A 47–year-old Caucasian man was self-referred for a second opinion concerning antiviral therapy for chronic hepatitis B. At week 48 of therapy with adefovir 10 mg daily, he had been advised by his primary care physician to discontinue treatment due to lack of efficacy. Rather than discontinuing therapy, the patient chose to continue with adefovir while awaiting the referral appointment.

At the time of consultation, the patient was asymptomatic and physical examination was unremarkable, without any stigmata of chronic liver disease, no hepatomegaly or splenomegaly. The patient brought with him the following laboratory data obtained at his last visit with his primary care provider 1 month prior: alanine aminotransferase (ALT), 37 U/L; platelet count, 120,000/mm³; HBV DNA, 2 x 10³ IU/mL (1 x 10⁴ copies/mL); and HBeAg positive. A test for anti-HBe had not been done at that time. Limited baseline laboratory data were available: ALT 121 U/L; HBV DNA, 2.4 x 10⁷ IU/mL (1.2 x 10⁸ copies/mL) and HBeAg positive. A liver biopsy report from 5 years ago was also available, which showed grade 2 stage 2 disease.

DECISION POINT: Would you recommend stopping or continuing anti-HBV therapy?

Discussion

(b) Although the patient remains HBeAg positive with 2000 IU/mL of HBV DNA, there is evidence of ALT normalization and modest viral suppression (a decrease of about 4 logs of virus) with his current adefovir regimen. Despite the response to date, however, adequate endpoints to support stopping of therapy have not yet been achieved. The ultimate endpoint for therapy for chronic hepatitis B is loss of hepatitis B surface antigen. Attainment of this endpoint, however, is uncommon with currently available agents and so other endpoints must be considered, such as HBeAg seroconversion, normalization of ALT, and reduction of HBV DNA. This patient should remain on anti-HBV therapy until adequate endpoints have been achieved. A subsequent decision is whether to continue the current regimen or modify the regimen to try to achieve better viral suppression.

The initial goal of antiviral therapy in this patient is to achieve HBeAg seroconversion with development of anti-HBe.^1,2 Patients who achieve this durable endpoint have diminished disease activity and a lower chance of hepatic complications.³ The likelihood of achieving HBeAg seroconversion while on nucleos(t)ide therapy increases with the duration of treatment.¹ In general, HBeAg seroconversion is accompanied by a marked decrease of HBV DNA to less than 10³ IU/mL with subsequent normalization of serum ALT activity.³ Discontinuation of oral antiviral therapy prior to achieving HBeAg seroconversion, even in the setting of significant HBV DNA suppression while on treatment, is associated with rapid recrudescence of disease evidenced by increased HBV DNA levels and abnormal ALT activity back to baseline levels.^4,5 Hepatic decompensation and deaths have also been reported when treatment with oral agents was terminated prematurely.

Cautious withdrawal of therapy can be considered for patients who achieve HBeAg seroconversion that persists for a further 6 to 12 months while still on treatment.¹ However, patients should be monitored at monthly intervals for the first 3 to 6 months after treatment withdrawal to monitor for reactivation of disease. Evidence of reactivation should prompt continuation of therapy.

With the decision to continue this patient's therapy, the next step is to decide whether to continue with adefovir monotherapy at the current dose and monitor for resistance at regular intervals, or to add—or switch to—another anti-HBV agent. While resistant mutations should be considered, they have not been reported during the first 48 weeks of treatment with adefovir, so that this is an unlikely cause for suboptimal viral suppression at this time.⁶ If this patient continues on adefovir, he will remain at risk for the development of adefovir-resistant mutations during subsequent years of therapy.⁷ Continued, regular monitoring of disease activity and levels of HBV DNA will be important to determine when to add an additional agent or to switch to other antivirals that may have more potency for this individual. The decision to continue adefovir or switch to or add another agent is subject to the clinical judgment of the clinician.

References

1. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.
2. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861.
3. McMahon BJ. The natural history of chronic hepatitis B virus infection. Semin Liver Dis. 2004;24:17-21.
4. Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002;51:597-599.
5. Zhang JM, Wang XY, Huang YX, et al. Fatal liver failure with the emergence of hepatitis B surface antigen variants with multiple stop mutations after discontinuation of lamivudine therapy. J Med Virol. 2006;78:324-328.
6. Hadziyannis S, Tassopoulos N, Chang T-T, et al. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy. Hepatology. 2005;42(suppl 1):754A.
7. Liaw YF. The current management of HBV drug resistance. J Clin Virol. 2005;34 (suppl 1):S143-146.