TreatmentUpdate 68, Volume 8, No 4; May-June 1996
Sean Hosein

In an attempt to find the 'best' therapy for the sight-threatening infection CMV retinitis researchers have studied the effects of intravenous

* foscarnet

* ganciclovir

* and both drugs in combination

on 279 subjects with AIDS who had CMV retinitis. Prior to entering this study, the subjects had CMV retinitis that had become worse despite treatment. Once entered into the study, researchers assigned the subjects to receive one of the three regimens mentioned above. Subjects and doctors knew which subjects received which drug. The average CD4+ cell counts ranged between 12 and 17 cells.

Foscarnet--89 subjects

Starting dose

Subjects received their starting dose (induction) of foscarnet 90 mg/kg of body weight twice daily for 2 weeks.

Maintenance dose

Subjects received foscarnet 120 mg/kg/day with one litre of saline solution.

If CMV retinitis became worse while on foscarnet doctors resumed giving the induction dose of foscarnet and then later reducing it to the maintenance dose. According to the study doctors, "[subjects] who [had] two consecutive relapses within a ten week period [were switched] to high dose ganciclovir."

Ganciclovir--dose and schedule--94 subjects

Starting dose

Subjects first received intravenous ganciclovir 5 mg/kg of body weight twice daily for 2 weeks.

Maintenance dose

Subjects then received ganciclovir 10 mg/kg once each day.

For those subjects whose retinitis became worse while on maintenance ganciclovir, the doctors prescribed ganciclovir 7.5 mg twice daily for a total of 15 mg/kg/day for 14 days. After this subjects received 10 mg/kg/day as maintenance. "Subjects who [had] two consecutive relapses within a ten week period [were switched] to foscarnet."

Combination--dose and schedule--96 subjects

Starting dose

Subjects in this group continued to receive the maintenance dose of whichever drug they used before entering this study. As well, they received the induction dose of the other drug for 2 weeks.

Maintenance

All subjects in the combination group received "both foscarnet 90 mg/kg/day once daily and ganciclovir 5 mg/kg/day also once daily. " Should worsening retinitis occur, they then received "both drugs at standard [treatment] doses (ganciclovir, 5 mg/kg every 12 hours, and foscarnet, 90 mg/kg every 12 hours) and [later switched] to combination maintenance therapy. [Subjects] who [had] two consecutive relapses within a 10 week period were treated according to best medical judgement."

Results--time

Doctors took photographs of the inside of the eye before, during and after treatment. Ophthalmologists then reviewed the pictures to see if the study drugs had any effect. At least half of the subjects in the following groups had CMV retinitis which became worse in the specified time:

* foscarnet - 2 months

* ganciclovir - 3.5 months

* combination - 4.3 months

These differences in the length of time it took for CMV retinitis to become worse was statistically significant; that is, not likely due to chance alone. All subjects who entered this study did so because neither of the drugs being used (foscarnet or ganciclovir) was able to stop the damage caused by CMV. Once enrolled in this study, some subjects who had used ganciclovir beforehand were switched to continued ganciclovir, foscarnet or combination. Switching these subjects to foscarnet rather than continued ganciclovir "had little effect" on the length of time it took for further damage to the retina. The same was true for foscarnet users.

Length of survival

Survival among subjects in the three arms of the study was similar. At least half of the subjects in the following groups survived for:

* foscarnet 8.4 months

* ganciclovir 9 months

* combination 8.6 months

These differences in survival time were not statistically significant. In a previous study researchers found that on average, subjects given foscarnet lived 4 months longer than subjects given ganciclovir. That study involved subjects at a different stage in the course of CMV retinitis. Subjects entering that study were "newly diagnosed [with] CMV retinitis." In the present study the subjects had retinitis which had grown worse despite treatment. As well, doctors noted that subjects given foscarnet as their first anti-CMV treatment in this study appeared to have lived slightly longer than subjects given ganciclovir.

Toxicity

The toxicity of ganciclovir is usually detected when the bone marrow produces less of the white blood cells called neutrophils. Doctors in this study were allowed to give subjects the bone marrow stimulant GM-CSF (granulocyte macrophage-colony stimulating factor, Filgrastimr(R), Sargramostimr(R)) in doses of "1 ug/kg/day to 10 ug/kg/day as needed." Doctors did find some bone marrow damage in subjects given ganciclovir, but no more than was expected. More subjects given combination therapy were likely to stop using their anti-CMV drugs than subjects given either foscarnet or ganciclovir. It is not clear why some subjects who received foscarnet lived longer than other subjects given ganciclovir. Perhaps the ganciclovir weakened their cell-mediated immunity.

REFERENCES:

1. The cytomegalovirus Retinitis Retreatment Trial. Combination foscarnet and ganciclovir therapy versus monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Archives of Ophthalmology 1996;114:23-33.

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Copyright © 1996 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca