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Previous studies reported that the hepatitis C virus (HCV) could help disseminate the hepatitis D virus (HDV) in vivo through the unrelated hepatitis B virus (HBV), but with essentially inconclusive results. To try to shed light on this still-debated topic, 146 anti-HCV-positive subjects (of whom 91 HCV/HIV co-infected, and 43 with prior HCV eradication) were screened for anti-HDV antibodies (anti-HD), after careful selection for negativity to any serologic or virologic marker of current or past HBV infection. One single HCV/HIV co-infected patient (0.7%) tested highly positive for anti-HD, but with no positive HDV-RNA. Her husband, in turn, was a HCV/HIV co-infected subject with a previous contact with HBV. While conducting a thorough review of the relevant literature, the authors attempted to exhaustively describe the medical history of both the anti-HD-positive patient and her partner, believing it to be the key to dissecting the possible complex mechanisms of HDV transmission from one subject to another, and speculating that in the present case, it may have been HCV itself that behaved as an HDV helper virus. In conclusion, this preliminary research, while needing further validation in large prospective studies, provided some further evidence of a role of HCV in HDV dissemination in humans. [ABSTRACT FROM AUTHOR]

miRNAs circulating in whole serum and HBsAg-particles are differentially expressed in chronic hepatitis B (CHB) and HBeAg-negative-HBV infection (ENI); their profiles are unknown in chronic hepatitis D (CHD). Serum- and HBsAg-associated miRNAs were analyzed in 75 subjects of 3 well-characterized groups (CHB 25, CHD 25, ENI 25) using next-generation sequencing (NGS). Overall miRNA profiles were consonant in serum and HBsAg-particles but significantly different according to the presence of hepatitis independently of Hepatitis D Virus (HDV)-co-infection. Stringent (Bonferroni Correction < 0.001) differential expression analysis showed 39 miRNAs upregulated in CHB vs. ENI and 31 of them also in CHD vs. ENI. miRNA profiles were coincident in CHB and CHD with only miR-200a-3p upregulated in CHB. Three miRNAs (miR-625-3p, miR-142-5p, and miR-223-3p) involved in immune response were upregulated in ENI. All 3 hepatocellular miRNAs of MiR-B-Index (miR-122-5p, miR-99a-5p, miR-192-5p) were overexpressed in both CHB and CHD patients. In conclusion, CHD and CHB patients showed highly similar serum miRNA profiling that was significantly different from that of individuals with HBeAg-negative infection and without liver disease. [ABSTRACT FROM AUTHOR]

Chronic hepatitis delta (CHD) affects approximately 10–20 million people worldwide and represents the most severe form of chronic viral hepatitis, as it is characterized by high rates of progression to cirrhosis and its complications (end‐stage liver disease, hepatocellular carcinoma). In the last 30 years, the only treatment option for CHD has been represented by the off‐label administration of Interferon (or Pegylated Interferon)‐alpha: antiviral treatment, however, resulted in suboptimal (20–30%) virological response and was burdened by several side effects, de facto contraindicating Interferon (IFN) administration in patients with more advanced liver disease. Recently, Bulevirtide (BLV), a first‐in‐class HBV‐HDV entry inhibitor blocking Na+‐taurocholate co‐transporting polypeptide (NTCP), has provided very promising efficacy data in Phase II and Phase III (interim analysis) trials as well as in preliminary real‐life reports. In July 2020, BLV has granted conditional approval by EMA for treatment of compensated CHD, at the dose of 2 mg/day by self‐administered subcutaneous injections. In Phase II and Phase III trials, BLV was evaluated at different doses (2 vs. 10 mg/day) for 24 or 48 weeks, either in monotherapy or in combination with PegIFN. Administration of BLV monotherapy for 24 or 48 weeks resulted in 50%–83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%–78% ALT normalization. Combination therapy with PegIFN provided synergistic effects. These results were replicated in real‐life studies and confirmed also in patients with advanced cirrhosis and clinically significant portal hypertension. BLV treatment was optimally tolerated, resulting only in an asymptomatic increase of bile acids. [ABSTRACT FROM AUTHOR]

