Hepatitis C Virus Genotype 1b Research Articles

Efficacy of ledipasvir/sofosbuvir with or without ribavirin for 12 weeks in genotype 1b HCV patients previously treated with a nonstructural protein 5A inhibitor-containing regimen.

The therapeutic benefit of adding ribavirin (RBV) to 12weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor-containing regimen is unclear. A total of 29 genotype 1b HCV patients who had failed prior daclatasvir (DCV) plus asunaprevir (ASV) treatment were retreated for 12weeks of LDV/SOF, with or without RBV. Antiviral efficacy and predictive factors associating with a sustained virological response at 24weeks (SVR24) were evaluated retrospectively. SVR24 was achieved in 67% (10/15) of patients who received LDV/SOF with, and 64% (9/14) without, RBV. The SVR24 rates were 80% in patients with, and 58% without, mild fibrosis (FIB-4 < 3.25). The SVR24 rate was lower with unfavorable IL28B rs8099917 SNP genotypes; specifically, the TT, TG and GG had SVR24 rates of 78%, 50% and 40%. The SVR24 rate was lower with a poor response to prior DCV plus ASV, where relapse, viral breakthrough and no response had SVR24 rates 71%, 58% and 0%. The SVR24 rate was lower with the number of NS5A resistance-associated substitutions (RAS), where 2, 3, 4 and 5 RAS had SVR24 rates of 78%, 67%, 50% and 0%. A patient with an NS5A-P32 deletion, which shows resistance to next-generation NS5A inhibitors, was retreated with LDV/SOF with RBV and achieved SVR24. The addition of RBV to 12weeks of LDV/SOF has little therapeutic benefit when retreating patients in whom a prior NS5A inhibitor-containing regimen had failed.

Cost-effectiveness of daclatasvir plus asunaprevir for chronic hepatitis C genotype 1b treatment-naïve patients in China.

BackgroundHepatitis C is the second fastest growing infectious disease in China. The standard-of-care for chronic hepatitis C in China is Pegylated interferon plus ribavirin (PR), which is associated with tolerability and efficacy issues. An interferon- and ribavirin-free, all-oral regimen comprising daclatasvir (DCV) and asunaprevir (ASV), which displays higher efficacy and tolerability, has recently been approved in China.ObjectivesThis study is to estimate the cost-effectiveness of DCV+ASV (24 weeks) for chronic hepatitis C genotype 1b treatment-naïve patients compared with PR regimen (48 weeks) in China.MethodsA cohort-based Markov model was developed from Chinese payer perspective to project the lifetime outcomes of treating 10,000 patients with an average age of 44.5 with two hypothetical regimens, DCV+ASV and PR. Chinese-specific health state costs and efficacy data were used. The annual discount rate was 5%. Base-case analysis and sensitivity analysis were conducted.ResultsFor HCV Genotype 1b treatment-naïve patients, DCV+ASV proved to be dominant over PR, with a cost saving of ¥33,480(5,096 USD) and gains in QALYs and life years of 1.29 and 0.85, respectively. The lifetime risk of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death was greatly reduced with DCV+ASV. Univariate sensitivity analysis demonstrated that key influencers were the discount rate, time horizon, initial disease severity and sustained virological response rate of DCV+ASV, with all scenarios resulting in additional benefit. Probabilistic sensitivity analysis demonstrated that DCV+ASV has a high likelihood (100%) of being cost-effective.ConclusionDCV+ASV is not only an effective and well-tolerated regimen to treat chronic HCV genotype 1b infection treatment-naïve patients, but also is more cost-effective than PR regimen. DCV+ASV can benefit both the public health and reimbursement system in China.

Association between human leucocyte antigen-DO polymorphisms and interferon/ribavirin treatment response in hepatitis C virus type 1 infection in Chinese population: a prospective study

ObjectiveThe human leucocyte antigen-DO (HLA-DO) gene located in the HLA non-classical class-II region may play a role in treatment response to hepatitis C virus (HCV). This study was conducted to...

