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Background and Aim: The accuracy for predicting virological outcomes of peginterferon-α and ribavirin therapy in patients with chronic hepatitis C is limited to approximately 80%, even with IL28B genotyping. Our in vitro study revealed that the numbers of (TA) dinucleotide repeats [(TA)n] of rs72258881, which is located in the promoter region of IL28B gene, might regulate IL28B transcription. We aimed to evaluate the usefulness of these host factors for predicting virological outcomes of this therapy in response-guided clinical settings., Methods: A nationwide, multi-center prospective study in Japan determined IL28B (rs8099917) genotype, (TA)n of rs72258881, and amino acid substitutions of hepatitis C virus and used these for multivariate analysis together with other parameters at pretreatment., Results: After enrolling 215 patients with genotype 1 and high viral load from 23 hospitals between October 2009 and February 2011, intent-to-treat analysis identified 202 patients in whom the final virological outcomes could be determined. Non-virological response by non-TT genotype was predicted with 79.7% accuracy. When combined with the (TA)n, the incidences of virological response tended to be higher in the longer (TA)n group, regardless of rs8099917 genotype. Multivariate logistic regression analysis revealed that rs8099917 non-TT genotype (P < 0.001), shorter (TA)n (P = 0.011), mutation of amino acid 70 in the virus core region (P = 0.029), and lower levels of serum albumin (P = 0.036) were independently associated with non-virological response., Conclusions: IL28B genotype and (TA)n of rs72258881 may independently affect virological outcomes of peginterferon-α and ribavirin as host factors, even in response-guided therapy., (© 2014 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background & Aims: MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis., Methods: We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular., Results: At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups., Conclusions: Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Rapid and early virological responses to peginterferon-alpha and ribavirin are predictive of sustained virological response (SVR) in hepatitis C virus (HCV) infection. We aimed at finding a simple rule to determine the shortest duration of dual therapy for all HCV genotypes, obtained by multiplying time to Initial Viral Response, IVR (first undetectable HCV-RNA) by 4 (Tailored Therapy-4, or TT4)., Method: 267 naïve HCV-infected patients with compensated liver disease were randomized (2:1) to the TT4 (n=180) or current standard-of-care (SoC, n=87) and received peginterferon-alpha plus ribavirin. Patients with HCV-RNA decrease ≤2log10 at week 12 or detectable HCV-RNA at week 24 discontinued treatment., Results: Both groups had comparable baseline characteristics, SVR rates were similar in the whole population (60.6% vs. 60.9%) and within each genotype subgroup (G1: 46.6% vs. 55.6%; G2: 90.2% vs. 94.4%; G3: 74.1% vs. 58.3%; G4: 45.8% vs. 33.3%). Relapse rate was higher in G1-TT4 than G1-SoC. Treatment duration in SVR patients was shorter in TT4 compared to SoC, both overall [25±15 vs. 36±12.1 weeks], and for subgroups: G1 [35.3±16.7 vs. 47.3±2.6 weeks], G2 [18.3±7.5 vs. 24±2.8 weeks], G3 [15.2±8.7 vs. 22.8±3 weeks] and G4 [26.9±13 vs. 48 weeks]., Conclusions: In HCV-naive patients, TT4-rule treatment yields similar SVR rates compared to SoC but with shorter treatment duration and remarkable cost reduction., (Published by Elsevier Ltd.)

Background & Aims: The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients., Methods: Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment)., Results: Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study., Conclusions: The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

This study aimed to determine the most suitable duration of pegylated-interferon (Peg-IFN)-plus-ribavirin combination therapy in patients infected with hepatitis C virus (HCV) genotype 2 who had not achieved rapid virological response (serum HCV RNA disappearance after 4 weeks of therapy). HCV genotype 2 patients (n = 182) with a high viral load received >80% of the standard Peg-IFN-plus-ribavirin dose for at least 24 weeks, and their final virological responses were studied. Patients were classified into "rapid virological response" and "non-rapid virological response" groups. The non-rapid virological response group was further divided into a "virological response at 8 weeks" (serum HCV RNA disappearance after 8 weeks of therapy) and a "non-virological response at 8 weeks" group. Factors related to rapid virological response and optimal therapy duration in the non-rapid virological response group were evaluated. Multivariate logistic regression analysis showed that subtype HCV genotype 2a (P = 0.0015) and low concentration of pretreatment serum HCV RNA (P = 0.0058) were independent factors in a rapid virological response. In the virological response at 8 weeks group, the sustained virological response rate after 24 weeks of therapy was significantly lower than after 36 weeks (P = 0.044) or after 48 weeks (P = 0.006), and was similar for 36- and 48-weeks. The cost for achieving (CAS) one sustained virological response was lowest with 36-week therapy. Prolongation of Peg-IFN-plus-ribavirin combination therapy to 36 weeks is suitable for achieving virological response at 8 weeks, given the high, sustained virological response rate and cost benefit., (Copyright © 2013 Wiley Periodicals, Inc.)

Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNα and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients.

Background: RNA detection in plasma/stool is the gold‐standard for diagnosis of hepatitis E virus (HEV) infection. The impact of viral extraction methods on HEV RNA detection is poorly investigated. Methods: We determined the limit of detection of the RealStar HEV RT‐PCR V2.0 Kit (altona Diagnostics, RS) utilizing 3 RNA extraction methods (COBAS® AmpliPrep Total Nucleic Acid Isolation Kit, TNAi Roche; MagNA Pure 96 DNA, Viral NA SV Kit, MgP; QIAamp Viral RNA mini Kit Qiagen; VRK) in plasma and stool. The most sensitive method was evaluated in a total of 307 longitudinal samples of patients with HEV infection (acute = 18/chronic = 36) and compared to results with the former diagnostic standard of our centre (TNAi/FastTrack Diagnostic; FTD). Results: The plasma‐LOD was 49, 94 and 329 IU/mL for extraction with MgP, VRK and TNAi respectively. In stool, the LOD was 21 IU/mL, 528 IU/mL and indefinable for extraction with TNAi, VRK and MgP respectively. Utilizing longitudinal patient plasma samples, MgP/RS revealed 56 HEV RNA‐positive samples in 158 negative samples as determined by TNAi/FTD. In stool, from 37 HEV negative samples (TNAi/FTD), 15 were positive with TNAi/RS. At end of treatment, 8 out of 27 chronically infected patients were RNA positive with MgP/RS, while classified negative with TNAi/FTD. A relapse occurred in 3 of these patients. Conclusion: Different methods for RNA extraction and quantification have a significant, compartment‐specific impact on the sensitivity of HEV detection. Knowledge about the favourable combinations of extraction and quantification has important implications for diagnosis and patients receiving antiviral therapy. [ABSTRACT FROM AUTHOR]

We aimed to determine whether the HCV viral load after four weeks of treatment (W4 VL) with direct-acting antiviral agents ( DAAs) predicts sustained virologic response ( SVR) in a real-world clinical setting. We identified 21 095 patients who initiated DAA-based antiviral treatment in the national Veterans Affairs ( VA) healthcare system from 01/01/2014 to 06/30/2015. Week 4 viral load was categorized as undetectable, detectable below quantification (DBQ), detectable above quantification (DAQ) with viral load ≤42 IU/ mL and DAQ with viral load >42 IU/ mL. Week 4 viral load was undetectable in 36.1%, detectable below quantification in 45.6%, DAQ ≤42 in 9.3%, DAQ >42 in 9.1%. Detectable above quantification was much more common and undetectable week 4 viral load much less common when tested with the Abbott RealTime HCV assay vs the Roche COBAS AmpliPrep/ COBAS TaqMan Version 2 assay. Compared to patients with undetectable week 4 viral load ( SVR=93.5%), those with detectable below quantification ( SVR=91.8%, adjusted odds ratio [ AOR] 0.79, P-value=.001), DAQ ≤42 ( SVR=90.0%, AOR 0.63, P-value<.001) and DAQ >42 ( SVR=86.2%, AOR 0.52, P-value<.001) had progressively lower likelihood of achieving SVR after adjusting for baseline characteristics and treatment duration. Among genotype 1-infected patients who were potentially eligible for 8-week sofosbuvir/ledipasvir monotherapy, we did not find evidence that treatment for 12 weeks instead of 8 weeks was associated with higher SVR, even among those with detectable above quantification. In summary, DBQ and DAQ W4 VL are very common in real-world practice, contrary to what was reported in clinical trials, and strongly predict reduced SVR across genotypes and clinically relevant patient subgroups. Whether and how week 4 viral load results should influence treatment decisions requires further study. [ABSTRACT FROM AUTHOR]

