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To elucidate the benefits of successful antiviral therapy in chronic hepatitis C (CHC) patients A total of 463 CHC patients who underwent pegylated interferon alfa and ribavirin therapy were classified as sustained virological response (SVR) or non-SVR based on response to antiviral therapy. We investigated disease progression to cirrhosis in non-cirrhotic patients, development of cirrhosis-related complications such as ascites, variceal bleeding, and hepatic encephalopathy in patients with cirrhosis, and development of hepatocellular carcinoma (HCC). Three hundred patients achieved SVR, and 163 were classified into the non-SVR group. The overall SVR rates were 64.8 %, and multivariate analysis showed that younger age, non-cirrhosis, HCV genotype 2 or 3, lower HCV RNA level (

Hepatitis B surface antigen (HBsAg) loss is the ideal clinical endpoint but is achieved rarely during oral antiviral treatment. A current unmet need in CHB management is achievement of HBsAg loss with a finite course of oral antiviral therapy, thereby allowing discontinuation of treatment. Significantly higher rates of HBsAg loss at 72 weeks post-treatment have been demonstrated when tenofovir disoproxil fumarate (TDF) was combined with pegylated interferon (PEG-IFN) for 48 weeks compared with either monotherapy. This analysis provides follow-up data at week 120.In an open-label, active-controlled study, 740 patients with chronic hepatitis B were randomly assigned to receive TDF plus PEG-IFN for 48 weeks (group A), TDF plus PEG-IFN for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or PEG-IFN for 48 weeks (group D). Efficacy and safety at week 120 were assessed.Rates of HBsAg loss at week 120 were significantly higher in group A (10.4%) than in group B (3.5%), group C (0%), and group D (3.5%). Rates of HBsAg loss and HBsAg seroconversion in group A were significantly higher than rates in group C (P 0.001 for both) or group D (HBsAg loss: P = 0.002; HBsAg seroconversion: P 0.001).The results of this analysis confirm the results from earlier time points which demonstrate the increased rate of HBsAg loss in patients treated with a finite course of PEG-IFN plus TDF compared with the rates in patients receiving either monotherapy.

The long-term trend of platelet count in chronic hepatitis C virus patients with sustained virological response (SVR) has rarely been investigated.To elucidate changes of thrombocytopenia after SVR, trajectory patterns of platelet count over time and their associated factors.From May 1999 to July 2005, a total of 135 patients (mean age 50.2 ± 11.1 years) that received interferon-α based regimen plus ribavirin were enrolled. Platelet counts were followed every 6 months prospectively. The patterns of platelet counts over time were identified by trajectory analysis.Mean follow-up duration was 4.4 ± 1.7 years (median 4.5; range 1.0-8.5 years). Baseline platelet count in all and thrombocytopenic patients increase significantly at the end of follow-up, from 172 ± 56 × 10(9)/l and 115 ± 21 × 10(9)/l to 196 ± 57 × 10(9)/l and 148 ± 37 × 10(9)/l, respectively (all p0.001). In patients with advanced fibrosis (n = 50), pretreatment platelet count also increased significantly (146 ± 45 × 10(9)/l vs. 173 ± 51 × 10(9)/l, p0.001). Twenty-six of 37 (69.2 %) patients with pretreatment mild thrombocytopenia (100-150 × 10(9)/l) had normalization of platelet count, while seven of 13 (53.8 %) patients with pretreatment moderate to severe thrombocytopenia (100 × 10(9)/l) had elevation of platelet count up to 100-150 × 10(9)/l. Three trajectory groups were identified, i.e., elevation (n = 43, 31.9 %), stationary (n = 79, 58.5 %), and decrease (n = 13, 9.6 %) groups. Multiple logistic regression showed pretreatment thrombocytopenia was the factor in elevation of platelet count (OR = 2.28, 95 % confidence interval = 1.01-5.11, p = 0.046).Platelet count increased significantly in patients with SVR after long-term follow-up. Patients with low baseline platelet count benefit more from SVR with respect to increased platelet count, compared to those with higher platelet count at baseline.

Sustained virologic response (SVR) to treatment of naive patients with chronic hepatitis C (HCV) with pegylated interferon and ribavirin is 50–60%. Patients who relapse have a poor response to re-treatment. We report a group of relapse patients with SVR to low-dose re-treatment after 6 months. Characterization of HCV relapse patients with very low viral load (VLVL) (HCV RNA

The response to pegylated interferon (peg-IFN) plus ribavirin therapy remains less than ideal with 40-50% of treated subjects failing to clear the virus. Moreover, retreatment is only minimally effective. Consensus interferon (c-IFN) has been shown to be efficacious in HCV genotype 1 patients who have failed therapy with peg-IFN.To evaluated the response to re-treatment of peg-IFN plus ribavirin partial-responders with c-IFN plus ribavirin.Forty-two subjects who had previously failed to clear virus after treatment with peg-IFN plus ribavirin were treated with c-IFN (15 μg/day) plus ribavirin (800-1,200 mg/day) until 12 months of therapy or a total of six consecutive months of PCR negativity was achieved.The study population consisted predominantly of males (71%), Caucasians (76%), with African Americans comprising the remaining 24%, subjects with HCV genotype 1 infection (81%) and 21% had cirrhosis by liver biopsy. The overall SVR rate was 29%. The only pretreatment variable that distinguished responders from partial-responders was the serum triglyceride level.The use of c-IFN plus ribavirin in the retreatment of prior peg-IFN plus ribavirin partial responders is essentially twice that achieved in prior re-treatment regimens consisting of a second course of peg-IFN plus ribavirin. These results will need to be evaluated against the use of triple therapy consisting of a peg-IFN plus ribavirin and a protease inhibitor. More studies utilizing c-IFN plus ribavirin with either a protease inhibitor or polymerase inhibitor need to be performed as well.

