Advances in treatment of hepatitis delta virus infection: Update on novel investigational drugs

Abstract

Chronic hepatitis delta virus (HDV) represents a rare but important co-infection in approximately 5% of patients with chronic hepatitis B virus (HBV) infection, and is associated with significant morbidity and mortality due to an increased risk for liver cirrhosis, liver failure, and hepatocellular carcinoma relative to HBV monoinfected individuals. The current treatment of chronic HDV infection includes the off-label use of pegylated interferon (IFN), which is limited by poor safety, tolerability, and efficacy. Guidelines of the major international liver organizations such as the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Asian Pacific Association for the Study of the Liver provide recommendations for contemporary diagnosis and management of chronic HDV infection, including the incorporation of bulevirtide, a newly licensed antiviral agent in Europe. Significant unmet medical needs remain in the treatment of HDV, and recent advances in drug development offer hope for meaningful advances in drug therapy which may improve virologic response rates and clinical outcomes. This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel IFNs (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139), and addresses future directions in HDV pharmacotherapy.

Key Words: Hepatitis D virus; Antiviral therapy; Interferon; Bulevirtide; Tobevibart; Elebsiran; Guidelines; Clinical trials

Core Tip: Current treatment of hepatitis delta virus (HDV) infection with off-label use of pegylated interferon (Peg-IFN) is limited by poor efficacy and safety. Guidelines of major international liver societies including the American Association for the Study of Liver Diseases, European Association for the Study of Liver and Asian Pacific Association for the Study of the Liver provide recommendations for contemporary management of HDV infection with Peg-IFN and/or bulevirtide. Significant unmet medical needs remain in the treatment of HDV and recent advances in drug development offer hope for significant improvement in virologic response rates and clinical outcomes. This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel interferons (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139), and report important advances with monotherapy and combination regimens which are associated with high rates of virologic response.

INTRODUCTION

Hepatitis delta virus (HDV) is a RNA virus with an estimated global prevalence of 4.5% among patients with hepatitis B virus (HBV) or approximately 12 million persons worldwide and an estimated prevalence of 4.6% in the United States[1,2]. Prevalence varies by region, with rates of 3% in Europe and 6% in Africa among HBV surface antigen (HBsAg)-positive individuals[1]. Patients who are infected with HDV often have a more severe clinical course with increased rates of hepatocyte necrosis and fulminant hepatitis, and chronic hepatitis D (CHD) significantly increases the risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma compared to HBV monoinfection[3,4]. Despite this, HDV is underdiagnosed in the United States and unfamiliar to many patients. Most critically, no FDA-approved therapies are available for HDV in the United States, and treatment has largely relied on off-label use of interferon (IFN) α or pegylated IFN (Peg-IFN) α2a which achieve modest efficacy, with viral response rates of 23%-57% after 24 weeks of treatment[5]. The European Medicines Agency (EMA) granted bulevirtide, a synthetic lipopeptide that prevents HDV from entering into hepatocytes, conditional marketing authorization in July 2020 and full marketing authorization in May 2023[6]. Fortunately, novel therapies are in the pipeline and have shown promise for the effective treatment of HDV. This review aims to summarize the current therapeutic options in development and provide clinicians, researchers, and both industry and policy stakeholders with an overview of the future paradigm of HDV management.

CURRENT TREATMENT

Peg-IFN alpha

For over 20 years, the only treatment available for HDV was Peg-IFN. The first documented use of IFN α for the treatment of HDV was reported by Rizzetto et al[7] in 1986 in the Journal of Hepatology. In 1994, a landmark study by Farci et al[8] treated a cohort of 14 patients with HDV infection with recombinant IFN α2a (9 million IU SC three times per week), recombinant IFN α2a (3 million IU SC three times per week), or no treatment for 48 weeks and reported normalization of serum alanine aminotransferase (ALT) in 10 patients, 3 patients, and 1 patient, respectively. Seven patients who received recombinant IFN α2a (9 million IU SC three times per week) achieved an undetectable HDV RNA. After cessation of treatment, five patients demonstrated a persistent biochemical response. In a follow up study[9], Farci et al[8] noted that with more sensitive HDV-RNA assays, all of the patients previously believed to have achieved an undetectable HDV RNA were confirmed to have positive HDV RNA. However, patients who achieved a virologic response with high dose of IFN α were reported to achieve higher rates of improvement in histological activity and long-term survival compared to untreated controls. Subsequent trials which have examined the use of Peg-IFN α in patients with HDV have demonstrated virologic response rates in 23% to 57% of patients[10-14].

