Hepatitis D virus in individuals with HIV and hepatitis B virus: current epidemiology, treatment and prevention.

Recent updates in hepatitis vaccination and the prevention of hepatocellular carcinoma.

Superinfection of other hepatitis viruses on top of chronic hepatitis B: The more, the worse

The major cause of liver cancer around the globe is hepatitis B virus (HBV), which also contributes to a large number of deaths due to liver failure alone. Hepatitis delta virus (HDV) is as potentially alarming as HBV since life threatening cases are 10 times more likely with HBV-HDV dual infection compared to HBV monoinfection. So far, there is no established effective treatment against HDV and the only preventive action suggested by the World Health Organization is to introduce HBV vaccination for children immediately after birth (newborns) and thus reduce the available pool for HDV infection. Here the main objective is to understand the complex dynamics of HBV-HDV infection in a human population that can inform public health policy makers on the level of different preventive measures required to eliminate HBV and HDV infections. Model simulations suggest that HBV vertical transmission and HBV vaccination rates for newborns are instrumental in determining HBV and HDV prevalence. A decrease in HBV prevalence is observed as vaccination coverage increases and it is possible to eradicate both HBV and HDV using high vaccination coverage of ≥80% in the long term. We further found that HDV presence results in lower HBV prevalence. An application of our model to China revealed that vaccinating every newborn in China will further prevent 1.69 million new infections by 2028 as compared to the current 90% vaccination coverage. Although, higher vaccination coverage of newborns should eliminate both HBV and HDV over a long time period, any short term strategy to eradicate HDV must include additional preventive measures such as HBV adult vaccination. Implementation of HBV adult vaccination programs at a rate of 10% per year over 15 years will further prevent 39 thousand new HDV infections in China by 2028 as compared to HBV vaccination programs solely for newborns.

The hepatitis delta virus and chronic hepatitis D.

