Ramazan Idilman

Historical epidemiology of hepatitis C virus (HCV) in selected countries

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV‐related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3–5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Hepatic Steatosis: Quantification by Proton Density Fat Fraction with MR Imaging versus Liver Biopsy

PURPOSE To determine utility of proton density fat fraction (PDFF) measurements for quantifying the liver fat content in patients with nonalcoholic fatty liver disease (NAFLD), and compare these results with liver biopsy findings. MATERIALS AND METHODS This retrospective study was approved by the institutional review board with waivers of informed consent. Between June 2010 and April 2011, 86 patients received a diagnosis of NAFLD. Ten patients did not accept liver biopsy and six patients had contraindications for magnetic resonance (MR) imaging. Seventy patients were included in this study. Seventy patients with NAFLD (40 men, 30 women; mean age, 44.7 years; range, 16-69 years) underwent T1-independent volumetric multiecho gradient-echo imaging with T2* correction and spectral fat modeling. Median time interval between MR imaging and liver biopsy was 14.5 days (range, 0-259 days). MR examinations were performed with a 1.5-T MR imaging system. Complex-based PDFF measurements were performed by placing regions of interest in Couinaud system segments V-VI and all liver segments from I to VIII. All liver biopsy specimens were retrieved from archives and evaluated by one pathologist for hepatic steatosis according to criteria from a previous study. Pearson correlation coefficient, receiver operating characteristics, and linear regression analyses were used for statistical analyses. RESULTS Mean PDFF calculated with MR imaging was 18.1% ± 9.5 (standard deviation). Close correlation for quantification of hepatic steatosis was observed between PDFF and liver biopsy (r = 0.82). PDFF was effective in discriminating moderate or severe hepatic steatosis from mild or no hepatic steatosis, with area under the curve of 0.95. The correlation between biopsy and PDFF-determined steatosis was less pronounced when fibrosis was present (r = 0.60) than when fibrosis was absent (r = 0.86; P = .02). CONCLUSION PDFF measurement by MR imaging provided a noninvasive, accurate estimation of the presence and grading of hepatic steatosis in patients with NAFLD. Hepatic fibrosis reduced the correlation between biopsy results and PDFF.

Pathogenesis of hepatitis B and C‐induced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is estimated to have an annual worldwide incidence of 0.25 to 1.2 million new cases per year. Both the prevalence and incidence of HCC vary markedly as a function of geography and the local prevalence of chronic viral hepatitis. Both chronic hepatitis B and chronic hepatitis C are recognized as risk factors for HCC. The prevalence of cirrhosis in individuals with HCC and chronic hepatitis B or C is reported to be 80.9% and 75.8%, respectively. HCC occurs at a lower rate in chronic viral hepatitis in the absence of cirrhosis. Moreover, hepatitis C virus (HCV) rather than hepatitis B virus (HBV) is associated with the majority of non‐cirrhotic cases of HCC. It is probable that the ongoing process of hepatocyte necrosis and liver cell renewal coupled with inflammation, which is characteristic of chronic viral hepatitis, causes not only nodular regeneration and cirrhosis but also progressive genomic errors in hepatocytes as well as unregulated growth and repair mechanisms leading to hepatocyte dysplasia and, in some cases, hepatic carcinoma. Current concepts concerning virus‐induced HCC are reported and discussed in the following review.

The impact of previous HBV infection on the course of chronic hepatitis C

OBJECTIVE:Individuals with chronic hepatitis C who are anti-HBc positive may carry an occult hepatitis B virus (HBV) infection that can affect their response to antiviral therapy.METHODS:In this study the prevalence of anti-HBc and HBV–DNA positivity was assessed in the serum and liver of 285 HCV–RNA-positive subjects treated with interferon-α at 5 mU/day for 12 months. The response to interferon (normal ALT and undetectable serum HCV–RNA) was evaluated at three different endpoints: 1) after 6 months; 2) at the end of treatment; and 3) 6 months after interferon discontinuation.RESULTS:Ninety individuals were anti-HBc positive (32%), 2 of these were HBV–DNA positive in serum and 7 in liver (8%). None of the anti-HBc-negative individuals was HBV–DNA positive in serum or liver. The prevalence of cirrhosis was greater in the anti-HBc-positive group than in the anti-HBc-negative group (p < 0.05), whereas HCV–RNA levels were lower. Anti-HBc-positive individuals had a lower response rate to interferon at 6 months and at the end of treatment as compared to anti-HBc-negative subjects (respectively 42% vs 66%, p < 0.01; and 32% vs 57%, p < 0.01). No difference between the two groups in terms of sustained response was detected 6 months after interferon discontinuation.CONCLUSIONS:The prevalence of anti-HBc is high among HCV-positive individuals. HCV-positive individuals who are anti-HBc positive have: 1) a higher prevalence of cirrhosis; 2) lower HCV–RNA levels; and 3) an impaired ability to respond to interferon treatment.

Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies.

Summary.  Although hepatitis B virus (HBV) reactivation in HBV carriers undergoing immunosuppressive therapy is clearly documented, the role of antiviral prophylaxis in such individuals is still controversial. The aim of this study was to determine the efficacy of lamivudine prophylaxis in HBV carriers with haemato/oncological malignancies, who receive chemotherapy. Eighteen HBV carriers with malignancy, who were candidates for chemotherapy, were enrolled. Eight subjects (three with leukaemia, four with lymphoma and one with multiple myeloma) were enrolled for prophylactic lamivudine therapy. The remaining 10 patients (six with leukaemia, three with lymphoma and one with breast cancer) were not treated with lamivudine and were used as a control. Lamivudine was administered beginning on the same day as the chemotherapy and was maintained for a year after chemotherapy was discontinued. No HBV‐related mortality was observed in either group. In the lamivudine‐treated group, none of the subjects had clinical, biochemical or serological evidence of HBV reactivation during the time they were receiving chemotherapy and after their chemotherapy was discontinued. In contrast, five of the 10 HBV carriers not receiving lamivudine therapy experienced a reactivation of HBV infection. This reactivation of HBV was observed during the chemotherapy in four with one individual experiencing a HBV activation 12 months after chemotherapy was discontinued. No lamivudine‐related major adverse effects were observed. Hence prophylactic lamivudine treatment in HBV carriers with haemato/oncological malignancy receiving chemotherapy prevents chemotherapy‐induced HBV reactivation.

Clinical trial: insulin‐sensitizing agents may reduce consequences of insulin resistance in individuals with non‐alcoholic steatohepatitis

Background  Currently, although only a few therapies normalize the liver test abnormalities with/without improving the liver histology, no pharmacologic therapy has proved to be effective for the treatment of non‐alcoholic steatohepatitis.

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)

Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB), treated with entecavir (ETV) or tenofovir (TDF), is unclear. We evaluated the incidence and predictors of HCC and the accuracy of existing HCC risk scores in Caucasian CHB patients receiving ETV/TDF. METHODS This large, multicentre, retrospective cohort study included 1666 adult Caucasian CHB patients under ETV/TDF for 39 months. CHB without cirrhosis, compensated and decompensated cirrhosis were present in 67%, 39%, and 3% of patients, respectively. The predictability of baseline parameters and three risk scores (GAG-HCC, CU-HCC, and REACH-B), developed in Asian patients, was assessed. RESULTS The cumulative probability of HCC was 1.3%, 3.4%, and 8.7% at year-1, year-3, and year-5 after ETV/TDF onset. Older age and lower platelets were strong independent HCC predictors in the total population and in the subgroups of cirrhotic and non-cirrhotic patients, while liver disease severity was an independent HCC predictor in the total population and in the cirrhotics. GAG-HCC, CU-HCC, and REACH-B risk scores were associated with HCC development only in the univariable but not in the multivariable analyses and offered poor to modest predictability. CONCLUSIONS HCC can still develop in Caucasian CHB patients treated with ETV/TDF. Besides the well-known predictors of HCC, such as older age, male gender and more advanced liver disease, lower platelets represent an independent factor of higher HCC risk. The applicability and predictability of HCC risk scores developed in Asian patients are poor or modest in Caucasian CHB patients, for whom different risk scores are required.

Natural history and treatment of chronic delta hepatitis

Summary.  Chronic delta hepatitis (CDH) represents a severe form of chronic viral hepatitis, induced by the hepatitis delta virus (HDV) in conjunction with the hepatitis B virus (HBV). Delta hepatitis may lead to disease in humans through co‐infection. The former leads to acute hepatitis which clinically can range from mild hepatitis to fulminant hepatitis and death. Severe or fulminant hepatitis is more often observed with HBV‐HDV co‐infection compared to HBV mono‐infection. Chronic infection after acute hepatitis B + D co‐infection is infrequent and similar to the rate in mono‐infected patients. CDH develops in 70–90% of patients with superinfection. CDH runs a more progressive course than chronic hepatitis B and may lead to cirrhosis within 2 years in 10–15% of patients. However, as with any immune‐mediated disease, different patterns of progression, ranging from mild to severe progressive disease, are observed. Active replication of both HBV and HDV may be associated with a more progressive disease pattern. Further, different HDV and HBV genotypes may contribute to various disease outcomes. CDH may be frequently associated with hepatocellular carcinoma development although recent studies provided conflicting results. The only established therapy for CDH is treatment with interferons for a duration of at least 1 year. On treatment, 6 month HDV RNA assessment may give clues as to whether to stop treatment at 1 year or continue beyond 1 year. New approaches to treatment of CDH are an urgent need of which the use of prenylation inhibitors appears the most promising.