title: Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Pinfang.Lin@bms.com
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Beata
authors.initials: B
authors.lastname: Nowicka-Sans
authors.forename: Brian
authors.initials: B
authors.lastname: Terry
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhang
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Ira
authors.initials: I
authors.lastname: Dicker
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gali
authors.forename: Helen
authors.initials: H
authors.lastname: Higley
authors.forename: Neil
authors.initials: N
authors.lastname: Parkin
authors.forename: Daniel
authors.initials: D
authors.lastname: Tenney
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Richard
authors.initials: R
authors.lastname: Colonno
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006515:Hepatitis B virus / Q000187:drug effects; D019694:Hepatitis B, Chronic / Q000188:drug therapy; D006801:Humans
chemical_list: D000998:Antiviral Agents; C413685:entecavir; D006147:Guanine