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Gay Men's Health Crisis
CMV Treatment Overview
Greg Lugliani
April 20, 1992
GMHC Treatment Issues 1992 Apr 20; 6(4): 20

Cytomegalovirus, a member of the herpes virus family, can cause severe infections in people with AIDS. The infection itself seems to hasten the progression of immune suppression caused by HIV in men.[1] Although studies of CMV in women are limited, one report showed that CMV was prevalent in women with inflammation of the cervix.[2] While up to 50% of the the general adult population in developing countries is believed to have latent (inactive) CMV infection,[3] pre-existing infection is almost universal among HIV- positive men.[4] When immune function is impaired, latent CMV can activate, causing life-threatening conditions which may affect the eye, colon, esophagus, brain and sometimes the lungs. Active CMV disease is seen in 44% of AIDS cases, usually in patients with T4 counts 100 or below.[5] The first manifestation of CMV disease usually involves the eye and is called retinitis. CMV retinitis occurs in about 20% of PWAs. Left untreated, CMV retinitis invariably results in blindness. Moreover, CMV is believed to be a major contributing factor to the death of AIDS patients.[6] Treatment and prophylaxis for CMV has not been one of the greatest success stories in AIDS research. However, with the recent development of non-I.V. administered CMV drugs, treatment may become less toxic and prophylaxis more possible.

Ganciclovir Until September 1991, the only available treatment for people with CMV infection was ganciclovir (brand name Cytovene). The drug, made by Syntex Corporation, has been used successfully to treat CMV retinitis and colitis. Ganciclovir is a nucleoside analog which stops CMV replication. The drug must be taken intravenously for life to prevent progression and reappearance of disease. Treatment, however, is administered through a permanently implanted catheter for daily infusions. When ganciclovir treatment begins to fail, restarting treatment (reinduction) with 5 mg/kg twice daily for 14 days is recommended. Maintenance therapy thereafter should be 5-6 mg/kg five to seven days a week.[7] While fairly effective in treating CMV infections, ganciclovir has many adverse effects which limit its use in individuals taking AZT. Ganciclovir causes severe damage to the bone marrow, which can result in anemia and neutropenia. Due to these side effects, AZT often must be stopped while taking ganciclovir. If the drugs are taken together, frequent blood monitoring is needed. Neutropenia resulting from ganciclovir may be prevented by using granulate colony stimulating drugs, such as GM-CSF or G-CSF. These, unfortunately are enormously expensive and are currently indicated for use in people with cancer.

While ganciclovir is effective in treating CMV disease, it is not a cure. One study presented in Florence showed that even with maintenance treatment, relapse was seen in 71% of 347 patients, 54% for those with CMV retinitis, after about 97 days.[8] In this study, patients with CMV colitis had a much worse prognosis than those with retinitis.

Oral Ganciclovir Other methods of administering ganciclovir are being studied to minimize expense and potential dangers of infection associated with the catheter. An oral version of the drug is under investigation, but no results are yet available from a study of the efficacy of oral ganciclovir, conducted at Mount Zion Medical Center in San Francisco. Additionally, researchers are exploring the effects of injecting ganciclovir directly into the eye as a treatment for CMV. In a phase I safety and efficacy study, slow intraocular delivery of the drug via an implanted device showed some potential.[9] Foscarnet This past September, the FDA approved foscarnet (brand name Foscavir) as an alternative treatment for CMV retinitis. Prior to FDA approval, foscarnet's manufacturer, Astra Pharmaceuticals of Sweden, made the drug available in the U.S. on a compassionate use basis, but it has been licensed in Europe for several years. Foscarnet is as effective as ganciclovir at halting CMV disease progression and in preserving vision in patients newly diagnosed with retinitis.[10] Unlike ganciclovir, however, foscarnet, has also demonstrated anti-HIV activity both in test tube studies and in humans.[11] Reports indicate that the drug is also active against herpes simplex virus (HSV), particularly in cases when HSV has become resistant to standard therapy with acyclovir.[12] Foscarnet has been used successfully in treating CMV infection of the esophagus and colon, bringing about long-term remission.[13] In one study, foscarnet induced remission in patients with gastrointestinal CMV disease who failed, or become resistant to ganciclovir.[14] Because foscarnet does not tend to cause bone marrow damage, it can be used together with AZT without causing the anemia and neutropenia associated with ganciclovir. However, foscarnet has serious side effects of its own. These include persistent nausea, renal toxicity, and seizures. During treatment with foscarnet, kidney function needs to be monitored for toxicity. In clinical trials which provided data to support foscarnet's approval, 33% of patients taking the drug developed significant impairment in kidney function.[15] The damage was reversible once the drug was stopped.

