CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

508 DTG VERSUS LPV/R IN SECOND LINE (DAWNING): OUTCOMES BY WHO- RECOMMENDED NRTI BACKBONE Michael Aboud 1 , Carlos Brites 2 , Hongzhou Lu 3 , Khuanchai Supparatpinyo 4 , Luis Hercilla 5 , Jörg Sievers 6 , Maria Claudia Nascimento 7 , Judy Hopking 8 , Mark Underwood 7 , Dannae Brown 6 , Martin Gartland 7 , Kim Smith 7 1 ViiV Healthcare, Branford, CT, USA, 2 Federal University of Bahia, Salvador, Brazil, 3 Fudan University, Shanghai, China, 4 Chiang Mai University, Chiang Mai, Thailand, 5 Hospital Nacional Alberto Sabogal Sologuren, Callao, Peru, 6 ViiV Healthcare, Brentford, UK, 7 ViiV Healthcare, Research Triangle Park, NC, USA, 8 GlaxoSmithKline, Uxbridge, UK Background: DAWNING is a non-inferiority study comparing dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) with a WHO- recommended regimen of lopinavir/ritonavir (LPV/r) + 2 NRTIs in HIV-1 infected adults failing first-line therapy (HIV-1 RNA ≥400 copies [c]/mL) of a non- nucleoside reverse transcriptase inhibitor (NNRTI) + 2 NRTIs (ClinicalTrials.gov: NCT02227238). Methods: Subjects were randomised (1:1, stratified by plasma HIV-1 RNA and number of fully active NRTIs) to 52 weeks of open-label treatment with DTG or LPV/r combined with 2 investigator-selected NRTIs, including at least one fully active NRTI based on Screening resistance testing. The primary endpoint was the proportion of subjects achieving HIV1 RNA <50 c/mL at Week 48 (Snapshot algorithm) with an interim analysis at Week 24. Post-hoc efficacy analyses were performed based on whether WHO-recommended second-line NRTIs were chosen per subjects’ first-line NRTIs; 59 subjects not taking WHO-recommended first-line NRTIs were excluded. Results: Of 968 subjects screened, only 78 (8%) were screen failures due to not having one fully active NRTI available; 624 were randomised and treated. At Week 24, DTG+2NRTIs was superior to LPV/r+2NRTIs, with 82% (257/312) and 69% (215/312) of subjects, respectively, achieving HIV-1 RNA <50 c/mL (adjusted difference 13.8%, 95% CI: 7.3% to 20.3%, p<0.001). The difference was mainly driven by lower rates of Snapshot virologic non-response in the DTG group. 56% (347/624) of subjects received WHO-recommended second-line NRTIs, and their response rates within each armwere higher than those for subjects who did not. Regardless of WHO-recommended NRTI use, response rates were higher with DTG versus LPV/r-based regimens (Table). The overall safety profile of DTG+2NRTIs was favourable compared to LPV/r+2NRTIs with more drug-related adverse events reported in the LPV/r group. In this analysis, there were no treatment-emergent primary integrase-strand transfer inhibitor or NRTI resistance mutations in the DTG group through the randomisation phase. Conclusion: In DAWNING, response rates were highest in subjects receiving DTG +WHO-recommended second-line NRTIs. Further, within each arm, subjects had higher response rates when receiving WHO-recommended versus other second-line NRTIs suggesting resistance testing to guide NRTI selection may not be necessary in this population. DAWNING provides important information to help guide second-line treatment decisions in resource-limited settings.

thymidine analog mutations (TAMs) that include M41L or L210W (n=4) in RT. Overall, 1.4% (8/572) of B/F/TAF treated patients experienced VF through W48. Of the 35 patients with preexisting F/TAF resistance, 1 (2.9%) experienced VF due to nonadherence. Postbaseline resistance analyses were conducted on viral isolates from 5 patients in the B/F/TAF group and 7 patients in the comparator groups. No patients on B/F/TAF developed de novo resistance to study drugs. One patient on boosted darunavir + ABC/3TC developed a treatment-emergent L74V substitution in RT. Conclusion: Low rates of virologic failure occurred among the 572 patients who switched to B/F/TAF, including the 35 with preexisting F/TAF resistance. Through W48 there was zero treatment-emergent resistance in B/F/TAF treated patients demonstrating the utility of B/F/TAF in HIV-1-suppressed patients. 507 IN SILICO CLINICAL TRIALS FOR EVALUATION OF HIV SHORT-CYCLE STRATEGIES Melanie Prague 1 , Chloé Pasin 1 , Linda Wittkop 1 , Pierre Duffau 2 , Estibaliz Lazaro 2 , Charles Cazanave 2 , Marc Vareil 3 , Fabrice Bonnet 2 , Rodolphe Thiébaut 1 1 INSERM, Bordeaux, France, 2 CHU de Bordeaux, Bordeaux, France, 3 Centre Hospitalier de la Côte Basque, Bayonne, France Background: The challenge associated with lifelong combination antiretroviral treatments (cART) taken by HIV infected patients have motivated the development of strategies for therapeutic relief. The cART simplification reduces toxicity and drug costs, and improves patients’ quality of life. Short- cycles treatment interruptions (SCT) have been shown as promising and are still under investigation (ANRS 170 QUATUOR, PENTA Trial group). We propose a pipeline for computer-based simulations of trials which aim at quantifying and predicting in silico the effect of SCT in order to accelerate and personalize their development. Methods: HIV and CD4+ T cells trajectories under treatment conditions were modelled using dynamical mechanistic models based on Ordinary Differential Equations (Perelson et al., Science, 2011; Prague et al., Biometrics, 2016). Data from 2550 patients of the ANRS CO3 Aquitaine HIV cohort were used and supplemented with information from in vitro assays (Siliciano et al., Lancet, 2011). Estimates of the in vivo cART effect were obtained from a populational statistical approach. Here, we focused on efavirenz (EFV)-based cART associated with two nucleosides analogues. Generating pseudo subjects with statistically controlled heterogeneity and using predictions based on parametric empirical Bayes, we simulate in silico data of realistic SCT trials. Computer-based success of the SCT is evaluated regarding the probability of detectable viral load and the mean basic reproduction number (R0, if R0 is below 1 the infection will die out in the long run) at 48 weeks. Results: We estimate that most of the investigated EFV-based cART will be potent enough to guarantee the success of 5/7 designs (5 days on, 2 days off cART). However, 4/7 designs will lead to more virological failure depending on patients’ characteristics. From Table 1, we can derive in silico results of the BREATHER PENTA 16 trial (Butler et al., Lancet HIV, 2016), which is a 5/7 design for EFV-based cART. Simulations predict 1% [0%; 11.9%] of 50 copies/mL virological failure and show a mean R0 of 0.82 [0.63; 0.99]. Because the 95% confidence interval includes the true outcome (8.1% of 50 copies/mL virological failure at 48 weeks), in silico and in vivo results are consistent. Conclusion: The computer-based approach correctly predicts the outcome of existing SCT trials. Thus, our pipeline for in silico trials is a promising tool for accelerating the development of novel strategies based on existing cART.

Poster Abstracts

509 INTEGRASE STRAND TRANSFER INHIBITOR (INSTI) EFFECTIVENESS IN ART-EXPERIENCED PATIENTS Thibaut Davy-Mendez , Sonia Napravnik, Oksana Zakharova, David Wohl, Claire E. Farel, Joseph J. Eron University of North Carolina Chapel Hill, Chapel Hill, NC, USA Background: Given increasing INSTI use among ART-experienced patients, we examined virologic and immunologic outcomes of INSTI therapy in the UNC CFAR HIV Clinical Cohort.

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