI MONET PROTEA DRV600
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Design Objective –Non inferiority in the proportion of patients with HIV-1 RNA < 50 c/mL at W48 (ITT analysis, missing/discontinuation/switch= failure, snapshot algorithm); lower limit of the 95% CI for the difference= - 12%, 80% power –CNS substudy : CSF HIV RNA at baseline and W48 –Neurocognitive function using a series of neuropsychological tests DRV/r 800/100 mg QD + 2 NRTIs (optimisation at D0**) DRV/r 800/100 mg QD Randomisation* 1 : 1 Open-label 282 HIV+ adults 1 st line ART 2 NRTIs + (PI or NNRTI) No history of prior virologic failure HIV-1 RNA < 50 c/mL Exclusion if nadir CD4 < 100/mm 3 or current CD4 < 200/mm 3 N = 137 N = 136 W48 * Randomisation was stratified on HCV antibody status (+ or -) ** TDF, ABC or ZDV + 3TC or FTC PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print W96 4-week run-in DRV/r + NRTIs PROTEA
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DRV/r QD + 2 NRTIs DRV/r QD monotherapy Mean age, years4345 Female15%19% Duration of ARV treatment, mean years5.35.7 On first NRTI combination71%58% On PI/r / On NNRTI76% / 23%69% / 26% HCV antibody positive10%9% Baseline CD4 cell count/mm 3 : > 350 / 200-35093% / 6%90% / 10% Nadir CD4 cell count/mm 3 : > 200 / 100-20078% / 20%70% / 26% Baseline HCV RNA < 50 c/ml98%100% AIDS7%10% Included in CNS substudy, N3437 Protocol defined treatment failure at W48, n (%)8 (6%)19 (14%) Baseline characteristics and patient disposition At baseline, 8 patients had a nadir CD4 < 100/mm 3 (5 in the monotherapy arm and 3 in the triple therapy arm), and were excluded from the Per Protocol population PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA
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HIV RNA < 50 c/mL at W48 (FDA snapshot analysis) DRV/r + 2 NRTIsDRV/r qd monotherapy 0 25 50 100 75 94.9 89.4 136 % 95.9 137123 86.1 ITT (primary endpoint)Per protocol N= Difference : - 8.7% (95% CI = - 15.5 ; - 1.8) 92 96.3 Switch-included analysis DRV/r monotherapy is not non inferior to DRV/r + 2 NRTI Primary analysis adjusting for treatment group, HCV status, nadir CD4 and previous PI use : DRV/r QD mono non inferior to triple therapy (≠ - 5.8%, 95% CI: - 11.51 to - 0.14), but difference still inferior statistically Per protocolITT 91.9 96.7 Difference : - 6.5% (95% CI = - 12.94 ; - 0.04) Difference : - 4.3% (95% CI = - 9.7 ; 1.2) Difference : - 4.7% (95% CI = - 10.5 ; 1) 136137123 Switch=failure analysis PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA
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HIV RNA < 50 c/mL at W48 (FDA snapshot analysis) by baseline nadir CD4 cell count DRV/r + 2 NRTIsDRV/r qd monotherapy 0 25 50 100 75 96.7 94.8 30 % 94.3 4110696 65.9 CD4 < 200/mm 3 CD4 ≥ 200/mm 3 N= Predictors of treatment failure (multiple regression model) : Low nadir CD4 (p = 0.005) Previous use of PI (p = 0.004) Genotype (3 patients with confirmed HIV RNA > 400 c/mL, 2 in monotherapy arm, 1 in triple therapy arm) No emergence of primary PI mutation ITT, switch=failure analysis PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA
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PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Most common adverse events : infections or infestations (32%) and gastrointestinal (16%) Serious adverse events, N = 14 (5%): 9 in the monotherapy arm and 5 in the triple therapy arm. One unrelated death in the monotherapy arm Grade 2-4 adverse events considered treatment-related –More common in the monotherapy (N = 12; 9%) than in the triple therapy arm (N = 2; 1%) –In the monotherapy arm, these were mainly gastrointestinal events and rises in cholesterol after discontinuation of TDF Discontinuation of DRV for adverse event –N = 5 (4%) in the monotherapy arm, N = 1 (1%) in the triple therapy arm Neurological adverse events, N = 27 (10%) : –13 in the monotherapy arm and 14 in the triple therapy arm –Most common AE = headache (N = 14) 1 case of encephalomyelitis in the monotherapy arm : –required hospitalization; HIV RNA detectable in plasma and CSF; re-suppressed and symptoms resolved after intensification with NRTIs including high-dose ZDV. NB : Nadir CD4 = 17/mm 3 Safety Hill AM. AIDS 2015;29 Epub ahead of print PROTEA
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Improvement of all neurocognitive scores at W48 in both groups (learning effect) No difference between arms in the global score (NPZ-5) over time W48 NPZ-5 score was very siginificantly associated to sex, race, and baseline NPZ-5 score (p < 0.0001). Alcohol consumption, smoking, history of cardiovascular events and age were also significantly associated. No effect of baseline HIV RNA, baseline CD4 count or nadir CD4. CNS substudy –At baseline, HIV RNA < 50/mL in the CSF in all patients –At W48 : CSF HIV RNA < 50 c/mL in all except 1 patient in the monotherapy arm : HIV RNA 654 c/mL, no symptoms, nadir CD4 : 166/mm3 –Mean CSF neopterin concentration (nmol/L) Monotherapy: 4.8±2.1 at baseline vs 6.2±4.3 at W48 Triple therapy: 4.8±1.3 at baseline vs 4.1±1.2 at W48 –Mean CSF albumin : normal range at W48 for both arms Neurocognitive function and CNS substudy PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA
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Summary –In patients with virologic suppression on standard first-line triple therapy (2 NRTIs + 1 NNRTI or 1 PI), once-daily DRV/r monotherapy did not show non inferior HIV RNA suppression at week 48 compared with a standard therapy of 2 NRTIs + once-daily DRV/r –A low nadir CD4 count (< 200/mm 3 ) was highly predictive of treatment failure in the monotherapy arm. –Two patients in the monotherapy arm with CD4 nadir < 200/mm 3 developed viremia in both CSF and plasma, with one symptomatic case –There was no difference in neurocognitive function or the risk of neuropsychiatric adverse events between DRV/r monotherapy and triple therapy PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA
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