STEP PERSPECTIVE, Volume 7, No. 2 -Summer/1995; A Publication of the Seattle Treatment Exchange Project e-mail: step@eskimo.com
Jane Woodward, Pharm D.

Medications available for the treatment of CMV disease include ganciclovir and foscarnet. Treatment begins with a higher dose of either drug as an "induction" phase that lasts 2-3 weeks. Because this disease will progress in virtually all people even after the induction phase, all people are then given a smaller dose of the same drug as the "maintenance" phase that will continue for the rest of the persons life. At this time, no drug has been approved by the FDA for prevention or prophylaxis of CMV.

Treatment of CMV disease has been limited by the fact that the medications available require intravenous administration, are expensive and fairly toxic. They are also only expected to halt or slow disease progression, not reverse damage already done, and their efficacy wanes with time. This loss of efficacy is often due to resistance of the virus, but could be due to inadequate concentrations of the drug within the eye, especially after prolonged maintenance therapy.1 Of the two drugs available on the market, ganciclovir is often preferred over foscarnet because of its ease of administration and lesser side effect profile. Ganciclovir's main toxicity is suppression of the bone marrow, while foscarnet often causes damage to the kidney and disruption of electrolyte balance.

Most clinicians have recommended initiation of therapy with ganciclovir, although there was some question of this after a trial comparing the two agents was halted early due to a survival advantage seen in people that were given foscarnet (12.6 months with foscarnet; 8.5 months with ganciclovir). This advantage was seen only in people with normal kidney function entering the trial. There was speculation that survival was decreased in the ganciclovir treated group because they were unable to take as much zidovudine due to both drugs causing suppression of the bone marrow from producing white blood cells. In the analysis however, the difference in survival was not accounted for entirely by antiretroviral use, and may have been due to foscarnet's own anti-HIV activity and ability to increase the activity of zidovudine. As was expected, foscarnet-treated people experienced more side effects than those on ganciclovir and were more likely to switch to ganciclovir than vice versa.2 Because of foscarnet's severe toxicity, its survival advantage may not be as important when considering quality of life. Some studies are being conducted with the two drugs used together, not only to see if they increase each other's effectiveness, but also in those people that seem to have two different strains of CMV, each responding differently to each drug.3

Research has also been conducted in other forms of therapy for CMV retinitis, the most successful being delivery of these toxic drugs only to eye tissue or local therapy. This is accomplished by injecting the drug directly into the eye (intravitreous injections) or the use of an implantable pellet that slowly releases the drug into the eye over a period of time. Advantages of local therapy of CMV retinitis with ganciclovir included achieving much higher concentrations of the drug in the eye where it is needed (4.1 mcg/ml with implant, 0.93 mcg/ml with intravenous), avoiding exposure of the body to the toxic effects of the drug, and avoiding use of an indwelling catheter. However, local therapy does not protect the uninfected eye, nor does it protect the rest of the body. Because CMV is a disease that is responsible for damage to many organ systems, the use of local therapy only will always have to be used with caution and frequent monitoring.

Intravitreous injections of both ganciclovir and foscarnet have been investigated, with more experience using ganciclovir. Results of these small trials have been reported and have utilized ganciclovir induction doses of 200 to 400 mcg twice weekly, then maintenance doses of 200 to 400 mcg weekly.4,5 Good response was seen, although progression did occur. One study added on intravitreous ganciclovir injections with intravenous therapy in people that appeared to have CMV retinitis that was resistant to both or either drugs given intravenously. Response was seen in 25 of 30 eyes, although progression occurred in 46% without maintenance intravitreous injections.6 Liposome coated ganciclovir has been used in a few case reports, its advantage being proposed as injections being required less frequently. Complications reported with intravitreal injections of ganciclovir have included retinal hemorrhage or detachment and endophthalmitis, an inflammation of the tissue of the eye.

Of the two forms of local therapy, implantable pellets appear to have more advantages and experience in literature. These devices also achieve much higher levels in the eye than with intravenous therapy, an advantage that may be associated with better efficacy and less development of resistance. Of these devices, most release medication from 4-8 months.

There are three notable trials that evaluated the efficacy of the implantable device. the first implanted 30 devices releasing 2 mcg/hr of ganciclovir in 22 people, most of which had already received intravenous ganciclovir. Ninety percent of these stabilized. Nine cases reactivated and the device was estimated to delay progression of disease on average 133 days.7 The second trial randomized those with non-sight threatening retinitis to receive 1 mcg/hr device immediately, or defer treatment until the disease progressed. There were 30 eyes enrolled in 26 clients. Those who received the device immediately progressed in 226 days compared to 15 days in the group who were assigned to deferred treatment.8 The most recent results were reported on a trial that compared IV ganciclovir to the device in 148 clients. The authors found that the intraocular pellet delayed progression 186 days while IV ganciclovir delayed progression 72 days.9 In all of these studies the device did not protect the other eye, or other organs from CMV disease. Reactivations frequently occurred in eyes with devices that were no longer releasing medication. Complications were similar to intravitreal injections, and most of those had a decrease in their vision immediately after surgery, although most cases resolved within 28 days. A device produced by Chiron will probably be submitted to the FDA for approval later this year.

