Entecavir demonstrates higher rates of improvement than lamivudine in patients with Hepatitis B

A phase 3 study evaluating the histologic and virologic improvement of hepatitis B antigen positive (HBeAg) patients randomized to either lamivudine or entecavir demonstrated that patients treated with entecavir had a significantly higher rate of histologic, virologic, and biochemical improvement. Researchers also observed less viral resistance with entecavir.

Patients in the double-blind, double-dummy, multicenter, randomized controlled trial published in the New England Journal of Medicine (NEJM) received entecavir 0.5 mg once daily or lamivudine 100 mg once daily for a minimum of 52 weeks. Of 1,056 screened patients aged ≥16 years, 715 were assigned, and 709 patients received at least 1 dose of either entecavir (n=354) or lamivudine (n=355).

The primary end point was histologic improvement at Week 48 with necroinflammatory fibrosis scores also being evaluated. Secondary end points also measured in the 48th week were a reduction in hepatitis B virus (HBV) DNA level from baseline and patients with undetectable HBV DNA; decrease in fibrosis scores; HBeAg loss; HBeAg seroconversion; and alanine aminotransferase (ALT) normalization <1.25 times the upper limit of normal (ULN). Patients who responded at Week 48 were followed for an additional 24 weeks to evaluate sustained virologic response (SVR) and serologic benefit. A safety analysis also was performed (n=709). The primary safety end point was the number of patients who discontinued treatment because of an adverse effect. Resistance analysis also was performed. A 2-stage efficacy evaluation was planned, initially testing non-inferiority to lamivudine. If non-inferiority was established, a second test for superiority was conducted.

In the primary end point at Week 48, 72% of entecavir-treated patients had a higher rate of histologic improvement compared with 62% of the lamivudine group (difference estimate [DE]=9.9; 95% CI, 2.6–17.2; P=.009). Improved fibrosis also was noted in the entecavir-treated patients (39% vs 35%; P=.41). Worsening of fibrosis scores was noted in 8% of entecavir-treated patients compared with 10% of lamivudine-treated patients. The ALT normalized in more entecavir-treated patients (68%) compared with the lamivudine group (60%). HBV was undetectable at Week 48 in 67% of entecavir-treated patients versus 36% of lamivudine-treated patients (DE=30.3; 95% CI, 23.3–37.3; P<.001).

Mean reductions in viral load from baseline were greater and statistically significant in the entecavir-treated patients compared with the lamivudine-treated patients (DE=–1.52; 95% CI, –1.78 to –1.27; P<.001) HBeAg loss and seroconversion occurred in the same percentage of individuals in both groups.

A protocol-defined response at Week 48 was observed in 74 entecavir-treated patients (21%) and 67 lamivudine-treated patients (19%). Virologic response was attained in 247 entecavir-treated patients (70%) versus 165 lamivudine-treated patients (46%). Nineteen entecavir-treated patients (5%) did not respond to treatment compared with 94 lamivudine-treated patients (26%).

For the protocol-defined response, 82% of entecavir-treated patients and 73% of lamivudine-treated patients had an SVR at Week 24 following therapy discontinuation. During the first year of administration, 63 lamivudine-treated patients had virologic rebound compared with 6 entecavir-treated patients.

Adverse effects were similar between the 2 treatment groups (eg, headache, upper respiratory tract infection, nasopharyngitis, and cough). There were 2 deaths in the lamivudine-treated patients, which were believed to be unrelated to the study. Resistance to entecavir following longer treatment courses is not unknown.

SOURCE Chang T-T, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HbeAg-positive chronic hepatitis B. New Engl J Med. 2006;354:1001–1010.