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Background & Aims Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. Methods 58 chronic HCV patients were treated with 12-week sofosbuvir + simeprevir (n = 19), sofosbuvir + daclatasvir (n = 19), or sofosbuvir + ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12 weeks post EOT. Mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid. Results All but one patient who relapsed achieved SVR. Mean age was 60 ± 11 years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV <15 IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13 weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir + ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43–45% and 17–30% in subjects who had HCV <15 IU/ml at weeks 2 and 4, respectively. Conclusions The use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16–20% per 100-treated persons. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatitis C recurrence after liver transplantation (LT) is the main problem of most transplant programs. We aimed at assessing the antiviral activity and safety of intravenous silibinin (SIL) administered daily during the peri-transplant period. Methods: This was a single-centre, prospective, randomized, double-blind, placebo-controlled study including 14 HCV-infected patients awaiting LT. Eleven patients received SIL and 3 placebo, for a maximum of 21days before LT and 7days after LT. Results: Among the patients who received more than 14days of pre-LT treatment, the median decrease in viral load (VL) was 2.31log10 (range 0.6–4.2) in the SIL-treated group (n=9) versus 0.30log10 (0.1–0.6) in the placebo group (n=3) (p =0.016). During the post-LT treatment, HCV-RNA levels were consistently and significantly (p =0.002) lower in the SIL group compared to placebo and decreased below the limit of quantification in 2 patients and below the limit of detection in 2 additional patients (all in the SIL-treated group). Peri-transplant treatment with SIL was well tolerated. Conclusions: This proof-of-concept study in patients in the waiting list for LT indicates that daily intravenous silibinin has evident antiviral properties and is well tolerated in the peri-LT period. A longer treatment regimen with silibinin (alone or in combination with other agents) should be assessed in clinical trials for the prevention of hepatitis C recurrence. [ABSTRACT FROM AUTHOR]

Background & Aims: In a previous study, advanced fibrosis was associated with worsening efficacy of antiviral therapy in HCV-transplant patients. We aimed at assessing whether changes in treatment policy, that is starting therapy at lesser stages of fibrosis, have resulted in improved efficacy. Methods: Efficacy (rapid, early, end-of-treatment, and sustained viral response (SVR)) and tolerability (peginterferon (pIFN)/ribavirin (RBV) doses, premature discontinuation, dose reductions, anemia, growth factors, transfusions) were compared between two non-contemporaneous cohorts of post-LT naïve patients treated with pIFN-RBV: Group 1 (n=44), a historical cohort of patients treated during the period 2005–2007 and Group 2 (n=70), patients treated more recently (2007–2010), where treatment was started once there was evidence of fibrosis. Results: SVR increased from 25% to 54% (p =0.002) due to a reduction in relapse rate. Comparing both cohorts, a decrease in the number of cirrhotic patients together with an increase in platelet count was observed in recent years. Additional non-intentional changes included: (i) an increase of patients treated under cyclosporine immunosuppression, (ii) treatment-related factors with an increase in patients treated with initial full pIFN and RBV doses, who developed anemia and hence required dose modifications and erythropoietin. Baseline factors associated with SVR were younger donor age, lack of cirrhosis or severe necroinflammation and the use of RBV at full doses at initiation while on-treatment variables were adherence and viral kinetics. Conclusions: Treatment in the absence of cirrhosis is associated with higher SVR warranting strict disease progression monitoring. A more aggressive approach, particularly regarding RBV dosage, is also associated with improved efficacy. Further studies are required to assess whether switching to cyclosporine will result in improved SVR. [ABSTRACT FROM AUTHOR]

