Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, carrying a greater risk of developing cirrhosis and its complications. For decades, pegylated interferon alpha (PegIFN-α) has represented the only therapeutic option, with limited virological response rates and poor tolerability. In 2020, the European Medicines Agency approved bulevirtide (BLV) at 2 mg/day, an entry inhibitor of hepatitis B virus (HBV)/hepatitis delta virus (HDV), which proved to be safe and effective as a monotherapy for up to 144 weeks in clinical trials and real-life studies, including patients with cirrhosis. Long-term BLV monotherapy may reduce decompensating events in patients with cirrhosis. The combination of BLV 2 mg with PegIFN-α increased the HDV RNA undetectability rates on-therapy but not off-therapy, compared with PegIFN monotherapy. However, combination therapy, but not BLV monotherapy, may induce hepatitis B surface antigen (HBsAg) loss in some patients. The PegIFN lambda study has been discontinued due to liver toxicity issues, while lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study. Nucleic acid polymer-based therapy is promising but large studies are still lacking. New controlled trial data come from molecules, such as monoclonal antibodies and/or small interfering RNA, that target HBsAg or HBV RNAs, which demonstrated not only profound HDV suppression, but also HBsAg decline.While waiting for new compounds to be approved as monotherapy or in combination, BLV monotherapy 2 mg/day remains the only approved therapy for CHD, at least in the European Union region.

The safety and tolerability of bulevirtide (BLV), a novel entry inhibitor of hepatitis delta virus, were evaluated in an integrated analysis of clinical trial results from patients with chronic hepatitis delta (CHD).

Week 48 on-treatment clinical and laboratory results from two Phase 2 trials (MYR203 [NCT02888106] and MYR204 [NCT03852433]) and one Phase 3 trial (MYR301 [NCT03852719]) were pooled (N = 269). Patients were grouped as follows: BLV 2 mg (n = 64), BLV 10 mg (n = 115), pegylated interferon-alfa (n = 39) and control (n = 51). The control group consisted of patients assigned to the delayed treatment group in Study MYR301.

Adverse events (AEs) that occurred more frequently with BLV 2 mg and BLV 10 mg versus control included increased total bile acid levels (20% and 17% vs. 0%), injection-site reactions (16% and 20% vs. 0%), headache (16% and 17% vs. 0%), pruritus (11% and 10% vs. 0%) and eosinophilia (9% and 4% vs. 0%). Increases in total bile acid levels were observed with BLV without clear correlation with AEs, such as pruritus, eosinophilia or vitamin D deficiency. Grade 3 or 4 study drug-related AEs occurred in a higher proportion of patients receiving pegylated interferon-alfa (51%) than with BLV 2 or 10 mg (3% and 4%, respectively). There were no serious AEs related to BLV, and no patients discontinued BLV due to an AE. Neither hepatic decompensation nor death occurred.

BLV monotherapy was safe and well tolerated through 48 weeks of treatment in patients with CHD.

NCT02888106, NCT03852433 and NCT03852719.

Accurate HDV RNA quantification is crucial for diagnosis and management of chronic hepatitis delta (CHD), yet a significant variability between assays exists. We compared three methods to quantify HDV RNA levels in untreated and bulevirtide (BLV)-treated patients with CHD.

Frozen plasma from untreated and BLV-treated patients with CHD were tested in a single-center retrospective study using three different assays: Robogene 2.0 HDV RNA Quantification Kit 2.0 (Roboscreen GmbH; limit of detection [LOD] 6 IU/ml on 7500 Fast Real-Time PCR System [Applied Biosystem]), EurobioPlex HDV PCR quantitative kit (Eurobio Scientific; LOD 100 IU/m) on CFX96™ real-time PCR detection system [Bio-Rad]), and AltoStar HDV RT-PCR RUO Kit 1.5 (Altona Diagnostics; estimated LOD <10 IU/ml) on the AltoStar®AM16.

Overall, 431 plasma samples from 130 patients with CHD (69 untreated and 61 BLV-treated) were studied. Compared with Robogene 2.0, EurobioPlex reported higher HDV RNA levels (3.78 [0.70-7.99] vs. 4.69 [2.00-8.19] log IU/ml, p <0.0001), with viremia higher than >0.5 log in 160 (69%). Likewise, HDV RNA levels were higher with AltoStar than with Robogene 2.0 (3.32 [0.70-7.37] vs. 3.91 [0.19-7.54] log IU/ml, p <0.0001), with AltoStar reporting HDV RNA levels >0.5 log in 127 (52%). Although virological response rates (≥2 log decline vs. baseline) at Weeks 24 (Robogene 2.0 vs. EurobioPlex and AltoStar) and 48 (Robogene 2.0 vs. AltoStar) were similar across assays, rates of HDV RNA undetectability significantly differed between the three assays at Weeks 24 and 72 (p = 0.003 and p = 0.02, respectively).

