Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

Growing Awareness: Limited Testing and Screening Bias for Hepatitis Delta Virus in Utah 2000-2021.

BACKGROUND: This study assessed the epidemiology of hepatitis delta virus (HDV) within the University of Utah UHealth health care system (2000-2021). METHODS: Analysis of HDV/HBV testing, diagnostic codes, liver enzymes, and comorbidities was performed. RESULTS: Among the 1962 HBV patients, only 22.2% underwent HDV testing, revealing an 8.3% positivity rate for HDV coinfections. This study observed a consistent increase in HBV and HDV cases, with higher HDV detection rates linked to increased testing. Limited HDV testing and potential screening biases were evident. DISCUSSION: Improved HDV testing and surveillance are crucial for early detection and implementation of targeted therapies.

Validation of Baveno VII criteria and other non-invasive diagnostic algorithms for clinically significant portal hypertension in hepatitis delta.

BACKGROUND & AIMS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) require validation in patients with hepatitis D virus (HDV)-related compensated advanced chronic liver disease (cACLD). Therefore, we aimed to validate existing NIT algorithms for CSPH in this context. METHODS: Patients with HDV-cACLD (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired HVPG and NIT assessment at Medical University of Vienna or Hannover Medical School between 2013 and 2023 were retrospectively included. Liver stiffness measurement (LSM), von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) were assessed. Individual CSPH risk was calculated according to previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno VII criteria and refined algorithms (Baveno VII-VITRO, Baveno VII-SSM) was evaluated. The prognostic utility of NITs was investigated in the main cohort and an independent, multicenter, validation cohort. RESULTS: Fifty-one patients (HVPG ≥10 mmHg/CSPH prevalence: 62.7%, varices: 42.2%) were included. Patients with CSPH had significantly higher LSM (25.8 [17.2-31.0] vs. 14.0 [10.5-19.8] kPa; p <0.001), VITRO (n = 31, 3.5 [2.7-4.5] vs. 1.3 [0.6-2.0] %/[G/L]; p <0.001), and SSM (n = 20, 53.8 [41.7-75.5] vs. 24.0 [17.0-33.9] kPa; p <0.001). Composite CSPH risk models yielded excellent AUROCs (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). Baveno VII criteria ruled out CSPH with 100% sensitivity and ruled in CSPH with 84.2% specificity. The Baveno VII 'grey zone' (41.1%) was significantly reduced by Baveno VII-VITRO or Baveno VII-SSM algorithms, which maintained diagnostic accuracy. Hepatic decompensation within 2 years only occurred in patients who had CSPH or met Baveno VII rule-in criteria. The prognostic value of NITs was confirmed in the validation cohort comprising 92 patients. CONCLUSIONS: Standalone and composite NIT/diagnostic algorithms are useful for CSPH diagnosis in patients with HDV-cACLD. Thus, NITs may be applied to identify and prioritize patients with CSPH for novel antiviral treatments against chronic hepatitis D. IMPACT AND IMPLICATIONS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) have been developed to identify patients with compensated advanced chronic liver disease (cACLD) at risk of decompensation, but conflicting data has been published regarding the accuracy of liver stiffness measurement (LSM) for the staging of fibrosis in patients infected with hepatitis D virus (HDV). In our study, including 51 patients with HDV-cACLD, LSM- and lab-based NITs yielded high AUROCs for CSPH. Moreover, only patients with CSPH or high non-invasively assessed CSPH risk were at risk of decompensation within 2 years, with the prognostic value of NITs confirmed in a validation cohort. Thus, NITs should be applied and updated in yearly intervals in clinical routine to identify patients with HDV-cACLD at short-term risk of clinical events; NITs may also guide prioritization for novel antiviral treatment options.

The diagnostic cascade for patients with hepatitis delta infection in France, 2018-2022: A cross-sectional study.