Background & Aims: Legalon® SIL (SIL) is a chemically hydrophilized version of silibinin that has exhibited high antiviral effectiveness against hepatitis C virus (HCV). Its main mode of action (MOA) remains unclear, with contradicting in vitro studies supporting either suppression of entry and cell-to-cell spread or suppression of viral RNA synthesis as the main MOA. We sought to provide new insights into SIL’s MOA in HCV genotype-1/4 patients receiving intravenous SIL monotherapy for 7days via mathematical modeling. Methods: Changes in HCV RNA in 25 patients receiving 10, 15, or 20mg/kg/day of SIL were analyzed and modeled using viral kinetic methods. Results: In 15 patients, the virus declined in a biphasic manner, in which a sharp drop between days 0 and 2 was followed by a slower second phase of decline. In 10 patients, the initial decline was weaker and the virus declined in a single phase over the 7-day period. The blocking production effectiveness, ε, was dose-dependent with mean ε =0.49 and 0.89 in the 10 or 15 and 20mg/kg/day dosing groups, respectively (p =0.02). The effectiveness of blocking viral infection, η, was estimated as 0.60 with no significant differences across dosing groups. For all patients, the mean rate of viral load decline measured between days 2 and 7 was high (0.3 log10 IU/ml/day), i.e., 4-fold higher than typically observed during the 2nd phase of (pegylated)-interferon-α±ribavirin treatment. Conclusions: Modeling HCV kinetics in vivo suggests that SIL may block both viral infection and viral production/release with its main dose-dependent effect being blocking viral production/release. [ABSTRACT FROM AUTHOR]

Background & Aims: We studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0–28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 Caucasian Americans (CA) with HCV genotype 1. Methods: We studied the relationship between IL28B 16 gene-related SNP rs12979860 and early viral kinetics (day 0–28) 17 during peginterferon and ribavirin treatment, in 171 African 18 Americans (AA) and 188 Caucasian Americans (CA) with HCV 19 genotype 1. Results: Compared to non-C/C genotypes, C/C was associated with greater declines in serum HCV RNA during phase 1 (day 0–2), phase 2 (day 7–28), and day 0–28 and higher response (undetected HCV RNA) rates at weeks 4 and 12 in AA and CA. A static phase and increases in HCV RNA from day 2 to 7 were more common in patients with non-C/C genotypes. C/C was also associated with higher week 24, 48, and 72 response rates in CA (p <0.01) but not in AA. At baseline, SNP genotype was the only independent predictor of phase 1; SNP genotype and phase 1 were independent predictors of phase 2 (p <0.001). There were no racial differences in HCV RNA declines during phase 1, day 2–7, phase 2, and day 0–28 with the same SNP genotype. AA with C/C and C/T genotypes had lower week 24, 48, and 72 (SVR) rates than did CA (p =0.03). SNP C/C predicted higher SVR rates in AA and CA with high baseline HCV RNA (⩾600,000IU/ml), and in CA with ⩾1log10 IU/ml decrease in HCV RNA from day 0 to 28. Conclusions: SNP rs12979860 is strongly associated with both phase 1 and phase 2 HCV RNA kinetics in AA and CA with HCV genotype 1. [Copyright &y& Elsevier]

Background & Aims: Single nucleotide polymorphisms (SNPs) associated with IL28B influence the outcome of peginterferon-α/ribavirin therapy of chronic hepatitis C virus (HCV) infection. We analyzed the kinetics of HCV RNA during therapy as a function of IL28B SNPs. Methods: IL28B SNPs rs8099917, rs12979860, and rs12980275 were genotyped in 242 HCV treatment-naïve Caucasian patients (67% genotype 1, 28% genotype 2 or 3) receiving peginterferon-α2a (180μg weekly) and ribavirin (1000–1200mg daily) with serial HCV-RNA quantifications. Associations between IL28B polymorphisms and early viral kinetics were assessed, accounting for relevant covariates. Results: In the multivariate analyses for genotype 1 patients, the T allele of rs12979860 (Trs12979860) was an independent risk factor for a less pronounced first phase HCV RNA decline (log10 0.89IU/ml among T carriers vs. 2.06 among others, adjusted p <0.001) and lower rapid (15% vs. 38%, adjusted p =0.007) and sustained viral response rates (48% vs. 66%, adjusted p <0.001). In univariate analyses, Trs12979860 was also associated with a reduced second phase decline (p =0.002), but this association was no longer significant after adjustment for the first phase decline (adjusted p =0.8). In genotype 2/3 patients, Trs12979860 was associated with a reduced first phase decline (adjusted p =0.04), but not with a second phase decline. Conclusions: Polymorphisms in IL28B are strongly associated with the first phase viral decline during peginterferon-α/ribavirin therapy of chronic HCV infection, irrespective of HCV genotype. [ABSTRACT FROM AUTHOR]