Chronic hepatitis Delta (CHD) is a rare and severe form of chronic viral hepatitis. Until recently, the only therapeutic approach has been the off‐label use of a 48 weeks course of PegInterferon alpha (PegIFNα), that was characterized by suboptimal efficacy and burdened by significant side effects that limited treatment applicability in patients with advanced liver disease. In July 2020, European Medicines Agency (EMA) conditionally approved the entry inhibitor Bulevirtde (BLV) at the dose of 2 mg/day for the treatment of adult patients with compensated CHD. Efficacy and safety of BLV in CHD have been evaluated in clinical trials either as monotherapy or in combination with PegIFNα. These results were confirmed by real‐life studies, which also evaluated long‐term BLV monotherapy in patients with advanced compensated cirrhosis. Notwithstanding these promising results there are still several issues to be addressed, such as the optimal duration of the treatment, the rates of off‐therapy responses, as well as the long‐term clinical benefits. This review summarizes updated and current literature data about clinical trials and real‐life studies with BLV monotherapy and/or in combination with PegIFNα. [ABSTRACT FROM AUTHOR]

miRNAs circulating in whole serum and HBsAg-particles are differentially expressed in chronic hepatitis B (CHB) and HBeAg-negative-HBV infection (ENI); their profiles are unknown in chronic hepatitis D (CHD). Serum- and HBsAg-associated miRNAs were analyzed in 75 subjects of 3 well-characterized groups (CHB 25, CHD 25, ENI 25) using next-generation sequencing (NGS). Overall miRNA profiles were consonant in serum and HBsAg-particles but significantly different according to the presence of hepatitis independently of Hepatitis D Virus (HDV)-co-infection. Stringent (Bonferroni Correction < 0.001) differential expression analysis showed 39 miRNAs upregulated in CHB vs. ENI and 31 of them also in CHD vs. ENI. miRNA profiles were coincident in CHB and CHD with only miR-200a-3p upregulated in CHB. Three miRNAs (miR-625-3p, miR-142-5p, and miR-223-3p) involved in immune response were upregulated in ENI. All 3 hepatocellular miRNAs of MiR-B-Index (miR-122-5p, miR-99a-5p, miR-192-5p) were overexpressed in both CHB and CHD patients. In conclusion, CHD and CHB patients showed highly similar serum miRNA profiling that was significantly different from that of individuals with HBeAg-negative infection and without liver disease.

The entry inhibitor bulevirtide (BLV) received conditional approval from the EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult-to-treat patients with HDV-related cirrhosis is presently unknown. Herein, we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to 3 years on a compassionate use program. Patients were also monitored for HBcrAg and HBV RNA levels, and HDV- and HBV-specific T-cell markers. In the patient who stopped BLV at week 48, after achieving a virological and biochemical response, the initial virological and biochemical rebound was followed by alanine aminotransferase normalization coupled with low HDV RNA and HBsAg levels. In the 2 patients treated continuously for 3 years, virological and biochemical responses were maintained throughout the treatment period even after dose reduction. In a patient with advanced compensated cirrhosis, liver function tests significantly improved, esophageal varices disappeared, and histological/laboratory features of autoimmune hepatitis resolved. Overall, no safety issues were recorded, as bile salt increase was asymptomatic. While serum HBV RNA levels remained undetectable in all patients, HBV core-related antigen levels showed a progressive, yet modest decline during long-term BLV treatment. No HDV-specific interferon-γ-producing T cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment. In conclusion, this report shows that continuous administration of BLV monotherapy for 3 years leads to excellent virological and clinical responses in patients with HDV-related cirrhosis who had contraindications to interferon-based therapies. [ABSTRACT FROM AUTHOR]

