CROI 2019 Abstract eBook
Methods: Using integrase sequences from the BC-CfE database (N=16,563), 27 integrase positions were identified as having amino acids that differed in prevalence between integrase-treated (primarily RAL and/or EVG) and naive individuals. All unique amino acid permutations at these positions were identified (N=288) and N=137 subtype B samples were selected as the representative samples. Extracted RNA was diluted to ~500 copies/mL and amplified in 12 independent RT-PCR reactions. Amplicons with no nucleotide mixtures at these positions were used to make recombinant viruses by co- transfection with linearized integrase-deleted pNL4.3 in CEM-GXR cells. To date, N=130 recombinant viruses were successfully harvested and sequenced to confirm the absence of mixtures at these codons and match to amplicon sequence. Titering and phenotyping were performed in MT4-LTR-EGFP cells, where infectivity data was collected using a SpectraMax i3 MiniMax 300 Imaging Cytometer. EC50s fold-change (FC) relative to a NL4.3 control were determined on day 3 or 4 post-infection. Results: The 130 variants phenotyped to date represent 88% of the observed sequence variation among the clinical samples at these 27 relevant integrase codons. Of these, 15%, 13%, and 30% had >3-FC for DTG, BIC and CAB, respectively. As expected, variants with the highest FC had G140S and Q148R/H. R263K was the only single variant conferring >3-FC for all three drugs. However, a variant harboring G163R/D232E also had >3-FC for all three drugs. The FC values were closely correlated between all three drugs tested. The greatest exceptions were variants with N155H/G163E or L74I/T97M/F121C/V151I/E157Q/ G163K, where both had >75-FC for CAB, while <3-FC for DTG and BIC. If new mutations or permutations are identified it is straightforward to select these for future phenotyping. Conclusion: Observed sequence variation can be used to efficiently generate panels of resistant viruses for phenotype analysis. We confirm broad cross- resistance between DTG, BIC, and CAB, and identify new patterns leading to decreased susceptibility to the newest integrase inhibitors. This work should be extended to non-subtype B variants. 144 DTG VS LPV/R (DAWNING): EFFICACY BY BASELINE NRTI RESISTANCE AND SECOND-LINE NRTI USE Dannae Brown 1 , Ruolan Wang 2 , Mark Underwood 2 , Judy Hopking 3 , Maria Claudia Nascimento 4 , Michael Aboud 4 , Jörg Sievers 4 1 ViiV Healthcare, Abbotsford, Australia, 2 ViiV Healthcare, Research Triangle Park, NC, USA, 3 GlaxoSmithKline, Uxbridge, UK, 4 ViiV Healthcare, Brentford, UK Background: DAWNING is a non-inferiority study comparing dolutegravir (DTG) + 2 nucleoside reverse transcriptase inhibitors (NRTIs) with 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 + 2 NRTIs. Methods: Subjects were randomised (1:1, stratified by Screening HIV-1 RNA and number of fully active NRTIs) to 52 weeks of open-label treatment with DTG or LPV/r + 2 investigator-selected NRTIs, including at least one fully active NRTI based on Screening resistance testing. The primary endpoint was the proportion of subjects with HIV1 RNA <50 c/mL at Week 48 (Snapshot algorithm). Post-hoc efficacy analyses were performed based on baseline NRTI resistance profile and NRTI use in the second-line background regimen (BR). Results: Of 624 subjects randomised and treated, 499 (80%) received <2 active NRTIs at baseline. Overall, 84% (261/312) of subjects on DTG versus 70% (219/312) on LPV/r achieved HIV-1 RNA <50 c/mL at Week 48 (adjusted difference 13.8%, 95% CI: 7.3% to 20.3%, p<0.001 for superiority). This difference was consistent regardless of the use of <2 or 2 fully active NRTIs in the BR. NRTI resistance was present in 561 subjects (90%) at baseline, M184V/I (alone or plus additional NRTI resistance-associated mutations [RAMs]) in 513 (82%), K65R in 187 (30%), and ≥1 thymidine-analogue mutations (TAMs) in 152 subjects (24%). Of subjects with M184V/I alone or plus ≥1 NRTI RAMs, 430 subjects (84%) took lamivudine (3TC) or emtricitabine (FTC) as part of their BR. Tenofovir disoproxil fumarate (TDF) was included in BR in the presence of K65R in 15 subjects while 86 subjects with 1 or more TAMs took zidovudine (AZT). Among subjects receiving 3TC or FTC in the presence of M184V/I, 85% (187/220) of subjects on DTG versus 72% (152/210) on LPV/r had HIV-1 RNA <50 c/mL at Week 48 (difference 12.6%, 95% CI: 4.9% to 20.3%). High responses were also observed in the DTG arm, when AZT or TDF were included in the BR in the presence of TAMs or K65R, respectively; however, subject numbers in these subgroups were small (Table 1).
