Search

Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an unfavourable outcome, with many patients developing liver cirrhosis, liver failure and eventually hepatocellular carcinoma within 5–10 years. The identification of the HBV/HDV receptor and the development of novel in vitro and animal infection models allowed a more detailed study of the HDV life cycle in recent years, facilitating the development of specific antiviral drugs. The characterisation of HDV-specific CD4+ and CD8+T cell epitopes in untreated and treated patients also permitted a more precise understanding of HDV immunobiology and possibly paves the way for immunotherapeutic strategies to support upcoming specific therapies targeting viral or host factors. Pegylated interferon-α has been used for treating HDV patients for the last 30 years with only limited sustained responses. Here we describe novel treatment options with regard to their mode of action and their clinical effectiveness. Of those, the entry-inhibitor bulevirtide (formerly known as myrcludex B) received conditional marketing authorisation in the European Union (EU) in 2020 (Hepcludex). One additional drug, the prenylation inhibitor lonafarnib, is currently under investigation in phase III clinical trials. Other treatment strategies aim at targeting hepatitis B surface antigen, including the nucleic acid polymer REP2139Ca. These recent advances in HDV virology, immunology and treatment are important steps to make HDV a less difficult-to-treat virus and will be discussed.

ObjectiveTo investigate the distribution and risk factors of hepatitis delta virus (HDV) infection in Cameroon.DesignWe tested for hepatitis B virus (HBV) surface antigen (HBsAg) and anti-HDV antibody 14 150 samples collected during a survey whose participants were representative of the Cameroonian adult population. The samples had already been tested for hepatitis C virus and HIV antibodies.ResultsOverall, 1621/14 150 (weighted prevalence=11.9%) participants were HBsAg positive, among whom 224/1621 (10.6%) were anti-HDV positive. In 2011, the estimated numbers of HBsAg positive and HDV seropositives were 1 160 799 and 122 910 in the 15–49 years age group, respectively. There were substantial regional variations in prevalence of chronic HBV infection, but even more so for HDV (from 1% to 54%). In multivariable analysis, HDV seropositivity was independently associated with living with an HDV-seropositive person (OR=8.80; 95% CI: 3.23 to 24.0), being HIV infected (OR=2.82; 95% CI: 1.32 to 6.02) and living in the South (latitude ConclusionWe found evidence for effective intra-household transmission of HDV in Cameroon. We also identified large differences in prevalence between regions, with cases concentrated in forested areas close to the Equator, as described in other tropical areas. The reasons underlying these geographical variations in HDV prevalence deserve further investigation.

ObjectiveChronic HBV/HDV infections are a major cause of liver cancer. Current treatments can only rarely eliminate HBV and HDV. Our previously developed preS1-HDAg immunotherapy could induce neutralising antibodies to HBV in vivo and raise HBV/HDV-specific T-cells. Here, we further investigate if a heterologous prime-boost strategy can circumvent T-cell tolerance and preclude HDV superinfection in vivo.DesignA DNA prime-protein boost strategy was evaluated for immunogenicity in mice and rabbits. Its ability to circumvent T-cell tolerance was assessed in immunocompetent hepatitis B surface antigen (HBsAg)-transgenic mice. Neutralisation of HBV and HDV was evaluated both in vitro and in immunodeficient human-liver chimeric mice upon adoptive transfer.ResultsThe prime-boost strategy elicits robust HBV/HDV-specific T-cells and preS1-antibodies that can effectively prevent HBV and HDV (co-)infection in vitro and in vivo. In a mouse model representing the chronic HBsAg carrier state, active immunisation primes high levels of preS1-antibodies and HDAg-specific T-cells. Moreover, transfer of vaccine-induced antibodies completely protects HBV-infected human-liver chimeric mice from HDV superinfection.ConclusionThe herein described preS1-HDAg immunotherapy is shown to be immunogenic and vaccine-induced antibodies are highly effective at preventing HBV and HDV (super)infection both in vitro and in vivo. Our vaccine can complement current and future therapies for the control of chronic HBV and HDV infection.

