Thank you for the opportunity to respond to the comments made by Drs. Su, Wu, and Lee. They raise several important points regarding the management of patients with lamivudine-resistant chronic hepatitis B.

Many aspects of the management of patients with chronic hepatitis B with lamivudine resistance have changed since the current study was initiated in 2001. Initial recommendations were to continue lamivudine therapy despite resistance to avoid rebound hepatic flare; these have subsequently evolved into a question of whether to switch or add-on antiviral therapy. The study described here extends prior observations that a switch from lamivudine to entecavir achieves clinically relevant histologic improvement, reduction in hepatitis B virus (HBV) DNA, and normalization of alanine aminotransferase compared to continued lamivudine, despite reduced in vitro sensitivity of the lamivudine-resistant virus compared to the wild-type virus. These results have been confirmed by independent studies conducted in China and Japan.1, 2

Greater awareness of the negative impact of viral resistance on treatment response has led to increased surveillance on the part of clinicians, and patients with virologic rebound due to resistance are now commonly identified much earlier in their treatment course, when HBV DNA is lower than in the current study. As Dr. Su and colleagues point out, the results of the current study with entecavir must be interpreted in the context of the high HBV DNA at entry. As described in our article, a subset of patients whose baseline HBV DNA was less than 7 log10 copies/mL were more likely (8/11, 73%) to achieve HBV DNA < 300 copies/mL during the study.

The value of switching antiviral treatment to adefovir or adding adefovir to continued lamivudine therapy in lamivudine-resistant patients has been studied in both controlled trials and large case series.3–7 These studies have consistently shown no improvement in HBV DNA reduction or alanine aminotransferase normalization with the add-on versus the switch strategies, but reduced emergence of adefovir resistance with the add-on strategy was demonstrated in those studies which followed patients beyond 12 months.

It is important to recognize, however, that the adefovir add-on strategy does not achieve HBV DNA reduction to less than 1000 copies/mL after 48 weeks in approximately 50% of patients when the baseline HBV DNA is greater than 106 copies/mL.8 Thus, there remains room for improvement. The current practice of adefovir add-on (to continued lamivudine) could theoretically be improved upon with the use of two more potent antivirals, such as entecavir and tenofovir, each of which has demonstrated better antiviral potency in lamivudine-resistant patients than lamivudine or adefovir, respectively.

The strategy of using a nucleoside and a nucleotide with nonoverlapping resistance profiles appears to offer the best opportunity to avoid further emergence of resistance in lamivudine-resistant patients. Controlled clinical trials combining entecavir with either adefovir or tenofovir are ongoing, and the optimal management strategy for patients who have developed resistance to lamivudine remains to be established.


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  • 1
    Yao G, Zhou X, Xu D, Wang B, Ren H, Liu J, et al. Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China. Hepatol Int 2007; 1: 372380.
  • 2
    Suzuki F, Toyoda J, Katano Y, Sata M, Moriyama M, Imazeki F, et al. Efficacy and safety of entecavir in lamivudine-refractory patients with chronic hepatitis B: randomized controlled trial in Japanese patients. J Gastroenterol Hepatol 2008; doi: 10.1111/j.1440-1746.2008.05455.x.
  • 3
    Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004; 126: 8190.
  • 4
    Peters MG, Hann HW, Martin P, Heathcote EJ, Buggisch P, Rubin R, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004; 126: 91101.
  • 5
    Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006; 44: 283290.
  • 6
    Fung J, Lai CL, Yuen JCH, Wong DKH, Tanaka Y, Mizokami M, et al. Adefovir dipivoxil monotherapy and combination therapy with lamivudine for the treatment of chronic hepatitis B in an Asian population. Antivir Ther 2007; 12: 4146.
  • 7
    Lampertico P, Vigano M, Manenti F, Iavarone M, Lunghi G, Del Ninno E, et al. Three years of adefovir and lamivudine combination therapy minimizes the risk of genotypic resistance to adefovir in lamivudine resistant patients. 42nd EASL Barcelona, Spain [Abstract]. J Hepatol 2007 46(Suppl 1): Abstract 57.

Morris Sherman M.D.*, * Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada.