Hope on the horizon: Emerging therapies for hepatitis D

Abstract

Current treatment options for hepatitis D are limited, with pegylated interferon-alpha (PEG-IFNα) being the only therapy available in the Asia-Pacific region. However, PEG-IFNα has limited efficacy and significant side effects. Pegylated interferon lambda acts on interferon-lambda (Type III) receptors predominantly expressed in hepatocytes. In 2023, bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D. This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide receptor on liver cells, which is the primary entry point for the virus. Recently, several new drugs have entered various stages of development, offering hope for improved hepatitis D virus (HDV) management. Two more viral entry inhibitors are HH003 and tobevibart. Other agents include nucleic acid polymers (REP 2139-Mg), prenylation inhibitors (lonafarnib), and RNA interference-based therapies (elebsiran). Emerging trials are now considering combination therapies, such as SOLSTICE, a Phase 2 clinical trial evaluating tobevibart alone or combined with elebsiran. The combination dosed monthly achieved > 50% virologic and biochemical response at 24 weeks of therapy. The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1, 2, and 3 trials. With these new treatments on the horizon, the prospects for improved HDV patient outcomes are promising.

Key Words: Hepatitis D; Hepatitis B; Treatment; Pegylated interferon; Bulevirtide; Nucleic acid polymers; Lonafarnib; Tobevibart; Elebsiran

Core Tip: New therapeutic options for hepatitis D are emerging, offering hope for improved treatment outcomes. Pegylated interferon-alpha is currently the primary treatment for hepatitis D, but it has limitations, including significant adverse effects and low response rates. Several novel therapies are being developed. Bulevirtide, HH003, and tobevibart are entry inhibitors. Other drugs include pegylated interferon-lambda, a type III interferon; lonafarnib, a prenylation inhibitor that prevents viral replication with synergistic effects when combined with pegylated interferon-alpha; REP 2139, a nucleic acid polymer that inhibits virus entry and replication; and small interfering RNAs, including elebsiran that interfere with translation of hepatitis B virus RNA.

INTRODUCTION

Hepatitis D virus (HDV) infection, also known as hepatitis delta, remains one of the most severe forms of viral hepatitis. HDV affects approximately 5% of individuals with chronic hepatitis B virus (HBV) infection, translating to an estimated 10-20 million people worldwide[1,2]. The highest prevalence is seen in some regions such as Central Asia, Eastern Europe, and parts of Africa. The virus is transmitted through contact with infected blood or body fluids, similar to HBV. HDV infection can occur either as a coinfection with HBV or as a superinfection in individuals already chronically infected with HBV[3]. As a satellite virus, HDV requires HBV surface antigen (HBsAg) for its life cycle. The pathophysiology of HDV is complex, involving the suppression of HBV replication through mechanisms that are not fully understood. This dual infection scenario often leads to more rapid progression of liver disease, including cirrhosis and hepatocellular carcinoma, compared to HBV infection alone[4,5].

The accelerated progression to liver-related complications underscores the urgent need for effective treatments for hepatitis D. However, the disease has been historically neglected, with limited therapeutic options available. Until recently, interferon-based treatment was the only option available, which showed modest efficacy and significant side effects. However, the past few years have witnessed remarkable progress in understanding HDV pathogenesis and developing novel therapeutic approaches. New drugs in development include drugs that prevent viral entry through sodium taurocholate co-transporting peptide (NTCP) receptor on the hepatocyte surface, inhibitors of prenylation of large delta antigen (HDAg), inhibitors of viral assembly and virus release, and inhibitors of HBV RNA to prevent HBsAg translation (Table 1, Figure 1). The proportion of patients with a ≥ 2 Log IU/mL decline of HDV RNA coupled with normalization of alanine aminotransferase (ALT) has been adopted as a reasonable endpoint in many new clinical trials[6].