Aim: To optimize the therapeutic efficacy of NS3/4A protease inhibitors, a multicenter prospective study was performed according to an algorithmbased on the Adherence, IL-28B Gene Allele and Viral Response Trial (AG & RGT). Methods: A total of 340 patients with genotype 1b hepatitis C virus (HCV) showing serum RNA levels of >5 log were enrolled. The duration of ribavirin/pegylated interferon (PEG IFN)-α-2b therapy was prolonged to 48weeks in patients with unfavorable IL28B alleles showing adherence rates of less than 80% for either drug during the first 12weeks even if RVR had been achieved, and in those in whom cEVR, but not RVR, was achieved; furthermore, to 72weeks in those showing partial early viral response. Results: The therapeutic outcomes were assessed in 282 patients, and the therapy was set to complete at 24weeks in 181 patients (64%) and to prolong to 48weeks or 72weeks in 71 patients (25%). The former group showed a SVR rate of 84%, while the latter group showed an SVR rate of 69% with a relapse rate of 7%. The SVR rate was 33% in the 30 patients (11%) in whom the therapy had to be discontinued in less than 12weeks. Thus, the results of intention-to-treat analysis revealed an overall SVR rate of 75%. Multivariate analysis identified prolongation of the duration of therapy as a significant factor associated with SVR. Conclusion: Triple therapy yielded a high SVR rate in the AG & RGT trial via attenuation of viral relapse by prolonged ribavirin/PEG IFN-α-2b administration. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend that interferon-based treatment of hepatitis C (HCV) genotype 2 or 3 in those with HIV coinfection should be for 48 weeks, especially if HCV PCR remains positive after 4 weeks of treatment. Aim: To examine a single-center experience using response-guided therapy (RGT) using pegylated interferon (PegIFN) and weight-based ribavirin (RBV) for treating HCV genotype 2 or 3 in those with HIV coinfection. Methods: Electronic medical records were used to identify patients with HCV genotype 2 or 3 HIV coinfection seen at the Toronto General Hospital Immunodeficiency Clinic from February 2003 to December 2012. HCV PCR was tested after every 4 weeks of treatment until it was negative (<50 IU/mL). RGT protocol was as follows: Those with HCV PCR first negative after 4 weeks (VR4) were treated 24 weeks; first negative after 8 weeks (VR8) treated 36 weeks and VR12 treated 48 weeks. Result: Database search identified 35 individuals with HCV genotype 2 or 3. Twelve were excluded. Total 23 patients completed the treatment and were included for data analysis. Eleven of 23 (48 %) achieved VR4 and eleven of 23 (48 %) achieved VR8. Only one individual had detectable viremia to week 12 and required 48 weeks of treatment. The majority (96 %) were successfully treated with <48 weeks of PegIFN-RBV therapy. One hundred percent achieved SVR with a response-guided HCV therapy. Conclusion: The use of response-guided therapy allows therapy to be shortened in the majority of individuals. HCV PCR testing should be performed every 4 weeks during the first 12 weeks of therapy until HCV PCR is negative. [ABSTRACT FROM AUTHOR]

