Hepatitis C Virus GT1b Research Articles

HCV genotype distribution in Istanbul: Adetailed 7 year epidemiological overview andimpact of Covid-19 pandemic.

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinomaworldwide. HCV has 8 genotypes (GT) and 86 subtypes and distribution of GTs varies based on geographical regions, transmission routes and even in cultural groups. The determination of viral genotype is crucial in choosing antiviral treatment, determining the duration of therapy, and monitoring treatment respose. Since 2014, with the usage of direct-acting antiviral agents (DAAs) in the treatment of HCV infections, a cure rate over 95% could be possible. Epidemiological data are important to combat a chronic HCV infections. Due to its geographical location, Turkey is like a bridge connecting Asia and Europe. Istanbul is the biggest and most crowded city of Turkey and has received immigration from many different countries, especially from Syria, in recent years and immigration still goes on. In addition, the COVID-19 pandemic has had devastating effects in our country. In this study, we determined the HCV genotypes in Health Sciences University Ümraniye Training and Research Hospital, in Istanbul between 2016 and 2022. Of the 322 patients analyzed during this 7-year period, HCV GT1b was the most prevalent GT in 65.2%, followed by GT3 in 15.5%, GT1a in 10.6%. Our data serve as a great mirror for HCV epidemiology in Turkey and contribute to global data.

Hepatitis C virus genotype diversity in Ningxia Hui autonomous region, Northwestern China

Hepatitis C virus (HCV) genotypes vary greatly in different regions. The aim of this study is to investigate the distribution of HCV genotypes in HCV infected patients, in Ningxia Hui Autonomous Region. Nucleic acid extraction and amplification were performed with test kits on 153 HCV infected patients serum samples. The HCV viral load was measured using reverse transcriptase PCR (RT-PCR) and HCV genotypes were determined. Among the 153 HCV-infected patients, 56 had genotype (GT)1b (36.60%), 45 had GT2a (29.40%), 23 had GT3a (15.00%), 14 had GT3b (9.20%),13 had GT6a (8.50%), 1 had GT1g (0.70%), 1 had GT6xa (0.70%). In GT1b, 21.40% were female and 78.60% were male; in GT2a, 42.20% were female and 57.80% were male;Males were most prevalent in genotypes 1b(39.30%), while female were most prevalent in genotype 2a(46.30%). Rare GT1g and GT6xa were also detected in males. The 41-50 year age group had the highest HCV prevalence of 32.00%. HCV GT1b is the predominant HCV genotype in Ningxia Hui Autonomous Region.

Novel 6-Aminoquinazolinone Derivatives as Potential Cross GT1-4 HCV NS5B Inhibitors.

Chronic hepatitis C virus (HCV) infections are a worldwide medical problem responsible for diverse types of liver diseases. The NS5B polymerase enzyme has become a very interesting target for the development of anti-HCV drugs owing to its fundamental role in viral replication. Here we report the synthesis of a novel series of 1-substituted phenyl-4(1H)-quinazolinone and 2-methyl-1-substituted phenyl-4(1H)-quinazolinone derivatives and evaluate their activity against HCV in HCV subgenomic replicon assays. The biological data revealed that compound 11a showed the highest activity against HCV GT1b at a micromolar concentration (EC50 = 0.984 µM) followed by compound 11b (EC50 = 1.38 µM). Both compounds 11a and 11b had high selectivity indices (SI = CC50/EC50), 160.71 and 71.75, respectively, which make them very interesting candidates for further development of more potent and selective anti-HCV agents.

