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Background & Aims: Until recently, pegylated interferon‐alfa‐2a (PEG‐IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG‐IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short‐term relapses within 24 weeks. The virological and clinical long‐term effects after prolonged PEG‐IFNa‐based treatment of hepatitis D are unknown. Methods: In the HIDIT‐II study patients (including 40% with liver cirrhosis) received 180 μg PEG‐IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 μg PEG‐IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy). Results: Until the end of follow‐up, 16 (13%) patients developed liver‐related complications (PEG‐IFNa + TDF, n = 5 vs PEG‐IFNa + placebo, n = 11; p =.179). Achieving HDV suppression at week 96 was associated with decreased long‐term risk for the development of hepatocellular carcinoma (p =.04) and hepatic decompensation (p =.009). Including complications irrespective of PEG‐IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG‐IFNa (16/102, p >.999) but was associated with a higher chance of HDV‐RNA suppression (p =.024, odds ratio 3.9 [1.3–12]). Conclusions: Liver‐related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG‐IFNa treatment. PEG‐IFNa treatment should be recommended to HDV‐infected patients until alternative therapies become available. Retreatment with PEG‐IFNa should be considered for patients with inadequate response to the first course of treatment. Clinical Trial registration: NCT00932971. [ABSTRACT FROM AUTHOR]

Background & Aims: Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient‐reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta. Methods: Here, we investigated quality of life (QOL) as assessed by the Short Form 36 Health Survey (SF‐36) in patients undergoing antiviral therapy with pegylated interferon alfa (PEG‐IFNa‐2a)‐based treatment in the HIDIT‐II trial. HIDIT‐II was a randomized prospective trial exploring PEG‐IFNa‐2a with tenofovir disoproxil (TDF) or placebo for 96 weeks in patients with compensated hepatitis delta. Surveys completed by 83 study participants before, during, and after treatments were available. Results: Overall, we observed a reduced QOL of HDV patients compared with a reference population, both in physical as well as mental scores. Interestingly, PEG‐IFNa‐2a treatment showed only minor impairment of the QOL during therapy. Moreover, HDV‐RNA clearance was not associated with relevant changes in physical or social SF‐36 scores, whereas an improvement of fibrosis during treatment was associated with increased QOL. Overall, slight improvements of the QOL scores were observed 24 weeks after the end of treatment as compared with baseline. TDF co‐treatment had no influence on QOL. Conclusions: Overall, our findings suggest that PEG‐IFNa‐2a was reasonably tolerated even over a period of 96 weeks by hepatitis D patients reporting SF‐36 questionnaires. Of note, several patients may benefit from PEG‐IFNa‐2a‐based therapies with off‐treatment improvements in quality of life. [ABSTRACT FROM AUTHOR]

Abstract Background Both C reactive protein (CRP) and procalcitonin (PCT) are well known acute phase reactant proteins. CRP was reported to increase in metabolic syndrome and type-2 diabetes. Similarly altered level of serum PCT was found in chronic liver diseases and cirrhosis. The liver is considered the main source of CRP and a source of PCT, however, the serum PCT and CRP levels in non-alcoholic fatty liver disease (NAFLD) were not compared previously. Therefore we aimed to study the diagnostic and discriminative role of serum PCT and CRP in NAFLD. Methods Fifty NAFLD cases and 50 healthy controls were included to the study. Liver function tests were measured, body mass index was calculated, and insulin resistance was determined by using a homeostasis model assessment (HOMA-IR). Ultrasound evaluation was performed for each subject. Serum CRP was measured with nephalometric method. Serum PCT was measured with Kryptor based system. Results Serum PCT levels were similar in steatohepatitis (n 20) and simple steatosis (n 27) patients, and were not different than the control group (0.06 ± 0.01, 0.04 ± 0.01 versus 0.06 ± 0.01 ng/ml respectively). Serum CRP levels were significantly higher in simple steatosis, and steatohepatitis groups compared to healthy controls (7.5 ± 1.6 and 5.2 ± 2.5 versus 2.9 ± 0.5 mg/dl respectively p < 0.01). CRP could not differentiate steatohepatitis from simple steatosis. Beside, three patients with focal fatty liver disease had normal serum CRP levels. Conclusion Serum PCT was within normal ranges in patients with simple steatosis or steatohepatitis and has no diagnostic value. Serum CRP level was increased in NAFLD compared to controls. CRP can be used as an additional marker for diagnosis of NAFLD but it has no value in discrimination of steatohepatitis from simple steatosis.

The role of low levels of HDV‐RNA during and after interferon therapy of hepatitis D is unknown. We re‐analysed HDV RNA in 372 samples collected in the HIDIT‐2 trial (Wedemeyer et al, Lancet Infectious Diseases 2019) with the Robogene assay (RA; Jena Analytics). Data were compared with the previously reported in‐house assay (IA). We detected HDV‐RNA in one‐third of samples previously classified as undetectable using the highly sensitive RA. Low HDV viraemia detectable at week 48 or week 96 was associated with a high risk for post‐treatment relapse, defined as HDV RNA positivity in both assays at week 120. HDV RNA relapses occurred in 10/15 (67%) patients with detectable low HDV RNA at week 48 and in 10/13 (77%) patients with low viraemia samples at week 96. In contrast, the post‐treatment relapse rate was lower in patients with undetectable HDV RNA in both assays during treatment. [ABSTRACT FROM AUTHOR]

