Summary Background In sub‐Saharan Africa, it is unknown whether hepatitis E virus (HEV) infection is a common precipitating event of acute‐on‐chronic liver failure (ACLF). Aims To estimate the prevalence of HEV infection in general population and assess whether HEV is a common trigger of ACLF in cirrhotic patients in The Gambia, West Africa. Methods We first conducted an HEV sero‐survey in healthy volunteers. We then tested cirrhotic patients with ACLF (cases) and compensated cirrhosis (controls) for anti‐HEV IgG as a marker of exposure to HEV, and anti‐HEV IgA and HEV RNA as a marker of recent infection. We also described the characteristics and survival of the ACLF cases and controls. Results In the healthy volunteers (n = 204), 13.7% (95% CI: 9.6–19.2) were positive for anti‐HEV IgG, and none had positive HEV viraemia. After adjusting for age and sex, the following were associated with positive anti‐HEV IgG: being a Christian, a farmer, drinking water from wells, handling pigs and eating pork. In 40 cases (median age: 45 years, 72.5% male) and 71 controls (39 years, 74.6% male), ≥70% were infected with hepatitis B virus. Although hepatitis B flare and sepsis were important precipitating events of ACLF, none had marker of acute HEV. ACLF cases had high (70.0%) 28‐day mortality. Conclusions Hepatitis E virus infection is endemic in The Gambia, where both faecal‐oral route (contaminated water) and zoonotic transmission (pigs/pork meat) may be important. However, acute HEV was not a common cause of acute‐on‐chronic liver failure in The Gambia.

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