Liver Safety Assessment in Clinical Trials of New Agents for Chronic Hepatitis B

Robert J. Fontana; Mark I. Avigan; Harry L. A. Janssen; Arie Regev; Poonam Mishra; Anuj Gaggar; Nathaniel Brown; Cynthia Wat; Patricia Mendez; Ryan T. Anderson; Bruce Given; Veronica Miller; Maria Beumont


J Viral Hepat. 2020;27(2):96-109. 

In This Article


Durable off-treatment clearance of HBsAg with or without anti-HBs seroconversion 48 weeks after discontinuation of therapy in patients with chronic hepatitis B virus (HBV) infection mirrors natural resolution of acute infection and is the current objective of anti-HBV therapy.[1] Referred to as functional cure, the seroclearance of HBsAg is expected to decrease the risk of developing hepatocellular carcinoma (HCC) and other complications of chronic liver disease.[2] Currently, approved agents for chronic HBV work either through direct suppression of HBV replication [oral nucleos(t)ide reverse transcriptase inhibitors (NrtIs)] or enhancement of the host immune response [eg Interferon (IFN)]. These therapies have been associated with both on treatment and post-treatment serum ALT 'flares' followed by subsequent improvements in serum aminotransferases, markers of HBV replication and liver histology in some patients.[3] However, the rate of HBsAg loss or seroconversion to anti-HBs during or after treatment with currently approved agents remains low (<1%/y).[4]

Over 40 investigational agents with varying mechanisms of action that help reduce or eliminate covalently closed circular DNA (cccDNA) and/or stimulate host immunity against HBV-infected hepatocytes are in development for the treatment of chronic HBV.[5] To achieve high rates of HBsAg loss, a combination of drugs with complementary mechanisms of action will likely be required.[2] Many of the current clinical trials aim for a finite duration of therapy followed by a post-treatment follow-up period to assess sustained response. Appropriate interpretation and management of serum ALT elevations during and after treatment, including differentiation between drug-induced liver injury (DILI), viral replication-induced flares and host-induced flares is paramount to the successful evaluation of these regimens while ensuring patient safety (Table 1).

Some of the challenges in interpreting liver safety data in ongoing studies of investigational agents for chronic HBV are highlighted in this paper. First, the frequency and severity of spontaneous serum ALT flares in untreated chronic HBV patients are reviewed. Second, serum ALT flares are categorized into those that reflect therapeutic responses to the study drug vs the emergence of drug-resistant virions during treatment, or a resurgence of viral activity after treatment discontinuation. To provide perspective, a synopsis of the liver safety signals observed during the registration trials of currently approved first-line NrtIs and Peg-IFN are reviewed. Third, we describe the incidence, phenotype and methods to establish a potential diagnosis of idiosyncratic DILI. Finally, recommendations for liver safety assessment and management in future studies of virally suppressed and treatment naïve chronic HBV patients receiving investigational agents are provided.