Symmetric dimeric adamantanes for exploring the structure of two viroporins: influenza virus M2 and hepatitis C virus p7.

BackgroundAdamantane-based compounds have been identified to interfere with the ion-channel activity of viroporins and thereby inhibit viral infection. To better understand the difference in the inhibition mechanism of viroporins, we synthesized symmetric dimeric adamantane analogs of various alkyl-spacer lengths.MethodsSymmetric dimeric adamantane derivatives were synthesized where two amantadine or rimantadine molecules were linked by various alkyl-spacers. The inhibitory activity of the compounds was studied on two viroporins: the influenza virus M2 protein, expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique, and the hepatitis C virus (HCV) p7 channels for five different genotypes (1a, 1b, 2a, 3a, and 4a) expressed in HEK293 cells using whole-cell patch-clamp recording techniques.ResultsUpon testing on M2 protein, dimeric compounds showed significantly lower inhibitory activity relative to the monomeric amantadine. The lack of channel blockage of the dimeric amantadine and rimantadine analogs against M2 wild type and M2-S31N mutant was consistent with previously proposed drug-binding mechanisms and further confirmed that the pore-binding model is the pharmacologically relevant drug-binding model. On the other hand, these dimers showed similar potency to their respective monomeric analogs when tested on p7 protein in HCV genotypes 1a, 1b, and 4a while being 700-fold and 150-fold more potent than amantadine in genotypes 2a and 3a, respectively. An amino group appears to be important for inhibiting the ion-channel activity of p7 protein in genotype 2a, while its importance was minimal in all other genotypes.ConclusionSymmetric dimeric adamantanes can be considered a prospective class of p7 inhibitors that are able to address the differences in adamantane sensitivity among the various genotypes of HCV.

FRI-144 - Risk of early de-novo hepatocellular carcinoma (HCC) in patients with genotype-1b HCV compensated cirrhosis treated with 3 direct-acting antivirals (DAAs) – a real life, multicenter study

FRI-144 - Risk of early de-novo hepatocellular carcinoma (HCC) in patients with genotype-1b HCV compensated cirrhosis treated with 3 direct-acting antivirals (DAAs) – a real life, multicenter study

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.

Evaluation of efficacy and safety of interferon-free “3D” regimen among patients with non-compensated cirrhosis caused by HCV genotype 1b infection

Objective:The first interferon-free regimen became available in Russia in 2015. It brought hope to HCV Gt1 patients with cirrhosis for whom interferon-based schemes found to be non-effective or contraindicated. 3D therapy was the only available etiotropic option for them. New safety data published after the start of our study significantly limited usage of this regimen among patients with non-compensated cirrhosis. The aim of this study was to evaluate efficacy and safety of the 3D interferon-free regimen among HCV Gt1b patients with non-compensated cirrhosis.Method:66 patients (26 males and 40 females) with HCV Gt1b and non-compensated cirrhosis were enrolled. All of them were treated with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin for 12 weeks. Ribavirin was discontinued after 4 weeks of therapy due to onset of new data on the efficacy of 3D regimen without ribavirin in Turquoise III study published in September 2015 before the change of package insert. Child-Pugh score was assessed before the start of antiviral therapy as follows: 21 patients (31,8%) – 9 points, 11 patients (16,7%) – 8 points, 34 patients (51,5%) – 7 points. The key method used to evaluate study results was modified intent-to-treat (mITT) analysis because number of analyzed patients within treatment period changed after withdrawal caused by safety reasons but followed by assessment of efficacy among patients who discontinued treatment. Per protocol (PP) method was also used in addition to mITT.Results:Aviremia after 14 days of treatment was reached among 35 out of 65 patients (53,8%), rapid virologic response – among 79,7% patients (51/64). Each patient who received full 12-week course of treatment (n=60) including those who discontinued due to safety reasons (n=3) between 14th and 30th days of therapy reached SVR12 and SVR24. Assessment of Child-Pugh score in 6 months after EOT demonstrated decrease by 3-4 points among 21 patients (33,9%) and by 1-2 points among 35 patients. 66,1% patients reached clinical improvement in MELD score. Treatment discontinuation was caused by progression of hepatic encephalopathy and/or jaundice (4 cases). Those adverse events regressed among majority of patients after discontinuation of therapy. 3 deaths were reported (bacterial endocarditis, progression of hepatic encephalopathy and bleeding from gastric ulcers) during treatment period and 1 death in follow-up period due to progression of hepatocellular carcinoma.Conclusion:3D therapy was effective in 100% patients (mITT) with HCV GT1b and non-compensated cirrhosis both among those who completed full therapy course and those who discontinued the therapy due to safety reasons. Safety analysis demonstrated that the rate of severe adverse events was comparable with natural course of HCV-infection in patients on non-compensated cirrhotic stage without antiviral treatment.