Background & Aims: Undetectable HCV RNA at 12weeks is the stopping rule recommended in HCV patients in whom previous treatment has failed. Whether earlier virological criteria may be useful for deciding treatment discontinuation remains subject of debate. The aim of this study was to identify, in HCV-1 non-responders and relapsers to IFN or Peg-IFN and ribavirin, the earliest and most accurate predictor of failure to respond to a new treatment combining Peg-IFN and ribavirin. Methods: Prediction of SVR was assessed using the area under the ROC (AUROC) curve of reduction in viral load at different time points. Results: This study included 151 patients (32% with extensive fibrosis or cirrhosis). A SVR was reached in 34% (21% in non-responders and 59% in relapsers). In non-responders, 1month was the most accurate time point for predicting SVR (AUROC: 0.787±0.075, p =0.0001). Thirty-seven percent of non-responders did not have a 1-log drop in viral load at 1month. All these patients had detectable HCV RNA at 3months (p <0.0001) and only 4% attained a SVR (p =0.004). The same high negative predictive value for SVR was found in sensitivity analysis restricted to non-responders to Peg-IFN and ribavirin. In contrast, in relapsers, undetectable HCV RNA at 3months was the earliest criterion with high negative predictive value (92%, p <0.0001). Conclusions: All HCV-1 non-responders who did not have a 1-log drop in viral load at 1month remained HCV-RNA-detectable at 3months, and only 4% attained a SVR. This new criterion can be used early on as a first stopping rule. [ABSTRACT FROM AUTHOR]

Genotypes 2 and 3 (G2/G3) of hepatitis C virus have been lumped together as ‘easy to treat’. As a result, guidelines recommend 24weeks of peginterferon/ribavirin for both. However, a closer look at trials shows that these genotypes are not the same, with G2 infection proving more responsive to peginterferon. The data supporting this conclusion are presented along with possible explanations for the differences observed. Ultimately, decisions must be made about therapy. Rapid virological response (RVR) may be the best parameter predicting successful antiviral therapy. For patients with G2 infection who achieve an RVR, shortened courses of therapy are effective. In contrast, for G3 patients without an RVR, there may be benefit to extending therapy to 48weeks; however, this requires confirmation in prospective studies. Using RVR to guide therapy may level the playing field between these ‘easy to treat’ genotypes. [Copyright &y& Elsevier]

Background & Aims: The human liver-uPA+/+-SCID mouse is currently the best small animal model available for viral hepatitis infection studies. Methods: We identify critical factors affecting animal survival, engraftment efficacy, kinetics of liver repopulation and virological outcome by analysing the data from 400 human hepatocyte transplantations and 115 subsequent HBV and/or HCV inoculations in this mouse model. Results: Almost one third of animals succumbed during the first week after hepatocyte transplantation. Only during this critical period, liver necrosis due to embolization of donor cells in the portal vein was observed. This may have caused a fatal acute liver failure that complicated the pre-existing chronic liver disease. From the second week onwards, confluent hepatocyte clusters repopulated the liver and restored its synthetic functions as evidenced by increasing human albumin levels in plasma. Xenogenic repopulation by human cells proceeded approximately 4-times slower compared to allogenic mouse hepatocytes. All HBV inoculations were successful, even in animals with low graft take. HCV infection rate varied substantially, although every donor cell type yielded infectable animals. A reproducible 100% HCV infectivity was reached with high quality inocula in animals with human albumin plasma levels >1mg/ml. Superior animal survival, adequate liver engraftment and a high viral infection rate were observed after transplanting cryopreserved commercial human hepatocytes. Conclusions: Our findings favour the use of commercially available, cryopreserved human hepatocytes for the humanization of the uPA+/+-SCID liver. While HBV infectivity criteria are less stringent, human albumin plasma levels exceeding 1mg/ml are required for a consistent HCV infection in chimeric mice. [ABSTRACT FROM AUTHOR]

