Chronic Hepatitis D—What Is Changing?

David Yardeni; Theo Heller; Christopher Koh

Disclosures

J Viral Hepat. 2022;29(4):240-251. 

In This Article

Current Therapies for HDV

The aforementioned virology of HDV has created a frustrating and challenging environment for the development of therapeutic options for this chronic infection. The utilization of host cellular replicative machinery by the virus rather than by its own proteins terminated the option of using an antiviral polymerase treatment strategy successfully used for HBV[33] and hepatitis C.[34] As HDV infection causes progressive liver disease, multiple clinical trials have attempted to achieve long-lasting viral eradication. The antivirals ribavarin[35] and famciclovir[36] were found to be ineffective. A multicenter randomized controlled trial of lamivudine for HDV was also unsuccessful.[37] The only strategy that appeared to offer a therapeutic response was the mounting of a nonspecific immune response in the liver using interferon alfa (IFN).[38] Still recommended by professional society guidelines today but never authorized for use by the FDA, weekly subcutaneous (SC) pegylated IFN alfa (PEG-IFN-α)-2a at 180 μg once weekly or PEG-IFN-α-2b at 1.5 μg/kg for 12 months was up until recently the only therapeutic option for patients.[33,39] Furthermore, for US patients, it remains the only therapeutic option available outside of clinical trials.

Interferon Alfa

The therapeutic outcomes used to determine success with IFN as evaluated in the Italian study by Farci et al. were the normalization of alanine aminotransferase (ALT) along with a negative PCR result for HDV RNA. In this initial study, three groups of 14 patients were randomized to receive either 9 or 3 million units of IFN- α-2a three times a week for 48 weeks vs no treatment[38] (Table 1). At 6 months post-treatment, 6 of the 14 patients receiving the higher dose of IFN had undetectable HDV RNA whilst 50% normalized ALT. However, long-term follow-up revealed that none of the patients achieved a sustained viral response (SVR). Interestingly, survival without a need for orthotopic liver transplantation 12 years after completion of the study was significantly better for the high-dose group (86% vs 39% and 31%), regardless of the measured outcomes.[40] Main adverse events (AE) reported were similar to previous AEs reported with the use of IFN for other indications. Flu-like symptoms experienced by most patients along with asthenia and mild alopecia were most observed in the high-dose group. Similar efficacy and safety outcomes were obtained when 1.5 μg/kg of PEG-IFN-α-2b was evaluated in a small 14 patient cohort.[41] The Hep-Net–International Delta Hepatitis Intervention Trial (HIDIT) group evaluated the use of either 180 μg once weekly PEG-IFN-α-2a with 10 mg of adefovir (31 patients) vs PEG-IFN-α-2a alone (29 patients) and adefovir alone for 48 weeks (30 patients).[42] In this study at week 48 and at 24 weeks post-treatment, none of the adefovir patients achieved a negative HDV RNA result whilst approximately a quarter of both PEG-IFN-α-2a groups achieved the negative RNA outcome. A similar outcome was seen for ALT normalization as well. However, as seen in the initial IFN study, long-term follow-up revealed that over 50% of HDV RNA-negative patients experienced late HDV RNA relapses.[43] In a post hoc analysis of these data, investigators found that measurement of HDV RNA response at week 24 of treatment had a strong negative predictive value for identifying null responders and thus could potentially help guide further IFN treatment.[44] During the HIDIT-II study, the group attempted to enhance treatment with PEG-IFN-α-2a by adding the newer nucleotide analogue (NA) tenofovir disoproxil fumarate (TDF) to a prolonged 96-week treatment regimen in comparison with weekly PEG-IFN-α-2a SC injections and placebo.[45] However, at week 96, no significant differences in the HDV RNA response were observed between the two groups. An attempt to maximize treatment duration for up to 240 weeks with PEG-IFN-α-2a dose titration up to 270 μg/week did not achieve a significant improvement to the results.[46] Interestingly, a recent analysis of patient outcomes following the long-term treatment in this trial revealed improved survival and reduced liver-related events in treatment-responsive patients.[47] Other than the low number of patients achieving a true SVR and the adverse events experienced by most patients, treatment with IFN also harboured the risk of hepatic decompensation in cirrhotic patients due to the induced hepatic inflammation. Furthermore, reports of autoimmune disease, psychiatric reactions, cardiac complications, hematologic abnormalities and even seizure activity have limited its use.[48] Thus, despite being a single treatment option for many years, IFN α monotherapy is still suboptimal.