Evolution of hepatitis C virus genotype 1a vs. 1b distribution inGermany between 2004 and 2018 - An analysis of 17093 patients from different real world registries

Hepatitis C virus (HCV) genotype (GT) 1 is the most common HCV GT in Western and Central Europe. Themain focus of this present work is to analyze the change of baseline characteristics of 17 093 HCV-patients with genotype 1a/1b with antiviral therapy in Germany between 2004 and 2018. We analyzed five periods: (i) 2004-2007, (ii)2008-2010, (iii) 2010-2013, (iv) 2014-2016, (v) 2017-2018. The present analysis is based on five German non-interventional registry studies and comprises data on 17 093 HCV-GT1 patients documented between 2004 and 2018 [ML17071, ML19464, ML21645, ML25724 (Peginterferon alfa-2a® non-interventional study [PAN]) and the German Hepatitis C-Registry (DHC-R). Overall, 7662 patients were infected with HCV GT1a and 9431 patients with HCV GT1b. GT1a patients were younger (46.5 years vs. 51.2 years) and more often male (70 % vs. 52 %). Previous or ongoing drug abuse was documented more frequently for GT1a patients throughout the study periods with highest frequencies in the most recent period (2017-2018; 44 % for GT1a and 10.3 % for GT1b). Metabolic comorbidities, such as those who are overweight and those with diabetes mellitus, were associated with HCV GT1b-infected women. The GT1a ratio increased from 33.6 % (2004-2007) to 50 % (2017-2018). A relevant change in the GT1a/1b ratio was observed over time in men (2004-2007: 38 %/63 %; 2017-2018: 59 %/41 %). In contrast, only 30 % of women had GT1a infection throughout all study periods without relevant changes. There were no regional differences within Germany in HCV GT1a/1b distribution despite a higher proportion of GT1b-infected women in East Germany in 2004-2007 (86 %). A marked increase of GT1a infection associated with drug use was observed in men, but not women, in Germany between 2004 and 2018. The present data show a fundamental change in HCV epidemiology, which has an impact on therapy management and general care of hepatitis C patients in Germany.

Cost–utility of sofosbuvir/velpatasvir versus other direct-acting antivirals for chronic hepatitis C genotype 1b infection in China

ObjectiveThis study aimed to estimate the cost–utility of sofosbuvir/velpatasvir (SOF/VEL) compared with other direct-acting antivirals (DAAs) in Chinese patients with hepatitis C virus (HCV).DesignA Markov model was developed to estimate...

World-wide Prevalence of Substitutions in HCV Genome Associated With Resistance to Direct-Acting Antiviral Agents

The efficacy of direct-acting antiviral agents against hepatitis C virus (HCV) infection can be compromised by substitutions in the HCV genome that occur before treatment (resistance-associated substitutions [RASs]). We performed a meta-analysis to determine the prevalence of RASs and their effects. We searched publication databases for studies of HCV RNA substitutions that mediate resistance to direct-acting antiviral agents. Findings from 50 studies of the prevalence of RAS in HCV, from 32 countries, were used in a meta-analysis. We retrieved the HCV RNA sequence from the Los Alamos HCV sequence database to estimate the prevalence of the RASs. The degree of resistance to treatment conferred by each RAS was determined based on fold-change in the 50% effective concentration of the drugs. Our final analysis included data from 49,744 patients with HCV infection and 12,612 HCV sequences. We estimated the prevalence of 56 RASs that encoded amino acids and 114 specific RASs. The average prevalence of RASs was highest in HCV genotype (GT) 6, followed by HCV GT1a, GT2, GT1b, GT3, and GT4. The highest prevalence of RASs observed encoded Q80K in NS3 to NS4A of HCV GT1a, Y93T in NS5A of GT1a, and C316N in NS5B of GT1b. The greatest number of RASs were observed at D168 in NS3 to NS4A, at Y93 in NS5A, and at C316 in NS5B. The prevalence of RASs and mutation burdens were high in Japan, the United States, Germany, Thailand, and the United Kingdom; low in Russia, Brazil, Egypt, and India; and intermediate in China, Canada, Australia, Spain, and France. In a meta-analysis, we found evidence for 114 RASs in HCV of different genotypes. Patients with HCV infection should be tested for RASs before treatment is selected, especially in regions with a high prevalence of RASs.

