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Objectives: Dilatation of the common bile duct (CBD) can be an ominous sign for malignancy of the pancreatobiliary tract; however, it has also been described as a presumably harmless side effect of opioid use. We investigated the prevalence and determinants of CBD dilatation among drug users receiving methadone maintenance therapy in the Netherlands., Methods: A cross-sectional study was conducted in a prospectively studied and well-defined cohort of drug users with chronic hepatitis C virus infection, attending the Public Health Service of Amsterdam, the Netherlands. Patients underwent abdominal ultrasonography as part of pretreatment screening. A multivariable logistic regression model was used to analyze potential demographic and drug use-related determinants of radiological CBD dilatation., Results: Between September 2004 and December 2011, 222 hepatitis C virus-infected drug users were evaluated. Dilatation of the CBD was found in 50 of 222 patients (22.5%), with a median diameter of 8.0 mm (interquartile range, 7.0 to 10.0; n = 43). Dilatation was associated with current use of methadone (adjusted odds ratio = 20.50; 95% confidence interval, 2.79 to 2.61 × 10(3)), independent of the current methadone dose, and with age per 10-year increase (adjusted odds ratio = 1.68; 95% confidence interval, 1.06 to 2.71). Regular use of heroin in the 6 months before ultrasonography was not found to be associated with dilatation., Conclusions: Dilatation of the CBD is common in drug users under methadone treatment and seems to be a harmless side effect of opioid agonists.

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients., (© 2013 John Wiley & Sons Ltd.)

Introduction: Hepatitis C virus (HCV) infection can lead to severe liver disease. Pregnant women are already routinely screened for several infectious diseases, but not yet for HCV infection. Here we examine whether adding HCV screening to routine screening is cost-effective., Methods: To estimate the cost-effectiveness of implementing HCV screening of all pregnant women and HCV screening of first-generation non-Western pregnant women as compared to no screening, we developed a Markov model. For the parameters of the model, we used prevalence data from pregnant women retrospectively tested for HCV in Amsterdam, the Netherlands, and from literature sources. In addition, we estimated the effect of possible treatment improvement in the future., Results: The incremental costs per woman screened was €41 and 0.0008 life-years were gained. The incremental cost-effectiveness ratio (ICER) was €52,473 which is above the cost-effectiveness threshold of €50,000. For screening first-generation non-Western migrants, the ICER was €47,113. Best-case analysis for both scenarios showed ICERs of respectively €19,505 and €17,533. We estimated that if costs per treatment were to decline to €3,750 (a reduction in price of €31,000), screening all pregnant women would be cost-effective., Conclusions: Currently, adding HCV screening to the already existing screening program for pregnant women is not cost-effective for women in general. However, adding HCV screening for first-generation non-Western women shows a modest cost-effective outcome. Yet, best case analysis shows potentials for an ICER below €20,000 per life-year gained. Treatment options will improve further in the coming years, enhancing cost-effectiveness even more.

Background: Egypt has high prevalence of hepatitis C virus (HCV) infection and intermediate prevalence of hepatitis B virus (HBV) infection; however, infection prevalence among Egyptian migrants is unknown. Considering the asymptomatic onset and development of disease in chronically-infected patients, many may remain undiagnosed., Aims: To evaluate an HCV- and HBV-screening programme designed to identify undetected infections among first-generation Egyptian migrants in Amsterdam, the Netherlands., Methods: In 2009 and 2010, viral hepatitis educational and screening sessions were established at Egyptian meeting places. Data regarding demographics and HCV risk factors were collected. Chronically infected participants were referred and followed up. Phylogenetic analyses were used to ascertain the geographic origin of infections., Results: Eleven of 465 (2.4%; 95% CI = 1.3-4.2%) migrants had HCV antibodies; 10/11 were HCV RNA positive. All had genotype 4a, and strains were typical of those of Egypt and the Middle East. Older age and exposure to parenteral antischistosomal therapy (PAT) were significantly associated with HCV. Anti-HBc prevalence was 16.8% (95% CI = 13.7-20.4%); HBsAg prevalence was 1.1% (95% CI = 0.5-2.5%). All had genotype D, typical of those of the Middle East. Most (9/10 HCV; 3/5 HBV) chronic infections were newly diagnosed; four of the HCV-infected individuals started treatment., Conclusions: Anti-HCV and HBsAg prevalence among Egyptian migrants was lower compared with the general Egyptian population, but higher than the general population of Western countries. Phylogenetic analyses suggest that all infections were from the region of origin. HCV-screening programmes should target first-generation Egyptian migrants, especially those of older age and those who received PAT., (© 2013 John Wiley & Sons A/S.)

Background: In this study, we aimed to identify baseline predictors of response in chronic hepatitis B patients treated with a combination of pegylated interferon (PEG-IFN)-α2a and adefovir., Methods: We treated 92 chronic hepatitis B patients (44 hepatitis B e antigen [HBeAg]-positive and 48 HBeAg-negative) with HBV DNA > 100,000 copies/ml (> 17,182 IU/ml) with PEG-IFN and adefovir for 48 weeks and followed them up for 2 years. Baseline markers for HBeAg loss, combined response (HBeAg negativity, HBV DNA levels ≤ 2,000 IU/ml and alanine aminotransferase [ALT] normalization) and hepatitis B surface antigen (HBsAg) loss were evaluated., Results: Two years after the end of treatment, rates of HBeAg loss and HBsAg loss in HBeAg-positive patients were 18/44 (41%) and 5/44 (11%), respectively. In HBeAg-negative patients, rates of combined response and HBsAg loss were 12/48 (25%) and 8/48 (17%), respectively. HBeAg-negative patients with HBsAg loss had lower baseline HBsAg levels than those without HBsAg loss (mean HBsAg 2.35 versus 3.55 log10 IU/ml; P < 0.001). They also had lower HBV DNA levels and were more often (PEG-)IFN experienced. Baseline HBsAg was the only independent predictor of HBsAg loss (OR 0.02; P = 0.01)., Conclusions: With combination therapy of PEG-IFN and adefovir for 48 weeks, a high rate of HBsAg loss was observed in both HBeAg-positive (11%) and HBeAg-negative (17%) patients 2 years after treatment ended. In HBeAg-negative patients, a low baseline HBsAg level was a strong predictor for HBsAg loss.

Background: More than two-thirds of hepatitis C virus (HCV) infections are associated with injecting drug use. Despite the wide availability of standard treatment with pegylated interferon and ribavirin, active drug users (DU) have limited access to HCV treatment. Physicians may be reluctant to prescribe treatment because of the presumed high risk of reinfection. However, data on reinfection in treated DU remain scarce., Methods: Active DU with chronic HCV infection were treated in a multidisciplinary setting. After achieving a sustained virologic response, patients were tested at 6-12-monthly intervals for HCV RNA. To distinguish between relapse and reinfection, sequence and phylogenetic analyses were performed on the NS5B region of the HCV genome. The incidence of reinfection was calculated using person-time techniques., Results: From April 2005 to March 2010, 69 active DU treated for HCV had sufficient follow-up, median 2.5 years (interquartile range, 1.6-3.7). Sustained virologic response was achieved in 42 patients (61%). During follow-up, 41 patients remained HCV RNA-negative; of these, two patients died. During treatment, five out of 41 injected drugs, which increased to 11 out of 41 after the end of treatment. One case of reinfection was observed, followed by spontaneous clearance of the virus. The overall incidence was 0.76/100 person-years (95% confidence interval 0.04-3.73). For only those individuals reporting injecting drug use, the incidence was 3.42/100 person-years (95% confidence interval 0.17-16.90)., Conclusion: We report a low incidence of HCV reinfection following treatment in DU participating in a multidisciplinary programme. Active drug use, including injecting, should not preclude access to treatment for HCV.

Large outbreaks of acute hepatitis E, caused by hepatitis E virus (HEV) genotypes 1 and 2, are known from developing countries with suboptimal sanitation infrastructure. An increasing incidence of HEV infections is being reported in industrialised countries, caused mainly by HEV genotypes 3 and 4, which are often found among pigs. Recent evidence suggests that in immunocompromised patients about 50% of the cases of acute hepatitis E evolve to chronic hepatitis with rapid progression to cirrhosis. Thus, HEV should be considered a cause of chronic hepatitis in immunocompromised patients, such as solid organ transplant recipients. Because an antibody response to HEV may be absent in these patients, an HEV RNA test should be carried out when serum liver tests are elevated over months. In small case series, ribavirin has been shown to represent a promising treatment option for chronic HEV infection. To increase the awareness for HEV infection in immunocompromised patients, a representative case report of an HEV-infected renal transplant recipient with chronic hepatitis E, successfully treated with ribavirin, is presented. Studies are required to determine the optimal duration of ribavirin therapy and to assess outcome for solid organ transplant recipients with chronic HEV infection.

Evolutionary analysis of hepatitis C virus (HCV) genome sequences has provided insights into the epidemic history and transmission of this widespread human pathogen. Here we report an exceptionally diverse set of 178 HCV genotype 2 (HCV-2) isolates from 189 patients in Amsterdam, comprising 8 distinct HCV subtypes and 10 previously not recognized, unclassified lineages. By combining study subjects' demographic information with phylogeographic and molecular clock analyses, we demonstrate for the first time that the trans-Atlantic slave trade and colonial history were the driving forces behind the global dissemination of HCV-2. We detect multiple HCV-2 movements from present-day Ghana/Benin to the Caribbean during the peak years of the slave trade (1700 to 1850) and extensive transfer of HCV-2 among the Netherlands and its former colonies Indonesia and Surinam over the last 150 years. The latter coincides with the bidirectional migration of Javanese workers between Indonesia and Surinam and subsequent immigration to the Netherlands. In addition, our study sheds light on contemporary trends in HCV transmission within the Netherlands. We observe multiple lineages of the epidemic subtypes 2a, 2b, and 2c (together 67% of HCV-2 infections in Amsterdam), which cluster according to their suspected routes of transmission, specifically, injecting drug use (IDU) and contaminated blood/blood products. Understanding the epidemiological processes that generated the global pattern of HCV diversity seen today is critical for exposing associations between populations, risk factors, and specific HCV subtypes and might help HCV screening and prevention campaigns to minimize the future burden of HCV-related liver disease.

In a cohort of 95 chronic hepatitis B patients, who were treated with peg-interferon and adefovir for 1 year, and who had 15% HBsAg loss (overall), no association was found between IL28B polymorphisms and HBeAg seroconversion or HBsAg clearance. These findings suggest that any association with outcome, if present, is less than that seen in chronic hepatitis C. Additional studies are needed to enlarge sample size and to refine our understanding of IL28B biology in the context of chronic hepatitis B response to immunomodulatory and direct antiviral therapy.

