Association of antiviral therapy with reduced disease progression in chronic Hepatitis B patients: Results from a nation-wide cohort study.

BACKGROUND AND AIMS: Although effective treatment in terms of inducing virological and biochemical response for chronic hepatitis B (CHB) is available, its effect on the clinical course of the disease has not yet been accurately estimated. Objective of this study was to evaluate the effect of antiviral therapy and its type [interferon +/- nucleos(t)ide analogs (NAs) vs. NAs] on the occurrence of a clinical event (liver decompensation, liver transplant, hepatocellular carcinoma and death from a liver-related cause) in CHB patients. METHODS: The study population was derived from the HEPNET-Greece, a nationwide cohort study aimed to evaluate the current epidemiological course of viral hepatitis. To account for time-dependent confounding, Cox marginal structural models were used to analyze data. RESULTS: Thirty out of 2,125 eligible patients experienced a clinical event during their follow-up. When comparing treated to untreated individuals, the hazard ratio (HR) for a clinical event was 0.39 (95% CI: 0.16-0.98; p =0.044) in the whole sample, whereas there were indications of a more intense effect in the subgroup of patients with cirrhosis at presentation (HR =0.16, 95% CI: 0.02-1.21; p =0.075). The effect of Interferon initiated treatment was not significantly different of that of NAs. There was some evidence, albeit not statistically significant, of a protective treatment effect on hepatocellular carcinoma development (HCC). CONCLUSIONS: Data from observational studies can provide useful inference, provided they are analyzed appropriately. The current study has shown that the available treatment options for CHB offer a significant clinical benefit to CHB infected individuals. Hippokratia 2016, 20(3): 214-221.

Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort.

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.

Genotype 4 HCV infection is difficult to cure with pegylated interferon and ribavirin. Results from a Greek Nationwide Cohort Study.

BACKGROUND AND AIM: Patients with genotype 4 (G4) chronic hepatitis C (CHC) are considered a difficult to treat population, although current data on G4 treatment responsiveness and duration are controversial. Greece represents a country with an intermediate prevalence of G4 infections, offering an opportunity to compare treatment outcomes by genotype and to identify potential prognostic factors for sustained virologic response (SVR). METHODS: All CHC patients from the HepNet.Greece, an ongoing nationwide cohort study on viral hepatitis, with known hepatitis C virus (HCV) genotype who received treatment with Peg-IFNa and ribavirin were analyzed. RESULTS: From 4443 patients, 951 (61.7% males, 78.4% Greeks, median age 40.6 years, 10% cirrhosis) fulfilled the inclusion criteria. G4 was found in 125 (13.1%) patients. Genotype distribution was not significantly different between Greeks and immigrants. Patients with G4 had similar odds of SVR compared to G1 but significantly lower compared to G2/G3. Age, treatment discontinuation, presence of cirrhosis and previous history of HCV-treatment were associated with lower probabilities of SVR. Ethnicity did not affect SVR for all genotypes while response to treatment was similar between Greek and Egyptian patients groups (35.7% vs 40.9%, p=0.660%) with G4 infection. The relation between SVR and genotype did not substantially change after adjustment for age, gender, cirrhosis, treatment interruption and history of HCV-treatment. CONCLUSIONS: The findings of this large cohort of CHC patients with a well balanced genotype distribution further supports the idea of considering G4 as a difficult to treat genotype. Further investigation is needed to identify genotype specific prognostic factors.

Cirrhosis but not neutropenia is associated with the development of infection in patients with chronic hepatitis C undergoing treatment with pegylated interferon-alpha and ribavirin.

Peginterferon-alpha (PegIFNa) frequently causes neutropenia, mainly due to bone marrow suppression. The aim of this study was to explore factors that are associated with infections during antiviral treatment. We analysed data from 275 chronic hepatitis C (CHC) patients with compensated liver disease who underwent 318 courses of PegIFNa and ribavirin. Neutropenia was defined as neutrophils <1000 cells/µL. Mean leucocytes count significantly decreased from baseline to treatment nadir (7081 ± 2182 vs 3293 ± 1331 cells/µL, P < 0.001), while neutropenia was observed in 32% during treatment. Thirty-one infections were observed. The incidence rate for infection was assessed at 1.46 infections per 100 person-months of therapy. The hazard rate for infection did not correlate with the neutrophils' nadir or the decrease in white blood cells. In multivariate Cox's regression analysis, cirrhosis was the only factor that was significantly associated with the occurrence of infection. Our data show that the development of bacterial infections during treatment with PegIFNa and ribavirin in patients with compensated CHC is not associated with reduction or the nadir of white cells or neutrophil counts. Baseline cirrhosis is the only factor related with infection during treatment. The common practice of dose adjustment or discontinuation of interferon should be revised; careful assessment of liver damage before therapy and close monitoring during therapy are essential in all patients receiving interferon-based regimes, to minimize the detrimental consequences of infections.