Sustained virological response (SVR) rates in patients with hepatitis C are heterogeneous and are influenced by a wide range of host and viral factors.To evaluate the efficacy of combination therapy with pegylated interferon alfa (PEG-IFN-α) and ribavirin (RBV), and document the SVR rates taking into consideration various predictive factors in patients with chronic hepatitis C (CHC) genotype 3.Ninety-seven treatment-naive patients with CHC genotype 3 (mean age 41.46±11.51 years, M:F ratio 79:18), who received a combination of PEG-IFN (α-2a or α-2b) and RBV were retrospectively analyzed (2006-2008) for the early virological response (EVR) at 12 weeks, end of treatment response (ETR), and SVR at 6 months.Eighty-four (86.6%) patients achieved EVR and 81 (83.5%) achieved ETR, while SVR was achieved in 65 (67.0%) patients. Of the 84 patients who achieved EVR, 77 (91.7%) achieved ETR and 61 (72.6%) achieved SVR at 6 months. Age and body mass index (BMI) were found to be important predictors (*P0.05) of SVR. CHC patients with a history of alcohol intake showed decreased SVR (52%) (*P=0.035) as compared to nonalcoholics (80%). Cirrhotic versus noncirrhotic patients showed no difference in SVR (54.5% vs. 70.7%) (P=0.157). Serum alanine aminotransferase (ALT) (P=0.169) and hepatitis C virus (HCV) RNA levels (P=0.42) also did not have an influence on the SVR.Combination therapy with PEG-IFN-α and RBV demonstrated good tolerability in CHC genotype 3 infection. Age, BMI, and alcohol consumption play an important role in determining treatment outcome.

Pegylated interferon (PEGIFN) and ribavirin combination is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. Studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV-infected patients have shown conflicting results.We performed a systematic review and meta-analysis of studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in HCV-infected patients naïve to treatment.Nine studies (five abstracts) with 3,546 patients (1,771 treated with PEGIFN alfa-2a) comparing PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV patients were analyzed. Efficacy outcomes were sustained virologic response (SVR) and treatment discontinuation rates due to serious adverse effects (SAE).Pooled data on outcomes (reported as odds ratios [ORs] with 95% confidence intervals [CIs]: [OR (95% CI)]) showed higher SVR in patients treated with PEGIFN alfa-2a as compared to treatment with PEGIFN alfa-2b [1.36 (1.07-1.73); P=0.01]. Subgroup analysis of good quality studies on SVR in genotypes 2 and 3 also favored PEGIFN alfa-2a over PEGIFN alfa-2b (1.91 [1.09-3.37]; P=0.02). SVR results obtained with the two types of IFN showed no impact of viral load and the presence or absence of cirrhosis. Treatment discontinuation rates due to SAE, reported in six studies (two abstracts) on 3,211 patients (1,604 treated with PEGIFN alfa-2a), were similar in the two types of PEGIFN [0.66 (0.37-1.16); P=0.15].PEGIFN alfa-2a has superior efficacy with higher SVR as compared to PEGIFN alfa-2b in treatment-naïve HCV-infected patients. The safety profile of the two types of PEGIFN was similar.

Studies of the retreatment with consensus interferon (CIFN) and ribavirin (RBV) of hepatitis C virus (HCV)-infected patients who failed prior pegylated interferon alfa/ribavirin (PEG-IFN/RBV) have found quite variable efficacy and tolerability of this therapy. As such, CIFN/RBV use and efficacy in clinical practice were evaluated within the Department of Veterans Affairs (VA), the largest national, integrated system for HCV care.The purpose of this study was to determine rates of sustained virologic response (SVR) and patterns of CIFN/RBV use in the VA. Methods included retrospective review of national VA data in HCV-infected patients who had previously failed≥12 weeks of PEG-IFN/RBV and were prescribed CIFN/RBV between October 1, 2003 and September 30, 2006.A total of 597 patients met the study criteria. CIFN was primarily dosed as 15 mcg subcutaneously daily combined with standard doses of RBV. Mean treatment duration was 21 weeks; CIFN was discontinued within 4 weeks in 24%. Hematological growth factors were used in 49%. Post-treatment viral loads were available in 385 patients. SVR to CIFN/RBV was achieved in 11%, and was significantly higher in prior PEG-IFN/RBV relapsers compared with nonresponders (31% vs. 6%, respectively; P0.0001). A 2-log10 or greater drop in HCV RNA after 24 weeks of PEG-IFN/RBV was a predictor of subsequent SVR to CIFN/RBV.CIFN/RBV was used frequently in clinical practice for retreatment of PEG-IFN/RBV. In this setting, early treatment discontinuation was common. Overall SVR was low, although response was significantly better in prior PEG-IFN/RBV relapsers and those who had a 2-log(10) or greater decline than in nonresponders.

Background Patients with chronic hepatitis C genotype 1 (HCV-1) and difficult-to-treat characteristics respond poorly to pegylated interferon alfa and ribavirin (RBV), and could benefit from an interferon with increased activity (consensus interferon or CIFN), favorable viral kinetics from daily dosing, and a longer duration of therapy. The purpose of this pilot study was to determine the efficacy and safety of daily CIFN + RBV for initial treatment of patients with HCV-1 infection. Methods Patients with difficult-to-treat characteristics (92% male, 33% African American, 78% Veterans Affairs [VA]; 67% high viral load, 59% stage 3–4 fibrosis, and mean weight of 204 lbs) were enrolled at seven VA and two community medical centers. They were randomized to daily CIFN (15 mcg/day SQ) and RBV (1–1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52–72 weeks (from time of viral response +48 weeks) (group B, n = 31). Results Intention to treat analysis for treatment groups A and B demonstrated 33% (11/33) and 32% (10/31) sustained virologic response (SVR), respectively. Only 2/31 patients in group B received more than 52 weeks of treatment. The overall group demonstrated a 31% (20/64) rapid virologic response rate (RVR), 54% (34/64) end of treatment virologic response and a 33% (21/64) SVR. Patients with RVR at 4 weeks, early virologic response from 8–12 weeks, and late virologic response from 16–24 weeks demonstrated SVR of 75% (15/20), 31% (4/13), and 22% (2/9), respectively. Overall early non-protocol discontinuation occurred in 26/64 (40%) patients. Conclusion Daily CIFN and ribavirin for initial treatment of HCV-1 patients has potential for achieving a relatively high RVR rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence.

Hepatic steatosis in hepatitis C virus (HCV)-infected patients has been shown to enhance the progression of liver fibrosis and decrease the response to antiviral therapy. We aimed to determine the role of HCV genotype 4 (HCV-G4) in the prevalence of hepatic steatosis, its impact on antiviral therapy, and its associations and predictive factors in comparison to HCV-G1-infected patients. Treatment-naive HCV patients who were started on pegylated interferon a-2b plus ribavirin therapy in two centers in Saudi Arabia were included. The severity of steatosis was assessed using the METAVIR and NAS (non-alcoholic fatty liver disease [NAFLD] activity score) scoring systems. Sustained virological response (SVR) was studied in relation to the degree of steatosis. Associations between steatosis and multiple demographic, laboratory, and virological factors were examined. HCV-G1 and HCV-G4 patients were compared. A total of 116 patients (HCV-G4 85 [73.3%]; HCV-G1 31 [26.7%]) were included. The mean age was 50.4 ± 10.7 years and 56.9% were males. In terms of steatosis grading using the NAS scoring system, 50% had steatosis grade 0, 26.7% grade 1, 14.7% grade 2, and 8.6% grade 3, while the overall staging of steatosis revealed that 43.1% had mild steatosis, 42.2% moderate, and 14.7% severe. Gamma-glutamyl transpeptidase (GGT), platelet count, body mass index (BMI), cholesterol level, presence of hyperlipidemia, liver histology stage, and grade were significantly correlated with hepatic steatosis in one or more of the statistical analyses. Twenty-two out of 55 patients (40.0%) had an SVR in the mild steatosis group, compared to 52.7% in the moderate group and 7.3% in the severe group (P = 0.03). The HCV genotype did not correlate with steatosis or SVR. Our study confirms the high prevalence of steatosis in HCV-G4 and HCV-G1 patients, but with no difference in the grade or score of steatosis between the two genotypes. The grade of steatosis correlates with GGT, platelet count, and BMI, while the NAS score of steatosis correlates with response to antiviral therapy.