Background: The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease., Methods: This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8)., Results: In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group., Conclusions: Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

Worldwide approximately 130-210 million people suffer from chronic hepatitis C. Adequate antiviral therapy reduces morbidity and mortality caused by chronic hepatitis C and prevents further spread of the hepatitis C-virus (HCV). The current standard treatment of chronic hepatitis C, consisting of the combination of pegylated interferon-α (peginterferon) and ribavirin, lasts 24-48 weeks, and is accompanied by significant side effects and has a suboptimal chance of success. Protease inhibitors, which have recently been registered, belong to a new class of medicines which directly affect the life cycle of HCV. Protease inhibitors, in combination with peginterferon and ribavirin, provide almost double the chance of curing in patients with HCV genotype 1. Treatment duration can be shortened in a considerable proportion of these patients. Since treatment with protease inhibitors can lead to resistant virus strains and this therapy leads to additional side effects, the complexity of treatment will increase.

Background: PHX1766 is a novel HCV NS3/4 protease inhibitor with robust potency and high selectivity in replicon studies (50% maximal effective concentration 8 nM). Two clinical trials investigated the safety, tolerability, pharmacokinetics and antiviral activity of PHX1766 in healthy volunteers (HV) and chronic hepatitis C patients, by use of a dose-adaptive overlapping clinical trial design., Methods: Two randomized, double-blind, placebo-controlled clinical trials were conducted. Single doses of PHX1766 or placebo were administered to 25 HV and six HCV genotype 1-infected patients (50 mg once daily -1,000 mg once daily, 250 mg twice daily and 100 mg of a new formulation of PHX1766 once daily). Multiple doses of PHX1766 or placebo were administered to 32 HV and seven HCV genotype 1-infected patients (50 mg once daily -800 mg twice daily)., Results: Oral administration of PHX1766 was safe and well tolerated at all dose levels with rapid absorption (time at which concentration maximum is reached of 1-4 h) and with mean terminal half-lives of 4-23 h. Multiple doses of PHX1766 800 mg twice daily in HCV patients produced an area under the plasma concentration-time curve from time of drug administration to the last time point with a measurable concentration after dosing accumulation ratio of 2.3. The mean maximal observed HCV RNA decline was 0.6 log(10) IU/ml in the first 24 h in the single-dose protocol and 1.5 log(10) IU/ml after 6 days of PHX1766 dosing., Conclusions: An overlapping, dose-adaptive single-dose and multiple-dose escalating design in HV and HCV-infected patients proved to be highly efficient in identifying a therapeutic dose. Although in vitro replicon studies indicated a robust HCV RNA viral decline of PHX1766, the study in HCV patients demonstrated only modest viral load reduction.

Background & Aims: Telaprevir, a hepatitis C virus NS3/4A protease inhibitor has significantly improved sustained viral response rates when given in combination with pegylated interferon alfa-2a and ribavirin, compared with current standard of care in hepatitis C virus genotype 1 infected patients. In patients with a failed sustained response, the emergence of drug-resistant variants during treatment has been reported. It is unclear to what extent these variants persist in untreated patients. The aim of this study was to assess using ultra-deep pyrosequencing, whether after 4 years follow-up, the frequency of resistant variants is increased compared to pre-treatment frequencies following 14 days of telaprevir treatment., Methods: Fifteen patients from 2 previous telaprevir phase 1 clinical studies (VX04-950-101 and VX05-950-103) were included. These patients all received telaprevir monotherapy for 14 days, and 2 patients subsequently received standard of care. Variants at previously well-characterized NS3 protease positions V36, T54, R155 and A156 were assessed at baseline and after a follow-up of 4±1.2 years by ultra-deep pyrosequencing. The prevalence of resistant variants at follow-up was compared to baseline., Results: Resistance associated mutations were detectable at low frequency at baseline. In general, prevalence of resistance mutations at follow-up was not increased compared to baseline. Only one patient had a small, but statistically significant, increase in the number of V36M and T54S variants 4 years after telaprevir-dosing., Conclusion: In patients treated for 14 days with telaprevir monotherapy, ultra-deep pyrosequencing indicates that long-term persistence of resistant variants is rare.

BACKGROUND  Treatment of hepatitis C with peginterferon and ribavirin is associated with psychiatric side-effects, frequently necessitating dose reduction or therapy cessation. AIM  To assess the efficacy of prophylactic escitalopram to prevent psychiatric side-effects during peginterferon and ribavirin treatment in a randomised, double-blind, placebo-controlled trial. METHODS  Seventy-nine hepatitis C patients were treated with peginterferon and ribavirin. Patients received escitalopram (n = 40, 10 mg) or placebo (n = 39), which was initiated together with peginterferon and ribavirin. Primary outcomes were an increase of two points or more on the items reported sadness, inner tension and impaired concentration of the Montgomery-Asberg Depression Rating Scale, and hostile feelings of the Brief Anxiety Scale. Secondary outcome was the development of depression diagnosed by the Mini-International Neuropsychiatric Interview. Measurements were performed at baseline, week 4, 12 and 24 during anti-viral treatment, and 24 weeks thereafter. RESULTS  The incidence of psychiatric side-effects was significantly lower in patients treated with escitalopram compared with placebo for all primary and secondary outcomes, except for impaired concentration: reported sadness 27.5 vs. 48.7% (P = 0.052), inner tension 17.5 vs. 38.5% (P = 0.038), impaired concentration 55.0 vs. 66.7% (P = 0.288) and hostile feelings 22.5 vs. 43.6% (P = 0.046) (escitalopram vs. placebo, Chi-squared test). The sum scores of all four endpoints showed an overall beneficial effect of escitalopram (P = 0.009, Mann-Whitney U-test). Depression occurred in 12.5% of the patients in the escitalopram-group vs. 35.9% in the placebo-group (P = 0.015, Chi-squared test). CONCLUSIONS  Prophylactic treatment with escitalopram is effective in the prevention of psychiatric side-effects during interferon-based treatment of hepatitis C., (© 2011 Blackwell Publishing Ltd.)

