790 Mutations Conferring Foscarnet Resistance in a Cohort of Patients with Acquired Immune Deficiency Syndrome and Cytomegalovirus Retinitis A. Weinberg*1, D. A. Jabs2, S. Chou3, B. K. Martin2, N. S. Lurain4, M. S. Forman2, C. Crumpacker5 1Univ of Colorado Hlth Sci Ctr, Denver; 2Johns Hopkins Univ Sch of Med, Baltimore, MD; 3Veterans Admin Med Ctr, Oregon Hlth Sci Univ, Portland; 4Rush Med Coll, Chicago, IL; and 5Beth Israel Deaconess Med Ctr, Boston, MA
Background: This study addresses the need to determine the clinical significance of genotypic and phenotypic resistance of cytomegalovirus (CMV) to foscarnet in patients (pts) with CMV retinitis and AIDS.
Methods: Urine and blood samples were prospectively collected from176 pts enrolled in the Cytomegalovirus Retinitis and Viral Resistance Study. Foscarnet susceptibility of CMV isolates was measured by plaque reduction assay (PRA) and DNA hybridization assay (DHA). Sequencing of the CMV DNA pol gene identified mutations associated with foscarnet resistance. Newly described or incompletely characterized mutations were fully characterized by marker transfer experiments. Statistical analysis was performed using Fisher’s exact test, kappa analysis, and Kaplan and Meier method.
Results: Thirty (30) CMV isolates from 14 pts were selected for molecular analysis of CMV DNA pol. Nine (9) isolates from 5 pts had foscarnet resistance mutations. Two (2) of these mutations, V787L and E756Q were confirmed for the first time by marker transfer experiments coupled with PRA. Seven (7) of 9 isolates with IC50 > 600 µM measured by DHA had mutations associated with foscarnet resistance, compared with 2 of 21 isolates with IC50 < 600 µM (p = 0.0005). Among 18 isolates tested by PRA, 5 had IC50 > 400 µM and all had foscarnet resistance mutations, whereas only 1 of the 13 isolates that did not meet resistance criteria by PRA had genotypic foscarnet resistance (p = 0.0007). Using these thresholds, 16 of 18 isolates tested by PRA and DHA had similar phenotypic foscarnet susceptibility patterns (p = 0.008). Among 44 pts treated with foscarnet for CMV retinitis, drug resistance was associated with estimated relative odds of progression of 14 (p = 0.016). The incidence of CMV resistance after 6, 9, and 12 months of foscarnet therapy was estimated at 13%, 24%, and 37%, respectively.
Conclusions: New foscarnet resistance mutations were confirmed. The occurrence of foscarnet resistance mutations predicts treatment failure of CMV retinitis in pts receiving foscarnet therapy. CMV resistance to foscarnet in pts with AIDS seems to follow the same time course previously described for ganciclovir resistance.