ObjectiveHepatitis D virus (HDV) is a defective virus that completes its life cycle only with hepatitis B virus (HBV). The HBV with HDV super-infection has been considered as one of the most severe forms of the chronic viral hepatitis. However, there is a scarcity of data on the global burden of HDV infection.DesignWe searched PubMed, Embase, Cochrane Library and China Knowledge Resource Integrated databases from 1 January 1977 to 31 December 2016. We included studies with a minimum sample size of 50 patients. Our study analysed data from a total of 40 million individuals to estimate the prevalence of HDV by using Der-Simonian Laird random-effects model. The data were further categorised according to risk factors.ResultsFrom a total of 2717 initially identified studies, only 182 articles from 61 countries and regions met the final inclusion criteria. The overall prevalence of HDV was 0.98% (95% CI 0.61 to 1.42). In HBsAg-positive population, HDV pooled prevalence was 14.57% (95% CI 12.93 to 16.27): Seroprevalence was 10.58% (95% CI 9.14 to 12.11) in mixed population without risk factors of intravenous drug use (IVDU) and high-risk sexual behaviour (HRSB). It was 37.57% (95% CI 29.30 to 46.20) in the IVDU population and 17.01% (95% CI 10.69 to 24.34) in HRSB population.ConclusionWe found that approximately 10.58% HBsAg carriers (without IVDU and HRSB) were coinfected with HDV, which is twofold of what has been estimated before. We also noted a substantially higher HDV prevalence in the IVDU and HRSB population. Our study highlights the need for increased focus on the routine HDV screening and rigorous implementation of HBV vaccine programme.

We sincerely appreciate Stockdale and colleagues1 for their critical consideration of our article. Herein, we tried to answer their concerns about the methodology of our meta-analysis.2 We used hepatitis D virus (HDV) antibody (both IgM and IgG) seropositivity as a measure of overall burden of HDV seroprevalence. Although anti-HDV IgM Ab assays may fail to detect low titres of antibodies and underestimate HDV seroprevalence,3 patients with a negative anti-HDV IgM results are less likely to progress into clinical disease.4 Majority of the included studies in our article used anti-HDV antibody assays and only two mentioned the use of RNA assays for the prevalence of HDV. Therefore, considering the wide application of the anti-HDV antibody assay as a measure of HDV seroprevalence,5 we used the similar method in our meta-analysis. We do not think it would be correct to extrapolate the prevalence of HBsAg based on our estimates of HDV seroprevalence among general population and mixed population (HBsAg carriers without risk factors such as intravenous drug use and high-risk sexual behaviours). This is because the general population and the mixed …

ObjectiveHepatitis delta virus (HDV) was shown to persist for weeks in the absence of HBV and for months after liver transplantation, demonstrating the ability of HDV to persevere in quiescent hepatocytes. The aim of the study was to evaluate the impact of cell proliferation on HDV persistence in vitro and in vivo.DesignGenetically labelled human sodium taurocholate cotransporting polypeptide (hNTCP)-transduced human hepatoma(HepG2) cells were infected with HBV/HDV and passaged every 7 days for 100 days in the presence of the entry inhibitor Myrcludex-B. In vivo, cell proliferation was triggered by transplanting primary human hepatocytes (PHHs) isolated from HBV/HDV-infected humanised mice into naïve recipients. Virological parameters were measured by quantitative real time polymerase chain reaction (qRT-PCR). Hepatitis delta antigen (HDAg), hepatitis B core antigen (HBcAg) and cell proliferation were determined by immunofluorescence.ResultsDespite 15 in vitro cell passages and block of viral spreading by Myrcludex-B, clonal cell expansion permitted amplification of HDV infection. In vivo, expansion of PHHs isolated from HBV/HDV-infected humanised mice was confirmed 3 days, 2, 4 and 8 weeks after transplantation. While HBV markers rapidly dropped in proliferating PHHs, HDAg-positive hepatocytes were observed among dividing cells at all time points. Notably, HDAg-positive cells appeared in clusters, indicating that HDV was transmitted to daughter cells during liver regeneration even in the absence of de novo infection.ConclusionThis study demonstrates that HDV persists during liver regeneration by transmitting HDV RNA to dividing cells even in the absence of HBV coinfection. The strong persistence capacities of HDV may also explain why HDV clearance is difficult to achieve in HBV/HDV chronically infected patients.

