Enhancing functional cure in patients with chronic hepatitis B infection

Abstract

Chronic hepatitis B infection affects 292 million people globally, and is a major risk factor of liver-related diseases. With the existing treatment by either nucleos(t)ide reverse transcriptase inhibitor (NRTI) or pegylated interferon, we can achieve on-treatment viral suppression for virtually all patients. Less than 20% of patients will have partial cure, i.e. off-therapy sustained virological suppression after stopping treatment, and they still have low-grade viraemia when taken off antiviral therapy. Disappointingly, only few percent of patients can achieve functional cure even on long-term therapy but once it is achieved, HBV DNA negativity can be maintained after stopping therapy. Moreover, even if HBV DNA is suppressed with current antiviral therapy, liver-related complications still arise. Functional cure is therefore the currently preferable and optimal treatment endpoint, which refers to sustained seroclearance of HBsAg with or without seroconversion of antibody to HBsAg. Functional cure is associated with improved clinical outcomes. The unsatisfactorily low rate of functional cure achieved by currently approved therapies triggers the on-going search for new treatment approaches. Cessation of long-term NRTI aiming at subsequent functional cure has led to heterogeneous results in patients with different baseline characteristics. Meticulous patient selection is required with efforts to identify patients with favorable factors including Caucasian ethnicity and low HBsAg level. For novel agents, reduction of viral burden and enhancement/ restoration of host immunity are equally important. There are multiple sites of target by novel agents by inhibition of viral entry to hepatocytes, knock down of the mRNA transcriptional activities, interference with the core protein functions to affect the viral encapsidation and cccDNA replenishment, and inhibition of HBsAg release from the cells. Host immunity can be boosted by toll-like receptor agonists, immune checkpoint inhibitors, T cell receptor modulation, and therapeutic vaccines. Most agents currently in clinical phase of development demonstrated favorable results in suppression of viral proteins and genomic materials, and some agents will enter phase 3 clinical trials for further evaluation. Safety data is of paramount importance. The future treatment regime will likely entail a combination of NRTI, virus-directing agent, and immunity-boosting agent. The best cocktail therapy is still unknown, and will need to be revealed by well-designed randomized controlled trials.