Discovery of New Inhibitors of Hepatitis C Virus NS3/4A Protease and Its D168A Mutant.

Hepatitis C virus (HCV) is a human pathogen with high morbidity. The HCV NS3/4A protease is essential for viral replication and is one of the top three drug targets. Several drugs targeting the protease have been developed, but drug-resistant mutant strains emerged. Here, we screened a library and synthesized a novel class of small molecules based on a tryptophan derivative scaffold identified as HCV NS3/4A protease inhibitors that are active against both wild type and mutant form of the protease. Only the compounds with predicted binding poses not affected by the most frequent mutations in the active site were selected for experimental validation. The antiviral activities were evaluated by replicon and enzymatic assays. Twenty-two compounds were found to inhibit HCV with EC50 values ranging between 0.64 and 63 μM with compound 22 being the most active. In protease assays, 22 had a comparable inhibition profile for the common mutant HCV GT1b D168A and the wild-type enzyme. However, in the same assay, the potency of the approved drug, simeprevir, decreased 5.7-fold for the mutant enzyme relative to the wild type. The top three inhibitors were also tested against four human serine proteases and were shown to be specific to the viral protease. The fluorescence-based cell viability assay demonstrated a sufficient therapeutic range for the top three candidates.

Efficacy and Safety of 12-week Interferon-based Danoprevir Regimen in Patients with Genotype 1 Chronic Hepatitis C.

Background and Aims: Genotype (GT) 1 remains the predominant hepatitis c virus (HCV) GT in Chinese patients. Over 80% of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860, which is favorable for interferon-based treatment regimens. This phase III clinical trial aimed to evaluate the efficacy and safety of the ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin regimen for 12 weeks in treatment-naïve mainland Chinese patients infected with HCV GT1 without cirrhosis.Methods: One hundred and forty-one treatment-naïve, non-cirrhotic HCV GT1 Chinese patients (age ≥18 years) were enrolled for this single-arm, multicenter, phase III MANASA study (NCT03020082). Patients received a combination of ritonavir-boosted danoprevir (100 mg/100 mg) twice a day plus subcutaneous injection of weekly pegylated-interferon α-2a (180 μg) and oral ribavirin (1000/1200 mg/day body weight <75/≥75 kg) for 12 weeks. The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment. The secondary end-points were safety outcomes, tolerability, virologic response over time and relapse rate.Results: All enrolled patients were HCV GT1-infected, and most among them (97.9%, 123/141) had the HCV GT1b subtype. Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype (87.2%, 123/141). Overall, 140 patients completed the 12-week treatment, and 97.1% (136/140) patients achieved sustained virologic response at 12 weeks (per protocol population group, 95% confidence interval: 92.9–99.2%). Only drug-related serious adverse event occurred. Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction. One patient discontinued treatment because of severe head injury in a car accident.Conclusions: The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin produced a sustained virologic response rate of 97.1% after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients, and was safe and well tolerated.Trial Registration Clinical-Trials.gov Identifier: NCT03020082

An integrated analysis of elbasvir/grazoprevir in Korean patients with hepatitis C virus genotype 1b infection.

Background/AimsIn the Republic of Korea, an estimated 231,000 individuals have chronic hepatitis C virus (HCV) infection. The aim of the present analysis was to evaluate the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) administered for 12 weeks in Korean patients who were enrolled in international clinical trial phase 3 studies.MethodsThis was a retrospective, integrated analysis of data from patients with HCV genotype (GT) 1b infection enrolled at Korean study sites in four EBR/GZR phase 3 clinical trials. Patients were treatment-naive or had previously failed interferon-based HCV therapy, and included those with human immunodeficiency virus coinfection or Child-Pugh class A cirrhosis. All patients received EBR 50 mg/GZR 100 mg once daily for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12, HCV RNA <15 IU/mL).ResultsSVR12 was achieved by 73 of 74 (98.6%) patients. No patients had virologic failure and one discontinued from the study after withdrawing consent. SVR12 rates were uniformly high across all patient subgroups. A total of 16 patients had nonstructural protein 5A resistance-associated substitutions at baseline (16/73, 22%), all of whom achieved SVR12. Adverse events (AEs) reported in >5% of patients were fatigue (6.8%), upper respiratory tract infection (5.4%), headache (5.4%), and nausea (5.4%). Thirteen patients (17.6%) reported drug-related AEs, two serious AEs occurred, and two patients discontinued treatment owing to an AEs.ConclusionsIn this retrospective analysis, EBR/GZR administered for 12 weeks was well-tolerated and highly effective in Korean patients with HCV GT1b infection.

