CMV Experimental Treatment Overview, Part II

NEWS #167 (January 15, 1993), looked at ganciclovir in
combination with G-CSF or GM-CSF, at ganciclovir eye
implants, and at oral ganciclovir.

Foscarnet

Foscarnet (brand name Foscavir) was the second drug approved
for treating CMV retinitis in persons with AIDS. In the U. S.,
government approval came only after much work by AIDS treatment
activists; in Europe, however the drug had long been used often
as first-line therapy. Foscarnet is also active against other
herpes viruses, and to a limited degree against HIV. It is
currently being tested in clinical trials as a treatment for CMV
colitis, acyclovir-resistant herpes simplex, and herpes zoster
infections. Risks of foscarnet include kidney toxicity,
electrolyte abnormalities, anemia, and penile ulcerations.
Individuals taking foscarnet must be carefully monitored by an
HIV-knowledgeable physician for these side effects.

One of the advantages of treatment with foscarnet is that
there seems to be a survival benefit greater than treatment with
ganciclovir. This may be due to its antiviral activity against
HIV. In one study of 234 people with CMV retinitis, average
survival was 12.6 months compared to an average survival time of
8.5 months for those treated with ganciclovir. ("Mortality in
Patients with the Acquired Immunodeficiency Syndrome Treated with
Either Foscarnet or Ganciclovir for Cytomegalovirus Retinitis."
Studies of Ocular Complications of AIDS Research Group, in
collaboration with the AIDS Clinical Trials Group. New England
Journal of Medicine, January 23, 1992, volume 326 number 4, pages
213- 220.)

Currently, foscarnet is given intravenously. An oral form
has been developed, and a single-dose pharmacokinetic study has
been completed in Europe. A phase II trial in Europe is expected
to start this spring.

Combination Therapy with Foscarnet and Ganciclovir

Ganciclovir- and foscarnet-resistant strains of CMV
eventually develop when these drugs are used, and disease
progression takes place. Combination use of the two drugs is now
being tested to see if it can delay these problems. AIDS
TREATMENT NEWS spoke with Mark Jacobson, M. D., Clinical
Professor of Medicine at the University of California in San
Francisco, who is conducting a phase I clinical trial of this
combination. He told us that the study is for maintenance
therapy, after an initial occurrence of CMV retinitis has been
treated with an induction therapy of ganciclovir. The 30
patients enrolled in this trial were randomized to maintenance
therapy with either daily alternating regimens of ganciclovir and
foscarnet, or concurrent therapy with both drugs. According to
Dr. Jacobson, "the time to progression of CMV retinitis in the
interim analysis was similar in the two groups -- ganciclovir and
foscarnet combined vs. ganciclovir and foscarnet alternating.
Based on our data, and we are still following a number of these
patients, it looks like the alternating regimen may be better
than the combined one because there is not a big difference in
time to progression; therefore the simpler regimen with only one
infusion per day would require less infusion time than the
combination regimen."

One German study presented at the VIII International
Conference on AIDS in Amsterdam reported on the treatment of
several patients with CMV retinitis who received both drugs (B.
Salzberger and others, abstract #PoB3253).

IVIG (Intravenous Immune Globulin)

Gamma globulin is a blood product containing antibodies
pooled from various blood donors. It gives the recipient a
passive immunity by increasing the amount of antibodies to CMV
(or other infections). There are many different preparations of
IVIG, including some prepared specifically for CMV. Side effects
of IVIG rarely occur, although there may be pain at the infusion
site, headache, and malaise.

Standard IVIG preparations, although not made for anti-CMV
use, may have varying amounts of anti-CMV antibodies, depending
on the donors of the blood used in each batch. A representative
of Baxter Pharmaceuticals we spoke with said that a physician
could request a preparation of Gammagard (Baxter's brand of IVIG)
with higher than average concentration anti-CMV antibodies.