Figure 1 Hepatitis D virus life cycle and therapeutic strategies. Hepatitis D virus (HDV) (and hepatitis B virus) entry is facilitated by the Sodium taurocholate co-transporting polypeptide (NTCP), which binds HBV surface antigen (HBsAg). Entry inhibitors, including Bulevirtide and monoclonal antibodies, can act to prevent viral entry. Replication of the HDV genome (HDV G) and the hepatitis B virus genome is nuclear, and one proposed mechanism of action of nucleic acid polymers is inhibition of this phase. HDV mRNA is used to make hepatitis D large antigen (HDAg-L). The HDAg-L is prenylated (which can be inhibited by prenylation inhibitors) and, along with HDV G, is used to assemble the HDV ribonucleoprotein (RNP). The HDV RNP is enveloped in the Golgi apparatus by HBsAg. Nucleic acid polymers can prevent the release of the HBsAg, while siRNA strategies can help reduce the amount of HBsAg made. The signaling pathways employed by interferons are given in the insets, and these mediate broader antiviral activity. (Created in BioRender (2025) https://BioRender.com/hrg3zi7). IFNα: Interferon-alpha.

Table 1 Diverse strategies target different stages of hepatitis D virus’s life cycle or indirectly disrupt hepatitis B virus processes essential for hepatitis D virus survival.

Drug	Phase of development	Route of administration and dosage	Mode of action
Pegylated interferon alpha	Extensively studies	Subcutaneous. 180 µg weekly	Enhances immune response and reduces viral replication
Pegylated interferon lambda	Phase 2 & 3	Subcutaneous. 120 & 180 µg weekly	Targets type III interferon receptors on hepatocytes, activating immune responses specifically in the liver
Bulevirtide	Phase 3	Subcutaneous. 2 mg (approved) & 10 mg daily	Inhibits entry of HDV by blocking NTCP, a receptor for HBV/HDV entry into hepatocytes
Huahui HH003	Phase 2	Intravenous. 10 & 20 mg/kg every 2 weeks	A human monoclonal antibody targeting the preS1 domain of the large envelope protein of HBV and HDV, preventing the binding of preS1 to NTCP
Tobevibart	Phase 2 & 3	Subcutaneous. 300 mg every 4 weeks	A monoclonal antibody that binds the antigenic loop of HBsAg. The drug inhibits the entry of HBV and HDV into naïve hepatocytes and reduces circulating HBsAg
Lonafarnib	Phase 3	Oral 50 mg twice a day (when given with ritonavir)	Inhibits prenylation of the large delta antigen, essential for HDV assembly and viral replication
Nucleic acid polymers	Phase 2	Intravenous. 500 mg weekly for 15 weeks followed by 250 mg weekly (when combined with pegylated interferon)	Blocks HDV envelope formation by targeting HBsAg. Prevents secretion of HDV virions from infected cells
Small Interfering RNAs (JNJ-3989, Elebsiran)	Phase 2 & 3	Subcutaneous. Every 4 weeks. JNJ 100 mg, Elebsiran 200 mg	Silence HBV genomic RNA, reducing viral replication and protein production, indirectly affecting HDV by reducing the supply of HBV envelope proteins required for HDV virion assembly

HDV: Hepatitis D virus; HBV: Hepatitis B virus; HBsAg: HBV surface antigen; NTCP: Sodium taurocholate co-transporting peptide.

Pegylated interferon-alpha

For many years, pegylated interferon-alpha (PEG-IFNα), has been the standard of care for chronic hepatitis D[7]. It works by modulating the immune response but is associated with significant limitations. The response rate is approximately 20%-30%[8,9]. Treatment typically lasts 48 weeks[10]. It is associated with significant adverse effects, limiting its tolerability. Significant side effects include flu-like symptoms, cytopenias, and neuropsychiatric complications, which limit its use. There is a substantial risk of post-treatment relapse[11]. The virologic response at week 24 (negative HDV RNA) can predict long-term response rates[12]. Despite these limitations, studies have shown that HDV RNA suppression with PEG-IFNα treatment correlates with improved clinical outcomes and a lower risk of developing complications in the long run[13]. The limited efficacy and poor tolerability of PEG-IFNα have spurred research into alternative and more targeted therapies.

