Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis.
The clinical significance of cytomegalovirus (CMV) foscarnet resistance was studied in patients with acquired immunodeficiency syndrome and CMV retinitis. Sequencing of the CMV pol gene was performed in 30 isolates. Phenotypic resistance was characterized by the DNA hybridization assay (DHA) in 30 isolates and by plaque-reduction assay (PRA) in 18 isolates. Nine isolates had foscarnet resistance mutations, including V787L and E756Q that were confirmed by marker transfer experiments. Seven of 9 isolates with a 50% inhibitory concentration (IC(50)) >600 microM by DHA had genotypic resistance, compared with 2 of 21 with an IC(50) < or =600 microM (P=.0005). By PRA, 5 isolates had an IC(50) >400 microM and genotypic resistance, whereas only 1 of 13 susceptible isolates had genotypic resistance (P=.0007). Sixteen of 18 isolates had concordant PRA and DHA phenotypes. Among 44 patients treated with foscarnet, drug resistance increased the risk of retinitis progression (odds ratio, 14; P=.016). The incidence of foscarnet resistance after 6, 9, and 12 months of therapy was 13%, 24%, and 37%, respectively.
Weinberg
Adriana
A
University of Colorado Health Sciences Center, Denver, Colorado, USA.
Jabs
Douglas A
DA
Chou
Sunwen
S
Martin
Barbara K
BK
Lurain
Nell S
NS
Forman
Michael S
MS
Crumpacker
Clyde
C
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000821:virology; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D015331:Cohort Studies; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D017726:Cytomegalovirus Retinitis / Q000188:drug therapy* / Q000821:virology; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D017245:Foscarnet / Q000494:pharmacology*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation; D010641:Phenotype; D014764:Viral Proteins
D000998:Antiviral Agents; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017245:Foscarnet; D004259:DNA-Directed DNA Polymerase