BACKGROUND AND AIMS: Chronic hepatitis D infection is the most severe form of viral hepatitis and can rapidly progress to cirrhosis or hepatocellular carcinoma. Despite recommendations for systematic screening of hepatitis B surface antigen (HBsAg)-positive individuals, data from real-world studies have reported a low frequency of hepatitis D (or delta) virus (HDV) screening. Our cross-sectional analysis evaluated the diagnostic cascade for hepatitis D infection in tertiary centres and described the characteristics of HDV-positive patients. METHODS: A total of 6772 individuals who tested HBsAg positive for the first time between 2018 and 2022 were retrospectively included. Demographic, clinical and laboratory data were analysed. RESULTS: A total of 5748 HBsAg-positive individuals (84.9%) were screened for HDV infection. The screening rate varied from 63% to 97% according to the screening strategy used in the centres including or not HDV reflex testing. The prevalence of HDV infection was 6.3%. HDV RNA levels were determined in 285 of the 364 (78.3%) HDV antibody screening-positive patients, and 167 (58.6%) had active HDV infection. 66.8% were males, with a mean age of 44.9 years. A total of 97.5% were born abroad, and 92.9% were HBeAg negative. At the time of diagnosis, HDV RNA levels were 6.0 Log UI/mL; 60.1% had alanine aminotransferase >40 U/L, and 56.3% had significant fibrosis (≥F2), including 41.6% with cirrhosis. The most common genotype was HDV-1 (75.4%). Coinfections were not uncommon: 7.4% were HIV positive, and 15.0% were HCV antibody positive. CONCLUSIONS: The present study highlights the need for increased screening and monitoring of HDV infection. Reflex testing helps to identify HDV-infected individuals.

Hepatitis Delta Virus Surveillance Practice among Clinicians in Nigeria: A Cross-Sectional Survey.

BACKGROUND: The near total absence of routine Hepatitis Delta Virus (HDV) screening in many countries in sub-Saharan Africa is a major challenge to understanding the burden of HDV in the region. AIM: To evaluate Hepatitis Delta Virus screening practices and associated factors among clinicians in Nigeria. METHODS: A cross-sectional study was conducted in June-July 2022, in which a self-administered questionnaire that inquired about HDV awareness, screening practices, and treatment options was shared electronically with consenting clinicians practicing in Nigeria. At the end of the survey, data was analyzed using descriptive and inferential statistics. The level of significance was set at 0.05. RESULTS: At the end of the survey, 210 of the 213 responses retrieved from respondents were analyzed. The respondent's mean age was 38.60 ± 7.27 years with a male-to-female ratio of 1:2.5. They comprised 13.8% gastroenterologists and 86.2% respondents in other areas of clinical medicine. The study showed that 89.5% of the respondents knew that HDV infection occurs only in hepatitis B virus (HBV)-infected individuals. Most (91.4%) respondents do not screen for HDV in chronic HBV patients, mainly due to the non-availability of screening tools and lack of awareness of any screening test for HDV. Research interest was reported as the reason for screening among clinicians who had ever screened for HDV. Pegylated interferon was the main regimen used for treatment by 87.5% of respondents. About 2% did not know treatment options for HDV. A significant association between knowledge of HDV infection and area of specialty, as well as the nature of medical practice was noted (P = 0.008 and 0.013, respectively). CONCLUSION: The study showed a high level of awareness of HDV dependency on HBV, for natural infection to occur. However, it documented very minimal HDV screening in clinical settings and factors affecting screening among clinicians.

Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta.