Background: The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection., Aim: To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773., Methods: The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg)., Results: Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) )., Conclusion: The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group., (© 2011 Blackwell Publishing Ltd.)

Background: Many individuals with hepatitis C virus (HCV) infection are undiagnosed., Purpose: This study describes the development and the use and outcomes of a mass media campaign, combined with an Internet risk assessment and an Internet-mediated blood-testing procedure for HCV to identify individuals infected with HCV in the general population., Methods: From April 2007 to December 2008, individuals in HCV risk groups were referred to an online, previously validated risk-assessment questionnaire at www.heptest.nl. Individuals at risk could download a referral letter for a free, anonymous HCV blood test in a nonclinical setting. Test results could be obtained online, 1 week later, using a personal log-in code. Anti-HCV-positive participants were requested to visit the Public Health Service for confirmation and RNA testing. Chronically HCV-infected individuals were referred for treatment. Data were analyzed in 2009-2010., Results: The website attracted 40,902 visitors. Of the 9653 who completed the questionnaire, 2553 were at risk for HCV (26.4%). Main reported risk factors were a blood transfusion prior to 1992 and noninjecting drug use. Of the 1480 eligible for the blood test, 420 opted for testing (28%). HCV antibodies were detected in 3.6% (n=15, 95% CI=2.1%, 5.7%); of the 12 with a chronic HCV infection, six began treatment., Conclusions: Internet-mediated risk-based testing for HCV has proved to be a feasible and effective strategy to identify undiagnosed HCV infection in the general population. All HCV-infected individuals belonged to hard-to-reach populations. Test uptake was 28%, which is high for an online project that includes blood testing. Because Internet-mediated testing is low-cost, this strategy holds promise for future screening., (Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Although hepatitis C virus (HCV) treatment has shown to be effective, uptake of treatment among active drug users is still low. The Drug Users Treatment for Chronic Hepatitis-C project aims to offer active drug users in Amsterdam HCV testing and treatment using a multidisciplinary approach., Methods: The study population comprises drug users participating in the Amsterdam Cohort Studies and drug users referred to the Drug Users Treatment for Chronic Hepatitis-C unit. Drug users were offered HCV testing and, if chronically infected, medical and psychiatric screening and HCV treatment. Various specialists collaborated to provide optimal care. We assessed test-uptake and treatment-uptake and outcomes., Results: Four hundred and ninety-seven Amsterdam Cohort Studies drug users were offered HCV testing: 449 out of 497 (90%) accepted. HCV antibodies were found in 267 out of 449 (60%): 183 out of 267 (69%) were HCV-viremic and 49 out of 183 (27%) were HIV-co-infected. Of the 134 HCV-monoinfected patients, 102 (76%) initiated additional medical screening and 44 started treatment by 1 July 2009. Sixty-two drug users referred from methadone clinics were also HCV-monoinfected, of whom 14 started treatment by 1 July 2009. In total 58 persons were treated: 16 (27%) with genotype 1 or 4, 42 (72%) with genotype 2 or 3. Eighty-four percent used methadone, 97% used drugs (heroin, cocaine or amphetamine) at least once in the 6 months before treatment, 19% were active injectors. Sixty-two percent used alcohol, 41% had psychiatric disease other than substance abuse. Of the 57 individuals with sufficient follow-up, 37 (65%) achieved sustained virological response., Conclusion: In a multidisciplinary setting, HIV-negative drug users with chronic HCV infection can be treated successfully despite active drug or alcohol use and psychiatric diseases. Therefore, access to HCV therapy using an integrated approach should be increased for this population.

Unlabelled: Narlaprevir (SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system. In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and as combination therapy with pegylated interferon-α-2b (PEG-IFN-α-2b) to HCV genotype 1-infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naïve and treatment-experienced). In period 1, narlaprevir was administered for 7 days as 800 mg three times daily without ritonavir or 400 mg twice daily with 200 mg ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of narlaprevir was administered in combination with PEG-IFN-α-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-α-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV-RNA was observed in both treatment-experienced and treatment-naïve patients during period 1, with a mean viral load decline of at least 4 log₁₀ in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naïve (≥ 60%) patients had undetectable HCV-RNA (< 25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naïve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with PEG-IFN-α-2b was safe and well tolerated., Conclusion: Narlaprevir administration resulted in a robust HCV-RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naïve HCV genotype 1-infected patients.

Chronic hepatitis B affects approximately 400 million people in the world with a substantial disease burden like liver cirrhosis and hepatocellular carcinoma (HCC). Treatment for chronic hepatitis B has improved dramatically in the last decade, resulting in more patients achieving a state of inactive disease. Currently two treatment strategies are available; treatment with peginterferon (peg-IFN) or nucleos(t)ide analogues with the aim to suppress hepatitis B virus (HBV) DNA to subsequently avoid the development of cirrhosis and HCC. Unfortunately, treatment with peg-IFN can be suboptimal with important adverse effects and nucleos(t)ide analogues provoke resistance. At present, no new promising compounds attacking the HBV life cycle are in development. However, for prediction of sustained response or treatment failure, data from the long-term large peg-IFN trials provide important response markers. For the future the focus is to achieve HBsAg loss and anti-HBs conversion which is the closest the treatment can get to a cure. This review summarizes the current treatment options with their response rates and discusses future strategies for chronic hepatitis B treatment.

