Bulletin of Experimental Treatments for AIDS, No. 26; September 1995
Mark Bowers; Treatment Hotline Manager at Project Inform and a frequent contributor to BETA.

The clinical manifestations of CMV and the drugs used to treat them are very different from those of the other herpes viruses. The usual diseases associated with CMV are retinitis, encephalitis, esophagitis, colitis, polyradiculopathy (a kind of peripheral neuropathy) and pneumonitis. Of these, the most common and most dreaded is retinitis, which leads to blindness if untreated and seldom strikes without some loss of eyesight. CMV disease is one of the most common opportunistic infections (OI) in people with AIDS, affecting 25-40%. The greatest amount of clinical research on CMV disease has been done on the prevention and treatment of CMV retinitis, which affects up to 15% of all PWA.

New technologies have been tested and new drugs are finding their place in the treatment of CMV retinitis. But while acyclovir effectively controls herpes simplex outbreaks with comparatively few side effects, the drugs that are active against CMV require careful evaluation of their toxicities before they can be used for treatment or prevention. Such an evaluation includes carefully weighing the disease management factors articulated by Mark Jacobson, MD, of the University of California at San Francisco: individualizing therapy, balancing side effects and different routes of drug administration and considering the cost of treatment.

Intravenous Ganciclovir and Foscarnet

The 2 drugs that are currently licensed by the Food and Drug Administration (FDA) for the treatment of CMV retinitis are ganciclovir (Cytovene) and foscarnet (Foscavir). For this indication, both drugs require intravenous (IV) administration for initial treatment, usually through a surgically implanted central access catheter in the chest. After initial treatment (called induction) to stop the progression of retinal deterioration, a maintenance treatment period follows. Maintenance therapy continues for life. The FDA-approved choices for maintenance are continuing the IV drug or switching to oral ganciclovir.

The choice of induction therapy is individualized. Ganciclovir is infused for one hour at 5 mg/kg every 12 hours for 2-3 weeks, then maintenance is given indefinitely at 6 mg/kg a day 5 days per week. At the maintenance therapy dose, the half-life of ganciclovir allows 2 days per week to be skipped; this is not true for foscarnet, which must be infused 2-3 times daily.

The normal intravenous dose for induction treatment with foscarnet is 60 mg/kg every 8 hours or 90 mg/kg every 12 hours for 2-3 weeks at a constant rate over 2 hours, requiring the use of an infusion pump. Renal toxicity must be constantly monitored, and adequate hydration using saline solution is important to protect the kidneys from damage by the drug. Maintenance therapy is usually at 90 mg/kg daily.

Ganciclovir and foscarnet interact with many drugs commonly used in the treatment of HIV disease or associated opportunistic infections. Ganciclovir is bone marrow suppressive. About 30% of people receiving ganciclovir experience significant neutropenia (fewer than 1,000 neutrophils/mm3). Neutrophil and platelet counts should also be closely monitored. Neutropenia can be corrected by using colony-stimulating factors (G-CSF [Neupogen] or GM-CSF [Leukine]). Clinicians at San Francisco General Hospital recommend 300 mcg (one vial) of Neupogen 3-7 times per week until counts rise above 1,000 cells/mm3. Other drugs that are bone marrow suppressive are often discontinued when ganciclovir is being used, including AZT (Retrovir), trimethoprim-sulfamethoxazole (Bactrim or Septra) and pyrimethamine (Daraprim), all commonly taken by people with AIDS. Normal neutrophil production usually returns within 22 days of stopping ganciclovir therapy or switching to foscarnet.

Foscarnet is potentially nephrotoxic (damaging to the kidneys). This is why patients are pre-treated with 1 liter of normal saline solution before being infused with foscarnet, and also why an infusion pump is needed to control the rate of infusion. Other nephrotoxic drugs may interact with foscarnet, including amphotericin B, aminoglycosides and pentamidine. Foscarnet leaves the body exclusively through the kidneys. Creatinine, a test of kidney function, must be monitored when foscarnet is in use. Concentrated foscarnet in the urine can cause ulcers on the genitals (penis, vulva) if excess urine is not blotted from the skin.

The use of IV pentamidine and foscarnet at the same time increases the risk of hypocalcemia (abnormally low levels of calcium in the blood), which may have fatal consequences. Foscarnet and AZT used together increases the risk of anemia. Foscarnet has anti-HIV effects of its own, so the discontinuation of AZT may not be as problematic with foscarnet as it may be with ganciclovir.

