Entecavir was safe, effective and comparable to other commonly used nucleoside analogues in terms of malignancy rates and disease progression, with a superior virologic response compared with nonentecavir medications, in patients with chronic hepatitis B (CHB) who were followed for up to 10 years, according to a report published in Clinical Gastroenterology and Hepatology.
Although entecavir has proved efficacious for treating people chronically infected with the hepatitis B virus (HBV), achieving viral replication suppression and effectively reducing disease progression, successful management may entail lifelong therapy. On the basis of preclinical findings of malignancies associated with entecavir, investigators sought to comparatively assess the long-term safety and efficacy profiles of entecavir vs similar nonentecavir medications used to combat CHB.
Between 2007 and 2009, the REALM study (ClinicalTrials.gov identifier: NCT00388674) was an international, multicenter, prospective, randomized trial that enrolled 12,378 participants (median age, 39.0 years; 75.8% male; 84.2% Asian) with CHB who were randomly assigned 1:1 to receive entecavir (n=6216) or another nonentecavir nucleoside analogue (n=6162) and followed-up every 6 months for 7 to 10 years. Alternate nonentecavir formulations included adefovir (71.7%), telbivudine (10.7%), and lamivudine (7.2%). A China subcohort of individuals treated with entecavir (n=2659) or nonentecavir medication (n=2646) evaluated patient virologic response over time, as measured by HBV DNA analysis (HBV DNA <50 IU/mL for at least 2 consecutive visits).
Primary outcomes were times to adjudicated clinical outcome events, including malignancies, HBV disease progression, and death, and rates of serious adverse events and clinical outcome events. Secondary outcomes included rates of hepatocellular carcinoma (HCC), malignant neoplasms, and nonhepatocellular carcinoma malignancies. In the China cohort, virologic response and its relationship to the clinical outcome events was the key endpoint. Cox proportional hazard modeling was used to calculate relative risk of being in the entecavir vs nonentecavir group, using hazard ratios (HRs) and 95% CIs.
There was no significant difference between the entecavir and nonentecavir groups in clinical outcome event timing for any of the primary endpoints, such as overall malignancies (HR, 0.93; 95% CI, 0.800-1.084; P =.36), disease progression (HR, 0.89; 95% CI, 0.769-1.030; P =.12), and death (HR, 0.85; 95% CI, 0.713-1.012; P =.068): No significant differences existed between groups in terms of secondary endpoints. Treatment-related serious adverse events were reported by 12 (0.2%) and 50 (0.8%) entecavir and nonentecavir patients, respectively.
For the China cohort subanalysis, a sustained virologic response was seen in 79.7% and 60.8% of the entecavir and nonentecavir groups, respectively. Viral suppression was associated with a reduction in the risk for hepatocellular carcinoma (HR, 0.03; 95% CI, 0.009-0.113) and liver-related CHB disease progression (HR, 0.09; 95% CI, 0.038-0.221), irrespective of treatment group.
Study limitations included unavailability of HBV DNA data outside of China and a relatively young study population that precluded comparing malignancies by age.
“These findings confirm the long-term safety of entecavir and its appropriateness for long-standing therapy of CHB as recommended by current guidelines,” noted the authors.
Disclosures: This study was sponsored by Bristol-Myers Squibb, with partial support by the Ministry of Science and Technology of China (2018ZX10301202 and 2017ZX10202202) and the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S131). Please see the original reference for a full list of authors’ disclosures.
Hou J-L, Zhao W, Lee C, et al. Outcomes of long-term treatment of chronic HBV infection with entecavir or other agents from a randomized trial in 24 countries [published online July 12, 2019]. Clinical Gastroenterol Hepatol. doi:10.1016/j.cgh.2019.07.010