CMV Experimental Treatment Overview (Part I)

by Giacomo egalovirus (CMV) is a virus which infects much of the general
population, and most persons with HIV. CMV rarely causes disease,
however, unless the immune system is suppressed -- as in recipients of
organ transplants who must take immunosuppressive drugs, or in persons
with AIDS. Those with T-helper counts under 50 are at greatest risk of
CMV disease, although it can occur at higher T-helper counts.

CMV retinitis, an infection of the retina of the eye which causes
blindness if untreated, occurs in 10 to 20 percent of people with AIDS
in the United States. CMV retinitis accounts for about 80 percent or
more of CMV disease in persons with AIDS. One eye is usually affected
first, and a two or three week intensive "induction" treatment with an
anti-CMV drug (ganciclovir or foscarnet, see below) is necessary to save
its sight. After the induction phase, patients are put on a lower
"maintenance" dose of one of the drugs, to prevent the retinitis from
continuing to progress. If the person does not use the maintenance
therapy, the retinitis will also affect the other eye within six months
in roughly 60 percent of the cases; with maintenance therapy, this is
reduced to about 15 percent.

CMV can also cause disease in the lungs, colon, adrenals,
esophagus, and other organs.

Because CMV retinitis can rapidly cause permanent vision loss,
persons with T-helper counts less than 200 should have regular eye
examinations, and must get medical attention immediately if vision
problems develop. (Although retinitis rarely occurs when T-helper
counts are above 50, there are other reasons for persons with AIDS to
have eye examinations; also, if retinitis occurs, it is important to
have already established a relationship with a CMV-knowledgeable
ophthalmologist.) While exposure to CMV can be detected by a test for
antibodies in the blood, this test does not tell whether or when CMV
disease will occur.

Two drugs -- ganciclovir and foscarnet -- have been approved by the
FDA for treating CMV retinitis by intravenous administration. While
known to be effective, both have serious drawbacks, and a number of
experimental treatments in various stages of development are being
tried. This article will look at new ways to use the standard
treatments, as well as experimental CMV treatments which are now being
developed.

Ganciclovir; Use of G-CSF or GM-CSF

Ganciclovir (brand name Cytovene; formerly called DHPG) has been
approved for CMV retinitis since 1990 (it is still being tested for CMV
colitis). When retinitis is first diagnosed, the patient receives twice
daily infusions of ganciclovir for two to three weeks (induction
therapy), and is then put on lower daily doses for maintenance. Without
the maintenance therapy, the retinitis may recur within a short period
of time. (An easier dosage schedule of three infusions every week for
maintenance therapy is currently being tested.)

Because ganciclovir is toxic to neutrophils (a class of infection-
fighting white blood cells), blood tests must be carefully monitored.
Ganciclovir-induced neutropenia (lack of enough neutrophils) can be life
threatening; fortunately it is usually reversible within a few days of
stopping therapy.

Since continuing CMV treatment is necessary, the best approach may
be to avoid or neutropenia by using either G-CSF (Neupogen) or GM-CSF
(Leukine). Both of these are substances produced by the body which
stimulate the growth of neutrophils. In one study presented at the
Eighth International Conference on AIDS in Amsterdam, patients were
randomized into a group which received ganciclovir alone, and another
group which received ganciclovir plus GM-CSF. Eighteen percent of the
patients receiving the combination developed neutropenia, compared to 45
percent of the patients receiving ganciclovir alone (abstract #MoA
0005).

Both G-CSF and GM-CSF are FDA-approved for treating low neutrophil
counts in other situations, but they are still being tested for
combination therapy with ganciclovir, so there is no official approval
yet, even though the drugs are in widespread use for this purpose and it
is clear that they can be effective. For now, these drugs must be
prescribed off label (meaning that while the FDA has approved the drug,
it has not specifically approved that particular use). Unfortunately,
there are still many physicians who will not prescribe these drugs off
label, even in severe cases of neutropenia. Insurance reimbursement can
also be a problem.

