During the first 15 years of the AIDS epidemic, cytomegalovirus disease was a major scourge for patients with AIDS -- and a major challenge for the healthcare professionals who treated those patients. The prevalence of this common viral infection approaches 100% in the populations that have been hardest hit by HIV, and prior to the era of potent combination antiretroviral therapy, CMV infection caused serious problems for up to half of those with CD4 counts below 50.
The vast majority of individuals with serious complications had retinitis, an inflammation of the inner eye that can lead to blurred vision, permanent damage to the lining of the eye, and eventually to blindness. Others suffered gastrointestinal disturbances, lung infections, or damage to the central nervous system. For many people with HIV, the potential for CMV to ravage their eyesight made it one of the most feared of the AIDS-related OIs. The daily intravenous infusions that were once required to slow the progression of CMV retinitis exacted a heavy toll, both in dollars and in quality of life, and patients were justly apprehensive about beginning infusion therapy.
Now, with the widespread adoption of multidrug antiretroviral therapies that include a protease inhibitor, things have changed markedly. Since early 1996, when saquinavir and ritonavir became commercially available in the United States and Europe, the incidence of new cases of CMV retinitis has declined dramatically. Moreover, recent reports indicate that some patients with CMV retinitis -- a disease that previously could be slowed or checked only by daily IV infusions, and that progressed whenever therapy was interrupted for more than a few weeks -- were able to stop their anti-CMV therapy for up to a year without ill effect, once they began combination antiretroviral therapy.
These findings suggest that advances in anti-HIV therapy have translated into a major reduction in CMV-related problems, at least for the moment. We do not yet know how long this "honeymoon" period will last, but because the improvements that we are seeing seem to be directly related to the effectiveness of these new treatments, the likelihood is that CMV retinitis will re-emerge as a problem in people who develop resistance to the new combination therapies. This prospect makes it all the more important for individuals on combination therapy to remain fully compliant with their assigned regimen and dosing schedule, so that the virus does not have an opportunity to mutate.
The standard treatments for CMV retinitis are ganciclovir and foscarnet. Both are administered intravenously twice a day for 14 days, after which patients are given the same dose once daily. Neither drug offers an advantage in treating CMV retinitis, but they have different side-effects profiles. The major toxic effect of ganciclovir is a reduction in infection-fighting white blood cells. Although this side effect is often managed successfully with Neupogen®, up to 5% of those treated with ganciclovir are forced to stop therapy because of adverse reactions to the drug. Foscarnet therapy presents its own set of problems: roughly 20% of patients who take this drug must abandon treatment because they develop severe neurologic problems, nausea, or other problems that arise from the toxic effects of this drug on the kidneys.
Considerable laboratory and clinical research has been devoted to attempts to develop more effective, less toxic treatments for CMV infections. These efforts are beginning to pay off, although nothing close to an optimally safe and effective treatment has been achieved.
An oral form of ganciclovir has been available for some time now. Although oral ganciclovir is not as effective as continued IV therapy as a means of suppressing CMV in infected individuals, the absolute benefits of IV maintenance therapy -- which requires the surgical implantation of a central venous catheter -- must be weighed against the less tangible benefits, chiefly improved quality of life, seen with oral therapy.
For many patients, the convenience of oral delivery may be the deciding factor. For healthcare professionals, who recognize that central venous catheters can sometimes be portals for infection, oral therapy -- combined with frequent monitoring for disease progression -- may also be preferable.
Oral ganciclovir therapy is probably adequate therapy for patients with lesions that do not threaten the optic disc or the fovea, the part of the retina most critical for visual acuity, but for patients with central lesions, oral ganciclovir alone does not provide sufficient protection.
Ganciclovir is also available as an intraocular implant. The implant offers the most efficacy of any initial treatment for CMV retinitis, probably due to the high concentrations of drug that it delivers to the inner eye. Implants contain enough ganciclovir to last about eight months. However, certain risks do accompany this treatment option. The implants need to be placed surgically, and the procedure can have complications that impair vision.
In addition, intraocular implants do not protect against CMV in the GI tract or the lungs, two common sites of infection. However, the results of a recent study indicate that combining oral ganciclovir therapy with an implant can substantially reduce the risks that the patient will develop CMV disease in the untreated eye or elsewhere in the body.
The F.D.A. recently approved another drug for use against cytomegalovirus infections. Cidofovir has the most potent activity against CMV of any of the available agents, and it does not need to be given daily. Therapy begins with two weekly IV infusions, followed by maintenance doses every other week. Because these infusions are given so infrequently, it is not necessary to implant a catheter, which is required when infusions are given daily.
Unfortunately, cidofovir therapy can cause irreversible kidney damage, which may progress to renal failure. Recent reports indicate that cidofovir can also cause prolonged, painful inflammation of the eye or decreased pressure within the eye, either one of which can lead to loss of vision. It is estimated that from one-third to one-half of patients will not be able to tolerate the toxic effects of cidofovir therapy.
In the era before protease inhibitors were widely available, most patients with CMV retinitis experienced disease progression despite antiretroviral treatment. Typically, these patients were re-treated with higher doses of their current drug or were switched from IV ganciclovir to foscarnet, or vice versa. A newer method is to combine these two drugs.
This has proven to be a particularly effective approach, one that is associated with a delay in progression that is more than twice as long as the delays achieved when either of these drugs is given alone to patients who have already experienced progression of their disease. Although most patients are able to tolerate the combined side effects of these two drugs, the length of time required for infusions of the two drugs can be daunting.
Another option is intraocular injections of either drug (on a weekly or biweekly basis). Intraocular ganciclovir implants have also been used in patients with progressive disease. These implants do slow disease progression, but patients who receive implants are at risk for systemic CMV disease. In Phase III clinical trials, weekly injections of the experimental drug fomivirsen have also slowed disease progression (see "Fomivirsen for CMV Retinitis" in this issue).
Cidofovir should now be regarded as a treatment option for patients who are failing ganciclovir or foscarnet. In one study, progression was halted for an average of 115 days on this regimen. The percentage of patients who were unable to tolerate this salvage regimen was similar to the percentage of patients who cannot tolerate cidofovir when it is given as initial therapy.
Although the ideal treatment for CMV retinitis remains elusive, the outlook is much brighter than it was even a few years ago. Devising the optimal treatment regimen for a particular patient may require some creativity on the part of healthcare providers, but that has been a characteristic of the treatment of HIV disease. Overall, the new drugs and new treatment strategies now available should result in longer periods of reasonable visual acuity for patients with CMV retinitis.
Roche Laboratories, the makers of ganciclovir (Cytovene), recently expanded a clinical trial of valganciclovir, a ganciclovir prodrug that has shown promise as a treatment for CMV retinitis. This trial is designed to assess the safety and efficacy of Roche's investigational drug in patients with newly diagnosed retinitis. HIV-positive patients with newly diagnosed CMV retinitis are eligible to participate in this study irrespective of CD4 count or viral load. There is no cost to patients who agree to participate in the Roche study at one of the 18 sites in the United States and Canada that are now enrolling patients. For further information clinicians should call 1-800-TRIALS-A.
Mark A. Jacobson, M.D., is Associate Professor of Clinical Medicine at UCSF School of Medicine, San Francisco General Hospital, San Francisco, CA.