Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
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.
Lin
Pin-Fang
PF
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Pinfang.Lin@bms.com
Nowicka-Sans
Beata
B
Terry
Brian
B
Zhang
Sharon
S
Wang
Chunfu
C
Fan
Li
L
Dicker
Ira
I
Gali
Volodymyr
V
Higley
Helen
H
Parkin
Neil
N
Tenney
Daniel
D
Krystal
Mark
M
Colonno
Richard
R
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
D000998:Antiviral Agents; C413685:entecavir; D006147:Guanine