The elimination of hepatitis D as a public health problem: Needs and challenges.

Infection with hepatitis D virus leads to liver disease and cancer most rapidly of all hepatitis viruses. However, knowledge about hepatitis D remains poor and the burden and impact are underestimated, even though some 12-15 million people mainly in low- and middle-income countries may be affected. Its epidemiology is changing, with increasing migration leading to increased risks of infection and disease. A recent Viral Hepatitis Prevention Board meeting reviewed the current epidemiological status, improvements in diagnostic testing, advances in the development of novel antiviral agents in phase III trials and the need for a greater public health response, such as new guidelines and recommended testing of all people newly identified as infected with hepatitis B virus for hepatitis D virus infection. It identified issues and needs for attention with regard to prevention, diagnosis and treatment.

What Is the Real Epidemiology of Hepatitis D Virus and Why so Many Mixed Messages?

The disease burden of HDV is poorly understood. Our review identified multiple reasons: (1) HDV infection rates are overestimated in the general population due to limited sample sizes, sampling high-risk populations, and significant regional variations, (2) estimates are based on chronic HBV populations, but HBV burden itself is uncertain, (3) there is a lack of testing in at-risk populations, (4) prevalence testing is based on HDV antibody testing and not HDV RNA, which distinguishes between active infection versus prior exposure, (5) older studies used less reliable testing and (6) HBV vaccination programs have affected HDV prevalence, but is often not accounted for.

Delta hepatitis epidemiology and the global burden of disease.

Delta Hepatitis is considered the most severe form of hepatitis, with varied prevalence, genotype distribution and risk factors worldwide. Current knowledge of global epidemiology is limited due to variable screening practices for HDV. Here, we summarize what is currently known about the prevalence of testing and prevalence of HDV positivity globally.

The Delta Delta: Gaps in screening and patient assessment for hepatitis D virus infection.

Hepatitis D virus (HDV) infection is highly prevalent in patients with chronic hepatitis B (CHB). AASLD guidelines recommend a risk-based screening approach. Our aim was to ascertain if the risk-based approach leads to appropriate HDV screening, identify targets to improve screening rates, and study HDV clinical burden. CHB patients screened for HDV from 01/2016 to 12/2021 were identified. Level of training and specialty of providers ordering HDV screening tests were determined. HDV seropositive (HDV+) patient charts were reviewed for the presence of individual risk factors per the AASLD guidelines to determine if they met screening criteria. The severity of liver disease at the time of HDV screening was compared between the HDV+ group and a matched (based on age, hepatitis B e antigen status, BMI and sex) HDV seronegative (HDV-) group. During the study period, 1444/11,190 CHB patients were screened for HDV. Most screening tests were ordered by gastroenterology (90.2%) specialists and attending physicians (80.5%). HDV+ rate was 88/1444 (6%), and 72 HDV+ patients had complete information for analysis. 18% of HDV+ patients would be missed by a risk-based screening approach due to unreported or negative risk factors (see Table). A significantly higher number of HDV+ patients had developed significant fibrosis (p = 0.001) and cirrhosis (p < 0.01) by the time of screening than HDV- (n = 67) patients. In conclusion, targeted interventions are needed towards trainees and primary care clinics to improve screening rates. Current risk-based criteria do not appropriately screen for HDV. It is time for universal screening of HDV in CHB patients.

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.

Screening for hepatitis D and PEG-Interferon over Tenofovir enhance general hepatitis control efforts in Brazil.