BACKGROUND & AIMS: HDV infection causes severe chronic liver disease in individuals infected with HBV. However, the factors associated with poor prognosis are largely unknown. Thus, we aimed to identify prognostic factors in patients with HDV infection. METHODS: The French National Reference Centre for HDV performed a nationwide retrospective study on 1,112 HDV-infected patients, collecting epidemiological, clinical, virological and histological data from the initial referral to the last recorded follow-up. RESULTS: The median age of our cohort was 36.5 (29.9-43.2) years and 68.6% of our cohort were male. Most patients whose birthplace was known were immigrants from sub-Saharan Africa (52.5%), southern and eastern Europe (21.3%), northern Africa and the Middle East (6.2%), Asia (5.9%) and South America (0.3%). Only 150 patients (13.8%) were French native. HDV load was positive in 659 of 748 tested patients (88.1%). HDV-1 was predominant (75.9%), followed by sub-Saharan genotypes: HDV-5 (17.6%), HDV-7 (2.9%), HDV-6 (1.8%) and HDV-8 (1.6%). At referral, 312 patients (28.2%) had cirrhosis, half having experienced at least 1 episode of hepatic decompensation. Cirrhosis was significantly less frequent in African than in European patients regardless of HDV genotype. At the end of follow-up (median 3.0 [0.8-7.2] years), 48.8% of the patients had developed cirrhosis, 24.2% had ≥1 episode(s) of decompensation and 9.2% had hepatocellular carcinoma. European HDV-1 and African HDV-5 patients were more at risk of developing cirrhosis. Persistent replicative HDV infection was associated with decompensation, hepatocellular carcinoma and death. African patients displayed better response to interferon therapy than non-African patients (46.4% vs. 29.1%, p <0.001). HDV viral load at baseline was significantly lower in responders than in non-responders. CONCLUSION: Place of birth, HDV genotype and persistent viremia constitute the main determinants of liver involvement and response to treatment in chronic HDV-infected patients. LAY SUMMARY: Chronic liver infection by hepatitis delta virus (HDV) is the most severe form of chronic viral hepatitis. Despite the fact that at least 15-20 million people are chronically infected by HDV worldwide, factors determining the severity of liver involvement are largely unknown. By investigating a large cohort of 1,112 HDV-infected patients followed-up in France, but coming from different areas of the world, we were able to determine that HDV genotype, place of birth (reflecting both viral and host-related factors) and persistent viremia constitute the main determinants of liver involvement and response to treatment.

High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection: longitudinal analysis of a German cohort.

BACKGROUND: Chronic hepatitis delta virus (HDV) infection causes severe liver disease which often leads to cirrhosis and hepatocellular carcinoma (HCC). Aim of this study was to establish the disease severity and prognostic factors for disease outcome by analysing frequencies of clinical events and their correlation with baseline virological and biochemical parameters as well as interferon and nucleos(t)ide analogue treatment choice. METHODS: We studied a single-centre cohort of 49 anti-HDAg-positive patients with HBsAg persistence for at least 6 months. Virological and biochemical parameters, interferon and nucleos(t)ide analogue treatment choice as well as clinical events during follow-up were analysed by retrospective chart review (mean follow-up time 3 years, range 0.25-7.67 years). RESULTS: Severe clinical events occurred in 11/49 hepatitis D patients, including HCC (8/49), death (8/49) or liver transplantation (2/49). HCCs only occurred secondary to liver cirrhosis and their event rates in this cohort of hepatitis D patients did not differ from a matched HBV mono-infected cohort with comparable frequency of liver cirrhosis. A stepwise multivariate logistic regression revealed low platelet count (p = 0. 0290) and older age (p = 0.0337) correlating most strongly with overall clinical events, while serum HDV RNA positivity at baseline did not correlate with any clinical outcome. Interferon-free but not nucleos(t)ide analogue-free patient care correlated with the occurrence of HCC at logistic regression, although only 3/18 interferon-treated patients demonstrated repeatedly negative HDV PCR results post therapy. CONCLUSIONS: Our data indicate that progressive liver disease at baseline plays a major role as predictive factor for overall clinical outcome of hepatitis D patients. In particular, HCC risk may not be underestimated in hepatitis D virus RNA negative hepatitis D patients with advanced liver fibrosis.

Molecular epidemiology and clinical characteristics of hepatitis delta virus (HDV) infected patients with elevated transaminases in Shanghai, China.

BACKGROUND: Patients coinfected with HBV and hepatitis D virus (HDV) have a greater risk of HCC and cirrhosis. The current study was undertaken to assess HDV genotype distribution and determine clinical characteristics of hepatitis delta virus (HDV) among HBsAg positive individuals in Shanghai. METHOD: This retrospective study involved 225 serum samples from HBsAg positive hospitalized patients from October 2010 to April 2013. HDV-specific RT-nested PCR was used to amplify HDV RNA. HDV genotypes were characterized by Next-generation sequencing (NGS), followed by phylogenetic analyses. HDV/HBV co-infected patients and HBV mono-infected patients were compared clinically and virologically. RESULTS: Out of the 225 HBsAg-positive serum samples with elevated transaminases, HDV-RNA was identified in 11 (4.9%) patients. The HBV loads in the HDV positive group were significantly lower than the HDV negative HBV-infected patients. The aminotransferase enzymes were significantly higher in HDV/HBV co-infected compared to HDV negative patients (P < 0.05). Phylogenetic analyses indicated that HDV-2 genotype being the predominant genotype, other HDV genotypes were not observed. HDV/HBV patients were significantly associated with a rather unfavourable clinical outcome. CONCLUSION: In summary, the prevalence of HDV infection in patients with elevated transaminases is not low and the predominance of HDV genotype 2 infection in Shanghai. This finding helps us to better understand the correlation of HDV/HBV co-infection. Moreover, Next-generation sequencing (NGS) technologies provide a rapid, precise method for generating HDV genomes to define infecting genotypes.

