New CMV drug won’t replace other therapies

Cost, compliance issues may influence treatment

A newly approved drug for treating cytomega lovirus (CMV) retinitis, injectable fomivirsen (Vitravene), has shown promise in premarketing clinical trials in AIDS patients with advanced CMV disease. According to the drug’s manufacturer, Isis Pharmaceuticals in Carlsbad, CA, fomivirsen belongs to a new class of drugs called "antisense technology," which work at the genetic level to interrupt the process by which proteins involved in human disease are produced.

"Traditional drugs are designed to interact with protein molecules that support or cause diseases throughout the body," according to Karen Handel, director of corporate communications at Isis. "Antisense drugs are designed to inhibit the production of disease-related proteins" by inhibiting the production of the protein encoded by the target RNA, she says.

Fomivirsen inhibits the production of viral proteins that are critical to the virus life cycle, thus delaying disease progression.

Data were presented earlier this year in Chicago at the Fifth Conference on Retroviruses and Opportunistic Infections on a multicenter phase-three study of previously untreated patients with greater than 25% retinal involvement. Eighteen patients received 0.05 ml fomivirsen (3.0 mg/ml) by intravitreal injection for three weekly doses followed by bimonthly maintenance doses of the drug. Ten additional patients were assigned to a deferred treatment group and were followed to progression before being given fomivirsen. All patients were followed for time to progression for CMV retinitis, which was determined using clinical criteria and with masked reading of fundus photographs. Ocular adverse events were assessed using complete bilateral ophthalmic exams. CD4 counts also were measured at baseline and throughout the study.

There was a median time to observed progression of 71 days for patients in the immediate treatment group vs. 13 days for patients in the deferred treatment group. CD4 counts were not significantly different between the two treatment groups. The most frequently reported side effects were transient increased intraocular pressure (18.5%), anterior chamber inflammation (15%), and vitritis (7%).

In other data provided by Isis Pharmaceuticals, an open-label study indicated that fomivirsen delayed progression of CMV retinitis for as long as 600 days.

Debra A. Goldstein, MD, assistant professor of ophthalmology and director of the Ocular HIV/AIDS Service at the University of Illinois in Chicago, was one of the investigators of fomi virsen for premarketing trials. She also is conducting current studies of the drug.

"It’s not effective in 100% of patients, but neither are any of the other therapies," she notes. "Ganciclovir is only effective in probably 90% of the people who are treated for the first time."

Goldstein uses the drug as first-line therapy in patients who have recently started highly active antiretroviral therapy (HAART) in hopes that there will be an immune response.

"That person would be a great [candidate] to put on this first-line rather than an acyclovir implant," she says. "My usual first-line is an acyclovir [Zovirax] implant."

In addition, patients who are resistant to ganciclovir (Cytovene) are appropriate candidates for fomivirsen therapy.

"The drug is being approved for use for maintenance of a once-a-month injection," Goldstein explains. "That’s a very reasonable thing."

The advantage of local fomivirsen therapy is that there are high concentrations of the drug where it is needed without systemic side effects.

"Ganciclovir [given] intravenously has a lot of side effects; the most prominent is [the effect] on the bone marrow," Goldstein says. "Foscarnet [Foscavir] has side effects on the kidneys."

Systemic therapy also requires long-term intravenous administration of drugs.

"On average, there is more than one episode of line sepsis per year per patient with a permanent indwelling [intravenous] catheter," Goldstein says. "When treating the patient locally, you avoid the [risk of] line sepsis."

Goldstein says she typically gives either 150 mcg or 330 mcg of fomivirsen every week (depending on the severity of disease) for three doses, with subsequent maintenance injections once every two or three weeks given indefinitely until the patient either has immune reconstitution or dies.

"In some patients, it causes some inflammation in the eye, and some patients will get [intraocular] pressure after the injection, but these are manageable side effects," Goldstein says.

Although she says fomivirsen is slightly more inflammatory than ganciclovir and foscarnet when given intravitreally, it is much less inflammatory than cidofovir (Vistide), another type of injection used to treat CMV retinitis.

Robert Nager, MD, a spokesman for the American Academy of Ophthalmology in San Francisco, is less enthusiastic about fomivirsen. He says it was approved based on studies with "very small numbers." But Goldstein says that because of newer effective systemic therapies, there are fewer and fewer patients with CMV retinitis to enroll in studies.

"With HAART therapy, the number of people with CMV has really gone down, so any trial of CMV is going to be small," she notes.

