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Hepatitis D virus (HDV) infection leads to the most severe form of chronic viral hepatitis and requires the attention of a liver specialist. In this review, I will recapitulate recent advances in the management of HDV, present background information on HDV infection as well as current chronic hepatitis D treatment, briefly examine the HDV life cycle and discuss new management strategies.

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. 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. 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 (r2=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. 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. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

Chronic hepatitis delta (CHD) represents the most severe form of viral hepatitis due to rapid disease progression towards liver cancer, leading to high morbidity and mortality. Hepatitis delta virus (HDV) can only infect individuals who are infected with hepatitis B. So far, there is no cure or vaccine for HDV. Existing treatment options, including pegylated interferon-α and hepatocyte entry inhibitors, offer limited efficacy. Emerging therapeutic strategies are focused on targeting various steps of the HDV life cycle or enhancing the host immune response to promote viral elimination. A defective antiviral immune response is increasingly recognized as a culprit for HDV persistence; however, the precise immunological mechanism associated with disease progression and pathogenesis has not been well defined. This review provides an update on the current understanding of host immune response in CHD, highlighting its role in both disease pathogenesis and viral clearance. A deeper understanding of these immune correlates may lead the way to novel treatment strategies, including immunotherapies targeting host immune response that can be used in combination with other antiviral therapies to achieve more effective and durable treatment outcomes.

Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) is difficult to treat. In this randomized trial, patients treated with peginterferon alfa-2a, with or without adefovir, were more likely to have HDV RNA clearance than those treated with adefovir alone. Hepatitis delta virus (HDV) is a defective RNA virus that requires coinfection with hepatitis B virus (HBV) to replicate. The HDV genome is encapsidated by hepatitis B surface antigen (HBsAg), which forms the viral envelope. The virus was first identified in 1977 in the serum of long-term carriers of HBsAg and was noted to have an increased prevalence among patients with liver damage. 1 In long-term carriers of HBV, HDV infection can result in fulminant acute hepatitis or severe chronic hepatitis, often progressing to cirrhosis and hepatocellular carcinoma. 2 – 6 Eight HDV genotypes have been suggested, 7 , 8 and both HDV and HBV . . .

Although liver biopsy is a well-established technique to assess fibrosis it has several limitations, including invasive nature, semi-quantitative assessment methods, significant sampling and observer variability, making precise assessment of hepatic fibrosis challenging. Accurate and reliable modalities are crucial for clinical trials to characterize hepatic fibrosis monitorization effectively. We aimed to perform 3-dimensional imaging of optically transparent liver samples by light-sheet microscopy (LSM) to quantify extracellular matrix (ECM) proteins. Fifty-seven MASLD, thirty-eight chronic hepatitis patients and twelve healthy individuals were included. Liver tissues were cleared with a CLARITY method. 3D imaging of ECM was performed via the newly developed LSM. Collagen Proportionate Volume (CPV) and Elastin Proportionate Volume (EPV) values were calculated by analysis of over 200 sections per sample through morphometry. We have optimized a method which achieves transparency of liver tissues in advanced fibrotic stages of MASLD and optimized non-destructive slide-free fibrosis pathology of whole fresh and FFPE liver biopsy samples. Cut-off values for CPV and EPV were established for fibrotic stages. CPV and EPV analysis showed a considerable optical section heterogeneity resulting in a fibrosis stage of variance within the sample. Volumetric image analysis for fibrosis staging revealed that only 44% and 47% of optical sections would be staged the same for F3 and F4, respectively. For the first time, our findings demonstrate a novel method of analyzing 3D digital pathology of liver fibrosis using in-house LSM. Volumetric imaging of whole liver biopsy samples showed that fibrosis heterogeneity occurs even in different sections.

( 2) Despite these observations and in striking contrast to HBV or hepatitis C virus, treatment for HDV has not changed in more than 3 decades and consists of the off‐label use of conventional or pegylated interferon alfa (PEG‐IFN alfa) for the chronic viral hepatitis setting. [...]a clinical concern might be the fate of retained HBsAg in hepatocytes. [...]we do not know if combination treatment using a staggered approach is better than simultaneous combination treatment.