Many individuals with hepatitis C virus (HCV) infection are undiagnosed. This study evaluates a risk assessment questionnaire, developed for use online to target blood-screening for HCV. Two hundred and eighty-nine patients with known HCV status completed a written questionnaire on prominent HCV risk factors. Questionnaires generated advice to seek testing if at least one risk factor was reported. Agreement of the testing advice with the HCV status of respondents was evaluated. Subsequently, we validated our questionnaire among 985 patients of an outpatient clinic for sexually transmitted infections. The post-test-probability-of-disease (PTPD) and diagnostic gain (PTPD minus prior probability of disease) were calculated. The questionnaire's sensitivity and specificity were 84.6% and 63.8%, respectively, and higher in the STI clinic patients. The PTPD of positive testing advice was 72.5% given HCV prevalence of 53.0%, yielding a diagnostic gain of 19.5%. Applying the estimated prevalence in the general Dutch population (0.1-0.4%), and the anticipated prevalence in the online project (1.0-6.0%), yielded diagnostic gains of 0.13-0.53% and 1.3-7.0%, respectively. We conclude that our questionnaire succeeded in selecting at-risk individuals as its testing advice agreed well with the HCV status. We suggest that the questionnaire be used online as a selection tool for HCV blood-screening in the general population.

Background: Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin is associated with suboptimal virological response rates and substantial side effects. This study describes the in vitro and in vivo development of JTK-652, a novel pyrrolopyridazin-derived HCV infection inhibitor., Methods: JTK-652 was evaluated in multiple cell lines using an in vitro HCV infection model consisting of HCV pseudotype vesicular stomatitis virus bearing HCV E1/E2 envelope proteins. Safety, tolerability, pharmacokinetics and efficacy of JTK-652 were tested in a randomized double-blind and placebo-controlled study in healthy male volunteers (n=36) and chronic hepatitis C patients. A total of 10 HCV genotype-1-infected patients (treatment-naive [n=2] and treatment-experienced [n=8]) with HCV RNA>1x10(5) IU/ml received an oral dose of 100 mg JTK-652 three times daily or placebo (8:2 ratio) for 4 weeks., Results: JTK-652 showed potent inhibitory activity against HCV genotype 1a and 1b pseudotype viruses bearing HCV E1/E2 envelope proteins in HepG2 cells and in human primary hepatocytes. No significant clinical laboratory, vital sign, ECG or physical examination abnormalities were observed during the Phase I trial. JTK-652 was found to be well tolerated. No significant changes in HCV RNA levels compared with baseline were observed at the end of treatment., Conclusions: Although results from the preclinical studies indicated that JTK-652 has well-established antiviral properties and a Phase I clinical trial has showed that JTK-652 was safe and well tolerated at a 100 mg three times daily dose level, plasma HCV RNA levels in chronically HCV-infected patients did not decrease during 28 days of dosing at a 100 mg three times daily dose level.

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is endemic in most parts of the world, with an estimated 170 million people infected worldwide and 3-4 million new cases each year. HCV-related end-stage liver disease is now the main indication for liver transplantation in the USA and Western Europe. Unfortunately, no vaccine or immunoglobulin is available to prevent HCV infection. Currently, HCV treatment consists of the combined administration of pegylated interferon and ribavirin for a period of 24-48 weeks, resulting in complete viral eradication in 40-80% of patients, depending on genotype, viral load and patient characteristics. This therapy is often accompanied with side-effects that affect compliance and reduce treatment outcomes. Recently, reliable in vitro culture systems have been developed which accelerated antiviral therapy research. Many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are evaluated in clinical trials. These new antiviral agents are expected to improve treatment significantly with potentially shorter treatment duration. The most promising antiviral agents will be reviewed.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) serves as a template for viral replication and plays a role in persistence of HBV infection. The origin and significance of cccDNA in plasma however, is not well understood. A sensitive, specific, and reproducible real-time PCR for detection and quantitation of cccDNA in plasma of chronic hepatitis B patients was developed and validated. Four HBV DNA reference panels, and 96 plasma samples of chronic hepatitis B patients were analyzed. Results were compared with total HBV DNA levels, individual ALT levels and the Histology Activity Index (HAI). This cccDNA assay had a lower limit of detection at 15 copies/PCR, a lower limit of quantitation at 91 copies/PCR and a correlation coefficient (R) of 0.98 (P < 0.0001). cccDNA was detected in two of four international panels. Significant correlation was found between cccDNA and total HBV DNA levels in both panels (R = 0.96, and R = 0.43) and in samples of the chronic hepatitis B patients (R = 0.88, P < 0.0001). In 57% of these samples cccDNA was detectable. Mean level of cccDNA was 0.16% of total HBV load. Plasma cccDNA levels were higher in HBeAg positive samples than in HBeAg negative samples (4.91 log copies/ml vs. 3.88 log copies/ml, P < 0.0001). Levels of total HBV DNA and HBV genotype did not influence cccDNA detection. ALT levels and HAI-score were not correlated with plasma cccDNA levels. These findings suggest that cccDNA levels in plasma are not the result of increased hepatocyte degeneration, but indicate that other mechanisms might be responsible.

Serial monotherapy and add-on regimes for treatment of chronic hepatitis B virus (HBV) infection may induce the accumulation of viral resistance mutations in patients, reducing the options for ongoing viral suppression. The induction of antiviral resistance by serial application of polymerase inhibitors does not necessarily imply that the subsequent combined use of the drugs will fail. Some HIV strains resistant to one polymerase inhibitor show increased susceptibility to another polymerase inhibitor. After failure of sequential lamivudine and adefovir monotherapy, two patients with hepatitis B changed to treatment with lamivudine plus adefovir and had renewed suppression of HBV. To study the mutational history of resistant HBV subpopulations in the two patients, a part of the HBV polymerase gene was amplified, cloned, sequenced, and analyzed for the presence of mutations, in sequential plasma samples. In both patients serial monotherapy caused the replacement in all HBV clones of wild-type virus by classical lamivudine resistant mutants (L180M and M204V/I), which were replaced subsequently by adefovir resistant mutants (A181V and N236T). When finally lamivudine was added to adefovir, the A181V adefovir mutation persisted in all clones and lamivudine-related mutations did not reappear. During 18 months of combination therapy, HBV-DNA levels decreased 10,000, respectively, 1,000-fold, despite the earlier resistance to lamivudine and adefovir. Although clinically insufficient, this effect indicates that HBV polymerase resistance mutations may be antagonistic, which is relevant if chronic HBV infection is to be treated by a combination of polymerase inhibitors., (Copyright 2009 Wiley-Liss, Inc.)