Objective Although hepatitis delta is considered an immune-mediated disease, adaptive immune responses to hepatitis delta virus (HDV) are hardly detectable. Thus, the role of other immune responses, including those mediated by natural killer (NK) cells, must be considered in HDV pathogenesis and in treatments with immune-stimulating agents such as interferon (IFN)α. However, the phenotype and function of NK cells in chronic HDV infection, or in HDV-infected individuals undergoing IFNα treatment, have not been extensively studied. Design We performed an extensive analysis of NK cells in chronically HDV-infected patients before and during treatment with IFNα, and compared the results with those for patients with HBV mono-infection as well as healthy controls. Results In untreated HDV-infected patients, a higher than normal frequency of NK cells was observed in peripheral blood with unaltered phenotypic NK cell differentiation status. In contrast, long-term IFNα treatment of HDV-infected patients caused a significant change in NK cell differentiation status, with selective loss of terminally differentiated NK cells and, in parallel, a relative enrichment in immature NK cell subsets. Treatment was associated with marked functional impairment of the NK cells, which was independent of the changes in NK cell differentiation status. Furthermore, treatment polarised NK cell IFN signalling from STAT4 towards STAT1 dependency. Strikingly, a high frequency of CD56 dim NK cells at baseline was positively associated with IFNα treatment outcome in the patients. Conclusions We describe in detail how HDV infection, and IFNα treatment of this infection, affects the NK cell compartment and what consequences this has for the functional capacity of NK cells.

We thank H Wedemeyer and F Negro for their critical commentary about our article.1 The authors acknowledge that the global disease burden of hepatitis D virus (HDV) is higher than previously estimated. However, they emphasised limitation of this systematic review and meta-analysis that about one-third of anti-HDV-positive patients can have undetectable HDV RNA levels and the global disease burden estimated by only anti-HDV-positivity rate might not reflect the true prevalence of HDV.2 We agree with the authors that synchronous detection of anti-HDV antibodies and HDV RNA is necessary to diagnose the …

BACKGROUND—The effect of hepatitis delta virus (HDV) infection on the clinical course of cirrhosis type B is poorly defined. AIMS—To investigate the impact of HDV status on morbidity and mortality in cirrhosis type B. PATIENTS/METHODS—Retrospective cohort study of 200 Western European patients with compensated cirrhosis type B followed for a median period of 6.6 years. RESULTS—At diagnosis, 20% of patients had antibodies to HDV (anti-HDV); median age was lower in anti-HDV positive cirrhotics (34 v 48 years respectively). Kaplan-Meier five year probability of hepatocellular carcinoma (HCC) was 6, 10, and 9% in anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 22, 16, and 19% and for survival they were 92, 89, and 83% respectively. Cox regression analysis identified age, albumin concentration, γ-globulin concentration, and HDV status as significant independent prognostic variables. After adjustment for clinical and serological differences at baseline, the risk (95% confidence interval) for HCC, decompensation, and mortality was increased by a factor of 3.2 (1.0 to 10), 2.2 (0.8 to 5.7), and 2.0 (0.7 to 5.7) respectively in anti-HDV positive relative to HDV negative cirrhotic patients. The adjusted estimated five year risk for HCC was 13, 4, and 2% for anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 18, 8, and 14% and for survival 90, 95, and 93% respectively. CONCLUSIONS—HDV infection increases the risk for HCC threefold and for mortality twofold in patients with cirrhosis type B. Keywords: delta hepatitis; prognosis; hepatocellular carcinoma; decompensation; survival