Hepatitis Delta virus (HDV) is a satellite of the Hepatitis B virus (HBV) and causes severe liver disease. The estimated prevalence of 15–20 million infected people worldwide may be underestimated as international diagnostic guidelines are not routinely followed. Possible reasons for this include the limited awareness among healthcare providers, the requirement for costly equipment and specialized training, and a lack of access to reliable tests in regions with poor medical infrastructure. In this study, we developed an HDV rapid test for the detection of antibodies against the hepatitis delta antigen (anti-HDV) in serum and plasma. The test is based on a novel recombinant large hepatitis delta antigen that can detect anti-HDV in a concentration-dependent manner with pan-genotypic activity across all known HDV genotypes. We evaluated the performance of this test on a cohort of 474 patient samples and found that it has a sensitivity of 94.6% (314/332) and a specificity of 100% (142/142) when compared to a diagnostic gold-standard ELISA. It also works robustly for a broad range of anti-HDV titers. We anticipate this novel HDV rapid test to be an important tool for epidemiological studies and clinical diagnostics, especially in regions that currently lack access to reliable HDV testing.

Background Co-infection between hepatitis B virus (HBV) and hepatitis delta virus (HDV) causes the severest chronic hepatitis and is associated with a high risk of cirrhosis and hepatocellular carcinoma (HCC). The Global Health Sector Strategy on Viral Hepatitis called for the elimination of hepatitis (− 65% mortality and − 90% incidence) by 2030. Our aims were to summarize key points of knowledge and to identify the gaps that need to be addressed to mount a public health response to HDV. Methods We performed a current literature review in terms of epidemiology by WHO regions, genotypes distribution and their pathogenicity, factors associated with HDV infection, mortality due to HDV infection, testing strategies and treatment. Results Prevalence of infection and genotypes are heterogeneous distributed, with highest prevalence in foci around the Mediterranean, in the Middle East, and in Central, Northern Asia and Eastern Asia. Persons who inject drugs (PWID) and migrants from highly endemic areas are highly affected. While antibody detection tests are available, HDV RNA tests of current infection are not standardized nor widely available. The few therapeutic options, including lofartinib, are not widely available; however several new and promising agents have entered clinical trials. Conclusion HDV infection is an poorly known cause of chronic liver disease. To mount a public health response, we need a better description of the HDV epidemic, standardized testing strategies and better treatment options.

Background To provide a clear picture of the current hepatitis B situation, the authors performed a systematic review to estimate the age- and region-specific prevalence of chronic hepatitis B (CHB) in Turkey. Methods A total of 339 studies with original data on the prevalence of hepatitis B surface antigen (HBsAg) in Turkey and published between 1999 and 2009 were identified through a search of electronic databases, by reviewing citations, and by writing to authors. After a critical assessment, the authors included 129 studies, divided into categories: 'age-specific'; 'region-specific'; and 'specific population group'. To account for the differences among the studies, a generalized linear mixed model was used to estimate the overall prevalence across all age groups and regions. For specific population groups, the authors calculated the weighted mean prevalence. Results The estimated overall population prevalence was 4.57, 95% confidence interval (CI): 3.58, 5.76, and the estimated total number of CHB cases was about 3.3 million. The outcomes of the age-specific groups varied from 2.84, (95% CI: 2.60, 3.10) for the 0-14-yearolds to 6.36 (95% CI: 5.83, 6.90) in the 25-34-year-old group. Conclusion There are large age-group and regional differences in CHB prevalence in Turkey, where CHB remains a serious health problem.

Standard treatment of hepatitis delta virus (HDV) infection remains pegylated‐interferon alfa (peg‐IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core‐related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN‐based treatment of hepatitis B virus (HBV) mono‐infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co‐infection undergoing peg‐IFNα treatment. The Hep‐Net‐International‐Delta‐Hepatitis‐Intervention Trial‐2 study included 120 patients co‐infected with HBV/HDV. Patients were treated for 96 weeks with peg‐IFNα and either tenofovir or placebo. Ninety‐nine patients with HDV‐RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg‐IFNα in patients with HBV/HDV co‐infection and could be a promising marker to determine treatment futility.