HBV‐DNA levels are low or even undetectable in the majority HDV‐infected patients. The impact of PEG‐IFNα on HBV‐DNA kinetics in HDV‐infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV‐RNA–positive patients were randomized to receive PEG‐IFNα‐2a plus tenofovir‐disoproxil‐fumarate (PEG‐IFNα/TDF, n = 59) or placebo (PEG‐IFNα/PBO; n = 61) for 96 weeks. At week 96, HBV‐DNA was still quantifiable in 71% of PEG‐IFNα/PBO‐treated patients but also in 76% of PEG‐IFNα/TDF‐treated patients, despite low HBV‐DNA baseline values. Surprisingly, a transient HBV‐DNA increase between weeks 12 and 36 was observed in 12 in PEG‐IFNα/TDF‐treated and 12 PEG‐IFNα/PBO‐treated patients. This increase was positively associated with HBsAg loss [(P = 0.049, odds ratio (OR) 5.1] and HDV‐RNA suppression (P = 0.007, OR 4.1) at week 96. Biochemical markers of cell death (M30 and ALT) were higher during the HBV‐DNA peak but no distinct systemic immune pattern could be observed by screening 91 soluble inflammatory markers. In conclusion, an early increase in HBV‐DNA during PEG‐IFNα‐2a therapy occurred in more than 20% of patients, even in TDF‐treated patients. This transient HBV‐DNA rise may indicate PEG‐IFNα–induced cell death and lead to long‐term HDV‐RNA suppression and HBsAg loss. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG‐interferon alpha‐2a (PEG‐IFNα‐2a) is the only effective treatment but its long‐term clinical impact is unclear. The aim of this study was to investigate the long‐term outcome after 48 weeks of pegylated interferon alpha‐2a therapy. We performed a retrospective follow‐up study of the Hep‐Net‐International‐Delta‐Hepatitis‐Intervention‐Study 1 (HIDIT‐I trial). Patients had received 48 weeks of treatment with either PEG‐IFNα‐2a plus adefovir dipivoxil (ADV) (Group I), PEG‐IFNα‐2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver‐related complications were defined as liver‐related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child‐Pugh scores B or C or an increase in Model for End‐stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG‐IFNα‐2a. Follow‐up data (at least 1 visit beyond post‐treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow‐up was 8.9 (1.6 ‐ 13.4) years. 19 patients were retreated with IFN‐based therapy: 42% (n = 8) in PEG‐IFNα‐2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long‐term follow‐up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. The annual event‐free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long‐term follow‐up of a large randomized clinical trial suggests that off‐treatment HDV RNA response to PEG‐IFNα‐2a treatment leads to improved clinical long‐term outcome. [ABSTRACT FROM AUTHOR]

Background: Both C reactive protein (CRP) and procalcitonin (PCT) are well known acute phase reactant proteins. CRP was reported to increase in metabolic syndrome and type-2 diabetes. Similarly altered level of serum PCT was found in chronic liver diseases and cirrhosis. The liver is considered the main source of CRP and a source of PCT, however, the serum PCT and CRP levels in non-alcoholic fatty liver disease (NAFLD) were not compared previously. Therefore we aimed to study the diagnostic and discriminative role of serum PCT and CRP in NAFLD. Methods: Fifty NAFLD cases and 50 healthy controls were included to the study. Liver function tests were measured, body mass index was calculated, and insulin resistance was determined by using a homeostasis model assessment (HOMA-IR). Ultrasound evaluation was performed for each subject. Serum CRP was measured with nephalometric method. Serum PCT was measured with Kryptor based system. Results: Serum PCT levels were similar in steatohepatitis (n 20) and simple steatosis (n 27) patients, and were not different than the control group (0.06 ± 0.01, 0.04 ± 0.01 versus 0.06 ± 0.01 ng/ml respectively). Serum CRP levels were significantly higher in simple steatosis, and steatohepatitis groups compared to healthy controls (7.5 ± 1.6 and 5.2 ± 2.5 versus 2.9 ± 0.5 mg/ dl respectively p < 0.01). CRP could not differentiate steatohepatitis from simple steatosis. Beside, three patients with focal fatty liver disease had normal serum CRP levels. Conclusion: Serum PCT was within normal ranges in patients with simple steatosis or steatohepatitis and has no diagnostic value. Serum CRP level was increased in NAFLD compared to controls. CRP can be used as an additional marker for diagnosis of NAFLD but it has no value in discrimination of steatohepatitis from simple steatosis. [ABSTRACT FROM AUTHOR]

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) α-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 α-2b (100 μg/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 α-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 α-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy. [Copyright &y& Elsevier]

It has been reported that fish oil protects the rat liver against acetaminophen (APAP) induced toxicity; however, this finding is controversial. The present study was undertaken to investigate the effects of fish oil-enriched diet on APAP-induced liver injury in Wistar rats. Rats were fed a diet supplemented with either 8% fish oil or 8% corn oil, or standard rat feed for 6 wk. After an overnight fast, rats in each group were given either 2 g/kg APAP or saline orally. Our findings showed that APAP increased serum alanine aminotransferase (ALT) and that this rise was potentiated in the presence of dietary fat. Further fish oil ingestion increased the glutathione (GSH) content in rat liver; however, this was not effective in protecting liver from APAP-induced toxicity. Data suggest that GSH may be necessary to detoxify APAP metabolites, which are known to induce hepatotoxicity but are increased by dietary fat. [ABSTRACT FROM AUTHOR]

Background Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response. Methods 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 g/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 g/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32 --52 the pegylated interferon dose was 50 g/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication.All included patients were followed up for 26 weeks after treatment. Findings 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0·91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%]vs 40 [29%];p=0·01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0·01): A, 42 (47%) patients; B, ten (44%); C,11 (28%); and D, 26 (25%). Interpretation Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment. [ABSTRACT FROM AUTHOR]