Current first-line hepatitis B therapies have been shown to be effective at viral suppression with low resistance rates. Given this success, we have been fortunate to see a reduction in the number of patients requiring liver transplantation for hepatitis B in the United States.1
The AASLD practice guidelines for hepatitis B suggest that, for HBeAg-positive individuals, antiviral therapy can be discontinued after at least 1 year of therapy, HBeAg seroconversion, and undetectable HBV DNA levels. A consolidation period of at least 6 months is recommended.2 However, as challenging and costly as it may be to keep patients adherent to long-term medications, some data suggest that HBeAg seroconversion may not be the ideal endpoint.
Fung et al previously reported that in 101 patients with lamivudine-induced HBeAg seroconversion, 82% of those who discontinued therapy had viral rebound at 4-year follow-up compared with those who continued lamivudine long term. In most patients who continued lamivudine after seroconversion, HBV DNA remained undetectable. Importantly, a cumulative incidence of 16% alanine aminotransferase flares was also noted in patients who stopped lamivudine.3 Another study by Reijinders et al4 also showed a cumulative serologic recurrence rate of 44%, and 70% in their study had either a virologic or serologic recurrence with long-term follow-up.
In this month’s journal, Chaung and colleagues retrospectively report on 88 Asian American patients with HBeAg seroconversion in 3 US sites. Forty percent of these patients received entecavir or tenofovir and 39 patients discontinued therapy after a median consolidation period of 12 months, whereas 49 patients continued therapy. Remarkably, 90% of those who discontinued therapy had viral relapse at a median time of 3 months. In those who had recurrence of viremia, viral levels returned to >1,000,000 IU/mL in 29% and to >10,000 in 71%. Further, ALT flares occurred in 38% of those who discontinued therapy. Serologic recurrence data were lacking in this study, likely because of the clinicians resuming the medications once virologic recurrence was noted.5
With the seminal data garnered from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus study, our knowledge about the relationship between high viral levels and the risk of cirrhosis and hepatocellular carcinoma drives us to more carefully examine these risks in HBV-infected patients with persistent viremia.6 If viral recurrence rates after HBeAg seroconversion and withdrawal of antiviral therapy are 70% to 90%, which patients, if any, should have medications discontinued and which patients can safely stop? The compensated cirrhotic patient is probably the patient in whom all clinicians pause before discontinuing therapy, even with seroconversion. This is because of the risk of biochemical and clinical flare associated with viral recurrence in the stable cirrhotic patient, thus pushing this patient closer to transplantation. Given recent data that fibrosis and cirrhosis are reversible with long-term antiviral hepatitis B therapy, perhaps we should keep these higher-risk patients on therapy.7 Some research in antiviral response durability suggests that younger individuals may have a better chance at a durable response,8,9 and these patients may also be less likely to have worrisome advanced fibrosis or cirrhosis; however, further studies are needed. Future studies examining these issues need to be consistent in definitions of response, viral and serologic recurrence, and consolidation.
In the meantime, discontinuation of those patients who have HBeAg seroconverted while on first-line oral antiviral therapy should be approached with setting of realistic expectations for the patient, close and prolonged monitoring of viral and serological recurrence, and weighing the risks of discontinuation based on underlying disease.
1. Kim WR, Terrault NA, Pedersen RA, et al. Trends in waiting list registration for liver transplantation for viral hepatitis in the United States. Gastroenterology. 2009;137:1680–1686
2. Lok AS, McMahon B. Chronic hepatitis B: update 2009. Hepatology. 2009;50:1–36
3. Fung J, Lai CL, Tanaka Y, et al. The duration of lamivudine therapy for chronic hepatitis B: cessation vs. continuation of treatment after HBeAg seroconversion. Am J Gastroenterol. 2009;104:1940–1946
4. Reijinders J, et al. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology. 2010;139:491–498
5. Chaung KT, Ha NB, Trinh HN, et al. High frequency of recurrent viremia after hepatitis B e antigen seroconversion and consolidation therapy. J Clin Gastroenterol. 2012;46:865–870
6. Chen JD, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology. 2010;138:1747–1754
7. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886–893
8. Lee HW, Lee HJ, Hwang JS, et al. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B. Hepatology. 2010;51:415–421
9. Wang L, Liu F, Liu YD, et al. Stringent cessation criterion results in better durability of lamivudine treatment: a prospective clinical study in hepatitis B e antigen-positive chronic hepatitis B patients. J Viral Hepat. 2010;17:298–304