CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

OLA+VL12. When this probability was decreased from 47% to 34% in a one-way sensitivity analysis, the ICER associated with OLA+VL12 increased to $562/QALY gained, compared to NT+VL12. Conclusion: Low-cost pre-treatment drug resistance testing with initial VL test at 12 months is very cost-effective compared to NT+VL12, in Kenya. Over time, testing for PDR has the potential to reduce the growth of PDR prevalence in resource-poor settings.

Poster and Themed Discussion Abstracts

495 EVOLUTION OF ARCHIVED HIV-1 QUASISPECIES IN INDIVIDUALS TREATED WITH DOLUTEGRAVIR Pierre Gantner 1 , Guinevere Q. Lee 2 , David Rey 1 , Thibault Mesplede 3 , Marialuisa Partisani 1 , Geneviève Beck-Wirth 4 , Jean-Pierre Faller 5 , Martin Martinot 6 , Mark Wainberg 3 , Samira Fafi-Kremer 1 1 Hôpitaux Univ de Strasbourg, Strasbourg, France, 2 BC Cntr for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada, 3 McGill Univ, Montreal, Quebec, Canada, 4 Groupe Hosp Regional– Mulhouse Sud Alsace, Mulhouse, France, 5 Hôpital Nord Franche Comté, Belfort, France, 6 Hôpital Civil de Colmar, Colmar, France Background: Integrated proviral DNA persists for decades even when antiretroviral therapy (ART) prevents active replication. Residual replication on ART and cell trafficking should increase the proviral DNA genetic variability over time. We assessed the dynamics of archived HIV quasispecies over 48 weeks in patients starting successful dolutegarvir- based regimen (DBR) using an ultra-deep sequencing technique. Methods: The DRONE study is an ongoing multicenter prospective longitudinal study including patients starting a DBR (NCT02557997). In the present substudy we enrolled 20 participants divided into four groups: treatment-naïve individuals who initiated a DBR during primary (PI, n=5) or chronic (CI, n=5) infection, and treatment-experienced individuals who started a DBR while in virological success for ≥10 years (VS, n=5) or in the aftermath of virological failure (VF, n=5). Peripheral blood mononuclear cells were collected at baseline and weeks 4, 24 and 48. HIV-DNA Integrase (IN) and V3 loop sequences were obtained by 454/pyrosequencing (Roche) and analyzed for resistance and viral diversity (Shannon entropy). Results: All patients achieved or maintained HIV-RNA < 50 copies/mL fromweeks 4 to 48. We detected emerging resistance mutations in the proviral DNA from five individuals, including the R263K substitution in one individual from the CI group at week 4. Proviruses from three patients from the VS group harbored various substitutions at position 50 (Patient 1: T50I at week 48; Patient 2: M50I (+ A124T) at weeks 4, 24 and 48; Patient 3: I50T at weeks 4 and 48, and I50M at week 24) and the N230S substitution was observed in one individual from the PI group at weeks 4 and 48. DBR was associated with a transient decrease in the proviral genetic diversity of either IN or V3 sequences at week 4, even in individuals who were previously successfully treated (Student’s t-test p<0.05). Conclusion: Our result show that (i) the R263K substitution can emerge and get archived under DBR (ii) the detection of R263K in proviruses is not associated with virological failure and (iii) multiple changes at position 50 can be detected over time in proviruses of individuals using DBR. Given that the R263K and M50I substitutions have been specifically associated with resistance against dolutegravir (and more recently, bictegravir), the identification of those emerging mutations in the proviral DNA and the transient decrease in viral diversity suggest that archived viral quasispecies continue to evolve on ART. 496 IMPACT OF CLINICALLY OBSERVED INTEGRASE MUTATIONS ON DOLUTEGRAVIR RESISTANCE Atsuko Hachiya , Masaaki Nakashima, Yoko Ido, Urara Shigemi, Masakazu Matsuda, Reiko Okazaki, Junji Imamura, Yoshiyuki Yokomaku, Yasumasa Iwatani Natl Hosp Org Nagoya Med Cntr, Nagoya, Japan Background: Dolutegravir (DTG), the second-generation integrase strand transfer inhibitor (INSTI), displays potent antiretroviral effects and superior resistance profiles. To date, HIV-1 integrase (IN) mutations associated with high-level DTG resistance have not yet been reported in the clinical settings. To explore potential DTG resistance mutations, we analyzed impacts of the IN mutations detected in clinical isolates. Methods: We set out isolation of raltegravir (RAL) resistant viruses from clinical samples during virological failure under RAL-based regimen. The clinically suspected resistance mutations were introduced into the IN region of HIV-1 DNA clone by site-directed mutagenesis. Drug susceptibility of the recombinant viruses was evaluated in a single-round replication assay using TZM-bl cells. Structural analyses of the IN-INSTI complexes were performed in silico . Results: Genotypic and phenotypic analyses demonstrated that over the time course of clinical samples, a novel combination of L74F/V75I mutations in the IN region conferred resistance to first-generation INSTIs. Next, we evaluated whether the addition of L74F alone or L74F/V75I to the major resistance mutations impacts on INSTI resistance level. The results showed that the addition of L74F to the major mutations, G140S/Q148H, increased the DTG resistance level (15-fold). In contrast, the L74F/V75I drastically enhanced the level of DTG resistance when combined with either N155H (>385-fold) or G140S/Q148H (100-fold). Notably, these combinational mutations also increased the resistance magnitude to cabotegravir (CAB) that is currently an investigational second-generation INSTI. DTG efficiently chelates two divalent metal ions of the IN catalytic center that are coordinated by the DDE motif (D64-D116-E152). On the IN-INSTI structure, the L74 and V75 residues are located at the β2 strand, which is juxtaposed to the β1 strand containing the D64 residue. This suggests an indirect structural impact of the L74F/V75I mutations to the catalytic center, leading high resistance to the second-generation INSTIs. Conclusion: This is the first report to demonstrate that clinically detected L74F/V75I mutations enhance the resistance level of the major mutations to all four currently available INSTIs. These findings will help understanding of superior resistance profiles of the second-generation INSTIs and providing insights into rational design of the next generation INSTIs.

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