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

Spontaneous Serum ALT Flares in Untreated CHB

Chronic HBV infection is characterized by a dynamic interplay between the host immune response and replication of the viral genome. The natural history of chronic HBV is often accompanied by spontaneous increases in serum ALT levels termed 'ALT flares' reflecting intra-hepatic necroinflammatory activity resulting from an expanded number of HBV specific T lymphocytes. Therefore, ALT flares signify immune-mediated destruction of infected hepatocytes and frequently occur in association with surges in viral replication.[6] Serum ALT level is used as a widely available, noninvasive measure of disease activity in untreated chronic HBV patients. Prior studies have demonstrated a moderate correlation between the level of serum ALT elevation and degree of hepatic inflammation on liver biopsy in untreated patients.[7,8]

A uniform laboratory definition of a spontaneous serum ALT flare in chronic HBV is lacking. Initially, flares were defined as an abrupt elevation of serum ALT exceeding 300 U/L in patients with a baseline serum ALT level of <200 U/L,[9] or by an abrupt elevation of serum ALT to >5× upper limit of normal (ULN) or an increase >3-fold baseline. More recently, an ALT flare has been defined as an ALT level >10× ULN and more than twice the baseline value.[10] All these definitions characterize flares as an abrupt ALT elevation commonly associated with an antecedent or simultaneous rise in serum HBV DNA (Table S1).

In persons who acquire chronic HBV infection early in life, ALT flares become more common during adulthood when patients transition from a phase of HBeAg-positive status (immune tolerant) to the phase of HBeAg-positive chronic hepatitis (immune active). In this situation, flares may be host-derived rather than virally induced, and although still poorly understood, they are most likely the result of a change in the regulation of viral antigen-specific T cells.[11] Moderate and severe spontaneous serum ALT flares commonly occur coincident to, or immediately after, an increase in serum HBV DNA levels.[12]

Several reviews have reported that spontaneous flares in untreated chronic HBV patients are often associated with an increase in host-derived immunity towards infected hepatocytes which in some cases can be associated with a decrease in viral parameters.[13] Although ALT flares occur in both untreated HBeAg-positive and HBeAg-negative patients, spontaneous flares are more frequently observed in HBeAg-positive patients, with an annual incidence of 5%-10%. A recent paper from the Hepatitis B Research Network indicates that men, patients who consume alcohol, and those subjects with a higher HBV DNA level were at greatest risk of developing a spontaneous serum ALT flare.[14] The development of precore and basal core promoter variants is frequently associated with periodic flares of liver cell necrosis interspersed with periods of normal serum ALT and low serum HBV DNA levels.[15] Flares in HBeAg-negative patients have thus been mainly attributed to increases in the concentration of these mutants in the liver and changes in the ratio of mutant to wild-type HBV. The levels of HBV DNA, HBeAg and/or HBsAg may decrease following the enhanced elimination or suppression of HBV, with HBeAg seroconversion observed in approximately 30% of patients.[16] Following the transition to the inactive phase, HBsAg seroclearance is reported at an annual rate of 0.7%-2.4%.[12]