Treatment of hepatitis C virus leads to economic gains related to reduction in cases of hepatocellular carcinoma and decompensated cirrhosis in Japan.

Hepatocellular carcinoma (HCC) is a serious complication of hepatitis C virus (HCV) infection. Sustained virologic response (SVR) for HCV is associated with a reduction in cirrhosis, HCC and mortality and their associated costs. Japanese HCV patients are older with higher prevalence of HCC. Here we used a decision-analytic Markov model to estimate the economic benefit of HCV cure by reducing HCC and DCC burden in Japan. A cohort of 10000 HCV genotype 1b (GT1b) Japanese patients was modelled with a hybrid decision tree and Markov state-transition model capturing natural history of HCV over a lifetime horizon. Treatment options were approved all-oral direct-acting anti-virals (DAAs) vs no treatment. Treatment efficacy was based on clinical trials and transition rates and costs obtained from Japan-specific data. Cases of HCC, decompensated cirrhosis (DCC) and quality-adjusted life years (QALYs) were projected for patients treated with DAAs vs NT. QALYs were monetized using a willingness-to-pay threshold of ¥4-to-¥6 million. Incremental savings with treatment were calculated by adding the projected cost of complications avoided to the monetized gains in QALYs. The model showed that DAA treatment vs no treatment, reduces 2057 cases of HCC and 1478 cases of decompensated cirrhosis and saves ¥850446.73 and ¥338229.90 per patient (ppt). Additionally, treatment can lead to additional 2.64 QALYs gained per patient. The indirect economic gains associated with treatment-related QALY improvements were ¥10576000, ¥13220000 and ¥15864000 ppt (willingness-to-pay thresholds of ¥4 million, ¥5 million and ¥6 million). Total economic savings of treatment with DAAs (vs no treatment) was ¥7526372.63, ¥10170372.63 and ¥12814372.63, at these different willingness-to-pay thresholds. In conclusion treatment of HCV GT1b with all-oral DAAs in Japan can lead to significant direct and indirect savings related to avoidance of HCC and DCC.

Amino acid substitutions in the hepatitis C virus core region predict hepatocarcinogenesis following eradication of HCV RNA by all-oral direct-acting antiviral regimens.

Impact of substitution of aa70 in the core region (Core aa70) in HCV genotype 1b (HCV-1b) on hepatocarcinogenesis following eradication of HCV RNA by direct-acting antiviral therapy is not clear. In a retrospective study, 533 patients with HCV-related chronic liver disease, with sustained virological response defined as negative HCV RNA at 12 weeks after cessation of direct-acting antiviral therapy, were examined to evaluate the relationship between Core aa70 substitution and hepatocarcinogenesis. Twelve patients developed hepatocellular carcinoma during the follow-up period. The cumulative hepatocarcinogenesis rates were 1.7% and 2.4% at the end of 1 and 2 years, respectively. Overall, multivariate analysis identified HCV subgroup (HCV-1b with Gln70(His70); P = 0.003) and age (>65 years; P = 0.049), as pretreatment predictors of hepatocarcinogenesis. In HCV-1b patients, multivariate analysis identified post-treatment Wisteria floribunda agglutinin positive Mac-2 binding protein (>1.8 COI; P = 0.042) and HCV subgroup (HCV-1b with Gln70(His70); P = 0.071), as predictors of hepatocarcinogenesis, including post-treatment parameter. In conclusion, Core aa70 substitution in HCV-1b at the start of direct-acting antiviral therapy is an important predictor of hepatocarcinogenesis following eradication of HCV RNA. This study emphasizes the importance of detection of Core aa70 substitution before initiating antiviral therapy.

