No abstract

During the course of chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) seroconversion to its antibody (anti-HBe) often coincides with normalization of liver biochemical test and clinical remission, but data regarding long-term outcome after spontaneous seroconversion are still scarce. Excluding patients with other virus(es) concurrent infection, 283 patients with chronic HBV infection were followed up for at least 1 year after spontaneous HBeAg seroconversion to anti-HBe. Follow-up studies included clinical, biochemical, and virologic evaluation and hepatocellular carcinoma (HCC) screening with ultrasonography and ␣-fetoprotein assay. During a median follow-up period of 8.6 years (range, 1 to 18.4 years) after HBeAg seroconversion in 283 patients, 189 (66.8%) showed sustained remission, whereas the remaining 94 (33.2%) experienced alanine aminotransferase (ALT) elevation over twice the upper limit of normal: 12 (4.2%) associated with HBeAg reversion, 68 (24%) with detectable serum HBV DNA but HBeAg negative, and 14 (4.9%) of undetermined causes. Of the 269 patients without evidence of cirrhosis at the time of HBeAg seroconversion, 21 (7.8%) developed cirrhosis with a cumulative incidence and relative risk significantly higher in patients developing active hepatitis than in patients with sustained remission (P < .05). HCC developed in 6 (2.2%) of the 283 patients, also with a significantly higher cumulative incidence in patients developing active hepatitis after HBeAg seroconversion (P < .005). In conclusion, the results suggest that spontaneous HBeAg seroconversion confers favorable long-term outcomes. However, active hepatitis still may develop and lead to cirrhosis and HCC. ( D uring the course of chronic hepatitis B virus (HBV) infection, presence of hepatitis B e antigen (HBeAg) often is associated with active and usually continuing liver disease, whereas HBeAg seroconversion to its antibody (anti-HBe) often coincides with loss of serum HBV DNA, normalization of liver biochemical test, clinical remission and subsidence of hepatic inflammatory activity, 1-4 and may even be followed by spontaneous HBV surface antigen (HBsAg) seroclearance. 5 Several studies have shown that the long-term outcome of the patients after interferon-related HBeAg seroconversion is favorable. 6-10 However, few studies have addressed the issue of long-term outcome after spontaneous HBeAg seroconversion. 11 Given the fact that most patients with liver cirrhosis and hepatocellular carcinoma (HCC) are seropositive for anti-HBe, it has even been suggested that the risk of HCC might increase when HBV infection became quiescent. 12 Therefore, we conducted this study to elucidate the long-term outcome after spontaneous HBeAg seroconversion in a large series of patients. Patients and MethodsPatients. The long-term follow-up study of our patients with chronic hepatitis B, as described previously, 5,10,13 has continued. By the end of 1998, a total of 1,345 HBeAg seropositive patients were confirmed to have chronic hepatit...

Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication, but its long-term use may be associated with HBV tyrosine-methionine-aspartate-aspartate (YMDD) motif mutation. To examine the clinical features and course after emergence of YMDD mutants, 55 patients who received lamivudine therapy over 104 weeks at our unit were assayed for YMDD mutation(s). Thirty-two of them were found to have the YMDD mutation. They continued lamivudine therapy and were followed up weekly or biweekly if clinically indicated. Thirty (93.7%) of them showed elevation of alanine transaminase (ALT), and 13 (40.6%) experienced acute exacerbation at 4 to 94 weeks (median, 24 weeks) after emergence of the YMDD mutant. The incidence of exacerbation is much higher than 4.3% in patients without the YMDD mutation (P ‫؍‬ .003). Compared with patients without exacerbation, patients with exacerbation had a significantly higher serum HBV-DNA level after emergence of the YMDD mutant (P F .005). Before exacerbation, serum HBV-DNA level was rising to its peak, followed by the peaking of ALT (247-2,010 U/L) 1 to 4 weeks later. Three patients developed hepatic decompensation, but then in association with hepatitis B e antigen (HBeAg) seroconversion, recovered. Of the 12 evaluable patients, 8 (75%) showed HBeAg seroconversion, and 3 showed mutant clearance within 1 to 5 months after exacerbation. In contrast, none of the patients without exacerbation showed HBeAg seroconversion (P F .001). These results indicate that acute exacerbations may occur after emergence of the YMDD mutation. The incidence, clinicopathological features, and subsequent course, and possibly the underlying immune mechanisms, are similar to those of wild-type HBV chronic infection. Because severe hepatitis may occur, patients should be followed carefully once the YMDD mutant emerges. (HEPATOLOGY 1999;30:567-572.)Lamivudine, the (Ϫ) enantiomer of 2Ј-deoxy-3Ј-thiacytidine, is a nucleoside analogue with potent antiviral effects against hepatitis B virus (HBV) both in vitro 1 and in vivo. [2][3][4] Complete viral suppression, as determined by negativity for serum HBV-DNA, may be achieved in most patients at a daily dose of 100 mg or greater. However, hepatitis B e antigen (HBeAg) clearance was seen in only a minority of patients. 3,4 In addition, mutations in the sequence of the conserved tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase may develop during lamivudine therapy in both immunosuppressed liver transplantation patients 5-7 and immunocompetent patients. 4,[8][9][10] In our 1-year trial of lamivudine for chronic hepatitis B, the incidence of YMDD mutations was 14%. 4 Although the patients with YMDD mutants still maintained an HBV-DNA or alanine transaminase (ALT) level lower than the baseline levels, and were not associated with a lower histological response, 4 the clinical significance and outcome of these mutations are not examined in detail. To examine the clinicopathological features and course of the patients after em...