CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

experienced patients. However, identifying three fully active agents presents a challenge for some multidrug resistant (MDR) HIV patients. Ibalizumab (IBA), a CD4-directed post-attachment HIV-1 inhibitor, is approved for MDR patients failing their ART regimen. We sought to determine if IBA had comparable and durable virologic efficacy in patients with one versus two other fully active agents. Methods: Patients received IBA 2000mg loading dose followed by 800mg doses every 2 weeks up to Week 25 in TMB-301. An optimized background regimen (OBR) with ≥1 additional fully active agent was added 7 days after starting IBA. Following completion of TMB-301, eligible patients continued to receive IBA every 2 weeks under study TMB-311. Results: In TMB-301, 12 of the 40 patients had one fully active agent paired with IBA (OSS1) and 18 patients had two fully active agents with IBA (OSS2). Baseline median viral load (VL) and CD4 counts were 65,000 and 20,000 copies/ mL and 57 and 89 cells/mm 3 for the OSS1 and OSS2 patients, respectively. In OSS1 patients, fully active agents in addition to IBA were fostemsavir (n=6), DTG (n=4), TDF (n=1), and RPV (n=1). Of these, 11 (92%) had >0.5log 10 VL decrease on IBA functional monotherapy after 7 days. At Week 25, 5 of the 7 OSS1 completers (71%) achieved <50 copies/mL, of which three were on fully active DTG. At Week 96, 5 of 7 OSS1 patients (71%) maintained viral suppression, which continued until they transitioned to commercial supply (some up to Week 124). In OSS2 patients, 13 of 18 (72%) reached a >0.5log 10 VL decrease after IBA functional monotherapy. At Week 25, 9 patients (50%) with OSS2 achieved <50 copies/mL, 7 of which were on a fully active DTG regimen, demonstrating similar virologic efficacy when IBA is paired with one or two fully active agents. At Week 96, viral suppression was maintained in 9 patients and they continued on IBA until commercial was available (some up to Week 140). Conclusion: Subgroup analyses of TMB-301/311 data show significant efficacy of IBA among patients with one or two other fully active agents, with durable responses regardless of the number of active agents. Patients who combined IBA with DTG showed impressive rates of suppression. Data support the long-term efficacy of IBA-based regimens that include two or three fully active agents. 508 A PHASE I DOSE-ESCALATION TRIAL OF HUMAN MONOCLONAL ANTIBODY N6LS IN HEALTHY ADULTS Alicia T. Widge 1 , Katherine V. Houser 1 , Martin R. Gaudinski 1 , Grace Chen 1 , Cristina Carter 1 , Somia P. Hickman 1 , Jamie Saunders 1 , Lasonji Holman 1 , Ingelise Gordon 1 , Sarah O’Connell 1 , Edmund V. Capparelli 2 , Mark Connors 3 , Richard A. Koup 1 , John R. Mascola 1 , for the VRC 609 study team 1 Vaccine Research Center, NIAID, Bethesda, MD, USA, 2 University of California San Diego, La Jolla, CA, USA, 3 NIAID, Bethesda, MD, USA Background: Developing monoclonal antibodies that broadly neutralize HIV-1 (bnMAbs) through passive transfer is a key goal in the prevention and treatment of HIV-1 infection. N6LS is a bnMAb isolated from a patient who was HIV infected for 21 years and was not on antiretroviral treatment. It was produced as an IgG1 with an LS mutation to the Fc region to increase half-life through increased binding affinity to the neonatal Fc receptor. N6LS targets the CD4-binding site (CD4bs) of the HIV-1 envelope glycoprotein and is a member of the VRC01 class of CD4bs antibodies. It is broader and more potent than VRC01, neutralizing up to 98% of viral strains. N6LS achieves this via two recognition characteristics. First, it is minimally insensitive to mutations in the variable gp120 V5 loop that typically diminish contacts and interrupt binding in other CD4bs antibodies. Second, it binds at a unique angle that avoids steric clashes with the highly glycosylated V5 region, which is a major mechanism of resistance for other bnMAbs in this class. Methods: We conducted a first-in-human dose-escalation open-label phase 1 clinical trial of N6LS in healthy HIV-1 negative adults aged 18-50 to determine its safety, tolerability, and pharmacokinetic (PK) profile. Three groups received a single IV dose of 5, 20, or 40 mg/kg, and one group received a single SC dose of 5 mg/kg. Two groups received three doses of either 5 mg/kg SC or 20 mg/kg IV at 12-week intervals. Results: We enrolled 23 volunteers between June 18, 2018 and February 12, 2019, including 9 (39%) males and 14 (61%) females. 22 participants received all N6LS administrations for a total of 42 product administrations. N6LS was safe and well tolerated with no SAEs or dose-limiting toxicities. No infusion reactions occurred. All reported reactogenicity was mild to moderate in severity. Initial PK up to 4 weeks following initial N6LS administration from 21 subjects showed that maximum (C max ) and 4 week post-infusion serum concentrations increased proportionally with antibody dose (Table 1). Estimated half-life exceeded 30

