[Chronic HBV and HDV infection]. / Chronische Hepatitis-B- und Hepatitis-D-Virusinfektion.

About 0,5% of the population in Germany has a chronic hepatitis B virus (HBV) infection. Untreated, chronic HBV infection can progress to liver cirrhosis and hepatocellular carcinoma (HCC). If diagnosed early, antiviral therapy can effectively prevent liver disease progression, but a cure is currently hardly achievable. About 5% of those chronically infected with HBV are also co-infected with the hepatitis D virus (HDV). HBV/HDV co-infection leads to liver cirrhosis in approximately 50% of patients within 5-10 years. Since 2020, the cell entry inhibitor bulevirtide is available as a specific therapy for HBV/HDV co-infection.

Long-Term Treatment with Bulevirtide in Patients with Chronic Hepatitis D and Advanced Chronic Liver Disease.

Bulevirtide (BLV) is approved for the treatment of chronic hepatitis D (CHD). Because only limited long-term experience has been reported, we aimed to evaluate the efficacy and safety of BLV treatment in patients with advanced chronic liver disease (ACLD). We performed a retrospective analysis of patients with CHD who received BLV 2 mg/day for >12 months at a tertiary center. Virological response (VR) was defined as a reduction in hepatitis delta virus-ribonucleic acid (HDV-RNA) ≥2 log10 from baseline or HDV-RNA negativity and biochemical response (BR) as gender-specific normalization of transaminases. We identified 14 patients (9 men, 5 women; median age of 48 years; interquartile range (IQR) of 37-55), of whom 12 (86%) had suggested or assumed ACLD according to Baveno VI criteria. The median duration of BLV treatment was 26 months (IQR 17-27). During treatment, the mean HDV-RNA level decreased from log10 5.58 IU/ml to levels between log10 2.19 IU/ml and log10 3.19 IU/ml. HDV-RNA negativity was achieved in up to 63% after 24 months. VR and BR were 86% and 43% after 12 months, 90% and 60% after 18 months, 75% and 75% after 24 months, and 100% and 50% after 30 months, respectively. Two nonpersisting viral breakthroughs were observed after 24 months of treatment. The Child Pugh score and model of end-stage liver disease (MELD) scores remained stable or improved in 12 patients (86%). Only one patient developed hepatic decompensation after 24 months of treatment with ascites requiring large-volume paracentesis which was not associated with viral breakthrough, portal vein thrombosis, or hepatocellular carcinoma. Treatment with BLV beyond one year is effective and safe for patients with CHD and ACLD. Liver function remained stable or improved during treatment in the vast majority of patients, and only one case of hepatic decompensation occurred during a median follow-up of 26 months.

What Is Hepatitis D Infection?

This JAMA Patient Page describes hepatitis D infection and its risk factors, outcomes of acute and chronic infection, diagnosis, treatment, and prevention.

Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis-A real-world case series.

BACKGROUND AND AIMS: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis. APPROACH AND RESULTS: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12). CONCLUSIONS: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis.

Characteristics and outcome of anti-hepatitis D virus positive patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Chronic hepatitis D virus (HDV) often leads to end-stage liver disease and hepatocellular carcinoma (HCC). Comprehensive data pertaining to large populations with HDV and HCC are missing, therefore we sought to assess the characteristics, management, and outcome of these patients, comparing them to patients with hepatitis B virus (HBV) infection. METHODS: We analysed the Italian Liver Cancer database focusing on patients with positivity for HBV surface antigen and anti-HDV antibodies (HBV/HDV, n = 107) and patients with HBV infection alone (n = 588). Clinical and oncological characteristics, treatment, and survival were compared in the two groups. RESULTS: Patients with HBV/HDV had worse liver function [Model for End-stage Liver Disease score: 11 vs. 9, p < .0001; Child-Turcotte-Pugh score: 7 vs. 5, p < .0001] than patients with HBV. HCC was more frequently diagnosed during surveillance (72.9% vs. 52.4%, p = .0002), and the oncological stage was more frequently Milan-in (67.3% vs. 52.7%, p = .005) in patients with HBV/HDV. Liver transplantation was more frequently performed in HBV/HDV than in HBV patients (36.4% vs. 9.5%), while the opposite was observed for resection (8.4% vs. 20.1%, p < .0001), and in a competing risk analysis, HBV/HDV patients had a higher probability of receiving transplantation, independently of liver function and oncological stage. A trend towards longer survival was observed in patients with HBV/HDV (50.4 vs. 44.4 months, p = .106). CONCLUSIONS: In patients with HBV/HDV, HCC is diagnosed more frequently during surveillance, resulting in a less advanced cancer stage in patients with more deranged liver function than HBV alone. Patients with HBV/HDV have a heightened benefit from liver transplantation, positively influencing survival.

