Best therapy for the easiest to treat hepatitis C virus genotype 1binfected patients

BACKGROUND The revolution in treatment of patients with chronic hepatitis C virus(HCV)infection dates back to the introduction of direct-acting antivirals(DAAs).The increase in efficacy was most pronounced in patients infected with genotype(GT)1b,as this was the most poorly responsive population to treatment during the interferon era.AIM To identify the most effective interferon-free therapy for GT1b-infected patients and to determine positive and negative predictors of virological response.METHODS This real-world retrospective analysis included patients chronically infected with GT1b HCV whose data were obtained from the multicenter observational EpiTer-2 database.Treatment effectiveness was evaluated for each therapeutic regimen as the percentage of sustained virological responses(SVR).Assessment of the safety was based on the evaluation of the course of therapy,the occurrence of adverse events including serious ones,deaths during treatment and in the post 12-wk follow-up period.RESULTS The studied population consisted of 11385 patients with a mean age of 53±14.8 years and a female predominance(53.4%).The majority of them were treatment-naïve(74.6%)and patients with cirrhosis accounted for 24.3%.Of the DAA regimens used,76.9%were GT-specific with ombitasvir/paritaprevir/ritonavir+dasabuvir±ribavirin being the most used option(32.4%).A total of 10903 patients responded to treatment resulting in a 98.1%in the per-protocol analysis after excluding 273 patients without SVR data.The effectiveness of all regimens exceeded 90%and the highest SVR of 98.9%was achieved in patients treated with a combination of glecaprevir/pibrentasvir.Logistic regression analyses showed that the virologic response was independently associated with female sex[odds ratio(OR)=1.67],absence of decompensated cirrhosis at baseline(OR=2.42)and higher baseline platelets(OR=1.004 per 1000/μL increase),while the presence of human immunodeficiency virus(HIV)coinfection significantly decreased the odds of response(OR=0.39).About 95%-100%of patients completed therapy irrespective of the drug regimen.At least one adverse effect occurred in 10.9%-36.3%and most of them were mild.No treatment related deaths have been reported.CONCLUSION We documented very high effectiveness and a good safety profile across all DAA regimens.Positive predictors of SVR were female sex,absence of decompensated cirrhosis at baseline and higher platelet count while HIV coinfection reduced the effectiveness.

Retreatment of patients with treatment failure of directacting 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 1 b(GT1 b) is founded in 70% of HCVinfected individuals. In this minireview, we summarize the retreatment regimens and their SVR rates for HCV GT1 b. 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 GT1 b-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 GT1 b-infected patients with treatment failure.

Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C

AIMTo evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older. METHODSThe present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment. RESULTSAmong the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively. CONCLUSIONBoth TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.

Should they wait?Two children under 3 years old infected by HCV 1b successfully treated by ledipasvir/sofosbuvir:A report of two cases

Although direct-acting antivirals(DAAs)have notably increased the sustained virological response(SVR)rates in hepatitis C virus(HCV)-infected adolescent patients,the efficacy and safety for young children under 3 years old remain unclear.Currently,no guidelines recommend DAA therapy for this situation worldwide.Furthermore,the China National Medical Products Administration has not approved any DAA for treating children below 12 years old.Here,we described the characteristics of two children approximately 2 years old,who were infected by HCV genotype 1b and had significant clinical symptoms.Both received 12 weeks of ledipasvir/sofosbuvir(Case 1:45.00 mg/200 mg per day,weight 17 kg;Case 2:33.75 mg/150 mg per day,weight 12 kg).They achieved SVR at 12 weeks after treatment completion without obvious treatment-related adverse effects.Therefore,the safety and benefits of ledipasvir/sofosbuvir treatment in children under 3 years old seem to be confirmed.Our findings require further evaluation.

Analysis of the effect of HCV resistance-associated substitutions on the short-term efficacy of DAA after single administration in three phase Ib clinical trials

As crucial factors in hepatitis C virus(HCV)management,resistance-associated substitutions(RASs)are associated with the treatment outcome of some direct-acting antiviral(DAA)-based regimens.In this study,we mainly analyzed the impact of baseline Y93 H or Y93 Y/H on the short-term efficacy after single administration of NS5 A inhibitors in three phaseⅠb clinical trials(yimitasvir phosphate,KW-136 and fopitasvir),and analyzed the prevalence of baseline RASs and treatment-emergent RASs.A total of 94 treatment-naive HCV genotype(GT)-1 b(n=63)and GT-2 a(n=31)Chinese patients were enrolled in three phase lb clinical trials.We investigated RASs in 77 patients with next generation or Sanger sequencing.In the 7-day trial of yimitasvir phosphate,the mean maximum HCV RNA decrease of patients with baseline Y93 H or Y93 Y/H was lower than that of patients without the mutation in the 30 mg and 200 mg cohorts(0.83 vs.2.45 log10 IU/mL and 1.92 vs.2.63 log10 IU/mL).In the3-day trial of KW-136,the mean maximum HCV RNA decrease in patients with baseline Y93 H or Y93 Y/H was lower than that of patients without the mutation in the 30,60 and 120 mg cohorts(1.58 vs.2.89 log10 IU/mL,3.16 vs.4.09 log10 IU/mL and3.00 vs.5.04 log10 IU/mL,respectively).In the 3-day trial of fopitasvir,only 30 mg group had baseline Y93 H or Y93 Y/H,and the average maximum HCV RNA decrease of patients with baseline Y93 H or Y93 Y/H was lower than that of patients without the mutation(1.45 vs.3.59 log10 IU/mL).In the three trials,baseline RASs were observed in 54 patients(70.1%;54/77).The most prevalent baseline RASs were Y93 H and Y93 Y/H(18.2%;14/77),followed by L3 IM(16.9%;13/77).The most common RASs after single administration of DAA were Y93 H and Y93 Y/H.Our data could provide reference for future clinical treatment and clinical trial.