The exact mechanism of Peg-IFN on HDV is yet unknown. Studies suggest that Peg-IFN inhibits the entry and assembly of HDV.15 Intrinsic HDV-induced IFN responses may suppress cell division-mediated HDV spread, but this is enhanced by exogenous IFN treatment, which may interfere with HDV entry into hepatocytes and inhibit HDV particle assembly and release, with the greatest effect observed among individuals with lower HDV titers at baseline[15]. Furthermore, HDV evades the body’s ability to recognize infection by counteracting host immune response[16]. Even in patients who initially respond to Peg-IFN, late virologic relapse is common, highlighting the inability of Peg-IFN to induce sustained immune control[14]. Moreover, Peg-IFN is associated with significant adverse effects, including bone marrow suppression, psychiatric decompensation, skin reactions, constitutional symptoms, and other autoimmune phenomenon, which contribute to poor tolerability and efficacy[10,12].

Oral nucleos(t)ide analogues (NA) such as adefovir or tenofovir disoproxil fumarate (TDF) are commonly prescribed for the treatment of chronic HBV in context of co-infection, but lack direct virological efficacy against HDV. As HDV relies on HBsAg for replication, it was hypothesized that suppressing HBV replication with NA may reduce HDV viremia. Unfortunately, the Hepatitis Delta International Intervention Trials (HIDIT-1 and HIDIT-2) confirmed that NA treatment with adefovir or TDF is not associated with improved virologic response for HDV infection[12,17]. Notably, late HDV RNA relapses were reported up to five to 10 years after treatment[14,18].

The HIDIT-1 study examined the role of Peg-IFN (180 μg SC weekly × 48 weeks) for the treatment of patients with HDV, with or without adefovir, and revealed that 24 weeks post-therapy, 28% of patients achieved undetectable HDV RNA level and 40% of patients achieved normalization of serum ALT[12]. Longer treatment periods have been suggested as a potential strategy to promote higher rates of HDV RNA undetectability and HBsAg loss. The HIDIT-2 study explored treating patients with HDV with a 96-week course of Peg-IFN α 2a with or without TDF[17]. In this cohort, 48% and 33% of patients who received Peg-IFN α 2a plus TDF and Peg-IFN α 2a alone, respectively, achieved undetectable HDV RNA at the end of the treatment period[17]. This study confirmed that the longer treatment period was associated with a marginal increase in HDV RNA response rate; however, reduced liver fibrosis on histological analysis was observed.

The strategy of extending treatment for longer than one year has been explored, and in 1998, a case report of a patient with HDV who lost HBsAg after 12 years of IFN α treatment was reported by the National Institute of Health (NIH)[19]. Smaller studies extending treatment to 2 years have been reported[20,21]. At the NIH, 13 patients were treated with Peg-IFN α for a median of 140 weeks and three patients reached undetectable HDV RNA and HBsAg seroconversion after 24, 37 and 202 weeks of treatment[22]. However, in several patients, extended treatment was not well tolerated. In conclusion, the strategy of prolonged treatment is possible and may be beneficial in a subset of patients.

The American Association for the Study of Liver Diseases (AASLD)[23], European Association for the Study of the Liver (EASL)[10], and Asian Pacific Association for the Study of the Liver (APASL)[24] all recommend considering treatment of patients with HDV with Peg-IFN α. AASLD, EASL, and APASL recommends a 12 month, 12-18 month, and 48 week course respectively. EASL also recommends the consideration of treatment with bulevirtide 2 mg daily as long-term therapy or a combination of Peg-IFN α and bulevirtide. A summary of these recommendations is provided in Table 1. All societies note that treatment should be individualized to the patient, risk factors, HBsAg status, and HDV RNA levels. Given the poor response to current therapy, all societies highlight the urgent need for new therapeutic agents to improve virologic response rates for patients with HDV.

Table 1 Current global society recommendations for hepatitis delta virus treatment.

Society	Therapy	Length of therapy
AASLD	Peg-IFN α	12 months
APASL	Peg-IFN α	12-18 months
EASL	Peg-IFN α for 48 weeks (finite therapy)
	Or Bulevirtide 2 mg daily (long term therapy)
	Or Peg-IFN α + Bulevirtide

AASLD: American Association for the Study of Liver Disease; APASL: Asia-Pacific Association for Study of Liver; EASL: European Association for the Study of the Liver; Peg-IFN: Pegylated interferon.