Ganciclovir Eye Implants

Another approach to limiting the toxicity of ganciclovir is a new
drug delivery system now being tested at the New England Eye Center of
the New England Medical Center, and at the University of Texas
Southwestern Medical Center in Dallas. In these trials, a tiny time-
release capsule containing ganciclovir is surgically implanted into the
eye. Two eye- implant systems are being investigated. One slowly seeps
ganciclovir into the eye for 120 days, and the other system seeps
ganciclovir for 240 days. According to Jay Duker, M. D., Director of
Vitreoretinal Service of the New England Eye Center, "the success rate
with both the 4-month implant and 8-month implant is running about 90 to
93%. What that means is that in the patients who immediately respond to
treatment, we have not had anyone reactivate with CMV retinitis as long
as there's medication left in the implant. We have had a certain
percentage, maybe ten percent, who have not responded at all to the
implant. So there are some patients who will not respond, but in the
ones that do seem to respond very well." One of the reasons for the
success of this drug delivery system is that it allows for a constant
rate of release of ganciclovir into the eye, while the amount of
intravenous ganciclovir peaks after slightly more than an hour, but then
leaves the eye without high levels until the next dose.

Phase III trials of this drug-delivery system will begin in the
first few months of 1993 at the New England Eye Center, and at nine
other sites across the country. There will probably be three protocols
in these phase III trials. One will be for newly diagnosed individuals
with CMV retinitis and will compare the 4- month implant, the 8-month
implant, and intravenous ganciclovir. The second protocol will be for
individuals failing intravenous therapy (foscarnet or ganciclovir) and
will compare the options of continuing on intravenous drug alone, or
continuing intravenous therapy with an implant. A third trial would be
for compassionate use of the drug delivery system.

Kevin Frost, a treatment activist with ACT UP/New York and TAG
(Treatment Action Group) who has worked on the development of these
protocols for almost a year, said that he "firmly believes we will have
a compassionate use protocol." One problem with a drug delivery system
that must be surgically implanted is that a surgeon trained in the
technique must do the procedure, so the compassionate use protocol will
probably be limited to the 10 sites across the U. S. where the phase III
trial will take place. Another problem is insurance or Medicaid
reimbursement for the cost of the surgery. According to Kevin Frost,
"when you start talking about this in terms of cost effectiveness and
Medicaid looks at it in terms of cost-effectiveness, there's absolutely
no question that it's cheaper to use the drug delivery system [compared
to the alternative of daily intravenous infusions]. As a matter of
fact, the Medicaid agencies in New York and Texas have already agreed to
pay for the procedure. My hope is that the national Medicaid program
will agree to pay for it within the next couple of months -- we will be
going to work on this very issue when the protocol is approved by the
FDA. "The phase III trial will probably take 6 to 9 months to enroll
patients and, because the implant lasts 8 months, it will take another 8
months before the trial closes. Then the data will have to be presented
to the FDA for drug approval. Hopefully, the company that produces this
device will make it available by compassionate use to those individuals
who have CMV retinitis that is progressing, but do not meet the
eligibility criteria of the trial.

The main risks with the eye implant are those associated with
surgery: hemorrhaging and infection. The incision line is small and not
visible without a close inspection of the eye. There is also a danger of
retinal detachment, but cases of detachment in the study appear to be
due to the disease process and not the drug-delivery system. Another
risk in administering ganciclovir this way is that CMV infection is
often systemic (in other organs in the body, not only in the eye), and
other parts of the body would not benefit from the eye implants.

It is also possible to inject ganciclovir directly into the eye,
although this method does not maintain a constant high level within the
eye like the implants described above.
Oral Ganciclovir

An oral version of ganciclovir, which would be much more convenient
than the intravenous drug and less expensive to administer, is currently
being investigated as a treatment for CMV retinitis at 22 sites across
the U. S. Oral ganciclovir has a bioavailability of six to ten percent
(meaning that only that fraction is absorbed when the drug is taken
orally). In this trial patients are randomized to either 1000 mg three
times a day or 500 mg six times a day of oral ganciclovir. The efficacy
of these regimens is being compared to that of a third arm in which the
patients receive IV ganciclovir at a dose of 5 mg/kilogram of body
weight every day.

Clinical trials of oral ganciclovir as a CMV prophylaxis for HIV-
infected individuals with low T-helper cell counts are now beginning
(see notice in "Announcements" section, below). According to Jay
Lalezari, M. D., co-director of HIV research at Mt. Zion Hospital in San
Francisco, "CMV is the last major opportunistic infection for which we
have no prophylaxis, so one is urgently needed. Our studies of oral
ganciclovir have shown it to be relatively safe and well tolerated, and
to have demonstrated activity in reducing titers of CMV infection in
people."

Note: The second and final part of this article will cover
foscarnet, combination ganciclovir/foscarnet therapy, IVIG, CMVIg,
MS-109, HPMPC, BW 256, etoposide, and hypericin.