Real-world safety and effectiveness of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in hepatitis C virus genotype 1- and 4-infected patients with diverse comorbidities and comedications: A pooled analysis of post-marketing observational studies from 13 countries.

SummaryOmbitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment‐naïve or ‐experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post‐treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off‐label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow‐up data at post‐treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2‐96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b‐infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro‐esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post‐baseline Grade 3‐4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real‐world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real‐world setting.

Comparison of Naturally Occurring Resistance-Associated Substitutions Between 2008 and 2016 in Chinese Patients with Chronic Hepatitis C Virus Infection.

Aims: The presence of pre-existing hepatitis C virus (HCV) resistance-associated substitutions (RASs) could attenuate viral susceptibility to direct-acting antiviral agents. The aim of this study was to better understand the differences among HCV RASs over time. We compared the prevalence and characteristics of naturally occurring HCV RASs in the NS3, NS5A, and NS5B genes between 2008 and 2016 in Chinese patients chronically infected with HCV genotypes (GT) 1b, 2a, 3a, 3b, and 6a. Methods: HCV RNA was extracted after serum samples were collected from 242 patients at treatment baseline, including 120 samples in 2008 and 122 samples in 2016. Reverse transcription and nested PCR were performed, and the PCR products of the NS3, NS5A, and NS5B regions were sequenced using the Sanger sequencing method. Finally, RASs were identified from the different viral strains. Results: In GT1b, the overall frequency of NS5A RASs in 2016 was significantly higher than that in 2008 (42.0% vs. 18.4%; p = 0.002). Among NS5A RASs, the most frequently detected RAS was Y93H (5.3% in 2008 vs. 15.9% in 2016; p = 0.035), which confers medium- to high-level resistance to the NS5A inhibitors: daclatasvir (DCV), ledipasvir (LDV), ombitasvir (OMV), and elbasvir. The frequency of NS5A L28 (low-level resistance to DCV/LDV/OMV) in 2016 was also higher than that in 2008 (11.6% vs. 1.3%; p = 0.027). In addition, the highest frequency of clinically relevant NS3 RASs was S122G/A/T (69.7% in 2008 and 72.5% in 2016) in HCV GT1b isolates, which had medium-level resistance to simeprevir and asunaprevir, followed by Y56F (7.9% in 2008 and 14.5% in 2016), which confers resistance to paritaprevir. Although NS5B C316N had the highest substitution rate in GT1b (80.2% in 2008 and 91.3% in 2016), it was associated with low-level resistance to sofosbuvir and dasabuvir. However, HCV RASs were rarely detectable at baseline in other genotypes or subtypes except GT1b in this study. Conclusion: The frequency of NS5A RASs in 2016 was significantly higher than that in 2008, especially at the L28 and Y93 substitution positions, which may be due to their better fitness compared with wild-type viruses.

Treatment With Grazoprevir/Elbasvir for Renal Transplant Recipients With Chronic Hepatitis C Virus Infection and Impaired Allograft Function.

