Sixth International Conference: Treatment of CMV Infections
CMV (cytomegalovirus) is responsible for several seriousopportunistic infections in people with AIDS. It most commonly
infects the retina of the eye (CMV retinitis), resulting in
blindness if untreated. CMV can also cause colitis and pneumonia
and can infect other organs, including the spleen. The one
approved treatment for CMV retinitis in the U. S. is intravenous
ganciclovir (also called DHPG). Because of its limited long-term
effectiveness, often serious side effects, and the inconvenience
of the intravenous formulation, alternative treatments for CMV
infections are urgently needed. In addition, very little is
known about the safety and effectiveness of ganciclovir or any
experimental treatment for other manifestations of CMV infection,
e.g. colitis and pneumonia; increased research attention in this
area is also crucial.
This article will cover the information presented at the
Conference on the use of ganciclovir by itself and in combination
with the experimental drugs ddI and GM-CSF. In addition, we will
discuss the unapproved drugs foscarnet (which is furthest along
the U. S. regulatory pipeline), oral ganciclovir, and TI-23
(anti-CMV monoclonal antibodies). Preliminary results of a study
on high dose intravenous acyclovir, which is FDA approved for
herpes infections, will also be summarized. Finally, we will
suggest some research directions which should be pursued
immediately to maximize the effectiveness and minimize the
toxicity of currently and soon to be available treatments for CMV
retinitis. (Note: for our last CMV update, see AIDS TREATMENT
NEWS #96, February 2, 1990.)
Intravenous Ganciclovir
Patients and health care workers familiar with ganciclovir
know that, although ganciclovir is quite effective in initially
stopping the progression of CMV retinitis, its long term
effectiveness is often limited, either by time, or by its serious
side effects. Data presented at the Conference shows that CMV
cultured from some patients develops resistance to ganciclovir
after three months of treatment, offering at least a partial
explanation for the time-limited effectiveness of this treatment
in many people with CMV infections. The amount of time for which
this drug is effective varies among patients. In a large study
of over 700 patients, almost half had experienced progression of
their retinitis in a mean of approximately 97 days (with a range
of 4 to 220 days); the other 56% had not experienced any
progression at the time the data was presented. (References to
this and other studies are listed at the end of this article.)
Although ganciclovir's effectiveness is often time-limited,
it is the only drug currently available in the United States for
use by people with CMV infections; it is important to learn how
to use it as safely, effectively and conveniently as possible
until better treatments are available, either by combining it
with other drugs and/or by altering the frequency of its
administration.
Ganciclovir with GM-CSF
Ganciclovir's most serious side effect is its depression of
the development of a type of white blood cells called
neutrophils. These cells are important in fighting off bacterial
infections. Many scientists and activists have believed that a
drug called GM-CSF (granulocyte macrophage colony stimulating
factor), which stimulates the growth of some types of white blood
cells in the bone marrow, might counter the neutropenia
(depressed neutrophil count) experienced by many people using
ganciclovir.
Preliminary results from a small study comparing one
patients treated with GM-CSF with others who received only
ganciclovir suggest that neutropenia severe enough to require
discontinuation of ganciclovir may be reduced with the use of
GM-CSF, although the differences between the two groups were not
outstanding.
What is the clinical significance of the small decreased
incidence of severe neutropenia? It is believed by many that
temporary or permanent discontinuation of ganciclovir contributes
to progression of CMV retinitis. Although the difference in
percentage of patients in the two groups who experienced
progression of their retinitis was not statistically significant,
the mean time to progression was 102 vs 156 days. There were
also fewer bacterial infections in those patients who received
GM- CSF (47%) than in those who did not (62%).
The preliminary results of this study appear to many to be
encouraging. There were some side effects, including more muscle
aches in the GM-CSF group, and an increase in the number of
another type of white blood cell called eosinophils. However, the
overall trend seemed to indicate that GM-CSF may help reduce some
of the adverse effects of ganciclovir and should be available to
patients who wish to use it. GM-CSF has long been one of the
drugs that treatment activists have advocated for immediate
expanded access before FDA approval.
Ganciclovir with ddI
Because ganciclovir and AZT have similar toxicities with
respect to bone marrow suppression and a decrease in the white
blood cell count, it was believed until recently by most doctors
and researchers that the two drugs should not be used together.
As the standard dose of AZT is lowered, more physicians are
recommending that patients may continue to take low doses of AZT
with ganciclovir, as long as their blood counts are monitored
frequently. With the widened availability of ddI, and the
knowledge that ddI does not depress white blood cell counts when
used alone, there is much hope that ganciclovir and ddI can be
used together safely. This combination would provide patients
with anti-retroviral therapy in addition to their anti-CMV
treatment.
