CROI 2016 Abstract eBook

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ACTG 5273 Randomized Trial of Second-Line ART Supports WHO Guidance Alberto M. La Rosa 1 ; Linda J. Harrison 2 ; BabafemiTaiwo 3 ; Carole L.Wallis 4 ; Lu Zheng 2 ; Peter S. Kim 5 ; Nagalingeswaran Kumarasamy 6 ; Mina Hosseinipour 7 ; JohnW. Mellors 8 ; Ann Collier 9 1 Asociación Civil Impacta Salud y Educación, Lima, Peru; 2 Harvard Sch of PH, Boston, MA, USA; 3 Feinberg Sch of Med, Northwestern Univ, Chicago, IL, USA; 4 BARCSA and Lancet Lab, Johannesburg, South Africa; 5 DAIDS, NIAID, NIH, Rockville, MD, USA; 6 YRG Cntr for AIDS Rsr and Educ, Chennai, India; 7 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 8 Univ of Pittsburgh, Pittsburgh, PA, USA; 9 Univ of Washington, Seattle, WA, USA Background: The WHO recommends boosted protease inhibitor + nucleos(t)ide reverse transcriptase inhibitors (NRTI) for second-line ART, but concerns about NRTI toxicity and cross-resistance have motivated the search for NRTI-free regimens. We hypothesized that boosted lopinavir (LPV/r) + raltegravir (RAL) would be virologically non-inferior to LPV/r + NRTIs as second-line ART in resource-limited settings. Methods: ACTG A5273 (SELECT) was a phase III, open-label, randomized, non-inferiority study conducted at 15 sites in 9 resource-limited countries. HIV-1-infected adults with viral load (VL) ≥1000 copies/mL (cpm) after 24 weeks (wks) of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen received LPV/r + RAL or LPV/r + NRTIs selected from an algorithm that included zidovudine for those failing tenofovir and vice versa. Non-inferiority was defined as the upper 2-sided 95% CI for the difference in cumulative probability of virologic failure (VF, confirmed VL >400 cpm at or after wk 24) estimated by Kaplan-Meier methods by wk 48 excluding 10%. Secondly, superiority was assessed by exclusion of 0. Genotypic drug resistance testing was performed retrospectively at study entry and VF. Results: 512 eligible participants were randomized; the majority were female (52%), black (64%) and infected with subtype C (81%). At study entry, median CD4 count was 135 cells/mm 3 ; VL 4.5 log 10 cpm, 96% had ≥1 NRTI IAS mutation and 52%≥3. By wk 48, the cumulative probability of VF was 10.3% (95% CI: 6.5%, 14.0%) in the RAL arm and 12.4% (8.3%, 16.5%) in the NRTI arm (See figure) with a weighted (by randomization stratification factors) difference (95% CI) of -3.4% (-8.4%, 1.5%) indicating LPV/r + RAL was non- inferior and not superior to LPV/r + NRTIs. Participants in the NRTI armwith a NRTI genotypic susceptibility score (GSS) >1 had a higher probability of VF versus those with GSS<1 (difference -8.4% [-16.6%, -0.3%]; P=0.04). In addition, having ≥3 NRTI mutations at study entry was associated with a lower probability of VF in both arms (HR 0.45 [0.30, 0.70], P<0.001). Conclusions: In the setting of extensive NRTI resistance without resistance testing the WHO recommendation of LPV/r + NRTIs for second-line ART is supported by the current study. LPV/r + RAL should be considered an alternative if NRTI toxicity is limiting. The strong association between NRTI resistance at study entry and improved response to second- line ART deserves further evaluation of mechanisms other than better adherence.

Oral Abstracts

31LB Cabotegravir+Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2Week 32 Results David A. Margolis 1 ; Juan González-García 2 ; Hans-Jürgen Stellbrink 3 ; Joseph J. Eron 4 ;YazdanYazdanpanah 5 ; Sandy Griffith 6 ; David Dorey 7 ; KimberleyY. Smith 1 ; PeterWilliams 8 ;William Spreen 1 1 ViiV Hlthcare, Research Triangle Park, NC, USA; 2 Inst for Hlth Rsr of La Paz Univ Hosp, Madrid, Spain; 3 ICH Study Cntr, Hamburg, Germany; 4 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5 INSERM U1137, Paris, France; 6 ViiV Hlthcare, Durham, NC, USA; 7 GSK, Mississauga, ON, Canada; 8 Janssen, Beerse, Belgium Background: Cabotegravir (CAB), an HIV INSTI and rilpivirine (RPV), an HIV NNRTI are both under development as long-acting (LA) injectable nanosuspensions. LATTE-2 was designed to select an intramuscular (IM) regimen of CAB LA + RPV LA and to evaluate the safety and efficacy of 2-drug IM ART, relative to 3-drug oral ART (CAB + ABC/3TC) when used to maintain viral suppression in HIV-1 infected adults. Methods: Phase 2b, multicentre, parallel group, open-label study in ART-naïve HIV infected adults. Enrolled patients that had a plasma HIV-1 RNA <50 c/mL during the 20-week Induction Period (IP) with daily oral CAB 30 mg + ABC/3TC were randomized 2:2:1 to IM CAB LA + RPV LA every 4 weeks (Q4W), every 8 weeks (Q8W), or remained on oral CAB + ABC/3TC (PO) in the Maintenance Period (MP). The primary endpoints evaluated antiviral activity by FDA snapshot algorithm, protocol defined virologic failure, and safety at a pre-specified 32 wks in MP (ITT Maintenance Exposed (ME)). Results: 309 pts were enrolled and treated (ITT-E): 91%male, 20% non-white, and 19%>100,000 c/mL HIV-1 RNA. After 20 wks of IP, 91% of pts achieved HIV-1 RNA <50 c/mL by snapshot and 286 pts were randomized to maintenance therapy. In the MP, 95% (Q8W) and 94% (Q4W) of pts maintained HIV-1 RNA <50 c/mL at W32 compared to 91% on PO (ITT-ME). Two pts had consecutive HIV-1 RNA >200 c/ml during MP (PO [1 at W8]; Q8W [1 at W4]), both without NRTI, NNRTI, or INSTI resistance. The most common drug-related AE was injection site pain (92% on IM arms) with 99% of injection site reactions (ISRs) being mild (82%) or moderate (17%). ISRs lasted a median of 3 days, decreased in frequency following the first injection, and led to 2 pt (<1%) withdrawals. Most common non-ISR AEs during MP were nasopharyngitis (20%), diarrhea (12%) and headache (14%) on IM arms and nasopharyngitis (25%), headache (7%), and diarrhea (5%) on PO CAB. SAEs during MP occurred in 6% of IM pts and 5% PO pts, none drug related, with 1 unrelated death (seizure [Q4W]). Nine pts withdrew fromMP due to AEs; Q8W (2%), Q4W (5%) and PO (2%). Treatment emergent lab abnormalities ≥ Grade 3 occurred in 16% of IM pts and 14% of PO pts during MP.

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CROI 2016