PEGYLATED INTERFERON LAMBDA

Pegylated interferon Lambda acts on interferon-lambda (Type III) receptors predominantly expressed in hepatocytes, inducing antiviral responses with potentially fewer systemic side effects compared to PEG-IFNα[14]. This was explored as an alternative to PEG-IFNα due to its more targeted action. A phase 2 study showed promising results, with significant reductions in HDV RNA levels. However, eight out of 33 patients suffered from hyperbilirubinemia, and treatment was discontinued[15]. A phase 3 trial (LIMT-2) was discontinued due to safety concerns, specifically hepatobiliary events and liver decompensation in some patients[16].

BULEVIRTIDE

Bulevirtide, formerly known as myrcludex-B, represents a significant breakthrough in treating chronic HDV infection. In July 2020, the European Medicines Agency granted conditional marketing authorization for bulevirtide for the treatment of chronic HDV infection in adult patients with compensated liver disease at a dose of 2 mg subcutaneously daily[17]. It was the first approved specific anti-HDV treatment. Bulevirtide is a myristoylated peptide and mimics a region of the pre-S1 HBsAg, which is recognized by NTCP receptor on the hepatocyte surface to allow HBV and HDV entry. The drug blocks viral entry by inhibitory competition and decreases the number of HDV-infected hepatocytes[18,19]. So, the drug prevents the virus from infecting new cells. Bulevirtide therapy is safe and well tolerated through 48 weeks of treatment[20].

A Phase Ib/II (MYR-201) study evaluated the safety and efficacy of bulevirtide at a dose of 2 mg/day. It involved 24 patients with chronic hepatitis delta, randomized into three arms: Bulevirtide monotherapy, bulevirtide combined with PEG-IFNα, and PEG-IFNα monotherapy. The study demonstrated that bulevirtide was well tolerated, and serum HDV RNA levels declined in all patients treated with bulevirtide. Notably, the combination of bulevirtide and PEG-IFNα resulted in undetectable HDV RNA at the end of therapy in 5 out of 7 patients. However, there was no significant decline in serum HBsAg levels[21].

A Phase II (MYR-202) study involved 120 patients treated with tenofovir and randomized to receive different doses of bulevirtide (2, 5, or 10 mg/day) or tenofovir monotherapy for 24 weeks[22]. About half of the patients had compensated cirrhosis. The study observed a dose-dependent reduction in HDV RNA and ALT levels, with virological response (2 Log reduction or undetectable HDV RNA) rates of 54%, 40%, and 77% for the 2, 5, and 10 mg bulevirtide groups, respectively. At week 48, an HDV RNA relapse occurred in 60%, 80%, and 83% of end-of-treatment HDV RNA responders in the bulevirtide 2, 5, and 10 mg/day treatment arms, and was associated with a moderate increase in ALT levels, highlighting the need for longer treatment durations.

A Phase 2 multicenter, open-label randomized trial (MYR203) assessed the efficacy and safety of bulevirtide or PEG-IFNα as monotherapy or a combination of bulevirtide with PEG-IFNα or tenofovir over 48 weeks, with an additional 24 weeks of follow-up. Sixty patients with chronic HBV/HDV co-infection were randomized into 4 treatment arms. The study showed that 48 weeks of bulevirtide treatment, either as monotherapy or in combination with PEG-IFN-α, led to significant HDV RNA decline with improvement in biochemical disease activity. Importantly, this study demonstrated the potential for a functional HBV cure alongside sustained HDV RNA suppression[23]. MYR204, a phase IIb study, showed that the combination of BLV with PEG-IFNα resulted in a more profound decline of HDV RNA, independently of the BLV dose, compared to either monotherapy, and was superior to bulevirtide monotherapy concerning an undetectable HDV RNA level at 24 weeks after the end of treatment[24].