BACKGROUND: Hepatitis D virus (HDV), which requires the presence of hepatitis B virus (HBV), is a deadly yet neglected disease that rapidly leads to liver cancer and disease-induced mortality. This co-dependence creates complex transmission dynamics that make it difficult to predict the efficacy of interventions aimed at HBV and/or HDV control in endemic regions, such as certain municipalities of Brazil, where up to 65% of HBV-infected persons are co-infected. METHODOLOGY: We created a mathematical model that captures the joint transmission dynamics of HBV and HDV, incorporating mother-to-child, sexual and household transmission. With an aim to minimize the number of total infections and disease-induced mortality in 2027, we then determined optimal strategies for Brazil and its sub-regions under a constrained budget, which was dynamically allocated among HBV and HDV screening, HBV and HDV treatment, HBV newborn and adult vaccination, and awareness programs. Three treatment options were considered, namely: Tenofovir, PEGylated-Interferon, and nucleic acid polymers (NAP). RESULTS: The additional cost of HDV screening and the use of a more expensive PEGylated-Interferon are offset by not wasting resources on treating co-infected persons with Tenofovir. The introductory price of NAP treatment must be less than $16,000 per course to become competitive with Tenofovir and PEGylated-Interferon in Brazil. CONCLUSION: Additional screening for HDV is beneficial, even in a low HBV and HDV endemic regions of Brazil. We recommend PEGylated-Interferon, wherever possible, for both HBV and HDV. If PEGylated-Interferon is not available in abundance, PEGylated-Interferon for co-infections and 4-year Tenofovir treatment for mono-infections is recommended.

Roadmap to control HBV and HDV epidemics in China.

PURPOSE: Hepatitis B virus (HBV) is endemic in China. Almost 10% of HBV infected individuals are also infected with hepatitis D virus (HDV) which has a 5-10 times higher mortality rate than HBV mono-infection. The aim of this manuscript is to devise strategies that can not only control HBV infections but also HDV infections in China under the current health care budget in an optimal manner. METHODS: Using a mathematical model, an annual budget of $10billion was optimally allocated among five interventions namely, testing and HBV adult vaccination, treatment for mono-infected and dually-infected individuals, second line treatment for HBV mono-infections, and awareness programs. RESULTS: We determine that the optimal strategy is to test and treat both infections as early as possible while applying awareness programs at full intensity. Under this strategy, an additional 19.8million HBV, 1.9million HDV infections and 0.25million lives will be saved over the next 10years at a cost-savings of $79billion than performing no intervention. Introduction of second line treatment does not add a significant economic burden yet prevents 1.4million new HBV infections and 15,000 new HDV infections. CONCLUSION: Test and treatment programs are highly efficient in reducing HBV and HDV prevalence in the population. Under the current health budget in China, not only test and treat programs but awareness programs and second line treatment can also be implemented that minimizes prevalence and mortality, and maximizes economic benefits.

Recognizing the impact of endemic hepatitis D virus on hepatitis B virus eradication.

BACKGROUND: Hepatitis delta virus (HDV) in conjunction with hepatitis B virus (HBV) increases adult morbidity and mortality. A number of studies have performed cost-benefit analyses for HBV interventions, but they have ignored the impact of HDV on these outcomes. METHODS: Using a mathematical model of HBV-HDV epidemiology, we compare health benefits and cost outcomes of four interventions: testing with HBV adult vaccination (diagnosis), diagnosis with antiviral treatment for HBV infections (mono-infections), diagnosis with antiviral treatment for HBV-HDV infections (dual-infections), and awareness programs. The relationship between optimal levels and outcomes of each of these interventions and HDV prevalence in HBV infected individuals ranging from 0 to 50% is determined. RESULTS: Over a 50 year period under no intervention, HBV prevalence, per capita total cost and death toll increase by 2.25%, -$11 and 2.6-fold respectively in moderate HDV endemic regions compared to mono-infected regions; the corresponding values for high HDV endemic regions are 4.2%, -$21 and 3.9-fold. Optimal interventions can be strategized similarly in mono and dually endemic regions. Only implementation of all four interventions achieves a very low HBV prevalence of around 1.5% in a moderate HDV endemic region such as China, with 2.8 million fewer deaths compared to no intervention. Although the policy of implementation of all four interventions costs additional $382 billion compared to no intervention, it still remains cost-effective with an incremental cost-effectiveness ratio of $1400/QALY. Very high efficacy awareness programs achieve less prevalence with fewer deaths at a lower cost compared to treatment and/or vaccination programs. CONCLUSION: HDV substantially affects the performance of any HBV-related intervention. Its exclusion results in over-estimation of the effectiveness of HBV interventions.

