Common bile duct dilatation in drug users with chronic hepatitis C is associated with current methadone use.

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.

Is adding HCV screening to the antenatal national screening program in Amsterdam, the Netherlands, cost-effective?

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.

Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with pegylated interferon-α2a and adefovir.

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.

Screening for hepatitis B and C in first-generation Egyptian migrants living in the Netherlands.

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.

Evaluation of persistence of resistant variants with ultra-deep pyrosequencing in chronic hepatitis C patients treated with telaprevir.

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.

Low incidence of reinfection with the hepatitis C virus following treatment in active drug users in Amsterdam.

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.

Colonial history and contemporary transmission shape the genetic diversity of hepatitis C virus genotype 2 in Amsterdam.

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.

[New class of medicines for chronic hepatitis C]. / Nieuwe klasse medicijnen voor chronische hepatitis C.

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.

Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.

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.

Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design.

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.

Using mass media and the Internet as tools to diagnose hepatitis C infections in the general population.

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.

Hepatitis C testing and treatment among active drug users in Amsterdam: results from the DUTCH-C project.

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.

Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients.

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.

Safety and antiviral activity of JTK-652: a novel HCV infection inhibitor.

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.

Detection of hepatitis B virus covalently closed circular DNA in paraffin-embedded and cryo-preserved liver biopsies of chronic hepatitis B patients.

BACKGROUND: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may become an important predictor for treatment outcome or long-term follow-up. AIM: To detect cccDNA in formalin-fixed, paraffin embedded (FFPE) and to compare with cryo-preserved liver tissue. METHODS: Biopsies of 56 chronic hepatitis B patients were collected. Cryo-preserved and FFPE liver biopsies were available from 37 out of 56 patients. Paraffin was extracted with 1 ml xylene, followed by 100% alcohol and acetone. For the detection of cccDNA, selective primers were used. For quantification of hepatocytes a commercial Taqman beta-actin control kit was used. RESULTS: The cccDNA was detected in 80% of FFPE and in 100% of cryo-preserved liver specimens. Recovery of hepatocytes and cccDNA was approximately a 100-fold lower in FFPE liver tissue, but intrahepatic cccDNA levels were comparable. In FFPE and cryo-preserved liver tissue, intrahepatic cccDNA levels correlated strongly with HBV DNA, hepatitis B e antigen (HbeAg), and plasma cccDNA levels. HbeAg positive chronic hepatitis B patients had significantly higher intrahepatic cccDNA levels compared with HBeAg negative patients (P<0.05). In HBeAg positive patients, no difference in intrahepatic cccDNA levels were seen between patients with active (histological activity index score>3; HBV DNA>20 000 IU/ml) and inactive hepatitis (histological activity index score

Inflammatory markers neopterin and alanine aminotransferase in HCV patients treated with HCV NS3.4A protease inhibitor telaprevir (VX-950) and/or peginterferon alfa-2a.

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.

Prediction of virologic response in difficult-to-treat chronic hepatitis C patients during high-dose interferon induction therapy.

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.

High incidence of type 1 diabetes mellitus during or shortly after treatment with pegylated interferon alpha for chronic hepatitis C virus infection.

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.

Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C.

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.