The burden and epidemiology of hepatitis B and hepatitis D in Georgia: findings from the national seroprevalence survey.

OBJECTIVES: The burden of hepatitis B virus (HBV) and hepatitis D virus (HDV) infections is unknown in Georgia. This analysis describes the prevalence of hepatitis B and coinfection with HDV and the demographic characteristics and risk factors for persons with HBV infection in Georgia. STUDY DESIGN: This is a cross-sectional seroprevalence study. METHODS: A cross-sectional, nationwide survey to assess hepatitis B prevalence among the general adult Georgian population (age ≥18 years) was conducted in 2015. Demographic and risk behavior data were collected. Blood specimens were screened for anti-hepatitis B core total antibody (anti-HBc). Anti-HBc-positive specimens were tested for hepatitis B surface antigen (HBsAg). HBsAg-positive specimens were tested for HBV and HDV nucleic acid. Nationally weighted prevalence estimates and adjusted odds ratios (aORs) for potential risk factors were determined for anti-HBc and HBsAg positivity. RESULTS: The national prevalence of anti-HBc and HBsAg positivity among adults were 25.9% and 2.9%, respectively. Persons aged ≥70 years had the highest anti-HBc positivity (32.7%), but the lowest HBsAg positivity prevalence (1.3%). Anti-HBc positivity was associated with injection drug use (aOR = 2.34; 95% confidence interval [CI] = 1.46-3.74), receipt of a blood transfusion (aOR = 1.68; 95% CI = 1.32-2.15), and sex with a commercial sex worker (aOR = 1.46; 95% CI = 1.06-2.01). HBsAg positivity was associated with receipt of a blood transfusion (aOR = 2.72; 95% CI = 1.54-4.80) and past incarceration (aOR = 2.72; 95% CI = 1.25-5.93). Among HBsAg-positive persons, 0.9% (95% CI = 0.0-2.0) were HDV coinfected. CONCLUSIONS: Georgia has an intermediate to high burden of hepatitis B, and the prevalence of HDV coinfection among HBV-infected persons is low. Existing infrastructure for hepatitis C elimination could be leveraged to promote hepatitis B elimination.

Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: A case report of 3 patients.

Short-term administration of the entry inhibitor myrcludex-B (MyrB) has been shown to be safe and effective in phase II studies in patients coinfected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). However, its effectiveness and safety are unknown during long-term and high-dose treatment of patients with compensated cirrhosis in real-life settings. Herein, we describe the first 3 European patients with HDV-related compensated cirrhosis who were treated with MyrB 10 mg/day for 48 weeks as a compassionate therapy. Liver function tests, bile acids, and virological markers were monitored every 4 weeks. HBV/HDV-specific T cell quantity (up to 48 and 36 weeks) and HBV RNA levels were also assessed in 2 cases. During MyrB treatment, HDV RNA levels progressively declined from 4.4 and 5.6 logs IU/ml to undetectability in 2 cases, and from 6.8 log copies/ml to 500 copies/ml for the other patient. Alanine aminotransferase normalised after 20, 12 and 28 weeks, respectively. A significant improvement in features of portal hypertension, liver function tests and alpha-fetoprotein levels were documented in 2 cases. In the male patient with histological and clinical stigmata of autoimmune hepatitis, IgG and immunoglobulins rapidly normalised. No significant changes in HBV surface antigen levels and circulating HBV/HDV-specific T cells were demonstrated; HBV DNA and HBV RNA levels remained undetectable throughout the study period. MyrB was well tolerated; patients remained fully asymptomatic despite a significant increase of bile acids. In conclusion, this report shows excellent safety and effectiveness of a 48-week course of MyrB 10 mg/day, combined with tenofovir disoproxil fumarate, for the treatment of HDV-related compensated cirrhosis.