The Phase 3 MYR301 trial, investigating longer treatment duration, has shown sustained virological response and biochemical improvement in interim analyses. The 96-week data from the Phase 3 MYR301 trial demonstrated sustained virological response in patients receiving a 2 mg or 10 mg daily dose, and improved biochemical response rates. Combined response (virological and biochemical) at 48 weeks was seen in 45% of treated patients with 2 mg and 48% of patients treated The with 10 mg subcutaneous daily doses[25]. Of 150 patients, 143 (95%) completed 96 weeks of the study. Of the patients with a suboptimal early virologic response at 24 weeks, 43% of non-responders and 82% of partial responders achieved virologic response at 96 weeks[26]. Both dose levels were well tolerated, and the study highlighted the potential for long-term treatment benefits. There were improvements in physical and hepatitis-related quality of life domains compared with those who did not receive therapy[27]. The MYR301 trial is collecting up to three years of data on treatment with bulevirtide, which will provide crucial insights into its long-term efficacy and safety profile.

A real-world study of a large cohort of patients with compensated cirrhosis (n = 244) showed that bulevirtide 2 mg/day monotherapy for up to 96 weeks was safe and effective (week 96: 79% virological, 64% biochemical, and 54% combined response). A retrospective study of 19 patients with liver Child-Pugh B decompensated cirrhosis showed similar virological and biochemical responses with off-label bulevirtide as observed in compensated liver disease[28]. NTCP polymorphisms may influence HDV RNA load and early response to bulevirtide[29].

BULEVIRTIDE WITH PEGYLATED INTERFERON

The combination of 10-mg bulevirtide plus PEG-IFNα was superior to bulevirtide monotherapy, considering an undetectable HDV RNA level at 24 weeks after the end of treatment. At 24 weeks after the end of the 48-week treatment, HDV RNA was undetectable in 12% of those in the 10-mg bulevirtide group, 17% of the patients in the PEG-IFNα group, 32% of those in the 2-mg bulevirtide plus PEG-IFNα group, and in 46% of those in the 10-mg bulevirtide plus PEG-IFNα group[24]. Phase II and phase III studies have demonstrated the safety and enhanced efficacy when combined with PEG-IFNα[17].

HUAHUI HH003

Huahui HH003 is a human monoclonal antibody targeting the preS1 domain of the large envelope protein of HBV and HDV. It prevents the binding of preS1 to NTCP, the cellular receptor for HBV and HDV, thereby blocking viral infection and re-infection of hepatocytes. In an open-label, phase 2 trial, adult patients (n = 9) were enrolled. The study showed favorable safety and tolerability, along with encouraging antiviral activity. HH003 significantly decreased HDV RNA levels and normalized ALT[30]. The drug received Breakthrough Therapy Designation in November 2024. NCT05861674, a Phase IIb study of HH003 in subjects with chronic HDV infection, has completed the treatment phase[31]. Treatment Group 1 received HH-003 20 mg/kg once every two weeks by intravenous infusion plus tenofovir alafenamide (TAF) for 48 weeks. The dose of HH-003 in Group 2 was 10 mg/kg, while the Control Group received TAF only. Now these patients are in the follow-up period.

TOBEVIBART

Tobevibart VIR-3434 is a potent monoclonal antibody that binds the antigenic loop of HBsAg. The drug inhibits the entry of hepatitis B and D viruses into naïve hepatocytes and reduces circulating HBsAg[32]. It works against all genotypes of hepatitis B and D. The drug is now being studied in combination with Elebsiran in the ECLIPSE program as discussed in the coming sections

LONAFARNIB

Lonafarnib, a prenylation inhibitor, represents another novel approach to HDV treatment. Inhibiting farnesyltransferase prevents the prenylation of HDV large antigen, which is essential for viral assembly and release. Lonafarnib boosted with low-dose ritonavir is a promising all-oral therapy, and maximal efficacy is achieved with PEG-IFNα addition[33]. The treatment was generally well-tolerated when administered with ritonavir.