Background: We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high). Methods: The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFNα-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFNα-2a (group A) or PEG-IFNα-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFNα-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFNα-2a/RBV (group E) or PEG-IFNα-2a/RBV/fluvastatin (group F). Results: Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation. Conclusion: In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Shortened courses of treatment with pegylated interferon alfa and ribavirin for patients with hepatitis C virus infection who experience rapid virologic response can be effective in appropriately selected patients. The cost-effectiveness of truncated therapy is not known. Objective: To assess the cost-effectiveness of response-guided therapy versus standard-duration therapy on the basis of best available evidence. Methods: We developed a decision model for chronic hepatitis C virus infection representing two treatment strategies: 1) standard-duration therapy with pegylated interferon alfa and ribavirin for 48 weeks in patients with genotype 1 or 4 and for 24 weeks in patients with genotype 2 or 3 and 2) truncated therapy (i.e., 50% decrease in treatment duration) in patients with rapid virologic response. Patients for whom truncated therapy failed began standard-duration therapy guided by genotype. We used a Markov model to estimate lifetime costs and quality-adjusted life-years. Results: In the base-case analysis, mean lifetime costs were $46,623 ± $2,483 with standard-duration therapy and $42,354 ± $2,489 with truncated therapy. Mean lifetime quality-adjusted life-years were similar between the groups (17.1 ± 0.7 with standard therapy; 17.2 ± 0.7 with truncated therapy). Across model simulations, the probability of truncated therapy being economically dominant (i.e., both cost saving and more effective) was 78.6%. The results were consistent when we stratified the data by genotype. In one-way sensitivity analyses, the results were sensitive only to changes in treatment efficacy. Conclusion: Truncated therapy based on rapid virologic response is likely to be cost saving for treatment-naive patients with chronic hepatitis C virus infection. Cost-effectiveness varied with small changes in relative treatment efficacy. [Copyright &y& Elsevier]

Background: The importance of the reduction in hepatitis C virus (HCV) RNA levels 4 and 12 weeks after starting peginterferon (PEG-IFN) and ribavirin combination therapy has been reported to predict a sustained virologic response (SVR) in patients infected with HCV genotype 1. We conducted a multicenter study to validate this importance along with baseline predictive factors in this patient subpopulation. Methods: A total of 516 patients with HCV genotype 1 and pretreatment HCV RNA levels ⩾5.0 log10 IU/mL who completed response-guided therapy according to the AASLD guidelines were enrolled. The reduction in serum HCV RNA levels 4 and 12 weeks after starting therapy was measured using real-time PCR, and its value in predicting the likelihood of SVR was evaluated. Results: The area under the receiver operating characteristics (ROC) curve was 0.852 for 4-week reduction and 0.826 for 12-week reduction of HCV RNA levels, respectively. When the cut-off is fixed at a 2.8-log10 reduction at 4 weeks and a 4.9-log10 reduction at 12 weeks on the basis of ROC analysis, the sensitivity and specificity for SVR were 80.9% and 77.9% at 4 weeks and were 89.0% and 67.2% at 12 weeks, respectively. These variables were independent factors associated with SVR in multivariate analysis. Among 99 patients who showed a delayed virologic response and completed 72-week extended regimen, the area under ROC curve was low: 0.516 for 4-week reduction and 0.482 for 12-week reduction of HCV RNA levels, respectively. Conclusions: The reduction in HCV RNA levels 4 and 12 weeks after starting combination therapy is a strong independent predictor for SVR overall. These variables were not useful for predicting SVR in patients who showed a slow virologic response and experienced 72-week extended regimen. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hepatitis C virus (HCV) RNA monitoring during antiviral therapy is essential for early prediction of treatment success and failure to peginterferon alfa/ribavirin (PEG-IFN/RBV) therapy. Objectives: In this multi-center study we assessed the clinical utility of the Abbott RealTime HCV assay for monitoring patients undergoing antiviral therapy for chronic infection with HCV genotypes (GT) 1–3. Study design: We analyzed serum from 361 patients with chronic hepatitis C who had been treated with PEG-IFN/RBV. The predictive value of rapid virologic response (RVR), partial (≥2log10 decline) and complete (HCV-RNA undetectable) early virologic response (pEVR/cEVR) based on RealTime HCV for achieving sustained virologic response was evaluated. In addition, the utility of RealTime HCV to tailor treatment duration according to individual virologic responses was studied in a subset of 136 GT 1 patients and compared to the reference tests, Versant HCV Quantitative 3.0 (bDNA) and Qualitative (TMA) assay. Results: At week 4 of therapy, patients with RVR had a 100% and 93.5% probability to achieve an SVR in GT 1 and GT 2/3 patients, respectively. At week 12, patients who did not achieve a pEVR had a 97.2% and 100% probability of not achieving an SVR. In addition, assignment of GT 1 patients to abbreviated or extended treatment durations based on low baseline HCV-RNA (<800,000IU/mL) and RVR or pEVR was highly concordant between RealTime HCV and bDNA/TMA assays (97.8% and 91.9%, respectively). Conclusions: The RealTime HCV assay is suitable for monitoring virologic response to PEG-INF/RBV therapy and tailoring treatment duration accordingly. [Copyright &y& Elsevier]