Preliminary results from an extremely small ongoing study
(five people) support the hope that ddI and ganciclovir can be
taken together without any additional toxicities. All of these
patients had taken AZT previously and four of them had had to
discontinue the AZT because of neutropenia. No one developed
decreased blood cell counts in the short time of the study (2-7
weeks). The initial findings are far from conclusive, but do
support the belief that ddI may well be a better anti-retroviral
than AZT for people who need to use ganciclovir.
Ganciclovir Three Times Per Week?
Ganciclovir is currently administered twice a day for 14
days (induction phase), followed by once a day, five days a week
administration as maintenance therapy. An Australian study
tested the use of ganciclovir three times per week in the
maintenance phase, at approximately twice the dose used in the
five days per week schedule. Although this study did not have a
control group with which to compare its results, it did find
rates of progression of CMV retinitis similar to those reported
in many other studies. 40% of the patients had experienced
progression of their retinitis at a mean of 4.1 months; 38%
continued to have inactive retinitis on maintenance therapy at a
mean of 6.1 months in the study. (As mentioned above, the large
ganciclovir study presented at the Conference reported 44%
progression at a mean of 97 days.)
Again, this study is not conclusive, but it does suggest
that ganciclovir may be used effectively less frequently than it
is being used now. Given the inconvenience of the intravenous
therapy, if this data were to be confirmed, it would be very good
news. We believe that this type of information is of critical
importance to people with AIDS and CMV infections and should be
seriously pursued by other researchers.
Ganciclovir for CMV Colitis
Very few studies have been conducted with treatments for CMV
infections other than retinitis. A single placebo-controlled
study of ganciclovir in colitis showed some improvement in weight
loss and significant improvement in progression to CMV retinitis
and laboratory assessment of infection as compared to the placebo
group. Unfortunately, although the incidence of diarrhea and
abdominal pain decreased in the ganciclovir group, the group
receiving placebo experienced the same degree of improvement in
these symptoms, suggesting that the drug was not responsible for
the improvements.
Ganciclovir appears to be useful in at least some aspects of
the treatment of CMV colitis; however no studies have been done
to answer such questions as whether treatment should be continued
indefinitely or just until symptoms resolve. Different doctors
and researchers have different opinions about ganciclovir
maintenance therapy in CMV colitis. Further investigation in
this area is certainly warranted.
Foscarnet
Given the limits of ganciclovir, the development of other
treatments for CMV infections is essential. Furthest along the
developmental and regulatory pipeline is foscarnet. Although
this drug also has serious limitations (can be toxic to the
kidneys; also requires daily intravenous infusion), it is
essential that more than one drug be available to treat this
viral infection. Data from the Conference continues to suggest
that foscarnet is effective in stopping CMV retinitis for a
limited time and delaying its future progression. The relapse
rates appear to be similar to those found with ganciclovir. In
addition, one study found a consistent decrease in p24 antigen
levels (in those who were initially p24 antigen positive); these
researchers concluded that due to it's potent anti-HIV and anti-
CMV activities, foscarnet may prove to be the treatment of choice
in CMV retinitis.
Foscarnet is not without its problems, however, and not all
scientists believe that it will prove to be superior to
ganciclovir. In addition to the already identified side effect of
reversible kidney toxicity, reversible penile lesions have also
been identified in a number of people taking foscarnet. These
lesions often require cessation of therapy to heal. Also, one
study found dose limiting neurotoxicity in 2 of 16 patients at a
seemingly more effective but higher dose of foscarnet. Finally,
another study demonstrated that, although calcium levels in the
blood were not altered, the two hormones involved in keeping
calcium levels steady in the body were elevated in people taking
foscarnet. The clinical implication of this observation is not
known at this time.
Comment
A note about the design of clinical trials for CMV
retinitis: Researchers do not like to design clinical trials
without a control group which receives either a placebo, no
treatment, a different treatment, or a different dosage of the
same treatment. In designing clinical trials for CMV, some
researchers have invented a new category which they call "non-
sight threatening CMV retinitis" based on the location of the CMV
lesions on the retina. They created this category of patients so
they could justify withholding treatment from one group to
compare against a treatment group. In their abstract, these
researchers write, "Data previously presented demonstrated that
[immediate treatment] was more effective than delay in postponing
progression of CMV retinitis." Any clinician treating patients
with CMV retinitis could have told them that. It is essential
that this dangerous distinction between non-sight threatening and
sight threatening retinitis not be used in any future clinical
trials of agents against CMV retinitis.
Ganciclovir vs Foscarnet...or Better Yet, Together?
It is believed by many researchers that foscarnet and
ganciclovir are approximately equally effective. A comparison
study of the two drugs under way in England has found that the
initial response of CMV retinitis may be a bit slower with
foscarnet than with ganciclovir. Although the mean time to
reactivation of the retinitis was about 4 months in both groups,
the British researcher stated that there may be a trend to later
and fewer reactivations with ganciclovir than with foscarnet.
