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

Summary Background 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. Aim To assess the impact of HBsAg loss on clinical outcomes following spontaneous and treatment‐related HBsAg loss. Methods 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. Results 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. Conclusion 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.