Long-term outcome of hepatitis delta in different regions world-wide: Results of the Hepatitis Delta International Network.

BACKGROUND AND AIMS: Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. METHODS: The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long-term follow-up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver-related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver-related death. RESULTS: Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow-up was 6.4 (.6-28) years. During follow-up, 195 patients (32%) developed a liver-related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow-up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa-based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. CONCLUSIONS: The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection.

Economic Impact of European Liver and Intestine Transplantation Association (ELITA) Recommendations for Hepatitis B Prophylaxis After Liver Transplantation.

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs.

A Review of HDV Infection.

Hepatitis D is the most severe viral hepatitis. Hepatitis D virus (HDV) has a very small RNA genome with unique biological properties. It requires for infection the presence of hepatitis B virus (HBV) and is transmitted parenterally, mainly by superinfection of HBsAg carriers who then develop chronic hepatitis D. HDV has been brought under control in high-income countries by the implementation of HBV vaccination, and the clinical pattern has changed to a chronic hepatitis D seen in ageing patients with advanced fibrotic disease; the disease remains a major health concern in developing countries of Africa and Asia. Every HBsAg-positive subject should be tested for HDV serum markers by reflex testing, independently of clinical status. Vaccination against HBV provides the best prophylaxis against hepatitis D. The only therapy available so far has been the poorly performing Interferon alfa; however, several new and promising therapeutic approaches are under study.

Hepatitis D (DELTA).

The hepatitis D virus (HDV) is unique in animal virology. It is the smallest of human pathogens, re- quires the HBsAg capsid of the hepatitis B virus (HBV) to assembly into infectious virions, and parasitizes the transcriptional machinery of the host. Hepatitis D is ubiquitous but prevalence varies throughout the world. It is the most severe form of chronic viral liver disorder. Vaccination against the HBV has decreased the circulation of HDV in industrialized countries but Hepatitis D remains a significant medical issue in many areas of the developing world.

Clinical Application of Droplet Digital PCR for Hepatitis Delta Virus Quantification.

Droplet digital PCR (ddPCR) is a novel developed PCR technology providing the absolute quantification of target nucleic acid molecules without the need for a standard curve and regardless PCR amplification efficiency. Our aim was to develop a ddPCR assay for Hepatitis Delta virus (HDV)-RNA viremia quantification and then evaluate its performance in relation to real-time PCR methods. Primers and probe were designed from conserved regions of HDV genome to detect all the 8 HDV genotypes; the World Health Organization (WHO)-HDV international standard was used to calculate the conversion factor transforming results from copies/mL to IU/mL. To evaluate the clinical performance of ddPCR assay, plasma specimens of HDV-infected patients were tested and results were compared with data obtained with two real-time quantitative PCR (RT-qPCR) assays (i.e., in-house assay and commercial RoboGene assay). Analyzing by linear regression a series of 10-fold dilutions of the WHO-HDV International Standard, ddPCR assay showed good linearity with a slope coefficient of 0.966 and R2 value of 0.980. The conversion factor from copies to international units was 0.97 and the quantitative linear dynamic range was from 10 to 1 × 106 IU/mL. Probit analysis estimated at 95% an LOD of 9.2 IU/mL. Data from the evaluation of HDV-RNA in routine clinical specimen of HDV patients exhibited strong agreement with results obtained by RT-qPCR showing a concordance correlation coefficient of 0.95. Overall ddPCR and RT-qPCR showed highly comparable technical performance. Moreover, ddPCR providing an absolute quantification method may allow the standardization of HDV-RNA measurement thus improving the clinical and diagnostic management of delta hepatitis.

Liver Transplantation in Hepatitis B/Hepatitis D (Delta) Virus Coinfected Recipients.

Hepatitis D is caused by the hepatitis D virus (HDV); it is the most severe form of viral hepatitis in humans, running an accelerated course to cirrhosis. There is no efficacious therapy, and liver transplantation provides the only therapeutic option for terminal HDV disease. However, HDV infection is prevalent in poor countries of the world with no access to liver transplant programs; liver grafting has been performed in high-income countries, where the prevalence of the infection has much diminished as a secondary effect of hepatitis B virus vaccination, and the demand for liver transplantation outlives in aging cirrhotics who acquired hepatitis D decades ago. This review describes the evolution of liver transplantation for HDV disease from its inception in 1987 to the present time, with an outlook to its future. It reports the progress in the prophylaxis of HDV reinfections to the success of the current standard of indefinite combination of hepatitis B virus antivirals with immunoglobulins against the hepatitis B surface antigen; however, the unique biology of the virus provides a rationale to reducing costs by limiting the administration of the immunoglobulins against the hepatitis B surface antigen.