Background: The ability to predict the outcome of peginterferon (PEG-IFN) and ribavirin combination therapy based on the reduction in hepatitis C virus (HCV) RNA levels at 4 weeks after starting the therapy and amino acid substitutions in HCV was to be confirmed. Methods: We measured the reduction in HCV RNA levels at 4 weeks after starting the combination therapy, as well as examining amino acid substitutions at residue 70 in the HCV core and within the interferon sensitivity-determining region (ISDR) of HCV non-structural protein 5A (NS5A), for 101 patients infected with HCV genotype 1b. The ability of these factors to predict a sustained virologic response (SVR) was analyzed. Results: When a 3 log reduction in HCV RNA levels at 4 weeks after starting therapy was set as the cut-off value, an SVR was achieved in 37 of the 46 patients (80.4%) with a ≥3 log decrease and in 4 of the 55 patients (7.3%) with a <3 log decrease. All 4 patients who achieved an SVR despite a <3 log reduction in HCV RNA levels at 4 weeks had an arginine at residue 70 in the HCV core and a non-wild-type sequence for the ISDR of HCV NS5A. Conclusion: A ≥3 log reduction in HCV RNA levels at 4 weeks after starting therapy indicates that a patient has a high likelihood of achieving an SVR as a final outcome. Additional information on the amino acid substitutions at residue 70 in the HCV core and within NS5A-ISDR will further increase the ability to predict a clinical response. [ABSTRACT FROM AUTHOR]

The management of chronic hepatitis C (CHC) is a rapidly evolving field. New treatment paradigms are emerging due to an improved understanding of the host-viral interaction and the recent development of novel anti-viral therapies. Nevertheless, combination therapy with pegylated interferon (PEG-IFN) and ribarivin (RBV) remains the cornerstone of the treatment of CHC and will likely remain so for the foreseeable future. Over the past decade treatment regimens involving peginterferon plus ribavirin therapy have evolved from initial fixed dosing schedules to more recent individualized response-guided schedules that utilize on-treatment virological responses to determine treatment duration. The future of CHC treatment in the near to medium term is likely to involve the use of PEG-IFN and RBV in conjunction with potent and specific direct acting anti-viral agents (DAA) (protease +/- polymerase inhibitors). This review will focus on the use of PEG-IFN and RBV in the treatment of CHC as well as provide insight into how DAA agents may be used with this therapy as we enter the era of specifically targeted antiviral therapy for HCV. [ABSTRACT FROM AUTHOR]

Treatment for hepatitis C is aimed at eliminating the virus and thus preventing the development of cirrhosis. The effectiveness of antiviral therapy with pegylated interferon and ribavirin is based upon inhibition of viral replication and successful viral clearance while maintaining minimal toxicity. The treatment of hepatitis C has evolved to a response-guided paradigm based on viral kinetic response. Using response-guided therapy, duration of therapy as short as 12–16 weeks may be adequate for those with genotypes 2 or 3, and 24 weeks may be sufficient for those with genotype 1 and low viral load who achieve rapid virologic response. On the other hand, extension of therapy beyond 48 weeks may be beneficial for those with genotype 1 and slow response or in the setting of high pretreatment viral load who do not achieve rapid virologic response by reducing relapse. As new viral kinetic data emerge with pegylated interferon and ribavirin, the tailoring of HCV treatment will allow shorter durations of therapy in some, and a greater chance of sustained response in others treated for longer durations. These paradigms will require further refinement in the era of direct-acting antiviral therapies. [ABSTRACT FROM AUTHOR]

