Switching ARVs in Virologically Suppressed Patients

Data Presentation

AI-073: Switching Suppressed Patients to EFV/FTC/TDF DeJesus E, et al. 48th ICAAC/46th IDSA, Washington, DC, Abst. H-1234 Phase IV, multicenter (55 US sites), open-label study (N=300) Primary Endpoint: Non-inferiority of STR vs. SBR for HIV-1 RNA <200 c/mL through Week 48 by TLOVR analysis Randomization 2:1 Stratify by PI or NNRTI Continue Switch VL<200 c/mL Stable ARV Regimen On 1st regimen or suppressed on previous PI regimen No H/O VF STR=EFV/FTC/TDF QD (n=203) SBR=Stay on Baseline Regimen (n=97)

AI-073: Results at 48 Weeks Virologic Failure STR 3, SBR 1 AE’s all grades STR: Higher incidence - Sleep disturbance 14% vs 0 -Dizziness 11% vs 1% -GI (nauseas, diarrhea) 6% vs 2% DC due to AE’sSTR 10 (5%), SBR 1 (1%) GFR (CG, MDRD) No significant changes Change TG (mg/dl) STR -20, SBR -3 (P=0.035) Pt preferenceSTR 91%, SBR 9% (P=0.001) % with HIV RNA <50 c/mL (TLOVR) Treatment Difference (STR – SBR) 95% CI:2.6% (5.9%, 11.1%) DeJesus E, et al. 48th ICAAC/46th IDSA, Washington, DC, Abst. H-1234

ANRS 138: Enfuvirtide to Raltegravir Switch in Highly Experienced Patients Patients with triple-class resistance and HIV RNA <400 c/mL Randomized to continue ENF (n=85) or switch to RAL (n=84) Median of 13.6 years prior ART and 2.3 years on ENF Week 24 Results: 89% <50 c/mL in both arms Virologic Failure: 1 in each arm (∆ = 0.01%, 95% CI -4.4, +4.5) No significant CD4 changes in either arm Grade 3/4 AE: 11% ENF arm, 19% RAL arm (P=0.12) Conclusion: Raltegravir maintains suppression when substituted for ENF in fully suppressive regimens De Castro N, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 572.

STARTMRK: RAL vs. EFV in ARV-Naïve Patients Lennox J, et al. 48th ICAAC/46th IDSA, Abst. H-896a RAL + TDF/FTC EFV + TDF/FTC Mean Change (mg/dL) Weeks Percent <50 Copies/mL % Non-inferiority P -Value < % CD4 Count Increase: 189 vs. 163 (p<0.05)

STARTMRK: Predictors of Success Subgroup analyses support consistent efficacy across multiple virologic and immunologic parameters % of Patients with HIV RNA Levels <50 copies/mL SubgroupRaltegravirEfavirenz Overall92%89% Baseline Plasma HIV RNA (c/mL)≤50,00095%87% >50,00090% ≤100,00093%89% >100,00091%89% Baseline CD4 Cell Counts (cells/mm 3 )≤5084%86% >50 to ≤20089%86% >20094%92% Lennox J, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 573.

D:A:D Study: PIs and Risk of MI Primary model Dyslipidemia Elevated blood pressure Diabetes mellitus Lipodystrophy Glucose All above + lipid-lowering and antihypertensive medication Lopinavir/r Indinavir RR of MI (95% CI) Effect of Adjustment for Latest Metabolic Factors * Approximate test for heterogeneity: P=0.02 IDV NFV LPV/r SAQ #PYFU: 68,469 56,529 37,136 44,657 #MI: RR/year (95% CI) Risk with Cumulative Exposure to PI Lundgren JD, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 42LB.

SWITCHMRK 1 & 2: Study Design Identical, multicenter, double-blind, randomized, active-controlled studies Enrolled pts with HIV RNA <50 c/mL on LPV/r BID regimen in combination with at least 2 NRTIs No limit on number of prior ART regimens Prior virologic failure not an exclusion No lipid lowering therapy for at least 12 weeks Randomized (1:1) to continue LPV/r or switch to RAL Eron J, et al. 16th CROI, Montreal, Canada, Abst. 70aLB. SWITCHMRK 1SWITCHMRK 2 RAL (N=174) LPV/r (N=174) RAL (N=176) LPV/r (N=178) HIV RNA ≤ 50 c/mL 94.3%92.5%96.0%95.5% Mean CD4 (cells/mm 3 ) LPV/r ≤ 1 yr16.7%17.8%17.6%18.5% Median yrs prior ART (min, max) 3.3 (0.3, 22.3) 3.6 (0.5, 20.2) 3.7 (0.5,19.2) 4.6 (0.6,16.3) Median # prior ART (min, max) 5.0 (4.0, 16.0) 5.0 (2.0, 5.0) 5.5 (3.0,13.0) 6.0 (4.0,14.0)

*Median Percent Change **Not prespecified for test SWITCHMRK 1 and 2: Mean Change in Lipids at Week 12 Eron J, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 70aLB.

RAL not non-inferior to maintaining LPV/r Further Analysis underway to assess affect of Tx experience on results 84% with confirmed HIV RNA >50 c/mL) in the RAL group were not on 1 st ART regimen; 66% with history of VF on prior regimen(s) SWITCHMRK 1 and 2: Virologic Outcomes (NC = F) Eron J, et al. 16th CROI, Montreal, Canada, Abst. 70aLB.

SWITCHMRK 1 & 2: Resistance Summary at Time of Failure Study Drug Virologic Failures (>400 c/mL) Study drug mutationsRTI mutations RAL 12 N155HK103N NoneV118I, M184V; V179D NoneV179E G140G/S, Q148R, Q148Q/H, N155N/H D67D/G, M184V, T215T/I; Y181C N155HM184M/V; K103R N155H, Q148Q/R, Y143Y/CD67D/N, K70K/R, M184V, K219Q Q148H, G140SM184V; K103N, P225H G140G/S, Q148R, Q148Q/H, N155N/H, Q148Q/RNone N155HNone Y143Y/S, Q148Q/RNone Not done LPV/r 4 L10I/V, G16G/E, L63S, A71A/T, V77INone Not done L10I, K20R, M36I, M46L, I54V, L63P, A71V, V82A, L90MK65R, D67N, K219E; K103R, Y181C V11V/I, L63P, V77INone Eron J, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 70aLB.

Switching ARVs in Virologically Suppressed Patients Debate/Discussion