Real‐world effectiveness and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for patients with chronic hepatitis C virus genotype 1b infection in Taiwan

The real-world effectiveness and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) remain limited for East Asian hepatitis C virus genotype 1b (HCV-1b) patients. The study aimed to evaluate the antiviral responses of PrOD-based regimens for HCV-1b patients in Taiwan. The study performed a retrospective analysis of 103 HCV-1b patients receiving PrOD with or without ribavirin (RBV) for 12weeks. Data were analyzed to assess the on-treatment and off-therapy HCV viral load and on-treatment adverse events. The pre-specified characteristics related to sustained virologic response 12weeks off therapy (SVR12 ) were compared. At treatment week 4, 100 of 102 patients (98.0%) had serum HCV RNA level <25IU/mL. The SVR12 was achieved in 101 of 103 patients (98.1%, [95% confidence interval: 93.2-99.5%]). All except one (99.0%) patients tolerated treatment well without treatment interruption. One cirrhotic patient discontinued treatment at week 1 due to hepatic decompensation. Twenty-four patients (23.3%) had ≥ grade 2 elevation in total bilirubin levels, and 21 of them (87.5%) had indirect type hyperbilirubinemia. The stratified SVR12 rates were comparable in terms of sex, age, body mass index, prior treatment experience, hepatitis B virus surface antigen status, RBV usage, baseline and week 2 viral load, renal function, and hepatic fibrosis stage. Paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without RBV are efficacious and generally well tolerated for treatment of HCV-1b patients in Taiwan.

Daclatasvir Plus Asunaprevir for the Treatment of Patients with Hepatitis C Virus Genotype 1b Infection: Real-World Efficacy, Changes in Liver Stiffness and Fibrosis Markers, and Safety.

Background/AimsThe treatment with daclatasvir plus asunaprevir (DCV+ASV) is associated with potent antiviral effects in patients with genotype 1b hepatitis C virus (HCV) infection. We investigated the real-world efficacy, changes in liver stiffness and noninvasive fibrosis markers, and the safety of DCV+ASV treatment in Korean patients.MethodsIn total, 363 patients with chronic hepatitis C were treated with DCV+ASV between August 2015 and January 2017. Finally, we analyzed the data of 270 patients who were monitored for at least 12 weeks after the end of treatment.ResultsThe mean age was 60.7 years, and females predominated (60.4%). Most patients (64.8%) were treatment-naïve, and 56 patients (20.7%) had cirrhosis. Two hundred fifty-seven (95.2%) and 251 (93.0%) patients achieved end-of-treatment responses and sustained virological responses at 12 weeks posttreatment (SVR12), respectively. The SVR12 rates were higher in patients who were <65 years of age, males, without cirrhosis and had lower HCV RNA levels. All LS values and fibrosis-4 and aspartate aminotransferase-to-platelet ratio index values declined from baseline to the time of assessment of SVR12.ConclusionsThe DCV+ASV therapy resulted in a high SVR12 and improved liver fibrosis; the treatment was well tolerated in patients with genotype 1b HCV infections.

Daclatasvir/asunaprevir worth its cost for chronic HCV genotype 1b

Daclatasvir/asunaprevir worth its cost for chronic HCV genotype 1b

The safety and efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 1b infection.