The D-LIVR study was a pivotal multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial investigating lonafarnib-based treatments for chronic HDV infection[34]. This was the largest HDV trial ever conducted, with 407 patients enrolled across more than 100 sites globally. The treatment duration was 48 weeks with a 24-week follow-up. There were four treatment arms: (1) Oral lonafarnib 50 mg BID + ritonavir 100 mg BID (n = 178); (2) Lonafarnib 50 mg BID + ritonavir 100 mg BID + PEG-IFNα (n = 125); (3) PEG-IFNα alone (n = 52); and (4) Placebo (n = 52). The primary endpoint was a composite endpoint at week 48 i.e., undetectable HDV RNA or ≥ 2 Log decline from baseline and normalization of ALT. The composite endpoint did not meet statistical significance in this study. In the Lonafarnib + Ritonavir arm, 14.6% of patients achieved ≥ 2 Log decline at 48 weeks, while in the Lonafarnib + Ritonavir + PEG-IFNα arm 32% of patients achieved ≥ 2 Log decline, and in the PEG-IFNα monotherapy 36.5%. Normalization of ALT was better in the triple combination (34.4% vs 24.7% in the oral arm), and so was the histological improvement (53% vs 33%). The most common adverse events were gastrointestinal symptoms. Therapy was discontinued in a significant number of patients: Lonafarnib + ritonavir 11.8%, triple combination 20.1%, PEG-IFNα 10.2%, and placebo 3.9%. There was a limited sustained response after treatment discontinuation (24 weeks post-treatment). Higher relapse rates were in monotherapy arms, and a need for maintenance therapy was identified.

NUCLEIC ACID POLYMERS

Nucleic acid polymers (NAPs) block HBV entry, subviral particle formation, and release of HBsAg, resulting in clearance of HBsAg and reduction or clearance of HBV DNA. NAPs block the production of HDV derived from a subviral particle-related assembly mechanism[35]. A phase 2 open-label clinical study evaluated REP 2139-Mg, a NAP, in patients with chronic HBV/HDV co-infection[36]. Patients received 500 mg REP 2139 intravenously weekly for 15 weeks, followed by a combination of REP 2139 250 mg and PEG-IFNα 180 μg subcutaneously once per week for 15 weeks, then monotherapy with PEG-IFNα continued for another 33 weeks (total duration of study 63 weeks). One year post-treatment, HBsAg was < 50 IU/mL in 5/12, HDV RNA was still negative in 7/12, and ALT was normal in 9/12. This combination treatment approach may provide a new option for HDV-infected patients.

RNA INTERFERENCE-BASED THERAPIES

Several RNA interference approaches are under investigation that inhibit the production of HBV proteins, including HBsAg, by targeting its RNA, which is crucial for HDV viral assembly and propagation. A phase 2 trial of JNJ-3989, a small inhibitory RNA (siRNA), has shown promising results in reducing HBsAg levels in REEF-2 study[37]. Elebsiran or VIR-2218 is another N-acetylgalactosamine-conjugated siRNA molecule. Elebsiran was evaluated in combination with PEG-IFNα in a Phase 2 open-label study (MARCH Study). 84 patients were enrolled. The trial design included multiple cohorts evaluating different combination sequences. The primary endpoint was HBsAg reduction at week 48. Results showed enhanced HBsAg reduction with combination therapy, Improved immunological responses, and an acceptable safety profile in combination[38]. As there is a significant decline in HBsAg levels with a potential indirect effect on HDV viral load, Elebsiran is now being tried in HDV patients

TOBEVIBART AND ELEBSIRAN COMBINATION

In an ongoing phase 2 SOLSTICE study, tobevibart 300 mg with elebsiran 200 mg were given subcutaneously once every 4 weeks up to 96 weeks. The response was compared with the tobevibart monotherapy cohort. Trial endpoints included virologic response and ALT normalization at week 24. High rates of virologic suppression were achieved in participants receiving tobevibart alone, or in combination with elebsiran, with > 50% achieving undetectable HDV RNA in the combination cohort. ALT normalization was > 50% at week 24 in both tobevibart monotherapy and combination cohorts. No treatment-related serious adverse events or ALT flares were observed[39].