Hepatitis delta virus testing, epidemiology and management: a multicentre cross-sectional study of patients in London.

BACKGROUND: Hepatitis delta virus (HDV) testing is recommended for all patients with hepatitis B virus (HBV) infection. HDV infection is associated with severe liver disease and interferon is the only available treatment. OBJECTIVES: To determine the rate of anti-HDV antibody testing in HBV patients; and to describe the epidemiology, clinical characteristics and management of HDV-infected patients at four hospitals in London. STUDY DESIGN: The anti-HDV testing rate was estimated by reviewing clinical and laboratory data. Cross-sectional data collection identified HDV-infected patients who had attended the study centres between 2005 and 2012. RESULTS: At a centre with clinic-led anti-HDV testing, 40% (67/168) of HBV patients were tested. Recently diagnosed HBV patients were more likely to be screened than those under long-term follow-up (62% vs 36%, P=0.01). At a centre with reflex laboratory testing, 99.4% (3543/3563) of first hepatitis B surface antigen positive samples were tested for anti-HDV. Across the four study centres there were 55 HDV-infected patients, of whom 50 (91%) had immigrated to the UK and 27 (49%) had evidence of cirrhosis. 31 patients received interferon therapy for HDV with an end of treatment virological response observed in 10 (32%). CONCLUSIONS: The anti-HDV testing rate was low in a centre with clinic-led testing, but could not be evaluated in all centres. The HDV-infected patients were of diverse ethnicity, with extensive histological evidence of liver disease and poor therapeutic responses. Future recommendations include reflex laboratory testing algorithms and a prospective cohort study to optimise the investigation and management of these patients.

Hepatitis delta: epidemiology, diagnosis and management 36 years after discovery.

With recent studies showing increased prevalence of hepatitis delta (HDV) even in the US, Australia, and some countries in Europe, and very high prevalence in endemic regions, HDV infection is far from being a disappearing disease. Although immigrants from endemic countries have been shown to have increased risk, studies have clearly shown that the disease is not solely appearing in traditional high-risk groups. Recent studies provide increasing evidence that sexual transmission may be an important factor in HDV infection spread. Based on the totality of evidence showing increased disease progression and substantially increased risk of cirrhosis in HDV-infected CHB patients, and the current studies showing higher than expected prevalence, it is time to call for HDV screening of all CHB patients. HDV viral load detection and measurement should be considered in all patients whether or not they are anti-HDV-positive. With universal screening of CHB patients for HDV, earlier diagnosis and consideration of treatment would be possible. Current treatment of HDV is IFN-based therapy with or without HBV antivirals, but current research indicates the possibility that prenylation inhibitors, entry inhibitors, HBsAg release inhibitors, or other therapies currently in the pipeline may provide more effective therapy in the future. In addition, universal screening would serve the important public health goal of allowing patients to be educated on their status and on the need for HDV-negative patients to protect themselves against superinfection and for HDV-infected patients to protect against transmission to others. Further studies and global awareness of HDV infection are needed.

A re-assessment of the epidemiology and patient characteristics of hepatitis D virus infection in inner city London.

