GMHC Treatment Issues; Volume 4 no. 2 April 6, 1990
Howard Rubin

Like oral or genital herpes (herpes simplex 1 and 2), CMV can reproduce in people with normally functioning immune systems and establish a latent infection. When the immune system controls CMV, the infected individual may have no symptoms or just have lymphadenopathy or a mononucleosis-like illness. CMV can be reactivated when someone becomes immunocompromised. In PWAs, the organs most commonly affected are the eyes, lungs, nervous system and intestinal tract. (A more detailed description of CMV can be found in Treatment Issues, Volume 2, Number 8).

Maintenance Therapy

Ganciclovir (DHPG) has been shown to have some efficacy in controlling active CMV disease. After an initial course of high- dose ganciclovir, patients must go on a maintenance dose, usually 6 mg/kg for five days a week, to suppress CMV. In one study of 18 PWAs with CMV retinitis in one eye, ganciclovir prevented development of disease in the unaffected eye. However, 60% of a similar group who did not receive ganciclovir developed retinitis in the other eye. Thus, secondary prevention with ganciclovir is necessary to prevent total blindness in most PWAs with CMV retinitis (1). Similarly in gastrointestinal disease, maintenance ganciclovir has prevented recurrence of esophagitis, colitis and rectal ulcers, and improved survival (2). For maintenance ganciclovir, patients need to have a catheter implanted, which allows direct access to the bloodstream. Syntex, ganciclovir's manufacturer, has developed an oral form of the drug which is in clinical trials in San Diego and San Francisco. Both ganciclovir and AZT are bone marrow suppressive, so the two are not usually given together. Some patients have been able to tolerate low doses of both drugs. An experimental drug called GM-CSF is being used in trials to stimulate production of the white blood cells that ganciclovir and AZT suppress. GM-CSF may allow patients to stay on AZT and ganciclovir together and for longer periods of time. (For information about trials using these drugs in combination, consult the AIDS Treatment Registry, the AmFAR Directory or call 1-800-TRIALS-A). There is not much experience with long-term use of ganciclovir as suppressive therapy. One problem that has begun to emerge is that some strains of CMV have developed resistance to ganciclovir.

Another drug in development as a treatment for CMV is Foscarnet, which also is active against other herpes viruses. Daily intravenous treatment with Foscarnet must also continue indefinitely. Although Foscarnet does not suppress the bone marrow, allowing patients to take it with AZT, it does cause kidney toxicity in about 15% of patients.

Primary Prophylaxis

It would be better, of course, to prevent any manifestation of CMV disease in patients at high risk. A couple of strategies look promising.

Researchers are now testing acyclovir (an antiviral drug that is currently used to treat other herpes infections) as a preventative treatment for CMV in PWAs who do not have active infections. Test-tube studies indicate that it inhibits the replication of CMV, but at much higher doses than are required to suppress herpes simplex or zoster viruses. Toxicity and side effects, which are dose-related, can include nausea, vomiting and headache.

Drs. Craig Metroka and H. Josefberg at St. Luke's/Roosevelt Hospital in New York City are conducting a study of the efficacy of high-dose oral acyclovir in the prevention of CMV in PWAs. From December 1987 to January 1989, they followed 60 patients who were at a high risk for CMV, based on low T4 cell counts. All were under 150 and the mean count was 75 (3). The regimen was 800 mg of acyclovir every four hours. Nineteen of the 51 patients on acyclovir were also on AZT. None of those taking acyclovir developed evidence of CMV. In contrast, three of nine patients who chose not to take the acyclovir developed CMV disease.

Dr. Metroka has continued his study through January 1990, enrolling 120 patients with T4 counts under 150 (mean count: 64) (4). The duration of follow-up ranges from 15.5 to 24 months. Only two out of 120 patients on acyclovir developed CMV disease; none developed signs of herpes infection, and 16 recovered from oral hairy leukoplakia.

