Hepatitis D - Emerging treatments | BMJ Best Practice US

Bulevirtide

Bulevirtide, an entry inhibitor, blocks HDV from entering hepatocytes by binding and inactivating the sodium/bile acid cotransporter. It is approved in Europe and the UK for the treatment of chronic HDV infection in plasma (or serum) HDV RNA-positive adults with compensated liver disease, but it is not approved in the US. It is recommended in European and UK guidelines.[1][59] In a multicenter, open-label study, 120 patients with chronic HDV infection were randomized to various doses of bulevirtide in combination with tenofovir, or to tenofovir alone, for 24 weeks. The primary endpoint was based on virologic response. There was a dose-dependent effect of bulevirtide on decline in HDV RNA, but the HDV RNA levels rebounded after the drug was stopped. Adverse effects were related to the elevation of serum bile acids, but pruritus was mild.[60] An ongoing phase 3 randomised trial of bulevirtide in 150 patients with chronic HDV infection over 144 weeks of treatment found that HDV RNA and ALT levels were reduced after 48 weeks of bulevirtide treatment compared with a control group receiving no treatment, with increasing response rates at 96 weeks relative to 24 and 48 weeks.[61] One phase 2b open-label study of 174 patients with chronic hepatitis D found that bulevirtide used in combination with peginterferon alfa-2a was superior to bulevirtide monotherapy in terms of undetectable HDV RNA at 24 weeks after the end of treatment.[62]

Lonafarnib

Lonafarnib, a prenylation inhibitor, inhibits the farnesyl transferase that is involved in modifying the hepatitis D virus (HDV) antigen so that it can be incorporated into the hepatitis B virus surface antigen (HBsAg). The efficacy of lonafarnib was demonstrated in a small pilot study of 14 patients with chronic HDV infection, followed over 28 days, with a dose-dependent drop in HDV RNA levels that correlated with the lonafarnib serum concentration.[63] By adding ritonavir (a protease inhibitor) to boost the lonafarnib serum level, the antiviral response improved and the gastrointestinal adverse effects decreased. Adding peginterferon alfa improved the antiviral effect further.[64] The D-LIVR study, which is yet to be published, randomized 407 patients with chronic HDV infection to receive lonafarnib boosted with ritonavir alone (all-oral) or in combination with peginterferon alfa (combination). The composite primary endpoint was a ≥2 log decline in HDV RNA and normalization of alanine transaminase (ALT) at the end of 48 weeks of treatment compared with placebo. Patients on the all-oral therapy and combination therapy showed a composite response of 10.1% (P=0.0044) and 19.2% (P <0.0001), respectively, compared with those receiving placebo (1.9%).[65] Similarly, histologic response (defined as ≥2-point improvement in histologic activity index and no worsening of Ishak fibrosis scoring) improved with treatment in 35 of 66 patients (53%, P=0.0139) in the combination group versus 8 of 30 patients (27%) receiving placebo. Lonafarnib has been granted orphan drug designation in some countries for the treatment of HDV infection, and is approved in some countries for other indications.

Tobevibart/elebsiran

The combination of tobevibart (an investigational monoclonal antibody) and elebsiran (an investigational small interfering RNA) has been granted fast-track designation by the Food and Drug Administration, following positive preliminary phase 2 trial data. The phase 2 clinical trial is ongoing.[66]