Potential conflict of interest: Nothing to report. See Article on Page 1739 Hepatitis D virus (HDV), the etiologic agent of hepatitis D or delta hepatitis, is a unique human virus that requires the hepatitis B surface antigen (HBsAg) of hepatitis B virus (HBV) for its replication and to establish infection. HDV, the only member of its own separate genus, Deltavirus, is the smallest known infectious viral agent of humans.1 The HDV virion, which measures 35‐37 nm in diameter, contains a single‐stranded circular ∼1,700‐nucleotide RNA genome of negative polarity, which encloses only a single functional open reading frame encoding the sole viral protein, the hepatitis delta antigen (HDAg). The HDAg is associated with the genomic RNA to form a ribonucleoprotein complex which is encapsulated by a lipid envelope containing the small, middle, and large HBsAg proteins.2 HDV exhibits a high degree of genetic heterogeneity, with estimated mutation rates between 3 × 10–2 and 3 × 10–3 base substitutions per genomic site per year.1 The virus has a wide geographic distribution with eight distinct genotypes. HDV genotype 1 is the most common genotype, being prevalent in North America, Europe, the Middle East, and North Africa; genotypes 2 and 4 are found predominantly in East Asia; genotype 3 is found exclusively in the Amazon basin in South America; and genotypes 5‐8, also known as African genotypes, are predominantly found in West and central Africa.3 HDV is a highly pathogenic virus, and clinical presentation of hepatitis D ranges from fulminant hepatitis, exacerbation of the course of underlying HBV infection, and acceleration of progression to cirrhosis, leading to early decompensation of liver function and hepatocellular carcinoma in the majority of patients.4 However, a benign course of HDV infection has also been observed in Greece, Samoa, and the Far East; whether this is related to various viral characteristics such as the infecting genotype or host genetics remains to be determined.4 Outbreaks of severe and fulminant hepatitis D have been reported from Brazil, Russia, Greenland, and Mongolia.3 The laboratory diagnosis of coinfection or superinfection with HDV is based on simultaneous detection of various serologic markers of HBV and HDV infection. The markers of acute HDV infection include, along with the markers of HBV infection, HDAg, HDV RNA, and immunoglobulins M and G (IgM and IgG, respectively) antibodies to HDV (anti‐HDV). These markers of HDV infection are present only transiently and disappear during early convalescence; IgM anti‐HDV and even IgG anti‐HDV also disappear with time in acute resolving HDV infection.3 Superinfection of HBsAg carriers, which almost always leads to chronic hepatitis D, is marked by absence of IgM antibody to hepatitis B core antigen and presence of all the other markers of HBV and HDV infections (Fig. 1). However, markers of HBV replication, especially HBV DNA, may be suppressed during the acute phase of HDV infection and remain undetectable.1 Chronicity of HDV infection is associated with persistence of HDAg, HDV RNA, and IgM and IgG anti‐HDV. HDV RNA is the gold standard for diagnosis of current HDV infection because assays for detection of HDAg are fraught with sensitivity and specificity issues. Quantitative assays of HDV RNA are useful for monitoring response to antiviral therapy, and the recent availability of a World Health Organization standard has further helped in optimizing assays across various centers and laboratories. Sequencing of HDV RNA–positive samples is a reliable way to determine the HDV genotype.5Figure 1: Serologic course of acute resolving (A) and chronic (B) HDV infection. Abbreviations: anti‐HBc, antibody to hepatitis B core antigen; anti‐HBs, antibody to HBsAg.The prevalence of HDV is a measure of anti‐HDV positivity among HBsAg positive carriers. It is estimated that 10 million to 20 million individuals (∼5% of chronic HBV patients) worldwide are coinfected with HDV.6 Vaccination against hepatitis B, which is also the default vaccination against HDV, resulted in a decrease of HDV prevalence in industrialized countries with the implementation of routine hepatitis B immunization of children and other populations.7 However, in several European countries (e.g., Germany, Italy, and England), which have large and increasing numbers of migrants from HDV‐endemic areas (e.g., eastern Europe and Turkey), HDV prevalence rates have remained unchanged.2 High‐risk populations like injection drug users continue to get impacted by superinfection with HDV, as has been observed in Europe and recently in the United States.7 Based on cross‐sectional studies, high rates of HDV infection, ranging from 10% to 70%, in HBsAg carriers have been reported from Nigeria, Gabon, India, Pakistan, Iran, the western Brazilian Amazon, Tajikistan, and Mongolia.6 A number of developing countries have reported a high endemicity of HDV, and prevalence rates of >20% have been reported; these include central Africa, mountainous regions of Venezuela and Colombia, Romania, Pakistan, Iran, the Amazon basin in South America, and Mongolia. However, reliable data on the accurate prevalence of HDV are not available from all regions due to either lack of testing of HBsAg carriers for HDV infection or lack of availability of anti‐HDV antibody assays with proven performance characteristics. In this context, the article by Chen et al. published in this issue of hepatology9 is of major significance. The authors found a substantially higher prevalence (∼60%) of HDV infections among HBV‐infected individuals identified in a national survey sampling of the Mongolian population. Of a total of 1,158 individuals chosen based on a three‐stage cluster sampling method to reflect the gender, age, and geographical origin representative of the entire country, 123 tested positive for HBsAg, of whom 75 (60%) tested anti‐HDV‐positive by a newly developed high‐throughput quantitative microarray antibody capture (Q‐MAC) assay that the authors describe.9 Modern diagnostic approaches, such as protein microarray–based Q‐MAC assays, allow for improvement in the sensitivities of various diagnostic assays. Protein microarrays have become an important tool in studies of protein–protein interactions, protein detection, and other applications in quantitative and functional proteomics and beyond. Protein microarrays are arrays of protein targets, frequently antibodies and/or antigens, immobilized on a solid support such as a glass slide. Plasmonic substrates, such as nanostructured plasmonic gold film, have been developed to improve the sensitivity and dynamic range of protein detection on microarrays and have been shown to detect cancer biomarkers and integrated human antibodies and antigens down to femtomolar ranges.10 Chen et al. have used this protein microarray technology to develop a Q‐MAC assay for sensitive quantitative fluorescent detection of anti‐HDV IgG from patient sera. The authors not only convincingly demonstrated the excellent performance characteristics of their Q‐MAC assay but also established quantitative thresholds of captured HDV antibody predictive of HDV RNA positivity. However, as the authors have righty stated, despite a good correlation between fluorescence intensity of the Q‐MAC assay and HDV RNA levels, determination of HDV RNA remains the gold standard for monitoring of treatment against hepatitis D. The Q‐MAC assay is rapid, requires a small volume of patient serum, and can easily be scaled to high‐throughput screening of large cohorts of HBsAg carriers for HDV infection. A true seroepidemiologic gauge of the prevalence of hepatitis D is to test HBsAg carriers only and estimate the prevalence rates using the HBsAg positives as the denominator. With this approach, Chen et al.9 found an alarming proportion of their HBsAg‐positive population in Mongolia superinfected with HDV. Compared to other HBsAg carriers, persons superinfected with HDV are at the highest risk for hepatocellular carcinoma, and HDV superinfection undoubtedly contributes to Mongolia's high rate of hepatocellular carcinoma. Assessments of HDV as a cause of excess morbidity and mortality among persons with HBV infection globally are limited by the lack of serologic studies. The data from Chen et al.9 highlight the importance of conducting such seroprevalence studies among HBsAg carriers in HDV‐endemic countries and high‐risk populations in developed countries. Given that an estimated 248 million are chronically infected with HBV worldwide and thus susceptible to superinfection with HDV, concerted efforts, like the one undertaken by the Hepatitis Delta International Network (http://hepatitis‐delta.org/), are needed for the determination of accurate estimates of hepatitis D disease burden, evidence‐based policies for HDV testing, and research to understand the biological mechanisms of HDV infection and find efficacious therapies for treatment of hepatitis D.

