When to Stop Therapy
Patients should be monitored at least every six months while receiving therapy with the oral agents, and more frequently when treated with peginterferon alfa-2a for the development of side effects and tolerance to therapy. Patients treated with peginterferon alfa-2a are treated for a fixed time period of one year. Therapy is stopped prematurely only if intolerable side effects develop, which occurs in less than 5% of patients. The traditional end-point of treatment for patients with HBeAg-positive CHB treated with oral agents is HBeAg seroconversion to anti-HBe in association with very low or undetectable serum HBV DNA.^2–6 Treatment is typically continued for an additional 6–12 months to reduce the likelihood of relapse. Some clinicians favor long-term treatment with oral agents for patients with cirrhosis, even after HBeAg seroconversion, to avoid the risk of relapse with associated decompensation. The end-point of treatment for patients with HBeAg-negative CHB with oral agents is unknown, and current data favor long-term therapy, since relapse rates are high if treatment is stopped when serum HBV DNA becomes undetectable. Preliminary data suggest that the relapse rates are lower, although still substantial, if treatment is stopped after several years of undetectable serum HBV DNA when treated with lamivudine or adefovir.^10,11

When to Alter Therapy
The time to alter therapy is treatment failure, either primary failure or in association with an inadequate response while receiving treatment with oral agents. The definition of primary treatment failure is a serum HBV DNA decline of less than 1 log10IU/ml at week 12 of treatment, and the definition of an inadequate virological response is a serum HBV DNA ≥2,000 IU/ml at week 24 of treatment.¹² For primary treatment failure, which is uncommon, the optimal strategy is to switch to a more potent drug or possibly a combination of drugs.¹² For an inadequate virological response, the optimal approach is to add another drug—preferably one that is more efficacious, or if such a drug is not available, then add one that is not cross-resistant—and repeat monitoring at three-month intervals. Monitoring after 48 weeks may be extended from three to six months if the virological response becomes complete.¹²

Another time to alter therapy by switching or adding another drug is the development of HBV antiviral drug resistance. Genotypic resistance with adefovir monotherapy is 29% after five years of therapy,¹³ and the cumulative rate of resistance with entecavir therapy is <1% in treatmentnaïve patients, and 39.5% in lamivudine-resistant patients after four years of therapy.¹⁴ Genotypic resistance with telbivudine occurs at intermediate rates between those of adefovir and entecavir versus lamivudine, with 21.6% of HBeAg-positive patients and 8.6% of HBeAg-negative patients experiencing resistance after two years of therapy.¹⁵ The telbivudine pivotal trial demonstrated that the greater the degree of viral suppression at week 24 of therapy, the better the outcomes after one to two years of therapy in terms of undetectable serum HBV DNA, HBeAg seroconversion, ALT normalization, and rate of HBV antiviral drug resistance.¹⁶ The reduced efficacy and higher rates of resistance seen in patients with serum HBV DNA >2,000 IU/ml at week 24 suggest consideration of intensified treatment, with a second or alternative agent. Table 5 summarizes the potential management of HBV antiviral resistance.² For patients with lamivudine resistance, which is the most common type of HBV antiviral drug resistance encountered, options include switching to or adding adefovir, with recent data favoring combination lamivudine plus adefovir. The latter strategy is favored because the rate of subsequent adefovir resistance is considerably higher using the switch strategy in the setting of pre-existing lamivudine resistance.^17–19 Potential future therapy for lamivudine resistance may be tenofovir or the combination of tenofovir plus emtricitabine.

Future Treatment of Chronic Hepatitis B
The indications for treatment and duration of therapy require a better understanding of the clinical significance of low HBV DNA levels, including after HBeAg seroconversion, which is associated with disease progression. New and emerging therapies under study for the treatment of CHB hold promise for improved treatment, e.g. tenofovir, which is in late phase III testing and is promising based on high potency and a low rate of resistance. Finally, the role of combination oral HBV antiviral treatment, the prime example for the management of co-infection with HIV infection, is undergoing clinical trial and holds promise to reduce the rate of resistance and possibly enhance efficacy. The most important future goal of oral therapy of chronic hepatitis B is to avoid the development of resistance by using drug(s) with a high genetic barrier to resistance or using combination therapy.