NOVEL THERAPIES

There are several pharmacological mechanisms that have been targeted by emerging investigational agents to achieve suppression of HDV RNA. These include: Entry inhibition, in which the agent blocks a receptor to prevent viral entry into the hepatocyte; prenylation inhibition, in which the agent inhibits prenylation of the large HDV antigen (L-HDAg) required for viral assembly; immunomodulators, including IFNs which enhance antiviral immune responses; HBsAg target drugs, in which the agent reduces HBsAg levels to impair viral assembly and release; RNA interference, in which the agent is used to degrade HBV RNA transcripts which are required for HDV replication; active site polymerase inhibitors, which are nucleotides which inhibit the HBV polymerase; and monoclonal antibodies, including a fully human monoclonal antibody that targets HBsAg. A summary of the novel therapies in phase II and III development are listed in Table 2.

Table 2 Novel therapeutic agents for hepatitis D infection in phase II or III development.

Therapeutic class	Therapeutic agents	Drug sponsor	Phase
Entry inhibitors	Bulevirtide	Gilead	III
	HH-003[61]	HuaHei	II
Prenylation inhibitor	Lonafarnib	Eiger InnoTherapeutics	III
Immunomodulators	Peginterferon Lambda	Eiger InnoTherapeutics	II
	Ropeg-IFN α2b (P1101)[62,63]	PharmaEssentia	II
HBsAg target drugs	REP 2139	Replicor	II
RNA interference molecule	JNJ-73753989 (JNJ-3989)	GlaxoSmithKline Pharmaceuticals	II (for HBV)
	Elebsiran (VIR-2218)[54,55]	Vir Biotechnology	II (for HBV, HDV)
	RBD 1016[64]	Ribocure	II
Active site polymerase inhibitor	ATI-2173[65]	Antios	II (terminated)
Monoclonal antibody	BJT-778[60]	Bluejay	II
	Tobevibart (VIR-3434)[54,55]	Vir Biotechnology	II

HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HDV: Hepatitis delta virus.

ENTRY INHIBITORS

Bulevirtide

Bulevirtide is an entry inhibitor currently in phase 3 of clinical trials in the United States and is the only approved therapy for HDV in Europe[25]. It is a synthetic lipoprotein that inhibits the sodium taurocholate co-transporting polypeptide (NTCP) which prevents HBV and HDV from entering hepatocytes and is administered as a daily subcutaneous injection[26]. Phase 2 and 3 clinical trials (MYR 303) have shown to reduce HDV RNA levels and ALT[6,27]. Overall, bulevirtide has been shown to be well-tolerated with the most common side effect being local injection site reactions[28]. However, adverse effects have been reported, including fatigue, nausea, and pruritus, as well as increased bile salt and aminotransferase levels[28]. NTCP is a bile acid transporter and its inhibition by bulevirtide leads to increased serum bile salt concentrations, often reaching 3- to 5-fold above the normal range[28,29]. The increase of bile salts during bulevirtide treatment is not correlated with decreased HDV viral levels[29]. While the clinical significance of bile salt elevation remains uncertain, the long-term implications of this observation will require further elucidation in future clinical trials and real-world observational cohort studies.

In a multicenter phase 2 clinical trial MYR202[28], patients were randomized into three bulevirtide doses (2 mg, 5 mg or 10 mg once daily) or TDF monotherapy for 24 weeks. The primary endpoint was a ≥ 2 Log₁₀ IU/mL decline of HDV RNA levels at 24 weeks, which was achieved in 54%, 50%, and 77% of patients treated with bulevirtide at increasing doses. However, patients on TDF monotherapy reached the primary endpoint in only 3% of patients. In addition, 43%, 50%, and 40% of patients normalized ALT in patients treated with bulevirtide 2, 5, and 10 mg once daily, respectively, compared with 6% of patients on TDF monotherapy. A composite endpoint of ≥ 2 Log₁₀ IU/mL decline in HDV RNA levels and ALT normalization was achieved in 21%, 28%, 37%, and 0% of patients treated with 2, 5, and 10 mg/day of bulevirtide and TDF monotherapy, respectively. However, 24 weeks after cessation of bulevirtide treatment, HDV RNA levels rebounded in a majority of patients.

