Delavirdine microbiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]
Microbiology
Mechanism of Action
Delavirdine is an NNRTI of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template:primer or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine. In addition, HIV-1 group O, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine.
In Vitro HIV-1 Susceptibility
In vitro anti-HIV-1 activity of delavirdine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and clinical isolates of HIV-1. IC50 and IC90 values (50% and 90% inhibitory concentrations) for laboratory isolates (n = 5) ranged from 0.005 to 0.030 μM and 0.04 to 0.10 μM, respectively. Mean IC50 of clinical isolates (n = 74) was 0.038 μM (range: 0.001 to 0.69 μM); 73 of 74 clinical isolates had an IC50 ≤0.18 μM. The IC90 of 24 of these clinical isolates ranged from 0.05 to 0.10 μM. In drug combination studies of delavirdine with zidovudine, didanosine, zalcitabine, lamivudine, interferon-α, and protease inhibitors, additive to synergistic anti–HIV-1 activity was observed in cell culture. The relationship between the in vitro susceptibility of HIV-1 RT inhibitors and the inhibition of HIV replication in humans has not been established.
Drug Resistance
Phenotypic analyses of isolates from patients treated with RESCRIPTOR as monotherapy showed a 50- to 500-fold reduced susceptibility in 14 of 15 patients by Week 8 of therapy. Genotypic analysis of HIV-1 isolates from patients receiving RESCRIPTOR plus zidovudine combination therapy (n = 79) showed resistance-conferring mutations in all isolates by Week 24 of therapy. In patients treated with RESCRIPTOR, the mutations in RT occurred predominantly at amino acid positions 103 and less frequently at positions 181 and 236. In a separate study, an average of 86-fold increase in the zidovudine susceptibility of patient isolates (n = 24) was observed after 24 weeks of combination therapy with RESCRIPTOR and zidovudine. The clinical relevance of the phenotypic and the genotypic changes associated with therapy with RESCRIPTOR has not been established.
Cross-Resistance
RESCRIPTOR may confer cross-resistance to other NNRTIs when used alone or in combination. Mutations at positions 103 and/or 181 have been found in resistant virus during treatment with RESCRIPTOR and other NNRTIs. These mutations have been associated with cross-resistance among NNRTIs in vitro.[1]
References
Adapted from the FDA Package Insert.