Non-sustained Virological Response Research Articles

Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy.

Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.

Impact of IL-12B Genetic Variants on Antiviral Treatment Response among Hepatitis B Patients in Pakistan

HBV is a continuous major global health concern. Genetic factors of hosts are known to play a role in HBV infection outcomes. This study aimed to reveal the association of IL-12b 3′ UTR variant rs3212227 in HBV patients. Genotyping was performed using ARMS-PCR to detect IL-12b rs3212227 polymorphism. The patients were categorized into groups based on their response to the antiviral therapy. Group I: non-sustained virological response (NSR); Group II: sustained virological responders (SVR); and Group III: HBV-positive fresh cases. ALT levels were measured to evaluate liver function, and viral load was determined to evaluate viral infectivity among the study groups. The variant genotype CC was found to be significantly associated with the non-sustained virological response to the antiviral therapy (with a p-value of 0.0117; OR = 2.914; RR = 1.556). It was also determined that the genotype CC was the most prevalent genotype among both genders in the NSR group. Viral load was found to be 6-fold higher in Group III compared to Group I and Group II. The results suggest that genotype CC is the most prevalent genotype in the NSR groups, and it is associated with a poor response to antiviral therapy in Pakistani patients with HBV infection.

Efficacy and Safety of Direct-Acting Antivirals in Elderly Patients with Chronic Hepatitis C: A Nationwide Real-Life, Observational, Multicenter Study from Turkey.

The number and proportion of elderly patients living with chronic hepatitis C are expected to increase in the coming years. We aimed to compare the real-world efficacy and safety of direct-acting antiviral treatment in elderly and younger Turkish adults infected with chronic hepatitis C. In this multicenter prospective study, 2629 eligible chronic hepatitis C patients treated with direct-acting antivirals between April 2017 and December 2019 from 37 Turkish referral centers were divided into 2 age groups: elderly (≥65 years) and younger adults (<65 years) and their safety was compared between 2 groups in evaluable population. Then, by matching the 2 age groups for demographics and pretreatment risk factors for a non-sustained virological response, a total of 1516 patients (758 in each group) and 1244 patients (622 in each group) from the modified evaluable population and per-protocol population were included in the efficacy analysis and the efficacy was compared between age groups. The sustained virological response in the chronic hepatitis C patients was not affected by the age and the presence of cirrhosis both in the modified evaluable population and per-protocol population (P = .879, P = .508 for modified evaluable population and P = .058, P = .788 for per-protocol population, respectively). The results of the per-protocol analysis revealed that male gender, patients who had a prior history of hepatocellular carcinoma, patients infected with non-genotype 1 hepatitis C virus, and patients treated with sofosbuvir+ribavirin had a significantly lower sustained virological response 12 rates (P < .001, P = .047, P = .013, and P = .025, respectively). Direct-acting antivirals can be safely used to treat Turkish elderly chronic hepatitis C patients with similar favorable efficacy and safety as that in younger adults.

Association of macrophage inhibitory factor -1 polymorphisms with antiviral efficacy of type 1b chronic hepatitis C

The expression of macrophage inhibitory factor-1 (MIC-1) increases in patients with chronic hepatitis C (CHC), but whether MIC-1 level and its polymorphism affect the antiviral efficacy of CHC has not yet been reported. The present study aimed to investigate the association between MIC-1 polymorphism and antiviral efficacy in patients with CHC genotype 1b (CHC 1b). A total of 171 patients with CHC1b were recruited. The polymorphisms of rs1059369 and rs1059519 in MIC-1 were detected by DNA sequencing. All patients received a standard dose of polyethylene glycol interferon + ribavirin (PR regimen), and divided into response, nonresponse, sustained virological response (SVR), and non-sustained virological response (NSVR) groups based on HCV RNA levels. The genotype distribution of the two single nucleotide polymorphisms (SNPs) did not differ between the response and nonresponse groups, SVR and non-SVR groups. However, the level of MIC-1 was positively correlated with ALT, AST, PIIINP, CIV, and HCV RNA (P < 0.05). Compared to before treatment, the level of MIC-1 in plasma was significantly decrease in the response group but not in the non-responsive group. Our results suggest that the level of MIC-1 in CHC1b is correlated with liver cell injury, liver fibrosis index, and viral load. However, the polymorphism of rs1059369 and rs1059519 may have negligible impact in expression of MIC-1 and efficacy of antiviral therapy in CHC patient.

