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Entecavir Exhibits Inhibitory Activity against Human Immunodeficiency Virus under Conditions of Reduced Viral Challenge

Pin-Fang Lin,^1* Beata Nowicka-Sans,¹ Brian Terry,¹ Sharon Zhang,¹ Chunfu Wang,¹ Li Fan,¹ Ira Dicker,¹ Volodymyr Gali,¹ Helen Higley,¹ Neil Parkin,² Daniel Tenney,¹ Mark Krystal,¹ and Richard Colonno^1,

Bristol-Myers Squibb Pharmaceutical Research and Development, Wallingford, Connecticut,¹ Monogram Biosciences, South San Francisco, California²

Received 11 October 2007/ Returned for modification 20 December 2007/ Accepted 25 February 2008

Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.

Published ahead of print on 3 March 2008.

Present address: Presidio Pharmaceuticals, 1700 Owens St., Suite 585, San Francisco, CA 94158.

This article has been cited by other articles:

• (2008). Entecavir Inhibits HIV at Reduced Viral Inoculum. JWatch Infect. Diseases 2008: 2-2 [Full Text]