A clinical trial is presently being conducted at Georgetown
University Medical Center comparing the efficacy of ganciclovir
plus IVIG to that of ganciclovir alone. In this pilot study, 20
people with CMV retinitis were given IVIG five times during the
ganciclovir induction. During maintenance therapy they received
IVIG weekly. According to Princy Kumar, M. D., the treatment
"was extremely well tolerated. Nobody had to be withdrawn
because of any complications related to the IVIG. " The efficacy
data is still being analyzed and will probably be available early
in 1993. While it is unknown whether or not IVIG can penetrate
the blood-retinal barrier (to reach the retina and the CMV
infection there), it penetrates into the cerebral-spinal fluid
well and this is an indication that it may also cross the blood-
retinal barrier.

CMVIg

CMVIg [Cytomegalovirus Immune Globulin Intravenous (Human),
brand name Cytogam] is an IVIG preparation which is specially
made to contain high concentrations of antibodies against CMV. It
is manufactured by the state of Massachusetts, and is approved by
the FDA for use in the prevention of CMV disease in kidney
transplant patients. Unfortunately, it was not studied in HIV-
infected individuals until recently, so it is only available off
label, by prescription, from the American Red Cross.

CMVIg is currently being studied for preventing CMV disease
in persons with HIV. A phase I safety study for HIV-infected
individuals with positive CMV blood cultures is being conducted
at the National Institutes of Health in Bethesda, Maryland. The
dose used in this trial is 150 mg per kilogram of body weight
every two weeks or every four weeks. This trial has enrolled
nine persons to date. One volunteer may have developed CMV
colitis on the trial. CMVIg is generally well tolerated, though
side effects include chills, muscle cramps, and fever.

Unfortunately this treatment is expensive, and because HIV
use of this preparation is off label, patients are unlikely to be
reimbursed by Medicaid or by their insurance companies. The cost
for 2.5 grams of this preparation is approximately $300 per vial,
so a person of average weight who used the same dose as in the
above trial would need to spend about $1000 per intravenous
infusion, not including the cost of administration.

MSL-109

MSL-109 is a genetically engineered monoclonal antibody
against CMV. A small phase I/II of ganciclovir with MSL-109 is
being conducted at Massachusetts General Hospital. The study
began in early 1990 and so far has enrolled seven individuals
with CMV retinitis. There is still one more slot for someone
recently diagnosed with CMV retinitis who has done induction
therapy with either foscarnet or ganciclovir. MSL-109 seems well
tolerated, although it is unclear whether the combination is
effective at slowing the time to progression in CMV retinitis
patients.

TI-23

TI-23 as another anti-CMV monoclonal antibody. Results of a
small human trial at the University of Arizona were presented at
the 1991 International Conference on AIDS [abstract #W. B. 2291].
The researchers concluded that the treatment was well tolerated,
and that CMV retinitis progression data was favorable compared
with historical controls. We do not have recent information.

HPMPC

HPMPC is a broad spectrum antiviral active against many
herpes viruses, including CMV. It is presently in phase I/II
testing in San Francisco, and at the National Institute of Health
in Bethesda, Maryland. The current trials are with HIV-infected
individuals who have no symptoms of CMV disease, but are at risk
for developing it because they have positive CMV urine cultures.
Gilead Sciences, the pharmaceutical company developing HPMPC,
announced on December 1, 1992, that preliminary data showed
evidence of anti-CMV activity in the phase I/II trial. According
to Jay Lalezari, M. D., who is conducting the trial at Mt. Zion
Hospital in San Francisco, "HPMPC has shown unprecedented
efficacy in reducing titers of CMV in urine and semen. Our only
concern is its potential for kidney toxicity. We are currently
recruiting ten more individuals to study the role of probenecid,
a drug we believe will protect the kidneys from toxicity.
Assuming we have a therapeutic window [a dose which is effective
but not too toxic to use], we should have a treatment protocol
available by this summer."