ECLIPSE is a clinical trial program starting in 2025 and investigating a novel therapeutic approach for chronic HDV infection, evaluating a combination of tobevibart and elebsiran. The combination therapy will act by targeting HBsAg production, removing circulating HBsAg, and inhibiting viral entry[40]. The clinical trials will evaluate a monthly dosing regimen and compare it against the current standard of care, and will potentially offer a new treatment option for chronic HDV patients. During these trials, reductions in HDV RNA levels will be measured, and normalization of ALT levels will be documented. The safety profile of the combination therapy, including the incidence of adverse events, will be monitored.

The ECLIPSE program consists of three main trials. Each trial is designed to assess different aspects of the combination therapy's efficacy and safety: ECLIPSE 1 and 2 are pivotal Phase 3 trials, while ECLIPSE 3 will provide additional supportive data. ECLIPSE 1 Compares the efficacy and safety of the tobevibart and elebsiran combination against deferred treatment in regions where bulevirtide is still not available, like the United States, or its use is limited. ECLIPSE 2 focuses on patients who have not achieved adequate viral suppression with bulevirtide therapy. ECLIPSE 3 is a Phase 2b head-to-head trial comparing the combination therapy with bulevirtide in bulevirtide-naïve patients.

Challenges and future perspectives

Despite the progress in HDV treatment research, several significant challenges remain[41]. HDV is often underdiagnosed due to the lack of standardized and accessible diagnostic tests. There is no universal screening recommendation, leading to potential underestimation of HDV prevalence. The limited access to diagnostic tools and the absence of systematic screening programs, particularly in low and middle-income countries, create significant epidemiological data gaps. HDV exhibits considerable genetic diversity, complicating the development of universal treatment strategies. The complex interaction between HDV, HBV, and the host immune system is not fully understood, impeding the development of targeted therapies. Since HDV replication relies on HBsAg, concurrent suppression of HBV with nucleos(t)ide analogs along with novel HBV-targeting agents may play a critical role in improving outcomes.

Recent trials have faced hurdles, including long-term safety concerns, duration of treatment, durability of virological response, and risk of relapse. Future research will be focused on the role of combination therapy, the place of maintenance therapy to prevent cirrhosis, and the impact of early treatment on clinical outcomes (e.g., cirrhosis and hepatocellular carcinoma). Ongoing research should also focus on the real-world effectiveness of new therapies, strategies to overcome financial and logistical barriers to treatment, develop biomarkers to predict treatment response and guide personalized therapy, the emergence of resistance, and relapse after treatment discontinuation. Consideration of baseline viral load and the importance of adherence support may affect the treatment outcome. The cost of treatment is high with limited accessibility, especially in resource-poor settings where HDV is more prevalent. Early treatment is warranted before cirrhosis development. Many therapies, including bulevirtide, are approved only for patients with compensated liver disease, leaving those with decompensated cirrhosis with limited options.

CONCLUSION

The landscape of hepatitis D treatment is rapidly evolving, with several promising therapeutic approaches under investigation. Viral entry inhibitors, including bulevirtide, represent a significant step forward, offering hope for improved management of this severe viral infection. However, the need for new therapeutic approaches remains urgent, given the limitations of current treatments and the severe progression of the disease. New treatment combinations will potentially improve patient outcomes. The ongoing studies will contribute to the development of standardized treatment protocols that can be adopted globally, enhancing the management of hepatitis D. Future research should focus on expanding epidemiological research, improving diagnostic capabilities, developing more effective and tolerable treatments, and further exploring combination therapies to enhance treatment efficacy, the research should also address the challenges of genetic diversity in HDV including genotypes and investigate the long-term outcomes of novel therapies. Continued research, international collaboration, and innovative approaches are essential to overcome the current barriers and improve outcomes for patients with HDV. As our understanding of the virus and its interactions with HBV and the host immune system deepens, we can hope for more targeted and effective treatments in the future.