Alternating Foscarnet and Ganciclovir

The Studies of the Ocular Complications of AIDS (SOCA) is a network of 11 university research sites with resident ophthalmologists, set up to conduct clinical research on CMV retinitis. SOCA recently completed a retreatment study designed to see if the combination of ganciclovir and foscarnet was better at preventing CMV disease progression than either drug alone. All participants had previously relapsed while on one therapy or the other. A total of 271 people received 1 of 3 treatments: (1) IV foscarnet (90 mg/kg twice daily for 2 weeks followed by maintenance at 120 mg/kg once daily); (2) IV ganciclovir (5 mg/kg twice daily for 2 weeks followed by maintenance at 5 mg/kg once daily); or (3) the combination (continuation of previous therapy with the addition of induction with the other therapy for 2 weeks followed by maintenance at 5 mg/kg daily of ganciclovir and 90 mg/kg daily of foscarnet).

The standard of comparison in most CMV retinitis studies is time to disease progression, defined as a 750 micron advance on the retina of the area affected by CMV. The median time to progression was 4.8 months on the combination, compared to 1.6 months for those on only foscarnet and 2.1 months for those on only ganciclovir. A significantly longer time to progression for those on the combination must be weighed against the associated decrease in quality of life, in part because of long daily infusion times and in part due to the combined toxicities of the 2 drugs. No study group enjoyed any survival advantage over any other.

Oral Ganciclovir Maintenance and Expected Approval for Prophylaxis

Oral ganciclovir was approved for maintenance therapy (following IV induction) in January 1995. A Phase I/II safety and efficacy study of oral ganciclovir for maintenance was conducted by the AIDS Clinical Trials Group (ACTG) and the Cytomegalovirus Cooperative Study Group (CCSG). Oral bioavailability, a measure of how much drug taken orally gets into the bloodstream compared with intravenous administration, ranged from 2.6% to 7.3%. The data suggest that oral absorption is prolonged at higher doses and that serious adverse events are rare. (Current European studies of hogh dose oral ganciclovir are expected to confirm these observations.) Time to disease progression was compared for 50 people on 4 different doses: 62 days for those taking 1g every 8 hours, 148 days for those taking 500 mg every 3 hours, 75 days for those taking 750 mg every 3 hours, 148 days for those taking 1 g every 3 hours, and 139 days for those taking 2 g every 8 hours. Nineteen (19) people who had positive cultures for CMV but no evid ence of disease or prior anti-CMV treatment were also given oral ganciclovir as prophylaxis. A Roche Bioscience (formerly Syntex) study of oral ganciclovir was stopped by its Data Safety and Monitoring Board (DSBM) because of the significant benefit experienced by the group treated with oral ganciclovir. All study participants taking placebo were offered the drug. A new drug application for prophylaxis was filed in May and FDA approval is expected this year.

Cidofovir (Vistide)

Cidofovir has been evaluated for use in treating retinitis by 2 groups using 2 different formulations. Gilead Sciences holds the license for the development of cidofovir in the United States. Recently published data from a study at the University of California at San Diego (UCSD) show that single injections of cidofovir into the eyes of 65 people with CMV retinitis results in a delay of disease progression similar to that seen with IV drugs. Although the study was uncontrolled, the results indicate that retinitis was controlled for 6 to 8 weeks. Some community ophthalmologists who are familiar with intraocular infections caution that side effects of the procedure, such as retinal detachment, are an increased risk.

Gilead Sciences will offer intravitreal injections of cidofovir to people who have failed or who are intolerant to ganciclovir and/or foscarnet beginning in August, 1995 (call Gilead at 415-476-6356). For more information see the June 1995 issue of BETA, pages 52-55.

Intravenous cidofovir offers an advance over IV ganciclovir and foscarnet, in that dosing is needed only once weekly or less. The most important adverse side effect of cidofovir is kidney damage, which can be minimized by IV hydration similar to that required prior to the administration of foscarnet. The use of the drug probenecid increases the concentration of cidofovir and allows for less frequent dosing while protecting agaist kidney damage. (For an in-depth discussion of recent studies of IV cidofovir, see BETA, June 1995, pp. 54-55.) Gilead has filed for Treatment Investigational New Drug (TIND) status for IV cidofovir for the treatment of CMV retinitis. TIND status would provide the drug free to qualified patients under the supervision of their physician(s). Call Gilead after October 1 for more information.