Background: Development of diabetes mellitus (DM) during or shortly after treatment with interferon alpha (IFN-alpha) in patients with chronic hepatitis C virus (HCV) infection has been reported sporadically. We prospectively screened for DM during and after IFN-alpha therapy for chronic HCV infection., Methods: Blood glucose levels of patients with chronic HCV infection were routinely assessed at all outpatient visits during and after treatment with pegylated-IFN-alpha (Peg-IFN-alpha) and ribavirin (Riba)., Results: Between December 2002 and October 2005, 189 non-diabetic patients were treated with Peg-IFN-alpha/Riba, of whom five developed type 1 DM (2.6%), three type 2 DM (1.6%) and one an indeterminate type of DM. Classical symptoms of DM were present in three patients who developed DM shortly after cessation of Peg-IFN-alpha/Riba. In the other patients, symptoms of DM were either indistinguishable from side effects caused by Peg-IFN-alpha/Riba or absent., Conclusion: Our study showed a high incidence of type 1 DM during Peg-IFN-alpha/Riba therapy for chronic HCV infection. Symptoms of DM may be absent or mistaken for Peg-IFN-alpha/Riba-associated side effects. To diagnose DM without delay, we propose routine assessment of blood glucose at all outpatient visits during and after Peg-IFN-alpha/Riba treatment in chronic HCV patients.

Objective: Neopterin is a marker of monocyte/macrophage activity. Alanine aminotransferase (ALAT) is a marker of hepatocyte injury. The aim of this study was to determine changes in neopterin and ALAT levels, as markers of inflammation, in two ancillary studies during two-phase 1b trials of hepatitis C virus (HCV) NS3.4A protease inhibitor telaprevir (VX-950), with or without peginterferon alfa-2a (Peg-IFN)., Material and Methods: Fifty-four chronic hepatitis C patients (genotype 1) received placebo or telaprevir, with or without Peg-IFN, for 14 days in two multiple-dose studies., Results: During administration of telaprevir, every patient demonstrated a >2-log decrease in HCV RNA. Mean neopterin and ALAT levels decreased in all four groups receiving telaprevir alone. In contrast, mean neopterin levels increased and ALAT levels decreased in the Peg-IFN plus telaprevir and Peg-IFN plus placebo groups., Conclusions: These data suggest that treatment of chronic hepatitis C patients with an HCV NS3.4A protease inhibitor ameliorates inflammation. The increase in neopterin levels and the decrease in ALAT levels during administration of Peg-IFN with or without telaprevir are in accordance with earlier observations showing that IFN reduces hepatocyte injury but increases monocyte/macrophage activity. The IFN-mediated immunomodulatory effects appear to remain intact when IFN is combined with telaprevir.

Objective: To determine (i) whether early viral kinetics or other markers during a modified treatment regimen are predictors of treatment outcome and (ii) whether fast responders can be treated for 24 weeks, without compromising the sustained virologic response (SVR) rate., Material and Methods: One hundred "difficult-to-treat" chronic hepatitis C patients (46 previous non-responders/relapsers (any genotype), 54 treatment-naive patients genotypes 1 and 4) were treated with triple antiviral induction therapy: amantadine hydrochloride and ribavirin, combined with 6 weeks interferon alfa-2b induction (weeks 1-2: 18 MU/day, weeks 3-4: 9 MU/day, weeks 5-6: 6 MU/day), thereafter combined with weekly peginterferon alfa-2b. Fast responders (>or=3 log(10) HCV RNA decline at week 4) were randomized to 24 or 48 weeks. Slow responders (<3 log(10) HCV RNA decline at week 4) were treated for 48 weeks. Treatment was stopped in patients with detectable HCV RNA at week 24., Results: Thirty-six patients achieved SVR: 28 of 60 fast responders (47%) versus 8 of 32 slow responders (25%, p<0.05). Relapse rates among fast responders treated for 24 or 48 weeks were 27% and 20%, respectively (p=NS). SVR in fast responders was independent of baseline HCV RNA >or= or <600,000 IU/mL. All treatment-naive patients with HCV RNA <5 IU/mL at week 1 or 2 achieved SVR; all treatment-naive patients with HCV RNA >or=5 IU/mL at week 16 became non-SVR. In previous non-responders/relapsers, the predictive value for SVR was 83% if HCV RNA was <5 IU/mL at week 2; all previous non-responders/relapsers with HCV RNA >or=5 IU/mL at week 8 became non-SVR., Conclusions: With high-dose interferon induction, SVR and non-SVR can be predicted reliably within 16 weeks. Fast responders can be treated for 24 weeks, and SVR is independent of baseline viral load in fast responders.

Hepatitis C is a blood-borne virus infection with an estimated 180 million infected individuals worldwide. Hepatitis C virus (HCV) infection may lead to liver failure and cancer of the liver. In 2004, in view of the improved treatment options, the Dutch Health Council again recommended that the groups at risk of HCV infection should be tracked down and informed, and that epidemiological studies should be conducted. Currently, there are few data on the prevalence of HCV infection in the Netherlands. HCV risk groups are (former) injecting drug users, haemodialysis patients and haemophiliacs, people treated with blood or blood products before 1992, people who have undergone certain invasive or medical procedures with insufficiently sterilised instruments, household contacts and partners of HCV-infected individuals and children born to HCV-infected mothers. Insight into the epidemiology of HCV infection in the Netherlands is necessary so that reliable estimates of the magnitude of hepatitis C as a public health problem can be made. Several projects for the detection of HCV infected individuals and epidemiological studies have started in 2007.