Genotype 1b (GT1b) is the most common subtype of the hepatitis C virus (HCV). We present an integrated analysis of 1070 participants with HCV GT1b infection from 30 countries who received elbasvir/grazoprevir for 12weeks. This is a retrospective analysis of data from participants with chronic HCV GT1b infection enrolled in 11 phase II/III clinical trials. All participants received elbasvir 50mg plus grazoprevir 100mg once daily for 12weeks. The primary end point of all studies was sustained virologic response 12weeks after completion of therapy (SVR12, HCV RNA <15IU/ml). SVR12 was 97.2% (1040/1070). Of the 30 participants who failed to attain SVR12, 15 relapsed and 15 had nonvirologic failure. Among participant subgroups, SVR12 was high in those with compensated cirrhosis (188/189, 99.5%), HIV co-infection (51/54, 94.4%), and baseline viral load >800,000IU/ml (705/728, 96.8%). Resistance-associated substitutions (RASs) at NS5A positions 28, 30, 31, or 93 were present in 21.6% of participants at baseline. SVR12 was 99.6% (820/823) in participants without baseline NS5A RASs and 94.7% (215/227) in those with baseline NS5A RASs. Serious adverse events occurred in 3.2% (34/1070) of participants, nine of which occurred after study medication was completed. Elbasvir/grazoprevir for 12weeks represents an effective treatment option for participants with HCV GT1b infection. SVR12 was high in all participant subgroups, including those with compensated cirrhosis, HIV co-infection, and high baseline viral load. CLINICALTRIALS. The trials discussed in this paper were registered with Clinicaltrial.gov as the following: NCT02092350 (C-SURFER), NCT02105662 (C-EDGE Co-Infection), NCT02105467 (C-EDGE treatment-naive), NCT02105701 (C-EDGE treatment-experienced), NCT01717326 (C-WORTHy), NCT02251990 (C-CORAL), NCT02105688 (C-EDGE COSTAR), NCT02252016 (C-EDGE IBLD), NCT02115321 (C-SALT), NCT02203149 (Japan phase 2/3 study), NCT02358044 (C-EDGE Head-2-Head).

Twelve weeks of ombitasvir/paritaprevir/r and dasabuvir without ribavirin is effective and safe in the treatment of patients with HCV genotype 1b infection and compensated cirrhosis: results from a real-world cohort study

ABSTRACTObjective: To explore the effectiveness and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV) for 12 weeks without ribavirin in adults with chronic HCV genotype 1b infection and compensated cirrhosis.Methods: Observational study of a prospective cohort of adult patients with HCV genotype 1b infection and compensated cirrhosis who received 12 weeks of OBV/PTV/r and DSV without ribavirin. Effectiveness was assessed by recording the percentage of patients achieving sustained virological response at week 12 post-treatment (SVR12). Safety outcomes were based on the incidence of adverse events.Results: Seventy-eight patients were included. The SVR12 rate was 96.1% (95%CI 89.2–99.2). Adverse events were recorded in 78.0% of patients. Of these, 97.7% were grade 1/2. One patient discontinued treatment prematurely owing to adverse events. Eighty-six interactions were detected in 43 patients (55.1%). Overall, 81.4% of interactions required close monitoring, alteration of drug dosage, or timing of administration. In 7.0% of cases, the interactions arose from contraindications that required the suspension of the concomitant drug. In 11.6% of cases, medicinal plants or foods were withdrawn.Conclusions: The simplified regimen of OBV/PTV/r+DSV administered for 12 weeks is effective and safe in patients with chronic HCV genotype 1b infection and compensated cirrhosis. No adverse reactions related to drug-drug interactions were recorded.

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies.