Bulevirtide—Entry Inhibitor

In August of 2020, a landmark event in the field of HDV treatment occurred when the European Medicines Agency (EMA) conditionally authorized the use of bulevirtide (previously named Myrcludex-B) for the treatment of HDV/HBV co-infection with or without NAs.[49] Subsequently, a request for a US FDA approval of bulevirtide for HDV infection was submitted by Gilead Sciences in November 2021.[50] Bulevirtide (BLV) is a first in its class virion entry inhibitor designed to block the bile acid transporter NTCP on the hepatocyte membrane and thus blocking both HBV and HDV virions from entering the cell.[51]

First human efficacy results in chronic HDV infection for the novel medication were shown in the MYR201-HBV/HDV from 2016[52] (Table 2). In this 3-arm study, patients were given either 2 mg of weekly SC BLV for 24 weeks followed by weekly 180 μg of PEG-IFN-α for 24 weeks, combination of similar dose BLV and PEG-IFN-α for 24 weeks followed by PEG-IFN-α only for 24 weeks and PEG-IFN-α only for 48 weeks. At the end of the first 24 weeks, the combination arm achieved a 2.6 log IU/ml decline in the HDV RNA along with 5 out of 8 patients testing undetected for HDV RNA whilst the BLV and PEG-IFN-α-only arms achieved a 1.67 and 2.2 log IU/ml decline, respectively, with 2 out of 8 patients in both groups achieving undetected HDV RNA. During the next MYR202 study, 120 patients were randomized to receive 2, 5 and 10 mg of SC BLV with TDF for 24 weeks followed by TDF or 48 weeks of TDF only.[53] At the end of treatment, median HDV RNA decline by 1.75, 1.6, 2.7 and 0.18 log IU/ml was noted for the three BLV groups and the TDF-only group.[54] The MYR203 study was a 4-arm study comparing SC BLV 2 mg/day alone, PEG-IFN-α alone or a combination of both with either 2 or 5 mg/day of BLV for 48 weeks.[55] Twenty-four weeks after completion of therapy, only the combination arms achieved undetectable HDV RNA. With 4 out of 15 patients and 8 out of 15 patients in the 2 and 5 mg combination arms respectively. An extension study comparing 5 mg of SC BLV twice daily with TDF to combination treatment of 10 mg SC BLV once daily with PEG-IFN for 48 weeks found undetected HDV RNA in 40% of the BLV-TDF group vs 86.7% of the BLV-PEG-IFN-α group at the end of treatment.[56] In the recent International Liver Congress of 2021, interim week 24 data results from MYR204 trial results were presented. In this 4-arm study, patients were randomized to either 48 weeks of PEG-IFN, PEG-IFN and SC BLV 2 or 10 mg followed by 48 weeks of BLV-only therapy and 96 weeks of SC BLV 10 mg-only group. At week 24 of therapy, a mean decline of ≥2 log IU/ml was achieved in 37.5% of PEG-IFN group, 86% of PEG-IFN-BLV 2 mg group, 90% of PEG-IFN-BLV 10 mg group and 72% of BLV 10 mg-only group.[57] Undetectable HDV RNA was found in 24% and 34% of patients in the combination arms. Interim week 24 data from MYR301 phase 3 study were presented at the same meeting.[58] In this study, 150 patients were randomized to receive either daily SC BLV at 2 or 10 mg for 48 weeks vs no treatment for 48 weeks followed by 96 weeks of daily 10 mg BLV. At week 24, 55.1% of patients in the 2 mg arm achieved an HDV RNA mean decrease of ≥2 log IU/ml. 68% achieved this target in the 10 mg arm whilst none of the patients achieved this target in the no-treatment arm. Of note, the only severe AE reported was in the no-treatment arm.

Throughout all BLV studies, no specific AE patterns were noted other than flares of hepatitis most likely related to the use of PEG-IFN-α rather than BLV. The only specific drug-related AE reported is bile acid elevation. This elevation stems directly from inhibition of the NTCP receptor, and its clinical significance remains so far unknown. No clinical symptoms of cholestasis have so far been reported; however, long-term implications of this finding are still pending.

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