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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]

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 & Aims Identifying advanced fibrosis in chronic hepatitis delta patients and thus in need of urgent treatment is crucial. To avoid liver biopsy, non-invasive fibrosis scores may be helpful but have not been evaluated for chronic hepatitis delta yet. Methods We evaluated eight non-invasive fibrosis scores in 100 HDV RNA-positive patients with available central histological reading. New cut-off values were calculated by using Receiver Operating Characteristics and Youden indexes. Predictors for the presence of ISHAK F3-6 were revealed by t-tests or Mann-Whitney tests. Results None of the tested scores had an area under the curve (AUROC) > 0.8 and performed according to our predefined requirements of a sensitivity of >80% and a positive predictive value (PPV) >90% - even after adaption. However, the ELF score was able to identify advanced fibrosis with a high sensitivity (93%) and PPV (81%), but relies on expensive extracellular matrix markers with bad availability in many endemic regions of HDV. Thus, we developed a novel non-invasive approach and identified low cholinesterase ( P=.002), low albumin ( P=.041), higher gamma glutamyl transferase, as well as older age ( P<.001) as predictors of fibrosis resulting in the Delta Fibrosis Score (DFS). The DFS performed with a sensitivity of 85% and PPV of 93% with an AUROC of 0.87. Conclusions Existing non-invasive fibrosis scores are either impracticable or do not perform well in chronic hepatitis delta patients. However, the new Delta Fibrosis Score is the first non-invasive fibrosis score specifically developed for chronic hepatitis delta and requires only standard parameters. [ABSTRACT FROM AUTHOR]

Background & Aims Aim of this study was to investigate whether a potential association exists between several single nucleotide polymorphisms ( SNPs) of the IL-28B gene (rs12979860, rs1188122, rs8099917, rs8105790, rs12980275) and HBsAg persistence. Further, a potential effect on the development of HBeAg-negative CHB vs. inactive HBsAg carrier state was assessed in a genotype D HBV cohort. A cohort of chronic HDV patients was also used to see if they behave differently compared to chronic HBV patients. Methods This study was conducted in three main patient cohorts: Group 1 consisted of 482 patients with HBsAg persistence. Of them 143 were inactive carriers, 94 had HBeAg-positive chronic hepatitis B ( CHB) and 245 had anti- HBe-positive CHB. Group 2 represents spontaneously recovered HBV patients; they were anti- HBs and anti- HBc positive. Group 3 consisted of 176 chronic hepatitis delta ( CHD) patients with antidelta and HDV- RNA positivity. DNA sequencing was performed for genotyping. Results When patients with HBsAg persistence were compared with spontaneously recovered patients, a significant difference was observed for rs8105790 ( P < 0.0001), rs12980275 ( P < 0.02). Patients who had the CC/ TC genotype for rs8105790 ( P < 0.0001) and AA genotype for 1188122 ( P < 0.02) were more likely to be inactive HBsAg carriers, when inactive HBsAg carriers were compared with HBeAg-negative CHB patients. Comparison of CHD patients vs. recovered HBV patients was parallel to that of HBV persistence vs. recovered HBV with similar significant differences in same SNPs. Conclusion These results suggest that IL-28B polymorphisms may contribute to HBsAg persistence and the development of the inactive HBsAg carrier state. [ABSTRACT FROM AUTHOR]

Background and Aims The presence of the hepatitis B virus ( HBV)-eAg in patients with hepatitis B is associated with higher HBV replication and with an increased risk to develop liver-related clinical endpoints defined as liver related death, liver transplantation, development of hepatocellular carcinoma and hepatic decompensation. The aim of this study was to investigate the role of HBeAg in patients co-infected with the hepatitis D virus ( HDV). Methods We studied virological markers of HBV and HDV infection and as well as biochemical and clinical features of liver disease in a cohort of 534 anti- HDV-positive patients. In addition, we compared the clinical long-term outcome of HBeAg-positive HDV-infected patients with HBeAg-negative control patients matched for age, gender and baseline- MELD score. Results HBeAg-positive hepatitis delta was detected in 71 of 534 patients (13.3%). HBeAg positivity was associated with a higher biochemical disease activity and higher HBsAg levels in HDV co-infected patients. Sixty one per cent of the HBeAg-positive HDV-infected patients presented with HBV DNA levels below 2000 IU/ml, at least once during follow-up. Both HBeAg-positive and -negative patients showed a similar severe clinical long-term course with about half of the patients developing a liver-related clinical complication after a median follow-up period of 51 months (range: 9-193 months). Conclusions HBV DNA levels are low in both HBeAg-negative and HBeAg-positive patients suggesting suppressive effects of HDV on HBV irrespective of the phase of HBV infection. The clinical long-term outcome of HBeAg-positive patients is not different to HBeAg-negative patients infected with the HDV. [ABSTRACT FROM AUTHOR]