Therapy of Chronic Viral Hepatitis: The Light at the End of the Tunnel?

Chronic viral hepatitis determines significant morbidity and mortality globally and is caused by three main etiological actors (Hepatitis B Virus, Hepatitis C Virus, and Hepatitis D Virus) with different replicative cycles and biological behaviors. Thus, therapies change according to the different characteristics of the viruses. In chronic hepatitis B, long term suppressive treatments with nucleoside/nucleotide analogues have had a dramatic impact on the evolution of liver disease and liver-related complications. However, a conclusive clearance of the virus is difficult to obtain; new strategies that are able to eradicate the infection are currently objects of research. The therapy for Hepatitis D Virus infection is challenging due to the unique virology of the virus, which uses the synthetic machinery of the infected hepatocyte for its own replication and cannot be targeted by conventional antivirals that are active against virus-coded proteins. Recently introduced antivirals, such as bulevertide and lonafarnib, display definite but only partial efficacy in reducing serum HDV-RNA. However, in combination with pegylated interferon, they provide a synergistic therapeutic effect and appear to represent the current best therapy for HDV-positive patients. With the advent of Direct Acting Antiviral Agents (DAAs), a dramatic breakthrough has occurred in the therapeutic scenario of chronic hepatitis C. Cure of HCV infection is achieved in more than 95% of treated patients, irrespective of their baseline liver fibrosis status. Potentially, the goal of global HCV elimination by 2030 as endorsed by the World Health Organization can be obtained if more global subsidised supplies of DAAs are provided.

Hepatitis B Virus Reactivation upon Immunosuppression: Is There a Role for Hepatitis B Core-Related Antigen in Patients with Immune-Escape Mutants? A Case Report.

The reactivation of hepatitis B virus (HBVr) in patients undergoing pharmacological immunosuppression is a potentially fatal clinical event that may occur in patients with overt or occult HBV infection. The risk of HBVr is mainly determined by the type of immunosuppressive therapy and the HBV serologic profile, with a higher risk in patients positive for the hepatitis B surface antigen (HBsAg), and a lower risk in HBsAg-negative/antibodies to core antigen-positive subjects. Notably, a considerable proportion of patients experiencing HBVr showed a high degree of variability of the HBV S gene, possibly leading to immune escape mutants. These mutations, usually in the "a-determinant" of the HBsAg, can cause diagnostic problems and consequently hamper the appropriate management strategy of patients at risk of HBVr. Here, we describe a case of HBVr in a patient with a diagnosis of chronic myeloid leukemia and a previous history of kidney transplant, providing evidence of the potential usefulness of hepatitis B core-related antigen measurement in patients with HBV immune-escape mutants at risk of viral reactivation.

The hepatitis D virus in Italy. A vanishing infection, not yet a vanished disease.

INTRODUCTION: Hepatitis D Virus (HDV) infection is vanishing in Italy. It is therefore believed that hepatitis D is no longer a medical problem in the domestic population of the country but remains of concern only in migrants from HDV-endemic areas. OBJECTIVES: To report the clinical features and the medical impact of the residual domestic HDV infections in Italy. METHODS: From 2010 to 2019, one hundred ninety-three first-time patients with chronic HDV liver disease attended gastroenterology units in Torino and San Giovanni Rotondo (Apulia); 121 were native Italians and 72 were immigrants born abroad. For this study, we considered the 121 native Italians in order to determine their clinical features and the impact of HDV disease in liver transplant programs. RESULTS: At the last observation the median age of the 121 native Italians was 58 years. At the end of the follow-up, the median liver stiffness was 12.0 kPa (95% CI 11.2-17.4), 86 patients (71.1%) had a diagnosis of cirrhosis; 80 patients (66.1%) remained HDV viremic. The ratio of HDV to total HBsAg transplants varied from 38.5% (139/361) in 2000-2009 to 50.2% (130/259) in 2010-2019, indicating a disproportionate role of hepatitis D in liver transplants compared to the minor prevalence of HDV infections in the current scenario of HBsAg-positive liver disorders in Italy. CONCLUSION: Though HDV is vanishing in Italy, a legacy of ageing native-Italian patients with advanced HDV liver disease still represents an important medical issue and maintains an impact on liver transplantation.

2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.

BACKGROUND: Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA). AIM: This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence. METHODS: Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations. RESULTS: Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4 weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1 year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen. CONCLUSIONS: These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.