Dr. Metroka's results have important implications. Given that a large number of PWAs develop CMV disease, trials combining acyclovir and AZT may have renewed importance. In addition, some studies have provided hints of synergism (increased anti-HIV effect) when AZT and acyclovir are combined.

Dr. Metroka's work represents an extension of recent studies on the use of acyclovir as CMV prophylaxis in people receiving organ transplants. Like PWAs, donor organ recipients are at increased risk for developing CMV disease, since medication taken to avoid organ rejection renders them immunodeficient. In the first study, fewer instances of CMV reactivation were observed in transplant patients given intravenous acyclovir than in those not on the drug, although 18 patients experienced kidney toxicity (5). Another randomized trial was conducted with oral acyclovir for transplant patients (6). During the first year after transplant, a significantly smaller number in the acyclovir group developed CMV (4 out of 53) than in the control group (15 out of 51).

In June 1988, Dr. Maxime Seligmann, of Hopital St. Louis in Paris, presented results from a study of acyclovir plus AZT vs. AZT alone at the Fourth International AIDS Conference. His results for the combination were encouraging although they still have not been published. For 48 weeks, 132 patients received a daily dose of 1000 mg AZT alone or in combination with 3200 mg acyclovir. A lower incidence of CMV was reported for patients on the combination (7).

Monoclonal Antibodies

At the University of Arizona, researchers have been pursuing a novel approach to controlling CMV with doses of anti-CMV antibodies produced outside of the body (8). This technique involves mass producing antibodies capable of suppressing CMV and giving them to patients as treatment. A Japanese firm called Teijin Unlimited is sponsoring the research. The treatment has been used with success in Japan for bone marrow transplant patients. In a small pilot study, 12 HIV-positive patients with CMV antibodies received a single dose of the drug, which was well tolerated. Patients with stable CMV disease are now being recruited for a multiple-dose study. Encouraging results have been seen so far: one patient with positive culture at entry became buffy coat-negative (a laboratory test for CMV) after one dose and has remained negative for eight weeks. However, the possibility remains that patients will develop antibodies that may neutralize these "foreign" anti-CMV antibodies although this has not yet been seen. Patients in the Tucson, Arizona area who are interested in this study should call the University of Arizona clinical trials information nunmber (602) 626-6887.

At New York University, Dr. Susan Zolla-Pasner is trying to develop monoclonal antibodies to CMV. To date, her lab has succeeded in reproducing a few antbodies, but they have not yet been used in people.

Other Possibilities

Attempts to find other agents for treatment and maintenance of CMV are currently under investigation. Dr. Douglas Dieterich has submitted protocols for trials of oral ganciclovir and FIAC, another oral drug being investigated for CMV, at NYU. It is much too early, he says, to indicate whether the drug will prove useful or not. FIAC is currently in trials in Seattle, San Diego, Bethesda and Birmingham. Intravitreal injections of ganciclovir (injections directly into the eye) have been successful in both treatment and prevention of recurrence of CMV retinitis, without any of the systemic side effects of intravenous ganciclovir (9).

Finally, Burroughs-Wellcome, maker of acyclovir, also is investigating a similar drug called desciclovir. Desciclovir is a "prodrug" of acyclovir, meaning that it is metabolized into acyclovir after absorption (10). The advantage of this drug is that it is much more efficiently absorbed, so patients might be able to take less and achieve the same results as high-dose acyclovir (11). Nothing has appeared in the medical literature about this drug since 1987, despite the fact that desciclovir was found to be as effective as acyclovir in the treatment of herpes zoster in doses of only 125 mg three times a day (12).

Acyclovir is by no means a cheap drug. Interestingly, its price has increased twice in the last few years, both times soon after AZT's price was lowered. For New York residents who have trouble paying for acyclovir, financial assistance is now available for those who qualify. The AIDS Drug Assistance Program (ADAP) has added acyclovir to the list of drugs it will cover. For more information, call 1-800-542-2437.

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