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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.

Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml−1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population., A first-in-human study of an antisense oligonucleotide targeting hepatitis B virus (HBV) RNA provides initial insights into this potential new therapeutic modality for individuals with chronic HBV infection.

Zanamivir is a potent and highly selective inhibitor of influenza neuraminidase in which the inhibition of this enzyme prevents the virus from infecting other cells and specifically prevents release of the new virion from the host cell membrane. It is available as an oral powder for inhalation and intravenous formulations. The current population pharmacokinetic model based on data from eight studies of subjects treated with the intravenous formulation (125 healthy adults and 533 hospitalized adult and pediatric subjects with suspected or confirmed influenza) suggested a decreased zanamivir clearance in pediatric and renal impairment adult subjects. It also indicates that b.i.d. dosing is necessary to keep the exposure in influenza infected subjects above the 90% inhibitory concentration values of recently circulating viruses over the dosing interval. In the exposure-response analysis (phases II and III studies), no apparent relationship was found between zanamivir exposure and clinically relevant pharmacodynamic end points.

Influenza infection causes substantial morbidity and mortality during seasonal epidemics and pandemics. Antivirals, including neuraminidase inhibitors, play an important role in the treatment of severely ill patients infected with influenza. Resistance is a key factor that can affect the efficacy of neuraminidase inhibitors (NAIs). It is a recommendation by regulatory authorities to monitor for resistance during the development of anti-influenza medications. An additional requirement by regulators is to examine amino acid sequences for minority species harbouring resistance substitutions. In a Phase III study of intravenous (IV) zanamivir respiratory samples were analysed for the presence of resistant quasi species using Next Generation Sequencing (NGS). In this study ten resistance substitutions, two of which were treatment emergent, were detected by NGS that otherwise would not have been detectable by Sanger sequencing. None of the substitutions were present at any other timepoints analysed. The effect these mutations have on clinical response is difficult to characterize; in fact, all patients from which these variants were isolated had a successful clinical outcome and the effect on clinical response was therefore likely minimal. Although NGS is becoming a routine method for nucleic acid sequencing and will detect substitutions previously undetected by Sanger sequencing, the value of this technique in identifying minority species with resistance substitutions that are clinically meaningful remains to be demonstrated, particularly with acute infections such as influenza.

Background Excessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases neutrophil activation and transmigration to areas of inflammation. This study evaluated the efficacy and safety of intravenous (IV) danirixin co-administered with oseltamivir for the treatment of adults hospitalized with influenza. Methods In this phase 2b, double-blind, 3-arm study (NCT02927431), influenza-positive participants were randomized 2:2:1 to receive danirixin 15mg intravenously (IV) twice daily (bid) + oral oseltamivir 75mg bid (OSV), danirixin 50mg IV bid + OSV, or placebo IV bid + OSV, for up to 5 days. The primary endpoint was time to clinical response (TTCR). Results In total, 10 participants received study treatment (danirixin 15mg + OSV, n = 4; danirixin 50mg + OSV, n = 4; placebo + OSV, n = 2) before the study was terminated early due to low enrollment. All participants achieved a clinical response. Median (95% confidence interval) TTCR was 4.53 days (2.95, 5.71) for danirixin 15mg + OSV, 4.76 days (2.71, 5.25) for danirixin 50mg + OSV, and 1.33 days (0.71, 1.95) for placebo + OSV. Adverse events (AEs) were generally of mild or moderate intensity; no serious AEs were considered treatment-related. Interleukin-8 levels increased in nasal samples (using synthetic absorptive matrix strips) and decreased serum neutrophil-elastase–mediated degradation of elastin decreased in danirixin-treated participants, suggesting effective target engagement. Conclusions Interpretation of efficacy results is restricted by the low participant numbers. The safety and tolerability profile of danirixin was consistent with previous studies. Clinical trial information The registration data for the trial are in the ClinicalTrials.gov database, number NCT02927431, and in the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) as GSK study 201023, EudraCT 2016-002512-40. Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com., In this phase 2b, randomized, placebo-controlled study of intravenous danirixin in hospitalized influenza patients, all participants achieved a clinical response; danirixin had an acceptable safety profile. Early termination due to low recruitment and small sample size limits interpretation.

