For patients with chronic hepatitis B virus (HBV) infection, up to 10 years of treatment with entecavir was safe and produced a superior rate of sustained virologic response, compared with other HBV nucleoside or nucleotide analogues in a global randomized clinical trial.
Virologic responses were confirmed and maintained in 80% of entecavir patients and 61% of patients who received other therapies, said Jin-Lin Hou, MD, of Southern Medical University in Guangzhou, China, and associates. Regardless of which treatment patients received, a sustained virologic response was associated with a significantly lower rate of liver-related hepatitis B virus (HBV) disease progression and hepatocellular carcinoma. Rates of serious treatment-related adverse events were 0.2% in the entecavir arm and 0.8% in the nonentecavir arm. Moreover, the primary outcome of time-to-adjudicated clinical outcome events “showed that entecavir treatment, compared with nonentecavir, was not associated with an increased risk of malignant neoplasms, including hepatocellular carcinoma, nonhepatocellular carcinoma malignancies, and overall malignancies,” they wrote in Clinical Gastroenterology and Hepatology.
Entecavir is approved for the treatment of adults with chronic HBV infection, and its long-term use has been linked to the regression of hepatic fibrosis and cirrhosis. In treatment-naive patients, genotypic resistance and virologic breakthrough are rare even after up to 5 years of entecavir therapy. Although human studies have not linked this treatment duration with an increased risk of adverse events, murine studies have identified benign and malignant tumors of the brain, lung, and liver in entecavir-treated mice and rats. “With the exception of lung tumors, which were limited to male mice, rodent tumors occurred only at entecavir exposures [that were] significantly higher than those achieved in human beings with standard approved doses,” the researchers wrote.
For the trial, they assigned more than 12,000 patients with chronic HBV infection to receive long-term treatment with entecavir or investigators’ choice of another HBV nucleoside or nucleotide analogue. Patients were from 229 centers in Asia, Europe, and North and South America, and a total of 6,216 received entecavir, while 6,162 received another therapy.
Compared with other HBV nucleoside and nucleotide analogues, long-term treatment with entecavir “provided a high margin of safety” and was not tied to higher rates of liver or nonliver malignancies, the researchers found. The carcinogenicity of entecavir in rodents did not appear to extend to humans. Furthermore, among 5,305 trial participants in China, a sustained virologic response was associated with a clinically and statistically significant reduction in the risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.04-0.22) and hepatocellular carcinoma (HR, 0.03; 95% CI, 0.009-0.113).
The results confirm the appropriateness of long-term entecavir therapy for chronic HBV infection, as recommended by current guidelines, Dr. Hou and associates concluded. However, patients in this trial were relatively young, with a median age of only 39 years. Therefore, the risk of entecavir-associated malignancies in older age cohorts could not be evaluated.
Bristol-Myers Squibb designed the study, performed statistical analyses, and funded the study and manuscript preparation. The Ministry of Science and Technology of China and the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program provided partial support. Dr. Hou disclosed grants and personal fees from Bristol-Myers Squibb, GlaxoSmithKline, and Novartis. Several coinvestigators also disclosed ties to Bristol-Myers Squibb and to several other pharmaceutical companies.
SOURCE: Hou J-L et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi: 10.1016/j.cgh.2019.07.010.