In early 2002, Mr. M, a 60-year-old school administrator, presented to his primary care physician with the complaint of fatigue. Laboratory testing showed abnormal results for liver function tests, including alanine aminotransferase (ALT) 91 IU/L and aspartate aminotransferase (AST) 73 IU/L. His serum albumin was slightly below normal at 3.4 g/dL and total bilirubin mildly elevated at 1.7 mg/dL. His white blood count and platelet count were 3600/mm³ and 132,000/mm³, respectively.

Based on these findings, hepatitis screening tests were ordered. Results showed that the patient was HBsAg+ and HBeAg+, with an initial HBV DNA viral load of 1.4 x 10⁹ copies/mL (2.55 x 10⁸ IU/mL) (see Fig. 1). The patient was negative for anti-HCV, anti-HDV, and HIV. A subsequent ultrasound examination showed mild echogenicity and no mass. A liver biopsy was obtained and showed inflammation grade 2/4 and fibrosis stage 3/4.

At the time of this patient's presentation and diagnosis, lamivudine was the only available oral drug. (Adefovir would not be approved until September of that year.) He was started on lamivudine 100 mg daily. Initially, there was a substantial reduction in HBV DNA and ALT levels. Within 12 months, however, both levels started to increase.

Figure 1

In January 2004, the patient was switched from lamivudine to adefovir 10 mg/d. His HBV DNA and ALT levels decreased steadily, but gradually, in the months following the switch. As of May 2006, his HBV DNA and ALT levels were 2.1 x 10⁶ copies/mL (4.55 x 10⁵ IU/mL) and 64 IU/L, respectively. The patient is well without signs or symptoms of hepatic decompensation. He remains HBeAg+.

Question: What is the best course of action now?

1. Keep the patient on adefovir 10 mg/d but monitor HBV DNA and ALT levels every 3 months
2. Add lamivudine
3. Switch to entecavir

Discussion

Adefovir resistance may be suspected in this patient based on the plateau of ALT levels greater than the upper limits of normal, and the inability to suppress the patient's serum levels of HBV DNA below 1 x 10⁵ copies/mL. Due to the patient's history of lamivudine resistance, switching to entecavir—rather than adding lamivudine—is the best course of action. Approval of entecavir for the treatment of chronic hepatitis B infection was based on results of full-scale randomized controlled trials in lamividine-resistant, as well as nucleoside-naive, patients.¹ This patient already has documented lamivudine resistance; thus, to add back lamivudine would also be suboptimal.

This patient's course is typical among those initially started on lamivudine before other oral options were available. Development of lamivudine resistance is common and can be seen as early as 3 to 6 months after treatment begins, with up to 70% of treatment-naive patients developing resistance after 4 years.² In this patient, resistance occurred as early as 12 months after the start of lamivudine therapy. By this time—September 2002—adefovir had been approved for the treatment of hepatitis B and was an agent of choice in the setting of lamivudine resistance. Although the significant decrease of Mr. M's HBV DNA and ALT levels in the months following the start of adefovir demonstrated an initial virologic and biochemical response, his HBV DNA and ALT levels after 2 years of adefovir therapy suggest a suboptimal response and the possibility of resistance.

In nucleoside-naive patients, the rate of adefovir resistance is low: 15% to 18% after 4 years.^3,4 However, in the setting of virologic failure (defined as a confirmed increase of ≥1 log₁₀ HBV DNA copies/mL above nadir or never suppressed below 10³ copies/mL), adefovir resistance-associated mutations may be found in up to 42% of patients.⁵ Moreover, preexisting lamivudine resistance in treatment-experienced patients increases the probability of adefovir resistance. Lee et al studied the rate of adefovir resistance in 57 lamivudine-resistant and 38 treatment-naive patients who received adefovir 10 mg/d for at least 48 weeks.⁶ Adefovir resistance was defined as the presence of either rtA181V/T or rtN236T mutation. After 48 weeks of therapy, 18% of the lamivudine-resistant patients had developed adefovir resistance compared with 0% of the nucleoside-naive patients (P < .01).

References

1. Baraclude^™ (entecavir). Product Information. Princeton, NJ: Bristol-Myers Squibb Company; 2005.
2. Lai C-L, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687-696.
3. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. 2005;352:2673-2681.
4. Locarnini S, Qi X, Arterburn S, et al. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB) [abstract 36]. Presented at: 40^th Annual Meeting of the European Association for the Study of the Liver; April 13-17, 2005. Paris, France.
5. Hepsera^® (adefovir dipivoxil). Product Information. Foster City, CA: Gilead Sciences, Inc; 2006.
6. Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385-1391.