Unlabelled: Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa-2a for 14 days. Previously untreated patients with genotype 1 hepatitis C were randomized to receive placebo and peginterferon alfa-2a (n = 4); telaprevir (n = 8); or telaprevir and peginterferon alfa-2a (n = 8). Telaprevir was given as 750 mg oral doses every 8 hours; peginterferon alfa-2a was given as weekly 180 mug subcutaneous injections. The median change in HCV RNA from baseline to day 15 was -1.09 log(10) (range, -2.08 to -0.46) in the placebo and peginterferon alfa-2a group; -3.99 log(10) (range, -5.28 to -1.26) in the telaprevir group, and -5.49 log(10) (range, -6.54 to -4.30) in the telaprevir and peginterferon alfa-2a group. Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa-2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa-2a. The majority of adverse events were mild. There were no serious adverse events or premature discontinuations. Twelve weeks after starting off-study standard therapy, HCV RNA was undetectable in all 8 patients in the telaprevir and peginterferon alfa-2a group, 5 patients in the telaprevir group, and 1 patient in the placebo and peginterferon alfa-2a group., Conclusion: This study confirmed the substantial antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir combined with peginterferon alfa-2a.

Background: In chronic hepatitis C patients with an initial virological response (IVR) during antiviral therapy (that is, HCV RNA becomes negative before week 16 of treatment) the significance of reappearing viraemia below the detection limit of PCR is not known. We studied this phenomenon in subsets of patients., Methods: We assessed HCV RNA at weeks 16 and 20 of therapy by PCR and by more sensitive transcription-mediated amplification (TMA) in 23 patients with breakthrough or relapse and in 34 patients with sustained virological response (SVR). All patients participated in a high-dose-interferon induction study for difficult-to-treat patients. Therapy consisted of amantadine hydrochloride and ribavirin, combined with interferon-alpha2b induction during the first 6 weeks and thereafter combined with weekly pegylated interferon-alpha2b., Results: Among the 57 IVR patients, we detected transient or persistent reappearance of low levels of HCV RNA in 10 of the 23 (43%) patients with eventual breakthrough or relapse; but in none of the 34 SVR patients. In 5 of 10 patients reappearing HCV RNA was only detectable by TMA., Conclusion: Reappearance of low levels of HCV RNA in patients with IVR predicts treatment failure.

Background & Aims: VX-950 specifically inhibits the NS3.4A protease of hepatitis C and has antiviral activity in vitro. This phase I, placebo-controlled, double-blind study evaluated the antiviral activity, pharmacokinetics, and safety of VX-950 in patients with chronic hepatitis C (CHC)., Methods: Thirty-four patients with genotype 1 CHC were randomized to receive placebo or VX-950 at doses of 450 mg or 750 mg every 8 hours or 1250 mg every 12 hours for 14 days. Of the 34 participants, 27 (79%) had failed prior treatment. Patients were monitored for safety and tolerability of VX-950. Plasma VX-950 concentrations and HCV RNA levels were measured., Results: VX-950 was well tolerated and had substantial antiviral effects: viral loads dropped > or =2 log(10) in all 28 patients treated with VX-950 and > or =3 log(10) in 26 (93%) of the 28 patients. In the 750-mg-dose group, which had the highest trough plasma drug concentrations, the median reduction of HCV RNA was 4.4 log(10) after 14 days. In the 450-mg and 1250-mg groups, the maximal effect was seen between days 3 and 7 of dosing, and median HCV RNA increased between days 7 and 14; median reductions at day 14 were 2.4 log(10) and 2.2 log(10), respectively. Median alanine aminotransferase levels decreased during dosing in all VX-950 groups., Conclusions: VX-950 was well tolerated and demonstrated substantial antiviral activity. Some patients had viral breakthrough during dosing, related to selection of variants with decreased sensitivity to VX-950. The results support further studies of VX-950 in patients with CHC.

A 9-year-old boy, a 15-year-old boy, and a 6-year-old girl were infected with chronic hepatitis C virus (HCV). They had no physical complaints and a virus genotype that was favourable to treatment with peginterferon-alpha and ribavirin. The younger boy and the girl had liver fibrosis and were treated for 6 months; the virus was eradicated from the boy's plasma and the fibrosis diminished, while the girl's plasma virus was again present shortly after the end of treatment. In the older boy with no fibrosis, treatment was temporarily suspended due to behaviour problems. HCV infection is a frequent cause of chronic hepatitis in children. A better understanding of its natural history, improvements in the efficacy of treatment, and more favourable outcomes seen in children compared with adults have gradually changed the consideration to treat children with chronic HCV infection over the last 10 years. The decision whether or not to treat depends primarily on the degree of liver damage, virus genotype, and the psychological condition and motivation of the patient. Screening patients at risk for chronic HCV infection and careful follow-up for liver damage in those with HCV infection have become even more important given the new insights regarding treatment.

Background/aims: Treatment of chronic hepatitis C with interferon can be ineffective due to relapse. We aimed to reduce the 40% relapse rate of 6 months interferon-ribavirin combination therapy by prolonging treatment to 18 months., Methods: Three hundred patients with treatment-naive hepatitis C, were randomized to 18 months combination therapy with interferon (3MU tiw) and ribavirin (1000-1200 mg/day), 18 months interferon combined with placebo, or 6 months combination therapy with interferon and ribavirin, in a double blinded manner. All 295 patients who received at least one dose of treatment were included in the intention to treat analysis., Results: At the end of treatment, HCV RNA was undetectable in 55 and 49% of those on 6 and 18 months combination therapy, respectively, versus 26% of those on monotherapy (P<0.001). The relapse rate was 38% for 6 months combination therapy, 38% for 18 months monotherapy, and only 13% for 18 months combination treatment (P=0.002). The sustained response rates were 34% for 6 months combination therapy, 16% for 18 months monotherapy and 43% for 18 months combination therapy (P<0.05)., Conclusions: Reduction of relapse rates to 15% or less is feasible by prolongation of interferon-ribavirin treatment to 18 months.

Thirty-seven chronic hepatitis C patients with virological relapse (VR) after previous interferon-alpha (IFN) or IFN/ribavirin (Riba) therapy, were re-treated. Patients were randomized for either IFN/Riba and amantadine (Ama) including a 2-week initial high IFN induction course (18 MU IFN daily) (group A) or the same 2-week IFN induction course combined with Riba/Ama, followed by Riba/Ama without IFN (group B). Treatment duration for both groups was 24 weeks with a 24-week follow-up thereafter. The inclusion in group B was prematurely stopped because all patients (n = 10) relapsed within 2 weeks after stopping IFN. Therefore, all subsequent patients were included in group A (n = 27). In group A, 44% achieved a sustained virological response (SVR) and 29% of the patients with an end-of-treatment virological response had a VR again. Of all pretreatment characteristics, only genotype non-1 patients had a significantly higher chance of achieving SVR (P < 0.001). Of the characteristics during treatment only a negative hepatitis C virus (HCV)-RNA test result in transcription-mediated amplification (TMA) at week 6 had a high predictive value for SVR, 80% in all patients and 92% in genotype non-1 patients. In conclusion, hepatitis C patients with a VR to previous antiviral treatment can be successfully re-treated with IFN induction combined with Riba/Ama for only 6 months, when they have genotype non-1 and a negative HCV-RNA test result in TMA 6 weeks after the start of therapy. Riba/Ama combination therapy without IFN does not prevent VR after 2 weeks high IFN induction.

Background: A rapid decrease of hepatitis C virus (HCV) RNA is interferon (IFN) dose-dependent, and a 3-log decline of HCV-RNA is a strong predictor of sustained virological response. In this study, viral kinetics of HCV RNA in patients treated with 18 MU interferon alpha (IFN-alpha) daily for 2 weeks are presented., Methods: Thirteen treatment-naive patients with chronic hepatitis C received 6 MU of IFN-alpha2a every 8 h for 2 weeks. Samples were obtained daily during the treatment period. HCV-RNA levels were determined using the quantitative VERSANT 3.0 bDNA assay (detection limit 520 IU/ml). When results were below the detection limit, HCV-RNA was measured by qualitative polymerase chain reaction (PCR) using the COBAS AMPLICOR HCV test, version 2.0 (detection limit of 50 IU/ml)., Results: In patients infected with genotype non-1, a 3-log decline of viral load was found 2.4 days after the start of induction therapy. Only one of three patients infected with genotype 1 had a 3-log decline in viral load within 14 days of the start of therapy. In four patients, a third phase of viral decline was observed. At the end of treatment, 10/13 (77%) and 7/13 (54%) patients were HCV-RNA-negative in quantitative assay and qualitative PCR, respectively. Only one of 13 patients achieved a sustained virological response (SVR)., Conclusion: Daily administration of 18 MU IFN-alpha to patients infected with genotype non-1 induces a 3-log decline of viral load within 2.4 days of the start of treatment. In patients infected with genotype 1, only one-third of patients have a 3-log decline at 11 days.

Background: In patients with chronic hepatitis C (HCV) Interferon-alpha (IFN) treatment for 12-18 months is more effective than 6 months in inducing a sustained virological response., Methods: In a multicenter, randomized, controlled trial, 88 patients with chronic HCV were enrolled (47 treated with IFN-alpha2b and 41 constituted an untreated control group). Treatment consisted of 5 million units (MU) IFN thrice a week (tiw) for 8 weeks and subsequently 2.5 MU IFN tiw for 16 weeks ('standard treatment'). After week 24 ('long-term treatment'), in virological non-responders treatment was continued using 5 MU IFN tiw for up to week 156, whereas in virological responders IFN was discontinued. In case of a virological relapse, treatment with 5 MU IFN tiw was restarted and continued up to week 156., Results: Sustained virological response rate was 6/47 (13%) after standard treatment and increased to 19/47 (40%) after long-term treatment (McNemar paired test; P = 0.002). Of the 18 patients with a breakthrough or relapse during or after standard treatment, 14 (78%) became sustained virological responders upon long-term treatment. Of the 4 patients who did not have a sustained virological response after long-term treatment, 3 did not receive complete treatment due to side effects and/or non-compliance. In patients who failed to respond to standard treatment, no virological response was observed during long-term treatment. In the control group, no spontaneous clearance of HCV was observed., Conclusions: Long-term IFN (re)treatment enhanced the virological sustained response rate significantly and was particularly effective in patients with a breakthrough or relapse following standard treatment.

We tested 50 heterosexual partners of hepatitis C viraemic (HCV) individuals, using second generation HCV antibody assays and a validated polymerase chain reaction assay. In none of them were HCV antibodies or HCV-RNA detected. The median duration of the sexual relationship was 13 years. This study, with the most sensitive techniques for detection of HCV, indicates that the risk of sexual transmission of HCV is absent or very low.