BackgroundDirect-acing antiviral agents are highly efficient treatment options for chronic hepatitis C virus (HCV) infection after renal allograft transplantation. Treatment options for patients with impaired graft function remain limited. Therefore, we assessed the effectiveness and safety of grazoprevir/elbasvir therapy for patients with chronic HCV infection and impaired renal allograft function.MethodsEleven renal allograft recipients with therapy-naïve HCV genotype (GT) 1a, 1b, or 4 were treated with the fixed-dose combination of elbasvir/grazoprevir without ribavirin for 12 weeks. All recipients exhibited impaired graft function with an average glomerular filtration rate lower than 30 mL/min per 1.73 m2. Clinical data were retrospectively reviewed for renal and liver function parameters. Patients were closely monitored for trough levels of immunosuppressive agents, viral load, laboratory values, and potential adverse effects.ResultsSeven (64%) patients exhibited a rapid virologic response within 4 weeks (HCV GT1a, n = 2; HCV GT1b, n = 5). The other 4 patients exhibited a virologic response within 8 weeks (HCV GT1b, n = 3; HCV GT 4, n = 1). All patients exhibited a sustained virologic response at week 12 after the end of treatment. Clinical measures of liver function improved substantially for all patients. Few adverse effects were reported. Impaired renal allograft function and proteinuria remained stable. For most patients, only moderate adjustments to the tacrolimus dosage were necessary for maintaining sufficient trough levels.ConclusionsThis treatment appears to be safe and effective for renal transplant recipients with impaired allograft function and is a promising treatment option for eradicating HCV infection in this patient population.

Ombitasvir/Paritaprevir/Ritonavir With or Without Dasabuvir and With or Without Ribavirin for Adolescents With HCV Genotype 1 or 4.

In adults, treatment of hepatitis C virus (HCV) infection with ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) with or without dasabuvir (DSV) and ±ribavirin (RBV) results in high rates of sustained virologic response (SVR). However, these regimens have not been investigated in adolescents. This ongoing, open‐label, phase 2/3 study evaluated the pharmacokinetics, safety, and efficacy of OBV/PTV/r+DSV±RBV treatment for 12 weeks in adolescents infected with HCV genotype (GT) 1 without cirrhosis (part 1) and the safety and efficacy of OBV/PTV/r±DSV±RBV treatment for 12 or 24 weeks in adolescents infected with GT1 or GT4 without cirrhosis or with compensated cirrhosis (parts 1 and 2). Patients were 12‐17 years of age and treatment naive or interferon experienced. Treatment regimens were based on HCV GT and cirrhosis status. Endpoints were SVR at posttreatment week 12 (SVR12), adverse events (AEs), and pharmacokinetic parameters. Thirty‐eight adolescents were enrolled, 66% were female patients, and 76% were White; 42%, 40%, and 18% of patients had HCV GT1a, GT1b, and GT4 infections, respectively. Median age was 15 years (range, 12‐17 years), and 1 patient had cirrhosis. The SVR12 rate was 100% (38/38; 95% confidence interval [CI], 90.8%‐100%). No treatment‐emergent grade 3 or 4 laboratory abnormalities were reported. No serious AEs occurred on treatment, and no AEs led to study drug discontinuation. The most common AEs were headache (21%), fatigue (18%), nasopharyngitis (13%), pruritus (13%), and upper respiratory tract infection (11%). Intensive pharmacokinetic results showed OBV, PTV, DSV, and ritonavir drug exposures were comparable to those seen in adults. Conclusion: Treatment with OBV/PTV/r±DSV±RBV was well tolerated and highly efficacious in adolescents with HCV GT1 or GT4 infection.

Cost-Effectiveness of Elbasvir/Grazoprevir Versus Daclatasvir Plus Asunaprevir in Patients with Chronic Hepatitis C Virus Genotype 1b Infection in China.