A Multicenter Study of Viral Hepatitis in a United States Hemophilic Population

A multicenter study of viral hepatitis in a United States hemophilic population

Epidemiological data on hepatitis delta virus (HDV) infection in Belgium are lacking. A multicenter questionnaire-based registry on HDV infection was collated between March 1, 2008 and February 28, 2009. It consisted of patients coinfected with hepatitis B virus (HBV) and HDV. The data samples were compared to those of a concurrent registry on HBV infection. Prospective data of patients with HBV-HDV coinfection were collected. Active HBV replication is defined as HBeAg positivity or HBV DNA > 2,000 IU/ml. Forty-four patients from 15 centers were registered. A comparison of 29 patients infected with HDV (registered in the concurrent HBV registry) was made against 785 HBV mono-infected patients. The seroprevalence of patients coinfected with HBV and HDV in Belgium is reported to be 3.7% (29/785), consisting solely of the HBV-HDV coinfected patients in the HBV registry. This rises to 5.5% (44/800) if all patients infected with HDV from the two registries combined are included. The patients coinfected with HBV and HDV had higher (P < 0.05) ALT values and more advanced liver disease (Metavir score ≥F2), but had less active HBV replication and lower HBV DNA titers when compared with the patients infected only with HBV. Additionally, the majority of HBV-HDV coinfected patient was male, and 13.6% (6/44) of the patients that were coinfected HBV and HDV were also infected with HCV. In conclusion, this study provided much needed epidemiological data on the current state of HDV infection in Belgium.

Hepatitis D virus (HDV) is a defective RNA virus that requires the hepatitis B envelope for its replication. Infection with HDVoccurs as co-infection or superinfection in persons infected with hepatitis B virus (HBV). Chronic HDVinfection usually follows superinfection of chronic HBV infection with HDV. Unlike some other infections, persistent HDV infection is associated with presence of HDV RNA, viral antigen (HDAg), and IgM and IgG antibodies to HDV [1]. HDV has a worldwide distribution with nearly 15 million people infected, especially in the Mediterranean Basin, the Middle East, Central Asia, West Africa, the Amazon Basin of South America and certain South Pacific islands [2]. In Nigeria, HBV infection is a major cause of liver disease [3]. In a previous report, HDVantigen was detected in 6.5% of patients with chronic HBV liver disease in Ife, South West Nigeria [4]. With measures for preventing HBV infection (including vaccination and safe blood transfusion), HDV infection may be on the decline [5]. However recent reports, including one from our locality, have tended to indicate otherwise [6, 7]. We set out to investigate the current status of HDV infection. After ethical approval, consecutive consenting patients attending the Gastroenterology Unit of Lagos State University Hospital, Lagos between September 2009 to November 2010 were recruited if they were positive for HBsAg for more than 6 months and had not received any antiviral therapy. A questionnaire was used to collect information on demographics, clinical features, liver biochemical tests and imaging results. Blood (10 mL) was collected in EDTA, and plasma was separated and stored at −20 C. IgG anti-HDV antibodies were assayed using an Elisa method (HDVAb kit; DIA PRO Diagnostic, Milan, Italy) according to the manufacturer’s protocol. The sensitivity and specificity of this assay kit are over 98%. A total of 245 patients (191 male) with age range 13–76 (mean [SD]034.6 [10.6]) years were studied. Of these, 178 were asymptomatic HBV carriers, whereas 67 had features of chronic liver disease (chronic hepatitis 22, cirrhosis 37 and liver cancer 8). Five (2.0%; 2 male) of these 245 patients tested positive to anti-HDV. These included 3 of 178 asymptomatic carriers and 2 of 67 patients with liver disease. Alanine aminotransferase (ALT) levels were mildly elevated in two anti-HDV positive persons and were normal in three. Our study patients with chronic HBV infection had a lower prevalence of anti-HDV antibody as compared to previous reports [4, 7] from our locality with prevalence rates of 6.5% for HDAg and 12.5% for HDV antibody, respectively. Possible explanations for this difference may relate to the characteristics of the study subjects, the assay or an actual reduction in disease burden. Among the previous studies, one by Ojo et al. [4] had smaller sample size, consisted of patients symptomatic for liver disease and the assay was for HDV antigen. The other study [7] included both symptomatic and asymptomatic persons, but had a larger sample size. Our study, as well as both the previous studies, were limited by the fact that testing for HDV RNA, a better marker of HDV infection, was not done. A true reduction in HDV prevalence rates over time is also possible; this could have resulted from measures to prevent HBV infection embarked during the last two decades. A recent study showing HBsAg prevalence of about 8% Part of this work was presented as a poster during the EASL Monothematic Conference in Istanbul, Turkey in September 2010. C. A. Onyekwere (*) : F. Duro-Emmanuel Department of Medicine, Lagos State University Teaching Hospital, Lagos, Nigeria e-mail: ifymobi@yahoo.com