Elderly patients with chronic hepatitis C virus (HCV) infection represent an understudied population, and little is known regarding the predictive factors for sustained virological response (SVR) to antiviral therapy in these patients. To evaluate the efficacy of pegylated interferon (PEG-IFN) and ribavirin therapy in chronic HCV patients aged 65 years, and identify pre- and on-treatment predictors of SVR. We studied 57 patients aged ≥65 years who underwent PEG-IFN and ribavirin treatment, evaluating the SVR rate and its association with pre-treatment demographic, clinical, biochemical, and virological parameters. Furthermore, we assessed whether 12-week serum HCV-RNA assessment might predict SVR. A SVR was obtained in 25 patients (45%). The only pre-treatment predictor of SVR was HCV genotype 2 and 3 (P = 0.02). A positive serum HCV-RNA or a decline in viral load ≤2log10 at week 12 had 100% negative predictive value for SVR. No major liver-related events or deaths occurred during therapy. Treatment was discontinued due to side effects—mainly cardiovascular—in 10 patients (17%). Pre- and on-treatment virological parameters can be used to identify elderly patients who are more likely to obtain a SVR to standard-of-care antiviral therapy for chronic HCV infection.

Background The recurrence of hepatitis C virus (HCV) after liver transplantation (OLT) leads to recurrent cirrhosis in up to 40% of patients. Aims To identify patients who profit the most from antiviral therapy and to delineate whether early treatment after OLT is effective to reach sustained virological response (SVR), we analyzed factors associated to SVR during pegylated interferon/ribavirin (PegIFN/RBV) therapy. Methods A retrospective analysis of efficiency and viral decline kinetics in 83 HCV-infected liver transplant recipients who received therapy with PegIFN/RBV was carried out. Results Forty-one of 83 (49.4%) patients became HCV RNA-negative. SVR was achieved in 26/83 (31.3%) patients. Viral decline of at least 2 log 10 (n = 47) at week 12 was significantly associated with an end-of-treatment (EOT) response. Eleven early viral response patients were not able to clear HCV RNA, whereas five patients without a 2 log decline achieved SVR. The highest predictive value for SVR was an undetectable viremia at week 24 (92%). Conclusions The outcome of antiviral combination therapy for HCV reinfection after OLT can be best predicted by week-24 virologic response. The high SVR rates in patients with detectable HCV RNA at week 12 might suggest a prolonged treatment protocol in liver transplant recipients.

Cyclosporine has antiviral activity in vitro against hepatitis C (HCV). We performed a pilot study to prospectively determine the antiviral effect of cyclosporine during therapy with PEGalfa-2a and ribavirin in liver transplant recipients with recurrent HCV infection. Patients with HCV recurrence (Ishak Fibrosis Stage ≥ 2) were enrolled for 2 years at the University of Florida. Thirty-eight patients were randomized to continued tacrolimus or switched to cyclosporine. Both groups received PEGalfa-2a and ribavirin. Twenty patients received tacrolimus and 18 cyclosporine, with a mean age of 53. Eighty-two percent were men, 84% Caucasian, and 90% genotype 1. In patients switched from tacrolimus to cyclosporine, HCV-RNA levels decreased by a mean of 0.39 million IU/ml during the 1 month prior to initiating PEG/RBV. Sustained viral response for cyclosporine was higher than in patients on tacrolimus receiving PEG/RBV therapy. This randomized controlled pilot study is the first in vivo study evaluating cyclosporine versus tacrolimus in liver transplant recipients undergoing antiviral therapy. Change from tacrolimus to cyclosporine led to a modest HCV RNA drop and appeared to enhance the antiviral response of PEG/RBV. A larger randomized study is necessary to see if cyclosporine offers any advantage over tacrolimus.

Patients with advanced fibrosis are at increased risk of severe outcomes if they develop acute infection with hepatitis A (HAV) or hepatitis B (HBV) viruses. There are no data on the efficacy of combined HAV/HBV vaccination in patients with advanced fibrosis. Our aim was to evaluate the response to the HAV and HBV vaccine alone or in combination for patients with chronic hepatitis C (HCV) and advanced fibrosis and to evaluate the impact of administering the vaccine while patients were receiving peginterferon for treatment of chronic HCV. In this prospective study of patients with advanced fibrosis (Ishak 3-6), those without serologic evidence of prior exposure were vaccinated with either Havrix HAV, Engerix( HBV, or the TWINRIX HAV/HBV combination vaccine as appropriate, and response was defined as the development of anti-HAV or anti-HBV surface antibodies. Of the 162 eligible patients, the prevalence of prior exposure to HAV and HBV was 30 and 18%, respectively. Of the 84 patients vaccinated, 38% received Havrix, 14% Engerix, and 48% TWINRIX. The response to the HAV vaccine was 75% in those receiving Havrix compared to 78% receiving TWINRIX. In contrast, the response to HBV vaccination was 42% in patients receiving Engerix compared to 60% in those vaccinated with TWINRIX (difference 18.3%; OR 0.29; 95% CI: 0.57-7.79). The presence of diabetes was the only risk factor identified for reduced HBV response (P = 0.01). Responses to both HAV and HBV vaccines when administered alone or in combination were lower than expected in patients with HCV and advanced fibrosis, especially in those with diabetes. The observation that the decline in HBV vaccine response was somewhat lower when this was administered alone as opposed to the combination A/B vaccine suggests that the administration of a combination vaccine may enhance the vaccination response to HBV.

