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Review
. 2013 Sep;1(1):51-8.
doi: 10.14218/JCTH.2013.00006. Epub 2013 Sep 15.

The Discovery and Development of a Potent Antiviral Drug, Entecavir, for the Treatment of Chronic Hepatitis B

Hong Tang  1 , Jamie Griffin  2 , Steven Innaimo  3 , Lois Lehman-Mckeeman  3 , Cyril Llamoso  3
Affiliations
Review

The Discovery and Development of a Potent Antiviral Drug, Entecavir, for the Treatment of Chronic Hepatitis B

Hong Tang et al. J Clin Transl Hepatol. 2013 Sep.

Abstract

Since the first approval of interferon for the treatment of chronic hepatitis B virus (HBV) infection in 1992, six additional antivirals have been developed: pegylated interferon-alfa2a, and the oral antivirals lamivudine, adefovir, telbivudine, entecavir and tenofovir. The availability of animal models for HBV infection and hepatocyte cell culture led to the discovery and development of oral antivirals targeted at HBV polymerase and reverse transcriptase, which inhibit viral replication. The discovery and development of entecavir, the first oral anti-HBV drug with both potent antiviral activity and a high genetic barrier to resistance, took more than 10 years before it was first approved in the USA. Since then, multiple real-life studies have provided data consistent with the findings of the registration trials and the long-term rollover study in terms of efficacy, resistance, and safety. Data from the long-term follow-up of patients enrolled in the registration studies showed that treatment with entecavir can lead to significant improvements in liver histopathology, and recent cohort studies have demonstrated that treatment with entecavir may reduce disease progression and the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. In addition, real-life studies suggest that entecavir may reduce HCC recurrence and increase survival rates in patients with HBV-related HCC post-surgical resection.

Keywords: Chronic hepatitis B; Development; Discovery; Entecavir; HBV DNA; Hepatitis B Virus; Resistance.

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Conflict of interest statement

Conflict of interest: All authors are Bristol-Myers Squibb employees

Figures

Figure 1
Figure 1. Novel nucleoside analogs discovered at Bristol-Myers Squibb
*Nucleoside analogs showing activity against varicella zoster virus (VZV) and herpes simplex virus (HSV).
Figure 2
Figure 2. Proportion of hepatitis Be antigen (HBeAg)-positive patients with undetectable hepatitis B virus (HBV) DNA (<300 copies/mL) at 48 weeks
NC = non-completer, i.e. failure [NC=F] in analysis.
Figure 3
Figure 3. Cumulative confirmed proportions of all treated patients who achieved undetectable levels of hepatitis B virus (HBV) DNA, normalization of serum alanine aminotransferase (ALT), or a serologic end point through 96 weeks of treatment
HBeAg, hepatis B e antigen; HBsAg,hepatis B surface antigen; ULN, upper limit of normal.
Figure 4
Figure 4. Proportion of hepatis Be antigen (HBeAg-negative patients with undetectable hepatitis B virus (HBV) DNA (<300 copies/mL) at 48 weeks
NC = non-completer, i.e. failure [NC=F] in analysis.
Figure 5
Figure 5. Improvement in histology and in Ishak fibrosis scores with long-term entecavir treatment
Figure 6
Figure 6. Cumulative probability of entecavir resistance (rtT184, rtS202, or rtM250) in the presence of lamivudine-resistance mutations (rtM204 and rtL180M) among nucleoside-naive hepatis Be antigen (HBeAg)-positive and HBeAg-negative patients during 6 years of treatment
See this image and copyright information in PMC

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