title: High dose oral ganciclovir treatment for cytomegalovirus retinitis.
abstract: BACKGROUND
  The oral formulation of ganciclovir is approved at a dose of 3.0 g/day for maintenance treatment of cytomegalovirus (CMV) retinitis following an initial induction course of intravenous (IV) anti-CMV therapy. Median time to progression of CMV retinitis is 12-20 days shorter with oral compared to IV ganciclovir maintenance, likely due to the limited oral bioavailability of ganciclovir.
  
  
  OBJECTIVE
  We hypothesized that higher systemic drug exposures associated with increased doses of oral ganciclovir would be associated with increased efficacy.
  
  
  METHODS
  Maintenance treatment of CMV retinitis with higher than standard doses of oral ganciclovir (>3.0 g/day) was studied in 281 AIDS patients with previously treated, stable retinitis randomized to 3.0, 4.5 or 6.0 g/day oral, or 5 m/kg/day IV ganciclovir. Graders unaware of treatment assignments determined retinitis progression using fundus photographs. Vision, other ophthalmic measures and safety were assessed open-label.
  
  
  RESULTS
  Median days to photographic progression were 41, 50, 57 and 70, respectively (P=0.052; 3.0 g vs. IV). Hazard ratios for progression relative to IV were 1.66, 1.28 and 1.19 (P=0.016 for 3.0 g). NONMEM-modeled estimates of average serum ganciclovir concentration area under the curve (AUC(0-24)) correlated best with time to progression (P=0.0019). Six grams per day oral ganciclovir was most similar in efficacy to IV, although broad confidence intervals prevented a conclusive comparison. Patients receiving oral ganciclovir had a lower frequency of sepsis and IV catheter events.
  
  
  CONCLUSIONS
  This study suggests that the efficacy of ganciclovir for the maintenance treatment of CMV retinitis improves with increasing total drug exposure (measured as average serum concentration AUC(0-24)). All four regimens of ganciclovir were reasonably well tolerated, with safety profiles similar to what has been reported in prior work.
authors.affiliation: Quest Clinical Research, 2300 Sutter Street, Suite 202 San Francisco, CA 94115, USA. drjay@questclinical.com
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Lalezari
authors.forename: Dorothy N
authors.initials: DN
authors.lastname: Friedberg
authors.forename: Jack
authors.initials: J
authors.lastname: Bissett
authors.forename: Michael F
authors.initials: MF
authors.lastname: Giordano
authors.forename: W David
authors.initials: WD
authors.lastname: Hardy
authors.forename: W Lawrence
authors.initials: WL
authors.lastname: Drew
authors.forename: Larry D
authors.initials: LD
authors.lastname: Hubbard
authors.forename: William C
authors.initials: WC
authors.lastname: Buhles
authors.forename: Mary Jean
authors.initials: MJ
authors.lastname: Stempien
authors.forename: Panos
authors.initials: P
authors.lastname: Georgiou
authors.forename: Donald T
authors.initials: DT
authors.lastname: Jung
authors.forename: Charles A
authors.initials: CA
authors.lastname: Robinson
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000150:complications / Q000188:drug therapy*; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D017726:Cytomegalovirus Retinitis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015774:Ganciclovir / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D016019:Survival Analysis; D016896:Treatment Outcome; D014792:Visual Acuity
chemical_list: D000998:Antiviral Agents; D015774:Ganciclovir