Hepatitis D: A Review.

Importance: Hepatitis D virus (HDV) infection occurs in association with hepatitis B virus (HBV) infection and affects approximately 12 million to 72 million people worldwide. HDV causes more rapid progression to cirrhosis and higher rates of hepatocellular carcinoma than HBV alone or hepatitis C virus. Observations: HDV requires HBV to enter hepatocytes and to assemble and secrete new virions. Acute HDV-HBV coinfection is followed by clearance of both viruses in approximately 95% of people, whereas HDV superinfection in an HBV-infected person results in chronic HDV-HBV infection in more than 90% of infected patients. Chronic hepatitis D causes more rapidly progressive liver disease than HBV alone. Approximately 30% to 70% of patients with chronic hepatitis D have cirrhosis at diagnosis and more than 50% die of liver disease within 10 years of diagnosis. However, recent studies suggested that progression is variable and that more than 50% of people may have an indolent course. Only approximately 20% to 50% of people infected by hepatitis D have been diagnosed due to lack of awareness and limited access to reliable diagnostic tests for the HDV antibody and HDV RNA. The HBV vaccine prevents HDV infection by preventing HBV infection, but no vaccines are available to protect those with established HBV infection against HDV. Interferon alfa inhibits HDV replication and reduces the incidence of liver-related events such as liver decompensation, hepatocellular carcinoma, liver transplant, or mortality from 8.5% per year to 3.3% per year. Adverse effects from interferon alfa such as fatigue, depression, and bone marrow suppression are common. HBV nucleos(t)ide analogues, such as entecavir or tenofovir, are ineffective against HDV. Phase 3 randomized clinical trials of bulevirtide, which blocks entry of HDV into hepatocytes, and lonafarnib, which interferes with HDV assembly, showed that compared with placebo or observation, these therapies attained virological and biochemical response in up to 56% of patients after 96 weeks of bulevirtide monotherapy and 19% after 48 weeks of lonafarnib, ritonavir, and pegylated interferon alfa treatment. Conclusions and Relevance: HDV infection affects approximately 12 million to 72 million people worldwide and is associated with more rapid progression to cirrhosis and liver failure and higher rates of hepatocellular carcinoma than infection with HBV alone. Bulevirtide was recently approved for HDV in Europe, whereas pegylated interferon alfa is the only treatment available in most countries.

Chronic hepatitis delta cirrhosis cured by adapting PEG-IFNα-2a + tenofovir disoproxil fumarate treatment duration until HBsAg loss.

As the loss of HBsAg during treatment of chronic hepatitis delta (CHD) is mandatory for definitive clearance and durable response, the optimal target of therapy should be complete response (CR), defined as loss of HDV RNA and HBsAg, plus development of anti-HBs. The optimal treatment duration of CHD is not well established. We present 2 cases of patients with CHD cirrhosis who were treated with prolonged Peg-IFNα-2a + tenofovir disoproxil fumarate until HBsAg loss, and who achieved CR after 46 and 55 months of treatment respectively. A personalized approach and prolonged treatment duration determined by HBsAg loss may increase the likelihood of CR in CHD.

What does quantitative HBsAg level mean in chronic hepatitis D infection?

