LAUSR

Chronic HDV requires the envelope (HBsAg) of HBV to enter the hepatocyte, spread intrahepatically, and disseminate. Chronic HDV is the most severe form of viral hepatitis. The risk of HCC and liver cirrhosis associated with chronic HBV is further deteriorated by coinfection with HDV, resulting in a relevant health burden.[1] However, HBV treatment with nucleoside analogues (NAs) has no effect on HDV replication,[2,3] which explains the unmet need for HDVspecific treatment. Until the recent past, the only therapeutic option for chronic HDV infection was interferon alfa (IFN) or pegylated IFN (PEGIFN). Treatment of viral hepatitis with IFN is not a specific direct antiviral therapy, but relies on the immune modulation triggered by IFN, which eventually leads to cure. The efficacy of IFN treatment is limited, with approximately 25%– 30% achieving virologic response (HDV RNA– negative) after 48 or 96 weeks of therapy, although relapses may occur during the followup period (even years later) (reviewed in Sandmann and Cornberg[4]). Nevertheless, longterm followup of patients infected with HDV revealed that the risk of developing clinical endpoints such as hepatic decompensation was lower in patients treated with IFNbased therapy than in patients receiving NAs alone.[5] However, due to the side effects of IFN therapy, its use is limited, and IFN is not specifically approved for the treatment of chronic HDV. Thus, to date, no specific medical treatment for this severe form of viral hepatitis has been fully approved by the relevant authorities. However, with the conditional approval of bulevirtide by the European Medicines Agency in 2020, an important step has been taken toward the treatment of chronic HDV infection. Bulevirtide is a myristoylated peptide derived from the preS domain of the HBsAg that inhibits HDV entry into hepatocytes by blocking the bile acid cotransporter NTCP.[6] Preliminary approval of bulevirtide was based on promising results from phase 2 clinical trials, but these have not yet been fully published (data summarized in Refs. 4 and 7). In a nutshell, bulevirtide was investigated in the combination with tenofovir or PEGIFN, and clinical endpoints such as alanine aminotransferase (ALT) normalization or HDVRNA decline were achieved more frequently in those treated with bulevirtide (data summarized in Refs. 4 and 7). The safety profile appears to be excellent, and the described increase in bile acids is asymptomatic and not associated with clinical findings to date. Data from larger phase 3 studies are expected in mid 2022. However, certain limitations must be considered when treating with bulevirtide. Clinically important longterm endpoints such as prevention of HCC, decompensation, liver transplantation, or liverrelated death have not been investigated. In addition, treatment endpoints that determine treatment duration remain unclear. Longterm observational studies are needed to verify that an effect on these clinical endpoints can be achieved and that the therapy does not have side effects in the longterm course. In addition, administration by daily subcutaneous injection for a long period of time may not be tolerated by all patients and could lead to compliance issues in daily practice. Some of these limitations (Table 1) may be overcome by the development of additional new drugs such as lonafarnib. Lonafarnib is an oral farnesyltransferase or prenylation inhibitor that was initially developed to treat progeria, a rare pediatric disease. Glenn et al. discovered that inhibition of prenylation of the large hepatitis delta antigen is a target to interfere with hepatitis D viral particle formation.[8] In a proofofconcept study published in 2015, Koh et al. showed that HDV viral load decreased significantly in a dosedependent manner in patients receiving lonafarnib.[9] However, the therapy with lonafarnib is associated with gastrointestinal adverse events such as nausea, vomiting and diarrhea, which are equally dose dependent. To achieve higher drug level, and thus optimal efficacy with lower doses of lonafarnib, the cytochrome P4503A4 inhibitor ritonavir can be used as already demonstrated in the LOWR1study.[10] In this issue of Hepatology, Yurdaydin et al. present the results of the LOWR2 trial, which assessed the effect of ritonavirboosted lonafarnib in different dosing regimens with and without PEGIFN. The study was designed as a singlecenter, openlabel, uncontrolled trial. A total of 55 patients were enrolled and assigned to three main treatment groups. Two groups were treated for 12 or 24 weeks with different doses of lonafarnib/ritonavir as alloral regimen. In the remaining group, the combination of ritonavirboosted lonafarnib with subcutaneous PEGIFN was investigated. The primary endpoint was a ≥ 2log decline in HDV RNA or Received: 24 February 2022 | Accepted: 24 February 2022