Contains fulltext : 89709.pdf (Publisher’s version ) (Closed access) Combination of peginterferon and ribavirin is the current therapy for chronic hepatitis C infection (HCV). Interstitial pneumonitis is a rare side-effect of HCV therapy and is an important cause of dose reduction or discontinuation, impairing success of antiviral therapy. We performed a review of the literature in order to present diagnostic modalities and possible treatments for pneumonitis and to offer guidelines. We searched for cases where pneumonitis as a side-effect of HCV treatment was documented. First we performed a literature search via PubMed and Web of Science interface and second we searched three drug toxicity databases. We systematically analyzed all case reports with respect to clinical manifestations, type of treatment, and outcome. A literature search revealed 19 articles, containing 25 case descriptions, while we traced 33 cases from the drug toxicity databases. Pneumonitis presented with any of the combination of fever, dyspnea, and cough and can arise with any type of (conventional or pegylated) interferon. Mortality secondary to pneumonitis was seen in 7% of cases, exclusively with peginterferon alpha-2b. In most cases therapy was discontinued and steroids were started. Interferon-induced pneumonitis during HCV treatment is a severe complication and should be recognized in order to prevent further pulmonary damage and/or death. 01 maart 2010

Insulin resistance is a candidate predictive factor for virological response to peginterferon plus ribavirin (PEG/RBV) therapy in chronic hepatitis C patients. We examined whether indices of insulin resistance could serve as a predictor of sustained virological response (SVR). Fifty-one patients with genotype 1b and high viral load who received PEG/RBV therapy for 48 weeks were included. Homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI) calculated from the 75-g oral glucose tolerance test and serum levels of soluble tumor necrosis factor receptor 2 (sTFNR2) were evaluated before therapy. Patients who achieved SVR had significantly lower HOMA-IR and sTNFR2 levels and a higher WBISI compared with non-SVR patients. The positive predictive value for SVR was 0.653 for a HOMA-IR of

Chronic hepatitis C (CHC) is the most common cause of chronic liver disease and is the leading cause of liver transplantation in the United States [1, 2]. It is a progressive disease that can lead to cirrhosis, liver failure, hepatocellular carcinoma, and death [1, 2]. Hence, it is very important that the disease be treated in its early stages, with the goal of obtaining sustained virologic response, which will effectively reduce the morbidity and mortality associated with this disease. The currently approved therapy for CHC is pegylated interferon plus ribavirin for 24 weeks or 48 weeks, based upon genotype [3]. The use of pegylated interferon and ribavirin combination therapy is associated with many side effects, and close monitoring of patients is required while they are on the therapy. We report an unusual case of marked flares in hepatic aminotransferases during each of two consecutive courses of pegylated interferon and ribavirin therapy for CHC genotype 2. There are very limited published data on the hepatotoxicity or liver enzyme flares associated with interferon therapy. In earlier data from a large retrospective study performed on 11,241 patients with chronic viral hepatitis (80% being CHC) treated with alfa interferon, only four patients had fatal side effects due to liver failure, and all four patients demonstrated a significant rise in aminotransferase levels [4]. It is possible that large, prospective, clinical trials may have revealed individual cases similar to our case but were not individually reported. Interferon maintenance trials, such as Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) and Colchicine versus Peg-Intron Long-Term (COPILOT) may ultimately demonstrate transient alanine aminotransferase (ALT) flares, but these include predominantly nonresponder subjects and have not yet been published. Moreover, natural flares of serum ALT values in CHC patients are not very well-defined.

Background and aim Viral load is used for the diagnosis and monitoring the treatment of chronic hepatitis B (CHB). These methods are molecular-based and are expensive. Previous studies suggest that quantitative hepatitis B surface antigen (HBsAg) studied by automated chemiluminescent microparticle immunoassay can be a surrogate marker. In this study, we aimed to investigate whether quantitative HBsAg correlates hepatitis B virus (HBV) DNA levels during CHB treatment. Methods The study included 18 patients (13 male, 5 female, mean age: 33 ± 9 years) with CHB. They were given pegylated interferon ± lamivudine for 52 months and serum samples were obtained in weeks 0, 4, 8, 24, 48, 52, and 76. HBV DNA was measured by TaqMan polymerase chain reaction (PCR; Erasmus MC, University Medical Center, Rotterdam, The Netherlands). Quantitative HBsAg was studied by automated chemiluminescent microparticle immunoassay (Architect HBsAg, Abbott, IL). Results HBV DNA levels were measured as follows: 9.66, 7.69, 7.06, 5.93, 5.89, 5.88, and 7.27 logarithmic genome equivalent/ml, respectively. The corresponding HBsAg quantitation results were 42,888, 31,176, 37,882, 27,277, 28,279, 29,471, and 31,535 IU/ml, respectively. They showed a significant correlation (canonical correlation = 0.85). Conclusions HBsAg studied by automated chemiluminescent microparticle immunoassay correlates with HBV DNA and can be a surrogate marker during the monitoring of the efficacy of HBV treatment.

In a prospective therapeutic trial, features of the hepatitis C quasispecies were investigated as possible markers of therapeutic response. Individuals chronically infected with hepatitis C genotype 1 received antiviral therapy consisting of alpha-interferon plus ribavirin. The study targeted the most rapidly evolving segment of the viral genome, hypervariable region 1 within the envelope-2 gene. Among individuals failing to clear virus in response to therapy, significant differences were observed between quasispecies of African-American and Caucasian subjects. While distance measures for synonymous substitutions were similar between racial subgroups, measures of distance at the amino acid level (nonsynonymous substitutions) varied significantly. Taken together, the observed patterns of variability corresponded to reduced host selection pressure against hypervariable region 1 in African-American nonresponders. Reduced selection pressure was present at baseline and persisted through treatment and follow-up, suggesting population stratification of host factors that influence selection pressure on hepatitis C virus.

The lower limit of detection of most polymerase chain reaction (PCR) assays for hepatitis C virus (HCV) RNA is 50 IU/ml, compared to 5 IU/ml for the transcription-mediated amplification (TMA) method. We retrospectively reviewed 57 patients to assess the predictive value of a positive TMA in the setting of a negative PCR during antiviral therapy. Patients were divided into (1) PCR-/TMA+ (discordant; n=21) and (2) PCR-/TMA-(concordant; n=36). Sustained virologic response (SVR) was decreased in the discordant group (48% vs. 75%; P=0.04). In discordant patients, SVR was more frequent in patients who had one positive TMA than in those who had two or more positive TMAs or one positive TMA and recurrent HCV RNA detectability by PCR during treatment (78% vs. 25%; P=0.03). Breakthrough occurred more frequently in discordant patients (24% vs. 3%; P=0.02). A positive TMA on two or more occasions in patients who have become PCR-negative on therapy indicates a high likelihood of treatment failure.

