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Switch to Lamivudine Not as Effective as Staying on Entecavir


Hepatitis B patients who switch to cheaper lamivudine (Epivir-HBV) after achieving undetectable HBV viral load and normal ALT on entecavir (Baraclude) are more likely to experience viral rebound.

Lamivudine was the first oral drug approved to treat chronic hepatitis B virus (HBV) infection, and it has proved to be effective in slowing disease progression and reducing the risk of liver decompensation and liver cancer.

Unfortunately, taking lamivudine over the long term results in high rates of drug resistance -- up to 76% after 8 years of treatment. In contrast, the newer drug entecavir has a very low resistance rate -- only about 1% after 5 years of monotherapy. This makes lamivudine less than ideal as a treatment for chronic hepatitis B.

Recognizing that early suppression of HBV predicts a positive outcome over time, including fewer drug-resistance mutations, James Fung and colleagues from the University of Hong Kong hypothesized that people with sustained undetectable HBV viral load while on entecavir might continue to do well if they switch to lamivudine, a weaker but less expensive drug. The lower cost of lamivudine -- especially in countries with large numbers of people with hepatitis B -- may have been a primary rationale for this study.

As described in the April 2011 issue of Hepatology, the researchers designed a 2-arm study to evaluate whether switching to lamivudine might provide optimal HBV suppression after patients took entecavir for 6 or more months. One half of the study participants remained on 0.5 mg/day entecavir for 96 weeks while the other half (with a few exceptions) switched to 100 mg/day lamivudine monotherapy for the duration of the study.

There were 50 participants in the study, largely men (72%). About 20% were hepatitis B "e" antigen (HBeAg) positive. All had been treated with 0.5 mg/day entecavir for 6 to 25 months prior to study entry and had normal alanine aminotransferase (ALT) and undetectable HBV DNA (< 60 copies/mL). There were 6 participants with compensated liver cirrhosis at study entry. Patients with elevated ALT or detectable HBV viral load were excluded from the trial. Other exclusion criteria included evidence of liver cancer and a history of decompensated cirrhosis.

Participants who were randomly assigned to take lamivudine switched back to entecavir for the remainder of the study if they showed was evidence of HBV virological rebound. If they developed lamivudine resistance, they were treated with a combination of lamivudine and adefovir (Hepsera).


  • At 96 weeks, all 25 (100%) of participants in the entecavir arm still had undetectable HBV viral load.
  • Participants in the lamivudine arm did not fare as well: 6 out of 25 (24%) experienced HBV viral rebound.
  • There were no significant differences in the time on entecavir or pre-treatment viral load between patients with and without virological rebound after switching to lamivudine.
  • No ALT elevation was seen in any participants in either arm of the trial through 96 weeks.
  • Among the participants taking lamivudine who experienced HBV rebound, 3 achieved undetectable viral load again after switching back to entecavir.
  • No new symptoms or serious adverse events occurred throughout 96 weeks.
  • 3 participants (12%) in the lamivudine arm developed lamivudine resistance, while none of the participants in the entecavir arm developed resistance mutations.

The researchers discussed several limitations of their study: 1) The length of treatment with entecavir was not controlled, since patients had been taking entecavir for at least 6 months -- but often much longer -- before joining the study; 2) Most of the study participants were HBeAg negative, and the results might vary if they had been HBeAg positive; and 3) Neither hepatitis B genotype nor rates of achieving undetectable HBV viral load were determined, so their effects on virological rebound could not be assessed.

Based on their findings, the researchers concluded, "Prior optimal viral suppression with entecavir did not confer any significant advantage in patients who switched to lamivudine." In fact, they continued, switching from entecavir to lamivudine "resulted in a virological rebound rate of 24% and a resistance rate of 12% after 96 weeks [2 years]."

Investigator affiliations: Hepatitis and Liver Clinic and State Key Laboratory for Liver Research, Queen Mary Hospital, Hong Kong.


James Fung, Ching-Lung Lai, John Yuen, et al. Randomized trial of lamivudine versus entecavir in entecavir-treated patients with undetectable hepatitis B virus DNA: Outcome at 2 Years. Hepatology 63(4): 1148-1153 (abstract). April 2011.