The risk of resistance or the development of resistance to antiviral agents during the treatment of chronic hepatitis B (CHB) infection presents the clinician with a number of hurdles. Due to the known complications that can occur once resistance emerges—including resistance to other medications, progressive liver disease, flares of inflammation, liver failure, liver transplantation, and death—strategies should be employed to reduce the likelihood of resistance and to promptly identify and manage patients who develop resistant mutants of the hepatitis B virus (HBV). Importantly, the development of resistance to one medication predisposes the individual to the development of resistance to other agents; therefore, a primary objective of treatment should be to avoid resistance.

Impact of Drug Resistance on Clinical Outcome

The development of drug-resistant mutants has been shown to negatively impact clinical outcome. The literature contains reports of acute flares of hepatitis, hepatic failure, urgent liver transplant in patients with cirrhosis, and death, as well as an increased risk of hepatocellular carcinoma (HCC) and graft failure in post-transplant patients.^1-4 In addition, the rate of seroconversion to anti-HBe is reduced in patients with antiviral resistance.¹ The development of resistance also decreases the rate of histologic improvement seen when viral suppression is effective. In long-term lamivudine studies, patients who developed YMDD mutations were less likely to experience improvements in necroinflammatory activity compared with those with wild type virus.⁵ Once resistance occurs during the use of an antiviral agent for HBV, rising DNA levels and increases in liver enzymes are seen.

In the seminal paper by Liaw,4 the impact of resistance has also been demonstrated in patients with advanced liver disease. This study assessed the effectiveness of lamivudine therapy in preventing disease progression. In those patients who have suppression of HBV DNA and no resistance, there were improved end-points of treatment. Patients developing YMDD mutations demonstrated a higher incidence of clinical decompensation than those without lamivudine resistance (11% and 5%, respectively).⁴ The proportion of patients experiencing disease progression was lower in the YMDD group than in the placebo group, but the benefit compared with those without YMDD mutations was decreased (see Figure 2).

Impacting the Potential for Antiviral Resistance

A number of strategies can be used to reduce the rate of antiviral resistance. Multiple studies have demonstrated that decreased rates of development of resistance are associated with deeper levels of viral suppression.^6-8 Agents that produce a rapid and strong suppression of viral replication are likely to be associated with a lower rate of resistance.⁹ Current data suggest that newer agents—for example adefovir and entecavir—are associated with lower rates of resistance than lamivudine.^1,10 Adefovir resistance does not develop for 2–3 years due to the requirement for mutations that change the efficacy of adefovir, which occur more rarely during mutations of the HBV genome. With resistance to entecavir, 3–5 mutations are required, as well as two preexisting mutations that are present only in patients with lamivudine resistance. Thus, the use of sequential monotherapy with weaker agents or medications with higher rates of resistance and compliance with treatment is imperative.⁹

It has been proposed that combination therapy with some medications, either at the beginning of therapy or early in the course of therapy (a ‘road-map’ or treatment decision point), may be the most appropriate option for patients with CHB. This combination therapy would theoretically convey two advantages:

• the most potent agent would provide an ‘additive’ effect and produce a deeper suppression of viral replication than the weaker single agent in the pair; and

• more importantly, the risk of treatment-emergent resistance would be reduced by targeting multiple sites, thus requiring multiple mutations to occur to produce antiviral resistance.^9,11,12

However, studies to date have shown conflicting results. A randomized, double-blind study comparing lamivudine monotherapy with lamivudine and adefovir combination therapy in treatment-naïve patients reported similar reductions in median HBV DNA level in both cohorts after 52 weeks of therapy (–4.80 and –5.41 log10 copies/ml, respectively)¹² and showed low rates of resistance, as demonstrated with ineferon and lamivudine.