Extremely potent, new hepatitis C virus (HCV) nonstructural 5A (NS5A) featuring substituted biaryl sulfate core structures was designed and synthesized. Based on the previously reported novel HCV NS5A inhibitors featuring biaryl sulfate core structures which exhibit two-digit picomolar half-maximal effective concentration (EC50) values against HCV genotype 1b and 2a, the new inhibitors equipped with the sulfate core structures containing diversely substituted aryl groups were explored. In this study, highly efficient, chemoselective coupling reactions between an arylsulfonyl fluoride and an aryl silyl ether, known as the sulfur(vi) fluoride exchange (SuFEx) reaction, were utilized. Among the inhibitors prepared based on the SuFEx chemistry, compounds 14, 15 and 29 exhibited two-digit picomolar EC50 values against GT-1b and single digit or sub nanomolar activities against the HCV GT-2a strain. Nonsymmetrical inhibitors containing an imidazole and amide moieties on each side of the sulfate core structures were also synthesized. In addition, a biotinylated probe targeting NS5A protein was prepared for labeling using the same synthetic methodology.

Clinical Findings of HCV Chronic Infection in Undocumented Immigrants and Low-Income Refugees in Three Areas of Southern Italy

Introduction and aim. In recent decades, Italy has become a land of immigration from countries suffering a socio-economic crisis. The aim of this study was to perform an organized screening to identify and offer care to immigrants with HCV infection.Material and methods. The screening, performed from 2012 to 2015, involved 1,727 immigrants in the Campania and Apulia regions in southern Italy. Results. Screening was accepted by 1,727 (85%) out of 2,032 immigrants interviewed; 70 (4.1%) of the 1,727 were anti-HCV-positive, all unaware of their serological condition, 31 (44.3%) of whom were HCV-RNA-positive and 39 negative. The 31 HCV-RNA-positive immigrants were further investigated at a third-level clinic of infectious diseases. The HCV viral load was 2.6 × 107 ± 7.7 ×107 IU/mL, and 35.5% showed HCV-genotype 1a or 1b, 23.8% genotype 2 and 22.6% genotype 3. Two immigrants had liver cirrhosis and, in accordance with the Italian Healthcare Authority guidelines, received an interferon-free regimen and achieved a sustained virological response (SVR); 18 had chronic hepatitis, 6 of whom with a high risk of progression and received interferon-based therapy, with SVR in 4, whereas 12 at low risk were put on a waiting list for future interferon-free treatment, once licensed. The remaining 11 HCV-RNA-positive immigrants were considered HCV inactive chronic carriers and were included in a long-term observational program.Conclusion. The screening program can be considered successful since it was accepted by 85% of the subjects interviewed and identified 70 anti-HCV-positive immigrants, all unaware of their clinical and virological condition.

MiR-215 Enhances HCV Replication by Targeting TRIM22 and Inactivating NF-κB Signaling.

PurposeHepatitis C virus (HCV) infection is a major cause of liver disease. Several miRNAs have been found to be associated with HCV infection. This study aimed to investigate the functional roles and possible molecular mechanisms of miR-215 in HCV replication.Materials and MethodsThe expression levels of miR-215 and TRIM22 were detected by quantitative real-time PCR (qRT-PCR) and western blot analysis in Con1b subgenomic genotype 1b HCV replicon cells (Con1b cells) and JFH1 full genome infecting Huh7.5.1 cells (Huh7.5.1 cells). HCV RNA levels were measured by qRT-PCR. The protein levels of NS3, NS5A, p65 subunit of NF-κB (p65), and phosphorylated p65 (p-p65) were determined by western blot analysis. The relationship between miR-215 and TRIM22 were explored by target prediction and luciferase reporter analysis.ResultsmiR-215 overexpression enhanced HCV replication in Con1b cells, while miR-215 knockdown suppressed HCV replication in Huh7.5.1 cells. TRIM22 was confirmed to be a direct target of miR-215. TRIM22 upregulation resulted in a decline in HCV replication, while TRIM22 inhibition led to enhancement of HCV replication. Additionally, exogenous expression of TRIM22 reversed the facilitating effect of miR-215 on HCV replication, while TRIM22 downregulation counteracted the inhibitory effect of miR-215 knockdown on HCV replication. Furthermore, miR-215 targeted TRIM22 to block the NF-κB pathway, and exerted a positively regulatory role on HCV replication.ConclusionmiR-215 facilitated HCV replication via inactivation of the NF-κB pathway by inhibiting TRIM22, providing a novel potential target for HCV infection.