Forty-Five Years after the Discovery of the Hepatitis D Virus: Where Do We Stand?

The discovery of the Australia Antigen in the mid-1960s led, in a few years, to the identification of the virus of Hepatitis B [...].

The changing context of hepatitis D.

The global epidemiology of hepatitis D is changing with the widespread implementation of vaccination against hepatitis B. In high-income countries that achieved optimal control of HBV, the epidemiology of hepatitis D is dual, consisting of an ageing cohort of domestic patients with advanced liver fibrosis who represent the end stage of the natural history of HDV, and of a younger generation of immigrants from endemic countries who account for the majority of new infections. As observed in Europe in the 1980s, the distinctive clinical characteristic of chronic hepatitis D in endemic countries is the accelerated progression to cirrhosis and hepatocellular carcinoma. Despite some recent progress, the therapeutic management of HDV remains unsatisfactory, as most patients are not cured of HDV with currently available medicines. This review article describes the current epidemiology and clinical features of chronic hepatitis D, based on the literature published in the last 10 years.

The medical impact of hepatitis D virus infection in Asia and Africa; time for a reappraisal.

Although hepatitis D is believed to be an important medical problem in Africa and many areas of Asia, the geographical distribution and prevalence rates of infection with the hepatitis D virus (HDV) vary considerably, are often inconsistent and sometimes conflicting. Discrepancies may depend on methodological problems, primarily on different modalities of patients' recruitment; these are analysed in this mini-review, in order to provide a uniform clinical approach when testing patients with chronic HDV disease.

Analytical and clinical evaluation of a novel assay for anti-HBc IgG measurement in serum of subjects with overt and occult HBV infection.

OBJECTIVES: We assessed the analytical and clinical performance of the Lumipulse® G HBcAb-N (Fujirebio, Japan) assay for IgG antibodies to hepatitis B core antigen (anti-HBc IgG) measurement in serum of subjects with overt and occult HBV infection (OBI). MATERIALS/METHODS: Serum anti-HBc IgG was assessed in 181 anti-HBc-positive subjects: 119 chronic hepatitis B (CHB) patients in different infection phases and 62 subjects (35 CHB and 27 OBI) with available liver specimens for HBV covalently-close-circular (ccc) DNA analysis. RESULTS: The anti-HBc IgG assay showed a linear dynamic range (R2 = 0.9967); lower limit of detection and quantitation were 0.5 IU/mL and 0.8 IU/mL. Reproducibility was 4.9% and accuracy 98.7%. Anti-HBc IgG levels varied according to HBV infection phase, linearly declined during antiviral treatment and resulted correlated to intrahepatic HBV cccDNA (r = 0.752, P < 0.001). CONCLUSIONS: The quantitative anti-HBc IgG assay exhibited appropriate analytical performance and may represent a diagnostic complement in CHB patients and OBI subjects.

The medical impact of hepatitis D virus infection in Uzbekistan.

BACKGROUND & AIMS: The hepatitis B virus (HBV) is endemic in Uzbekistan but the medical impact of infection with the HBV-dependent hepatitis D virus (HDV) is unknown in the Country. An Hepatology Center was recently established at the Institute of Virology in Tashkent, which has set up a database enlisting patients with chronic viral liver disorders from all over Uzbekistan; it provides an observatory on the current scenario of viral hepatitis in the Country. METHODS: The prevalence of HBV monoinfection, hepatitis C virus (HCV) infection and HDV superinfection on hepatitis B surface antigen (HBsAg)-positive cirrhosis was determined in 6589 patients with viral cirrhosis collected in the last 3 years. RESULTS: Of 1089, 1150 and 1455 carriers of the HBsAg with cirrhosis recruited in 2016, 2017 and 2018, 834 (76.5%), 926 (80.5%) and 1224 (84%) respectively, had antibody to the HDV. In 2016, 2017 and 2018, the prevalence of HDV infection has been 41%, 45% and 49.1% respectively, largely exceeding the prevalence of HBV monoinfection (12.5%, 11% and 9.3% respectively) and surpassing the prevalence of HCV in 2017 and 2018 (44% and 41.5% respectively). The median age of the patients with HDV cirrhosis was 39 years, distinctly lower than that of HBV and HCV patients (46 and 55). CONCLUSIONS: Superinfection with the HDV is present in over 80% of the HBsAg-positive cirrhosis in Uzbekistan. The HDV appears to be the major cause of advanced viral liver disease and of juvenile cirrhosis in the Country.