OBJECTIVE: In hepatitis delta virus (HDV) infection, which is an important etiological cause of chronic liver disease, the relationship between serum quantitative HBsAg level and fibrosis and histological activity was investigated. METHODS: Between 2014 and 2020, 98 patients with chronic HDV infection (53 noncirrhotic, 45 cirrhotic) participated in this prospectively designed study. Quantitative HBsAg levels of the patients were measured and their relationship with the stage of chronic liver disease was compared with histological activity index (HAI), fibrosis score and HDV RNA, model for end-stage liver disease score and other biochemical parameters. RESULTS: All patients were infected with genotype 1 (100%). HBeAg was positive in 8 (8.1%) of the patients. A correlation was found between quantitative HBsAg level and HDV RNA level in patients with both cirrhotic (r = 0.568; P < 0.001) and noncirrhotic (r = 0.644; P < 0.001) HDV infection. Alanine transaminase (P = 0.001; r = 0.495) and aspartate transaminase (P = 0.001; r = 0.511) levels correlated with quantitative HBsAg levels, more prominently in noncirrhotic patients. There was a correlation between quantitative HBsAg level and histological activity index (HAI) in patients with noncirrhotic HDV infection (P < 0.001; r = 0.664). In receiver operating characteristic analysis, both quantitative HBsAg (for cutoff: 1000; sensitivity 76%; specificity 17%; P = 0.335) and HDV RNA (for cutoff: 100000; sensitivity 2%; specificity 98%; P = 0.096) were not predictive markers for cirrhosis. CONCLUSION: Quantitative HBsAg level can be evaluated as an indicator of viral replication and histological activity in patients with chronic delta hepatitis without cirrhosis. We think that quantitative HBsAg level will be useful in the management of chronic HDV infection, especially in noncirrhotic patients.

Chronic hepatitis D-What is changing?

Hepatitis D virus (HDV) infection is a chronic viral disease of the liver that is still largely considered to be incurable due to lack of effective treatment options. Without treatment, the risk for the development of advanced liver disease, cirrhosis and hepatocellular carcinoma is significantly high. Currently, new therapeutic options are emerging out of ongoing phase 3 clinical trials, promising a new hope of cure for this devastating liver infection. Recently, bulevirtide, a first in its class HDV entry inhibitor, has received conditional authorization of use from the European Medicines Agency (EMA) and was also submitted for approval in the United States. Other novel therapeutic options in clincal trials include interferon lambda, the prenylation inhibitor lonafarnib and nucleic acidic polymers (NAPs). This review describes all recent advances and ongoing changes to the field of HDV therpaeutics.

Hepatitis D virus dual infection increased the risk of hepatocellular carcinoma compared with hepatitis B virus mono infection: A meta-analysis.

BACKGROUND: Hepatitis delta virus (HDV) is a defective virus that relies on the supply of hepatitis B surface antigen (HBsAg) from hepatitis B virus (HBV) to assemble HDV virions and infect hepatocytes. However, controversy remains in whether the presence of HDV increases the risk of hepatocellular carcinoma (HCC). Our aim is to evaluate the influence of HDV on the risk of HCC through a systematic review and meta-analysis. METHODS: A review of all English-language literature was conducted in the major medical databases using the subject search terms "hepatocellular carcinoma," "liver cancer," "hepatic tumor," and "hepatitis delta." A meta-analysis of the qualifying publications was then performed. RESULTS: The meta-analysis included 21 studies, which revealed a significantly higher risk of HCC among patients with HDV/HBV dual infection (odds ratio [OR] = 2.08, 95% confidence interval [CI], 1.37-3.14, p < 0.01) compared with those with HBV monoinfection. Those with HDV/HBV dual infection remained at higher risk of HCC in the subgroup analysis, irrespective of the status of hepatitis C virus (HCV) or human immunodeficiency virus (HIV) coinfection and in different ethnicities. The HCC risk remained higher in patients with HDV/HBV dual infection with heterogeneous fibrosis stage (OR = 2.04, 95% CI, 1.31-3.17, p < 0.01). The difference in the risk of HCC between HDV/HBV dual infection and HBV monoinfection was not statistically significant in patients with cirrhosis or advanced fibrosis (OR = 1.84, 95% CI, 0.48-7.02, p = 0.37). However, this subgroup comprised only two studies. CONCLUSION: HDV and HBV dual infection significantly increase the risk of HCC development compared with HBV monoinfection.

Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues.

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11-19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35-24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03-6.54, P < 0.001), male gender (HR/CI 2.69/1.29-5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03-1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04-19.09, P = 0.04) and BMI (HR/CI 1.11/1.03-1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.

Persistent Control of Hepatitis B Virus and Hepatitis Delta Virus Infection Following REP 2139-Ca and Pegylated Interferon Therapy in Chronic Hepatitis B Virus/Hepatitis Delta Virus Coinfection.