The MYR203 study[30] evaluated the combination of bulevirtide 2 mg, 5 mg, or 10 mg with Peg-IFN α 2a or bulevirtide 10 mg with TDF for 48 weeks. Results showed that 24 weeks after completion of treatment, patients achieved HDV RNA below the level of detection in 0%, 53.3%, 26.7%, 6.7%, 6.7%, and 33% when treated with Peg-IFN α 2a only, 2 mg of bulevirtide with Peg-IFN α 2a, 5 mg of bulevirtide with Peg-IFN α 2a, 2 mg of bulevirtide only, 10 mg of bulevirtide with Peg-IFN α 2a, and 10 mg of bulevirtide with TDF respectively. Post treatment, 20% of patients who received 2 mg of bulevirtide and Peg-IFN α 2a reached undetectable HBsAg levels. The combination of bulevirtide and peg-IFN is associated with highest reported rate of sustained virologic response in the treatment of HDV infection.

Furthermore, the MYR204 study[31] examined treatment outcomes in patients receiving Peg-IFN α 2a monotherapy for 48 weeks; bulevirtide 2mg or 10 mg daily with Peg-IFN α 2a weekly for 48 weeks, then bulevirtide at same dose for 48 weeks; or 10 mg of bulevirtide for 96 weeks. 24 weeks after the end of treatment, 46% of patients who received 10mg of bulevirtide plus Peg-IFN α 2a had persistently undetectable HDV RNA vs 12% of patients treated with 10 mg of bulevirtide alone.

PRENYLATION INHIBITOR

Lonafarnib

Lonafarnib inhibits farnesyltransferase, an enzyme that prenylates the L-HDAg, which is essential for viral assembly and secretion of HDV, inhibiting the production of the virus[32].

Lonafarnib is also in phase 3 clinical trials. It has been shown to be effective in stopping HDV. The LOWR HDV-1 study[33] compared lonafarnib monotherapy to combination therapy of lonafarnib with Peg-IFN or ritonarvir. In patients on lonafarnib monotherapy, higher dosages achieved greater decreases in HDV viral load; however, it was also associated with greater gastrointestinal effects such as nausea, diarrhea, and weight loss. Lonafarnib is metabolized by CYP3A4, and ritonavir is a CYP3A4 inhibitor[33]. By combining lonafarnib with ritonavir, lonafarnib plasma levels were increased on a lower dose, resulting in better anti-viral effects and reduced adverse effects compared to lonafarnib monotherapy[33]. This was also seen when Peg-IFN α was combined with lonafarnib. LOWR-2[34] looked at the optimal combination of lonafarnib and ritonavir with and without Peg-IFN α. It shows the combination of lonafarnib (25 mg or 50 mg) with ritonavir and Peg-IFN α has the most robust antiviral activity[35]. LOWR-3[36] and LOWR-4[37] looked at dose-escalation therapy with lonafarnib and ritonavir.

The current phase 3 clinical trial (D-LIVR)[38] is evaluating the safety and efficacy of lonafarnib-based regimens such as lonafarnib with ritonavir and lonafarnib with ritonavir and Peg-IFN-α2a for 48 weeks. Top-line results confirmed that 19.2% of patients receiving triple therapy, 10.1% of patients receiving lonafarnib with ritonavir, 9.6% of patients receiving Peg-IFN-α2a alone, and 1.9% of patients receiving placebo reached both HDV RNA decrease of ≥ 2 Log₁₀ IU/mL and ALT normalization 48 weeks after treatment[39]. However, more importantly, patients who received either triple or double combination therapies had statistically significant improvements in histology compared to patients who received Peg-IFN-α2a only or placebo.

IMMUNOMODULATORS

Peg-IFN-λ

Peg-IFN-λ is an immunomodulator that binds to the type III IFN receptor complex, leading to the induction of IFN-stimulated genes, inhibiting viral replication[40]. By specifically targeting type III IFN receptors, which are expressed primarily on hepatocytes and certain immune cells, patients have fewer systemic side effects than those that target the type I IFN receptor. In phase 2 LIMT-1 trial[41], 16% and 36% of patients receiving 120 and 180 μg/week of Peg-IFN-λ respectively achieved HDV RNA levels below the limit of quantification 24 weeks post-treatment. 11% and 14% of patients on 120 and 180 μg/week of Peg-IFN-λ respectively reached ALT normalization 24 weeks post-treatment. 51.5% of patients experienced an adverse effect such as hyperbilirubinemia leading to dose interruption, reduction or discontinuation. Other side effects included fatigue, headache and nausea. In the phase 3 LIMT-2 trial, patients with CHD received either Peg-IFN-λ 180 μg weekly for 48 weeks or no treatment for 12 weeks followed by Peg-IFN-λ for 48 weeks. However, this trial was discontinued in 2023 due to four patients who experienced hepatobiliary events which resulted in liver decompensation[42].

The Lambda IFN combo Therapy (LIFT) study[43] looked at the combination of lonafarnib, ritonavir, and Peg-IFN-λ and found 78% of patients taking this combination therapy had ≥ 2 Log₁₀ IU/mL decrease in HDV RNA levels; however, only 12% of patients continued to have undetectable HDV RNA at both 12 and 24 weeks post therapy[35]. This emphasizes the difficulty of achieving cure.

HBSAG TARGET DRUGS

Nucleic acid polymers

Nucleic acid polymers are phosphorothioate oligonucleotides that inhibit the assembly and secretion of subviral HBsAg particles from hepatocytes[44]. These agents reduce the circulating HBsAg levels and indirectly inhibit HDV replication and virion formulation as HDV relies on HBsAg to form its envelope.

REP 2139 is in phase 2 clinical trials. The REP 301 clinical trial[45] was a non-randomized, open label, phase 2 clinical trial that looked at patients who received 500 mg weekly of REP 2139 intravenously for 15 weeks, followed by a combination therapy with 250 mg REP 2139 and 180 μg Peg-IFN α2a weekly for 15 weeks, then 180 μg Peg-IFN α2a weekly for 33 weeks. 91.6% of patients became HDV RNA negative during treatment with 75.0% of patients remaining HDV RNA negative at the end of the treatment, and 58.3% remaining HDV RNA negative at 1 year follow up. Serum aminotransferases normalized in 75.0% of patients. However, all 12 patients in the study experienced adverse events including anemia, neutropenia, thrombocytopenia, elevated aminotransferases, and hyperbilirubinemia.

The REP 401 study[46] compared the safety and efficacy of REP 2139-Mg and REP 2165-Mg both in combination with TDF and Peg-IFN-α2a in patients with chronic hepatitis B (CHB). In chronic HBeAg negative HBV and HDV coinfection, the HBsAg decline during REP 2139-Ca and Peg-IFN treatment was accompanied by HDV RNA loss, and 58.3% of patients had persistent undetectable HDV RNA for 2 years.

RNA INTERFERENCE MOLECULES

JNJ-73753989 (JNJ-3989)

JNJ-73753989 or JNJ-3989 is a short-interfering RNA (siRNA) that binds to the RNA-induced silencing complex which degrades HBV RNA transcripts[47], and was developed with the aim of achieving functional cure of CHB, as defined by HBsAg loss (HBsAg < 0.05 IU/mL) and undetectable HBV DNA 24 weeks post end of treatment. JNJ-3989 significantly reduces all HBV proteins including pregenomic RNA, HBsAg, hepatitis B e antigen and HBV DNA[47], and by lowering HBsAg levels, JNJ-3989 may indirectly inhibit HDV replication by impairing the assembly and secretion of HDV virions. JNJ-3989 is conjugated to N-acetylgalactosamine (GalNAc) ligands for targeted delivery to hepatocytes.

Results from phase 2a and 2b clinical trials show JNJ-3989 reduces HBsAg in patients with CHB[47]. 97.4% of patients who received JNJ-3989 every four weeks had ≥ 1 Log10 IU/mL decrease of HBsAg levels from baseline with no reported serious adverse events[48]. The most common treatment-related adverse events were injection site reactions[48]. The two-part REEF-D[49] trial evaluated patients with CHD treated with 100mg JNJ-3989 every 4 weeks with nucleos(t)ide analogs for up to 144 weeks. Preliminary interim data looking at 48 weeks showed patients treated with JNJ-3989 experienced a greater decrease in HDV RNA compared to placebo, and 23.5% of patients achieved both ≥ 2 Log₁₀ IU/mL decrease in HDV RNA levels and ALT normalization. However, 71% of patients experienced ALT elevations starting around week 8 and 20 during which HDV RNA rebounded, leading to treatment discontinuation[49]. This led to the exclusion of patients with liver cirrhosis and with both HBsAg > 10000 IU/mL and HDV RNA > 100000 IU/mL from part 2 of the study[50]. Besides ALT elevations, no other serious adverse events were observed, including among four patients who continued treatment with JNJ-3989 for up to 144 weeks[50].

