IFNs are cytokines and a regular component of the human immune system with intrinsic antiviral properties. The IFNs interact with the cell surface receptors of virus-infected cells, upregulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. This pathway downstream activates multiple IFN-stimulated genes, the products of which have numerous antiviral effects, including, but not limited to, inhibition of viral replication [16]. Pegylation of IFN results in slower clearance, thereby increasing its half-life [17]. IFN is the only class of medication recommended by the American Association for the Study of Liver Diseases (AASLD) HBV treatment guidelines, 2016 [18].

IFNα was the first molecule ever evaluated in the treatment of HDV. Administered subcutaneously at a dose of 9 million units (MU) three times weekly, it achieved approximately a 50% virological and biochemical response at 48 weeks of treatment. However, most of the patients relapsed weeks after cessation of therapy [15]. The unacceptable adverse effect profile, thrice weekly injection schedule, and high relapse rates post-treatment were the significant limitations. Long-term follow-up of IFNα-treated patients has reported better survival rates, lower HDV viral replication, and lower fibrosis rates years after treatment [19].

PEG-IFNα, the advent of which allowed a shift from thrice weekly to once-a-week injection therapy. Trials with PEG-IFNα-2a (180 µg/week) or PEG-IFNα-2b (1.5 µg/kg/week) for 48 weeks to 96 weeks reported HDV-RNA negativity rates of 17% to 46% at 6 months to 12 months post-treatment follow-up [20]. A meta-analysis comprising 13 studies involving 475 patients treated with PEG-IFNα revealed a pooled virological response of 29% and a biochemical response of 33% at 24 weeks post-treatment [21]. The European Association for the Study of the Liver (EASL), 2023 practice guidelines recommend considering PEG-IFN, preferably PEG-IFNα, for 48 weeks to treat chronic HDV infection with compensated liver disease [8]. The treatment limitations include an overall suboptimal response, an adverse effect profile, and the need for parenteral administration of the medication. IFN therapy is not recommended in patients with decompensated liver disease. Also, IFN treatment has been linked with the onset of autoimmune hepatitis [8].

PEG-IFNλ has demonstrated antiviral effects with a more favorable adverse effect profile compared to PEG-IFNα. The IFNλ receptor is preferentially expressed in the liver, lung, and gut, compared to the ubiquitous expression of the IFNα receptor, which explains its better adverse effect profile [22]. Human liver chimeric mouse model studies have reported reduced intrahepatic HDAg and HDV RNA levels with PEG-IFNλ, which are comparable to those observed with PEG-IFNα [23]. The LIMT-1, phase II trial, with PEG-IFNλ, reported a 24-week post-treatment virological response of 36% and 16%, respectively, with subcutaneous injections of 180 µg/week and 120 µg/week, for 48 weeks. Hepatobiliary adverse effects requiring drug interruption was encountered with both dosages in this trial [24]. The LIMT-2 phase III trial, which evaluated PEG-IFNλ at 180 µg/week in compensated liver disease, was discontinued in 2023 due to concerns about hepatobiliary complications, which led to hepatic decompensation [25]. Considering the overall mediocre response rates, a narrow therapeutic index, the need for parenteral therapy, and the emergence of safer, novel medications, PEG-IFNλ may be pushed into oblivion in the HDV therapeutic landscape. However, future research may reveal that its immunological effects are beneficial when combined with direct antiviral agents, possibly at a lower dose and in specific patient populations.

Several trials have evaluated the role of nucleos(t)ide analogues (NA) in treating HDV-HBV infection. Lamivudine, famciclovir, entecavir, and tenofovir have been evaluated as monotherapy, with no clinically meaningful response in HDV infection [26–29]. The EASL, 2023 recommends using NA in patients with HBV-HDV infection, guided by the indications for HBV and not targeting HDV [8].

Bulevirtide interacts with the hepatocyte NTCP and blocks the entry of the HDV/HBV into the hepatocyte [30]. Hepatocyte entry blockade results in diminished immune-mediated hepatocyte injury, subsequent viral replication, and a reduction in viral load, leading to a biochemical and virological response. Multiple MYR trials since 2015 have demonstrated the safety and efficacy of bulevirtide [31–33]. The MYR 202 dose-finding trial estimated that subcutaneously administered doses of 2 mg and 10 mg per day were effective in HDV infection [32]. In a phase III trial, Wedemeyer et al. [34] reported that at least a 2 log10 IU/mL reduction in HDV-DNA levels and normalization of ALT were achieved in nearly half of the subjects at 48 weeks. Studies have demonstrated a good safety profile, with non-specific symptoms, such as leukopenia and thrombocytopenia, reported in 2–8% of the subjects. Dose-dependent elevation of bile acid levels has been reported consistently across studies, but asymptomatic and reversible upon drug discontinuation [35]. The fact that NTCP is a natural bile acid transporter explains the elevation of bile acids with bulevirtide therapy [36]. Due to its efficacy and safety profile, bulevirtide received conditional approval for treating chronic HDV infection in Europe in 2020. The EASL Practice Guidelines, 2023, suggest considering bulevirtide in all patients with chronic HDV and compensated liver disease; however, it notes that the duration and dose have yet to be defined [8]. Beyond the trials, real-world studies from France, Italy, and Austria reported excellent virological response rates and safety profiles with bulevirtide administered at 2 mg and 10 mg daily [37–39]. Bulevirtide monotherapy in cirrhosis reportedly reduces the progression to decompensation and mortality [40]. The off-label use of bulevirtide in patients with decompensated cirrhosis was associated with similar biochemical and virological responses; however, further data from randomized trials would be required to confirm these benefits [41].