Background & Aims: The pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Methods: Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180μg/week) plus ribavirin (11mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Results: Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p =0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (δ), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p =0.013], 0.27 vs. 0.11day−1 [p= 0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p =0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p =0.114). Genotype 1 had a significantly lower δ compared to genotype 3 (median 0.14 vs. 0.23day−1 [p =0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC50) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p =0.034]). Conclusions: Both the HCV-infected cell loss rate (δ) and the maximum effectiveness of the first dose of PEG-IFN-α-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV. [Copyright &y& Elsevier]

Background/Aims: Analysis of hepatitis C virus (HCV) RNA kinetics in compartments other than plasma may help in understanding HCV replication and identifying clinically significant patterns of treatment response. Methods: After 6 weeks of pegylated interferon-α2a/ribavirin therapy, 74 chronic hepatitis C patients were randomized to individualized or standard treatments for another 42 weeks. HCV RNA was quantified in peripheral blood mononuclear cells (PBMCs) by TaqMan-based real-time PCR and compared to plasma HCV RNA. Results: HCV RNA declines in PBMCs and plasma were comparable during the initial 12 weeks of therapy (Spearman’s rank correlation range over different time points, 0.73–0.97). However, a delay of HCV RNA decay in PBMCs, expected if kinetics in PBMCs only reflected kinetics in plasma, was rarely observed. For many patients, HCV RNA decline in PBMCs started as early as in plasma and for some of them the kinetics strongly differed in the two compartments, hinting at a compartment-specific HCV replication and treatment effect. Fast viral decay in PBMCs was associated with sustained virological response, but viral kinetics in PBMCs added only minor predictive information compared with kinetics in plasma. Conclusions: Future kinetics studies of HCV RNA during therapy with new antivirals should take into account their compartment-specific effect. [Copyright &y& Elsevier]

The on-treatment virological response to pegylated interferon plus ribavirin therapy is a useful tool in the management of patients with chronic hepatitis C. The time at which hepatitis C virus RNA becomes undetectable by a sensitive PCR assay has a huge impact on the probability of achieving a sustained virological response, particularly in genotype 1 patients, and may be useful in selecting patients for prolonged therapy. Indiscriminate extension of treatment in patients with hepatitis C virus genotype 1 is not beneficial. However, there is a subgroup of patients – the so-called ‘slow responders’ – who benefit from extending treatment from 48 to 72 weeks and can be readily identified after 4–12 weeks of combination therapy. Thus, it is important to distinguish slow responders from null responders. In the TeraVIC-4 study virological relapse rates were significantly lower, and sustained virological response rates were significantly higher, in those treated for 72 weeks with peginterferon alfa-2a (40kDa) plus ribavirin (45% vs. 32% with 48 weeks, P =0.014). Patients are best served by quantitative determination of the hepatitis C virus RNA level at weeks 4, 12 and 24. The results of these determinations can then be used to tailor the length of therapy. [Copyright &y& Elsevier]

Background/Aims : Recombinant human albumin-interferon alfa (alb-IFN) is a novel 85.7-kD recombinant protein consisting of interferon alfa-2b genetically fused to human serum albumin. Methods : A phase 2, open-label, dose-ranging study was conducted in IFN-alfa-naïve patients with genotype 1 chronic hepatitis C to evaluate the antiviral activity, safety, and pharmacokinetics of alb-IFN. Fifty-six patients were enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts of 200, 450, 670, 900, and 1200μg. Results : A 2 log10 IU/mL or greater reduction in hepatitis C virus (HCV) RNA at Week 4 was observed in 69% (18/26) of patients who received the higher alb-IFN doses of 900 and 1200μg. The mean HCV RNA reduction at Week 4 in these two higher-dose cohorts was 3.2 log10 IU/mL. Modeling of viral kinetics demonstrated a biphasic response that was dose dependent. Adverse events were mostly mild to moderate in severity. The most common adverse events were headache (73%), chills (63%), fatigue (61%), and arthralgia (55%). The median terminal half-life was 141h consistent with previous alb-IFN data from IFN-alfa-experienced patients. Conclusions : Alb-IFN demonstrated significant antiviral activity and was well tolerated in patients with HCV genotype 1 infection. [Copyright &y& Elsevier]