Active hepatocellular carcinoma is an independent risk factor of direct-acting antiviral treatment failure: A retrospective study with prospectively collected data.

Previous studies from western countries have reported that active hepatocellular carcinoma (HCC) was associated with direct-acting antiviral (DAA) treatment failure. We sought to examine this issue in an Asian cohort. A retrospective cohort study was conducted on hepatitis C virus (HCV)-infected patients with advanced fibrosis who were treated with DAAs at our hospital between January 2017 and June 2018. We treated 1021 HCV-infected patients during this period. A total of 976 of those patients were enrolled in a per-protocol analysis, including 556 (57.2%) who had genotype 1b infections, and 314 (32.3%) who had genotype 2 infections. The mean age of all 976 patients was 65.5 years, and 44.5% were male. 781 of the patients had no HCC, 172 had inactive HCC, and 23 had active HCC. Non-sustained virologic response (SVR) was noted in 10 (1.3%) patients without HCC, 5 (2.9%) patients with inactive HCC, and 4 (13.0%) patients with active HCC. After adjustment for confounders, active HCC (versus inactive HCC and non-HCC) was associated with non-SVR (adjusted odds ratio [AOR] = 24.5 (95% confidence interval [CI] = 4.4-136.9), P<0.001). Next, we excluded the 23 patients with active HCC from the multivariate analysis. After adjustment for confounders, inactive HCC (versus non-HCC) was not associated with non-SVR (AOR = 3.1 (95% CI = 0.94-9.95), P = 0.06). Active HCC was associated with non-SVR, while inactive HCC was not. We thus suggest the deferral of DAA treatment until after the complete radiological response of HCCs to treatment.

Efficacy and safety of direct-acting antivirals for hepatitis C in the elderly: A systematic review and meta-analysis.

Since the introduction of direct-acting antivirals (DAAs) severalstudies have reported high efficacy and safetyin Hepatitis C infected patients, even in those earlier considered difficult-to-treat. We aimed to assess the efficacy and safety of DAA therapy in elderly patients. The PubMed MEDLINE, Embase and Cochrane databases were searched through July 2018. Two independent researchers extracted data and assessed the quality and risk of bias. Risk ratios (RRs) were pooled using random effects models. The primary outcome was efficacy of DAA therapy assessed by the RR for non-sustained virologic response (SVR) among patients aged <65 vs ≥65years. Overall, we identified 63 studies including 34 082 patients treated with different DAAs. Risk for non-SVR was comparable in patients <65 and ≥65years of age (RR 1.00, 95% CI 0.86-1.15; P=0.979) and even lower in a subgroup analysis of cirrhotic patients ≥65years of age (RR 0.59, 95% CI 0.35-0.99, P=0.044). Risk for non-SVR was similar between age groups in all other subgroup analyses. Elderly patients had a significantly increased risk of adverse events (AEs) (RR 1.30, 95% CI 1.11-1.52, P=0.001), but not for serious adverse events (P=0.43) or treatment discontinuation (P=0.15). Risk for anaemia if treated with additional ribavirin was 2.84 (95% CI 1.73-4.66, P<0.001) in elderly patients compared to patients <65years. Our results show that DAAs are highly effective and safe in elderly patients. Ribavirin should be avoided in the elderly as more AEs and particularly anaemia is observed. Further cost-effectiveness analyses are needed to evaluate the socio-economic benefit of treating elderly people without advanced liver disease.

HCV core antigen is a useful predictor during pegylated-interferon/ribavirin therapy in patients with hepatitis C virus genotype 1b

Enzyme immunoassays for quantifying hepatitis C virus (HCV) core antigen (Ag) have been proposed as an alternative to HCV RNA detection. The present study aimed to investigate the early kinetics of serum HCVcAg and its usefulness in predicting virological responses.The clinical data of 135 patients with chronic hepatitis C treated with pegylated interferon alpha (PEG-IFN-α) and ribavirin was retrospectively collected. The patients were grouped according to their treatment outcomes as follows: sustained virological response (SVR), nonsustained virological response (N-SVR), and relapse.Higher HCVcAg and HCV RNA levels were observed in patients in the N-SVR group than in the other groups at baseline. HCVcAg better predicted rapid virological response (RVR) compared with HCV RNA and had a predictive value similar to that of HCV RNA for SVR and early virological response. In the relapse group, HCV RNA decreased to 0 after 48 weeks, whereas HCVcAg was still detectable, indicating that HCVcAg more sensitively predicted relapse in antiviral therapy than HCV RNA.For patients treated with PEG-INF-α and ribavirin, HCVcAg may more sensitively predict relapse than HCV RNA.

Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C without sustained response to combination therapy.

Although antiviral therapy reduces development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), HCC often develops in patients with non-sustained virologic response (non-SVR). We aimed to evaluate risk factors for HCC in HCV patients with non-SVR. From March 2002 to December 2013, 800 patients with CHC who had received combined pegylated interferon (peg-IFN)/ribavirin (RBV) therapy without achieving SVR were enrolled. Main outcome measure was HCC development. Variables were cirrhosis, platelet count, α-fetoprotein (AFP) levels, aspartate aminotransferase (AST) to platelet ratio index (APRI), and IL28B polymorphism (CT+TT). One-hundred of 800 non-SVR patients developed HCC within a median 53.5-months follow-up. Cumulative incidence of HCC for all patients was 1.4%, 5.6% and 12.3%, respectively, at 1st, 3rd and 5th years of follow-up. In univariate analysis, patients who developed HCC tended to have LC (p<0.001), lower platelet counts (<150×109/l, p<0.001), higher AFP levels (≥20ng/ml, p<0.001), higher Fib-4 levels (p<0.001), higher APRI levels (p<0.001), IL 28B polymorphism (CT+TT) (p<0.001) and higher incidence of diabetes mellitus (DM) (p=0.019). Multivariate analysis in overall patients revealed that cirrhosis (HR: 2.94, 95% CI: 1.81-4.77,p<0.001), IL28B rs12979860 (CT+TT) polymorphisms (HR: 3.22, 95% CI: 2.17-4.78, p<0.001), and high APRI levels (≥2.57) (HR: 2.32, 95% CI: 1.47-3.67, p<0.001) were independent risk factors for HCC. Liver cirrhosis, high APRI levels, and IL28B rs12979860 at baseline are independent risk factors for HCC development in patients without SVR after peg-IFN combination therapy.

Rapid Changes in Serum Lipid Profiles during Combination Therapy with Daclatasvir and Asunaprevir in Patients Infected with Hepatitis C Virus Genotype 1b.

Background/AimsChanges in lipid profiles in patients infected with hepatitis C virus (HCV) during direct-acting antiviral therapy have been reported in recent years. However, the clinical aspects of disturbed lipid metabolism in chronic HCV infection have not been fully elucidated.MethodsDynamic changes in serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and apolipoprotein levels in patients infected with HCV genotype 1b were examined during combination therapy with daclatasvir (DCV) and asunaprevir (ASV).ResultsTotal, LDL−, and HDL-cholesterol levels increased rapidly and persistently after week 4. Apolipoprotein (apo) A-I, apo B, apo C-II, and apo C-III levels were significantly higher at week 4 than at week 0. In contrast, apo A-II and apo E levels were significantly lower. The differences in LDL− and HDL-cholesterol levels were positively correlated with those of apo B and apo A-I, respectively. Interestingly, in patients with non-sustained virological response, these cholesterol levels decreased rapidly after viral breakthrough or viral relapse. Furthermore, similar changes were observed for apo A-I, apo B and apo C-III levels.ConclusionsClearance of HCV using combination therapy with DCV and ASV results in rapid changes in serum lipid profiles, suggesting an influence of HCV infection on disturbed lipid metabolism.