days in all 15 subjects with at least 12 weeks of PK results. This preliminary analysis has shown that N6LS demonstrates linear PK with a promising half-life for infrequent administration. Conclusion: N6LS was safe and well tolerated by IV and SC administration and displayed encouraging PK parameters. Given its high neutralization breadth and potency, N6LS is a promising candidate for inclusion in HIV-1 prevention and therapeutic strategies.

509 PREEXISTING RESISTANCE AND B/F/TAF SWITCH EFFICACY IN AFRICAN AMERICANS Kristen Andreatta 1 , Michelle L. D'Antoni 1 , Silvia Chang 1 , Ross Martin 1 , Christiana Blair 1 , Sean E. Collins 1 , Kirsten L. White 1 1 Gilead Sciences, Inc, Foster City, CA, USA Background: The BRAAVE 2020 study is evaluating the safety and efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among virologically suppressed adults with HIV in the US who identify as Black or African American. Here, we present resistance analyses and impact on virologic outcomes at Week 24. Methods: Participants with prior treatment failure and documented resistance to NNRTIs, PIs and/or NRTIs were eligible for enrollment with the exception of tenofovir resistance (K65R/E/N, 3 or more thymidine analogue mutations [TAMs], or T69-insertions); primary INSTI resistance (-R) was exclusionary. Pre-existing drug resistance was assessed with historical genotypes and retrospectively with baseline proviral DNA genotyping (GenoSure Archive, Monogram Biosciences). Participants with exclusionary resistance detected post-randomization were allowed to remain on study. Outcomes were determined by last on-treatment HIV-1 RNA through Week 24. Results: Of the 493 participants analyzed for efficacy, 328 switched to B/F/ TAF and 165 stayed on their 3-drug baseline regimen (SBR). Cumulative baseline protease and reverse transcriptase data from historical and/or proviral genotypes were available for 96% (471/493). Pre-existing primary NRTI-R, NNRTI-R, and PI-R substitutions were observed in 15% (70/471), 21% (101/471), and 13% (60/471), respectively. The most commonly detected NRTI-R substitutions were M184V/I in 11% (51/471) and TAMs in 7.2% (34/471). Baseline integrase data were available for 91% (450/493). Primary INSTI-R was detected post-randomization in 4.2% (19/450) by proviral genotype. Resistance substitutions were similar across treatment groups (Table 1). Among B/F/ TAF-treated participants, >99% (326/328) were suppressed at their last visit through Week 24 including 100% (44/44) with NRTI-R (31 of whom had archived M184V/I), 99% (68/69) with NNRTI-R, 100% (34/34) with PI-R, and 100% (15/15) with INSTI-R. Four participants were analyzed for resistance development on study (3 B/F/TAF, 1 SBR); none had treatment emergent resistance to study drugs. Conclusion: Pre-existing resistance was common among suppressed Black Americans switching to B/F/TAF, notably M184V/I, TAMs, and NNRTI-R. High rates of virologic suppression were maintained through 24 weeks of B/F/TAF treatment and there were no failures with resistance, indicating that B/F/ TAF is an effective treatment option for patients with or without pre-existing resistance to NNRTIs, PIs, or non-tenofovir NRTIs.

Poster Abstracts

CROI 2020 181

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