Introduction 

Chronic hepatitis B virus (HBV) infection has high global burden (prevalence of 254 million cases as of 2022) with a relatively stable trend in HBV-related deaths. Current management guidelines for chronic hepatitis B recommend antiviral therapy for individuals with non-cirrhotic chronic hepatitis B only if they have significant liver fibrosis or elevated alanine aminotransferase (ALT) concentrations, even in the presence of moderate or high viraemia (HBV DNA ≥10 000 IU/mL). However, studies have consistently shown that ALT is neither sensitive to nor specific for detecting underlying liver conditions. Hence, this interim analysis was conducted to support the use of early antiviral treatment in individuals with non-cirrhotic hepatitis B.

Aim

To assess the efficacy of early antiviral treatment in preventing serious liver-related adverse events in individuals with non-cirrhotic chronic hepatitis B and moderate or high viraemia but normal or mildly elevated ALT concentrations

Patient Profile 

Method

Study Design

• ATTENTION trial interim analysis, prespecified at 4 years
• Randomised, controlled trial
• Patients were randomly assigned to either oral tenofovir alafenamide (25 mg daily) or no antiviral treatment (observation group); safety population comprised of participants who received at least one dose of the study treatment
• Median follow-up was 17.7 months

Endpoints

• Primary endpoint: hazard ratio (HR) for the composite of hepatocellular carcinoma, hepatic decompensation (e.g., development of portal hypertensive complications including ascites, gastro-oesophageal varices or Child-Pugh score of ≥7), liver transplantation, or death from any cause
• Secondary outcome: virological, biochemical, and serological responses (hepatitis B surface antigen seroclearance, hepatitis B e antigen seroclearance, and HBeAg seroconversion in patients who were HBeAg positive at baseline)

Results 

Efficacy 

• Tenofovir alafenamide group had 79% lower risk of the composite primary endpoint as compared to the observation group over a total of 1179 person-years of follow-up (incidence rate: 0.33 vs. 1.57 per 100 person-years, resp., hazard ratio 0.21 [97.5% CI 0.04–1.20]; p=0.027, Figure 1)
• The mean medication adherence was 98.4% in the tenofovir alafenamide group when followed up for at least 6 months, 
• In participants with normal ALT concentrations (≤40 U/L) at baseline, tenofovir alafenamide group was not associated with any event included in the primary composite outcome, whereas observation group reported eight events (1.78 per 100 person-years, p=0.0054)
• In a sensitivity analysis conducted to account for the possibility that hepatocellular carcinoma was present before enrolment, the hazard ratio forthe primary endpoint was 0.13 (p=0.027)
• Among those HBeAg positive at baseline, no cases developed hepatocellular carcinoma in tenofovir alafenamide group as compared to three cases in the observation group (incidence rate of 2.68 per 100 person-years)
• Among HBeAg negative participants, tenofovir alafenamide group was linked to lower incidence of events included in the composite primary outcome vs. the observation group (0.42 vs. 1.30 per 100 person-years) 
• Virological response was achieved by significantly more participants in the tenofovir alafenamide group versus in the observation group (p<0.0001)
• The proportion of participants with normal ALT concentrations was significantly higher in the tenofovir alafenamide group versus the observation group (p<0.0001)
• Among the participants with elevated ALT concentrations at baseline who were followed up for at least 6 months, the rate of ALT normalisation was significantly higher in the tenofovir alafenamide group than in the observation group (p<0.0001) 
• HBeAg seroclearance rates did not differ between the two groups in patients who were HBeAg positive at baseline (23% vs.18%; p=0.53)
• HBsAg seroclearance occurred in one participant in the tenofovir alafenamide group and in two in the observation group

Figure 1: Effect of tenofovir on the composite primary endpoint versus the observation group

Safety   

Conclusions 

• This interim trial showed that early antiviral treatment with tenofovir alafenamide in patients with non-cirrhotic chronic hepatitis B and moderate or high viraemia reduced the risk of hepatocellular carcinoma and other liver-related serious clinical events as compared to those in the observation group, even in the absence of significant ALT elevation
• These findings support updating existing clinical guidelines to recommend early antiviral therapy in these patients to effectively prevent hepatocellular carcinoma and other serious clinical adverse events
• ATTENTION was the first randomised trial to specifically assess the efficacy and safety of early treatment with tenofovir alafenamide in preventing serious liver-related adverse events in non-cirrhotic chronic hepatitis B and moderate or high viraemia (serum HBV DNA ≥10 000 IU/mL) and normal or mildly elevated ALT concentrations, who were not typically indicated for antiviral treatment.

Lancet Gastroenterol Hepatol 2025; 10: 295-305