Currently, there are limited therapeutic options available for chronic hepatitis C (HCV) patients who fail treatment with peginterferon alpha (PEG IFN) + ribavirin (RBV). An option is retreatment with a second course PEG-IFN + RBV. However, the virologic clearance with this option is unknown. Thus, we evaluated the outcome of our cohort of patients with chronic HCV who achieved a sustained viral response when retreated with PEG IFN plus RBV after having no response to an initial course of PEG IFN plus RBV. Nonresponse to treatment was defined as failure to achieve an early virologic response by week 12 or presence of detectable HCV RNA at week 24 or after completion of PEG-IFN + RBV therapy. Twenty patients (12 [60%] men; 8 [40%] women) were treated with PEG IFN alpha-2b plus RBV and PEG IFN alpha-2a plus RBV. The mean age of the patients was 50 years, 85% were white, 95% had genotype 1, and 35% had cirrhosis. Prior to the first course of PEG IFN plus RBV, 12 (60%) of 20 patients had no prior treatment for Hepatitis C. After the second course of PEG IFN plus RBV, 2 (10%) of 20 patients achieved a sustained virologic response. These results suggest marginal benefit of retreatment of patients with chronic HCV with another course of PEG IFN plus RBV after they have not responded to an initial course of PEG IFN plus RBV.

Hepatitis C virus (HCV) infection refractory to previous therapy is common. Treatment of patients with refractory disease is difficult and less studied. Pegylated interferon alpha-2b plus ribavirin is used for treatment of HCV patients naïve to therapy. We conducted a randomized study for refractory HCV patients using a high- vs. a low-dose pegylated interferon alpha-2b and ribavirin protocol. Our aim was (1) to determine the efficacy of pegylated interferon alpha-2b plus ribavirin to eradicate HCV in previously treated individuals and (2) to compare a low-dose to a high-dose regimen. One hundred fifty-two patients were initiated in the study, 112 (74%) were male and 40 (26%) female. Nineteen percent of patients obtained a sustained viral response (SVR) in the high-dose arm. Prior relapsers had the highest SVR rates: 50% in non-genotype 1 and 34% in genotype 1. The odds of achieving a SVR were six times higher in previous relapsers. The rate of SVR in genotype 1 patients who were nonresponders to prior therapy was only 8%. All patients who achieved a SVR had no detectable virus at week 24. However, only half of those who had undetectable viral titers at week 24 achieved a SVR. In conclusion, retreatment of patients with refractory hepatitis C infection with interferon alpha-2b and ribavirin combination therapy is well tolerated and gives modest response rates. The most important factor in predicting response to therapy is the manner of response to previous treatment. The likelihood of response to treatment can be predicted from the viral titers at 24 weeks.

Registration trials regarding pegylated interferon treatment of hepatitis C have created great expectations for improved results, but there is little information on actual outcomes in everyday hospital practice. We aimed to define the effectiveness of this treatment in a hospital setting. Seventy-four naïve patients with hepatitis C treated with 12 kD-pegylated-interferon-alpha-2-b/ribavirin (PEG-IFN) were retrospectively analyzed in comparison with 54 patients treated with IFN-alpha-2-b/ribavirin (STANDARD IFN) and with results of three main registration trials. Overall sustained viral response rates were 46% in the STANDARD IFN group and 54% in PEG-IFN group, ranging from 48-61% in similar arms of the registration trials considered, although more of our patients presented comorbidity and high-grade fibrosis, and our dosages at outset of PEG-IFN were lower than optimal (mean 1.18 microg/kg BW). In our hospital setting, the effectiveness of PEG-IFN/ribavirin therapy appeared similar to that reported in large registration trials.

The object of this study was to evaluate the viral factor, especially the quasispecies, as predictive of sustained virologic response. We studied the quasispecies, genotype, viral load, and hepatitis C (HCV) cAg in 41 patients with chronic hepatitis C treated with interferon and in 84 with interferon and ribavirin. In the interferon group, responders presented a lower viral load. From logistic regression analysis of patients treated with interferon plus ribavirin, independent predictors for sustained virologic response were genotype 3a, a low baseline viral load andor=3 bands quasispecies. Genotype and viral load presented higher specificity and positive predictive value than did quasispecies. In patients with genotype 1, viral loador=5 x 10(5) IU/mL andor=3 quasispecies were predictive for sustained virologic response. In conclusion, the predictive factors of virologic response are genotype, viral load, and quasispecies. Quasispecies did not improve on the genotype or the viral load as predictors of virologic response.

Despite major advances in therapy of hepatitis C over the past decade, nearly half of the patients treated with the currently available regimens do not clear the virus. Therefore, there is a large unmet need for more effective therapy for patients who have failed pegylated interferon plus ribavirin therapy. We describe a case of a HCV genotype 1b patient who had failed previous combination therapies of interferon plus ribavirin and pegylated interferon plus ribavirin and was subsequently successfully treated with a novel triple drug combination consisting of interferon-gamma plus interferon alfacon plus ribavirin with the outcome of a sustained virologic response. This triple drug therapy combination could be an option for patients who have failed therapies with currently available pegylated interferons plus ribavirin. Prospective randomized studies are required to evaluate the effectiveness and tolerability of this regimen in this patient population.

It is known that there is a very high incidence of hepatocellular carcinoma (HCC) among patients with type C chronic hepatitis and cirrhosis, and alpha -fetoprotein (AFP) has been widely used as a diagnostic marker for HCC. However, there are some patients showing continuous high AFP values but no evidence of HCC, and some studies have defined such patients as a high-risk group for HCC. In vitro study has shown that interferon (IFN) inhibits cell proliferation and enhances apoptosis as well as specific cytotoxic T lymphocytes against HCC, resulting in direct anticancer actions. In this study, we investigated the effect of IFN on AFP changes in chronic hepatitis C patients. Of 40 patients with chronic hepatitis C in whom diagnostic imaging confirmed the absence of HCC, 24 patients showed high pretreatment AFP values (high AFP group: AFP level10 ng/dl; mean +/- SD, 46.3 +/- 41.5 ng/dl) and 16 showed low pretreatment AFP values (low AFP group: pretreatment AFP levelor = 10 ng/dl; mean +/- SD, 5.3 +/- 2.2 ng/dl). Pretreatment clinical parameters were statistically evaluated in relation to the AFP value. In the high AFP group, the platelet count, albumin level, and prothrombin (%) were significantly lower (P = 0.047, P = 0.0002, and P = 0.044, respectively), suggesting that AFP value increases with advancing liver disease. Subsequently 27 patients were administered IFN (IFN group), and the remaining 13 patients were administered Stronger Neo-minophagen C (SNMC), a glycyrrhizin preparation (SNMC group), as a control group receiving liver-protective therapy. Alanine aminotransferase was reduced in both the IFN and the SNMC group (mean, 132.56 to 60.07 mg/ml [P0001] and 147.85 to 56.23 mg/ml [P = 0.0240], respectively). AFP was significantly reduced in the IFN group (mean, 30.03 to 12.65 ng/ml; P = 0.0034), but there was no significant change in AFP in the SNMC group (mean, 29.70 to 39.17 ng/ml). AFP is useful for diagnosing HCC; however, some patients show a persistently high AFP level in the absence of HCC, and these patients have been described as a high-risk group for HCC. In this study, we found that IFN therapy but not SNMC universally reduced the AFP baseline. Since AFP is a significant predictor for HCC, therapeutic strategies for hepatitis C, e.g., long-term low-dose IFN treatment, may reduce hepatocarcinogenesis.

