Treatment-emergent Substitutions Research Articles

512. Interim Results of a Prospective Cohort Study to Monitor the Emergence of Resistance in Immunocompromised Non-Hospitalized Patients With COVID-19 Who Were Treated with Sotrovimab in Great Britain: LUNAR Study

Abstract Background Immunocompromised (IC) patients are at risk of adverse COVID-19 outcomes. The risk of treatment emergent resistance may be high in this population. This study investigated clinical and virological outcomes in sotrovimab-treated IC patients in Great Britain while the Omicron variant was predominant. Methods IC, non-hospitalized patients aged ≥ 18 years who were infected with SARS-CoV-2 and received early treatment with sotrovimab 500 mg IV for COVID-19 as per standard of care were included in this multicenter, single arm, observational prospective cohort study. Nasal/oropharyngeal samples were collected at baseline, Day (D) 7, 14, and 28 (+/-2 days) for viral load and sequencing analyses. Clinical (hospitalization, respiratory support, intensive care unit [ICU] admission and death) and safety outcomes were assessed through D28. This interim analysis included patients enrolled from 1 July 2022–31 January 2023. Results Among 195 patients (median age: 58 years), 56% were female, 86% were white, and 98.5% had ≥ 1 COVID-19 vaccine dose prior to enrollment. All patients received sotrovimab within 8 (median: 2) days of diagnosis. Absolute median viral load declined from 7.46 log10 copies/mL at baseline to 0.55 log10 copies/mL at D28 (Table 1). Of 189 patients with spike consensus sequencing data, all harbored the Omicron variant, with 32 sublineages identified. Omicron BA.4, BQ.1, BE.9, BA.5.1.18, and BN.1 were most common in this data cut. We also plan to present interim data on treatment emergent substitutions. No patients were hospitalized due to COVID-19. Six (1.3%) patients had all-cause hospitalizations; none were admitted to ICU. One patient (0.5%; infected with Omicron CH.1.1) with progressive neuromuscular disease needed high flow oxygen/non-invasive mechanical intervention and died on D18 (death deemed not COVID-19 related by investigator) (Table 2). Three mild sotrovimab-related adverse events were reported.Table 1:Summary of absolute viral load (log10 copies/mL) through Day 28, as measured by qRT-PCR from nasal/oropharyngeal swabsNote: Baseline log10 viral load was defined as the non-missing assessment taken at Day 0, excluding the negative viral load results. The post-baseline viral load values with Ct value > 38 were imputed as half the lower limit of detection (i.e. 453 copies/mL*0.5=226.5). Negative viral loads were defined as Ct ≥ 45 and were imputed as 3.57 copies/mL. These imputed values were used to derive log10 viral loads. Ct, cycle threshold; IV, intravenous; qRT-PCR, quantitative real-time reverse transcriptase polymerase chain reactionTable 2:Summary of clinical outcomes through Day 28Notes: N = Number of participants in Completer population (defined as all participants who were enrolled, exposed to study intervention [sotrovimab], and who had been followed for 30 days or discontinued from the study early); n = Number of participants with data available. ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; IV, intravenous Conclusion Sotrovimab-treated patients had reduced viral load by D7 which further decreased through D28, despite being IC and infected with Omicron subvariants (reduced in vitro neutralization has been reported for some of the subvariants). Few severe clinical outcomes were reported (all unrelated to COVID-19). Disclosures Judith Breuer, MD, GSK: Funding to conduct study|MRC/UKRI: Grant/Research Support|National Institutes of Health: Grant/Research Support|NIHR: Senior investigator|UKNIHR: Grant/Research Support|Vir Biotechnology, Inc: Funding to conduct study|Wellcome Trust: Grant/Research Support Myriam Drysdale, PhD, GSK: Employee|GSK: Stocks/Bonds Jill Walker, PhD, GSK: Employee|GSK: Stocks/Bonds Jennifer Han, MD, GSK: Employment|GSK: Stocks/Bonds Magdalena Gorczycka, MSc, GSK: Employee|GSK: Stocks/Bonds Alicia Aylott, MSc, GSK: Employee|GSK: Stocks/Bonds Melissa K. Van Dyke, PhD, GSK: Employee|GSK: Stocks/Bonds Helen Birch, PhD, GSK: Employee|GSK: Stocks/Bonds Elizabeth McKie, PhD, GSK: Employee|GSK: Stocks/Bonds David M. Lowe, FRCP, PhD, Biotest: Speaker fees|Blood Cancer UK: Grant/Research Support|Bristol Myers Squibb: Grant/Research Support|British Society of Antimicrobial Chemotherapy: Grant/Research Support|Gilead: Speaker fees (educational video)|GSK: Funding to conduct study|Langland: Speaker fees|LifeArc: Grant/Research Support|Merck: Personal fees for a round-table discussion|National Institute of Health Research: Grant/Research Support|Octapharma: Travel, accommodation and conference fees|UK Medical Research Council: Grant/Research Support|Vir Biotechnology, Inc: Funding to conduct study

304. Viral resistance analysis in the COMET-PEAK study: sotrovimab treatment in participants with mild-to-moderate COVID-19