About 100,000 cases of acute hepatitis B virus (HBV) infection occur annually in South America. The overall prevalence of HBV infection in low risk populations ranges from 6.7% to 41%, while hepatitis B surface antigen (HBsAg) rates range from 0.4% to 13%. In high endemicity aboriginal or rural populations, perinatal transmission may play a major part in the spread of HBV. In urban populations, however, horizontal transmission, probably by sexual contact, is the predominant mode of spread, with higher rates of HBV positivity in lower socioeconomic groups. High risk populations such as health care workers and haemodialysis patients show higher rates of HBV infection than comparable populations elsewhere. The risk of posttransfusion hepatitis B remains high in some areas. Concomitant HBV infection may accelerate the chronic liver disease seen in decompensated hepatosplenic schistosomiasis. In the north, the prevalence of hepatitis delta virus (HDV) infection ranks among the highest in the world. In the south, the problem appears negligible although it is increasing within high risk urban communities. HDV superinfection has been the cause of large outbreaks of fulminant hepatitis. The cost of comprehensive or mass vaccination programmes remains unaffordable for most South American countries. Less expensive alternatives such as low dose intradermal schedules of immunisation have been used with success in selected adult subjects.

Introduction Ethnicity is associated with certain HBV phenotypes which in turn affect prognosis. Methods We performed a search for patients with HBV DNA measured at GSTT(March 2007 to March 2015). sAg+ve patients were analysed for:Ethnic group,HIV,Hep C and D co-infection,eAg status, ALT and viral load. Phenotypes were assigned to patients at diagnosis and at last f/up.ALT cut offs were >30 U/L for men and >20 U/L for females.The American Association for the Study of Liver Disease guidelines divide HBV phenotype into 4 groups although a recent study defined an “Indeterminant” group for patients who do not fit into any phenotype Results 1799 patients were sAg+ve,mean f/up duration was 39.2 months(SD 41.2).45% of the cohort were lost to f/up.47% were male, mean age at diagnosis was 36(No difference between ethnicities).82% were eAg-ve,1.5% Hepatitis D+ve,10% HIV+ve,2% hepatitis C+ve. 49% of the cohort were African/Afro-Caribbean,14% Caucasian,10% Chinese,1.5% South Asian, 2.6% South East Asian(other than Chinese),0.3% Arab,3.4% Mixed,2.3% unknown,6.6% “other”. The table shows HBV phenotype at diagnosis compared to last f/up in all patients and then according to the 3 main ethnic groups.Rates of seroconversion and treatment are also shown. 90.5% of African/Afro-Caribbeans were eAg-ve compared to 71% of Caucasians and 63.9% of Chinese(P Comparing the 3 largest ethnic groups only,in 2007,70% were African/Afro-Caribbean,19% Caucasian,11% Chinese compared to 51%,36% and 13% respectively in 2014. Conclusion Ethnicity is significantly associated with HBV phenotypes with a higher percentage of immunotolerants being Chinese and a higher percentage of African/Afro-Caribbeans being inactive. Compared to 2007,a higher percentage of HBV patients in 2014 were Caucasian reflecting changes in immigration.This may affect HBV outcomes and demand on Hepatology services. Disclosure of Interest None Declared

Hepatocyte expression of pre-S1 and pre-S2 in relation to hepatitis B virus replication (hepatitis B virus-DNA in serum and HBcAg in the liver), histological activity and hepatitis delta virus superinfection was studied by indirect immunofluorescence on frozen sections of liver specimens from 68 patients with chronic hepatitis B virus infection. All 44 patients with chronic type B hepatitis had pre-S1 and pre-S2 display in the liver. The distribution of pre-S1 in the liver was membranous in one, mixed membranous and cytoplasmic in 12, and cytoplasmic in 31. The distribution of pre-S2 was membranous in one, mixed membranous and cytoplasmic in 26, and cytoplasmic in 17. Membranous expression of pre-S1 was significantly more prevalent in patients with active hepatitis B virus replication than in those without (13/28 v 0/16, p < 0.001), regardless of the histological activity, as was membranous expression of pre-S2 (27/28 v 0/16, p < 0.001). In contrast, a significantly higher extent of cytoplasmic expression of pre-S1 and pre-S2 was noted in patients without active hepatitis B virus replication than in those with. Of 24 patients with chronic type D hepatitis virus, eight had active hepatitis B virus replication, and the other 16 did not. The distribution and quantitative expression of pre-S1 and pre-S2 in the liver in these patients also correlated significantly with the status of hepatitis B virus replication and, moreover, showed little or no difference from those without hepatitis delta virus infection. In conclusion, all patients with chronic type B hepatitis had synthesis and display of pre-S1 and pre-S2 in the liver. The distribution and quantitative expression of pre-S1 and pre-S2, however, were closely related to the status of hepatitis B virus replication, but not to the histological activity. Hepatocyte expression of pre-S1 and pre-S2 in chronic type D hepatitis also correlated significantly with status of hepatitis B virus replication, and was not modulated by concurrent hepatitis delta virus infection.