HDV RNA levels quantified by EurobioPlex and AltoStar were 1 and 0.5 logs higher than those quantified by Robogene 2.0, respectively. HDV RNA undetectability rates during BLV treatment were assay-dependent.

Management and diagnosis of chronic hepatitis delta (CHD) require standardized tests for HDV RNA quantification. Quantification of HDV RNA is significantly influenced by the quantification method, with EurobioPlex detecting approximatively 1 log and AltoStar 0.5 log IU/ml more than Robogene 2.0, respectively. The HDV RNA undetectability rates during BLV monotherapy significantly differed among assays. These findings are of clinical relevance as patients who achieve negative viremia during BLV monotherapy might be entitled to stop therapy successfully.

In the last few years there have been innovations in HDV therapy which have brought new excitement in the scientific community also considering the few therapeutic opportunities. Recently, new molecular targets have been identified, both in monotherapy and in combination with peginterferon alpha (PegIFNα). Evaluating this review of the literature of the last ten years, HDV-related chronic hepatitis seems to have become a potentially curable disease, a statement that was unthinkable a few years ago. There are old and new weapons at our disposal. The old weapons are PegIFNα and recently PegIFN-lambda (PegIFNλ). PegIFNα, for which there are more data, appears to be an excellent combination regimen, if not contraindicated, both for Bulevirtide (BLV), data supported by important clinical trials and real-world studies, and probably for lonarfanib, although in the latter case the results are not yet definitive as the studies are fewer. However, data on long-term follow-up are needed.

Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFNα-2a), with 24-week follow-up.

Ninety patients were enrolled into six arms of 15 each (A-F); 60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFNα-2a 180 μg once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFNα-2a 180 μg QW; (C) BLV 5 mg QD + Peg-IFNα-2a 180 μg QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFNα-2a 180 μg QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72.

At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log10 IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment.

BLV combined with Peg-IFNα-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment.

NCT02888106.

Background: Hepatitis delta virus (HDV) infection represents the most severe form of viral hepatitis and is a significant global health challenge. Bulevirtide (BLV) is a novel therapeutic treatment that has resulted in variable response rates in HBV/HDV-coinfected patients. We evaluated clinical, virological, and polymorphic factors for the purpose of predicting BLV treatment success. Methods: Thirty HBV/HDV-coinfected patients received BLV monotherapy (2 mg/day) for 24 to 48 weeks. Baseline (BL) serum samples were collected to assess clinical parameters and virological markers (HDV RNA, HBV DNA, HBsAg, HBcrAg, anti-HBc IgG) at treatment weeks 24 (TW24) and 48 (TW48). Additionally, full-genome HDV sequencing and a phylogenetic analysis were performed. Finally, analyses of the HDAg protein sequence and HDV RNA secondary structure were conducted to evaluate potential associations with treatment response. Results: A significant reduction in HDV RNA levels was observed at TW48, with a virological response (HDV RNA undetectable or ≥2 Log decline from BL) achieved by 58% of patients. Median BL levels of anti-HBc IgG were significantly different between virological responders (39.3 COI; interquartile range [IQR] 31.6-47.1) and virological non-responders (244.7 COI; IQR 127.0-299.4) (p = 0.0001). HDV genotype 1e was predominant across the cohort, and no specific HDAg polymorphisms predicted the response. However, secondary structure analysis of HDV RNA revealed that a specific pattern of internal loops in the region 63-100 nucleotides downstream of the editing site may influence treatment response by impacting editing efficacy. Conclusions: This study revealed key factors influencing BLV efficacy in HBV/HDV coinfection. Lower baseline anti-HBc IgG levels strongly correlated with a positive virological response, suggesting that the liver's inflammatory state affects treatment success. Additionally, the analysis of HDV RNA secondary structure in patients receiving BLV treatment revealed a higher editing efficiency in virological responders, highlighting areas for further research.

Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD.

In an open-label, randomised, phase III trial, 150 patients with CHD and compensated liver disease were stratified by cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire, and Fatigue Severity Scale.

Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2 mg bulevirtide reported significant improvements compared with controls on the Hepatitis Quality of Life Questionnaire domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs. controls. Fatigue Severity Scale scores remained stable across treatment groups throughout. At week 48, patients in the 2 mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale.

Patient-reported outcomes indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD.

ClinicalTrials.gov Identifier, NCT03852719.

Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared with those who did not receive therapy (control group).

Hepatitis D virus (HDV) prevalence data and country-specific HDV guidelines are not widely available in the Gulf Cooperation Council (GCC) states. We developed consensus recommendations to guide healthcare professionals, policymakers, and researchers in improving HDV management and patient health outcomes in three GCC states: Kuwait, Saudi Arabia, and the United Arab Emirates. A consensus panel comprising hepatology experts (n = 6) from the three GCC societies was formed. The panel identified two broader areas related to clinical practice (screening and diagnosis, and treatment and management), addressed critical questions, and developed draft recommendations in February 2024. The strength of the final set of recommendations was subjected to consensus voting in March 2024. A majority was defined apriori with a two-thirds vote (67%). The paper outlines those recommendations alongside showcasing the current epidemiology of HDV in the GCC states, emphasizing the variability in prevalence, demographic patterns, and region-specific risk factors. It also highlights the current state of screening and diagnosis practices, identifying key obstacles, such as access to advanced screening protocols and diagnostic tools. Furthermore, HDV treatment landscape and preventative strategies are outlined, focusing on vaccination, public health initiatives, and the crucial role of public awareness and education. Ethical and sociocultural considerations are discussed, underscoring the importance of culturally sensitive healthcare practices. These recommendations present a comprehensive overview of the challenges and strategies for managing HDV in these states. Policy recommendations are provided to support HDV management, including standardizing care protocols and promoting public health measures.

The objective of this study was to know the prevalence and clinical-epidemiological characteristics of patients with chronic infection due to hepatitis D virus (HDV).

A retrospective descriptive study was carried out on patients with HDV infection under follow-up in a hospital in 2023. All patients carrying HBsAg were tested for antibodies against HDV. HDV RNA detection was performed in all antibody-positive samples. The medical records were reviewed.

Of the 340 patients carrying HBsAg, 24 (7.1%) had anti-HDV antibodies, and 6 (25%) had detectable HDV RNA (chronic infection). The prevalence of chronic hepatitis in HBsAg carriers was 1.8%. All patients had a genotype 1 infection. Half of the patients were of African origin and 29.2% were Spanish. Of the 6 patients with chronic infection, 5 (83.3%) had cirrhosis and 2 (33.3%) had hepatocellular carcinoma. Half of the patients had some exacerbation of the disease during follow-up. Of the 18 patients without viremia, 2 (11.1%) presented cirrhosis (one recently diagnosed). The mean follow-up time of patients without viremia was 13.5 years.

The prevalence of chronic HDV hepatitis in our area is low and in all cases it presents as an advanced disease, with exacerbations during follow-up. Patients without viremia have probably resolved the infection, as viremia was not detected in any moment.

More than 12 million individuals worldwide are chronically infected with the hepatitis D virus (HDV). HDV infection is the most severe form of viral hepatitis since it requires hepatitis B virus co-infection and accelerates progression to cirrhosis and hepatocellular carcinoma. Therefore, treatment modalities to slow the progression of the disease are essential but not yet available. In addition, no antiviral treatment to date has been shown to reliably eradicate HDV. Pegylated interferon (PEG-IFN) is the only universally used treatment to suppress HDV RNA replication and improve liver inflammation and fibrosis. This treatment can be completed in 12-18 months, but cure rates remain low, and success does not reliably increase with the addition of a nucleos(t)ide analog. PEG-IFN therapy is also limited by poor tolerability and multiple adverse effects, including neutropenia, thrombocytopenia, and neuropsychiatric symptoms. Newer antiviral therapies in development target unique aspects of HDV viral replication and show promising results in combination with PEG-IFN for long-term HDV RNA suppression. These newer antiviral therapies include buleviritide (which blocks HDV entry), lonafarnib (which prevents HDV assembly), and REP-2139 (which prevents HDV export). In this manuscript, we discuss the characteristics of HDV infection and review the new antiviral therapies approved for treatment and those under investigation.

Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis, with a high risk of developing hepatocellular carcinoma (HCC) and liver-related mortality. Risk stratification is needed to guide HCC surveillance strategies and to prioritize treatment with antiviral agents.

We conducted a multicenter retrospective cohort of anti-hepatitis D virus (HDV)-positive individuals managed at sites in the Netherlands and the United Kingdom. We studied the 5-year cumulative incidences of HCC and liver-related events (first of HCC, liver transplantation, and liver-related mortality), in the overall cohort and among relevant subgroups.

We analyzed 269 anti-HDV-positive individuals with a median follow-up of 4.3 years in which 47 first events occurred. The 5-year cumulative incidences of HCC and liver-related events were 3.8% and 15.6% in the overall cohort. The 5-year cumulative incidence of HCC and liver-related events for individuals without cirrhosis was 0% and 0.9% compared with 12% and 41.3% for individuals with cirrhosis (P < .001). The 5-year cumulative incidence of HCC and liver-related events was 0% and 2.1% among individuals with low PAGE-B scores, compared to 3.2% and 21.1% with intermediate and 25.4% and 45.5% with high-risk scores (P < .001). We found comparable results for the Fibrosis-4 score. Findings were consistent regardless of cirrhosis or detectable HDV RNA (P < .001).

Anti-HDV-positive individuals are at high risk of adverse liver-related outcomes. The incidence of HCC was negligible among individuals without cirrhosis and among individuals with low baseline PAGE-B and/or Fibrosis-4 scores. Therefore, these scores can be used to guide HCC surveillance strategies and potentially also for treatment prioritization.

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.

Infection with the hepatitis delta virus (HDV), a unique RNA virus that requires hepatitis B virus (HBV) antigens for its assembly, replication, and transmission, causes severe viral hepatitis. Compared to HBV monoinfection, HDV infection increases the risk of severe liver disease, necessity for liver transplant, and mortality. Global HDV prevalence estimates vary from 5% to 15% among persons with HBV, but screening guidelines for HDV are inconsistent; some recommend risk-based screening, while others recommend universal screening for all people with HBV. Among primary care providers (PCPs) in the US, there is a lack of awareness and/or insufficient adherence to current recommendations for the screening of HDV infection and management of chronic HDV.

Publications were obtained by conducting literature searches between July and August 2022 using the PubMed database and by manual searches of the retrieved literature for additional references. Information was synthesized to highlight HDV screening and management strategies for PCPs. Best practices for PCPs based on current guidelines and comanagement strategies for patients with HBV and HDV infection were summarized.

We recommend universal screening for HDV in patients positive for hepatitis B surface antigen. Confirmed HDV infection should prompt evaluation by a liver specialist, if available, with whom the PCP can comanage the patient. PCPs should counsel patients on the expected course of the disease, lifestyle factors that may influence liver health, need for consistent disease monitoring and follow-up, and risk of disease transmission. Screening is suggested for sexual partners, household contacts, and family members, with HBV immunization recommended for those found to be susceptible. There are currently no US Food and Drug Administration-approved therapies for HDV infection; thus, management is limited to treatments for chronic HBV infection plus long-term monitoring of liver health.

PCPs can be a valuable point of care for patients to access HDV/HBV screening, HBV immunization, and education, and can comanage patients with HBV and/or HDV infection.

Pegylated interferon alpha 2a continues to be used for the treatment of chronic hepatitis D. The reported on-treatment virologic response varies between 17 and 47%, with relapses in more than 50% of these patients. No stopping rules have been defined, and the duration of the treatment is not clearly established, but it should be between 48 and 96 weeks. In total, 76 patients with compensated liver disease treated with peg-interferon according to the Romanian National protocol for the treatment of hepatitis D were retrospectively included. The duration of treatment was up to 96 weeks, with the following stopping rules: less than a 2 log HDV RNA decrease by week 24 and less than a 1 log decrease every 6 months afterwards. Six months after stopping the treatment, it can be restarted for unlimited cycles. The inclusion criteria were aged above 18, HBs Ag-positive, HDV RNA detectable, ALT above ULN and/or liver fibrosis at least F1 at liver biopsy, or Fibrotest and/or Fibroscan higher than 7 KPa and/or inflammation at least A1 at liver biopsy or Fibrotest. We monitored our patients for a total period of 4 years (including those that repeated the cycle). After the first 6 months of treatment, 27 patients (35.5%) had a greater than 2 log HDV RNA decrease, 19 of them achieving undetectable HDV RNA. Seventeen patients (22.3%) had undetectable HDV RNA 24 weeks after stopping 96 weeks of treatment, and none relapsed in the following 2 years. Of these 17 patients, 6 were cirrhotic, and 4 had F3. Undetectable HDV RNA at 24 weeks was the only parameter that predicted a long-term suppression of HDV RNA. In 49 patients, the treatment was stopped after 6 months according to protocol, but it was restarted 6 months later. Five of these patients finished a 48-week course of treatment; none achieved undetectable HDV RNA. During the first course of therapy, 45 patients had at least one moderate adverse reaction to treatment. In one patient, the treatment was stopped due to a serious adverse event (osteomyelitis). Treatment doses had to be reduced in 29 patients. The virologic response at week 24 can select the patients who will benefit from continuing the treatment from those who should be changed to another type of medication when available.

