Krzysztof Simon

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel

Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country‐specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel.

Sustained HBeAg and HBsAg Loss After Long-term Follow-up of HBeAg-Positive Patients Treated With Peginterferon α-2b

BACKGROUND & AIMS The aim of this study was to evaluate the long-term sustainability of response in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with pegylated interferon (PEG-IFN) alpha-2b alone or in combination with lamivudine. METHODS All 266 patients enrolled in the HBV99-01 study were offered participation in a long-term follow-up (LTFU) study. Patients were treated with PEG-IFN alpha-2b (100 mug/wk) alone or in combination with lamivudine (100 mg/day) for 52 weeks. Initial response was defined as HBeAg negativity at 26 weeks posttreatment. For the LTFU study, patients had one additional visit after the initial study (mean interval, 3.0 +/- 0.8 years). RESULTS Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A-infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001). CONCLUSIONS HBeAg loss after treatment with PEG-IFN alpha-2b alone or in combination with lamivudine is sustained in the majority of patients and is associated with a high likelihood of HBsAg loss, particularly in genotype A-infected patients. Therefore, PEG-IFN alpha-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy.

Early on‐treatment prediction of response to peginterferon alfa‐2a for HBeAg‐negative chronic hepatitis B using HBsAg and HBV DNA levels

Peginterferon alfa‐2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B (CHB). This study investigated the role of early on‐treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg‐negative patients receiving peginterferon alfa‐2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow‐up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa‐2a, n = 53, versus peginterferon alfa‐2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa‐2a treatment for HBeAg‐negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on‐treatment adjustments of peginterferon therapy for HBeAg‐negative CHB. (HEPATOLOGY 2010)

Adding pegylated interferon to entecavir for hepatitis B e antigen–positive chronic hepatitis B: A multicenter randomized trial (ARES study)

Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long‐term therapy may be required. We investigated whether adding on pegylated interferon (Peg‐IFN) to ETV therapy enhances serological response rates. In this global investigator‐initiated, open‐label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg‐IFN add‐on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add‐on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg‐IFN add‐on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6‐14.0; P = 0.004). Eleven (13%) of the add‐on‐treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add‐on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg‐IFN add‐on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. Conclusion: Although the primary endpoint was not reached, 24 weeks of Peg‐IFN add‐on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add‐on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg‐IFN add‐on therapy may facilitate the discontinuation of nucleos(t)ide analogs. (Hepatology 2015;61:1512–1522)

A Randomized Trial of Peginterferon α-2a With or Without Ribavirin for HBeAg-Negative Chronic Hepatitis B

OBJECTIVES:Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon α-2a with ribavirin might improve sustained response rates.METHODS:Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon α-2a 180 μg weekly plus placebo) or combination therapy (peginterferon α-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients.RESULTS:At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline −3.9 vs. −2.6 log copies/ml, P<0.001 and −0.56 vs. −0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia.CONCLUSIONS:Treatment with peginterferon α-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.

A randomized, placebo‐controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double‐blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1‐3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2‐point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent‐to‐treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754‐1767).

Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B.

Peginterferon (PEG‐IFN) treatment of hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG‐IFN treatment affects serological and virological response. A total of 214 HBeAg‐positive CHB patients treated with PEG‐IFN±lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non‐WT (detectable mutants at PC/BCP) by line‐probe assay. Response was assessed at 6 months posttreatment and through long‐term follow‐up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non‐WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non‐WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non‐WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15‐7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26‐24.63, P = 0.013) and patients with non‐A genotypes with detectable mutants had a low probability of response. Conclusion: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG‐IFN for HBeAg‐positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG‐IFN therapy. (HEPATOLOGY 2012;56:67–75)

Durable hepatitis B surface antigen decline in hepatitis B e antigen-positive chronic hepatitis B patients treated with pegylated interferon-α2b: relation to response and HBV genotype.

BACKGROUND On-treatment decline of serum hepatitis B surface antigen (HBsAg) may reflect the immunomodulatory effect of pegylated interferon (PEG-IFN) for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). We compared HBsAg decline across HBV genotypes between combined responders (HBeAg loss and HBV DNA<10,000 copies/ml at week 78), HBeAg responders (HBeAg loss with HBV DNA>10,000 copies/ml) and non-responders. METHODS HBsAg was measured at baseline, on-treatment and 6 months post-treatment in 221 HBeAg-positive CHB patients treated with PEG-IFN with or without lamivudine for 52 weeks, and in a representative subgroup of 142 patients at long-term follow-up (LTFU; mean 3.0 years). RESULTS On-treatment HBsAg decline significantly varied according to HBV genotype (A and B more than C and D; P<0.001). On-treatment HBsAg decline also differed between patients with a combined response (n=43) and those without (n=178; 3.34 versus 0.69 log IU/ml decline at week 52; P<0.001). Among patients without a combined response, no difference was observed between HBeAg responders (n=41) versus non-responders (n=137). HBsAg decline was sustained in combined responders and progressed to 3.75 log IU/ml at LTFU. Patients with a combined response achieved pronounced HBsAg declines, irrespective of HBV genotype, and those who achieved HBsAg levels <1,000 IU/ml at week 78 had a high probability of a sustained response and HBsAg clearance through LTFU. CONCLUSIONS On-treatment HBsAg decline during PEG-IFN therapy for HBeAg-positive CHB depends upon HBV genotype. Patients with a combined response to PEG-IFN achieve a pronounced HBsAg decline, irrespective of HBV genotype, which is sustained through 3 years of off-treatment follow-up.

Real-world effectiveness and safety of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C: AMBER study.

Virologic and safety outcomes of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) therapy have shown high sustained virologic response (SVR) rates and good tolerability in most patient populations in pre‐registration studies.

Prevalence and risk factors of HCV infection in Poland.

Background According to small studies carried out in preselected populations, the estimated prevalence of anti-hepatitis C virus (HCV) antibodies in Poland ranges from 0.6 to 2.1%. Aims The aim of this study was to evaluate the prevalence of anti-HCV and HCV RNA among patients and healthcare workers. Methods Anti-HCV antibodies were measured (Elecsys, Roche) in serum samples from 26 057 adults, consecutive patients or healthcare workers, from hospitals and out patient clinics not involved in the management of liver diseases. The majority of them (18 233) consented to fill out an anonymous questionnaire related to possible risk factors for HCV infection. Anti-HCV-positive samples were assessed for HCV RNA (Cobas Amplicor, Roche). A multivariate logistic regression model and the &khgr;2 test or the Fishers exact test were applied. Results Anti-HCV antibodies were detected in 1.9% of individuals, and 31% of them demonstrated HCV RNA, which varied from 26% in hospitals to 66% in specialistic out-patient clinics. Prevalence of anti-HCV was significantly lower in healthcare workers (1.42%) than in patients (1.92%). Significant independent risk factors for anti-HCV positivity were as follows: male sex, more than three hospitalizations in a lifetime, blood transfusions before 1992, and intravenous drug use. The only significant risk factor for HCV RNA was intravenous drug use. An analysis carried out for multispecialistic hospitals demonstrated significantly lower prevalence of HCV RNA positivity in healthcare workers. Conclusion Prevalence of anti-HCV in the Polish population studied was up to 1.9%, but active infection could be diagnosed in only 31% of them. Intravenous drug use, blood transfusions before 1992, multiple hospitalizations, and male sex increase the risk of HCV infection.