Background/Aims: The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response. Methods: Serum HCV-RNA was frequently quantified in patients with chronic hepatitis C (n=270) treated with peginterferon alfa-2a (180μg/week) and ribavirin (1000–1200mg/day). After 6 weeks patients were classified as rapid (RVR), slow (SPR), flat (FPR), or null responders (NUR) and randomized within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy (48 weeks) or shorter combination therapy (24 weeks) for RVR, triple therapy with histamine (1mg/day) (48 weeks) or prolonged combination therapy (72 weeks) for SPR, triple therapy for FPR, and high-dose peginterferon (360μg/week) plus ribavirin for NUR patients. Results: Patients were categorized as RVR (n=171), SPR (n=65), FPR (n=10), or NUR (n=22). Overall end-of-treatment and sustained virologic response rates were 77 and 60% in the individualized and 77 and 66% in the standard treatment arm, respectively. Histamine in addition to peginterferon and ribavirin and high-dose peginterferon plus ribavirin did not improve virologic response rates in patients with FPR and NUR, respectively. Conclusions: An improvement in virologic efficacy was not achieved with the available individualized treatment options. [Copyright &y& Elsevier]

Background/Aims: Currently, there are no effective therapies available for patients with chronic hepatitis C who have failed to respond to optimal interferon alfa-based regimens. The aims of this pilot study were to assess the antiviral activity and safety of interferon gamma in chronic hepatitis C. Methods: Patients with chronic hepatitis C, genotype 1, who had not responded to or who had relapsed after therapy with interferon alfa and ribavirin were enrolled in a trial of interferon gamma 1b given in doses of 100, 200 or 400μg subcutaneously three times weekly for 4 weeks. Frequent blood samples were obtained for HCV RNA levels. Results: Fourteen patients were enrolled. Geometric mean HCV RNA levels remained unchanged. Serum aminotransferase levels also did not change, while there were significant decreases in neutrophil counts (−41% from baseline) and hematocrit (−5%). Low grade fever and malaise were common with the first injection of interferon gamma, but no serious side effects were encountered. Conclusions: Although relatively well tolerated, interferon gamma in doses of 100–400μg thrice weekly had no effect on HCV RNA levels in patients with chronic hepatitis C who had failed to achieve a sustained response to interferon alfa-based therapies. [Copyright &y& Elsevier]

Background/Aims: To elucidate the mechanisms of action of interferon (IFN) against hepatitis C virus (HCV), we studied the serum HCV dynamics of free-virions (FV) and immune-complexes (IC) in patients treated with IFN.Methods: FV and IC were separated by immunoprecipitation using anti-human immunoglobulin and quantified serially using real-time detection-polymerase chain reaction.Results: Initially [1st phase (0–24 h)], the FV decreased more rapidly compared to IC [exponential decay slope (EDS)=1.78±0.42 vs. 0.99±0.31 log10/day, P<0.001; half-life=5.65±2.02 vs. 12.5±2.83 h, P<0.0001], but at the 2nd phase (1–14 days), half-life of FV was significantly longer than that of IC (101±117 vs. 14.2±1.08 h, P<0.005). Regarding response to IFN, the decline slope was not significantly different at the 1st phase, but at the 2nd phase, the FV-HCV RNA decreased more slowly in non-responders than in sustained responders to IFN (EDS=0.05±0.02 vs. 0.34±0.19 log10/day, P<0.005; half-life=186±112 vs. 15.3±1.85 h, P<0.005).Conclusions: The presence of escape mutants from the neutralizing antibodies may be involved in resistance to IFN. Analyzes of FV- and IC-HCV dynamics are useful for predicting the IFN efficacy and understanding the mechanism of IFN action in chronic hepatitis patients. [Copyright &y& Elsevier]

Background/Aims: To address the molecular mechanism for enhanced antiviral efficacy associated with a frequent dosing of interferon (IFN)-beta.Methods: Serum hepatitis C viral (HCV) dynamics, double-stranded RNA-activated protein kinase (PKR) mRNA and MxA mRNA levels in peripheral blood mononuclear cells (PBMC) were analyzed serially in 140 patients who were randomly assigned to a twice daily (3 MU bid) or once daily (6 MU qd) administration group.Results: In twice daily group, the rate of HCV decline during the second phase was 2-fold greater than in the once daily group (P=0.04). Peak PKR and MxA gene expression levels in the first phase (observed 4 h after a single administration) were 2-fold higher in the once daily group. However, the expression in the second phase was maintained at a significantly higher level in the twice daily group. Initial and peak expression levels were related to initial viral load. Basal expressions in PBMC were significantly correlated with those in the liver tissue (PKR, r=0.81; MxA, r=0.75, respectively, P<0.0001).Conclusions: Our data suggest that elimination of HCV-infected cells is enhanced by twice daily dosing of IFN-beta, and that this enhanced effect is associated with a higher intracellular expression of PKR and MxA during the second phase. [Copyright &y& Elsevier]

Background/Aims: The mechanism of variable response to interferon (IFN) monotherapy in patients infected with HCV genotype 2a is still unclear. Here we investigated the response in a large group of patients infected with genotype 2a.Methods: We evaluated 394 consecutive non-cirrhotic naive patients infected with genotype 2a who received IFN monotherapy for 24 weeks, including initial aggressive induction therapy. Of these, 97 were also evaluated for early viral kinetics in serum and treatment efficacy.Results: The overall sustained response (SR) rate was 68.3% (viral load <1.0 Meq/ml (82.4%); ≥1.0 (52.4%)). Multivariate analysis identified five independent factors associated with SR; viral load <1.0 Meq/ml, total IFN dose ≥700 million units, hepatocyte steatosis none or mild, albumin ≥3.9 g/dl, and alanine aminotransferase ≥75 IU/l. The kinetic study showed that serum viral clearance at ≤1 week was the best predictor of SR, and persistence at ≥ 4 weeks was a predictor of non-SR.Conclusions: Our study suggests that viral, host and IFN treatment-related factors determine the response to IFN monotherapy in patients infected with HCV genotype 2a. Further, we report that IFN monotherapy is very effective for patients with genotype 2a, especially for those with low viral load; and that early viral kinetics is useful as a predictor of the response. [Copyright &y& Elsevier]

Background/Aims: Baseline factors and early decline in serum hepatitis C virus RNA are predictive of sustained virological response to interferon therapy in patients with chronic hepatitis C. We evaluated the prognostic value of baseline factors and early viral RNA among patients treated with peginterferon alfa-2a (40KD).Methods: Data were pooled from three randomized trials involving 814 patients treated with peginterferon alfa-2a (40KD) (90, 135, or 180 μg). Stepwise and multiple logistic regression identified independent baseline factors associated with response. Receiver operating characteristic curves for both absolute values and log10 decline in viral RNA at 4, 8, 12 and 24 weeks of therapy were created.Results: Independent prognostic factors for sustained virological response included viral genotype non-1, low pretreatment viral load, age (<40 years), no cirrhosis and body weight (<85 kg). In addition, alanine aminotransferase quotient (>3) and histological activity index score (>10) were also independently prognostic. Receiver operating characteristic curves showed that detectable or less than 2-log10 decline in viral RNA at week 12 predicted sustained virological non-response (negative predictive value is 98%).Conclusions: In patients with chronic hepatitis C treated with peginterferon alfa-2a (40KD), the decision to continue or stop treatment can be made as early as week 12. [Copyright &y& Elsevier]