New direct-acting antivirals (DAAs) have high efficacy and tolerability in the treatment of hepatitis C virus (HCV) infection. The objective of this study was to assess the cost-effectiveness of elbasvir/grazoprevir (EBR/GZR) versus daclatasvir plus asunaprevir (DCV + ASV) in Chinese patients with chronic HCV genotype (GT) 1b infection stratified by cirrhosis status and treatment history. A cohort state-transition model was constructed to simulate the course of chronic HCV infection in patients stratified by cirrhosis status and treatment history. The model projected lifetime outcomes and costs in terms of HCV treatment, laboratory tests, clinical procedures, and hospitalizations. Mean age of the study cohort at baseline was 45years, based on published sources. Sustained virologic response (SVR) rates were derived from clinical trials. Healthcare resource utilization and health utilities were extracted or estimated from published studies in Chinese populations. The stability of the base-case analysis was validated by deterministic and probabilistic sensitivity analyses. In each subpopulation of Chinese patients, treatment with EBR/GZR dominated treatment with DCV + ASV, with lower costs and higher quality-adjusted life-years (QALYs). Sensitivity analysis demonstrated that EBR/GZR was the cost-effective option compared to DCV + ASV in 77.4-97.4% or 94.1-100% of model simulations in Chinese treatment-naïve or treatment-experienced patients, respectively, as the cost-effectiveness threshold changed from zero to US$24,150/QALY (three times GDP per capita in China). Treatment with EBR/GZR was the cost-effective option for patients with chronic HCV GT1b infection in China, regardless of cirrhosis status or treatment history.

Elbasvir/grazoprevir in Asia-Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection.

The prevalence of hepatitis C virus (HCV) infection in Asian countries is high. This study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from Asia‐Pacific countries and Russia. In this phase 3, randomized, placebo‐controlled, double‐blind study, treatment‐naive participants with HCV genotype (GT) 1, 4, or 6 infection were randomized to EBR 50 mg/GZR 100 mg (immediate‐treatment group [ITG]) or placebo (deferred‐treatment group [DTG]) once daily for 12 weeks (Protocol PN‐5172‐067, NCT02251990). The primary efficacy variable was a nonrandomized comparison of sustained virologic response at 12 weeks after the end of therapy (SVR12) for the ITG with a historical control. The primary safety outcome was a randomized comparison between the ITG and DTG. Three hundred thirty‐seven participants were randomized to the ITG (n = 251) or DTG (n = 86); 199 (59.2%) participants were Asian, and 250 (74.4%) had HCV GT1b infection. Overall, 232/250 (92.8%) participants in the ITG achieved SVR12 (97.5% confidence interval, 89.1, 96.5). Of the 18 participants who failed to attain SVR12, 1 was lost to follow‐up and 17 had virologic failure, 13 of whom had HCV GT6 infection. The incidence of adverse events was similar between participants receiving EBR/GZR and placebo (50.8% versus 51.2%; difference, −0.3%; 95% confidence interval, −12.3, 11.9). Conclusion: EBR/GZR for 12 weeks provides an effective and well‐tolerated regimen for chronic HCV GT1 infection in treatment‐naive people from Asia‐Pacific countries and Russia, particularly for the large population with GT1b infection. EBR/GZR is not recommended for the treatment of individuals with HCV GT6 infection. (Hepatology Communications 2018;2:595‐606)

Successful retreatment with grazoprevir and elbasvir for patients infected with hepatitis C virus genotype 1b, who discontinued prior treatment with NS5A inhibitor-including regimens due to adverse events.

BackgroundSustained virologic response (SVR) by interferon and interferon-free treatment can results in the reduction of advanced liver fibrosis and the occurrence of hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). Recent interferon-free treatment for HCV shortens the duration of treatment and leads to higher SVR rates, without any serious adverse events. However, it is important to retreat patients who have had treatment-failure with HCV non-structural protein 5A (NS5A) inhibitor-including regimens. Combination of sofosbuvir and ledipasvir only leads to approximately 100% SVR rates in HCV genotype (GT1b), NS5A inhibitor-naïve patients in Japan. This combination is not an indication for severe renal disease or heart disease, and these patients should be treated or retreated with a different regimen.Case summaryRetreatment with HCV non-structural protein 3/4A inhibitor, grazoprevir, and HCV NS5A inhibitor, elbasvir, successfully eradicated HCV RNA in three patients with HCV genotype 1b infection who discontinued prior interferon-free treatments including HCV NS5A inhibitors due to adverse events within 2 weeks.ConclusionRetreatment with the 12-week combination regimen of grazoprevir and elbasvir is effective for HCV GT1b patients who discontinue the HCV NS5A inhibitor-including regimens within 2 weeks. The treatment response may be related to the short duration of initial treatment, which did not produce treatment-emergent RASs.