The nucleic acid polymer REP 2139 inhibits assembly/secretion of hepatitis B virus (HBV) subviral particles. Previously, REP 2139-Ca and pegylated interferon (pegIFN) in HBV/hepatitis delta virus (HDV) coinfection achieved high rates of HDV RNA and hepatitis B surface antigen (HBsAg) loss/seroconversion in the REP 301 study (NCT02233075). The REP 301-LTF study (NCT02876419) examined safety and efficacy during 3.5 years of follow-up. In the current study, participants completing therapy in the REP 301 study were followed for 3.5 years. Primary outcomes were safety and tolerability, and secondary outcomes were HDV functional cure (HDV RNA target not detected [TND], normal alanine aminotransferase [ALT]), HBV virologic control (HBV DNA ≤2,000 IU/mL, normal ALT), HBV functional cure (HBV DNA TND; HBsAg <0.05 IU/mL, normal ALT), and HBsAg seroconversion. Supplemental analysis included high-sensitivity HBsAg (Abbott ARCHITECT HBsAg NEXT), HBV pregenomic RNA (pgRNA), HBsAg/hepatitis B surface antibody (anti-HBs) immune complexes (HBsAg ICs), and hepatitis B core-related antigen (HBcrAg). Asymptomatic grade 1-2 ALT elevations occurred in 2 participants accompanying viral rebound; no other safety or tolerability issues were observed. During therapy and follow-up, HBsAg reductions to <0.05 IU/mL were also <0.005 IU/mL. HBsAg ICs declined in 7 of 11 participants during REP 2139-Ca monotherapy and in 10 of 11 participants during follow-up. HDV functional cure persisted in 7 of 11 participants; HBV virologic control persisted in 3 and functional cure (with HBsAg seroconversion) persisted in 4 of these participants. Functional cure of HBV was accompanied by HBV pgRNA TND and HBcrAg

High Prevalence of Chronic Viral Hepatitis and Liver Fibrosis Among Mongols in Southern California.

BACKGROUND: Mongolia is a highly endemic region for chronic hepatitis B (HBV), hepatitis delta (HDV), and hepatitis C (HCV) infections. Aim of this study was to comprehensively characterize chronic viral hepatitis among Mongols living in Southern California. METHODS: Three screening events were conducted between August and November 2018, with 528 adult Mongols tested for HBV and HCV. HBsAg (+) individuals (CHB) underwent additional testing for HDV RNA and anti-HDV. Liver tests, platelet count, and FibroScan™ were performed on CHB and chronic HCV (CHC) individuals. RESULTS: Fifty-one out of 534 were HBsAg reactive (9.7%), and all were foreign-born. Mean age of CHB individuals was 37.8 (range 18-69) years. Forty-six out of 51 were HBeAg (-). HBV genotypes were exclusively D2 or A1. Twenty-one out of 51 (41.2%) were anti-HDV (+) and 17/51 (33.3%) were HDV RNA (+). HDV RNA (+) individuals had significantly higher ALT, fibrosis-4 score, and liver stiffness compared to HDV RNA (-) individuals. Incidence of advanced fibrosis was higher in HDV RNA (+) individuals (57% vs. 13%, p = 0.013). Forty-eight (9.1%) individuals were anti-HCV (+) and 19 (3.6%) were HCV RNA (+). Mean age of CHC individuals was 40.2 (range 28-71) years. Prevalence of anti-HCV (+) was higher among those born between 1945 and 1965 versus those born after 1965 (18.8% vs. 7.9%, p = 0.025). Genotype 1b was predominant. Incidence of cirrhosis was 7% among all participants. CONCLUSIONS: Mongols living in the USA are at high risk for CHB and CHC infections. One-third of CHB individuals had CHD superinfection with advanced fibrosis. Universal screening for viral hepatitis in Mongols in the USA is mandatory.

New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies.

