Drug-specific mutation (Appendix Table 1) was detected by the development of resistant HBV YMDD mutations (mutation in amino acid sequence tyrosine, methionine, aspartate, aspartate) at the end of lamivudine treatments (31, 41–42, 49, 59, 63, 71, 73, 78, 80, 86–90) or at follow-up after the therapies (64, 79) (Appendix Table 1). Lamivudine administration increased the rates of YMDD mutation compared with placebo by 43% (41, 80). Longer treatments for 60 weeks versus 48 weeks resulted in larger rates of mixed and pure YMDD mutations (88). Adefovir versus placebo increased rates of emerging amino acid substitutions in the HBV-RT domain and rates of rt221Y amino acid substitution but not rt134D, rt219A, rt91I, rt134N, rt54H, and rt145M substitutions (63, 86). Longer treatments for 240 versus 114 weeks increased rates of adefovir-resistant mutations (42). However, combined therapy with adefovir plus lamivudine reduced the rates of YMDD compared with lamivudine monotherapy in patients with chronic hepatitis B and YMDD mutant HBV (71), with random differences in wild-type mutations. Interferon-α2b combined with lamivudine reduced rates of mutation compared with lamivudine alone, but with inconsistent effect sizes across 6 studies (31, 59, 73, 80, 87, 89). Pegylated interferon-α2a with lamivudine compared with pegylated interferon-α2a alone increased mutation in HBeAg-positive patients (49). The same study reported reduced rates of mutations with pegylated interferon-α2a or peginterferon-α2a combined with lamivudine than with lamivudine monotherapy (49). At follow-up after treatments, interferon-α2b alone or combined with lamivudine resulted in lower rates of mutations compared with lamivudine alone (79).