Hepatitis B virus and hepatitis delta virus subtypes circulating in Algeria and seroprevalence of HDV infection.

BACKGROUND: Little is known about molecular characteristics of HBV strains circulating in Algeria and there are few data regarding HDV infection. OBJECTIVES: The aim of this study is to describe the genetic diversity of HBV and HDV strains existing in Algeria and to determine the seroprevalence of HDV infection. STUDY DESIGN: Plasma samples from 134 patients were analyzed by enzyme immunoassay method for HBV and HDV serological markers. Genotyping of HBV and HDV strains were performed using direct sequencing followed by phylogenetic analyses of the PreS1 and R0 region of the HBV and HDV genome respectively. RESULTS: The PreS1 gene was successfully amplified in 119 patients (82 males and 37 females). Phylogenetic analysis of HBV strains revealed the presence of genotypes D (86.5%) and A2 (11.76%). The subgenotypes D are distributed as follows: HBV/D7 (43.5%), HBV/D3 (24.75%), HBV/D1 (16.8%) and HBV/D2 (14.85%). A recombinant between genotypes A, E and D was found. The seroprevalence of HDV infection among HBV carriers was less than 5.35%. Only one isolate of HDV genotype 1 was identified. CONCLUSIONS: Our data indicate the predominance of HBV subgenotype D7 and a low prevalence of HDV infection.

A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus-infected mongolians.

Hepatitis delta virus (HDV) causes the most severe form of human viral hepatitis. HDV requires a hepatitis B virus (HBV) coinfection to provide HDV with HBV surface antigen envelope proteins. The net effect of HDV is to make the underlying HBV disease worse, including higher rates of hepatocellular carcinoma. Accurate assessments of current HDV prevalence have been hampered by the lack of readily available and reliable quantitative assays, combined with the absence of a Food and Drug Administration-approved therapy. We sought to develop a convenient assay for accurately screening populations and to use this assay to determine HDV prevalence in a population with abnormally high rates of hepatocellular carcinoma. We developed a high-throughput quantitative microarray antibody capture assay for anti-HDV immunoglobulin G wherein recombinant HDV delta antigen is printed by microarray on slides coated with a noncontinuous, nanostructured plasmonic gold film, enabling quantitative fluorescent detection of anti-HDV antibody in small aliquots of patient serum. This assay was then used to screen all HBV-infected patients identified in a large randomly selected cohort designed to represent the Mongolian population. We identified two quantitative thresholds of captured antibody that were 100% predictive of the sample either being positive on standard western blot or harboring HDV RNA detectable by real-time quantitative PCR. Subsequent screening of the HBV+ cohort revealed that a remarkable 57% were RNA+ and an additional 4% were positive on western blot alone. CONCLUSION: The quantitative microarray antibody capture assay's unique performance characteristics make it ideal for population screening; its application to the Mongolian HBV surface antigen-positive population reveals an apparent ∼60% prevalence of HDV coinfection among these HBV-infected Mongolian subjects, which may help explain the extraordinarily high rate of hepatocellular carcinoma in Mongolia. (Hepatology 2017;66:1739-1749).

Antiviral treatment and liver-related complications in hepatitis delta.

Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG-IFNα) is effective in only 25%-30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long-term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti-HDV-positive patients who were followed for at least 6 months in a retrospective single-center cohort (mean time of follow-up, 5.2 years; range, 0.6-18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty-nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNα)-based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver-related death developed in 55 patients (40%). Patients who received IFNα-based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi-square and Kaplan-Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long-term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07-0.9). Loss of HDV RNA during follow-up was more frequent in IFNα-treated patients and strongly linked with a lower likelihood to experience liver-related complications. CONCLUSION: IFNα-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414-425).

Hepatitis B, C and D virus genotypes detected in HBsAg- or anti-HCV-positive people from the Republic of Moldova.

