High dose oral ganciclovir treatment for cytomegalovirus retinitis.
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.
Lalezari
Jacob P
JP
Quest Clinical Research, 2300 Sutter Street, Suite 202 San Francisco, CA 94115, USA. drjay@questclinical.com
Friedberg
Dorothy N
DN
Bissett
Jack
J
Giordano
Michael F
MF
Hardy
W David
WD
Drew
W Lawrence
WL
Hubbard
Larry D
LD
Buhles
William C
WC
Stempien
Mary Jean
MJ
Georgiou
Panos
P
Jung
Donald T
DT
Robinson
Charles A
CA
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
D000998:Antiviral Agents; D015774:Ganciclovir