Chronic hepatitis D (CHD), a global health problem, manifests as the most severe form of viral hepatitis. The causative agent, HDV, is the smallest known human virus; it replicates its circular single-stranded RNA genome in the nucleus of hepatocytes. HDV requires HBV-encoded envelope proteins for dissemination and de novo cell entry. However, HDV can also spread through cell division. Following entry into hepatocytes, replicative intermediates of HDV RNA are sensed by the pattern recognition receptor MDA5 (melanoma differentiation antigen 5) resulting in interferon (IFN)-ß/λ induction. This IFN response strongly suppresses cell division-mediated spread of HDV genomes, however, it only marginally affects HDV RNA replication in already infected, resting hepatocytes. Monotherapy with IFN-α/λ shows efficacy but rarely results in HDV clearance. Recent molecular insights into key determinants of HDV persistence and the accelerated development of specifically acting antivirals that interfere with the replication cycle have revealed promising new therapeutic perspectives. In this review, we briefly summarise our knowledge on replication/persistence of HDV, the newly discovered HDV-like agents, and the interplay of HDV with the IFN response and its consequences for persistence. Finally, we discuss the possible role of IFNs in combination with upcoming therapies aimed at HDV cure.

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

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

Innate immune recognition and modulation in hepatitis D virus infection.

Hepatitis D virus (HDV) is a global health threat with more than 15 million humans affected. Current treatment options are largely unsatisfactory leaving chronically infected humans at high risk to develop liver cirrhosis and hepatocellular carcinoma. HDV is the only human satellite virus known. It encodes only two proteins, and requires Hepatitis B virus (HBV) envelope protein expression for productive virion release and spread of the infection. How HDV could evolve and why HBV was selected as a helper virus remains unknown. Since the discovery of Na+-taurocholate co-transporting polypeptide as the essential uptake receptor for HBV and HDV, we are beginning to understand the interactions of HDV and the immune system. While HBV is mostly regarded a stealth virus, that escapes innate immune recognition, HBV-HDV coinfection is characterized by a strong innate immune response. Cytoplasmic RNA sensor melanoma differentiation antigen 5 has been reported to recognize HDV RNA replication and activate innate immunity. Innate immunity, however, seems not to impair HDV replication while it inhibits HBV. In this review, we describe what is known up-to-date about the interplay between HBV as a helper and HDV's immune evasion strategy and identify where additional research is required.

Chronic hepatitis D and hepatocellular carcinoma: A systematic review and meta-analysis of observational studies.

BACKGROUND & AIMS: Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis but its role in the development of hepatocellular carcinoma (HCC) remains debated. We conducted a systematic review and meta-analysis of epidemiological studies to examine whether CHD is associated with an increased risk of HCC. METHODS: We searched PubMed, Embase and Web of Science, as well as study references and conference proceedings. We considered cohort and case-control studies allowing the calculation of effect estimates for the association between CHD (exposure) and HCC (outcome) in comparison to chronic hepatitis B. Data extraction and quality evaluation (using the Newcastle-Ottawa scale) were performed independently by 2 authors. Data were pooled using random-effects models. RESULTS: Ninety-three studies (68 case-control studies including 22,862 patients and 25 cohort studies including 75,427 patients) were included. Twelve studies accounted for confounders, in either study design or analysis (10 of which were cohorts), and 11 cohorts were prospective. The overall analysis showed a significantly increased risk of HCC in patients with CHD, despite substantial study heterogeneity (pooled odds ratio 1.28; 95% CI 1.05-1.57; I2 = 67.0%). The association was particularly strong in the absence of heterogeneity for prospective cohort studies (pooled odds ratio 2.77; 95% CI 1.79-4.28; I2 = 0%), and studies with HIV-infected patients (pooled odds ratio 7.13; 95% CI 2.83-17.92; I2 = 0%). CONCLUSIONS: We found a significantly higher risk of HCC in patients with CHD. Although further studies are needed to definitively exclude a potential bias due to antiviral treatments, our findings highlight the rationale for improved screening of hepatitis D virus infection in patients with chronic hepatitis B, and the urgent need for novel and effective antiviral therapies. LAY SUMMARY: Hepatitis D virus (HDV) is a defective pathogen requiring hepatitis B virus (HBV) to complete its life cycle. Chronic hepatitis D is the most severe form of chronic viral hepatitis, increasing the risk of cirrhosis, liver decompensation and death compared to HBV monoinfection. However, the association between HDV infection and increased risk of hepatocellular carcinoma is debated. We conducted a systematic review and found that patients with HDV infection had a significantly higher risk of developing hepatocellular carcinoma than those with HBV monoinfection.

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

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