Annual Change in FIB-4, but not in APRI, was a Strong Predictor for Liver Disease Progression in Chinese Patients with Chronic Hepatitis C

Background: Previous studies showed a significant prognostic value of 3-year and 5-year evolution of noninvasive fibrosis tests in European chronic hepatitis C (CHC) patients with or without HIV. It is uncertain whether this conclusion can be extrapolated to Chinese patients and whether the assessment of noninvasive fibrosis tests in a shorter time interval still has a prognostic value. Objectives: The study aimed to assess the prognostic value of changes of aspartate aminotransferase-to-platelet ratio (APRI) and fibrosis-4 (FIB-4) in consecutive years in Chinese CHC patients. Methods: There were 173 CHC patients enrolled in 2 centers in this retrospective study. APRI and FIB-4 were calculated every 12 ± 2 months. The average difference between 2 adjacent calculations was defined as an annual change (AC). Risk factors were evaluated by Cox proportional regression models. Results: Cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver-related death developed in 29 patients during the median follow-up of 47.0 (29.5 - 72.0) months. Baseline FIB-4 and APRI, Child-Pugh class C, non-sustained virologic response (SVR) to interferon (IFN) or Pegylated IFN plus ribavirin, and AC of FIB-4 were significantly associated with liver disease progression. AC of FIB-4 (P 3.25 and AC of FIB-4 > 0.22, or non-SVR and AC of FIB-4 > 0.22 had the highest cumulative incidence of liver disease progression among the 4 groups identified according to baseline FIB-4 and AC of FIB-4, or SVR and AC of FIB-4. Conclusions: An increased FIB-4 over time is an independent risk factor of liver disease development in Chinese CHC patients. Monitoring FIB-4 annually may help physicians to predict prognosis in CHC patients.

Clinical Efficacy and Post-Treatment Seromarkers Associated with the Risk of Hepatocellular Carcinoma among Chronic Hepatitis C Patients

This follow-up study enrolled chronic hepatitis C patients to evaluate the treatment efficacy and to identify post-treatment seromarkers associated with risk of hepatocellular carcinoma (HCC) among patients with a sustained virological response (SVR) or nonsustained virological response (NSVR). A total of 4639 patients who received pegylated interferon and ribavirin during 2004–2013 were followed until December 2014. HCC was confirmed through health examinations and data linkage with a national database. A total of 233 HCC cases were reported after 26,163 person-years of follow-up, indicating an incidence of 8.9 per 1000 person-years: 6.9 for SVR and 21.6 for NSVR per 1000 person-years. The associated risk of HCC in patients with SVR was 0.37 (0.22–0.63) for those without cirrhosis and 0.54 (0.31–0.92) for those with cirrhosis compared with their respective counterparts with NSVR. Among patients with SVR, advanced age, male gender, cirrhosis, decreased platelet count, and increased aspartate aminotransferase and α-fetoprotein levels were associated with HCC (p < 0.001). The treatment of chronic hepatitis C patients before they developed cirrhosis showed a higher efficacy than did the treatment of those who had already developed cirrhosis. Patients with SVR may still have a risk of HCC and need to be regularly monitored.

Prediction of liver stiffness hepatocellular carcinoma in chronic hepatitis C patients on interferon‐based anti‐viral therapy

The purpose of this study was to evaluate the usefulness of liver stiffness measurement (LSM) for assessing the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients receiving interferon (IFN) therapy. One hundred fifty-one CHC patients who underwent LSM and received IFN therapy were included in the estimation cohort, and 56 were included in the validation study. The cumulative HCC incidences were evaluated using Kaplan-Meier plot analysis and the log-rank test. Multivariate Cox proportional hazard analyses were used to estimate the hazard ratios (HRs) of variables for HCC. In the estimation cohort, 9 of 151 patients developed HCC during the median follow-up time of 722 days. Multivariate analysis identified three independent risk factors for HCC: LSM (≥ 14.0 kPa, HR 5.58, P = 0.020), platelet count (< 14.1 × 10(4) /μL, HR 5.59, P = 0.034), and non-sustained virological response (HR 8.28, P = 0.049). The cumulative incidence of HCC development at 3 years was 59.6%, 8.2%, and 0.0% in patients with all three risk factors, one to two risk factors, and none of these risk factors, respectively. The incidence of HCC was significantly different between these groups (P < 0.001). In the validation cohort, HCC incidence was also significantly different with respect to these risk factors (P = 0.037). LSM, platelet count, and IFN-therapeutic effect could be used to successfully stratify the risk of HCC in patients receiving IFN therapy and demonstrate the usefulness of LSM before IFN therapy for the management of CHC patients.

α‐Fetoprotein is a surrogate marker for predicting treatment failure in telaprevir‐based triple combination therapy for genotype 1b chronic hepatitis C Japanese patients with the IL28B minor genotype

Even when treated with telaprevir-based triple therapy, some patients fail to achieve a sustained virological response. This study identified factors related closely to treatment failure. A total of 146 Japanese genotype 1b chronic hepatitis C patients were enrolled in this prospective, multicenter study and received a 24-week regimen of triple therapy. The end-of-treatment response rate was significantly lower in patients with the interleukin 28B (IL28B) (rs8099917) non-TT genotype (85.2%) than in those with the TT genotype (100%, P = 0.0002). Multiple logistic regression analysis identified high α-fetoprotein levels as an independent factor related to non-end-of-treatment response in patients with the non-TT genotype. A cut-off value of 20 ng/ml was determined for a non-end-of-treatment response; sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 75.0%, 95.7%, 75.0%, 75.0%, and 92.6%, respectively. Multiple logistic regression analysis for a sustained virological response identified the IL28B TT genotype, low α-fetoprotein levels, non-responders, and a rapid virological response. The sustained virological response rate was significantly lower in patients with the non-TT genotype (59.3%) than in those with the TT genotype (96.7%, P < 0.0001). In patients with the non-TT genotype, α-fetoprotein was the most significant predictor for non-sustained virological response by univariate analysis. A cut-off value of 7.4 ng/ml α-fetoprotein was determined for non-sustained virological response; sensitivity, specificity, PPV, NPV, and accuracy were 63.6%, 87.5%, 77.8%, 77.8%, and 77.8%, respectively. For the non-TT patients, serum α-fetoprotein levels may be a surrogate marker for predicting treatment failure in telaprevir-based therapy for genotype 1b chronic hepatitis C.

Early phase viral kinetics of chronic hepatitis C patients receiving telaprevir-based triple therapy: A comparison of two real-time PCR assays

Monitoring hepatitis C virus (HCV) kinetics during antiviral treatment is recommended for determining the best form of treatment management. We compared the measurement of HCV RNA by two Real-time PCR assays during the first 12weeks phase of telaprevir in combination with pegylated interferon α2b and ribavirin treatment for chronic hepatitis C patients. The viral kinetics of 65 patients with HCV genotype 1b was assessed. HCV RNA was tested at baseline, on day 3, and every week from 1 to 12 by both the first-generation Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV (CAP/CTM) assay and the Abbott RealTime HCV (ART) assay. A total of 910 serum samples were obtained from the 65 patients. Of these, 168 (28.5%) of the 590 samples HCV RNA negative by CAP/CTM were positive by ART. In contrast, 17 (3.9%) of the 439 samples HCV RNA negative by ART were positive by CAP/CTM. The rates of HCV RNA negativity by ART at weeks 3, 4, and 5 were significantly lower than those by CAP/CTM (21.5% vs. 50.8%, 36.9% vs. 70.8% and 44.6% vs. 81.5%; P<0.001, P<0.0001 and P<0.05, respectively). Although the ART is superior for the determination of HCV RNA negativity, the predictive value of detectable HCV RNA for non-sustained virological response (non-SVR) by CAP/CTM is higher than by ART at weeks 4, 6, and 8. We also found that 16 (24.6%) by CAP/CTM and 28 (43.1%) by ART had a reappearance of residual HCV RNA during the telaprevir treatment period. However, the reappearance of residual HCV RNA was not associated with non-SVR. In conclusion, a significant difference was found between the two real-time PCR assays for the assessment of virological response based on undetectable HCV RNA.

Neutralizing Antibodies in Patients with Chronic Hepatitis C, Genotype 1, against a Panel of Genotype 1 Culture Viruses: Lack of Correlation to Treatment Outcome