Background Central venous stenosis and occlusion (CVO) is an increasing problem in the growing hemodialysis population. Sequelae include loss of access, loss of sites suitable for future venous access, and venous hypertension. Endoluminal techniques are often unsuitable to treat long-standing stenoses, and open surgery confers higher morbidity and is not appropriate in many patients. Case We present a case of long-standing central venous stenosis with an ipsilateral functioning fistula but with significant symptoms and signs of venous hypertension. The stenosis was not considered appropriate for endoluminal treatment, and the patient was considered to be at too high risk for open surgery. The Hemodialysis Reliable Outflow (HeRO) (Merit Medical Systems, UT) device was used to bypass the fistula to the superior vena cava via the contralateral internal jugular vein. Conclusions This case demonstrates the utility of the HeRO device in cases of long-standing CVO necessitating contralateral bypass. This technique confers the benefits of open surgery while minimizing the associated risks.

Background Danirixin (DNX), a selective and reversible CXC chemokine receptor 2 antagonist, inhibits neutrophil transmigration and activation. This study assessed the safety, tolerability, and clinical effect of DNX with and without oseltamivir (OSV) in adults with acute, uncomplicated influenza. Methods This was a placebo-controlled, double-blind, Phase IIa study. Participants (18–64 years) with influenza-like symptoms (onset ≤48 hours) and positive influenza rapid antigen test were randomized 2:1:2:1 to DNX, placebo, DNX+OSV, or OSV (75 mg each, administered twice daily for 5 days) and followed for 28 days. Primary endpoints included frequency of adverse events (AEs) and serious AEs (SAEs). The effect of DNX on virologic response and clinical effect on influenza symptoms were secondary endpoints. Results A total of 45 participants were enrolled, 35 of whom were confirmed influenza positive by polymerase chain reaction analysis. The highest incidence of AEs was in the placebo group (4 of 7, 57%), followed by the DNX+OSV (7 of 16, 44%), DNX (3 of 15, 20%), and OSV (0 of 7, 0%) groups. One SAE (T-wave abnormality) was reported in the DNX group (unrelated to treatment). No differences in viral load assessments were observed among treatment groups. Conclusions Danirixin treatment was well tolerated and did not impede viral clearance.

We present a case of angiosarcoma at an arteriovenous fistula site in a non-immunocompromised patient presenting as a soft tissue swelling with associated findings suggestive of lung malignancy, metastases and bleeding diathesis. This patient died of an otherwise unexplained subdural haematoma. Given the ability of this tumour to metastasise early and the poor prognosis of angiosarcoma without adequate resection, this needs to be considered early in any differential diagnosis of soft tissue masses near an arteriovenous fistula.

BACKGROUND: Children with severe influenza infection may require parenteral therapy if oral or inhaled therapies are ineffective or cannot be administered. Results from a study investigating intravenous (IV) zanamivir for the treatment of hospitalized infants and children with influenza are presented. METHODS: This phase II, open-label, multicenter, single-arm study assessed the safety of investigational IV zanamivir in hospitalized children with influenza. Safety outcomes included treatment-emergent adverse events (TEAEs), clinical laboratory measurements, and vital signs. Clinical outcomes, pharmacokinetics, and virologic efficacy data were collected as key secondary outcomes. RESULTS: In total, 71 children received treatment with investigational IV zanamivir (exposure comparable to 600 mg twice daily in adults). TEAEs and serious TEAEs (STEAEs) were reported in 51 (72%) and 15 (21%) patients, respectively. The mortality rate was 7%, and median durations of hospital and ICU stays were 6 and 7.5 days, respectively. No STEAEs or deaths were considered related to IV zanamivir treatment, and no patterns of TEAEs, laboratory abnormalities, or vital signs were observed. The mean zanamivir exposures from 34 patients with normal renal function who received 12 mg/kg, 14 mg/kg, or 600 mg of IV zanamivir ranged from 64.5 to 110 hour·µg/mL. The median change from baseline in the viral load was −1.81 log10 copies per mL after 2 days of treatment. CONCLUSIONS: The safety profile of IV zanamivir was favorable, with no drug-related STEAEs reported. The majority of children experienced virologic response and clinical improvement during the treatment course. Systemic zanamivir exposures in children were consistent with adults.

