PROCAARE: CLINICAL SCIENCE--PROPHYLAXIS--CMV

[Albert Shaw <ashaw@usa.healthnet.org>]

KEYWORDS: PROPHYLAXIS/ CYTOMEGALOVIRUS/ ORAL GANCICLOVIR/ RETINITIS

Reference: Spector, S.A., McKinley, G.F., Lalezari, J.P., Samo, T., 
Andruczk, R., Follansbee, S., Sparti, P.D., Havlir, D.V., Simpson, G., 
Buhles, W., Wong, R., Stempien, M.J. for the Roche Cooperative Oral 
ganciclovir Study Group (1996).  Oral ganciclovir for the prevention of 
cytomegalovirus disease in persons with AIDS.  New Engl. J. Med. 334: 1491-7.

This prospective, randomized, double-blind, placebo-controlled trial 
enrolled 725 patients with AIDS; patients with CD4 counts below 50/mm3 
were eligible, as were those with counts below 100/mm3 and a history of 
an AIDS-defining opportunistic infection.  All had either a positive CMV 
serology or urine culture; however, subjects with a prior history of CMV 
disease or treatment were excluded, and all participants underwent a 
baseline dilated eye examination by experienced ophthalmologists prior to 
randomization.

486 patients received oral ganciclovir at 1000 mg tid with food, and 239 
were randomized to placebo.  99% were male, and 82% white.  The median 
CD4 count was 22/mm3.  Dilated eye examinations and CMV urine cultures 
were obtained every two months.  Nearly all (94%) patients were taking 
antiretroviral agents; high dose oral acyclovir for up to four weeks, or 
intravenous acyclovir for up to two weeks for acute herpesvirus 
infections was permitted, as was up to 1000 mg per day of oral acyclovir 
for suppression of recurrent herpes simplex disease (468 patients used 
acyclovir).

The primary endpoint of the study was the diagnosis of CMV disease.  
Retinitis was diagnosed on dilated funduscopic examination; in addition 
to consistent clinical syndromes, pneumonia, and GI tract disease 
required confirmation by biopsy, and polyradiculopathy required 
demonstration of CMV by culture or PCR.  The median duration of follow-up 
was 367 days.  Notably, 66% of the placebo group and 59% of the 
ganciclovir group stopped randomized therapy; intention-to-treat analysis 
was employed.

The 12-month cumulative rate of CMV disease was 26% in the placebo arm 
and 14% in the ganciclovir group (relative risk [RR] 0.51, 95% confidence 
interval 0.36-0.73, p<0.001).  Among the 85 subjects with baseline CD4 
counts above 50/mm3, the RR was 0.24 (0.07-0.84, p=0.02); for patients 
with less than 50/mm3, the RR was 0.55 (0.38-0.79, p=0.001).  This 
protective effect was independent of the use of antiretroviral agents or 
acyclovir.

Not surprisingly, CMV retinitis was the most commonly occurring 
manifestation of CMV infection; the 12-month incidence of retinitis was 
24% in the placebo group and 12% in the ganciclovir group (p<0.001).  
Though there appeared to be some effect on CMV GI tract disease reported 
by investigators (7% placebo vs. 3% ganciclovir, p=0.003), the incidence 
of biopsy-proven GI disease was 2% in both groups.  

Baseline urine cultures were positive in 44% of the placebo group and 41% 
of the ganciclovir group.  After two months of randomized therapy, 43% of 
the placebo arm, but only 10% of those receiving ganciclovir remained 
positive (p<0.001).  Interestingly, patients with baseline negative CMV 
urine cultures had a 12-month incidence of 22% in the placebo group and 
11% in the ganciclovir group (RR 0.49, 0.28-0.83, p=0.007).

However, survival was unaffected overall, with cumulative 12-month 
mortality rates of 26% and 21% for the placebo and ganciclovir groups, 
respectively (p=0.14).  The rate of CMV disease or death was 43% in the 
placebo arm and 29% in the ganciclovir group (RR 0.65, 0.51-0.84, 
p<0.001). 

Oral ganciclovir was well-tolerated, with 16% of the placebo and 19% of 
the ganciclovir groups withdrawing from the study because of adverse 
effects.  The most common reported adverse effect were GI symptoms, 
occurring in 75% of subjects, though these were equally distributed 
between placebo and ganciclovir-receiving patients.  Though the 
incidences of neutropenia and anemia were not significantly different 
between the two arms, the use of G-CSF or erythropoietin was 
significantly more frequent in the ganciclovir group.  21% of the 
ganciclovir arm vs. 13% of the placebo group had elevated serum 
creatinine values of greater than 1.5 mg/dl (p=0.03).

This study indicates that oral ganciclovir can be effective in patients 
with advanced AIDS for the prevention of CMV disease, though overall 
survival was unchanged.  Further studies are needed to confirm these 
findings, delineate optimal dosing and more sharply define those patients 
most likely to benefit (though these results would suggest that patients 
with CD4 counts below 50/mm3, and possibly below 100/mm3, may be good 
candidates).