TY - JOUR
T1 - Mutations conferring foscamet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis
AU - Weinberg, Adriana
AU - Jabs, Douglas A.
AU - Chou, Sunwen
AU - Martin, Barbara K.
AU - Lurain, Nell S.
AU - Forman, Michael S.
AU - Crumpacker, Clyde
N1 - Funding Information:
Financial support: National Eye Institute, National Institutes of Health (NIH) (grant EY10268 to D.A.J.); National Center for Research Resources, NIH (grant M01-RR00052 to Johns Hopkins University School of Medicine [to D.A.J.]; National Institute of Allergy and Infectious Diseases, NIH (cooperative agreement U10-AI38858 to the Adult AIDS Clinical Trials Group Cytomegalovirus Laboratories, grant AI41690 to C.C., and contract HD-33162 to A.W); Fogarty International Center (grant TW00974 to S.C.). D.A.J. is the recipient of a Research to Prevent Blindness Senior Scientific Investigator Award.
PY - 2003/3/1
Y1 - 2003/3/1
N2 - The dinical 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 (IC50) >600 μM by DHA had genotypic resistance, compared with 2 of 21 with an IC50 ≤600 μM (P = .0005). By PRA, 5 isolates had an IC50 >400 μM 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.
AB - The dinical 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 (IC50) >600 μM by DHA had genotypic resistance, compared with 2 of 21 with an IC50 ≤600 μM (P = .0005). By PRA, 5 isolates had an IC50 >400 μM 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.
UR - http://www.scopus.com/inward/record.url?scp=0037332358&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037332358&partnerID=8YFLogxK
U2 - 10.1086/368385
DO - 10.1086/368385
M3 - Article
C2 - 12599051
AN - SCOPUS:0037332358
SN - 0022-1899
VL - 187
SP - 777
EP - 784
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 5
ER -