During the first 15 years of the AIDS epidemic, cytomegalovirus disease was a major scourge for patients with AIDS -- and a major challenge for clinicians who treated those patients. The prevalence of latent CMV infection approaches 100% in the populations that have been hardest hit by HIV, and prior to the era of potent combination antiretroviral therapy somewhere between one-fifth and one-half of patients with CD4 counts below 50 cells/mm3 developed end-organ damage due to CMV.
The vast majority of these patients experienced retinitis; others suffered gastrointestinal involvement, pulmonary infection, or invasion of the central nervous system. For many patients, the potential for CMV to ravage their eyesight made it one of the most feared opportunistic pathogens. 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 therapy that includes an HIV protease inhibitor, the natural history of AIDS-related CMV disease has 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.(1, 2) Moreover, recent reports indicate that some patients with established 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.(3-5)
These observations suggest that advances in anti-HIV therapy have translated into a major reduction in CMV-related morbidity, at least for the moment. We do not yet know how long this "honeymoon" period will last, but the finding that up to half of patients treated with protease inhibitors develop resistance to these powerful drugs raises the concern that the incidence of CMV retinitis may increase as protease resistance does, and that patients whose eye disease is currently in "remission" may relapse at some future date.(6)
CMV retinitis may be asymptomatic, but it usually presents with visual changes. The most common complaints include blurry vision, floaters, blind spots (scotomata), decreased acuity, and photophobia. Any HIV-infected patient with these symptoms should be evaluated by an ophthalmologist who is familiar with HIV infection and its sequelae.
The standard treatments for CMV retinitis are ganciclovir and foscarnet. Ganciclovir is administered intravenously at a dose of 5 mg/kg twice a day for 14 days as induction therapy. Maintenance is with the same dose, once daily. Foscarnet is given IV at a dose of 90 mg/kg twice daily, also for a two-week induction period; after induction, maintenance therapy is once daily, at a dose of 90 mg/kg.
Neither drug offers an advantage in efficacy for treating CMV retinitis, but they have different side-effects profiles. The major toxic effect of ganciclovir is neutropenia, which is dose-limiting in 16% of patients; it is often managed successfully with G-CSF (Neupogen®). Thrombocytopenia is another, less common, side effect of treatment with ganciclovir. Foscarnet may produce nephrotoxicity, as reflected in increased serum creatinine or ionized hypocalcemia, and this can cause severe neurologic problems and/or nausea. Roughly 20% of patients experience a dose-limiting adverse reaction to therapy with foscarnet.
Considerable laboratory and clinical research has been devoted to attempts to develop more efficacious, less toxic treatments for CMV infections.(7) These efforts are beginning to pay off, although nothing close to an optimally safe and effective treatment has been achieved. This article will provide a brief synopsis of all of the currently available treatments for CMV retinitis, to help clinicians develop treatment strategies for affected patients.
Oral: An oral form of ganciclovir has been available for some time now. Although the oral formulation is poorly absorbed, concentrations of drug that inhibit CMV in vitro can be achieved by this route. Current data on the use of oral ganciclovir as maintenance therapy are somewhat disappointing, when those results are compared to continued IV maintenance therapy. However, the absolute benefits of IV therapy, which requires continuous central venous catheter access, 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 clinicians, 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 does not provide sufficient protection.
The major advantages of oral ganciclovir are a significant reduction in neutropenia and the elimination of the risk of central-line sepsis. Other roles are being explored for oral ganciclovir, particularly as primary prophylaxis and as an element of combination anti-CMV therapy.
Implants: 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 intravitreal concentrations of drug that it delivers. Implants contain enough ganciclovir to last about eight months. However, certain risks do accompany this treatment. The implants need to be placed surgically, and the procedure may contribute to retinal detachment. In two studies involving the implants, about 10% of participants had complications that adversely affected their vision, most commonly retinal detachment.(8, 9)
In addition, intraocular implants do not protect against extraocular CMV infections: clinical trials have shown an increase in CMV-related GI, CNS, and pulmonary disease in patients who received ganciclovir implants but no systemic therapy. However, the results of a recent study indicate that coadministration of chronic oral ganciclovir therapy with the implant can substantially reduce the risks that the patient will develop CMV in the contralateral eye or extraocular disease.(10)
The contralateral eye is not protected with unilateral implants, and patients who choose this option should be aware that most implant recipients experience a transient decrease in acuity in the implanted eye. Despite these caveats, intraocular implants are an attractive option for some patients, particularly those with central lesions who still have reasonable vision in the affected eye. (For more information about ganciclovir implants, see "Two advances in the treatment of CMV retinitis," Vol. 1, No. 1, page 8).
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. With an intracellular half-life of 65 hours, cidofovir does not need to be given daily. Current dosing calls for an induction of 5 mg/kg IV weekly for two weeks, followed by maintenance doses of 3 to 5 mg/kg every other week. Accordingly, no central line is necessary; patients can usually tolerate infrequent peripheral infusions.
Unfortunately, cidofovir can cause irreversible nephrotoxicity, which may progress to renal failure. Early signs of kidney damage include proteinuria and increased serum creatinine. It is estimated that from one-third to one-half of patients will not be able to tolerate the nephrotoxic effects of cidofovir and/or the GI symptoms associated with probenecid, which is administered concurrently with cidofovir.(11) The rationale for coadministration of probenecid, which is taken up by proximal renal tubule cells, is that it may ameliorate kidney damage. Saline infusions are also recommended.
Recent reports indicate that cidofovir can also cause prolonged uveitis (painful inflammation of the anterior eye) or hypotony (decreased intraocular pressure), either one of which can lead to loss of vision.
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 induction doses of their current drug. In patients who do have repeated breakthrough episodes of retinitis, alternative treatment strategies are warranted. One option, which has been utilized for some time, is to switch the patient 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 as monotherapy.(12) 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). There are also case reports concerning the use of intraocular ganciclovir implants in patients with progressive disease. These implants have been associated with decreased disease progression, but patients who receive implants are at risk for retinal detachment and extraocular disease.
Cidofovir should now be regarded as a treatment option for patients who are failing ganciclovir or foscarnet. In one study, patients who had evidence of disease progression after a median of four re-induction periods with ganciclovir or foscarnet were treated with cidofovir at a dose of 5 mg/kg IV every other week. Progression was halted for a median of 115 days on this regimen.(13) 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.
Several novel anti-CMV drugs are currently undergoing clinical trial. These experimental agents include a potent anti-CMV benzimidazole riboside, antisense compounds, intravitreal formulations of cidofovir, and a valine ester of ganciclovir with good bioavailability (see box). Although early reports have been disappointing, anti-CMV monoclonal antibodies are still in development. In addition, there is in vitro evidence of synergism between cidofovir and ganciclovir or foscarnet. We are sure to hear more about these combinations, either from clinical studies or anecdotal reports.
Although ideal treatment for CMV retinitis remains elusive, the outlook is much brighter than it was even a few years ago. The optimal treatment regimen for individual patients may require some creativity on the part of clinicians, but that is par for the course in this epidemic. The new drugs and new treatment strategies discussed in this review should result in longer periods of reasonable visual acuity for patients with CMV retinitis.
1. Palella F, Moorman A, Delaney K, et al. Declining morbidity and mortality in an ambulatory HIV-infected population. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 1997. Abstract I-17.
2. Baril L, Jouan M, Caumes E, et al. The impact of highly active antiretroviral therapy on the incidence of CMV disease in AIDS patients. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 1997. Abstract I-31.
3. Torriani FJ, MacDonald JC, Karavellas M, Freeman WR. Lack of progression after discontinuation of maintenance therapy for cytomegalovirus retinitis in AIDS patients responding to highly active antiretroviral therapy. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 1997. Abstract I-33.
4. Tural C, Sirera G, Andreu D, et al. Long lasting remission of cytomegalovirus retinitis without maintenance therapy in HIV+ patients. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 1997. Abstract I-36.
5. Whitcup SM, Fortin E, Nussenblatt RB, et al. Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis. JAMA 1997; 277: 1519-20.
6. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725-32.
7. Jacobson MA. Treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. New Engl J Med 1997; 337: 105-114.
8. Martin DV, Parks DJ, Mellow SD, et al. Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant; a randomized controlled clinical trial. Arch Ophthalmol 1994; 112: 1531-9.
9. Musch DC, Martin DF, Gordon JF, Davis MD, Kuppermann BD. Ganciclovir Implant Study Group. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997; 337: 83-90.
10. Martin D, Kuppermann B, Wolitz R, et al. Combined oral ganciclovir and intravitreal ganciclovir implant for treatment of patients with cytomegalovirus retinitis: a randomized controlled study. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 1997. Abstract LB-9.
11. Lalezari JP, Stagg RJ, Kuppermann BD, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS; a randomized, controlled trial. Ann Intern Med 1997; 126: 257-63. Studies of Ocular Complications of AIDS Research Group, AIDS Clinical Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial: a randomized, controlled trial. Ann Intern Med 1997; 126: 264-74.
12. Studies of Ocular Complications of AIDS Research Group, AIDS Clinical Trials Group. Combination foscarnet and ganciclovir therapy vs. monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS: the Cytomegalovirus Retreatment Trial. Arch Ophthalmol 1996; 114: 23-33.
13. Lalezari JP, Kemper C, Stagg R, et al. A randomized, controlled study of the safety and efficacy of intravenous cidofovir (CDV, HPMPC) for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS. 11th International Conference on AIDS, Vancouver, B.C., Canada, July 7-12, 1996. Abstract 226.
Mark A. Jacobson, M.D., is Associate Professor of Clinical Medicine, UCSF School of Medicine, San Francisco General Hospital, San Francisco, CA.
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. Data presented at the 4th Conference on Retroviruses showed that once-daily dosing with oral valganciclovir resulted in serum concentrations of active drug that were comparable to the levels achieved when IV ganciclovir is administered at the induction doses of 10 mg/kg/day.
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.