To elucidate the influence of a glycyrrhizin therapy on hepatocarcinogenesis rate in interferon (IFN)-resistant hepatitis C, we retrospectively analyzed 1249 patients with chronic hepatitis with or without cirrhosis. Among 346 patients with high alanine transaminase value (twice or more of upper limit of normal), 244 patients received intravenous glycyrrhizin injection and 102 patients did not, after judgment of IFN resistance. Crude carcinogenesis rates in the treated and untreated group were 13.3%, 26.0% at the 5th year, and 21.5% and 35.5% at the 10th year, respectively (P = .0210). Proportional hazard analysis using time-dependent covariates disclosed that glycyrrhizin treatment significantly decreased the hepatocarcinogenesis rate (hazard ratio 0.49, 95% confidence interval 0.27-0.86, P = .014) after adjusting the background features with significant covariates. Glycyrrhizin injection therapy significantly decreased the incidence of hepatocellular carcinoma in patients with IFN-resistant active chronic hepatitis C, whose average aminotransferase value was twice or more of upper limit of normal after interferon.

Currently available prognostic tools are inadequate to discern the molecular basis of the heterogenic response in hepatitis C virus (HCV)-infected patients treated with the current standard of therapy. The expression and biological function of immune mediators have been shown to be critical in all phases of the immune response to HCV infection and likely therefore influence host response. Herein, a biometric multiplex serum cytokine assay was utilized to characterize the immunomodulatory effects of host response in 10 HCV patients. Serum levels of 17 cytokines were compared before and after 1 month of treatment and against controls. Overall serum cytokine levels were significantly higher in patients (P < 0.05) than controls. Additionally, viral titers decreased in all patients after 1 month of therapy, as did overall serum cytokine levels in the cohort (P < 0.05). To assess relationships between changes in cytokine levels and changes in viral titer, the cohort was divided into three statistically distinct subgroups based on changes in viral titers. Specific sets of cytokines decreased in each group: decreases in CCL4, interleukin (IL)-2, CXCL8, and IL-1β correlated with the greatest drops in viral titer, decreases in IL-5, granulocyte colony stimulating factor (G-CSF), and CCL4 correlated with moderate drops in viral titer, and only CCL2 correlated with the lowest drops in viral titer. Interestingly, decreases in CCL4 levels correlated with decreases in viral titers in all patients. CCL4 controls leukocyte influx and thus propagates inflammation. In conclusion, these data raise the possibility that characteristic changes in host response modulate the therapeutic response, demonstrating the prognostic power of serum cytokine profiling in chronic HCV.

In an attempt to improve the efficacy of antiviral therapy for chronic hepatitis C, a three-drug combination of pegylated interferon alpha-2b, ribavirin, and amantadine has been suggested. Despite the initial enthusiasm, the role of amantadine in the treatment of chronic hepatitis C remains controversial. In a multi-center, open-label clinical trial, the potential efficacy and safety of this triple combination regimen were assessed. In this open-label pilot study, two separate patient populations with chronic hepatitis C and viremia were enrolled: treatment-naive and those who had failed a previous course of treatment. Patients were started on pegylated interferon alpha-2b at a dose of 1.5 microg/kg weekly with ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for 4 weeks, followed by pegylated interferon alpha-2b, 0.5 microg/kg weekly, ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for another 20 weeks. Patients with undetectable HCV RNA at week 24 continued this regimen for a total of 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (50 IU/mL) after 24 weeks of follow-up were considered to have SVR. Health-related quality of life and safety data were also collected. Sixty-nine treatment-naive and 99 nonresponder patients with chronic hepatitis C were enrolled in the study. Of all patients enrolled, 74% were male, aged 47.27+/-5.76 years; their body mass index (BMI) was 28.87+/-5.05 kg/m2, 79.4% were white, 85% had HCV genotypes 1 and 4, and 36% had cirrhosis. Their baseline HCV RNA was 689,242+/-698,030 IU/mL, with a baseline ALT of 107.25+/-79.08. Of the entire cohort, 35 (21%) discontinued early due to side effects or loss to follow-up. Significant anemia (hemoglobin,10 g/dL) occurred in 11% (19/168), while severe anemia (hemoglobin,8.5 g/dL) occurred in 0.6% (1/168). In the treatment-naive group, sustained virologic response (SVR) was 34.3%, versus 19.4% for the group who had previously failed to respond to a course of treatment (P = 0.01). For both groups combined, virologic response after 24 weeks of therapy was 40.5%, with an end-of-treatment virologic response of 35.7% and a SVR of 26.2%. Patients with genotypes 1 and 4 had lower response rates than those with genotypes 2 and 3 (SVR, 21 vs. 46%; P = 0.001). Patients with advanced fibrosis (Metavir stages 3 and 4) tended to have lower response rates than those with minimal or mild fibrosis (Metavir stages 0-2) (SVR, 10 vs. 30%; P = 0.08). African-American patients with HCV had lower response rates than Caucasians or other ethnic groups (SVR, 4 vs. 29 vs. 20%; P = 0.04). Age, gender, and BMI did not affect SVR. The addition of amantadine to pegylated interferon alpha-2b and ribavirin does not seem to increase the efficicacy of this regimen.

Despite advances in the therapy of chronic hepatitis C, a large number of patients do not respond to current therapies. The study objective was to assess whether a combination of interferon (IFN) alfacon-1 and ribavirin improves the response rate compared with a combination of INF alpha-2b and ribavirin in chronic hepatitis C subjects. The study was designed as an open-label, prospective, randomized, controlled study; 128 subjects with chronic hepatitis C were randomized to INF alfacon-1, 15 microg three times per week, plus ribavirin, 1 g/day, or IFN-alpha2b, 3 million units three times per week, plus ribavirin, 1 g/day for 48 weeks. The end point of the study was a sustained viral response, defined as undetectable HCV RNA at 24 weeks post 48 weeks of treatment. Overall, 57% of subjects in the INF alfacon-1/ribavirin group achieved a sustained antiviral response, compared with 40% of subjects in the IFN-alpha2b/ribavirin group (P = 0.052). In the subset of subjects with a high viral load, HCV RNA was successfully eradicated in more individuals who received INF alfacon-1/ribavirin than subjects who received IFN-alpha2b/ribavirin (57 versus 31%; P = 0.025). Among individuals with genotype 1 and a high viral load, the sustained antiviral response was significantly higher with INF alfacon-1/ribavirin than with IFN-alpha2b/ribavirin (46 versus 14%; P = 0.019). Adverse events were similar in both treatment groups. In conclusion, this study demonstrated that the combination of INF alfacon-1 and ribavirin provides a significantly better treatment response compared with the combination of IFN-alpha2b and ribavirin in chronic HCV subjects infected with genotype 1 and a high viral RNA load.

There are no established therapeutic regimens for hepatitis C virus (HCV) patients who relapse following treatment with interferon alpha-2b and ribavirin or those who break through while on interferon alpha-2b and ribavirin. We therefore evaluated various combination therapies in HCV patients who relapsed or experienced a viral breakthrough. Patients (n = 124) were randomized to 48 weeks of treatment with once-weekly subcutaneous injections of 180 microg pegylated (peg-) interferon alpha-2a plus oral ribavirin (800-1000 mg/day), mycophenolate mofetil (2 g/day), amantadine (200 mg/day), or ribavirin and amantadine and followed for an additional 24 weeks. The sustained virologic response was higher in patients administered peginterferon alpha-2a plus ribavirin (38%) or ribavirin and amantadine (45%) than in those administered peginterferon alpha-2a plus mycophenolate mofetil (17%) or amantadine (10%). As in previous studies, patients with genotype non-1 and those with lower viral loads had better responses than those with genotype 1 and high viral loads, though the differences did not reach significance. The four treatment regimens had similar safety profiles, except that patients receiving ribavirin had greater maximal hemoglobin decreases. These findings suggest that the combination of peginterferon alpha-2a plus ribavirin or with ribavirin and amantadine is effective in some HCV patients who relapse after treatment with interferon alpha-2b plus ribavirin.

Acute pancreatitis is a rare complication of interferon (IFN) and ribavirin (RBV) therapy. The aim of this study was to determine the incidence, clinical presentation, and outcome of acute pancreatitis in patients with chronic hepatitis C virus (HCV) infection treated with IFN and RBV combination therapy. We conducted a retrospective review of 1706 HCV-infected patients treated with IFN alpha-2b and RBV. The diagnosis of drug-induced acute pancreatitis was made based on the presence of epigastric pain, elevated amylase and lipase levels, and the absence of other identifiable causes of pancreatitis. Acute pancreatitis was diagnosed in 7 of 1706 HCV-infected patients (0.4%; 95% CI, 0.2 to 0.8%) who were treated with IFN alpha-2b and RBV. The mean age of the patients (four males and three females) was 51.4 +/- 4.7 years and the median duration of therapy prior to development of pancreatitis was 12.0 weeks (range, 4.0-21.0 weeks). All patients presented with epigastric pain associated with nausea, vomiting, and/or fever. The median amylase and lipase values at the time of diagnosis of pancreatitis were 330.0 U/L (range, 182.0-1813.0 U/L) and 500.0 U/L (range, 171.0-2778.0 U/L), respectively. IFN and RBV were discontinued in all patients at the time of diagnosis and six of the seven patients were hospitalized; one patient refused hospital admission. Pancreatitis resolved in all seven patients and none of these individuals had recurrent pancreatitis during a median follow-up of 18.0 months (range, 3.0-27.0 months). In conclusion, IFN and RBV combination therapy is a potential cause of drug-induced pancreatitis in patients with chronic HCV. In these individuals, pancreatitis is often severe enough to warrant hospital admission, although symptoms resolve promptly after discontinuation of antiviral therapy.

An estimated 3.2 million people have chronic hepatitis C (HCV) infection in the United States [1]. Treatment with pegylated alfa interferon and ribavirin for 24–48 weeks is the standard treatment for HCV with sustained virological response rates of over 50% [2–4]. Interferon alfa has immunomodulatory actions and has been implicated in the development of several autoimmune diseases [5]. Interferon-induced sarcoidosis (IIS) has been reported previously with the use of standard interferon alfa but there is limited data with pegylated interferon, with a few reports of cutaneous and pulmonary sarcoidosis occurring [5–16]. There are no published reports of hepatic sarcoidosis developing with pegylated interferon alfa use. We report a case of the development of hepatic sarcoidosis during treatment with pegylated interferon alfa 2b and ribavirin with pathological confirmation of granulomatous inflammation on liver biopsy and an elevated serum angiotensin converting enzyme (ACE) level. The case is important in that it illustrates that elevation of liver enzymes during treatment, particularly if associated with a decline in HCV viral load, should be concerning for another process and lead to a liver biopsy. Case Report

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Post-transplant hepatitis C is a major challenge after liver transplantation (LT). Antiviral therapy is associated with lower efficacy in the post-transplant setting.The purpose of this study was to determine the safety and effect of intravenous interferon (IFN) during the anhepatic phase of LT on hepatitis C viral load.Fifteen consecutive subjects undergoing liver transplant for hepatitis C cirrhosis were enrolled in the study, ten of which received study drug and five subjects served as controls. Cases received weight-based ribavirin and subcutaneous IFN at time of incision followed by intravenous IFN at the start of the anhepatic phase. Adverse events and viral levels were recorded. Repeated measures ANOVA was employed to test for differences over time, between the groups, and time by group interaction.All subjects had genotype 1 virus. Hepatitis C viral load was lower at week 4 in cases compared to controls (769,004 ± 924,082 IU/ml and 2,329,896 ± 3,731,749 IU/ml, respectively), but did not reach statistical significance (p = 0.50). Three subjects developed adverse events related to IFN including pulmonary edema, rejection, and neutropenia.Intravenous IFN administered during the anhepatic phase of liver transplant did not prevent graft reinfection and was associated with manageable adverse events. This regimen could be further studied if direct acting antiviral agents alone are insufficient for treating post-transplant hepatitis C.

The efficacy of various regimens using interferon-alpha (IFN-alpha) in the treatment of hepatitis C virus (HCV) infection was analyzed in a meta-analysis of 33 randomized clinical trials (RCTs). The results of the meta-analysis showed increased complete and sustained ALT response rates in patients receiving IFN 3 MU three times a week for six months compared with patients receiving placebo or no treatment. The dose effect (6 MU three times a week versus 3 MU three times a week) on complete ALT response rate at the end of treatment was significant, with a mean 10% improvement at both six and 12 months. There also was a significant dose effect on sustained response for 12 months treatment, with a mean 17% improvement. There was a significant treatment duration effect on sustained response rate at 3 MU three times a week and 6 MU three times a week, with a mean improvement of 16% (or = 12 months vs six months) with 3 MU three times a week. Due to adverse events, we conclude that the best efficacy-risk ratio favors IFN treatment with 3 MU three times a week for at least 12 months. The results of our RCT comparing three IFN regimens showed that patients receiving 3 MU three times a week for up to 18 months exhibited significant improvements in histological activity score, normalization of serum ALT concentrations, and sustained response compared with patients receiving a lower dose or shorter duration of treatment with IFN. Together, these results support the conduct of another RCT to evaluate the hypothesis that long-term, continuous IFN treatment may significantly reduce the incidence of cirrhosis in patients with HCV infection.

Following preliminary reports of small studies that suggested a clinically important enhanced benefit from combination therapy with interferon-alpha (IFN) and ribavirin over IFN monotherapy in chronic hepatitis C, a meta-analysis of data from these studies was performed to estimate the efficacy and tolerability of combination therapy in chronic hepatitis C. Records were obtained from 59 patients who had received combination therapy with IFN 3 MU three times weekly and ribavirin 1000-1200 mg daily for six months and were followed for six months after stopping combination therapy. Outcome measures included the percentage of patients showing ALT normalization and HCV-RNA negativity six months after therapy (sustained response) and the percentage of patients stopping therapy because of side effects. Sustained response was observed in 21% of IFN nonresponders and in 60% of patients who had relapsed after IFN. For naive patients, the estimated sustained response rate was 52%; the observed response rate was 46%. No serious adverse effects were noted; less than 10% of patients discontinued study medication. This meta-analysis of IFN-ribavirin combination therapy for chronic hepatitis C suggests that combination therapy results in a two- to threefold greater efficacy than IFN monotherapy, whereas side effects are similar to IFN monotherapy, with the exception of ribavirin-induced anemia. Interferon-ribavirin combination therapy might become the next step in antiviral therapy for chronic hepatitis C.

In order to evaluate the histological treatment response in patients with chronic hepatitis C virus (HCV) infection, different histological scoring systems have been developed. The scoring systems provide means of statistically comparing histopathological parameters in serial liver biopsies and have thus become important requirements of therapeutic trials. Patients with biochemical and virological responses to interferon (IFN) also improve histologically during treatment. However, after treatment cessation, many patients will have a biochemical/virological relapse. These short-term responders also relapse histologically, thus limiting the long-term benefit of a single treatment course, although, repeated courses of IFN in short-term responders may retard histological deterioration. In contrast, sustained biochemical/virological responders seem to have a durable histological response with a continuous and gradual improvement of all necroinflammatory parameters and fibrosis posttreatment.

Short-term (end-of-treatment) responses (ETR) to interferon (IFN) therapy for chronic hepatitis C are encouraging; however, the relapse rate is high, and long-term response is obtained in only 12-25% of patients. The Australian Hepatitis C Study Group conducted a trial of 230 patients that compared the standard 3 MU three times a week six-month course of IFN-alpha2b with 5 MU three times a week for six months (5 MU group) or 3 MU three times a week for two years (two-year group). ETR (normalization of serum aminotransferase level until the end of treatment) rates based on an intent-to-treat analysis were 64% for the 5 MU group and 58% for the combined 3 MU groups. After six months of treatment, the overall relapse rate was 71%, and the long-term response (LTR; continued normal aminotransferase until six month follow up) rate did not differ significantly between the 3 MU (17% of all treated, 27% ETR) and 5 MU groups (20% of all treated, 31% ETR). In contrast, among the 46 patients who exhibited an ETR in the two-year group, 27 (59%) had a LTR to IFN, resulting in an overall LTR rate of 33% for all patients treated for up to two years (P0.001 compared with 3 MU group). Among these 46 subjects, 11 did not complete the full two-year course, including eight who withdrew due to adverse effects. Nine of these 11 patients had received at least 12 months of therapy. All 18 LTR subjects tested (irrespective of treatment group) were serum HCV-RNA negative at the 12-month follow-up evaluation. Improvement in hepatic inflammation was significantly greater among those treated for two years compared with six months, but there was no reduction in fibrosis score in any group. Among the entire study group, treatment duration, liver histology, and liver function (assessed by antipyrine clearance test) were the only independent predictors of ETR, although HCV genotype was closely related to histological severity (eg, cirrhosis was present in 60% of type 1 and 18% of type 3). Viral load and duration of infection were additional predictors of LTR; however, there were insufficient data to determine whether prolonging treatment beyond six months overcomes the negative impact of these predictors. Continuing IFN therapy for at least 12 months decreases the relapse rate by 50% and thereby improves the LTR rate compared with a six-month treatment course. However, our experience of 24 months of treatment indicates that initial IFN treatment courses of this duration are not well tolerated by approximately 20% (8/46) of patients and are unlikely to improve the results obtained with 12-18 months of treatment.

The efficacy of short-course (three months), low-dose (3 million units three times a week) interferon as treatment for acute hepatitis C was evaluated in a meta-analysis of controlled trials. Nine studies (five randomized and four nonrandomized) found by MEDLINE search were eligible for analysis. The outcomes assessed were the rate of patients with normal serum aminotransferases (all trials) and without HCV RNA in blood (five trials) after posttreatment follow-up. Eight trials compared interferon to no treatment, and one compared different schedules of interferon. The methodological quality of the studies was high. However, all trials had been planned for a short-term evaluation based on biochemical and virological outcomes alone. Significant differences were observed between interferon and control groups for both the assessable end points. Overall rate differences were +0.31 (P < 0.0001; 95% confidence interval +0.20 to +0.41) for aminotransferases normalization and +0.44 (P < 0.0001; 95% confidence interval +0.33 to +0.56) for HCV RNA clearance. In conclusion, a short course of low-dose interferon administered to patients with acute hepatitis C is significantly more effective than no treatment in obtaining viral clearance and normal aminotransferases 12 months after stopping treatment. Further long-term prospective cohort studies assessing outcomes of clinical relevance (ie, the rate of chronicity of infection and disease) are necessary before recommending interferon for acute hepatitis C.