Approximately 350 million people worldwide have been infected with hepatitis B virus (HBV).¹ Chronic HBV infection results in 4,000–5,500 deaths annually in the US and one million people worldwide.² Fortunately, over the past decade antiviral agents have revolutionized the management of chronic HBV infection and reduced the risk of liver disease progression.³ Antiviral agents include nucleoside analogs (lamivudine, telbivudine, and entecavir) and acyclic phosphonate nucleotides (adefovir and tenofovir). However, a major drawback of oral antiviral therapy is treatment failure and genotypic resistance (see Table 1). This article will focus on clinical consequences, mechanisms, diagnosis, prevention, and management options for antiviral resistance in chronic hepatitis B.

Consequences of Drug Resistance
There are important clinical consequences of antiviral resistance. Several studies have demonstrated a loss of initial efficacy after resistance occurs. For exa mple, a rebound in HBV DNA, often back to pre-treatment levels, may occur,^4,5 the probability of hepatitis B eantigen (HBeAg) seroconversion is reduced, reversal of initial histological improvement can be seen,⁶ and there is a higher risk for hepatic decompensation and even death.^7,8 As has been seen with chronic HIV infection, development of antiviral resistance to one medication may limit the utility of future treatment options due to crossresistance. Limited evidence supporting this was provided in one study, which showed a low rate of entecavir resistance among treatment-naïve patients (<2% after three years of continuous therapy),⁹ but in the presence of pre-existing lamivudine mutation, resistance rates reached 50% at five years.^9,10 It should be noted, however, that the design of this study stipulated that treatment should be discontinued when patients met certain response criteria, so that few patients remained on treatment after five years. Therefore, the results were based on a very limited population. In addition, the dose of entecavir was also changed in a subgroup of patients failing to reach study end-points, which may have altered the apparent incidence of resistance. Lamivudine resistance was associated with an accelerated rate of liver disease progression in a landmark study of 651 HBV patients in Taiwan with advanced hepatic fibrosis or cirrhosis compared with those who were treated but did not develop lamivudine resistance.³ Therefore, antiviral resistance in HBV has important clinical consequences and clinicians must have a working knowledge of antiviral resistance in order to avoid or minimize these adverse outcomes.

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