INTRODUCTION[|]This prospective study aimed to determine the prevalence of anti-HDV seropositivity among subjects who had previous hepatitis B virus (HBV) infection.[¤]METHODS[|]Subjects who were admitted to the gastroenterology inpatient clinic of our hospital between August 2016 and July 2017 were screened for previous HBV infection. The subjects who had HBV serology compatible with resolved HBV infection were recruited in the study, and the seroprevalance of anti-HDV was studied. Participants answered a short questionnaire regarding their family history of chronic hepatitis B (CHB) and chronic hepatitis D (CHD) infection and risk factors for transmission. Subjects who were anti-HDV positive were recalled for a control visit, and HBV-DNA and HDV-RNA were assayed in the blood samples of the responders.[¤]RESULTS[|]Among 554 subjects who had previous HBV infection, 53 (9.6%) were anti-HDV positive. The mean age was 63.1+-15.4 years in the anti-HDV-positive group and 65.9+-15.6 years in the anti-HDV-negative group (p=0.19). The most common risk factor for both groups was dental procedures (89% vs 80%, p=0.33). Anti-Hbc IgG, anti-Hbs, and anti-HBeAg seropositivity did not differ between the anti-HDV-positive and -negative groups (for all, p>0.05). Although HDV-RNA was not detectable in all studied samples, only one subject had detectable HBV-DNA in the anti-HDV-positive group.[¤]DISCUSSION AND CONCLUSION[|]This study highlighted the prevalence of anti-HDV among subjects who had resolved HBV infection. Long-term follow-up studies, including after the resolution of both infections, are needed to explore HBV–HDV interactions and the behavioral patterns of these viruses.[¤]

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Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-d sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients’ age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg (p < 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection.

The first step in the diagnosis of hepatitis delta virus (HDV) infection is testing HBsAg-positive individuals for the antibody to the HD antigen (anti-HD). In anti-HD-positive patients, the next step is testing for HDV RNA in serum to determine whether the antibody reflects an ongoing active HDV infection (HDV-RNA-positive) or represents a serologic scar to past HDV infection (HDV-RNA-negative). In the HDV-positive individual with liver disease, it is critical to distinguish acute HDV/hepatitis B virus (HBV) coinfection from chronic HDV superinfection in HBsAg carriers; the course, prognosis, and management of the two conditions are different. The differential diagnosis can be achieved through the scrutiny of the battery of HDV and HBV markers, which combine in patterns characteristic for each condition. Standardized competitive and μ-capture commercial assays are available to determine the IgG and IgM antibody to HDV. Several in-house assays were developed to determine HDV RNA in serum; the sensitivity threshold of current polymerase chain reaction-based assays is 10 copies of HDV RNA/mL. Unfortunately, HDV-RNA assays are not yet standardized and the results from different laboratories often are not comparable due to different sensitivities. The development of an international reference HDV-RNA standard remains an unmet diagnostic need. [ABSTRACT FROM AUTHOR]

Background: Hepatitis delta virus (HDV) causes severe liver disease. Aims: To investigate the quantitative HDV-RNA, HBsAg and hepatitis B virus (HBV)DNA levels in correlation to histological, biochemical and demographical parameters in patients with chronic HDV infection as similar data in a large series of HDV patients are missing. Methods: Eighty HDV patients were recruited in Germany, Turkey and Greece; quantitative determination of HDV-RNA, HBsAg and HBV-DNA was performed by real-time polymerase chain reaction, the Architect HBsAg assay and Cobas TaqMan HBV test respectively. Results: All patients were infected with HDV-genotype 1. Thirty-five patients (48%) had significant fibrosis (Ishak 3–4) and 15 (20.5%) had cirrhosis. HDV viraemia ranged from 1.1 × 103 to 8.4 × 107 copies/ml with 60% of patients showing HDV-RNA levels above 105 copies/ml accompanied by low HBV viraemia (<105 copies/ml). However, HDV-RNA and HBV-DNA levels showed no direct inverse correlation. HDV-RNA correlated positively with HBsAg and negatively with age. HBsAg correlated negatively with age and positively with histological grading. Only γ-glutamyltranspeptidase was independently associated with cirrhosis ( P=0.032), while no biochemical parameter was associated with grading. Conclusions: (i) HBsAg levels correlated with HDV viraemia in chronic HDV. (ii) Biochemical parameters did not accurately indicate the stage and grade of liver disease in chronic HDV and thus liver biopsy seems to remain the major tool for the evaluation of delta hepatitis patients. [ABSTRACT FROM AUTHOR]