The correlation of neutralizing antibodies to treatment outcome in patients with chronic hepatitis C virus (HCV) infection has not been established. The aim of this study was to determine whether neutralizing antibodies could be used as an outcome predictor in patients with chronic HCV, genotype 1, infection treated with pegylated interferon-α and ribavirin. Thirty-nine patients with chronic hepatitis C, genotype 1a or 1b, with either sustained virologic response (n = 23) or non-sustained virologic response (n = 16) were enrolled. Samples taken prior to treatment were tested for their ability to neutralize 6 different HCV genotype 1 cell culture recombinants (1a: H77/JFH1, TN/JFH1, DH6/JFH1; 1b: J4/JFH1, DH1/JFH1, DH5/JFH1). The results were expressed as the highest dilution yielding 50% neutralization (NAb50-titer). We observed no genotype or subtype specific differences in NAb50-titers between patients with chronic HCV infection with and without sustained virologic response when tested against any of the included culture viruses. However, NAb50-titers varied significantly with a mean reciprocal NAb50-titer of 800 (range: 100–6400) against DH6/JFH1 compared to a mean NAb50-titer of 50 (range: <50–400) against all other included isolates. Subsequent studies demonstrated that the efficient neutralization of DH6/JFH1 could be linked to engineered adaptive mutations in the envelope-2 protein. In analysis of envelope 1 and 2 sequences of HCV, recovered from a subset of patients, we observed no apparent link between relatedness of patient sequences with culture viruses used and the corresponding neutralization results. In conclusion, pre-treatment levels of neutralizing antibodies against HCV genotype 1 isolates could not predict treatment outcome in patients with chronic HCV infection. High neutralization susceptibility of DH6/JFH1 could be correlated with adaptive envelope mutations previously highlighted as important for neutralization. Our study emphasizes the importance of using multiple culture viruses for neutralization studies and contributes to the current knowledge about neutralizing epitopes, important for future therapeutic- and vaccine-studies.

Association of IL28B genotype and viral response of hepatitis C virus genotype 2 to interferon plus ribavirin combination therapy

The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24-week IFN plus ribavirin, were recruited into the study protocol of total 48-week IFN plus ribavirin. In 24-week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non-sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48-week regimen to 10 patients of non-sustained virological response at the first course of 24-week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24-week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy.

1200 ANTIVIRAL ACTIVITY OF EP-NI266, A POTENT NUCLEOTIDE HCV POLYMERASE INHIBITOR

1198 HCV NS3/4A PROTEASE RESISTANCE-ASSOCIATED VARIANTS (RAVS) IDENTIFIED IN GENOTYPE 1A PATIENTS EXHIBIT DIFFERENCES IN PHENOTYPIC RESISTANCE TO BOCEPREVIR AND TELAPREVIR IN GENOTYPE 1A REPLICON CELLS S. Black, P. McMonagle, R. Chase, S. Curry, R.J.O. Barnard, D.J. Hazuda, A.Y. Howe, J.A. Howe, R.A. Ogert. Merck & Co., Inc., Kenilworth, NJ, USA E-mail: robert.ogert@merck.com Background: The HCV NS3 protease inhibitors boceprevir (BOC) and telaprevir (TPV) in combination with pegylated interferon alpha-2 plus ribavirin (PR) have been approved for treatment of HCV genotype 1 (GT 1) infection. The major RAVs identified in nonsustained virologic response (SVR) GT 1a infected patients were similar for BOC and TPV. These RAVs were analyzed for phenotypic resistance to BOC and TPV using an in-vitro GT 1a replicon assay. Methods: RAVs were detected by population sequencing in samples from SPRINT-2 (treatment naive) and RESPOND-2 (prior nonresponder/relapser) patients. RAVs were engineered into a GT 1a replicon derived from the H77 1a strain. Replicon cell lines were treated with BOC or TPV for 3 days, and HCVRNA was quantified by Taqman real time PCR analysis. Results: For patients treated with BOC, RAVs were detected in 53% of non-SVR patients with NS3 sequences available. In BOC treated, non-SVR HCV GT 1a infected patients; the most common RAVs were V36M, T54S and R155K. T54A and A156S/T were also identified in HCV GT 1a non-SVR treated patients but were observed more frequently in HCV GT 1b. A similar pattern of HCV GT 1a RAVs was identified in TPV treated patients (Bartels DJ, et al. Hepatology. 2011;54(S1):1328). These RAVs were analyzed for resistance to BOC and TPV in a GT 1a replicon assay. T54A and T54S produced similar fold-shifts in EC50 with BOC and TPV. However, V36M, R155K and A156S each produced a larger fold-shift in resistance to TPV than BOC. The fold shift in EC50 for each RAV was 2to 6-fold for BOC and 5to 16-fold for TPV. Also, the V36M + R155K double variant resulted in a >20-fold increase in EC50 for TPV but <10-fold for BOC.