Background & Aims: Assessing hepatitis C virus (HCV)-RNA levels is integral to response-guided therapy. Rules for early discontinuation and determination of treatment duration were mainly established with HCV-RNA assays with a detection limit of ⩽50IU/ml (COBAS Amplicor™ HCV [CA]). The currently used real-time PCR-based COBAS Ampliprep™/COBAS-TaqMan™ HCV (CAP-CTM) test has a detection limit of approximately 10IU/ml. It is unknown whether shortening of treatment duration to 16/24 weeks in patients with rapid virological response at week 4 (RVR) and viral loads between 10 and 50IU/ml is possible. Methods: We reanalysed stored serum from two large, multinational, randomized trials in which patients were treated with peginterferon alfa-2a/ribavirin (n =962). Results of CAP-CTM with truly undetectable HCV RNA and those <15IU/ml, which includes patients with residual viraemia (<15), were compared with the originally obtained results using the CA assay. Results: RVR rates were comparable for CA (<50) and CAP-CTM (<15) with 32% and 32% for genotype (gt) 1 and 50% and 49% for gt2/3 patients, respectively. A significantly smaller number of samples really had truly undetectable HCV RNA by the CAP-CTM assay (24% for gt1, 37% for gt2/3). However, sustained virological response rates after shortened treatment (16/24weeks) were not significantly different in patients with a RVR <50, a RVR <15 and RVR undetectable (82%, 83%, 83% for 24weeks gt1 and 95%, 95%, 94% for 16weeks gt2/3). Conclusions: Shortening the treatment duration to 16/24weeks can be performed on the basis of a RVR with HCV-RNA concentrations <15IU/ml by the CAP-CTM assay. [Copyright &y& Elsevier]

Abstract: Background: The “response-guided therapy” based on response of hepatitis C virus (HCV) during antiviral combination therapy with peginterferon and ribavirin is important for patients with HCV genotype 1. However, the sensitivity of previous assays for serum HCV RNA is limited. Objectives: We evaluated the changes in serum HCV RNA during the combination therapy using a novel method for measurement based on real-time PCR. Study design: Changes in serum HCV RNA during the combination therapy were reanalyzed using TaqMan PCR assay in 144 patients with chronic HCV genotype 1b infection who underwent the therapy under HCV RNA monitoring with the Amplicor Monitor assay. Treatment duration was elongated from 48 weeks to 72 weeks in 17 patients based on the time when serum HCV RNA became negative. Results: In 9 of 144 (6.3%) patients, serum HCV RNA transiently appeared again on the TaqMan PCR assay after having previously become negative. At the point of reappearance, the Amplicor Monitor assay gave a negative result in all patients, and no flare of alanine aminotransferase activity was observed. Each of the 9 patients achieved an end-of-treatment response but relapsed after the end of treatment, including 3 patients in whom the treatment duration was elongated to 72 weeks. Conclusions: Attention should be paid to this phenomenon in the antiviral treatment for patients with HCV infection. The transient reappearance of HCV RNA in the serum indicates a high likelihood of relapse, and is likely to be missed without frequent measurements by a sensitive detection method. [Copyright &y& Elsevier]

The average age of patients initiating therapy for HCV is increasing, with older patients exhibiting lower responses to therapy than younger patients. Identification of those older patients likely to respond needs to be addressed. Using data from 569 genotype-1 patients enrolled in two phase III studies (NV15801/NV15942) randomized to peginterferon alfa-2a (40KDa) 180 μg/week plus ribavirin 1000/1200 mg/day for 48-weeks, we investigated factors associated with sustained virological response (SVR; undetectable HCV-RNA 24-weeks post-treatment) in patients >50 years. SVR rates among patients ≤50 was greater than those >50 years (52% vs 39%; P = 0.0073). Older patients with a rapid virological response (RVR; undetectable HCV-RNA at treatment week 4) or complete early virological response (cEVR; detectable HCV-RNA at week 4 but HCV-RNA <50 IU/mL at week-12) demonstrated high SVR rates (83% and 61% respectively). Older patients had lower cumulative peginterferon alfa-2a exposure and significantly lower cumulative ribavirin exposure (252 g vs 304 g in younger patients; P < 0.0001). Higher relapse rates were observed in older patients (41% vs 25%; P = 0.0042). Cumulative drug exposure and achievement of RVR or cEVR were significantly predictive of SVR by multiple logistic regression analysis in patients >50 years. Other baseline characteristics predictive of SVR in those >50 years of age were lower baseline HCV-RNA level ( P = 0.0067), higher ALT-ratio ( P = 0.0113) and absence of cirrhosis ( P = 0.0482). Response rates were high among patients >50 years without cirrhosis who maintained adequate drug exposure and those achieving an RVR or cEVR. More frequent dose modifications of ribavirin in those >50 years likely contributed to the observed higher relapse rates. [ABSTRACT FROM AUTHOR]