Persons interested in volunteering for this study can call
Dr. Jay Lalezari, Mt. Zion Hospital HIV Clinical Research,
415/476-6356.

[Note: AIDS TREATMENT NEWS is preparing a longer article on
HPMPC, and on PMEA, a potential drug which is chemically related
to HPMPC but has both anti-CMV and anti-HIV effects.]

Acyclovir; BW256

Acyclovir has very little effect against CMV, but some HIV-
infected individuals with low T-helper cells have tried to
prevent CMV disease with high-dose acyclovir. A major clinical
trial at 19 centers in Europe and Australia for individuals at
risk for developing CMV disease has found that taking 800 mg of
acyclovir four times a day failed to stop progression to CMV
disease. However, there appeared to be a survival benefit for
the group treated with acyclovir. (There is some controversy
among physicians about this conclusion, since no one is sure how
the drug might be working.)

According to Kenneth Mayer, M. D., Director of the Brown
University AIDS Program and Research Director of the Fenway
Community Health Center, the "acyclovir may be acting in several
ways that may preserve life. Laboratory tests have shown that if
you add herpes simplex or CMV to cells which were previously
latently infected with HIV, the co-infected cells can be
activated and produce HIV. "

A new drug being developed by Burroughs-Wellcome, BW256, is
rapidly turned into acyclovir when metabolized by the body. Blood
levels of BW256 reach three to four times that of oral acyclovir,
making it a better candidate than acyclovir for CMV prophylaxis.
A phase I safety trial using this drug in HIV-infected
individuals with less than 150 T-helper cells is currently
underway at Johns Hopkins, and a protocol for an efficacy trial
is being developed. At this time it is not certain whether the
possible anti-CMV efficacy or a possible survival benefit will be
studied.

Etoposide (VePesid or VP-16)

Etoposide is an agent approved for use as a cancer
chemotherapy; it is currently being tested for treating AIDS-
associated Kaposi's Sarcoma (KS), and with other chemotherapies
for treating AIDS-associated non-Hodgkin's lymphoma. Side
effects of this drug include severe bone marrow suppression,
nausea, vomiting and hair loss. In the test tube this drug can
"turn off" the CMV virus by inhibiting an enzyme (topoisomerase-
2) found in the cells. Nobody knows what dose might be used to
achieve the drug level which showed anti-CMV effect in the test
tube studies.

AIDS TREATMENT NEWS interviewed one person with AIDS who
tried, with his physician, to find an effective dose. This
person had no CMV disease, but was at risk because of low T-
helper cell count and positive blood and urine cultures for CMV.
After taking etoposide, he lost all of his hair, and his
hematocrit level fell dangerously. He felt very ill from the
toxic effects of the drug, and went off etoposide after about one
month. In his case the blood culture and urine culture for CMV
remained positive. Despite this one anecdotal case where the
treatment appears to have failed, this drug should be studied
further for possible use in treating CMV. Perhaps data collected
in the clinical trials of etoposide for KS and for lymphoma d be
analyzed to see if t is any anti- CMV effect in these patients,
who will be taking the drug anyway.

Hypericin

Hypericin is a compound derived from the herb St. John's
wort, and in test tube studies shows activity against both HIV
and CMV. A synthetic form of hypericin has also been
manufactured. There have been no clinical trials using hypericin
for CMV disease, and we have not heard of anyone trying it for
this purpose. An early trial of hypericin as an HIV treatment is
underway. [Note: for more information about hypericin as an
experimental antiviral, see AIDS TREATMENT NEWS # 146, February
1992].

Notes:

(1) Other CMV drugs are in preclinical development. We did not
include them in this article because they are not yet in human
use, and we have little information about them at this time.

(2) For background on CMV, see "CMV Infection," by Douglas
Dieterich, M. D., in PAACNOTES, October 1992. This article
includes 34 literature references. It only covers the FDA-
approved CMV treatments, ganciclovir and foscarnet.