Importantly, regardless of small differences in efficacy, most
patients on both treatments required an interruption or change in
their medication at some point during treatment; many of those
who did switch therapies responded to the second drug.
As expected, both drugs have their limitations. However,
because of their different toxicities, they may be more effective
if used concurrently or in alternation than when used alone.
Clinicians and researchers familiar with the two drugs find that
people respond differently to each, but that what is most
important is having an alternative treatment available if the
first one does not work.
Comment
What should be the next step in testing ganciclovir and
foscarnet? Researchers associated with the AIDS Clinical Trials
Group (ACTG), the government sponsored research group, are
currently designing a comparative study of ganciclovir and
foscarnet, to determine which one is a better treatment. But as
we already know (and the English study supports), neither of
these treatments is ultimately satisfactory on its own. People
often either experience a relapse of their retinitis or have to
discontinue treatment due to serious side effects. What seems
clear is that, given the reality at this time of two imperfect
drugs, the most important information we need now is how best to
use them together. This is the same question that is starting to
be asked about the use of the anti-retroviral drugs AZT, ddC and
ddI.
Instead of asking which one works better, we need to ask if
it would be more efficacious and less toxic to use the two drugs
concurrently or in alternation. (We have heard a report that one
or more doctors may be using them concurrently now.) If used
concurrently, how much of each drug should be combined? If used
in alternation, when should they be switched? Business as usual
in this case would be to compare the two drugs alone; business as
usual is a luxury that people with AIDS cannot afford,
particularly in this case. We believe that the next step should
be to design a trial which intelligently examines options for
using these two drugs together.
Note that activists have been pressuring foscarnet's
manufacturer, Astra Pharmaceuticals, to release the drug broadly
on compassionate use for about two years. In the United States,
foscarnet is still only available to those patients who qualify
for, and have access to, a clinical trial.
Other Treatment Possibilities: High Dose Intravenous Acyclovir
A very small study suggested that high dose intravenous
acyclovir, taken with AZT, may be an acceptable alternative
treatment for people who are intolerant of or have failed
ganciclovir or for those patients who cannot tolerate both AZT
and ganciclovir together but wish to continue taking AZT.
Patients were initially treated with ganciclovir and
switched to intravenous acyclovir plus AZT for maintenance. The
published abstract of this study states that 2 of the initial
eight patients treated experienced progression of retinitis at
weeks seven and eight after the completion of the ganciclovir
induction. This study is ongoing and is too small at this time
to allow us to draw any reliable conclusions.
TI-23 (CMV Monoclonal Antibody)
Results from a small, dose ranging study of intravenous TI-
23, a monoclonal antibody against CMV, suggested that this
approach may be a safe alternative to other anti-CMV drugs
currently available or being studied. Since this drug is a
foreign protein, it was important to make sure that the body
would not create antibodies against the drug as a normal immune
response. No such antibodies were detected and there were no
objective side effects observed in the CMV positive, asymptomatic
patients who were studied.
This study was not designed to determine if the drug is
effective; the second phase of the study, which is currently
ongoing in symptomatic patients with CMV infection, was reported
to be showing encouraging early results.
Oral Ganciclovir
Alternatives to intravenous treatment for CMV infections are
greatly desirable; preliminary data was presented at the
Conference on an oral form of ganciclovir. Although this study
was designed to determine safety rather than effectiveness, some
preliminary observations can be made. At the doses studied so
far in this initial dose-ranging study (designed to find the
maximum tolerated dose), all 11 of the patients had experienced a
relapse of their CMV retinitis in a median time of 62 days (range
of 3 to 131 days). There were no problems observed with
toxicity, although resistant strains of CMV were isolated in two
of the patients.
With the formulation of the drug which was tested, only 6-8%
of the drug was found to be active in the blood stream. It is
possible that if better formulations of the drug can be
developed, effectiveness will be improved.
Other Possibilities
Other oral drugs, such as FIAC and HPMPC, are also in
development but no data was presented on them at the Conference
(See ATN 94 for information about FIAC and ATN 76 and 96 for
information on HPMPC.)
References
Ganciclovir and GM-CSF: F. B. 92
Ganciclovir and ddI S. B. 474
Ganciclovir 3 times per week: Th.B. 433
Ganciclovir in colitis: F. B. 94
Foscarnet: Th.B. 434, Th.B. 435, Th.B. 436,
Th.B. 437, Th.B. 438*, Th.B. 439, Th.B. 440,
F. B. 96 *non-sight threatening
Foscarnet vs Ganciclovir: F. B. 95
Intravenous Acyclovir: Th.B. 441, TI-23, Th.B. 442
Oral Ganciclovir: F. B. 9
source: AIDS Treatment News