Molecular epidemiology of hepatitis C virus (HCV) in Greece: temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates.

This study aimed to estimate the overall HCV genotype distribution and to reconstruct the HCV genotype-specific incidence in Greece during the recent decades. It also focused at the identification of genotype 4 subtype variability in Greek isolates. A total of 1686 chronically infected HCV patients with detectable serum HCV RNA by RT-PCR, belonging to different risk groups were studied. Amplified products from the 5'-noncoding region were typed using a commercially available assay based on the reverse hybridization principle. The HCV genotype-specific incidence was estimated using a previously described back calculation method. HCV genotype 1 was the most prevalent (46.9%) followed by genotype 3 (28.1%), 4 (13.2%), 2 (6.9%) and 5 (0.4%). A high prevalence of genotype 1 (66.3%) in haemophilia patients was recorded whereas HCV genotype 3 was found mainly among patients infected by I.V. drug use (58.2%). Data on the temporal patterns of HCV genotype-specific incidence in Greece revealed a moderate increase (1.3-1.6 times) for genotypes 1 and 4, and a decrease (1.5 times) for genotype 2 from 1970 to 1990, whereas there was a sharp (13-fold) increase for genotype 3. The molecular characterization of 41 genotype 4 HCV isolates belonging to various risk groups revealed that, subtype 4a was the most frequently detected (78%). Phylogenetic comparison of the Greek 4a isolates with all HCV-4a isolates reported worldwide so far revealed a topology which does not discriminate Greek isolates from the others. HCV-4 does not represent a recent introduction in Greece.

Future trends of HCV-related cirrhosis and hepatocellular carcinoma under the currently available treatments.

SUMMARY: The epidemic of hepatitis C virus (HCV) infection is a major public health issue. We conducted a comprehensive analysis to estimate future HCV-related morbidity and mortality, using a model which is the first to take into account currently available treatments. We reconstructed the incident infections per year in the past that progressed to chronic hepatitis C (CHC) in Greece. Then, the natural history of the disease was simulated in subcohorts of newly infected subjects in the presence or absence of treatment using yearly estimates of the number of treated patients obtained from national databases. Annual estimates of the incidence and prevalence of CHC by fibrosis stage, hepatocellular carcinoma (HCC) and mortality were obtained up to 2030. The current proportion of naïve CHC patients receiving treatment in Greece is 1.2% per year. Treatment of 1.2-10% of naïve CHC patients per year would reduce the cumulative number of incident cirrhosis and HCC cases from 2002 to 2030 by 10.8-39.4% and 12.8-39.8%, respectively and decrease the number of prevalent cirrhosis and HCC cases in 2030 by approximately 17-48% compared with the number estimated under the assumption of no treatment. Approximately 17 cirrhosis cases or six HCC cases or 10 premature deaths would be prevented for every 100 treated patients. However, the prevalent cirrhotic/HCC cases because of HCV and HCV-related deaths would not plateau until 2030. Despite the introduction of effective treatment, HCV-related morbidity and mortality will likely increase during the next 20-30 years in Greece. Intensive primary prevention efforts coupled with increased access to the currently available treatments are necessary to control the chronic consequences of HCV epidemic.

Autoimmune pancreatitis.

Autoimmune pancreatitis is a type of idiopathic pancreatitis. It is also referred to as sclerosing pancreatitis, lymphoplasmatocytic sclerosing pancreatitis, chronic pancreatitis with irregular stenosis of the main pancreatic duct and as sclerosing pancreatocholangitis. Clinical characteristics of autoimmune pancreatitis are jaundice, abdominal pain, weight loss and diabetes mellitus. Radiologically, there is diffuse enlargement of pancreas with stenosis of pancreatic duct without calcifications in the pancreatic parenchyma. In autoimmune pancreatitis, antibodies against lactoferrin and carbonic anhydrase have been detected, but they are not specific because they are present in some other autoimmune diseases too. Also in autoimmune pancreatitis, there are increased levels of gammaglobulins and characteristically high titres of IgG4, which are a subtype of IgG. Autoimmune pancreatitis is usually treated successfully by prednisolone.

Impact of interferon-alpha therapy on liver fibrosis progression in patients with HBeAg-negative chronic hepatitis B.

The possible effect of interferon-alpha (IFNa) on liver fibrosis progression has not been adequately studied in chronic hepatitis B. We evaluated 147 patients with HBeAg-negative chronic hepatitis B who had > or =2 liver biopsies and had been treated with IFNa (n = 120) or had remained untreated (n = 27). The median interval between the two biopsies was 24 (12-160) months. All biopsies were scored blindly by a single liver histopathologist according to the classification of Ishak et al. (J Hepatol 1995; 22: 696-699). IFNa induced sustained biochemical response in 30, initial response and subsequent relapse in 57 and no response in 33 patients. Fibrosis improved in 17.5% of treated (sustained responders: 40%, relapsers: 9%, nonresponders: 12%) and 4% of untreated patients and worsened in 34% (sustained responders: 7%, relapsers: 40%, nonresponders: 48%) and 70% of cases, respectively (P = 0.002). The annual rate of fibrosis progression was worse in the untreated (0.427 +/- 0.119) than in treated patients (0.067 +/- 0.052, P = 0.001). However, the fibrosis progression rate in the untreated patients was not significantly different than the net fibrosis progression rate (after subtraction of IFNa duration) in nonresponders or relapsers. In multivariate analysis, worse fibrosis progression rate was associated with older age (P = 0.010), worse baseline grading score (P < 0.001), lower baseline fibrosis (P = 0.035) and the type of response to IFNa (P = 0.032). In conclusion, in HBeAg-negative chronic hepatitis B, IFNa significantly reduces the rate of fibrosis progression, but such an effect is mainly observed in patients with sustained biochemical responses. In relapsers and nonresponders, fibrosis benefit equals the treatment period. The strongest factor associated with fibrosis progression is the change in necroinflammatory activity.

The effect of adherence to therapy on sustained response in daily or three times a week interferon alpha-2b plus ribavirin treatment of naive and nonresponder chronic hepatitis C patients.

The aim was to demonstrate adherence to treatment has been suggested to enhance rates of sustained response in patients with hepatitis C. In this study, we evaluated the effect of drug dosage reduction or the duration of the expected therapy in patients treated with interferon (IFN)-alpha2b plus ribavirin. Virologic response rates were re-analysed according to compliance to therapy in (i) 301 naive and (ii) 142 nonresponders to previous IFN therapy treated with either IFN 5 MU TIW for 8 weeks followed by IFN 3 MU TIW for 40 weeks plus ribavirin or IFN 3 MU QD for 16 weeks followed by IFN 3 MU TIW for 24 weeks plus ribavirin. Patients were separated into those who adhered to > or =80% of their intended treatment schedule (dose of both drugs and duration) and those who did not. Compliance to treatment resulted in significantly higher response rates in both groups of patients: 43.93% compared with 6.90% of noncompliant naive patients and 30.77% compared with 10.53% of nonresponder patients. Compliance to treatment was found to have a similar effect when the results were analysed according to HCV genotype. Our findings suggest that compliance to treatment for > or =80% of the intended treatment schedule results in significantly higher sustained response rates in both naive and nonresponder patients. Consequently, every effort should be made to improve patient adherence to therapy.

Reconstructing and predicting the hepatitis C virus epidemic in Greece: increasing trends of cirrhosis and hepatocellular carcinoma despite the decline in incidence of HCV infection.

In this study, a comprehensive methodology for modelling the hepatitis C virus (HCV) epidemic is proposed to predict the future disease burden and assess whether the recent decline in the incidence of HCV may affect the future occurrence of cirrhosis and hepatocellular carcinoma (HCC) cases. Using the prevalence of HCV, the distribution of chronic hepatitis C (CHC) patients within the various transmission groups and their infection-onset times, it was possible to reconstruct the incident infections per year in the past that progressed to CHC in Greece. The natural history of the disease was simulated in subcohorts of newly infected subjects using transition probabilities derived either empirically between fibrosis stages 0-4 or from literature review. Annual estimates of the incidence and prevalence of CHC by fibrosis stage, HCC and mortality in Greece were obtained up to 2030. HCV incidence peaked in the late 1980s at five new infections/10,000 person-years. Under the assumption of 20-100% decline in HCV incidence after 1990, the cumulative number of incident cirrhosis and HCC cases from 2002-2030 was projected to be lower by 9.6-48.2% and 5.9-29.5%, respectively, than that estimated under the assumption of no decline. However, the prevalent cirrhotic/HCC cases and HCV-related deaths are predicted to decline in the next 30 years only under the assumption of complete elimination of new HCV infections after 1990. Despite the progress in the reduction of HCV transmission, primary prevention does not seem adequate to reverse the rise in the incidence of cirrhosis and HCC.

A randomized trial to assess the efficacy of interferon-alpha daily in combination with ribavirin in the treatment of naïve patients with chronic hepatitis C.

A randomized trial was conducted to assess the efficacy of interferon-alpha (IFN) daily in combination with ribavirin in 301 naïve patients with chronic hepatitis C (CHC). Patients were randomized to receive ribavirin 1.2 g daily (QD) for 48 weeks with either IFN 5 MU (thrice weekly) TIW for 8 weeks followed by IFN 3 MU TIW for 40 weeks (IFN TIW, n = 154) or IFN 5 MU QD for 8 weeks followed by IFN 3 MU QD for 16 weeks followed by IFN 3 MU TIW for 24 weeks (IFN QD, n = 147). Treatment discontinuation rates, because of adverse events, were similar in the two arms (14.9% in IFN TIW and 14.3% in IFN QD, P = 0.87). The proportion of patients with sustained virological response (SVR) was 27.9% for patients treated TIW and 38.8% for those treated QD (P = 0.046). According to logistic regression analysis, patients in the IFN QD arm had 1.7 times higher probability of achieving SVR, than those receiving IFN TIW (P = 0.038). Low baseline viral load (P = 0.017) and genotype non-1 (P = 0.036) were associated with higher SVR rates. Combination of IFN/ribavirin for 48 weeks is more effective when IFN is administered daily for the first 24 weeks in naïve patients with CHC.

A randomized trial to assess the efficacy of interferon alpha in combination with ribavirin in the treatment of interferon alpha nonresponders with chronic hepatitis C: superior efficacy of high daily dosage of interferon alpha in genotype 1.

A randomized trial was conducted to assess the efficacy of daily (QD) or thrice weekly (TIW) administration of interferon-alpha (IFN) in high doses in combination with ribavirin (1.0-1.2 g/day) in patients with chronic hepatitis C (CHC) who were nonresponders to previous IFN monotherapy. Interferon was administered as 10 MU IFN (QD or TIW) for 4 weeks, followed by 5 MU IFN (QD or TIW) for 20 weeks, and then by 3 MU IFN (QD or TIW) for 24 weeks. Sustained virological response (SVR) was evaluated in 142 patients who received at least one dose of medication. One-fourth of the patients achieved SVR, 26% of those treated with IFN QD and 25% of those treated with IFN TIW (P = 0.85). For genotype 1 patients, SVR rates were 32.4 and 15.8% for IFN QD and IFN TIW, respectively, whereas for genotype non-1 patients the corresponding SVR rates were 20.6 and 36.4%, respectively (test of homogeneity: P = 0.031). This finding was further confirmed by multivariate logistic regression analysis where a statistically significant interaction (P = 0.012) was found between treatment and HCV genotype indicating that the IFN QD regimen was superior to IFN TIW among genotype 1 patients whereas, among genotype non-1 patients, the two treatments were similar (odds ratio of SVR in IFN QD vs IFN TIW: 3.33 among genotype 1 patients, 95% CI: 1.00-11.14). In conclusion, re-treatment of patients not responding to previous IFN monotherapy with a combination of high daily dose of IFN with ribavirin may be beneficial for genotype 1 infected patients.