Hepatitis D virus (HDV) is a defective liver-tropic virus that needs the helper function of hepatitis B virus (HBV) to infect humans and replicate. HDV is transmitted sexually or by a parenteral route, in co-infection with HBV or by super-infection in HBV chronic carriers. HDV infection causes acute hepatitis that may progress to a fulminant form (7%-14% by super-infection and 2%-3% by HBV/HDV co-infection) or to chronic hepatitis (90% by HDV super-infection and 2%-5% by HBV/HDV co-infection), frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma (HCC). Peg-interferon alfa the only recommended therapy, clears HDV in only 10%-20% of cases and, consequently, new treatment strategies are being explored. HDV endemicity progressively decreased over the 50 years from the identification of the virus, due to improved population lifestyles and economic levels, to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs. Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic, unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments, lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.

BackgroundThe geographic distribution of the hepatitis B virus (HBV) and the hepatitis D virus (HDV) genotypes is uneven. We reconstructed the temporal evolution of HBV and HDV in Yakutia, one of the regions of Russia most affected by HBV and HDV, in an attempt to understand the possible mechanisms that led to unusual for Russia pattern of viral genotypes and to identify current distribution trends.MethodsHBV and HDV genotypes were determined in sera collected in 2018–2019 in Yakutia from randomly selected 140 patients with HBV monoinfection and 59 patients with HBV/HDV. Total 86 HBV and 88 HDV genomic sequences isolated in Yakutia between 1997 and 2019 were subjected to phylodynamic and philogeographic Bayesian analysis using BEAST v1.10.4 software package. Bayesian SkyGrid reconstruction and Birth–Death Skyline analysis were applied to estimate HBV and HDV population dynamics.ResultsCurrently, HBV-A and HDV-D genotypes are prevalent in Yakutia, in both monoinfected and HDV-coinfected patients. Bayesian analysis has shown that the high prevalence of HBV-A in Yakutia, which is not typical for Russia, initially emerged after the genotype was introduced from Eastern Europe in the fifteenth century (around 600 (95% HPD: 50–715) years ago). The acute hepatitis B epidemics in the 1990s in Yakutia were largely associated with this particular genotype, as indicated by temporal changes in HBV-A population dynamics. HBV-D had a longer history in Yakutia and demonstrated stable population dynamics, indicating ongoing viral circulation despite vaccination. No correlation between HBV and HDV genotypes was observed for coinfected patients in Yakutia (r = − 0.016069332). HDV-2b circulates in Russia in Yakutia only and resulted from a single wave of introduction from Central Asia 135 years ago (95% HPD: 60–350 years), while HDV-1 strains resulted from multiple introductions from Europe, the Middle East, Central Asia, and different parts of Russia starting 180 years ago (95% HPD: 150–210 years) and continuing to the present day. The population dynamics of HDV-1 and HDV-2 show no signs of decline despite 20 years of HBV vaccination. The Birth–Death Skyline analysis showed an increase in the viral population in recent years for both HDV genotypes, indicating ongoing HDV epidemics.ConclusionsTaken together, these data call for strict control of HBV vaccination quality and coverage, and implementation of HBV and HDV screening programs in Yakutia.