Ocular Implants

Implants of a small device that releases ganciclovir into the vitreous humor of the eye continuously for 6 months have been clinically tested in a Phase I study at the National Eye Institute (NEI). Thirty eyes (belonging to 26 volunteers who had non-sight-threatening CMV retinitis) were either implanted with the devices or received deferred therapy. The time to disease progression was 15 days for the deferred therapy group and 226 days for the implanted group. Participants experienced no systemic toxicities nor any catheter-related toxicities, which are a risk when receiving infusions. There are risks from the implanting procedure, including bleeding and reduced vision.

A second study of the ganciclovir implants, manufactured by Chiron Vision, compared the effectiveness of 2 different release rates of the implant to IV ganciclovir in 180 people with previously untreated CMV retinitis. The median time to progression for the IV group was 72 days compared to 186 days for the implants. No difference was seen in time to progression between the 2 release rates. Those in the IV group who experienced disease progression were given implants. There was no difference among the groups in the rate of development of CMV disease outside the eye. Chiron Vision has applied for approval from FDA.

Implants offer a true advance in the treatment of retinitis: time to progression is 2-3 times longer than with currently approved therapies. The operation to implant the ganciclovir device is performed under local anesthesia on an outpatient basis, and surgical complications are not common. No central venous access is needed, and any extraocular disease that develops might be treated (off-label) with oral ganciclovir.

An expanded access program is open only to those who have failed or cannot tolerate IV ganciclovir or foscarnet. Chiron Vision can be contacted at 800-244-7668. Roche Bioscience, manufacturer of ganciclovir, is currently sponsoring a study to compare implants to implants plus oral ganciclovir and to IV ganciclovir alone. The study recruits both newly diagnosed and previously treated individuals who have CMV retinitis. For more information, see the March 1995 issue of BETA, page 73.

Ocular Injections

In addition to the injections done with cidofovir, ophthalmologists have been injecting either ganciclovir or foscarnet directly into affected eyes for many years. One French study highlighted the drawbacks to such injections: 141 of 151 eyes that were injected experienced some scarring. There are no controlled data to indicate that the incidence of retinal detachment with injections is higher than the statistical average, but this is nonetheless a concern.

Antisense Drug

Isis Pharmaceuticals has been clinically testing an antisense drug for CMV. An antisense drug is designed to bind the messenger RNA made by CMV. If the RNA is bound and degraded, the virus cannot replicate. Twenty-two volunteers who had failed intravenous foscarnet or ganciclovir received injections every 2 weeks in a safety study. Last December, Isis began 3 larger efficacy studies, one of which is still open to volunteer participants. Two of the studies were halted because 4 of 23 eyes treated with ISIS 2922 developed stippling (retinal spots), possibly due to a previously undetected toxicity of the antisense drug. The study that remains open offers weekly injections of ISIS 2922 followed by injections every other week to people who have failed other CMV treatment options. Contact ISIS at 619-929-3898 and ask about study CS7.

This has been a watershed year for advances in the treatment and prevention of CMV retinitis. More options are available than ever before, and the drugs now available offer a longer period of time without advancement of retinitis. Cidofovir can be administered less frequently by the IV route than currently approved drugs, and its protection is longer lasting. Oral ganciclovir will soon be approved for primary prevention of retinitis, which will allow those who are already using the drug to be reimbursed by insurance plans. Eye implants offer longer lasting protection from advances in retinitis than any other treatment to date. Finally, combination strategies will be available that may be better than previous combinations (IV ganciclovir and IV foscarnet) and will have fewer, more tolerable side efects.

Sources

Jacobson MA and others. Current management of cytomegalovirus disease in patients with AIDS. AIDS Research and Human Retroviruses 10: 917-22, 1994.

Jacobson MA and others. Randomized Phase I trial of two different combination foscarnet and ganciclovir chronic maintenance regimens for AIDS patients with cytomegalovirus retinitis: AIDS Clinical Trials Group protocol 151. Journal of Infectious Diseases 170: 189-93, 1994.

Kirsch LS and others. Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with AIDS. Ophthalmology 102: 533-42, 1995.

Martin DF and others. Treatment of cytomegalovirus with an intraocular sustained-release ganciclovir implant: a randomized controlled clinical trial. Archives of Ophthalmology 112: 1531-39, 1994.

Reese RE and others. Handbook of Antibiotics. Little, Brown and Company, Boston. 1993.

Spector SA and others. Pharmacokinetic, safety, and antiviral profiles of oral ganciclovir in persons infected with HIV: a Phase I/II study. Journal of Infectious Diseases 171: 1431-7, 1995.

950901
BETA2603

Copyright © 1995 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182.  beta@sfaf.org  http://www.sfaf.org/beta.html