Hepatitis D virus was first described by Mario Rizzeto in 1977, and it is considered chronic viral hepatitis with the poorest prognosis. Despite its discovery almost 50 years ago, progress in its diagnosis and treatment has been scarce until recent years. The approval of bulevirtide has shed some light for patients with Chronic Hepatitis D, although important gaps regarding its use in therapy as well as about the epidemiology and diagnosis of the disease need to be addressed.

Approximately 12-72 million people worldwide are co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). This concurrent infection can lead to several severe outcomes with hepatic disease, such as cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, being the most common. Over the past few decades, a correlation between viral hepatitis and autoimmune diseases has been reported. Furthermore, autoantibodies have been detected in the serum of patients co-infected with HBV/HDV, and autoimmune features have been reported. However, to date, very few cases of clinically significant autoimmune hepatitis (AIH) have been reported in patients with HDV infection, mainly in those who have received treatment with pegylated interferon. Interestingly, there are some patients with HBV infection and AIH in whom HDV infection is unearthed after receiving treatment with immunosuppressants. Consequently, several questions remain unanswered with the challenge to distinguish whether it is autoimmune or "autoimmune-like" hepatitis being the most crucial. Second, it remains uncertain whether autoimmunity is induced by HBV or delta virus. Finally, we investigated whether the cause of AIH lies in the previous treatment of HDV with pegylated interferon. These pressing issues should be elucidated to clarify whether new antiviral treatments for HDV, such as Bulevirtide or immu-nosuppressive drugs, are more appropriate for the management of patients with HDV and AIH.

Hepatitis D Virus (HDV), although a small defective virus, poses a substantial public health challenge due to lack of awareness, underrecognized prevalence, and limited treatment options. Universal HDV screening within hepatitis B virus (HBV) cohorts is essential to address this issue. Despite its aggressive nature, effective HDV therapies have remained elusive for over four decades.

Advances in understanding HDV's biology and clinical behavior offer potential therapeutic breakthroughs, fostering optimism. As insights grow, effective and targeted therapies are being developed to improve HDV management.

This review delves into HDV's intricate structure and biology, highlighting formidable hurdles in antiviral development. It emphasizes the importance of widespread screening, exploring noninvasive diagnostics, and examining current and emerging innovative therapeutic strategies. Moreover, the review explores models for monitoring treatment response. In essence, this review simplifies the complexities of effectively combating HDV.

Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown.

In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 μg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 μg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy).

Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p = .179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p = .04) and hepatic decompensation (p = .009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p > .999) but was associated with a higher chance of HDV-RNA suppression (p = .024, odds ratio 3.9 [1.3-12]).

Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment.

NCT00932971.

HDV use the cell enzymes for its own replication, and the HBsAg as an envelope. There is an urgent need to develop new drugs for chronic hepatitis D (CHD). Pegylated interferon alpha (PEG-IFNα) (direct-antiviral and immune modulator) has been used and recommended by scientific guidelines, although not approved, with moderate efficacy and poor tolerability. There are several drugs in development which target the host: bulevirtide (BLV), lonafarnib (LNF), nucleic acid polymer, and others.

Diagnosis of HDV exposure is based on clinical assays of anti-hepatitis D antibody and current infection with hepatitis D RNA PCR. The role of hepatitis D antigen testing is not yet defined. RT-qPCR is the gold standard for measuring HDV RNA viral load, which is used to assess response to the treatment of HDV infection. Gaps in testing include poor sensitivity of antigen testing and quantitative HDV RNA accuracy can be affected by the genotypic variability of the virus and variation in laboratory techniques. There is also a limitation in HDV testing due to access, cost, and limited knowledge of testing indications. Droplet digital PCR promises to be a more accurate method to quantify HDV RNA. Also, the recent development of a rapid HDV detection test could prove useful in resource-limited areas.

Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level <100 IU/mL and HBV DNA Collapse

Hepatitis delta virus (HDV) only infects patients with hepatitis B virus (HBV) due to its reliance on HBV surface proteins to form its envelope. With shared routes of transmission, HDV coinfection is estimated to occur in 15% of patients with HIV and HBV. However, HDV is often underdiagnosed and may be missed particularly in people living with HIV (PLWH) who are already on antiretroviral therapy with anti-HBV activity and coincidental HBV suppression. At the same time, HDV causes the most severe form of chronic viral hepatitis and leads to faster progression of liver disease and hepatocellular carcinoma. Thus, increased recognition and effective treatment are paramount, and as novel treatment options approach global markets, the study of their efficacy in PLWH should be pursued.

To compare the effectiveness of seven major interventions [Bulevirtide (BLV), Interferon (IFN), Nucleoside analogs (NAs), BLV + IFN, BLV + NAs, IFN + NAs, and Placebo] to treat chronic hepatitis D.

We followed PRISMA-NMA guidelines, searched databases (Cochrane Library, PubMed, EMBASE, and Web Of Science) for eligible randomized controlled trials (RCTs), and applied STATA17.0 software to execute the meta-analysis.

We included 14 randomized controlled trials (814 patients) comparing seven different interventions. The results of the network meta-analysis showed that: ① Sustained virological response (after 24 weeks of follow-up): Four intervention groups (BLV + IFN, IFN alone, IFN + NAs, and NAs alone) were effective (relative risk (RR) = 13.30, 95% confidence interval (Cl) [1.68,105.32], RR = 12.13, 95% Cl [1.46,101.04], RR = 5.05, 95% Cl [1.68,15.19], RR = 5.03, 95% Cl [1.66,15.20]), with no statistically significant differences between the four groups. The top three in probability rankings were: BLV + NAs, BLV + IFN, and BLV alone (surface under the cumulative ranking curve (SUCRA) = 86.8%, 80.3%, and 48.4%; ② Sustained biochemical response (after 24 weeks of follow-up): BLV + IFN and IFN were superior to BLV (RR = 14.71, 95% Cl [1.14,189.07], RR = 16.67, 95% Cl [1.39,199.52]). The top three were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 86.9%,81.2%, and 64.3%). ③ Histological response: NAs were superior to BLV (RR = 2.08, 95% Cl [1.10,3.93]), whereas the difference between other treatment regimens was not statistically significant, and the top three in the probability ranking were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 75.6%, 75.6%, and 61.8%).

IFN, IFN + BLV, and IFN + NAs were effective in clearing HDV RNA and normalizing alanine aminotransferase levels; however, IFN and IFN + NAs had a high rate of viral relapse at 24 weeks post-treatment follow-up. There was no additional benefit of adding NAs to IFN therapy for chronic hepatitis D; however, the combination of IFN + BLV significantly improved short-term HDV RNA clearance, which showed strong synergistic effects. The seven regimens included in the study did not contribute significantly to liver histological improvement. Therefore, the IFN + BLV combination has the most potential as a treatment option to improve the long-term prognosis or even cure chronic hepatitis D.

This systematic evaluation and meta-analysis was registered with PROSPERO under the registration number: CRD42022314544.).

Hepatitis D virus (HDV) was first described in 1977 and is dependent on the presence of hepatitis B surface antigen (HBsAg) for its entry into cells and on the human host for replication. Due to the envelopment with the hepatitis B virus (HBV) envelope, early phases of HDV entry resemble HBV infection. Unlike HBV, HDV activates innate immune responses. The global prevalence of HDV is estimated to be about 5% of HBsAg positive individuals. However, recent studies have described a wide range of prevalence between 12 to 72 million individuals. Infection can occur as super-infection or co-infection. The diagnosis of active HDV infection involves screening with anti HDV antibodies followed by quantitative PCR testing for HDV RNA in those who are HBsAg positive. The diagnostic studies have evolved over the years improving the validity and reliability of the tests performed. HDV infection is considered the most severe form of viral hepatitis and the HDV genotype may influence the disease course. There are eight major HDV genotypes with prevalence varying by geographic region. HDV treatment has been challenging as HDV strongly depends on the host cell for replication and provides few, if any viral targets. Better understanding of HDV virology has led to the development of several therapeutic agents currently being studied in different phase II and III clinical trials. There is increasing promise of effective therapies that will ameliorate the course of this devastating disease.

