Long-term monitoring shows hepatitis B virus resistance to... : Hepatology (original) (raw)

Viral Hepatitis

Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy#

Tenney, Daniel J.1*†; Rose, Ronald E.1; Baldick, Carl J.1; Pokornowski, Kevin A.1; Eggers, Betsy J.1; Fang, Jie1; Wichroski, Michael J.1; Xu, Dong1; Yang, Joanna1; Wilber, Richard B.1; Colonno, Richard J.1¶

1 Bristol-Myers Squibb Company Research and Development, Wallingford, CT

¶ Presidio Pharmaceuticals Inc., San Francisco, CA

* Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492

Email:[email protected]

Received August 20, 2008; accepted December 25, 2008.

Published online 11 March 2009 in Wiley InterScience (www.interscience.wiley.com).

# Potential conflict of interest: The studies were performed at Bristol-Myers Squibb by employees of Bristol-Myers Squibb. Study participants have been informed of potential conflicts of interest.Drs. Wilber, Eggers, Colonno, Baldick, Tenney, Pokornowski, and Xu own stocks in Bristol-Myers Squibb.

† fax: 203-677-6088

Abstract

Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V ± L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (≥300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (≥1 log10 rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved <300 copies/mL HBV DNA subsequently developed ETVr. Conclusion: Long-term monitoring showed low rates of resistance in nucleoside-naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance. (Hepatology 2009.)