This study will evaluate the efficacy and safety of peginterferon alfa-2a or ADV, in participants with lamivudine-resistant HBeAg-positive chronic hepatitis B. Participants will be randomized to receive either peginterferon alfa-2a for 48 weeks in combination with oral lamivudine for the first 12 weeks, or ADV for 72 weeks in combination with oral lamivudine for the first 12 weeks. The anticipated time on study treatment is 72 weeks, and the target sample size is 255 individuals.

Inclusion Criteria:

• Adult participants 18-65 years of age
• Hepatitis B surface antigen (HBsAg)-positive, HBeAg-positive, and anti-HBs-negative for greater than or equal to (>=) 6 months
• Receiving lamivudine currently, and for >=6 months
• hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) decreased >=2 log during lamivudine treatment on >=1 occasion
• Absence of cirrhosis confirmed by liver biopsy in previous 6 months

Exclusion Criteria:

• Other drugs with activity against HBV within the prior 6 months, except lamivudine
• Antiviral, anti-neoplastic, or immunomodulatory therapy less than or equal to (<=) 6 months before study - Active infection with hepatitis A, C, or D virus, or human immunodeficiency virus
• Decompensated liver disease
• Medical condition associated with another chronic liver disease