Abstract Background Sotrovimab is a human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike (S) protein. COMET-PEAK was a 3-part, phase 2 study that evaluated intravenous (500 mg) and intramuscular (500 mg and 250 mg) administration of sotrovimab in outpatients (n=353) with mild-to-moderate COVID-19. We assessed amino acid substitutions in the SARS-CoV-2 S protein and circulating variants of concern/interest (VOC/VOI) in COMET-PEAK participants (enrolled Feb–July 2021). Methods Mid-turbinate (Part A) or nasopharyngeal (Part B/C) samples were obtained from all participants at Baseline and Post-Baseline visits. Next generation sequencing of the SARS-CoV-2 S gene was conducted using Illumina MiSeq with a ≥5% allelic frequency cut-off for samples with a viral load above 3.0 log10 copies/mL. Baseline, post-baseline and treatment-emergent (TE) substitutions were assessed, and prevalence of VOC/VOI was evaluated. Phenotypic analyses of epitope substitutions were conducted using a pseudotyped virus assay. Results In total, 282/353 participants had sequencing results for ≥1 visit (253 baseline, 248 post-baseline), and 219 had paired baseline and post-baseline sequences; among these, 149 (68%) had TE substitutions in the S protein (26 [12%] in the epitope). E340K was the predominant TE substitution in the epitope (15 [7%]). Across all arms 92/245 (38%) experienced virologic rebound, 8 of whom (Part A: 2; Part B: 2; Part C: 4) had TE substitutions in the epitope; none had evidence of clinical progression to severe disease. Prevalence of VOC/VOI or single amino acid substitutions of concern was 94% (266/282); the most frequent were Alpha (Part A: 8/16 [50%]; Part B: 75/128 [59%]) and Delta (Part C: 99/122 [81%]). Of 7 participants with evidence of clinical progression, none had S protein substitutions in the epitope and all had VOC/VOI (3 Alpha, 3 Delta, 1 Gamma). Sotrovimab effectively neutralized most epitope substitutions tested in vitro; P337L and E340A/K/V conferred significantly reduced susceptibility. Conclusion There was no evidence that sotrovimab epitope substitutions were associated with clinical progression or virologic rebound. These data are consistent with those from the COMET-ICE study. Funding Vir Biotechnology/GSK (NCT04779879). Disclosures Phillip J Yates, PhD, GlaxoSmithKline: Employee Jennifer Moore, MD, GlaxoSmithKline: Employee Jennifer Han, MD, GlaxoSmithKline: Employee Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Jill Walker, PhD, GlaxoSmithKline: Employee.

Retreatment of patients with treatment failure of direct-acting antivirals: Focus on hepatitis C virus genotype 1b.

The recent development of direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection could lead to higher sustained virological response (SVR) rates, with shorter treatment durations and fewer adverse events compared with regimens that include interferon. However, a relatively small proportion of patients cannot achieve SVR in the first treatment, including DAAs with or without peginterferon and/or ribavirin. Although retreatment with a combination of DAAs should be conducted for these patients, it is more difficult to achieve SVR when retreating these patients because of resistance-associated substitutions (RASs) or treatment-emergent substitutions. In Japan, HCV genotype 1b (GT1b) is founded in 70% of HCV-infected individuals. In this minireview, we summarize the retreatment regimens and their SVR rates for HCV GT1b. It is important to avoid drugs that target the regions targeted by initial drugs, but next-generation combinations of DAAs, such as sofosbuvir/velpatasvir/voxilaprevir for 12 wk or glecaprevir/pibrentasvir for 12 wk, are proposed to be potential solution for the HCV GT1b-infected patients with treatment failure, mainly on a basis of targeting distinctive regions. Clinicians should follow the new information and resources for DAAs and select the proper combination of DAAs for the retreatment of HCV GT1b-infected patients with treatment failure.

Hepatology highlights

Hepatology highlights

Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir.

Sofosbuvir (Sovaldi, SOF) is a nucleotide analog prodrug that targets the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase and inhibits viral replication. High sustained virological response rates are achieved when SOF is used in combination with ribavirin with or without pegylated interferon in subjects with chronic HCV infection. Potential mechanisms of HCV resistance to SOF and other nucleos(t)ide analog NS5B polymerase inhibitors are not well understood. SOF was the first U.S. Food and Drug Administration (FDA)-approved antiviral drug for which genotypic resistance analyses were based almost entirely on next-generation sequencing (NGS), an emerging technology that lacks a standard data analysis pipeline. The FDA Division of Antiviral Products developed an NGS analysis pipeline and performed independent analyses of NGS data from five SOF clinical trials. Additionally, structural bioinformatics approaches were used to characterize potential resistance-associated substitutions. Using protocols we developed, independent analyses of the NGS data reproduced results that were comparable to those reported by Gilead Sciences, Inc. Low-frequency, treatment-emergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced virological failure were also noted and further evaluated. The NS5B substitutions, L159F (sometimes in combination with L320F or C316N) and V321A, emerged in 2.2%-4.4% of subjects who failed SOF treatment across clinical trials. Moreover, baseline polymorphisms at position 316 were potentially associated with reduced response rates in HCV genotype 1b subjects. Analyses of these variants modeled in NS5B crystal structures indicated that all four substitutions could feasibly affect SOF anti-HCV activity. SOF has a high barrier to resistance; however, low-frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection.