Treatment Issues, Vol. 11, No. 4/5; April 1997
Jill Cadman

There were initial concerns about safety, especially regarding the risk of retinal detachments. Daniel F. Martin, M.D., in Atlanta, a major figure in the pre-approval implant trials, was among the first to voice these concerns. But CMV disease itself leads to retinal detachments in a large proportion of patients. Cumulative one-year risk ranges from 24% to 50%, according to various reports. Hence, it is not easy to pinpoint the cause of a detachment in an implanted eye.

After having performed the operation on hundreds of patients, Dr. Martin now feels that the problem was somewhat overstated. Although he maintains there is an increased risk in the range of 5% to 10% in the first two months after the implant surgery, he estimates that the one-year risk is about the same as for those patients on systemic treatment.

Similarly, Murk-Hein Heinemann, M.D., of Cornell University Medical College, presented a study in May at the Association for Research in Vision and Ophthalmology (ARVO) that found a total 4.8% detachment rate following implantation (abstract 3415-B16). The Cornell study concluded that detachment is an uncommon complication with the implant.

Dr. Martin stated that CMV activity itself is probably the single most important risk factor in retinal detachment, followed by location and extent of disease. "Every time you get a [CMV] reactivation, you get areas of atrophy and small holes can develop in the retina. It makes sense that an implanted eye over time is going to have lower risk because you don't get the multiple reactivations that you do with IV meds."

Joseph Eviatar, M.D., an ophthalmologist in New York City, also voiced early worries about the risk of retinal detachment. He now concurs with Dr. Martin's observation that the rate of detachments appears to be about the same with the implant as with systemic treatment. Dr. Eviatar said that his experiences have been overwhelmingly positive. "Patients have had their CMV controlled for six to eight months with a single implant and have been able to preserve vision. Most patients have a couple of weeks of slight blurring of vision immediately after the surgery, but that usually resolves."

There have been problems in the past obtaining insurance reimbursement for the implants, which cost about $4,000 plus surgery expenses. These seem to have been largely resolved. Anyone having difficulty with reimbursement or lack of insurance coverage may call Chiron Vision's patient assistance program at 800/EYE-IMPL.

Concurrent Systemic Treatment

The implant is able to deliver medication directly to the infected retina, but it does not protect the retina in the other eye or the rest of the body from the spread of CMV. For that reason, most patients are also taking oral ganciclovir as adjunctive therapy. A large, ongoing trial sponsored by Roche (Protocol 2304) compares the implant plus 4.5 grams of oral ganciclovir versus the implant plus oral placebo versus intravenous ganciclovir alone. Results of this trial are expected this summer and will document the value of systemic ganciclovir protection, both in oral and IV formulation.

Documenting the value of systemic protection is critical. Oral, not to mention IV, ganciclovir is a hard drug to take. Therapy requires 12 to 18 pills a day, at a cost of at least $15,000 a year. Many patients on oral, as well as IV, ganciclovir experience bone marrow suppression, evidenced by reduced numbers of white blood cells (29% of patients on the oral formulation) and red blood cells (19%). Intravenous Neupogen (G-CSF) or Epogen (erythropoietin) can counteract the effect on white or red blood cells, respectively. On the other hand, all patients not on systemic medication must be monitored closely so that treatment can begin at the first sign of CMV progression to new tissue.

Replacing Vitrasert: Immediate or Deferred?

The Vitrasert implant, which effectively prevents progression of CMV retinitis as long as it releases adequate amounts of drug, requires replacement every five to eight months. Inserting the implant is performed under local anesthesia, and patients can go home the same day. The whole procedure takes 30 to 45 minutes. Nonetheless, replacement is serious surgery and carries with it various risks, such as the retinal detachments noted above and temporarily clouded vision. But waiting for CMV reactivation before replacing the implant risks further damage to the retinal tissue. This damage may lead to permanent loss of visual acuity or function.

With the advent of highly active antiretroviral therapy (HAART), some doctors hoped that improvements in CD4 counts would translate into lower risk for reactivation of CMV disease, calling into question the need for pre-planned implant replacement. However, increasing a patient's CD4 count through HAART does not always prevent CMV reactivation. Dr. Martin stated, "I stopped doing scheduled exchanges for awhile and was disappointed. I had some patients with very high CD4 counts and their CMV reactivated at about the same time I would have expected."

Dr. Martin advises those who have Zone 1 (central) disease to have scheduled replacements because they cannot afford to take a chance on loss of vision. For those with Zone 2 (peripheral) disease, Dr. Eviatar stated, "If the patient is doing better systemically and the lesion is not site-threatening, I think it's reasonable to wait and see how they respond. It may be that with the protease inhibitors, they are better able to control the CMV on their own or with oral ganciclovir."

The Effect of Anti-HIV Treatment on CMV

A letter published in the May 21 issue of the Journal of the American Medical Association (JAMA) describes four patients on HAART (including nucleoside analogs and protease inhibitors) who were able to control CMV retinitis without using any specific anti-CMV medication. After initiating HAART, all of the patients' CD4 cell counts increased to over 200. Three patients discontinued treatment with either oral or IV ganciclovir and the CMV retinitis remained inactive, so far for four, five and seven months. The fourth patient refused any CMV treatment and his active retinitis spontaneously resolved and remained inactive for more than 12 months.

Caution should be used when interpreting this small number of case reports. The first author of the letter and clinical director of the National Eye Institute, Scott Whitcup, M.D., stated, "We will need more information before recommending that all people with CMV retinitis and elevated CD4 counts stop their anti-CMV medications." Dr. Whitcup would not recommend coming off anti-CMV medication outside of a carefully picked patient population with extremely close supervision.

Mark Jacobson, M.D., and colleagues at the University of California San Francisco presented a study at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract 353) representing the other end of the spectrum. The Jacobson study looked at five patients who had CMV retinitis diagnosed despite a CD4 count of 200 or more. Four to 24 weeks before the diagnosis, all patients had CD4 counts below 85, and four to eight weeks before the CMV diagnosis, all patients had initiated HAART. The researchers then examined data from 76 consecutive patients enrolled in a treatment trial for CMV retinitis. During the period from July, 1995 through February, 1996, only one patient out of 27 had CD4 counts above 50 and zero out of 27 patients had CD4 counts above 100. From March, 1996 (when HAART became widely available) through August, 1996, 14 out of 49 patients had CD4 counts above 50 and seven out of 49 had CD4 counts above 100. The investigators concluded that the immunological benefits of HAART may not fully protect against CMV retinitis, which may occur more commonly now in patients with CD4 counts above 50.

The authors of the JAMA letter suggest that such cases of CMV may be due to subclinical (asymptomatic) CMV retinitis existing prior to the onset of HAART. Dr. Whitcup notes that retinitis developed in patients in the Jacobson study shortly after initiation of HAART and feels that CMV would have eventually emerged in these patients in any case. Dr. Whitcup has seen his own patients develop such symptoms of CMV retinitis as vitreous floaters shortly after starting on HAART. It is possible that HAART cannot immediately protect a patient who already has a subclinical case of retinitis, but it may be protective against CMV progression over the longer run no matter what the initial status of the disease.

Dr. Whitcup said, "I have yet to see someone develop CMV retinitis who has been on HAART for over three months and whose CD4 counts are over 50 -- although I think there may be cases out there where that occurs." Of course those who have been on combination therapy for extended periods may experience "HAART failure" and subsequent CD4 count declines. Once CD4 counts fall below 50, there will be renewed risk for CMV progression.

The National Eye Institute is seeking to recruit AIDS patients with non sight-theatening CMV retinitis for further study at the NIH. A small 12-person trial will attempt to provide further insight into when it is appropriate to discontinue CMV treatment in patients on HAART. Anyone interested in this trial should contact Cheryl Perry at 301/435-4559.

Improvements in the Pipeline

As people survive longer with AIDS, eight-month implants appear more insufficient than ever. Chiron Vision is now developing a second generation implant called Vitrasert II that will release ganciclovir for a minimum of 18 months and possibly last as long as 24. Chiron hopes to start pilot human studies (phase I) by the end of the year. There also is room for improvement in oral ganciclovir for maintenance therapy to prevent CMV reactivation. The current standard three-gram dose is not as effective as IV ganciclovir. Raising the daily dose of oral ganciclovir to 4.5 grams works better (see Treatment Issues, September 1996, pages 4-5), but requires even more pills and expense. Roche's ganciclovir prodrug (RS-79070) is much more absorbable in the gut than the present version of ganciclovir and breaks down into the active form once in the body. The prodrug's oral bioavailability is about 61%, compared to about 8% for the current oral formulation. Data presented by Roche this past winter at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract LB19) demonstrated that the same levels of serum ganciclovir can be achieved with the prodrug as with IV ganciclovir.

Providing that the pharmaceutical companies move forward, the future standard of care might employ Vitrasert II to treat the local manifestation of CMV retinitis for two years and one pill of ganciclovir prodrug per day to control extra-ocular disease. This treatment strategy would avoid what Dr. Martin calls "the emotional roller coaster of going back and forth from induction to maintenance therapy," which is the current experience of most people with CMV retinitis.

As this article was being readied for press, Hoffmann-La Roche announced that it was deferring development of the ganciclovir prodrug -- see Roche Puts Ganciclovir Prodrug Program On Hold.

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