1Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases & Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY.
Chronic hepatitis D infection results in the most severe form of chronic viral hepatitis but currently lacks effective treatment options. Therapy with pegylated interferon alpha (PEG-IFNα) is recommended for finite treatment duration by major liver societies. Still, it is plagued by low rates of sustained virologic response (SVR) and frequent relapses even if SVR is achieved. Recently, a wave of new investigational therapies has come under evaluation, including bulevirtide, lonafarnib, pegylated interferon lambda (PEG-IFNλ), and REP-2139 creating new excitement in HDV. However, there has been significant variability in the endpoints used to evaluate these new therapeutics. One of the recently introduced endpoints is characterized by a decline in HDV RNA by 2-logs, with or without achieving an undetectable serum HDV RNA, as a marker of virologic response. Furthermore, this measure has been combined with alanine aminotransferase (ALT) normalization, also known as a biochemical response, to formulate the primary endpoint of several late-stage studies. Per recent guidance by the United States Food and Drug Administration (FDA), these should be surrogate endpoints that will ultimately portend long-term clinical benefits. These clinical benefits may include reducing the risk of progression to cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, and mortality. However, the optimal way to measure success in HDV clinical trials remains unknown and will continue to evolve.