In this review, different approaches that have been utilized in clinical studies to overcome the challenge of HDV were discussed. Mounting a systemic immune response by using the current widely available 48-week treatment with PEG-IFN-α has provided unsatisfying long-term results at the cost of sometimes intolerable adverse events. The benefits of the novel more liver-specific interferon lambda are definitely an improvement for patients and can potentially allow for the combination of innate immune response activation with other novel therapies against HDV. Such an approach has already shown promising results in the recent LIFT study where interferon lambda was successfully combined with the novel prenylation inhibitor lonafarnib. The ongoing phase 3 D-LIVR study will hopefully provide satisfying data concerning the use of lonafarnib with or without immune system activation by PEG-IFN-α. Further clinical studies on a much larger group of patients, expanding the encouraging results seen in the REP 301 study are also eagerly anticipated. Finally, the conditional approval of the first in its class entry inhibitor, bulevirtide by the EMA along with its recent submission for US FDA approval has given hope that widespread use of this medication will provide successful real-world data for this very promising medication. Part of the still ongoing challenge of HDV is the definition of successful treatment. Although hoped for and a reasonable goal, it is not yet clear if a clear-cut SVR for most patients as achieved with HCV treatment is truly feasible in HDV treatment. It is possible that chronic treatment that can be tolerated by the patient will be a reasonable option for prevention of advanced liver disease and its complications. It also remains to be seen whether a single-drug approach would be enough to overcome this devastating chronic disease or perhaps a combination of different medications and approaches that attack different targets within the viral life cycle will bring us the final downfall of HDV.
AE, adverse events; ALT, alanine aminotransferase; BLV, bulevirtide; DHBV, duck HBV; EMA, European Medicines Agency; FDA, Food and Drug Administration; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HDV, hepatitis D virus; LHDAg, large delta antigen; LNF, lonafarnib; NA, nucleoside/nucleotide analogues; NAP, nucleic acid poylmers; NTCP, sodium taurocholate co-transporting polypeptide; PEG-IFN, pegylated interferon; RNP, ribonucleoprotein; RTV, ritonavir; SHDAg, small delta antigen; SVR, sustained viral response; TDF, tenofovir disoproxil fumarate.
Data Availability Statement
The authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials.
J Viral Hepat. 2022;29(4):240-251. © 2022 Blackwell Publishing