Ezetimibe is a lipid-lowering drug that acts by inhibiting the Niemann-Pick C1-Like 1 protein receptors on enterocytes, which are essential for the absorption of luminal cholesterol. Additionally, it exhibits inhibitory effects on NTCP, the hepatocyte entry receptor for HBV and HDV. Abbas et al. [42] reported a ≥ 1 log reduction in HDV-RNA with a 12-week course of ezetimibe in a phase II trial. Further evaluation, with a larger number of subjects, is required to prove the efficacy of ezetimibe in HDV infection.

Lonafarnib, an orally administered farnesyltransferase inhibitor, is being tested for the treatment of HDV infection. Prenylation refers to a post-translational modification that involves the covalent addition of lipid groups to the polypeptide chains, mainly at the C-terminus. Farnesylation is a type of prenylation in which a farnesyl group is added and catalyzed by the enzyme farnesyltransferase [43]. Prenylation of HDAg is a critical post-translational modification that facilitates its interaction with HBsAg and the subsequent release of virions from the hepatocyte. Blockade of prenylation prevents the release of nascent HDV virions from hepatocytes. Hence, prenylation inhibitors result in a lower circulating viral load and a better virological response [7]. Phase II trials have yielded a statistically significant reduction in HDV-RNA, with no major adverse effects; however, the ALT trends did not differ from those of the placebo [44]. The phase III D-LIVR trial evaluated ritonavir-boosted lonafarnib, PEG-IFNα monotherapy, the combination of ritonavir-boosted lonafarnib with PEG-IFNα, and placebo in patients with compensated liver disease. The composite endpoint, ALT normalization, and at least a 2-log drop in HDV-RNA at 48 weeks was achieved in nearly 10% and 20% of the ritonavir-boosted lonafarnib and ritonavir-boosted lonafarnib with PEG-IFNα arms, respectively [45]. Higher doses of lonafarnib reportedly have higher gastrointestinal disturbances. Ritonavir boosting allows for lower lonafarnib dosage and, thereby, better tolerability [46].

Nucleic acid polymers (NAPs) are amphipathic oligonucleotides with a polyanionic backbone that interact with the viral envelope proteins, including the HBsAg. After interacting with NAPs, the envelope proteins fail to bind to host receptors, thereby preventing the virus from entering the cell. Again, the NAPs migrate into hepatocytes and interact with the nascent HBsAg, preventing the exit of newly formed virions [43]. Furthermore, limited data suggests engagement of HSPG/NTCP by NAPs, further impeding viral entry [47]. REP 2139 is a candidate NAP currently under evaluation for HBV and HBV-HDV coinfections. Reports of phase II trials, with REP 2139 chelates combined with PEG-IFN, are promising in HBV-HDV coinfection [48, 49]. However, the combination therapy of REP 2139 and PEG-IFN was associated with significant ALT elevations, requiring further evaluations for its safety [50].

Viral RNA silencers utilize small interfering RNAs to silence the viral RNA. ALN-HDV belongs to this class of medications and is currently in preclinical trials for the treatment of HDV [51].

GI-18000, a candidate immune response stimulator, is undergoing preclinical trials for the treatment of various diseases, including HBD-HDV infections. The proposed mechanism involves the activation of specific host T-cells to target hepatocytes infected with HBV and HDV [52].

Combination therapy, utilizing the synergic and complementary effects of multiple HBV/HDV-targeted medications, should technically offer advantages over monotherapy. Following this principle, numerous drug combinations have been and are being evaluated in the management of HDV.

NA-IFN/PEG-IFN: Several studies evaluated this combination in HDV infection, with most reporting futility or clinically irrelevant results. Wedemeyer et al. [53], 2011, evaluated Adefovir and PEF-IFN as monotherapies and combination therapies in HBV-HDV infection. There was no significant difference in HDV-RNA negative status at 48 weeks between PEG-IFN and Adefovir-PEG-IFN subgroups [53]. Boyd et al. [29] failed to demonstrate a clinically relevant response with tenofovir-PEG-IFN therapy. The study by Wolters et al. [54] was unable to support the use of lamivudine-IFN in HBV-HDV infection. The meta-analysis by Rong et al. [55] reported no additional benefit in adding NA to IFN preparation.

Bulevirtide-PEG-IFN: Multiple recent trials have reported favorable outcomes when bulevirtide is combined with PEG-IFN to treat HDV infection. Asselah et al. [56] evaluated the benefits of combination therapy compared to bulevirtide or PEG-IFN monotherapy. They reported a significantly higher undetectable status for HDV-RNA at 24- and 48-week post-treatment follow-up. Both 2 mg and 10 mg of bulevirtide yielded superior results at 24 weeks, but only 10 mg dosage had benefits at 48 weeks [56]. A meta-analysis of multiple drug combinations in HDV infection reported a combination of bulevirtide and IFNs to be the most potential treatment option [55]. The results of the French Early Access Program, with bulevirtide at 2 mg/day, combined with PEG-IFNα at 180 μg/week, estimated HDV virological responses of 84% and 94%, respectively, at 24 weeks and 48 weeks of treatment [37].

Bulevirtide-NA: In case reports, the bulevirtide-tenofovir combination was associated with improved liver function and virological response [57]. The MYR202 evaluated different doses of bulevirtide in combination with tenofovir and tenofovir monotherapy. The trial reported significantly higher levels of HDV virological response at the end of therapy with all combinations; however, 24 weeks post-treatment, most patients experienced viral rebound [32]. Hence, the beneficial effects of this combination require further validation, including for the optimal duration of therapy.

Lonafarnib-IFN/PEG-IFN/NA: A phase II study evaluating the combination of lonafarnib and lonafarnib-PEG-IFNα reported virological response rates of 46% and 89%, respectively, at 24 weeks of therapy [58]. The LOWR HDV-1 study reported a better virological response with ritonavir- and lonafarnib and an even more substantial response with lonafarnib-PEG-IFNα [46]. The phase II LIFT-HDV study analyzed a combination of PEG-IFNλ, ritonavir, and lonafarnib and reported a 77% virological response at the end of 24 weeks of therapy, as well as a 23% response 24 weeks after the end of treatment [59].

In brief, combination therapies for HDV infection are likely more efficacious than monotherapy owing to the synergistic effects of medications. The pharmacotherapeutic options for patients with HDV infection are summarized in Table 1, while Figure 3 depicts the mechanism of action of these medications.

Human immunodeficiency virus (HIV): The management of HDV in patients with HIV is an area of interest as both infections, at least to some extent, share similar modes of transmission. IFN-based monotherapies have been utilized in the treatment of HIV-coinfected, non-decompensated liver diseases with modest response rates. Bulevirtide monotherapy in five patients infected by the HDV-HBV-HIV triad complicated with cirrhosis and clinically significant portal hypertension was associated with a progressive reduction in HDV RNA and transaminases, with good tolerance and no detectable drug-to-drug interactions [60]. de Lédinghen et al. [61] administered bulevirtide, 2 mg, with or without PEG-IFNα in HIV-coinfected patients. At 44 weeks, 52.6% and 71.4% of patients achieved virological response with monotherapy and combination therapy, respectively. The regimens were well-tolerated and had no deleterious effects on CD4 counts or HIV viral loads [61]. However, these studies were non-randomized and involved only a small number of patients; larger, better-designed studies are needed to substantiate the benefits. There is a lack of data to suggest a role for other novel molecules in the treatment of HDV in people living with HIV infection.

Decompensated liver diseases: Regardless of etiology, the optimal management of decompensated liver disease is hepatic transplantation. The use of IFN-based therapies is generally discouraged in such cases owing to the risk of worsening hepatic function [62]. Bulevirtide, though approved for treatment in compensated liver disease, has been used off-label in the treatment of decompensated diseases with similar virological and biochemical response rates [41]. Data are lacking regarding the role of other agents in this subset of patients. Hepatitis B immunoglobulin and NA is associated with a lower risk of HDV recurrence post-liver transplantation. The European Liver and Intestine Transplantation Association recommends lifelong combination therapy of immunoglobulin and NA following liver transplant in HDV infected [63].

Pediatric: Currently, there is a dearth of data regarding HDV management in children. Trials from Greece and Pakistan reported the safety of conventional IFN in children; however, the efficacy was not encouraging [64, 65]. PEG-IFNs were also employed in the treatment of HDV in the pediatric population; again, they were not supported by governing bodies or guidelines [66]. The European Medicines Agency permits the use of bulevirtide at a dose of 2 mg daily for children over three years of age and weighing more than ten kilograms. However, the safety and efficacy of bulevirtide remain unestablished in individuals under 18 years of age [67].

Pregnancy: Convention and PEG-IFN are contraindicated, while there is no published literature to support the use of novel anti-HDV agents during pregnancy. Universal precautions and optimal management of HBV infection are believed to prevent the other to child transmission of HBV infection [68].