MICROBIOLOGY

Mechanism of Action

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases a , b , g , and d are not inhibited by EFV.

The concentration of EFV inhibiting in vitro replication of wild-type laboratory adapted strains and clinical isolates by 90-95% (IC_90-95) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. EFV demonstrated antiviral activity against most non clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses. EFV demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine (DLV) and nevirapine (NVP), NRTIs (abacavir, didanosine, emtricitabine, lamivudine [LAM], stavudine, tenofovir, zalcitabine, zidovudine [ZDV]), PIs (amprenavir, indinavir [IDV], lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. EFV demonstrated additive to antagonistic antiviral activity in vitro with atazanavir. EFV was not antagonistic with adefovir, used for the treatment of hepatitis B virus infection,or ribavirin, used in combination with interferon for the treatment of hepatitis C virus infection.

In vitro: HIV-1 isolates with reduced susceptibility to EFV (>380-fold increase in IC₉₀ value) emerged rapidly under in vitro selection. Genotypic characterization of these viruses identified mutations resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/ Y181C in RT.

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