In the Republic of Moldova, little is known about hepatitis B, C and D virus (HBV, HCV, HDV) genotypes, although the genetic variant may influence the course and outcome of disease. For HBV genotyping, 301 hepatitis B surface antigen (HBsAg)-positive sera collected in 2010 and 2011 from drug users, prison inmates, commercial sex workers, and the general population in different geographical regions were investigated. The 31 HBsAg-positive sera collected in 2011 were also tested for HDV. Eighty-eight anti-HCV-positive sera collected between 2010 and 2011 from the general population and health care workers were used for HCV genotyping. Phylogenetic analysis of 84 HBV sequences showed that most of the viruses belonged to genotype D (n = 82, 97.6%), predominantly to the subgenotype D1/D2 cluster (n = 75/82, 91.5%). One sequence (74110) clustered as an outlier to this cluster, and six sequences belonged to subgenotype D3. Only two subgenotype A2 sequences were found. Cloning of six samples with ambiguous sequence chromatogram signals showed no mixed infections. Phylogenetic analysis of HCV sequences from 66 patients showed a predominance of subtype 1b (n = 63, 95.5%). Two sequences belonged to subtype 3a, and one to subtype 2a. HDV RNA belonging to genotype 1 was found in two sera (2/31, 6.5%). Thus, genotypes prevalent in Europe were detected for all three hepatitis viruses. For both HBV and HCV, one genotype was dominant, while occasional other variants seem to be restricted to certain cohorts and/or transmission routes.

Molecular characterization of the full-length genome sequences of HDV strains circulating in Tunisia.

While Tunisia is endemic for hepatitis B virus (HBV), a recent large-scale retrospective study, revealed a very low prevalence (2%) of hepatitis Delta virus (HDV) (Yacoubi et al. in J Clin Virol 72:126-132, 2015). All strains were classified within the genotype 1 (HDV-1) as assessed by nucleotide sequencing of the so-called 'R0' region of the genome described previously. In this study, we aimed to determine the full-length genome sequence of HDV isolates in order to fully characterize the HDV strains spreading in Tunisia. Eleven HDV antibody and RNA positive samples were obtained from the 1615 clinical samples previously studied. The whole genome sequence was obtained for 5 strains by sequencing and realignment of four overlapping regions covering the entire genome, followed by extensive phylogenetic analyses. Tunisian sequences segregated together with Turkish and African sequences and showed 60% GC content. Alignment with an HDV-1 consensus sequence revealed that they exhibited several point mutations in different functional domains of the delta proteins that, according to previous studies, might possibly affect their properties. In conclusion, the first full-length genome sequences of Tunisian HDV isolates are provided, isolates which are closely related to Turkish and Sub-Saharan Africa strains, supporting the hypothesis for the spread of HDV-1-strains from Africa via Tunisia to Turkey, before spread to the rest of the world.

Epidemiology and phylogenetic analysis of hepatitis D virus infection in Australia.

BACKGROUND: The incidence and trends of the hepatitis D virus (HDV) in Australia have not been recently assessed, and the circulating genotypes have never been determined. AIM: To characterise the current virology and epidemiology of HDV. METHODS: Notifiable disease surveillance and laboratory testing data were analysed to assess demographics, risk factors and trends. HDV serology and RNA testing were performed on requested samples from 2010 to 2016. Sequencing of a 500-nucleotide amplicon of the delta antigen and phylogenetic analysis of the strains from 2009 to 2016 were also conducted. RESULTS: Ninety HDV notifications were reported to the Victorian Department of Health and Human Services between 2010 and 2016. The majority (64.4%) of those diagnosed were born overseas, most commonly in Sudan, Pakistan and Vietnam. Over the same period, 190 patients tested positive for anti-HDV serology and 166 for HDV RNA. Sequencing of isolates from 169 individuals between 2009 and 2016 found that 80.5% strains were genotype 1, 16% genotype 5 and 3.5% genotype 2. Phylogenetic analysis confirmed the relatedness of strains from birth country, demonstrated the presence of the 'Pacific Island' genotype 1 strain in Queensland and supported possible transmission in correctional facilities and within families. CONCLUSIONS: This study demonstrates the ongoing need for routine HDV screening and engagement in clinical care for people living with HBV in Australia. Epidemiological findings highlight the diversity in those affected and provide insights into local and global geographic distribution and transmission patterns.