Nevertheless, Nager says he prefers the ganciclovir implant (Vitrasert) over fomivirsen. The implant is placed behind the lens of the eye and it releases the drug slowly for about eight months. To his knowledge, there are no studies comparing the two treatments.

Which is better: Implant or injection?

"I think the real issue would be, how does Vitravene work compared with Vitrasert?" Nager asks. "Vitrasert really keeps the eye inactive for about 220 days. If the [efficacy] is equal, then the argument could be made that fomivir sen [is better because] Vitrasert is more of a surgical procedure. But I have a patient who is very, very sick, and we’re going to give him a Vitrasert so he doesn’t have to deal with shots every week. Vitravene is more difficult for patients. Plus, you run the risk of having infections because you’re putting shots in peoples’ eyes more frequently than if they have a Vitrasert."

Although the implant has the drawback of requiring that the patient undergo major surgery every eight months for a new implant, Nager says he believes patients would rather undergo infrequent surgery than have an intravitreal injection on a regular basis.

"With the implant, you put it in once, and you follow patients, but you basically don’t have to worry about them," he says. "I put an implant in and see them every month and I really almost never have to do anything. Vitravene involves injecting them every month."

Nager says he would use fomivirsen in patients who are "profoundly resistant" to ganciclovir. "One of the advantages of vitravene is there is no resistance known to this," he says. "I’d say if they couldn’t have a Vitrasert because they were profoundly resistant to ganciclovir, then it would be a good choice."

Ronni Lieberman, MD, associate professor of ophthalmology at Mount Sinai School of Medicine in New York City, has investigated fomivirsen. She says almost 100% of her practice consists of patients with CMV retinitis.

"No one is going to argue that Vitrasert is tremendous," she notes. "It’s one operation, it works for eight months, and it’s a fairly benign operation."

But there is a downside to the surgery, Lieberman adds.

"This is an operation," she says. "You can have complications with operations. What I say to every patient before I operate on them is that you have a 3% chance of getting an infection and a 3% chance of getting a hemorrhage and all of these things, but if it happens to you, it’s 100%. So although the risk is small, if it happens, these are all devastating complications."

In addition, as patients continue to undergo repeated implant surgery, their risk for complications goes up as well.

What about the price tag?

"And the dirty little secret that nobody wants to talk about is that Vitrasert is not cheap," Lieberman says. "The Vitrasert costs $4,000 to buy from Chiron [the manufacturer]. Then the patients or their insurance have to pay the hospital for OR time, nurses’ time, medications, a separate bill for anesthesia and preadmissions testing, and a separate bill for your medical doctor who has to give you clearance. This is a lot of money."

She estimates it may cost $10,000 or more to insert Vitrasert. Although fomivirsen probably won’t be inexpensive, Lieberman estimates that in patients on HAART, fomivirsen may be the best therapy. (The cost of fomivirsen was unavailable from Isis.)

"If you put Vitrasert in a patient on HAART therapy, you will have spent that $10,000," she says. "You’ve given them that eight months of treatment. You’ve spent that $10,000. If somebody comes on day one and you decide to give them Vitravene, you inject them, that’s $100 for the doctor’s fee. They then continue on their Vitravene for three to four months, and we’ll see what their viral load and [CD4] cell count is. And if indeed their eye looks lovely and their [CD4] cells have come up and their viral load has come down, you may very well just decide to skip the injection and wean them off the Vitravene. I’ve done that with a lot of patients. You haven’t guaranteed buying eight months of treatment. From a medical-economic point of view, you’ve spent all your money up front with the Vitrasert."

Lieberman says she places patients on many different regimens for CMV retinitis, from local to intravenous therapy to implants. "The bottom line is that every patient is different," she says. "They have different immune systems, they have different kidney function, they are on different HAART therapy, they’re in a different course of the illness, and they’ve got different psychosocial factors."

In patients who are noncompliant, she may consider Vitrasert, because she is concerned that they may not show up for follow-up appointments for weekly or monthly therapies. For a single mother with no health insurance who can’t afford Vitrasert, intravitreal injections with fomivirsen or other drugs may be the best therapy.

"Vitravene is an excellent drug that has had excellent results in many patients," Lieberman explains. "It is certainly my choice for first- or second-line therapy in some patients. But there is no drug I would say I’d use unequivocally ahead of other drugs. Every patient is different. You have to weigh the pros and cons of every drug with every patient."