ABSTRACT- Sera from 111 patients with chronic viral hepatitis and from 55 cases with other liver disorders were assayed for serum inhibitory factor. The prevalence of this immunosuppressive factor was very similar between chronic hepatitis B (61%), chronic hepatitis delta (57%) and chronic hepatitis C (68%). At the same time, serum inhibitory factor was never detected in the other disorders studied. The presence of this inhibitory factor was detected in a significantly higher percentage (p < 0.05) of HBeAg, HBV-DNA positive cases (75%) than in anti-HBe positive, HBV-DNA negative cases (44.4%). In chronic hepatitis delta, this immunosuppressive factor was also related to HDV-RNA positivity. The detection of this serum immunosuppressive factor in chronic viral hepatitis and its association with a high viral replication level implies a possible role of this factor in the immune pathogenic mechanism in infectious viral hepatitis. [ABSTRACT FROM AUTHOR]

Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-d sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients’ age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg (p < 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection. [ABSTRACT FROM AUTHOR]

Objective: This prospective study aimed to determine the prevalence of anti-HDV seropositivity among subjects who had previous hepatitis B virus (HBV) infection., Methods: Subjects who were admitted to the gastroenterology inpatient clinic of our hospital between August 2016 and July 2017 were screened for previous HBV infection. The subjects who had HBV serology compatible with resolved HBV infection were recruited in the study, and the seroprevalance of anti-HDV was studied. Participants answered a short questionnaire regarding their family history of chronic hepatitis B (CHB) and chronic hepatitis D (CHD) infection and risk factors for transmission. Subjects who were anti-HDV positive were recalled for a control visit, and HBV-DNA and HDV-RNA were assayed in the blood samples of the responders., Results: Among 554 subjects who had previous HBV infection, 53 (9.6%) were anti-HDV positive. The mean age was 63.1±15.4 years in the anti-HDV-positive group and 65.9±15.6 years in the anti-HDV-negative group (p=0.19). The most common risk factor for both groups was dental procedures (89% vs 80%, p=0.33). Anti-Hbc IgG, anti-Hbs, and anti-HBeAg seropositivity did not differ between the anti-HDV-positive and -negative groups (for all, p>0.05). Although HDV-RNA was not detectable in all studied samples, only one subject had detectable HBV-DNA in the anti-HDV-positive group., Conclusion: This study highlighted the prevalence of anti-HDV among subjects who had resolved HBV infection. Long-term follow-up studies, including after the resolution of both infections, are needed to explore HBV-HDV interactions and the behavioral patterns of these viruses., Competing Interests: Conflict of Interest: On behalf of all authors, the corresponding author states that there is no conflict of interest.

Abstract: Hepatitis delta virus (HDV) consists of a circular single-stranded RNA genome which assembles two viral proteins and acquires a lipid envelope in which the hepatitis B surface antigens (HBsAg) are embedded. HDV does not encode its own polymerase, but exploits a cellular enzyme for its replication. A better understanding of the mechanisms of HDV replication mechanism would provide new insights for antiviral strategies. Based on genomic variability, eight major genotypes of HDV have been identified, which differ as much as 40% in the nucleotide sequence. The cloning of HDV-RNA has provided genetic probes for the measurement of HDV-RNA in serum and liver; the sensitivity of HDV-RNA detection improved significantly when the reverse transcriptase-polymerase chain reaction (PCR) technique was introduced. As no commercial test is standardized for viral load detection, home-made assays have been developed in the different referral centers, which may not be comparable. Quantification of HDV in serum by real-time PCR has been recently proposed in the management of chronically infected patients. No specific inhibitors of HDV are available at present and, in spite of the crucial relationship between HDV and HBV, drugs that block HBV have only a theoretical but no sound effect on HDV replication. [ABSTRACT FROM AUTHOR]