Background Neuraminidase inhibitors are effective for the treatment of acute uncomplicated influenza. However, there is an unmet need for intravenous treatment for patients admitted to hospital with severe influenza. We studied whether intravenous zanamivir was a suitable treatment in this setting. Methods In this international, randomised, double-blind, double-dummy, phase 3 trial, we recruited patients aged 16 years or older with severe influenza admitted to 97 hospitals from 26 countries. We randomly assigned patients (1:1:1 stratified by symptom onset

A zanamivir postapproval efficacy study was conducted in children ( n = 279) in Japan during three influenza seasons. Pharyngeal swab specimens ( n = 714) were obtained for detailed resistance analysis. From 371 cultured viruses, 3 viruses (A/H1N1) from two subjects showed reduced susceptibility to zanamivir at day 1 (before treatment), 1 had an N74S amino acid substitution (fold shift, 46), and 2 (day 1 and day 2) had a Q136K amino acid substitution (fold shifts, 292 and 301). Q136K was detected only in cultured virus and not in the swab. From the remaining 118 cultured viruses obtained during or after treatment with zanamivir, no shifts in virus susceptibility were detected. Neuraminidase (NA) population sequencing showed that viruses from 12 subjects had emergent amino acid substitutions, but 3 with susceptibility data were not zanamivir resistant. The remainder may be natural variants. Further analysis is planned. Hemagglutinin (HA) sequencing showed that viruses from 20 subjects had 9 HA amino acid substitutions that were previously implicated in resistance to neuraminidase inhibitors in in vitro assays or that were close to the receptor binding site. Their role in in vivo resistance appears to be less important but is not well understood. NA clonal sequence analysis was undertaken to determine if minority species of resistant viruses were present. A total of 1,682 clones from 90 subjects were analyzed. Single clones from 12 subjects contained amino acid substitutions close to the NA active site. It is unclear whether these single amino acid substitutions could have been amplified after drug pressure or are just chance mutations introduced during PCR.

Intravenous zanamivir (IVZ) is a neuraminidase (NA) inhibitor (NAI) under investigation for the treatment of subjects hospitalised with influenza. The study included 130 symptomatic, hospitalised adults with influenza. Subjects received IVZ for 5-10 days. Viruses were cultured and analysed for susceptibility to zanamivir. Mean IC50s (n = 50) (±SD) for influenza A/H1N1pdm09, A/H3N2 and influenza B were 0.20 ± 0.06, 0.26 ± 0.07 and 1.61 ± 0.35 nM, respectively, and are comparable to data observed for sensitive isolates. A total of 185 NA and 180 haemagglutinin (HA) sequences were obtained from 123 subjects; the majority did not contain resistance substitutions. Four influenza A/H1N1pdm09 viruses from four subjects harboured NA resistance substitutions: three, Y155H, D199G and S247N, were present at Day 1 before IVZ exposure and the fourth, E119D/E, was detected at Post Treatment +5 Days but was not present at 5 other timepoints. Five subjects harboured virus with treatment-emergent NA substitutions not associated with resistance; N63D, V83A, W190C, M269K (A/H1N1pdm09) and R210K (A/H3N2). Viruses from fifteen subjects harboured HA resistance substitutions, (A/H1N1pdm09) one emerged during treatment: S162N (Day 5). Five viruses harboured treatment-emergent HA substitutions (A/H1N1pdm09) not associated with resistance: E81K, V108L, S164D, D168N and S185N. 10/92 subjects with A/H1N1pdm09 harboured a D222 HA substitution, which has been associated with increased virulence. The emergent substitutions are not associated with resistance but may have arisen due to selection pressure during IVZ treatment or by chance. In this study, there was evidence for resistance selection in a post treatment sample but the resistant variant did not persist in later visit samples.

Background: Viruses resistant to zanamivir have been generated in vitro, but no resistant virus has yet been isolated from a zanamivir-treated immunocompetent patient. In contrast most resistant viruses isolated from oseltamivir-treated patients correspond to those selected in vitro. However, despite mutations being in conserved residues in the neuraminidase (NA) they do not confer resistance in all NA subtypes. Objectives and methods: We have used reverse genetics and the recombinant baculovirus expression system for investigating reasons for the lack of isolation of zanamivir-resistant H3N2 viruses and for further exploring subtype-specific oseltamivir resistance. Results: H3N2 viruses generated by reverse genetics with H274Y, R292K E119V and E119D mutations were rescued. Those with E119G, E119A or R152K mutations could only be rescued in the presence of exogenous NA and after passage in the absence of exogenous NA only isolates that had reverted to the wild-type NA or, surprisingly, E119G/A to E119V NA were isolated. Mutations conferring zanamivir resistance significantly affected enzyme activity, virus replication or NA thermal stability. E119V viruses were stable and grew to similar titres as wild-type virus, consistent with their isolation from oseltamivirtreated patients. Mutations conferring oseltamivir resistance in N1 (H274Y) and B (R152K) NAs also conferred resistance in recombinant G70C N9 NA expressed in insect cells. Conclusions: These data suggest that zanamivir-resistant H3N2 viruses may not readily arise in vivo due to their poor viability. The G70C N9 NA may also provide a useful model for understanding the structural basis of subtype-specific drug resistance.

Objectives: To investigate the emergence of resistance to GW433908 (908), a protease inhibitor (PI) with demonstrated antiviral efficacy, safety and tolerability, when administered once daily (q.d.) with low dose ritonavir (908/r). Design: A 48-week Phase III open-label study (SOLO, APV30002) in which antiretroviral therapy-naive patients (n = 649) were treated with 908/r, (1400 mg/200 mg, q.d.) or nelfinavir [1250 mg, twice daily (b.i.d.)] with two nucleoside reverse transcriptase inhibitors (NRTI), abacavir (300 mg, b.i.d.) and lamivudine (150 mg, b.i.d.). Methods: Viral genotype and phenotype were analysed at baseline and on treatment up to 48 weeks and beyond. Results: Emergence of genotypic resistance was significantly different between the 908/r q.d. and the nelfinavir b.i.d. treatment arms for both PIs (0 versus 50%; P < 0.001) and the NRTI (13% versus 69%; P < 0.001) received. In the nelfinavir arm the key protease mutations D30N and/or L90M were frequently observed. The absence of protease resistance mutations and reduced incidence of NRTI resistance mutations in the 908/r q.d. arm was confirmed by phenotyping, which showed a lack of PI cross-resistance. Conclusions: The absence of resistance to 908 or cross-resistance to other PIs, and reduced NRTI resistance, following a 908/r q.d. regimen supports the use of this boosted PI early in therapy.

Background Zanamivir is a neuraminidase (NA) inhibitor used for the treatment of influenza. There is an unmet need for a parenteral influenza antiviral therapy to treat hospitalized patients. Therefore the safety and efficacy profile of intravenous zanamivir (IVZ) was examined in Japanese patients with severe influenza. Methods The primary objective of this study was to evaluate the safety of IVZ in Japanese patients. Clinical outcome and virological data were also assessed as secondary measures. Patients hospitalized with influenza were treated with IVZ 600 mg twice daily for five days. Results A total of 21 subjects received IVZ; 17 subjects (81%) were infected with influenza A/H3N2 and 3 (14%) were infected with influenza B. One subject was not laboratory confirmed influenza-positive. Thirteen subjects received the first dose of IVZ within two days of the onset of influenza symptoms and six subjects had been treated with prior influenza antiviral therapy. Overall adverse events (AEs) and serious adverse events (SAEs) were reported in 13 (62%) and 4 (19%) subjects, respectively. There were no patterns of AEs or SAEs. Median time to clinical response and time to virological improvement were approximately 4 days (range 0.5–22) and 3 days (range 2–5), respectively. Conclusions In this study there were no new significant safety findings or patterns of AEs related to IVZ and therefore the safety profile was confirmed for a small sample of Japanese hospitalized patients with influenza. In addition, improvements in clinical and virological measures suggestive of the clinical usefulness were also observed. ClinicalTrials.gov NCT01527110; GSK NAI115215.

Background. Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. Methods. Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed. Results. One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1–11) a median of 4.5 days (range, 1–7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. Conclusions. Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. Clinical Trials Registration {"type":"clinical-trial","attrs":{"text":"NCT01014988","term_id":"NCT01014988"}}NCT01014988.

Development of in vitro resistance to GW640385, a new human immunodeficiency virus type 1 protease inhibitor, was studied. Variants characterized included one with 50-fold resistance and amino acid substitutions L10F/G16E/E21K/A28S/M46I/F53L/A71V (protease) and L449F/P453T (Gag). The A28S substitution substantially reduced replication capacity.

Parts of the F gene from 16 mumps viruses derived from vaccines and clinical isolates were amplified using the polymerase chain reaction and their nucleotide sequences were determined. Over a region of 111 nucleotides, eight regions of variability were detected with a maximum of six (5.4%) changes occurring between any two virus strains. The Jeryl Lynn and Urabe vaccine strains were clearly different from each other and from wild virus isolated from cases of non-vaccine-associated mumps. In contrast, viruses isolated from the cerebrospinal fluid and throat in cases of meningitis and parotitis following vaccination with the Urabe strain were identical to this strain. We conclude that the vaccine was the source of these infections.