Hepatitis D Virus (HDV) is the simplest RNA virus with a unique circular genome. It is a defective RNA virus because it has to rely on Hepatitis B Virus (HBV) to assemble new virions and propagate infection. Without HBV, HDV would be unable to finish its life cycle; therefore, it is called the satellite virus of HBV. Approximately 350 million people worldwide are chronically infected with HBV. Although there is only about 5% of HBV carriers infected with HDV, the risk is that it could lead to the most severe forms of hepatitis— fulminant hepatitis. Also, antivirals against HBV do not ameliorate hepatitis D. It has long been unclear to what extent cellular immune responses attribute to liver disease and why immune responses fail to control viral replication in persistent HDV infection. Recently, two studies in mouse model have given some hints on the relation between innate immunity and HDV infection. One of the two studies, using hNTCP-transgenic mice to investigate how innate and adaptive immunity affect the clearance of HDV. Their data indicated that it is innate immunity but not adaptive immunity plays a role in HDV clearance. Pattern-recognition receptors (PRRs), which detect pathogens and initiate host antimicrobial responses such as producing type I interferons and proinflammatory cytokines, are important parts of innate immunity. We are interested in whether such unique circular RNA structure of HDV can be recognized by specific host PRRs. The other studies, using chimeric mice with humanized liver to analyze regulation of genes in host liver after HDV infection. Genes of PRRs in sensing viral nucleic acid are indeed up-regulated after HDV infection. According to those preliminary observation, we would like to further explore such matter in cell models; hence, a stable HDV infection system is needed. In this study, we used two specific HepG2 cell lines (HepG2-hNTCP-C4 and HepG2-hNTCP-SW1) which both stably overexpress an HBV entry receptor, human Sodium taurocholate cotransporting polypeptide (NTCP). Our results showed only NTCP-C4 cells are susceptible to HDV infection, and at 1000 genome equivalent/ cell, only 0.46% of the cells were infected at Day 6 post infection. To see a 4.3% infection rate, the genome equivalent/ cell would need to increase to 5000. In addition, with the aim of enhancing infection efficiency, we tried different conditions during HDV infection by adjusting concentration of PEG and DMSO. However, it seems that increase of PEG concentration or addition of DMSO both not improve the infection process. For our final goal is to find out possible PRRs detecting hepatitis delta virus, and evaluate how anti-viral response be initiated via this cell system in the future. HDV infection rate has to reach a certain level to induced sequential host immune responses. To see immune signaling mechanisms, a 50% infection rate might be necessary. We hope this infection model could shed light on the interactions between host immunity and HDV infected cells, and provide help in future study.

Hepatitis B virus (HBV) vaccination is recommended for HIV patients. Despite the relative success of HBV vaccination, breakthrough infections can occur infrequently in patients, and it can be due to occult HBV infection, vaccine unresponsiveness and/or emergence of escape mutants. This study assessed the presence of occult HBV infection and S gene escape mutants in HIV-positive patients after HBV vaccination. Ninety-two HIV-positive patients were enrolled in this study, including 52 responders to HBV vaccine and 40 non-responders. All of the cases received HBV vaccine according to routine HBV vaccination protocols. The presence of HBV-DNA was determined by real-time polymerase chain reaction (PCR). In HBV-DNA positive samples, the most conserved regions of S gene sequences were amplified by nested PCR and PCR products were sequenced. Occult HBV infection was detected in two cases. Glycine to arginine mutation at residue 145 (G145R) within the 'a' region of the S gene was detected in one of the occult HBV infection cases who was in the non-responder group. This study showed that the prevalence of occult HBV infection and vaccine escape mutants was low in our HBV-vaccinated HIV-positive patients in both responder and non-responder groups, so there was no alarming evidence indicating breakthrough HBV infection in our vaccinated HIV-positive cases.

The incidence of hepatitis B virus (HBV) infection in dialysis populations has declined over recent decades, largely because of improvements in infection control and widespread implementation of HBV vaccination. Regardless, outbreaks of infection continue to occur in dialysis units, and prevalence rates remain unacceptably high. For a variety of reasons, dialysis patients are at increased risk of acquiring HBV. They also demonstrate different disease manifestations compared with healthy individuals and are more likely to progress to chronic carriage. This paper will review the epidemiology, modes of transmission and diagnosis of HBV in this population. Prevention and treatment will be discussed, with a specific focus on strategies to improve vaccination response, new therapeutic options and selection of patients for therapy.

Population-level interventions to improve the health outcomes of people living with hepatitis B: an Evidence Check brokered by the Sax Institute for the NSW Ministry of Health, 2022.