Editorial: baseline hepatitis B virus haplotype number may help predict a functional cure in patients with chronic hepatitis B treated with nucleotide analogues

This article is linked to Wagner et al papers. To view these articles, visit https://doi.org/10.1111/apt.17299 and https://doi.org/10.1111/apt.17364 Hepatitis B virus (HBV) chronic infection continues to be one of the greatest health challenges worldwide.1 Serum hepatitis B surface antigen (HBsAg) loss is associated with functional remission and improved long-term outcomes. It has been accepted as the definition of a functional cure (also referred to as clinical cure) of chronic HBV infection.2 A functional cure is now considered to be the most ideal treatment target for patients with chronic hepatitis B (CHB) because achieving functional cure can minimise the risk of decompensated cirrhosis and hepatocellular carcinoma.2 A significant decrease or elimination of covalently closed circular DNA (cccDNA) in the liver is the key to achieving functional cure.3 Serum surrogate indicators that can reflect the activity and level of cccDNA in hepatocytes are expected to predict the occurrence and maintenance of functional cure.3, 4 In addition to quantitative HBsAg, the cccDNA-derived HBcrAg, quantitative anti-HBc, and anti-HBs, as well as HBV RNA, are also reported to predict functional cure. However, these serum markers have limited accuracy, and we still need to explore more effective indicators. Revill et al studied the relationship between baseline HBV genome length haplotype number and the possibility of achieving functional cure.5 There were differences in the distribution of baseline haplotype numbers between different HBeAg states and HBV genotypes. Although the baseline haplotype number did not predict seroconversion from HBeAg to anti-HBe, a baseline haplotype number ≤2 proved predictive of HBsAg clearance from serum in cohorts of HBeAg-positive patients infected with genotype A or D treated within clinical trials of tenofovir or tenofovir alafenamide. The finding of a baseline haplotype number ≤2 provides a new indicator for the clinical screening of patients who may be more likely to obtain functional cure. It also has the effect of encouraging patients with CHB who have low haplotype numbers to adhere to long-term antiviral therapy. To achieve a functional cure in these patients, we should actively explore effective antiviral therapy strategies to optimise the possibility. Whether functional cure can be maintained after antiviral drug withdrawal is also of great concern. Pegylated interferon-α (peg-IFNα)-based antiviral strategy is considered the best choice to pursue a functional cure,6, 7 and the level of HBcrAg and anti-HBs at the end of peg-IFNα therapy is related to the maintenance of functional cure.8, 9 We are curious to know whether a low haplotype number can also predict the achievement and maintenance of functional cure in patients with peg-IFNα therapy. Combining baseline haplotype numbers with HBcrAg and HBV RNA to predict functional cure more accurately may become feasible. Yu-Jing Li: Writing – original draft (equal); writing – review and editing (equal). En-Qiang Chen: Conceptualization (lead); investigation (lead); project administration (lead); resources (lead); writing – original draft (equal); writing – review and editing (equal). Declaration of personal interest: EQC served as a speaker and consultant for Gilead. Data sharing is not applicable to this article as no new data were created or analyzed in this study.