OBJECTIVES: To re-assess the prevalence and patient characteristics of hepatitis D virus (HDV) infection among hepatitis B patients in inner city London. METHODS: All hepatitis B patients attending clinics over a 52 months period were tested for HDV antibody. All reactive samples were also tested for anti-HDV IgM and RNA. The characteristics of HDV seronegative patients first seen in the calendar year 2008 were compared with all HDV seropositive patients in the cohort. RESULTS: Of 1048 hepatitis B patients, 11 had equivocal anti-HDV serology (1%) and 22 were HDV seropositive (2.1%, 95%CI 1.39-3.16%); 12 were anti-HDV IgM positive and 15 HDV RNA positive. No patient with equivocal anti-HDV serology had detectable HDV RNA. Five HDV seropositive patients were intravenous drug users (22.7%); 17/22 were from abroad with 11/22 (50%) from sub-Saharan Africa. HDV seropositive patients had poorer laboratory parameters and were more likely to have evidence of cirrhosis. Triple infected (HIV/HBV/HDV) patients were also more likely to have cirrhosis than HIV/HBV dually infected patients. CONCLUSIONS: The prevalence of HDV in hepatitis B patients in inner city London was about 2%. The role of migration from endemic countries should be recognised.

[Epidemiology of viral hepatitis]. / Epidemiologija virusnih hepatitisa.

Understanding the country-specific epidemiology of disease, which may vary greatly among countries, is crucial for identifying the most appropriate preventive and control measures. An overview of the local epidemiology of viral hepatitis in Croatia is given in this paper. The overall prevalence of hepatitis B in Croatia is low (less than 2% HBsAg carriers in the general population). Hepatitis B incidence and prevalence began to decline significantly following the introduction of universal hepatitis B vaccination in 1999. Information on HBsAg seroprevalence is derived from routine testing of certain subpopulations (pregnant women, blood donors) and seroprevalence studies mostly targeted at high-risk populations. Universal childhood vaccination against hepatitis B remains the main preventive measure. We recommend testing for immunity one to two months after the third dose of hepatitis B vaccine for health-care workers. The incidence and prevalence of hepatitis C have also been declining in the general population. The main preventive measures are ensuring safety of blood products, prevention of drug abuse, and harm reduction programs for intravenous drug users. Hepatitis A incidence has declined dramatically since fifty years ago, when thousands of cases were reported annually. In the last five years, an average of twenty cases have been reported per year. The reduction of hepatitis A is a consequence of improved personal and community hygiene and sanitation. Hepatitis D has not been reported in Croatia. The risk of hepatitis D will get to be even smaller as the proportion of population vaccinated against hepatitis B builds up. Hepatitis E is reported only sporadically in Croatia, mostly in persons occupationally in contact with pigs and in travelers to endemic countries. In conclusion, Croatia is a low prevalence country for hepatitides A, B and C. Hepatitis D has not been reported to occur in Croatia and there are only sporadic cases of hepatitis E. Since hepatitis A is a rare disease occurring sporadically, which is a consequence of improved sanitation and hygiene, hepatitides B and C are the main causes of viral hepatitis in Croatia. The introduction of universal mandatory hepatitis B vaccination of schoolchildren in 1999 resulted in a decrease in the incidence of hepatitis B, which is most pronounced in adolescents and young adults, and further decrease in the incidence and prevalence is expected as the pool of susceptible individuals decreases through vaccination. The incidence of hepatitis C is decreasing as well. In spite of a relatively favorable epidemiological situation, hepatitis B and C are still a significant public health burden with an estimated 25,000 persons chronically infected with HBV and about 40,000 persons chronically infected with HCV in Croatia.

Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead.

Hepatitis D is caused by infection with the hepatitis D virus (HDV) and is considered to be the most severe form of viral hepatitis in humans. Hepatitis D occurs only in individuals positive for the HBV surface antigen (HBsAg) as HDV is a defective RNA viroid that requires HBsAg for transmission. At least eight different HDV genotypes have been described and each has a characteristic geographic distribution and a distinct clinical course. HDV and HBV coinfection can be associated with complex and dynamic viral dominance patterns. Chronic HDV infection leads to more severe liver disease than HBV monoinfection and is associated with accelerated fibrosis progression, earlier hepatic decompensation and an increased risk for the development of hepatocellular carcinoma. So far, only IFN-alpha treatment has proven antiviral activity against HDV in humans and has been linked to improved long-term outcomes. Studies conducted in the past 2 years on the use of PEG-IFN-alpha show that a sustained virologic response to therapy, measured in terms of undetectable serum HDV RNA levels, can be achieved in about one quarter of patients with hepatitis D. Novel alternative treatment options including prenylation inhibitors are awaiting clinical development for use in hepatitis D.