The Epidemiology of Hepatitis D Virus in North Africa: A Systematic Review and Meta-Analysis.

BACKGROUND: Hepatitis D virus (HDV) infection has been considered a serious neglected pandemic, particularly in developing countries. The virus causes a more severe disease than mono infection with hepatitis B virus (HBV). The epidemiology of HDV is not well documented in North Africa, which is known to be endemic for HBV. In this study, we explored the prevalence of HDV infection and also attempted to identify factors associated with hepatitis D positive status among chronic hepatitis B patients in North Africa. METHODS: The electronic databases PubMed, Embase, Scopus, Science Direct, Web of Science, and Google Scholar were comprehensively searched for all papers published between January 1, 1998, and December 31, 2017, using appropriate strategies containing all related keywords, including North Africa, names of countries in the region, and all permutations of hepatitis D virus. The estimated prevalence of HDV in North Africa was calculated as an average of the pooled infection prevalence in each country weighted by the ratio of the country's hepatitis D virus population to the study's sample size in the survey data analysis. FINDINGS: A total of 312 studies were identified and 32 were included in this study, with a total sample of 4907 individuals screened for HDV. There was considerable variability in the prevalence estimates of HDV within the countries of the region. The overall prevalence of HDV in the general population of North Africa was 5·01% (95% CI: 1·25-8·27) and in liver disease patients it was 20.7% (95% CI:9.87-44.53). Genotype-1 was the most prominent genotype reported in five published studies. Ten studies reported on HDV RNA in participants who were seropositive for HDV, and four studies highlighted the impact of demographic factors (sex and age). No study showed the impact of risk factors on the prevalence of HDV in North Africa. INTERPRETATION: This review provides a comprehensive assessment of the burden of HDV in Northern Africa. There were significant differences in seroprevalence, study population, and diagnostic testing between the countries in the region. The results presented here will alert health professionals to implement clear policies based on evidence to diminish the burden of HDV infection. Such measures may include but are not restricted to improving the laboratory diagnostic tests and initiating patient data registries and blood screening. Further epidemiological and research studies are needed to explore the risk factors, coinfections, and approaches to increase testing for HDV, particularly in high-risk subpopulations, such as intravenous drug users and immigrants, and to define the consequences of HDV infection in North Africa.

[Chronic hepatitis B and D (delta) : Current and future treatments]. / Chronische Hepatitis B und D (delta) : Gegenwärtige und zukünftige Therapien.

BACKGROUND: Worldwide, hepatitis B virus (HBV) infection is among the 30 leading causes of death, despite effective vaccination and therapeutic options. Chronic hepatitis delta (coinfection with hepatitis D virus) leads to a rapid disease progression. AIMS: Based on current international guidelines and studies, an overview about present and future therapeutic options for chronic hepatitis B and delta is provided. RESULTS: Therapy with nucleoside or nucleotide analogues leads to nearly complete HBV DNA suppression, which is associated with regression of liver fibrosis and a lower risk for the development of hepatocellular carcinoma. Therapy of chronic hepatitis delta with pegylated interferon alfa achieves only low response rates with high risk for virological relapse. Various therapeutic approaches are currently being investigated in preclinical and clinical studies and have led to a significant reduction of hepatitis B surface antigen (HBsAg) and HDV RNA. CONCLUSION: Current therapies of chronic HBV infection can effectively reduce subsequent complications. New therapeutic approaches promise functional cure (HBsAg loss) of HBV infection and effective treatment options for patients with chronic hepatitis delta.

Impact of Tenofovir on Hepatitis Delta Virus Replication in the Swiss Human Immunodeficiency Virus Cohort Study.

We analyzed changes in hepatitis B virus and hepatitis delta virus (HDV) viral loads (VL) during tenofovir-containing antiretroviral therapy among patients with a replicating HDV infection in the Swiss HIV Cohort Study. Only 28.6% experienced a ≥2.0 log reduction in HDV RNA, and 14.3% had undetectable HDV VL within 5 years.