Ioannis Ketikoglou

Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study

Objective To evaluate the risk and predictors of hepatocellular carcinoma (HCC) in HBeAg-negative chronic hepatitis B patients of the large HEPNET.Greece cohort study who received long-term oral antivirals starting with lamivudine monotherapy. Design Retrospective analysis of HCC incidence in HBeAg-negative chronic hepatitis B patients from a retrospective–prospective cohort who were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for ≥12 months. Setting A nationwide network of liver centres. Patients 818 patients were included: 517 with chronic hepatitis B only; 160 with compensated cirrhosis; 56 with decompensated cirrhosis; 85 with unclassified disease severity. Interventions All patients were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy. Main outcome measures Development of HCC. Results During a median follow-up of 4.7 years, HCC developed in 49 (6.0%) patients. The 5-year cumulative incidence of HCC was higher in patients with cirrhosis than in those with chronic hepatitis B only (11.5% vs 3.2%, respectively; p<0.001). HCC developed in 0.7%, 6.7% and 11.7% of patients <50, 50–60 and >60 years old, respectively (p<0.001). Virological on-therapy remission did not significantly affect the incidence of HCC in all patients or those with cirrhosis, but it showed a trend for lower HCC incidence in patients with chronic hepatitis B only (p=0.076). In multivariate analysis, age, gender and cirrhosis were independently associated with HCC risk regardless of virological remission. Conclusions Long-term therapy with nucleos(t)ide analogue(s) starting with lamivudine monotherapy does not eliminate HCC risk in HBeAg-negative chronic hepatitis B. The risk of HCC is particularly high in patients with cirrhosis, who should remain under HCC surveillance even during effective therapy. Older age and male gender remain independent risk factors for HCC, while virological on-therapy remission does not seem to significantly reduce the overall incidence of HCC.

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

Summary.  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 ≥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.

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.

Predictors of sustained virological response in Greek and Egyptian patients with hepatitis C genotype 4: Does ethnicity matter?†

Hepatitis C virus genotype 4 (HCV‐4) is spreading beyond Africa and the Middle East but data regarding treatment with pegylated interferon alpha and ribavirin of European populations infected with HCV‐4 remains limited. Interestingly, European (vs. Egyptian) origin has been associated with lower sustained virological response rates. Hence the aim of this study was to investigate the treatment outcomes of Greek (vs. Egyptian), treatment‐naïve patients infected with HCV‐4 (subtype a) and to identify factors influencing response rates. One hundred seventy‐seven consecutive patients (mean age: 44.6 ± 10.2, males: 143/177; 80.8%, Egyptians: 76/177; 42.9%) treated over a 7‐year period at the Hepatology clinics of three tertiary care hospitals in Greece were retrospectively evaluated. Overall, sustained virological response was achieved in 75/177 (42.4%) of the cohort without a significant difference between the two ethnic groups [Greek: 44/101 (43.6%); Egyptian 31/76 (40.8%), P = 0.7598]. In multivariate analysis, it was found that ethnicity was not associated with an impaired response but age ≥45 years [odds ratio (OR): 0.4225, 95% confidence interval (CI): 0.2135–0.8133; P = 0.0134], diabetes (OR: 0.2346, 95% CI: 0.0816–0.0674; P = 0.0071), advanced liver fibrosis (OR: 0.3964, 95% CI: 0.1933–0.8133; P = 0.0116), and treatment suspension (OR: 0.1738, 95% CI: 0.0482–0.6262; P = 0.0075) showed an independent negative association with response to antiviral treatment. In contrast to previous European data suggesting Egyptian ethnicity to be a positive predictor for a sustained virological response, there was no influence of Greek versus Egyptian ethnicity on treatment outcomes. Higher age, advanced liver fibrosis, and diabetes have been shown to reduce significantly response rates in patients infected with HCV‐4. J. Med. Virol. 84: 1217–1223, 2012.

Long‐term adefovir plus lamivudine therapy does not decrease creatinine clearance in HBeAg‐negative chronic hepatitis B patients

As there are concerns about potential nephrotoxicity of nucleotide analogues, we evaluated renal function parameters during long‐term adefovir and lamivudine combination therapy.

Hepatitis C virus genotyping in Greece: Unexpected high prevalence of genotype 5a in a Greek island†

Hepatitis C virus (HCV) genotype 5 (G5) is a rare genotype reported mainly in South Africa. However, increasing data suggest the sporadic presence of this genotype in different European countries. To assess the epidemiology of HCV‐G5 in Greece, genotyping was performed in 973 consecutive patients infected with HCV, referred to 7 hepatology centers throughout Greece, from January 2005 to December 2009. Genotype 5a (19 patients, 1.9%) was the fifth most prevalent genotype after genotype 1 (408 patients, 41.9%), genotype 3 (318 patients, 32.7%), genotype 4 (158 patients, 16.2%), and genotype 2 (70 patients, 7.2%). The majority of patients infected with G5 (16/19,84.2%) were referred to the General Hospital of Rhodes, an island in south‐east Greece. The HCV genotype distribution in that particular island, indicates a particularly high G5 prevalence of 12.8%, after genotype 1 (40%), genotype 3 (28%), and genotype 4 (15%). Among the patients from Rhodes infected with G5 (n = 16), 13 (81.2%) were females. The mean age was 62.3 ± 6.5 years, significantly older than the patients infected with other HCV genotypes (mean age 40.6 ± 7.2, P < 0.0001). Nine out of the 16 cases (56.2%) presented features of high pre‐treatment viral loads. Advanced liver fibrosis (Metavir F3–F4) was found in four out of five performed liver biopsies. Ten patients received treatment with pegylated interferon plus ribavirin and a sustained viral response were achieved in six cases. The source of infection is unknown but parenteral iatrogenic routes of transmission seem to have contributed significantly to the spread of genotype 5a in this region. J. Med. Virol. 84:223–228, 2012.

Pegylated interferon alfa-2b pen device and ribavirin treatment for patients with chronic hepatitis C: an evaluation of patient satisfaction.

Objective The aim of this study was to evaluate the satisfaction of patients with chronic hepatitis C who used the pegylated interferon α-2b pen device. Methods Patients from multiple centers in Greece were recruited to participate in this noninterventional, observational study. Patients received pen device training for at least 6 weeks before treatment and used questionnaires to provide feedback (rating scale: 1–4, negative; 5–7, positive) on training, medication preparation and injection, and appreciation of the device. Results were analyzed with standard statistical analysis and multivariate logistic regression. Results In total, 507 patients (mean age, 43.5 years), 77.4% of whom were treatment naive, participated in the study. Overall, 84.2% of patients rated training positively, 67.4% of patients rated medication preparation positively, and 88.3% of patients rated medication injection positively. Appreciation of the pen device treatment method was rated positively by 82.2% of patients. Intravenous drug users were more likely to rate medication injection positively (P=0.0284) and to appreciate this method of drug delivery (P=0.0328) than other patients. Patients with lower levels of education were less likely to rate training positively (P=0.0202) and showed less appreciation for this route of drug delivery (P=0.0341) than other patients. Treatment-naive patients were more likely to provide positive responses about the overall procedure than were treatment-experienced patients (odds ratio: 1.932; P=0.032). Adverse events were reported by 6.4% (29 of 453) of patients. Conclusion Patients were satisfied with the pegylated interferon α-2b pen device; therefore, good treatment adherence is expected with its use.