Seizures occur because foscarnet causes electrolyte imbalances. Not surprisingly, the drug is not recommended for individuals with a history of seizures. By regularly monitoring electrolyte levels, including calcium and magnesium levels, seizures can be avoided. Such monitoring, along with kidney surveillance, is recommended two to three times a week during initial foscarnet treatment (14-21 days), and then once every week or two thereafter during lifelong therapy.

Foscarnet for Maintenance One study reported in Florence observed forty patients with CMV retinitis.[16] The two doses of foscarnet used for maintenance therapy were 120 mg/kg/day and 100 mg/kg/day. Data showed that the higher dosage was more effective in delaying CMV retinitis progression than the lower dose. The rate of CMV progression was 67% in the low-dose group and 50% in the high-dose group. Another study of twice daily administration of foscarnet resulted in a 97% response rate for healing retinal lesions caused by CMV.[17] Foscarnet infusions are more inconvenient to the patient because they take twice as long and usually require an additional infusion of saline to prevent kidney toxicity.

Foscarnet vs. Ganciclovir Interim results reported in October from the Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial, conducted by the National Eye Institute in collaboration with NIAID, involved 240 subjects. Data suggest that patients with CMV retinitis who take foscarnet live 50% longer than those on ganciclovir (12 vs. 8 months).[18] During the trial, however, 40% of the patients assigned to foscarnet switched to ganciclovir because of nausea.[19] The patient survival rates found in the trial were widely publicized last fall, but a number of questions about the results remain. For example, a high percentage of patients switched from foscarnet to ganciclovir, and that factor was not measured into results. Further study of comparative survival rates with the two drugs is warranted.

The prices of the drugs are also worth comparing. Ganciclovir costs approximately $10,000 a year, while foscarnet is an astronomical $30,000 (see Treatment Briefs on page 8 for Foscarnet Phone Zap). Both drugs are reimbursable through private insurance and are covered by AIDS Drugs Assistance Program (ADAP) in New York State. Astra Pharmaceuticals, maker of Foscavir, has developed a reimbursement program, called, of all things, FAIR. The program can be accessed by calling 1-800-388-4148.

Ganciclovir Plus Foscarnet The combination of foscarnet and ganciclovir for treatment of CMV retinitis is the subject of many studies. Phillip Pizzo, at the National Cancer Institute, is observing the combination in a five year old HIV-infected girl. Dr. Pizzo reported that the two drugs together may be effective in treating CMV retinitis that has become resistant to treatment with either agent alone. However, further study is merited.[20] Monoclonal Antibodies A new potential therapy for CMV, under observation and yielding initial results, is monoclonal antibodies. Monoclonal antibodies are manufactured DNA recombinant technology which are injected into a person with CMV to neutralize the virus. Human monoclonal antibodies have been tested in bone marrow transplant recipients with positive early results.[21] In a study reported in Florence, conducted at the University of Arizona, monoclonal antibodies were genetically constructed from mice antibodies and made into a compound called TI-23. The compound was given in doses from 40 to 80 mg to 13 HIV-infected participants with CMV.[22] Eight patients with retinitis and 13 with CMV colitis were treated for almost a year. Retinitis was noted to progress in half of the patients; in three patients no progression was noted. Gastrointestinal symptoms cleared in two of three patients. TI-23 was well tolerated with no evidence of toxicities. Further investigation with the compound is warranted.

FIAU FIAU is an oral antiviral nucleoside that seems to have activity against many of the herpes viruses, including CMV. It is thought to be fairly toxic. A study from Florence indicates that the drug was relatively well tolerated but caused gastrointestinal problems in some people.[23] Further studies are urged by the authors of the report to determine whether the drug might be a viable antiviral in people with AIDS.

Acyclovir and Acyclovir Prodrug Recently, much attention has turned to the use of high-dose (3200-4000 mg/day) acyclovir as treatment and prophylaxis for CMV. Reports indicate that oral acyclovir (brand name Zovirax) may have some anti-CMV activity. The most recent study from England showed that while high-dose acyclovir may extend survival, it appears to lack the ability to prevent CMV disease. (For more details, see Treatment Issues, Vol 6. No. 2).

Another Burroughs Wellcome, called BW256 breaks down in the body into a form of acyclovir that is more quickly absorbed. This drug, also available in an oral form, is ready to enter trials.It will be administered at doses between 3-4 grams daily. Treatment Issues will report further on BW256, as developments allow.

Conclusion While CMV has often yielded discouraging treatment results, some headway has been made in the past years of investigation. None of the therapies currently available offers convenient, affordable, or non-toxic treatment of this prevalent OI. More research is needed to discover possible treatments for therapies that will effectively treat CMV without toxic side effects. Two hopeful prospects are HPMC (made by Gilead Pharmaceuticals) and Cyclobut-G (made by Bristol-Myers Squibb).

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