Editorial Board: Emmet B. Keeffe, MD (Chair);

Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD

HBV Watch^™

Timely Information for Practicing Physicians

APRIL 2003

ADEFOVIR DIPIVOXIL TREATMENT OF HEPATITIS B VIRUS (HBV) INFECTION

Treatment of HBeAg-negative chronic hepatitis B. Adefovir dipivoxil (Hepsera^™, Gilead Sciences) is a nucleotide analogue that has demonstrated potent antiviral activity against HBV in phase I and II clinical trials. Stephanos Hadziyannis et al from the Adefovir Dipivoxil 438 Study Group conducted a double-blind study in which 185 chronic HBV patients who were HBeAg-negative were randomized in a 2:1 ratio to receive 10 mg of adefovir dipivoxil or placebo daily for 48 weeks. At week 48, 77 of 121 (64%) adefovir dipivoxil-treated patients compared to 19 of 57 (33%) patients in the placebo group had improvement of histological liver abnormalities as measured by the Knodell necroinflammatory score (p <0.001). Alanine aminotransferase (ALT) levels had normalized in 72% and 29% of patients in the adefovir dipivoxil and placebo groups, respectively (p <0.001). Moreover, HBV DNA levels became undetectable by polymerase chain reaction (PCR) in 51% of patients treated with adefovir dipivoxil, while undetectable HBV DNA levels were not achieved in any of the placebo patients (p <0.001). No HBV polymerase mutations associated with resistance to adefovir dipivoxil were observed, and the safety profile of adefovir dipivoxil was similar to that of placebo. These results demonstrated that 48 weeks of adefovir dipivoxil therapy was safe and effective treatment for HBeAg-negative chronic hepatitis B. (Hadziyannis SJ, et al. N Engl J Med 2003;348:800-807)

Treatment of HBeAg-positive chronic hepatitis B. Patrick Marcellin et al from the Adefovir Dipivoxil 437 Study Group performed a double-blind study in which 515 chronic HBV patients who were HBeAg-positive were equally randomized to receive 10 mg of adefovir dipivoxil, 30 mg of adefovir dipivoxil, or placebo daily for 48 weeks. At week 48, greater percentages of 10 mg or 30 mg adefovir dipivoxil-treated patients compared to placebo patients had improvement of liver histology as measured by the Knodell necroinflammatory score (53% [p <0.001], 59% [p <0.001], and 25%, respectively), normalization of serum ALT levels (48% [p <0.001], 55% [p <0.001], and 16%, respectively), HBeAg seroconversion (12% [p = 0.049], 14% [p = 0.01], and 6%, respectively), and undetectable serum levels of HBV DNA by PCR assay (21% [p <0.001], 39% [p <0.001], and 0%, respectively). No HBV polymerase mutations associated with resistance to adefovir dipivoxil were identified. The safety profiles of the treatment groups were similar except that mild to moderate serum creatinine elevations occurred more frequently in the 30 mg adefovir dipivoxil treatment group. These results showed that 48 weeks of daily adefovir dipivoxil therapy was safe and effective treatment for HBeAg-positive chronic hepatitis B. The 10-mg adefovir dipivoxil dose has a more favorable risk-benefit profile for long-term treatment. (Marcellin P, et al. N Engl J Med 2003;348:808-816)

ACUTE EXACERBATION OF HBV INFECTION

Lamivudine therapy in hepatic decompensation. Hepatic decompensation during an acute exacerbation of chronic HBV infection is associated with a high mortality rate. Rong-Nan Chien and coworkers at Chang Gung University (Taipei, Taiwan) treated 60 consecutive chronic HBV patients with acute exacerbation and hepatic decompensation with lamivudine 150 mg daily. A historical control group comprising 31 chronic HBV patients hospitalized within the 6 months immediately prior to the initiation of this study was analyzed for comparison. Acute exacerbation was defined as an abrupt elevation of serum ALT to >300 U/L in patients whose baseline ALT levels were <5 times the upper limit of normal (ULN) and whose serum bilirubin levels were within the normal limit, or a 2-fold elevation of ALT to >5 times the ULN. Hepatic decompensation was manifested by jaundice and prolongation of the prothrombin time to >3 seconds, ascites, or hepatic encephalopathy. After a median treatment period of 6 weeks (range, 1-48 weeks), all of the lamivudine-treated patients with a baseline serum bilirubin level <20 mg/dL (n = 25) had survived, while 25% (5 of 20 patients) of comparable patients in the control population had died (odds ratio, 2.667 [95% CI, 1.787-3.979]; p = 0.013). However, the mortality rates of the 2 treatment groups were similar for the subpopulation of patients with a baseline serum bilirubin level ³20 mg/dL. These results indicate that lamivudine may be effective therapy for chronic HBV patients in acute exacerbation with early hepatic decompensation. (Chien R-N, et al. J Hepatol 2003;38:322-327)

Population study of spontaneous HBeAg seroconversion. M-F. Yuen and others at the University of Hong Kong reviewed data from 3063 Chinese patients with chronic HBV infection. Among this large population were 756 patients who had experienced at least one acute exacerbation episode (an increase in ALT to >1.5 times the ULN after excluding other common causes of elevation) and were HBeAg-positive. HBeAg seroconversion occurred within 3 months in 297 patients (38.8%). The percentages of HBeAg-positive patients with peak ALT levels 1.5-2 times the ULN, >2-5 times the ULN, and >5 times the ULN who developed HBeAg seroconversion within 3 months of the acute exacerbation were 27.2%, 35.6%, and 46.4%, respectively. In 110 evaluable patients, median HBV DNA levels were found to be lower after, compared to before, HBeAg seroconversion (p <0.0001). In addition, HBeAg-positive patients who had not undergone seroconversion, compared to anti-HBe-positive patients, had a longer median duration of acute exacerbation (p = 0.011), higher median peak ALT levels (p <0.0001), and higher peak serum alpha-fetoprotein levels (p <0.0001). This analysis shows that the HBeAg seroconversion rate was higher in those patients with higher peak ALT levels during acute exacerbation and provides epidemiological data that will be useful for the design of future clinical trials. (Yuen M-F, et al. Gut 2003;52:416-419)

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