Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).

Gilead Sciences.

Gilead Sciences.

Background The availability of reference genomes has revolutionized the study of biology. Multiple competing technologies have been developed to improve the quality and robustness of genome assemblies during the past decade. The 2 widely used long-read sequencing providers—Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT)—have recently updated their platforms: PacBio enables high-throughput HiFi reads with base-level resolution of >99%, and ONT generated reads as long as 2 Mb. We applied the 2 up-to-date platforms to a single rice individual and then compared the 2 assemblies to investigate the advantages and limitations of each. Results The results showed that ONT ultralong reads delivered higher contiguity, producing a total of 18 contigs of which 10 were assembled into a single chromosome compared to 394 contigs and 3 chromosome-level contigs for the PacBio assembly. The ONT ultralong reads also prevented assembly errors caused by long repetitive regions, for which we observed a total of 44 genes of false redundancies and 10 genes of false losses in the PacBio assembly, leading to over- or underestimation of the gene families in those long repetitive regions. We also noted that the PacBio HiFi reads generated assemblies with considerably fewer errors at the level of single nucleotides and small insertions and deletions than those of the ONT assembly, which generated an average 1.06 errors per kb and finally engendered 1,475 incorrect gene annotations via altered or truncated protein predictions. Conclusions It shows that both PacBio HiFi reads and ONT ultralong reads had their own merits. Further genome reference constructions could leverage both techniques to lessen the impact of assembly errors and subsequent annotation mistakes rooted in each.

In this analysis of the ASTRAL trials (non-opioid substitution therapy [OST], n = 984; OST, n = 51) evaluating the once-daily, pan-genotypic regimen of sofosbuvir/velpatasvir for hepatitis C virus infection, OST did not impact completion, adherence, sustained virologic response (SVR12), or safety. SVR12 was 96% (95% confidence interval, 87%, >99%) in those receiving OST.Keywords. HCV; OST; PWID; sofosbuvir; velpatasvir.People who inject drugs (PWID) are disproportionately affected by hepatitis C virus (HCV) infection [1]. People with a history of injection drug use include those who have stopped injecting, those with recent injecting, and those receiving opioid substitution therapy (OST; eg, methadone or buprenorphine), some of whom may also have recently injected drugs. Data are lacking on HCV treatment outcomes with interferon-free direct-acting antiviral agents (DAAs) among people receiving OST, particularly people with genotypes (G) other than HCV G1. The phase 3 ASTRAL 1-3 trials evaluated the efficacy and safety of sofosbuvir/velpatasvir in patients with chronic HCV genotypes 1-6 [2, 3]. People receiving stable OST were eligible for inclusion, but people with clinically relevant illicit drug use within 12 months or a positive urine drug test at screening were excluded. No drug screens were performed during or following treatment. These clinical trial populations are highly selected, included people on stable OST, excluded people with recent drug use, and may not be representative of recent PWID populations. However, there are little data on interferon-free DAA therapy among people receiving OST.The aim of this post hoc analysis was to evaluate treatment completion, adherence, sustained virologic response (SVR), and safety of sofosbuvir/velpatasvir in people receiving OST without drug use at screening. METHODS Study Participants and DesignFrom 18 July 2014 to 19 December 2014 participants were enrolled in 3 international, multicenter, randomized open-label trials, including ASTRAL 1-3 (ClinicalTrials.gov: NCT02201940, NCT02220998, and NCT02201953) [2,3]. A fixed-dose combination tablet of sofosbuvir/velpatasvir 400 mg/100 mg was administered for 12 weeks in patients with chronic HCV genotypes 1-6. These studies have been described previously [2,3].Participants receiving OST were eligible for inclusion in the ASTRAL studies. Patients were excluded if they had clinically significant drug use within 12 months of screening (as assessed by the investigator) or a noncannabinoid detected by a positive urine drug test during the screening phase not explained by a prescription medication. No drug screens were performed during or following treatment. Study EndpointsIn this analysis, endpoints included treatment completion, adherence (≥90% of doses), SVR12, safety (adverse events [AEs] and serious AEs), and reinfection. The analysis population included all randomized patients who received at least 1 dose of sofosbuvir/velpatasvir. Adherence was calculated by dividing the number of total doses received during therapy...

Summary In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon‐alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon‐free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38–46% in Korea. This single‐arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12‐week duration) in chronic genotype 2 HCV‐infected treatment‐naive and treatment‐experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment‐naive and 100% (24/24) of treatment‐experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on‐treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment‐emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all‐oral, interferon‐free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.

Background & AimsIn Taiwan, patients with chronic hepatitis C virus (HCV) infection are currently treated with pegylated interferon‐alpha plus ribavirin, but interferon‐based regimens can be poorly tolerated, especially by those with advanced liver disease and the elderly. Sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, is approved in Europe, the USA and Japan for treating chronic HCV infection. This phase 3b study examined the efficacy and safety of sofosbuvir plus ribavirin in Taiwanese patients with chronic genotype 2 HCV infection ± compensated cirrhosis.MethodsIn this multicentre, open‐label, phase 3b (NCT02021643) study, 87 patients (n = 43, treatment‐naive; n = 44, treatment‐experienced) received 12 weeks of treatment with sofosbuvir plus weight‐based ribavirin. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12). Safety and pharmacokinetic data were also collected.ResultsAll 87 patients (100%; 95% confidence interval, 92–100%) achieved SVR12, including the 13 patients with compensated cirrhosis. The most common treatment‐emergent adverse events (AEs) were insomnia (16%, 14/87) and upper respiratory tract infection (16%, 14/87). No grade 3 or grade 4 AE was reported. There was one serious AE (biliary colic), which was deemed unrelated to study treatment. Laboratory abnormalities other than ribavirin‐related reductions in haemoglobin were uncommon.ConclusionsThe results from this phase 3b study demonstrate that 12 weeks of treatment with the interferon‐free regimen sofosbuvir plus ribavirin is effective and well tolerated in both treatment‐naive and treatment‐experienced Taiwanese patients with chronic genotype 2 HCV infection.

SUMMARY. GS-5816 is an inhibitor of the hepatitis C virus (HCV) NS5A protein that has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. The aim of this study was to evaluate the safety, antiviral activity and pharmacokinetics of once-daily doses of GS-5816 in patients with genotype 1-4 HCV infection. Patients with genotype 1-4 HCV infection were randomized to 3 days of GS-5816 at doses ranging from 5 to 150 mg or placebo. Adverse events were recorded, and plasma samples obtained for analysis of pharmacokinetics, HCV RNA and NS5A sequencing studies. GS-5816 5-150 mg for 3 days was well tolerated and resulted in rapid declines in HCV RNA that were sustained over the dosing period. In patients treated with the 150 mg dose of GS-5816, the mean maximal HCV RNA declines were 4.0, 4.0, 4.4, 3.3 and 3.5 log 10 IU/mL in patients with genotype 1a, 1b, 2, 3 and 4 HCV infection, respectively. Pretreatment NS5A resistance-associated polymorphisms were detected in 31% (22/70) of patients. Genotype 1 and 3 HCV-infected patients without pretreatment NS5A resistance-associated polymorphisms had greater declines in HCV RNA than patients with resistance-associated polymorphisms. Plasma pharmacokinetics were supportive of once-daily dosing. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.