Pooled analysis of HCV genotype 1 resistance-associated substitutions in NS5A, NS3 and NS5B pre-and post-treatment with 12 weeks of daclatasvir, asunaprevir and beclabuvir.

Daclatasvir (DCV; non-structural [NS]5A inhibitor) plus asunaprevir (ASV; NS3 inhibitor) plus beclabuvir (BCV; non-nucleoside NS5B inhibitor) is an approved regimen for hepatitis C virus (HCV) genotype (GT)-1 treatment in Japan. A comprehensive analysis of pre-treatment and treatment-emergent HCV resistance to this regimen ± ribavirin (RBV) was performed. Data were pooled from five Phase 2/3 studies of DCV+ASV+BCV±RBV given for 12 weeks to GT-1a- or GT-1b-infected patients. The prevalence and impact of pre-treatment resistance-associated substitutions (RAS) in NS5A, NS3, and NS5B on sustained virological response (SVR) was assessed, as were emergent RAS and their post-treatment persistence. Baseline NS5A RAS (GT-1a: M28T, Q30H/L/R/S, L31M, Y93C/H; GT-1b: L31I/M, Y93C/H) were present in 5% (26/561) of GT-1a and 16% (85/537) of GT-1b sequences. SVR12 for GT-1b without RBV was 100% (82/82) with RAS and >99% (427/428) without RAS. For GT-1a, SVR12 without RAS was 97% (85/88) with RBV and 92% (410/447) without RBV; SVR12 with RAS was 100% (2/2) with RBV and 54% (13/24) without RBV. Baseline NS3 (at R155 or D168) and NS5B (at P495) RAS were rare (≤1%). Treatment-emergent NS5A RAS (mostly Q30E/H/K/R±Y93H/N) in GT-1a persisted 60 weeks post-treatment, while NS3 RAS (mostly R155K) and NS5B-P495L/S were no longer detected after 48 or 24 weeks, respectively. DCV+ASV+BCV±RBV was highly efficacious in HCV GT-1 infection, including HCV GT-1b with NS5A RAS. The fitness of treatment-emergent RAS post-treatment was NS5A > NS3 > NS5B; NS3 and NS5B RAS were generally replaced by wild-type sequence within 48 weeks.

Successful retreatment with sofosbuvir plus ledipasvir for cirrhotic patients with hepatitis C virus genotype 1b, who discontinued the prior treatment with asunaprevir plus daclatasvir: A case series and review of the literature.

BackgroundInterferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)-infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ∼70% SVR rates.Case summaryThree HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment.ConclusionRetreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment.

The influence of immunosuppressants on direct-acting antiviral therapy is dependent on the hepatitis C virus genotype.

Direct-acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified. Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation-related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real-time polymerase chain reaction or luciferase assay. Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P≤.01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P≤.01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT. For patients with HCV GT2a, GT3a, or GT4a infection, mTOR-based immunosuppressive therapy may be beneficial. CNI-based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection.

Integrated pharmacokinetic/viral dynamic model for daclatasvir/asunaprevir in treatment of patients with genotype 1 chronic hepatitis C.

In order to develop an integrated pharmacokinetic/viral dynamic (PK/VD) model to predict long-term virological response rates to daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV), a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The IC50 values of DCV and ASV were estimated to be 0.041 and 2.45 μg/L, respectively, in GT1A patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GT1A patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GT1B patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs.