Direct-acting Antiviral Failure Research Articles

Resistance-associated substitutions in patients with chronic hepatitis C virus genotype 4 infection.

Data on the prevalence of resistance-associated substitutions (RASs) and their implications for treatment with direct-acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4-infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA-naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P<.0001). RASsL28V, L30R and M31L pre-existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein-protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n=2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance-tailored retreatment using first- and second-generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first-line treatment regimens.

Efficacy of sofosbuvir/velpatasvir/voxilaprevir in direct-acting antiviral experienced patients with hepatitis C virus.

Report the real-world experience of the efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in chronic hepatitis C virus (HCV) infected patients who have previously experienced a direct-acting antiviral (DAA) containing regimen. Consecutive patients who have previously failed or did not tolerate a DAA containing regimen for chronic HCV who was treated with SOF/VEL/VOX were studied. Baseline clinical and laboratory data including NS5A RAS mutation testing were collected. SOF/VEL/VOX resulted in an end of treatment undetectable HCV viral load in all patients and a sustained virologic response 12 rate of 100% despite the presence of NS5A RAS mutation, HIV infection, and cirrhosis. Treatment with SOF/VEL/VOX was well tolerated and there were no adverse events. SOF/VEL/VOX is well tolerated and effective in treating patients who have been exposed to prior DAA therapy outside of clinical trials. SOF/VEL/VOX should be considered as the first-line regimen in HCV infected patients who have experienced prior DAA failure.

NS5A resistance – associated substitutions in chronic hepatitis C patients with direct acting antiviral treatment failure in Turkey

ObjectivesChronic hepatitis C (CHC) is now a more curable disease with new direct acting antivirals (DAA). Although high sustained virologic response rates, failures still occur in DAA regimens. Our objective in this study was to characterize the real-life presence of clinically relevant resistance – associated substitutions (RASs) in the HCV NS5A gene in CHC patients whose DAA regimen has failed. MethodsThe study enrolled 53 CHC patients who experienced failure with DAA regimen as the prospective longitudinal cohort between 2017–2019. Genotypic resistance testing was performed via the viral population sequencing method and The Geno2pheno HCV tool was used for RAS analysis. ResultsThe most frequent failure category was relapse (88%) followed by non-responder (12%). For a total of 36% of patients, RASs was detected in NS5A, Y93H was the most detected RAS in GT1b infected patients (89%). ConclusionsThis study establishes an HCV failure registry for Turkey in which samples were combined with clinical, virologic and molecular data of adult patients whose DAA therapy failed. RASs can occur in CHC patients with DAA treatment failures. Evaluation of RAS after DAA failure is very important before re-treatment is initiated to prevent virologic failure.

Marked heterogeneity in the diagnosis of compensated cirrhosis of patients with chronic hepatitis C virus infection in a real-world setting: A large, multicenter study from Japan.

The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent. In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen. Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching. Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis.

Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1–3 Infections

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

From the Editor’s Desk…: October 2019

From the Editor’s Desk…: October 2019

Intention-to-treat assessment of glecaprevir + pibrentasvir combination therapy for patients with chronic hepatitis C in the real world.

We assessed the problems and efficacy of glecaprevir + pibrentasvir (GLE/PIB) therapy for patients infected with hepatitis C virus (HCV) in the real world. A total of 423 patients infected with HCV who started treatment at eight different centers in Japan were enrolled in the study. Glecaprevir (300mg) and pibrentasvir (120mg) were given once daily for 8weeks to 246 non-cirrhotic direct-acting antiviral (DAA)-naive patients with HCV genotype (GT)-1 or-2, and for 12weeks to patients who: were DAA-naive cirrhotic (n = 55), had experienced DAA failure (n = 78), were cirrhotic and had DAA failure (n = 37), and were other GT-1/2 (n = 7). Anti-HCV efficacy was defined as a sustained virologic response 12weeks post-treatment (SVR12). The evaluation was undertaken in an intention-to-treat (ITT) population and in patients who were assessed at SVR12 (modified ITT population). In the ITT population, 220 (89%) patients on the 8-week regimen and 164 (93%) patients on the 12-week regimen achieved SVR12. The 30 dropout patients were predominantly men and with GT-2. All other DAA-naive GT-1 patients achieved SVR12. The 12-week regimen resulted in 100% SVR12 in 41 GT-2 patients. Nine patients did not achieve SVR12: two DAA naive with GT-2a, two GT-3b patients, two GT-1 patients with discontinuation, and three other GT-1 patients with a history of DAA failure. Four of seven patients who discontinued treatment due to severe adverse effects weremore than 75years old. Glecaprevir + pibrentasvir had a remarkable anti-HCV effect in GT-1 and GT-2 patients, but not in GT-3b patients. Although this therapy was reasonably safe, it is necessary to carefully consider elderly and dropout patients.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure

Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs

Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.

Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations: A 2019 Update.

It has been estimated by the World Health Organization (WHO) that over 71 million people were infected with the hepatitis C virus (HCV) in 2015. Since then, a number of highly effective direct-acting antiviral (DAA) regimens have been licensed for the treatment of chronic HCV infection: sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. With these treatment regimens, almost all chronic HCV-infected patients, even including prior DAA failures, can be treated effectively and safely. It is therefore likely that further development of DAAs will be limited. In this descriptive review we provide an overview of the clinical pharmacokinetic characteristics of currently available DAAs by describing their absorption, distribution, metabolism, and excretion. Potential drug–drug interactions with the DAAs are briefly discussed. Furthermore, we summarize what is known about the pharmacodynamics of the DAAs in terms of efficacy and safety. We briefly discuss the relationship between the pharmacokinetics of the DAAs and efficacy or toxicity in special populations, such as hard to cure patients and patients with liver cirrhosis, liver transplantation, renal impairment, hepatitis B virus or HIV co-infection, bleeding disorders, and children. The aim of this overview is to educate/update prescribers and pharmacists so that they are able to safely and effectively treat HCV-infected patients even in the presence of underlying co-infections or co-morbidities.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00774-0) contains supplementary material, which is available to authorized users.

Upcoming direct acting antivirals for hepatitis C patients with a prior treatment failure.

Despite the high efficacy of direct acting antivirals (DAAs) not all patients successfully clear hepatitis C virus infection, in fact, approximately 1–3% fail to reach a sustained virological response 12 weeks after end of treatment. DAA failures are characterized by advanced liver disease, specific genotypes/subtypes and resistance associated substitutions to the DAA class they have been treated with. Current European Association for the Study of the Liver guidelines recommend three therapeutic options for such patients. The first is a 12 week course of sofosbuvir (SOF), velpatasvir (VEL) and voxilaprevir (VOX), which has shown to be effective in 90–99% of patients and was granted A1 level recommendation. The second option, reserved for patients who have predictors of failure consists in 12 weeks regimen with glecaprevir (GLE) and pibrentasvir (PIB), effective in 90–97%. Finally, although not supported by published data, for especially difficult to treat patients there should theoretically be a benefit in prolonged combinations of SOF+GLE/PIB or SOF/VEL/VOX±ribavirin. This review presents the latest evidence from both clinical trials and real-life on such therapeutic strategies.

Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity

Patients infected with hepatitis C virus (HCV) have an increased risk of developing type 2 diabetes. HCV infection is linked to various liver abnormalities, potentially contributing to this association. We show that HCV infection increases the levels of hepatic selenoprotein P (SeP) mRNA (SEPP1 mRNA) and serum SeP, a hepatokine linked to insulin resistance. SEPP1 mRNA inhibits type I interferon responses by limiting the function of retinoic-acid-inducible gene I (RIG-I), a sensor of viral RNA. SEPP1 mRNA binds directly to RIG-I and inhibits its activity. SEPP1 mRNA knockdown in hepatocytes causes a robust induction of interferon-stimulated genes and decreases HCV replication. Clinically, high SeP serum levels are significantly associated with treatment failure of direct-acting antivirals in HCV-infected patients. Thus, SeP regulates insulin resistance and innate immunity, possibly inducing immune tolerance in the liver, and its upregulation may explain the increased risk of type 2 diabetes in HCV-infected patients.

Transjugular Intrahepatic Portosystemic Shunt: A Possible Risk Factor for Direct-Acting Antiviral Treatment Failure in Patients With Hepatitis C?

Direct‐acting antiviral (DAA) therapies have revolutionized the treatment of chronic hepatitis C virus infection, achieving sustained virological response (SVR) rates of >90% even in patients with advanced liver cirrhosis. Having observed an unusual case of repeated DAA therapy failures in a patient with a transjugular intrahepatic portosystemic shunt (TIPS), we assessed a possible association between prior TIPS placement and DAA failure. A structured search of our clinical database revealed 10 patients who had received DAA therapy after TIPS placement. At the time of therapy, most patients (8; 80%) presented with a Child‐Pugh score B, and the following DAA regimens were used: sofosbuvir/ledipasvir ± ribavirin (5 patients), sofosbuvir/daclatasvir ± ribavirin (3), sofosbuvir/velpatasvir (2), and sofosbuvir/velpatasvir/voxilaprevir (1). In total, 5 patients (50%) achieved an SVR, whereas a virological relapse occurred in the other half of the cases, including 2 patients with multiple relapses. In this patient cohort, SVR rates were unusually low for all regimens: sofosbuvir/ledipasvir ± ribavirin, 3/5 (60%); sofosbuvir/daclatasvir ± ribavirin, 2/3 (66%); sofosbuvir/velpatasvir, 0/2 (0%); and sofosbuvir/velpatasvir/voxilaprevir, 0/1 (0%), and patients with a TIPS made up a relevant proportion of DAA failures in patients with cirrhosis at our center: sofosbuvir/ledipasvir, 2/18 (11%); sofosbuvir/daclatasvir, 1/4 (25%); sofosbuvir/velpatasvir, 2/3 (66%); and sofosbuvir/velpatasvir/voxilaprevir, 1/1 (100%). Conclusion: We observed a high rate of virological relapse in patients with a TIPS who received DAA treatment and therefore postulate that TIPS placement may be a possible risk factor for DAA failure due to the profound hemodynamic changes evoked by the intervention. Longer treatment duration or addition of ribavirin might be warranted in these patients.

Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection.

Until recently, interferon-free anti-hepatitis C virus (HCV) therapy for genotype 2 (GT2) HCV-infected hemodialysis patients was an unfulfilled medical need. Recent clinical trials of glecaprevir and pibrentasvir (G/P) for hemodialysis patients showed high efficacy and safety; however, the number of GT2 HCV-infected patients, especially Asian patients, was limited and most of them were treated with a 12-week regimen. In this prospective multicenter study, we aimed to investigate the efficacy and safety of G/P in Japanese hemodialysis patients with GT2 HCV infection. Twenty-seven Japanese hemodialysis patients with GT2 HCV infection who were started on with 8- or 12-week G/P regimen between November 2017 and June 2018 were included and followed up for around 12weeks after treatment completion. Among the 27 included patients, 13 non-liver cirrhosis (LC) and direct-acting antivirals (DAAs)-naïve patients were treated with 8weeks of G/P and 14 patients with LC (n = 13) or history of failure of DAAs (n = 1) were treated with a 12-week regimen. The overall sustained virological response at 12weeks after treatment completion (SVR 12) was 96.3% (26/27). All patients with 8weeks of treatment achieved SVR12. Two patients discontinued the therapy at 2 and 11weeks after treatment initiation. The patient who discontinued at 2weeks due to pruritus alone failed to respond to G/P. No patients experienced lethal adverse events during the therapy, and the most common adverse event was pruritus. An 8- or 12-week G/P regimen is highly effective and safe in GT2 HCV-infected hemodialysis patients.

Rescue therapy for chronic hepatitis C virus infection after repeated treatment failures: Impact on disease progression and risk of hepatocellular carcinoma.

Retreatment after previous failure of direct-acting antivirals for hepatitis C virus (HCV) infection is a challenging decision. The importance of achieving viral eradication on modification of disease progression and outcome, including the risk of hepatocellular carcinoma (HCC), remains a critical issue to be evaluated. One hundred patients with repeated failure of sofosbuvir and ribavirin or triple therapy with sofosbuvir, ribavirin, and daclatasvir were divided into a study group (n = 50) given rescue therapy (sofosbuvir, daclatasvir, simeprevir, and ribavirin) or a control group (n = 50) matched for age, sex, and pretreatment variables (Child-Turcotte-Pugh score and Fibrosis-4 score). Follow-up was undertaken after the last non-response to detect serious adverse events, such as hepatic decompensation and development of HCC. The study group achieved sustained virologic response (SVR) in 47 of 50 (94%) patients. The control group had significantly higher HCC rates than the study group (7 vs. 1 patients), with an odds ratio of 5.44. The rescue therapy was associated with significantly longer time to the occurrence of adverse events. Repeated treatment failures were associated with progression of FibroScan values in the control group (21 ± 4.5 vs. 10 ± 1.5kPa, P = 0.001); achieving SVR in the study group stopped fibrosis progression despite non-significant increase from baseline (13.2 ± 3.2 vs. 10.6 ± 0.6, P = 0.12). Rescue treatment for HCV infection was highly effective in achieving SVR, less expensive than the newer agents, and is associated with diminished risk of serious adverse events, mainly HCC in these patients.

Predictors of Direct-Acting Antivirals Failure in Patients with Chronic Hepatitis C Virus in Ivory Coast: About 5 Cases

Context and Aim: Direct-acting antivirals are the therapeutic revolution in the management of viral hepatitis C, but often with a few cases of failure. The aim of this study was to identify factors that may be implicated in the failure of direct-acting antiviral therapy in patients with hepatitis C virus in Ivory Coast. Methodology: This was a cross-sectional and descriptive study with a retrospective compendium of data from the year 2016 to the year 2018. This study included all patients with chronic viral hepatitis C, patients naive to antiviral treatment, or pre-treated patients in whom a failure to treatment with direct-acting antiviral has been diagnosed. Results: During the study period, 5 patients out of 14 cases of therapeutic failure were included, i.e. 35.71%. Most of the patients were over 50 years (4 out of 5) and predominantly female (3 out of 5). High blood pressure was the most common comorbidity (3 out of 5 patients). Genotype 1 was found in 4 patients versus 1 case of genotype 2. None of the patients had hepatitis B or HIV coinfection. A viral load > 6log was found in 4 patients at baseline. All our patients had hepatic cytolysis. Two of them were cirrhotic. All 4 cases of genotype 1 benefited from the combination sofosbuvir + ledipasvir for 12 weeks and the case of genotype 2 from the combination sofosbuvir + ribavirin for 24 weeks. The resistance mutations were observed mainly on the sequencing of NS5A at the Y93H, L31M, 28L, 30T, 31V, 58S and 93H genes and a case of mutation on the N3 gene sequencing. Conclusion: Age > 50 years, comorbidities (high blood pressure), polymedication, female gender, genotype 1b, viremia > 6log, and cytolysis were the profile of patients with treatment of HCV by direct-acting antiviral failure.