Costs and efficacy of "on demand" low-dose immunoprophylaxis in HBV transplanted patients: experience in the Romanian program of liver transplantation.

BACKGROUND: HBV in liver transplant (LT) patients is associated with good outcomes and the challenges are primarily focused around optimizing prophylactic regimens with hepatitis B immune globulin (HBIG) and minimizing related costs. AIM: To identify recurrence rates in patients transplanted for HBV or HBV+HDV infection in whom a combined "on demand" low-dose HBIG was used, maintaining low anti-HBs titres (not below 50 IU/L). METHODS: Medical records of 42 patients transplanted for HBV or HBV+HDV induced cirrhosis between April 2000 and September 2007 at Fundeni Clinical Institute were analyzed. Patients received immunoprophylaxis with lamivudine and HBIG (10,000 IU within anhepatic phase and daily within the first postoperative week, followed by 2,500 IU on demand). HBV recurrence rates and survival during follow-up were evaluated using the Kaplan Meier method. RESULTS: HBV recurrence rate was 4.8% after a median of 1.8 years. Three year patient survival rate was 70%. None of the patients died due to liver failure related to HBV recurrence. Using our "on demand" low-dose administration of HBIG, the total mean cost for HBIG and lamivudine for patient per month of survival was 598.3 Eur. The projected monthly cost for the "ideal" schedule/patient was 2,017 Eur. CONCLUSION: Individualization of immunoprophylaxis after LT for HBV related disease according to the lowest protective anti-HBs titers in combination with lamivudine is probably the best approach for non-replicative pre-LT patients in terms of costs and efficacy.

Assessment of delta virus infection in Venezuelan high-risk population for hepatitis B virus.

HDV infectivity particularly related to sexual activity has been difficult to establish. We investigated the prevalence of HDV in a high risk urban male population currently evaluated for HIV infection. Fourth-eight homosexual or bisexual men (96% positive for HIV) being routinely followed in the outpatient clinic, 40 sera obtained randomly from male homosexuals and 24 HBsAg carriers were examined by ELISA and Western Blot. HDV RNA was assessed by slot-blot after hybridization with cDNA probe from a recombinant plasmid (pS-1). [None of the 48 male subjects or from a recombinant plasmid (pS-1).] None of the 48 male subjects or from the randomly selected homosexuals tested positive for anti-HDV. HDV RNA searched in a selected group of sera from either high risk population or from HBsAg carriers proved also to be negative. We suggest that factors other than HBV chronic bearing and/or sexual promiscuity should be associated with HDV spread.

Hepatitis B in Latin America: epidemiological patterns and eradication strategy. The Latin American Regional Study Group.

A comprehensive epidemiological analysis of hepatitis B virus (HBV) endemicity and transmission in Latin America was carried out to suggest policies and strategies for the use of hepatitis B vaccine in the region. The pattern of HBV endemicity based on available data from blood bank screening programmes and clinical and epidemiological studies varied widely: it was low in temperate South America, Mexico and some Caribbean islands; moderate in Brazil, Andean countries, part of central America and the Caribbean; and high in Hispaniola, St. Kitts/Nevis and in the Amazon basin (parts of Brazil, Peru, Venezuela, Colombia). Statistical estimates of HBV-related morbidity showed that greater than 150,000 acute HBV cases occur per year. As the endemicity of HBV varies considerably, different prevention strategies should be applied in this area. The highest priority should be the prevention of perinatal and early childhood transmission, but vaccination of adults belonging to high-risk groups should also be recommended.