The clinical course of 10 liver transplant recipients who had hepatitis B virus (HBV) and five recipients with HBV and D (delta) infection before transplantation is described. Six patients who underwent eight transplants died. The estimated one and two year survival rates in patients with HBV only before transplantation were 74% and 67% respectively. The estimated one and two year survival in patients with HBV and HDV infection beforehand was 100%. Graft infection by HBV occurred in 8 of 10 patients infected with HBV only; and in 4 of 5 patients with previous HBV and HDV infection. There was a widely variable time from transplantation to the appearance of HBV markers in liver or serum, ranging from 6-331 days. Hepatitis D antigen (HDAg) appeared in three grafts very rapidly after transplantation at 4, 8, and 37 days respectively. Graft infection by HBV was accompanied by significant liver injury in six allografts in five recipients. In particular, there was a striking morphological appearance in five infected livers in which the hepatocytes became progressively enlarged and distorted as they accumulated huge amounts of hepatitis B surface and core antigens (HBsAg, HBcAg). These features were accompanied by pericellular fibrosis and cholestasis but little associated inflammation. This syndrome carried a poor prognosis. A gradual progression to cirrhosis occurred in one additional liver. Finally, recurrent HBV infection was a principal or a contributing factor in all deaths. The presence of HBcAg and inflammation in he native liver increased the risk of HBV induced tissue damaged in the graft whereas HDV infection in the host liver seemed to reduce the risk of significant HBV induced tissue damage in the allograft. These data suggest that post transplant HBV infection is accompanied by a variety of changes in the liver allograft, some of which are unique to the transplanted liver and may result in impaired allograft function.

An 18 yr old previously well male Taiwanese was admitted with malaise, anorexia, and jaundice for two weeks. Results of liver tests were compatible with acute hepatitis. On day 1, he was seronegative for HBsAg, IgM anti-HAV, IgM anti-HBc, IgM anti-CMV, and IgM EBV capsid Ab, but positive for anti-delta in association with anti-HBc and anti-HBs. At follow up on day 5 HBsAg converted to positive with decreasing titre of anti-HBs. On day 19, the titre of HBsAg increased concomitantly with loss of anti-HBs. The results of these serological profiles indicated that this patient was a previously unrecognised HBsAg carrier, who developed acute hepatitis delta virus superinfection with transient loss of HBsAg. This phenomenon should be kept in mind in the serodiagnosis of acute viral hepatitis, especially in areas of high HBV prevalence.

ObjectiveHepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk of liver cancer. Efficient therapeutic approaches against HDV are absent.DesignHere, we combined an RNAi loss-of-function and small molecule screen to uncover host-dependency factors for HDV infection.ResultsFunctional screening unravelled the hypoxia-inducible factor (HIF)-signalling and insulin-resistance pathways, RNA polymerase II, glycosaminoglycan biosynthesis and the pyrimidine metabolism as virus-hepatocyte dependency networks. Validation studies in primary human hepatocytes identified the carbamoyl-phosphatesynthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme and estrogen receptor alpha (encoded by ESR1) as key host factors for HDV life cycle. Mechanistic studies revealed that the two host factors are required for viral replication. Inhibition studies using N-(phosphonoacetyl)-L-aspartic acid and fulvestrant, specific CAD and ESR1 inhibitors, respectively, uncovered their impact as antiviral targets.ConclusionThe discovery of HDV host-dependency factors elucidates the pathogenesis of viral disease biology and opens therapeutic strategies for HDV cure.