In this retrospective study, 1-year entecavir treatment of chronic delta hepatitis was ineffective. However, 3 of 13 patients showed a virologic response, which may be linked to shift of the dominant virus or, alternatively, to immune-mediated viral clearance.Background. Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) to propagate infection and cause disease. Entecavir is a nucleoside analog with potent antiviral efficacy, and in the woodchuck animal model it also decreased hepatitis B virus (HBV) cccDNA and woodchuck surface antigen. The aim of this study was to investigate the efficacy of entecavir in chronic hepatitis D (CHD).Methods. This single-center study was conducted in patients with compensated liver disease. All patients had to have detectable hepatitis HDV RNA and elevated levels of alanine aminotransferase (ALT). Entecavir was given at a dosage of 1 mg/d for 1 year. The primary end point was achievement of undetectable HDV RNA at the end of treatment.Results. Thirteen consecutive patients were assessed. All patients had detectable HDV RNA, and 8 had detectable HBV DNA at baseline. At the end of treatment, HBV DNA became undetectable in all patients (P = .001). No significant decline in HDV RNA, ALT, or quantitative HBsAg levels was observed. The primary end point of undetectable HDV RNA at the end of treatment was achieved in 3 patients who had significantly lower baseline HDV RNA levels than nonresponders (2.99 log10 copies/mL ± .70 vs 4.68 ± .97; P = .0185). In all 3 patients, ALT levels were also normal at the end of treatment.Conclusions. One year of entecavir treatment is ineffective in CHD. Any generalized beneficial effect of nucleoside/nucleotide analog treatment may necessitate prolonged treatment. Patients with CHD with HBV dominance, which is likely to occur in the later phases of CHD, may be a reasonable patient cohort in which to target nucleoside/nucleotide analog therapy. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) is a subviral agent of hepatitis B virus (HBV), and its life cycle is dependent on HBV. It is commonly accepted that HDV has eight distinct genotypes. In this study, the complete nucleotide sequences of HDV genomes isolated from nine Turkish patients were obtained by RT-PCR using two pairs of primers that cover the entire HDV genome. PCR products were sequenced directly. The results showed that these 9 isolates were approximately 1680 base pairs in length and clustered in the genotype HDV-1 branch when phylogenetic analysis was done with the sequences together with the complete sequences of HDV genomes representing each genotype retrieved from GenBank. Analysis of a portion of the large hepatitis D antigen (L-HDAg) gene showed that sequence similarity among these Turkish isolates is between 87.4 and 97.1%, and the Turkish isolates have the most sequence similarity to HDV-1 (90.5%), while they have the least sequence similarity to HDV-3 (64.1%). Full-genome analysis indicates that the sequence similarity is between 80.7 and 95.4%, and the highest sequence similarity is 84.8% (between the Turkish isolates and HDV-1). The lowest sequence similarity is 56.4% (between the Turkish isolates and HDV-3). In conclusion, phylogenetic analysis shows that the Turkish HDV isolates belong to HDV-1. [ABSTRACT FROM AUTHOR]

Background: Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis.Methods: In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585.Findings: Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups.Interpretation: Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV.Funding: National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hepatitis delta virus (HDV) RNA viral load measurement is critical in diagnosis and monitoring the response to antiviral treatment. Objectives: Our aim is to design a real time PCR method for accurate quantitation of HDV RNA in clinical specimens using an armored RNA as external standard, and an intrinsic internal control. Study design: A plasmid bearing delta antigen region of genotype I HDV genome was used to develop an armored RNA. Serial dilutions of the armored HDV RNA standard with 1012 copy/mL were used as standards for quantitation. A primer–probe set derived from HDAg region was used in one step EZ RT PCR kit chemistry which uses rTth enzyme allowing reverse transcription and polymerization in the same tube. The kit also uses the advantage of uracil-N-glycosylase (UNG) enzyme treatment to prevent PCR contamination. Results: The established assay has a dynamic range of 102–1011 copy/mL with a PCR efficiency of 96.9%. Detection limit was 858±32copy/mL with 95% confidence interval. Intra- and inter-assay variabilities were low for high, medium and low levels of viremia. Incorporation of freely circulating GAPDH in serum into the assay as an intrinsic internal control prevented false negative results and failures in PCR amplifications due to inhibitors, inefficient extraction procedures or enzymatic reactions. Conclusion: In conclusion, this study defines a novel assay for sensitive and reliable quantification of HDV RNA using an armored HDV RNA as a standard and GAPDH in plasma or serum as an intrinsic internal control in a single tube. [Copyright &y& Elsevier]