Is entecavir ideal for the treatment of lamivudine-refractory chronic hepatitis B?

We read with interest the excellent article by Sherman et al. demonstrating that 96 weeks of entecavir therapy resulted in superior biochemical, virological, and serological benefit compared to continued lamivudine therapy for those with lamivudine-refractory chronic hepatitis B (CHB).1 Nevertheless, we consider the application of ongoing nucleoside analog for treatment of lamivudine-refractory CHB would elicit some concerns. The current strategies for the management of lamivudine-refractory CHB include add-on adefovir therapy, a switch to entecavir therapy, and a switch to tenofovir therapy.2 In this study, the enrolled patients could not achieve optimal responses after lamivudine therapy, and more than 50% of them also had failed to improve on interferon therapy previously, so their immunity might be impaired for the clearance of hepatitis B virus (HBV). Hence, long-term antiviral therapy might be necessary for sustained viral suppression. In this study, only 10% of the patients with 48-week entecavir therapy had durable virological response. More importantly, 5% of patients in this study had preexisting entecavir-resistance substitutions plus lamivudine-resistance substitutions at baseline. The long-term use of entecavir would substantially increase the incidence of drug resistance under the background of lamivudine resistance. Entecavir is excellent for naïve patients with CHB, because the drug exhibits high potency for viral suppression and high genetic barrier for drug resistance.3 Nevertheless, in the case of lamivudine-refractory CHB, add-on or switch to nucleotide analogs seemed to be more suitable than ongoing nucleoside analogs in concern of drug resistance. In a recent recommendation from an Italian workshop,4 for patients with suboptimal response or resistance to lamivudine, add-on adefovir or tenofovir is favored. Lamivudine therapy has been reported to induce HBV S gene mutation.5 The study implied that a vaccine-escape mutant might be selected under the pressure of antiviral therapy. If we could not suppress the virus appropriately, the efficacy of vaccine might one day be threatened and the transmission of occult HBV might occur frequently. Hence, rapid viral suppression is crucial to avoid the selection of vaccine-escape mutants. This study also demonstrated that low baseline serum HBV DNA level in lamivudine-refractory CHB was associated with fewer incidences of subsequent entecavir resistance. This means that an earlier switch to entecavir, while serum HBVDNA levels were relatively low at the time of detection of suboptimal response, could achieve more potent viral suppression and lower rates of resistance for entecavir. Likewise, for those who had suboptimal viral response or viral breakthrough during adefovir therapy, but were not associated with adefovir-resistant mutations, tenofovir still exhibited effective viral suppression.6 However, for patients with adefovir-resistant mutants detected by genotypic analysis, tenofovir might not be sufficient to suppress HBV. Instead, the combination of tenofovir with the nucleoside analog emtricitabine achieved more potent and sustained viral suppression. Consequently, if we continue to use the same class of antiviral therapy, close biochemical, virological, and genotypic surveillance is mandatory for a roadmap to avoid the emergence of drug-resistant mutations.7, 8 Although more prospective, randomized, head-to-head studies might be needed to draw this conclusion, to switch or add-on other classes of antiviral therapy seems to be more appropriate if possible. Chien-Wei Su* §, Jaw-Ching Wu , Shou-Dong Lee* §, * Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, § Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.