HBsAg loss in HIV/HBV coinfected patients: Hepatitis B cure insights and implications

HIV (human immunodeficiency virus)/HBV (hepatitis B virus) coinfection remains a significant public health challenge. HIV infection affects the natural course of chronic HBV infection, with HIV/HBV coinfected patients experiencing higher liver-related morbidity, hospitalization rates, and mortality than those with HBV monoinfection. Surprisingly, an increasing number of studies have shown that hepatitis B surface antigen (HBsAg) clearance rates in HIV/HBV coinfection can reach over 10%, which is significantly higher than in HBV monoinfection. In this review, we summarize the predictive factors for HBsAg clearance observed in HIV/HBV coinfection, including baseline HBsAg levels, baseline HBV DNA levels, baseline CD4+T cell-counts, and immune reconstitution inflammatory syndrome-related hepatic flare. Based on current evidence, we further discuss a potential mechanism for HBsAg clearance: HIV-induced immunodeficiency, particularly the depletion of CD4+ T cells, may unexpectedly disrupt preexisting HBV-specific tolerance. After antiretroviral therapy (ART) in HIV/HBV coinfected individuals, partial immune system reconstitution occurs, and the reconstituted immune system, no longer tolerized by HBV, effectively clears HBV-infected hepatocytes, triggering transient hepatitis and ultimately achieving a functional cure through HBsAg clearance. Additionally, emerging data suggest that the underlying immunological mechanisms of HBsAg clearance in HIV/HBV coinfection may primarily involve: PD-1/PD-L1 pathway inhibition, cytokine induction promoting immune cell recruitment and an inflammatory environment, and natural killer (NK) cell functional remodeling. These collective observations highlight the important role of immune modulation in HBV clearance, providing insights that can facilitate the development of a functional HBV cure. Identifying the mechanisms involved in HBsAg loss in HIV/HBV patients may facilitate the development of drugs that mimic these anti-HBV responses.