Effect of interferon therapy on first and second recurrence after resection of hepatitis C virus‐related hepatocellular carcinoma

Several investigators have shown that interferon (IFN) therapy can suppress the recurrence of hepatocellular carcinoma (HCC) after curative treatment. We investigated the effect of IFN therapy on the first and second HCC recurrence following hepatic resection of hepatitis C virus (HCV)-related HCC. Subjects included 166 patients who had undergone curative resection for a single HCV-related HCC. We analyzed the outcome after initial hepatic resection and risk factors of a second HCC recurrence following treatment for the first HCC recurrence. Using multivariate analysis, a non-sustained virological response (non-SVR) was significantly associated with a high incidence of first HCC recurrence. The rate of second HCC recurrence tended to be higher in the non-SVR group than in the SVR group. In the patients with recurrence of multiple tumors or who received non-curative treatment for recurrent HCC, the second HCC recurrence rates were significantly higher. Multivariate analysis demonstrated that non-curative treatment for first HCC recurrence was an independent risk factor for a second HCC recurrence. Among the patients who received curative treatment for their first HCC recurrence, the rates of second recurrence were significantly higher in the non-SVR group than in the SVR group. Multivariate analysis also revealed that SVR was independently associated with prevention of a second HCC recurrence. These results suggest that on first HCC recurrence, a curative treatment should be considered in order to prevent a second recurrence if possible. In addition, IFN therapy contributes to improved prognosis after curative treatment, even in patients with recurrent HCC.

Type 2 diabetes mellitus and chronic hepatitis C: Which is worse? Results of a long-term retrospective cohort study

BackgroundThe long-term outcome in patients with chronic hepatitis C and type 2 diabetes mellitus treated with interferon and ribavirin is unclear. We compared incidence of liver-related events and mortality rates between hepatitis C virus-positive patients with or without diabetes mellitus, and the incidence of diabetes-related events between diabetic patients with and without hepatitis C. MethodsRetrospective study of 309 patients with chronic hepatitis C. Incidence of liver-related events, diabetes-related events and mortality rates were assessed over a mean follow-up of 11.02±4.9 years. Results50 (16%) chronic hepatitis C patients had diabetes mellitus. Diabetics showed a higher number of diabetes- and liver-related events than non-diabetics (10% vs 1.5%, p=0.006; 18% vs 5.7%, p=0.007, respectively) with a mortality of 14% vs 1.5% (p=0.0003). Baseline cirrhosis (p=0.002) and non-sustained virological response (p=0.01) were independent risk factors for liver events; diabetes mellitus (p=0.01) and hypertension (p=0.0017) were independent factors for diabetes-related events. ConclusionsIn patients with chronic hepatitis C, comorbidity with diabetes mellitus was associated with a higher mortality rate and incidence of liver/diabetes-related events. Independent risk factors for liver-related events were the non-response to antiviral therapy and cirrhosis at baseline.

Double-Filtration Plasmapheresis plus Interferon-β for HCV-1b Patients with Non-Sustained Virological Response to Previous Combination Therapy

Background and Aims: Double-filtration plasmapheresis (DFPP) together with interferon (IFN) administration produces a substantial reduction in the viral load during the early stages of treatment. Methods: Based on their responses to previous pegylated IFN and ribavirin (PEG-IFN/RBV) therapy, 20 patients were divided into null virological response (NVR; n = 12) and relapse (n = 8) groups. DFPP was used in combination with IFN-β/RBV with subsequent administration of PEG-IFN-α2a/RBV therapy (DFPP + IFN-β/RBV then PEG-IFN/RBV). Early viral dynamics was assessed, focusing especially on complete early virological response (cEVR) associated with sustained virological response. Additionally, the interleukin 28B gene, the IFN/RBV resistance-determining region, the IFN sensitivity-determining region and the core regions were analyzed. Results: Rapid virological response was achieved in 0% (0/12) of NVR and in 75% (6/8) of relapse patients, with a significant difference between the two groups (p = 0.001). Similarly, cEVR was achieved in 8% (1/12) of NVR and in 88% (7/8) of relapse patients, with a significant difference between the two groups (p = 0.037). By multivariate logistic regression analysis, interleukin-28B major was a significant determiner of cEVR (odds ratio = 24.19, p = 0.037). Conclusion: DFPP + IFN-β/RBV then PEG-IFN/RBV therapy is indicated more for relapse than for NVR patients.