Bulevirtide (BLV) is a HDV/HBV entry inhibitor that is associated with virologic response (responders, HDV-RNA undetectable or ≥2 log10 IU/ml decrease from baseline) in >50% of patients after a 24-week treatment. However, some patients only achieve a <1 log10 IU/ml decline in HDV-RNA after the 24-week treatment (non-responders). Here, we report a viral resistance analysis in participants receiving BLV monotherapy who were non-responders or experienced virologic breakthrough (VB, i.e., two consecutive increases in HDV-RNA of ≥1 log10 IU/ml from nadir or two consecutive HDV-RNA detectable results if previously undetectable) from the phase II MYR202 and phase III MYR301 study.

Deep-sequencing of the BLV-corresponding region in HBV PreS1 and of the HDV HDAg gene, as well as in vitro phenotypic testing, were performed for the participant with VB (n = 1) and non-responders (n = 20) at baseline (BL) and Week 24 (WK24).

No amino acid exchanges associated with reduced susceptibility to BLV within the BLV-corresponding region or within HDAg were identified in isolates from any of the 21 participants at BL or at WK24. Although variants (HBV n = 1; HDV n = 13) were detected at BL in some non-responders or in the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was detected in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log10 IU/ml), and responders regardless of the presence of HBV and/or HDV polymorphisms.

No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment.

This is the first study investigating the development of resistance in patients treated with BLV. Excluding resistance to BLV as an explanation for an insufficient decrease in HDV-RNA levels during BLV therapy is an important finding for patients, clinicians, and researchers. It demonstrates that BLV has a high barrier to resistance, indicating it is safe and suitable for long-term treatment, although long-term surveillance for resistance should be performed. Our results hint at other still unknown mechanisms as an explanation for the persistence of serum HDV-RNA during inhibition of viral entry.

NCT03546621 and NCT03852719.

Treatment of hepatitis D virus (HDV) infection has been based on the administration of interferon-alfa for more than three decades. First studies to treat HDV-infected patients with type 1 interferons were already performed in the 1980s. Several smaller trials and case series were reported thereafter. During the mid 2000s the use of pegylated interferons for hepatitis D was established. Since then, additional trials were performed in different countries exploring strategies to personalize treatment including extended treatment durations. The overall findings were that about one-quarter to one-third of patients benefit from interferon treatment with persistent suppression of HDV replication. However, only few patients achieve also functional cure of hepatitis B with HBsAg loss. Importantly, several studies indicate that successful interferon treatment is associated with improved clinical long-term outcomes. Still, only a proportion of patients with hepatitis D can be treated with interferons. Even though alternative treatments are currently developed, it is likely that pegylated interferon-alfa will still have an important role in the management of hepatitis D - either alone or in combination. Therefore, better biomarkers are needed to select patients with a high likelihood to benefit from interferon-based treatments. In this review we are discussing basic principles of mode of action of interferon alpha against HDV, summarize previous data on interferon treatment of hepatitis D and give an outlook on potential combinations with novel drugs currently in development.

Hepatitis delta virus (HDV) is a satellite RNA virus that requires the presence of hepatitis B virus (HBV) for its replication. HDV/HBV co-infection is often associated with a faster disease progression of chronic hepatitis in comparison to HBV mono-infection. Therefore, the development of novel antiviral therapies targeting HDV represents a high priority and an urgent medical need. In this review, we summarize the ongoing efforts to evaluate promising HDV-specific drugs, such as lonafarnib (LNF), pegylated interferon lambda (PEG-IFN-λ) and their use as a combination therapy. Furthermore, we review the most recent developments in the area of anti-HBV drugs with potential effects against HDV, including therapeutic agents targeting hepatitis B surface antigen (HBsAg) expression, secretion and function. Finally, we consider the important insights that have emerged from the development of these potential antiviral strategies, as well as the intriguing questions that remain to be elucidated in this rapidly changing field.

Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment for compensated CHD. Three phase 3 studies with two new compounds are ongoing for the treatment of CHD. In this context, surrogate markers of treatment efficacy have been well defined for chronic hepatitis B (CHB) (7) and chronic hepatitis C (8) but not for CHD. The aim of this review is to give a perspective on treatment endpoints in CHD. For this, we took guidance from CHB studies and tried to make suggestions which differed according to finite versus prolonged treatment durations and also took into account the different characteristics of the new compounds.

Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.

Epidemiological studies and recent metanalyses addressing hepatitis D have reported a wide variation in the prevalence of the disease. Between 4.5% to 15% of all hepatitis B surface antigen (HBsAg) positive patients are thought to harbor the hepatitis D virus. The emergent variation in prevalence can be attributed to several factors. Unsurprisingly, published literature shows that the prevalence of the disease is higher in areas where aggregate viral hepatitis infections are endemic and amongst groups with high-risk practices facilitating the horizontal transfer. Meanwhile, the natural history of the disease is influenced by the genotype of the virus, the hepatitis D virus (HDV) RNA levels, HBV-HDV codominance, HBsAg titers, HBV genotype, nutritional status, HIV co-infection, and prior treatment. Together these factors contribute to the accelerated development of fibrosis and the increased risk of hepatocellular carcinoma. Superinfection with genotype 1 results in rapid progression to cirrhosis with lower rates of remission. Genotype 3 follows an aggressive course but shows a good response to interferon therapy. Other genotypes have better outcomes. The course of the disease leading to these outcomes can be tracked by HDV-specific models integrating clinical surrogate markers and epidemiological factors such as age, region, alanine aminotransferase (ALT), gamma-glutamyl transferase, albumin, platelets and cholinesterase, and liver stiffness.

First discovered over 40 years ago, the hepatitis delta virus (HDV) is a unique RNA virus, requiring hepatitis B virus (HBV) antigens for its assembly, replication, and transmission. HBV and HDV can be acquired at the same time (coinfection) or HDV infection can occur in persons with chronic HBV (superinfection). Screening guidelines for HDV are inconsistent. While some guidelines recommend universal screening for all people with HBV, others recommend risk-based screening. Estimates of the global HDV prevalence range from 4.5 to 14.6% among persons with HBV; thus, there may be up to 72 million individuals with HDV worldwide. HDV is the most severe form of viral hepatitis. Compared to HBV monoinfection, HDV coinfection increases the risk of cirrhosis, hepatocellular carcinoma, hepatic decompensation, mortality, and necessity for liver transplant. Despite the severity of HDV, there are few treatment options. Pegylated interferon (off-label use) has long been the only available treatment, although bulevirtide is conditionally approved in some European countries. There are many potential treatments in development, but as yet, there are few effective and safe therapies for HDV infection. In conclusion, given the severity of HDV disease and the paucity of treatments, there is a great unmet need for HDV therapies.

Hepatitis D virus (HDV) is a defective virus that requires the hepatitis B virus to complete its life cycle and cause liver damage in humans. HDV is responsible for rare acute and chronic liver diseases and is considered the most aggressive hepatitis virus. Acute infection can cause acute liver failure, while persistent infection typically causes a severe form of chronic hepatitis which is associated with rapid and frequent progression to cirrhosis and its end-stage complications, hepatic decompensation and hepatocellular carcinoma. Major diagnostic and therapeutic innovations prompted the EASL Governing Board to commission specific Clinical Practice Guidelines on the identification, virologic and clinical characterisation, prognostic assessment, and appropriate clinical and therapeutic management of HDV-infected individuals.

A severe course has been described in early studies on chronic hepatitis D (CHD), with faster pace towards liver cirrhosis with subsequent high liver-related morbidity and mortality in the majority of patients. Earlier studies have included risk groups as people using intravenous drugs (PWID) or those with multiple co-morbidities. During the last decade, the epidemiological landscape of CHD has changed with domestic cases decreasing while increasing cases of CHD consisting of younger persons immigrating from endemic regions to low-endemic regions. Recently, further insights into the spectrum of the disease with an indolent disease course in a substantial proportion of persons with CHD have been gained. At diagnosis, ≥30%-50% had already established liver cirrhosis. Older age, liver cirrhosis, co-infection with HIV and lack of interferon (IFN) therapy are the main predictors of worse clinical outcome. The newly introduced and upcoming antivirals against CHD are highly anticipated, considering the historically low virological response rates to antiviral therapy. Further knowledge is needed to fully comprehend the natural course and the spectrum of this severe form of viral hepatitis. This is also to be able to evaluate the long-term effects of the new antivirals on disease progression.

Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes.

In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group.

A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P = 0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups.

After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.).