Long-term monitoring of HBsAg kinetics and prediction of HBsAg clearance in patients with chronic hepatitis B treated with nucleoside/nucleotide analogues
Loss of hepatitis B surface antigen (HBsAg) with or without seroconversion to anti-HBs antibodies is considered the ideal endpoint of antiviral therapy in patients with chronic hepatitis B. In interferon-treated patients, quantitative determination of HBsAg levels over time has been shown to help identify those likely to clear HBsAg. In patients treated with nucleos(t)ide analogues (NUCs), long-term kinetics of HBsAg are as yet unstudied, and the role of quantitative determination of HBsAg levels in tailoring NUC treatment duration needs to be clarified. METHODS: HBsAg levels (measured with Architect, Abbott) and HBV DNA levels (measured by real-time PCR) were examined in 583 serial serum samples taken from 30 patients with chronic hepatitis B receiving various successive schedules of NUCs over several years of follow-up, including lamidudine, lamivudine plus adefovir, eventually switched to tenofovir or entecavir. The median age of the patients was 57.6 years (range: 37.3-87.6), 80% were male and 43% of them had cirrhosis. Kinetics of HBsAg level were plotted and the average HBsAg reduction per year was calculated for all patients, in order to predict the needed duration of therapy before HBsAg clearance. RESULTS: The median follow-up was 93 months, i.e. almost 8 years (range 49-123 months). For each patient, an average of 19±6 serial samples was available (range 8-41). HBsAg levels slightly increased during therapy in 3 patients, including 2 who lost their HBV DNA (<20 IU/mL) and remained HBV DNA-negative for 28 and 71 months, respectively. One patient lost HBsAg after 72 months of undetectable HBV DNA; his average HBsAg level reduction was 0.74 Log IU/year. In the remaining 26 patients, HBsAg levels slowly and constantly decreased during therapy. The number of years needed to clear HBsAg after HBV DNA became undetectable was calculated in each patient: the distribution ranged from 6 to 181 years. Overall, 3 patients were predicted to clear HBsAg in 10 years or less, 5 within 10 to 20 years, 5 within 20 to 30 years and 13 in more than 30 years. The number of years needed to clear HBsAg was not related to any baseline parameter, nor to the duration of undetectable HBV DNA. CONCLUSIONS: This study reports very long-term follow-up of HBsAg level kinetics in patients with chronic hepatitis B treated with NUCs. We found that HBsAg clearance is a rare and late event, in most cases unlikely to occur during the patient’s lifetime. As a result, the goal of NUC therapy should remain the maintainance of HBV DNA at undetectable levels, and stopping NUC therapy is unlikely in the vast majority of patients.
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