Comparison of direct sequencing and Invader assay for Y93H mutation and response to interferon‐free therapy in hepatitis C virus genotype 1b

Virologic failure of interferon-free therapy has been associated with Y93H mutation in the non-structure 5A region in hepatitis C virus (HCV) genotype 1b, and screening is recommended. A simple assay based on Q-Invader technology was developed for Y93H mutant screening to reduce cost and effort. The present study sought to compare two methods of detection of Y93H mutation and to evaluate the effect of Y93H mutation on response to interferon-free therapy. Y93H mutation was examined in 258 patients with HCV genotype 1b using both direct sequencing analysis and the polymerase chain reaction (PCR)-Invader assay. Daclatasvir and asunaprevir or ledipasvir and sofosbuvir therapy was administered to 205 patients whose sustained virological responses (SVR) were checked. Hepatitis C virus was detected in 232 of 258 patients by direct sequencing and in 236 of 258 patients by the PCR-Invader assay. Forty of 231 cases were defined as Y93 mutation by direct sequencing, and 46 of 236 cases were defined as Y93 mutation by the PCR-Invader assay. SVR of patients who were Y93H by direct sequencing, Y93H by the PCR-Invader assay, and Y93H by both methods was 62.5%, 82.4%, and 50%, respectively. The sensitivity of the PCR-Invader assay was similar to that of direct sequencing analysis; however, the PCR-Invader assay had a better ability to detect minor strains. Combination of the two assays would improve prediction of the response to daclatasvir and asunaprevir, but Y93H mutation had little effect on SVR in ledipasvir and sofosbuvir therapy.

Daclatasvir and asunaprevir treatment in patients infected by genotype 1b of hepatitis C virus with no or subtle resistant associated substitutions (RAS) in NS5A-Y93.

In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan, daclatasvir and asunaprevir (DCV+ASV), in chronic hepatitis C patients infected HCV genotype 1b with no or subtle amount of baseline resistant associated substitutions (RAS). Among 924 patients registered in our multicenter study, 750 patients who were proven not to be infected with NS5A-Y93H RAS by direct sequencing and to have no or subtle amount (less than 20%) of NS5A-Y93H RAS by probe assays (Cycleave or PCR invader assay) were included in this study. We investigated the anti-viral effect and factors associated with SVR12. In statistical analysis, P < 0.05 was considered as significant. The SVR12 rate in this population was 92.1% (562/618). Factors associated with SVR12 were male (odds ratio: 2.128; 95%CI: 1.134-4.000, P = 0.019); lower serum γGTP (odds ratio: 1.007; 95%CI: 1.002-1.012, P = 0.006); lower HCV-RNA (odds ratio: 1.848; 95%CI: 1.087-3.145, P = 0.023), and RVR (odds ratio: 6.250; 95%CI: 2.445-15.873, P < 0.001). No patients with γGTP ≧ 80 IU/L without RVR showed SVR12 (0/4, 0%) and one patients with γGTP ≧ 20-< 80 IU/L and HCV-RNA ≧ 6.5 logIU/mL without RVR (5/10, 50%) and two female patients with RVR but γGTP ≧ 80 IU/L and HCV-RNA ≧ 6.5 logIU/mL (7/13, 53.8%) showed a low SVR12 rate. In the present study, we showed a good viral response with DCV-ASV treatment and identified four predictive factors associated with SVR12. These four markers could be a good predictive markers for the viral effect of this treatment regimen in patients with no or subtle amount of RAS in NS5A-Y93.

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

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