Antiviral Combination Therapy with Interferon/Peginterferon Plus Ribavirin for Patients with Chronic Hepatitis C in Germany: A Health Technology Assessment Commissioned by the German Agency for Health Technology Assessment

Objective: The purpose of this health technology assessment (HTA), commissioned by the German Agency for HTA at the German Federal Ministry of Health and Social Security, was to systematically review the evidence on effectiveness and cost-effectiveness of antiviral treatment (AVT) for initial chronic hepatitis C (CHC) and to apply these data in the context of the German health care system. Methods: A systematic literature search was conducted to identify randomised controlled trials (RCTs), meta-analyses, and HTAs that evaluated initial AVT for CHC. A modified version of the German Hepatitis C Model (GEHMO) -- a decision-analytic Markov model -- was used to determine long-term morbidity, life expectancy, quality of life, costs and cost-effectiveness of different treatment strategies. Model parameters were derived from German databases, international RCTs, and a Cochrane Review. Results: Overall, 9 RCTs, 2 HTA reports, 1 Cochrane review, and 2 meta-analyses examining medical effectiveness of antiviral combination therapy, as well as 7 economic evaluations, met the inclusion criteria. These studies indicate that combination therapy with peginterferon plus ribavirin produced the highest sustained virological response rates (54-61%), followed by interferon plus ribavirin with 38-54%, and interferon monotherapy with 11-21%. Based on international cost-effectiveness studies, interferon plus ribavirin is cost-effective compared to interferon monotherapy. No published articles were available regarding cost-effectiveness of peginterferon plus ribavirin. In our decision analysis, these findings were confirmed and the discounted incremental cost-effectiveness ratio for peginterferon plus ribavirin was € 9,800 per quality-adjusted life-year gained compared to interferon monotherapy (as the next best non-dominated strategy). Sensitivity analyses showed robust results across a wide range of model parameters. Conclusions: This HTA suggests that initial combination therapy prolongs life, improves quality of life, and is cost-effective in patients with CHC. Combination of peginterferon and ribavirin is the most effective and efficient treatment strategy among the examined options

Hepatitis B and C Viruses and Hepatocellular Carcinoma

Chronic liver disease is responsible for over 1.4 million deaths annually  [1] and is characterized by permanent inflammatory processes that predispose to liver cancer and in particular hepatocellular carcinoma (HCC). In healthy liver, inflammatory processes stimulate growth and repair and restore normal liver architecture. However, if liver inflammation becomes chronic, the balance of damage versus regeneration in the liver is disrupted and can lead to the formation of excessive scar tissue, termed fibrosis. In the long-term, an exacerbation of fibrosis will lead to cirrhosis, which is characterized by abnormal liver architecture and function and is associated with a significant reduction in overall health and wellbeing. At cirrhotic stages, liver damage is often irreversible or difficult to treat. Cirrhosis leads frequently to death from liver failure or to HCC (Figure 1). Indeed, HCC is the first cause of death in cirrhotic patients [2], and is a tumor with poor prognosis, ranking third in terms of death by cancer. Furthermore, it is the fifth most prevalent cancer worldwide, with 800,000 new cases per year in the world [2,3]. [...

Hepatitis B and C in Europe: an update from the Global Burden of Disease Study 2019.

BackgroundIn 2016, the World Health Assembly adopted the resolution to eliminate viral hepatitis by 2030. This study aims to provide an overview of the burdens of hepatitis B virus (HBV) and hepatitis C virus (HCV) in Europe and their changes from 2010 to 2019 using estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.MethodsWe used GBD 2019 estimates of the burden associated with HBV-related and HCV-related diseases: acute hepatitis, cirrhosis and other chronic liver diseases, and liver cancer. We report total numbers and age-standardised rates per 100 000 for mortality, prevalence, incidence, and disability-adjusted life-years (DALYs) from 2010 to 2019. For each HBV-related and HCV-related disease and each measure, we analysed temporal changes and percentage changes for the 2010-19 period.FindingsIn 2019, across all age groups, there were an estimated 2·08 million (95% uncertainty interval [UI] 1·66 to 2·54) incident cases of acute hepatitis B and 0·49 million (0·42 to 0·57) of hepatitis C in Europe. There were an estimated 8·24 million (7·56 to 8·88) prevalent cases of HBV-related cirrhosis and 11·87 million (9·77 to 14·41) of HCV-related cirrhosis, with 24·92 thousand (19·86 to 31·03) deaths due to HBV-related cirrhosis and 36·89 thousand (29·94 to 45·56) deaths due to HCV-related cirrhosis. Deaths were estimated at 9·00 thousand (6·88 to 11·62) due to HBV-related liver cancer and 23·07 thousand (18·95 to 27·31) due to HCV-related liver cancer. Between 2010 and 2019, the age-standardised incidence rate of acute hepatitis B decreased (-22·14% [95% UI -35·44 to -5·98]) as did its age-standardised mortality rate (-33·27% [-43·03 to -25·49]); the age-standardised prevalence rate (-20·60% [-22·09 to -19·10]) and mortality rate (-33·19% [-37·82 to -28·13]) of HBV-related cirrhosis also decreased in this time period. The age-standardised incidence rate of acute hepatitis C decreased by 3·24% (1·17 to 5·02) and its age-standardised mortality rate decreased by 35·73% (23·48 to 47·75) between 2010 and 2019; the age-standardised prevalence rate (-6·37% [-8·11 to -4·32]), incidence rate (-5·87% [-11·24 to -1·01]), and mortality rate (-11·11% [-16·54 to -5·53]) of HCV-related cirrhosis also decreased. No significant changes were observed in age-standardised rates of HBV-related and HCV-related liver cancer, although we observed a significant increase in numbers of cases of HCV-related liver cancer across all ages between 2010 and 2019 (16·41% [2·81 to 30·91] increase in prevalent cases). Substantial reductions in DALYs since 2010 were estimated for acute hepatitis B (-27·82% [-36·92 to -20·24]), acute hepatitis C (-27·07% [-15·97 to -39·34]), and HBV-related cirrhosis (-30·70% [-35·75 to -25·03]). A moderate reduction in DALYs was estimated for HCV-related cirrhosis (-6·19% [-0·19 to -12·57]). Only HCV-related liver cancer showed a significant increase in DALYs (10·37% [4·81-16·63]). Changes in age-standardised DALY rates closely resembled those observed for overall DALY counts, except for HCV-liver related cancer (-2·84% [-7·75 to 2·63]).InterpretationAlthough decreases in some HBV-related and HCV-related diseases were estimated between 2010 and 2019, HBV-related and HCV-related diseases are still associated with a high burden, highlighting the need for more intensive and coordinated interventions within European countries to reach the goal of elimination by 2030.FundingBill & Melinda Gates Foundation

A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C

Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome. Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome

Is Response to Anti-HCV Treatment Predictive of Mortality in HCV/HIV Positive Patients?

BACKGROUND: Long-term clinical outcomes after HCV treatment of HIV/HCV patients are not well described. We aimed to compare the risk of all-cause and liver-related death according to HCV treatment response in HIV/HCV patients in the multi-cohort study COHERE. METHODS: All patients who had started PEG-interferon + ribavirin (baseline) and followed for ≥72 weeks after baseline were included. Patients were categorized into three response groups depending on treatment duration and HCV-RNA measured in the window 24-72 weeks after baseline. Patients who received ≥24 weeks of therapy were defined as responders if their last HCV-RNA measured between 24-72 weeks after baseline was negative, and having "unknown response" if HCV-RNA was unknown. Non-responders were treated for less than 24 weeks or were HCV-RNA+ between 24-72 weeks after baseline.Mortality rates were compared using survival analysis, and Cox regression used to compare hazard ratios of death between response groups. RESULTS: 3,755 patients were included: 1031 (27.5%) responders, 1,639 (43.6%) non-responders and 1085 (28.9%) with unknown response. Rates (per 1,000 PYFU, 95% CI) of all-cause death were 17.59 (14.88-20.78), 10.43 (7.62-14.28) and 11.00 (8.54-14.23) for non-responders, responders and unknown responders, respectively. After adjustment, the relative hazard (non-responders vs. responders) for all-cause death, liver-related death and non-liver-related death was 1.53 (95% CI 1.06-2.22), 3.39 (95% CI 1.32-8.75) and 1.22 (95% CI 0.80-1.84), respectively. CONCLUSION: HIV/HCV patients with a favourable virological response to PEG-interferon + ribavirin had reduced risk of all-cause and liver-related death, while there was no difference in risk of non-liver-related death when comparing responders and non-responders

All-Cause Mortality and Causes of Death in the Swiss Hepatitis C Cohort Study (SCCS).

With direct-acting antiviral agents (DAAs), mortality rates and causes of death among persons with hepatitis C virus (HCV) infection may change over time. However, the emergence of such trends may be delayed by the slow progression of chronic hepatitis C. To date, detailed analyses of cause-specific mortality among HCV-infected persons over time remain limited. We evaluated changes in causes of death among Swiss Hepatitis C Cohort Study (SCCS) participants from 2008 to 2016. We analyzed risk factors for all-cause and cause-specific mortality, accounting for changes in treatment, fibrosis stage, and use of injectable drugs over time. Mortality ascertainment was completed by linking lost-to-follow-up participants to the Swiss Federal Statistical Office death registry. We included 4700 SCCS participants, of whom 478 died between 2008 and 2016. The proportion of unknown causes of death decreased substantially after linkage, from 42% to 10%. Leading causes of death were liver failure (crude death rate 4.4/1000 person-years), liver cancer (3.4/1000 person-years), and nonliver cancer (2.8/1000 person-years), with an increasing proportion of cancer-related deaths over time. Cause-specific analysis showed that persons with sustained virologic response were less at risk for liver-related mortality than those never treated or treated unsuccessfully. Although the expected decrease in mortality is not yet observable, causes of death among HCV-infected persons have evolved over time. With the wider use of DAAs, liver-related mortality is expected to decline in the future. Continued monitoring of cause-specific mortality will remain important to assess the long-term effect of DAAs and design effective interventions

IL28B genetic variants and gender are associated with spontaneous clearance of hepatitis C virus infection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90125/1/j.1365-2893.2011.01497.x.pd

Hepatitis B virus infected health care workers in the Netherlands, 2000-2008

In response to the confirmed transmission of hepatitis B virus (HBV) from a surgeon to several patients in the Netherlands, a ‘Committee for Prevention of Iatrogenic Hepatitis B’ was established in 2000. During the years 2000–2008, the committee reviewed 99 cases of HBV-infected health care workers. Fifty of them were found to perform exposure prone procedures (EPPs). Because of high levels of HBV DNA (>100,000 copies/ml), a ban on performing EPPs was applied in 11/50 cases; 25/50 low-viremic health care workers were allowed to continue EPPs while their HBV load was being monitored; and 14/50 cases had stopped working or changed profession. In five restricted workers who started oral antiviral treatment, HBV replication was persistently suppressed, enabling the ban on EPPs to be lifted. Throughout the European Union different levels of HBV viremia have been chosen, above which health care workers are not allowed to perform EPPs. It remains unknown how this affects the safety of patients. Application in the Netherlands of a European or a British guideline would have, respectively, doubled or tripled the number of restricted health care workers