Elbasvir plus grazoprevir for patients with chronic hepatitis C genotype 1: A multicenter, real-world cohort study focusing on chronic kidney disease

The real-world effectiveness and safety of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C (HCV) infection and chronic kidney disease (CKD) have not been fully elucidated. This study assesses elbasvir (EBR) plus grazoprevir (GZR) for patients with HCV genotype 1 infection in the clinical setting, focusing on CKD stage 3-5D. This multicenter, real-world cohort study consisted of 282 Japanese patients who were treated with EBR (50 mg) plus GZR (100 mg) for a fixed 12-week duration. We evaluated the sustained viral response rate 12 weeks after the end of treatment (SVR12), longitudinal liver and renal parameters, and adverse effects according to the cirrhosis and CKD status. Of those enrolled, 89 (31.6%) were CKD stage 3–5 and 21 (7.4%) were CKD stage 5D (hemodialysis-dependent). The overall and CKD stage 3-5D SVR12 rates in the per protocol populations were 98.6% (272/276) and 98.1% (101/103). High SVR12 rates were observed in almost all groups, except for prior all-oral DAA failure with NS5A resistance-associated substitutions. There was no significant change during treatment or follow-up period in estimated glomerular filtration rate, irrespective of CKD status. In contrast, the serum complement level (C3 and C4) increased, with significance for C3. Serious adverse effects were very rare, both in the groups with normal eGFR and CKD, and discontinuation was required for only six (2.1%) patients. EBR plus GZR for HCV genotype 1 was highly effective with a low rate of adverse effects, regardless of CKD status. In addition, liver parameters and complement levels improved longitudinally.

Quantitative analysis of serum chemokines associated with treatment failure of direct-acting antivirals in chronic hepatitis C

Although serum chemokine levels have been reported to influence the outcome of interferon-based treatment in patients with chronic hepatitis C, their effect on the hepatitis C virus (HCV) response to direct-acting antiviral agents (DAAs), which can achieve high rates of a sustained virological response (SVR), is largely unknown. To clarify this relationship, 9 chemokines (eotaxin, GRO-α, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, and SDF-1α) were quantified before, during, and after DAA treatment using serum samples obtained from 57 patients with chronic hepatitis C. All baseline median chemokine levels were significantly higher in patients with chronic hepatitis C than in healthy subjects (P < 0.05). In particular, lower MIP-1β (≤71.5 pg/mL) and higher RANTES (>671.5 pg/mL) levels were significantly associated with patients who failed to clear HCV RNA (P = 0.0039 and 0.013, respectively). Prediction of a clinical response based on a combination of these chemokines demonstrated high sensitivity (82%), specificity (85%), negative predictive value (95%), and area under the curve (0.833). The non-SVR rate (56.3%; 9 of 16) was significantly higher in patients with low MIP-1β and high RANTES compared with other combinations. Moreover, baseline MIP-1β and RANTES were both additive and independent for predicting a non-SVR. Apart from an increase in eotaxin, all chemokines became decreased in patients with a SVR. In conclusion, a combination of serum MIP-1β and RANTES levels may be predictive of a treatment response to DAAs in Japanese patients with chronic hepatitis C.

MRNA for Selenoprotein P, a Hepatokine, Binds RIG-I Protein and Inhibits the RIG-I-Mediated Type I Interferon Response

The liver is a multifunctional organ with roles in metabolism, detoxification, and the immune response. Liver secretory selenoprotein P (SeP), a hepatokine, causes insulin resistance in the liver and peripheral muscle. We showed hepatitis C virus (HCV) infection increased serum SeP levels, which may explain the increased risk of type 2 diabetes in patients with HCV infection. Increased SeP mRNA (SEPP1 mRNA) in hepatocytes inhibited type 1 interferon response by means of undefined unique mechanisms. We revealed SEPP1 mRNA directly bound to retinoic acidinducible gene I (RIG-I), a virus RNA sensor, and inhibited RIG-I activity. The robust induction of interferon-stimulated genes (>1000-fold) and repression of HCV replication (>10-fold) were observed in hepatocytes in which SEPP1 mRNA was knocked down. Clinically, high SeP serum levels were significantly associated with treatment failure of direct actingantivirals for HCV. Thus, SeP regulates insulin resistance and innate immunity, possibly inducing immune tolerance in the liver.

High frequency of multiclass HCV resistance-associated mutations in patients failing direct-acting antivirals: real-life data.

Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel. Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes. The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; P<0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10/10), only 71.8% (28/39) of GT1b or GT3a failures had RAS (P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections. Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.