Conclusion: In DAWNING, response rates were high in subjects receiving DTG+2NRTIs regardless of pre-existing resistance to one of the NRTIs in the BR, including in subjects using 3TC or FTC in the presence of M184V/I. In WHO interim guidance on HIV treatment, DTG+2NRTIs is now a recommended second-line treatment option for patients failing an NNRTI-based regimen.
145LB THERAPEUTIC ACTIVITY OF PGT121 MONOCLONAL ANTIBODY IN HIV- INFECTED ADULTS Kathryn E. Stephenson 1 , Boris Julg 2 , Jessica Ansel 1 , Stephen R. Walsh 1 , Chen S. Tan 1 , Lori Maxfield 1 , Peter Abbink 1 , Huub C. Gelderblom 3 , Frances Priddy 3 , Allan C. deCamp 4 , Roberto Arduino 5 , Edwin DeJesus 6 , Georgia Tomaras 7 , Michael S. Seaman 1 , Dan Barouch 1 1 Beth Israel Deaconess Medical Center, Boston, MA, USA, 2 Massachusetts General Hospital, Boston, MA, USA, 3 International AIDS Vaccine Initiative, New York, NY, USA, 4 Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 5 University of Texas at Houston, Houston, TX, USA, 6 Orlando Immunology Center, Orlando, FL, USA, 7 Duke University, Durham, NC, USA Background: PGT121 is a recombinant human IgG1 mAb that targets a V3 glycan-dependent epitope region of HIV Env. PGT121 is a potent neutralizing antibody in vitro and has been shown to prevent and treat simian-human immunodeficiency virus in rhesus monkeys. Here we present safety, pharmacokinetic (PK) and antiviral efficacy data from the first-in-human phase 1 clinical trial of PGT121 conducted in the United States. Methods: The first part of the study was a randomized, double blinded, dose escalation, placebo-controlled trial of PGT121 in adults who were HIV- uninfected (HIV-, N=20) and HIV-infected on ART (HIV+/ART+, N=15). PGT121 was given once at 3, 10, and 30 mg/kg IV and 3 mg/kg SC (N=5/group, 4:1 Ab/ placebo). The second part of the study was an open label trial of PGT121 given once at 30 mg/kg IV in HIV-infected adults not on ART with high VL (3.3-4.8 log cp/ml, N=9) and low VL (2-2.6 log cp/ml, N=3). All participants were monitored for reactogenicity for 3 days and adverse events (AEs) for 56 days. PK and virologic assessments were performed through 6 months. The lower limit of quantification (LLOQ) of VL was 1.6 log cp/ml. Results: PGT121 was safe and well-tolerated with no related mod/severe AEs. The elimination half-life of PGT121 was ~22 days in HIV- and HIV+/ART+ groups, with variation by dose and route. In viremic HIV+ individuals not on ART, PGT121 showed antiviral efficacy in 5/9 participants in the high VL group with a median drop in VL of 1.7 log cp/ml (1.3-2.1) by d10. These individuals showed PGT121 sensitive virus at baseline but developed rebound by d28 with emergence of resistance. In the low VL group, PGT121 decreased VL to
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