Perhaps the most notable advance in the treatment of CMV infections came in January of this year with the approval of oral ganciclovir. This drug was approved based on the results of trials that gave all clients induction treatment with IV ganciclovir then randomly assigned them to oral treatment or continued IV ganciclovir as maintenance therapy. Those assigned to oral treatment progressed 5-12 days earlier than those on IV maintenance therapy. Because of this, oral ganciclovir was approved at a dose of 1 gram 3 times daily for use only in people after they have gone through induction therapy with IV ganciclovir and have very stable retinitis10 (product information). Side effects are similar with both forms of this medication. Bone marrow suppression may be less with oral ganciclovir, probably due to lower amounts of drug in the body. Currently, higher doses of oral ganciclovir are being studied; up to 2 grams 3 times daily to improve drug levels and, it is hoped, efficacy.

Oral ganciclovir is also being studied for its utility in preventing CMV infections. Preliminary results of a prophylaxis trial have been presented in meetings this year in 725 HIV+ people with CD4 counts less than 50 cells/mm3 or less than 100 cells/mm3 with an AIDS-defining opportunistic infection. The trial was stopped early because an advantage was seen in the ganciclovir arm. Twenty percent of those treated with ganciclovir developed a CMV infection compared with 39% given placebo. The dose used was the same; 1 gram 3 times daily and similar side effects were seen and mostly involved bone marrow suppression.

There are many concerns about oral ganciclovir and the potential for its expanded use in people living with HIV. The first of these is its absorption, which is very poor from the stomach. Taking the drug with food helps it to be absorbed better, but the concentrations in the body are still less than with those obtained with the IV preparation. These low levels may predispose people to develop infections with viruses likely to be resistant to ganciclovir, limiting options for treatment. Unfortunately, there has been no information from the prophylaxis trial about those that did develop CMV disease despite being on ganciclovir. It is possible that the clients were not absorbing the drug; however, it could also be due to viral resistance.

Investigation of oral ganciclovir also revealed a drug interaction with didanosine (ddI), an antiretroviral commonly used with ganciclovir because it does not have the bone marrow suppressive effects of zidovudine (AZT). The amount of ddI in the body increases and average of 111% when given with ganciclovir, potentially increasing the risk of ddI side effects, especially peripheral neuropathy. It is unclear at this time how this occurs, and if it occurs with IV and oral ganciclovir.

Another important issue with oral ganciclovir is its cost. At doses of 3 grams daily, a month's supply will cost on average $1,400.00, not far from the price most infusion companies charge to administer IV ganciclovir. Although an indwelling catheter and all its potential complications are eliminated with oral ganciclovir, the drawback is also that of adding 12 more 250 mg capsules per day to an already complicated drug regimen. It is difficult to predict the direction in which treatment and prevention of CMV retinitis are heading in the near future, although it is encouraging that new delivery systems are becoming available. Therapy is seriously limited by the toxicities and limitations of existing drugs, and it appears that newer investigational anti-CMV drugs still cause serious side effects. Cidofovir (HPMPC) is currently being tested and looks promising, although its effects on the kidney may seriously hamper its use. It may be that a combination of different drugs or especially different delivery systems using both local and systemic therapy will be used together to protect and treat the entire body from CMV, not just the eyes.

Jane Woodward is a pharmacist, currently in practice at the University of Washington.

References

1. Kuppermann BD, Quinceno JI, Flores-Aguilar M et.al. Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: Implications for therapy. JID 1993;168:1506-9

2. Studies of Ocular Complications of AIDS Research Group, AIDS Clinical Trials Group. Mortality in patients with the acquire immunodefficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. NEJM 1992;326:213-20

3. Friedberg DN, Metroka CE, William DC. Response of CMV retinitis to combination therapy with ganciclovir and foscarnet; clinical evidence for multi-strain infection. Int Conf AIDS 1993 June 6-11;9(1):335 (abst #PO-B08-1318).

4. Wolitz R. Intravitreal ganciclovir in patients with progressive retinitis. Int Conf AIDS 1993 June 6-11;9(1);424(abst# PO-B16-1736)

5. Verdejo J, Gonzalez-Guijarro J, Polo RM et. al. Intravitreal ganciclovir treatment for cytomegalovirus (CMV) retinitis. Int Conf AIDS 1992 Jul 19-24;8(2); 5116 (abst# PO-B-3175)

6. Cribblin K, Orlleana J, Liberman R. Intravitreal ganciclovir in patients resistant to ganciclovir and/or foscarnet. Int Conf AIDS 1992 Jul 19-24;8(2);B113 (abst# PO-B-3159)

7. Anand R, Nightinggale SD, Fish RH et al. Control of cytomegalovirus retinitis using sustained release of intraocular ganciclovir. Arch Opthalmol 1993;111:223-27

8. Martin DF, Parks DJ, Mellow SD et. al. Treatment of cytomegalovirus retinitis with an intraocular sustained release ganciclovir implant. Arch Opthalomol 1994;112:1531-39

9. Not available at this time.

10. Knospe V, Katlama C, Rozenbaum W et. al. A randomized controlled study of the efficicay and safety maintenance treatment with IV and oral ganciclovir I the prevention of recurrence of cytomegalovirus retinitis in AIDS patients. Int Conf AIDS 1993 Jun 6-11;9(1):345 (abst# PO-B07-1257).

These articles were provided by the Seattle Treatment Education Project - Copyright (c) 1997 - Seattle Treatment Education Project. Noncommercial reproduction encouraged. Distributed by AEGIS - http://www.aegis.com
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