Entecavir in treatment-naïve patients is a potent agent, with reports of continued efficacy with accumulation of more patients who were HBV DNA negative; normalization of ALT over 96 weeks of therapy has also been reported in HBeAg-positive and -negative patients. This more potent effect is seen in the absence of lamivudine resistance and a cumulative result confirmed HBV DNA levels <300 copies/ml in 80% and 94% of entecavir-treated patients, respectively.^19,20 Entecavir, at a dose of 1mg qd, has demonstrated efficacy in patients with lamivudine refractory disease.¹⁷ Forty-eight weeks of therapy resulted in a significantly greater mean change (decrease) from baseline HBV DNA levels in the entecavir cohort compared with those who continued lamivudine therapy (–5.14 and –0.48 log10 copies/ml, respectively; p<0.0001). In addition, histologic improvement (defined as ≥2-point decrease in Knodell necroinflammatory score and no worsening of fibrosis) occurred in 55% of patients after 48 weeks of entecavir therapy compared with only 28% of the lamivudine cohort (p<0.0001).¹⁷ After 48 weeks of therapy, virologic responders (HBV bDNA <0.7MEq/ml, HBeAg-positive) continued therapy for a further 48 weeks. All other patients discontinued therapy. The cumulative results at weeks 96 and 144 demonstrated that 30% and 40%, respectively, of patients in the entecavir group achieved undetectable levels of HBV DNA (<300 copies/ml) compared with 1% of those receiving lamivudine therapy at 96 weeks (p<0.0001).^10,21 Currently, the resistance rate to entevavir in patients with pre-existing lamivudine-resistance mutations is 31% at three years. This very high rate of resistance has now led many experts to recommend that entecavir be used in combination with a nucleotide analog such as adefovir or tenofovir, based on in vitro data.²²

Conversely, if adefovir is the first therapy used and resistance occurs, lamivudine, entecavir, and tenofovir have been demonstrated to be effective.^2,23 There are insufficient data at this time to indicate whether switching to, or addition of, an alternative agent is the optimal strategy for this special population. However, the current algorithm—i.e., the US algorithm—would propose add-on therapy as opposed to a switch.

Summary

De novo resistance to antiviral medications has now been reported during long-term treatment of CHB infection with all medication licenses and in latestage development. The development of medication resistance is associated with a negative impact on clinical outcome, and consequently careful evaluation of, for example, the INNOLiPA assay is required to enable early identification of patients with resistant mutations. More importantly, choosing a medication with the lowest rate of resistance and the deepest level of viral suppression should be of paramount importance. Alternatively, a combination of medications could be used, although this is a more complex and costly method of decreasing the risk of resistance. In patients who develop antiviral resistance, the options are an add-on or alternative agent with complementary effects. Future studies are required, with tenofovir as both monotherapy and combination with entecavir, and a nucleotide or tellbivudine with a nucleotide, in order to determine the optimal approach. Agents such as entecavir and tenofovir (currently not licensed for CHB), which produce a rapid and sustained suppression of viral replication and are associated with lower rates of resistance, are clearly leading choices in HBV management. Telbivudine now demonstrates lower levels of viral resistance, shown to be 6% at 48 weeks and 22% at 96 weeks as defined by a 1 log rise in HBV DNA over nadir or a HBV DNA level over 105. De novo combination therapy, which targets multiple sites within the POL, has been suggested as an additional option to reduce the likelihood of resistance. Current phase III and IV trials should help to define the role of these combinations with nucleoside and nucleotide analogs. Preliminary data suggest that the rate of resistance is lower with combination therapy, but that an increase in efficacy does not occur. As more data emerge, the approach to patients with resistant mutants will evolve further. In the meantime, ensuring compliance and utilizing efficacious agents with low rates of resistance that do not compromise future treatment options will reduce the likelihood of treatmentemergent resistance and improve patient outcomes.