Systematic review with meta‐analysis: the impact of functional cure on clinical outcomes in patients with chronic hepatitis B

Although hepatitis B surface antigen (HBsAg) loss is considered the ideal therapeutic endpoint for the treatment of chronic hepatitis B virus (HBV) infection, its impact on clinical outcomes remains uncertain.To assess the impact of HBsAg loss on clinical outcomes following spontaneous and treatment-related HBsAg loss.We searched PUBMED, Embase, the Cochrane library, and published abstracts through to May 2021 for studies that reported HBsAg loss, had >1 year of follow-up and reported at least one clinical outcome in adults with chronic HBV infection.We identified 57 studies (258 744 HBsAg-positive patients, 63 270 with HBsAg loss). Based on 24 studies including 160 598 patients with and without HBsAg loss, HBsAg loss was associated with a non-significant 23% relative risk reduction of developing hepatocellular carcinoma (HCC) compared to those who remained HBsAg-positive (RR = 0.77; 95% CI: 0.38-1.57). In subgroup meta-analysis of 10 studies, treatment-related HBsAg loss was associated with a non-significant higher pooled proportion of HCC (0.94%) compared to spontaneous HBsAg loss (0.45%). HCC development after HBsAg loss was significantly higher in males, those with underlying cirrhosis, and those with a family history of HCC. HBsAg loss was associated with lower pooled proportions of incident cirrhosis, hepatic decompensation, overall and liver-related mortality compared to no HBsAg loss. Substantial heterogeneity was noted across studies for all outcomes.HBsAg loss is associated with a reduced risk of clinical outcomes. However, several shortcomings in the published studies prevent a more definitive conclusion on the potential benefits of HBsAg loss.