Elebsiran (VIR-2218) and Tobevibart (VIR-3434)

Elebsiran is a siRNA molecule designed to target common areas of the HBV genome[35,51]. By reducing HBV RNA, VIR-2218 indirectly suppress HDV replication. It is conjugated to GalNAc ligands, allowing for hepatocyte-specific delivery and enhanced efficacy[35]. In phase 1 and 2 clinical trials, VIR-2218 was shown to decrease HBsAg levels[52].

Tobevibart is a monoclonal antibody that targets an epitope within HBsAg, neutralizing HBV and HDV infection. Preclinical studies in human liver-chimeric mice have demonstrated that VIR-3434 reduces HBsAg levels and HBV and HDV viremia, highlighting its potential as a therapeutic agent for CHB[53].

Elebsiran in combination with tobevibart are in phase 2 clinical trials for treatment of both HBV and HDV[]54-56]. Early data from the SOLSTICE trial[57,58] showed elebsiran-tobevibart combination therapy achieved the greatest and fastest decline of HDV RNA (-4.3 Log₁₀ IU/mL) compared to monotherapy (-1.4 Log₁₀ and -2.0 Log₁₀ IU/mL, elebsiran and tobevibart respectively) and at week 48 of treatment, up to 83% of patients on combination treatment (tobevibart 300 mg SC q2 weeks and elebsiran 200 mg SC q4 weeks) achieved undetectable HDV RNA. No grade 2 ALT elevations have been reported to date with either monotherapy or combination therapy, and approximately 50% of subjects on combination elebsiran-tobevibart achieved ALT normalization by week 24.

DISCUSSION

Currently, there is no FDA approved treatment for HDV, and existing therapies have limited efficacy and are poorly tolerated. Peg-IFN has substantial adverse effects including bone marrow suppression and psychiatric decompensation, which leads to poor patient acceptance and adherence. Furthermore, fewer than 50% of patients who receive Peg-IFN have virological clearance on treatment. Bulevirtide has been studied in phase 2 and 3 trials which confirmed improved efficacy in achieving virologic response for HDV infection on-treatment and improved rates of sustained virologic response off-treatment in combination with peg-IFN. Although given full marketing authorization by the EMA in 2023, bulevirtide was rejected by the United States FDA in 2022, reportedly due to issues with manufacturing and delivery[59]. Unfortunately, this limits potential treatment options for millions of patients living with HDV in the United States.

Investigational therapies have aimed to target various steps in the HDV’s unique replication cycle to achieve viral response. Although many potential therapies have demonstrated ability to suppress HDV RNA, sustained viral response remains a challenging therapeutic endpoint. HDV is often characterized as a “stealth” virus, undermining the body’s own IFN signaling in acute and chronic infections to evade host immune response[16]. Unfortunately, current understanding of the interplay between HDV and the body’s IFN response system remains limited and a priority area for research. Therefore, combination therapies have been examined to improve rates of virologic response. However, no single or combination therapy has been confirmed to achieve high rates of sustained viral response after completion of treatment, although recent data from the MYR204 clinical trial with bulevirtide plus peg-IFN offers encouraging findings. During the interim, several novel therapies including bulevirtide monotherapy[27], elebsiran-tobevibart combination therapy[55], and BJT-778 monotherapy[60] have demonstrated robust antiviral responses as defined by suppression of HDV RNA to undetectable levels on treatment. Independent of sustained virologic response, suppression of HDV RNA and normalization of serum ALT has been associated with histological improvement, and a decreased risk of liver events such as cirrhosis and hepatocellular carcinoma. Ongoing public health efforts to prevent new HDV infection through HBV vaccination remain important in decreasing the epidemiologic burden of chronic HDV[59]. Future research to identify and study novel investigational agents targeting HDV offers great hope for patients with HBV-HDV coinfection who face disproportionate morbidity and mortality, and significant unmet medical need in antiviral treatment[60-65].

CONCLUSION

Although there is currently no FDA approved therapy for the treatment of HDV, multiple investigational therapies are being studied in clinical trials. Available data confirm promising advances in virologic responses with entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel IFNs (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139). Future research is needed to confirm the efficacy and safety of single and combination therapy regimens to clarify optimal treatment approaches and improve clinical outcomes.