Seattle Treatment Education Project: STEP Perspective - Volume 4,
Most presentations about treatment of cytomegalovirus (CMV)
disease focused on ways to decrease the side effects of therapy.
In herpesevirus (HSV), acyclovir (ACV) resistance remains the
foremost problem in therapy. Some of the more promising options
are reviewed below.
Standard therapy. CMV disease in HIV infection is frequent,
with CMV retinitis occurring in 10 to 20 percent of people with
AIDS in the U.S. Retinitis comprises up to 80 percent of CMV
disease in HIV infection, with gastrointestinal involvement
being the next most common manifestation. There is evidence that
active CMV infection may in turn activate HIV infection, so
control of CMV may in itself prevent progression of HIV disease.
CMV disease occurs when HIV infection is relatively progressed,
usually when CD4 counts fall below 100. Currently, standard
therapy consists of either ganciclovir (GCV) or foscarnet
intravenously--at high doses for three weeks then at lower doses
indefinitely to prevent relapse. Both drugs are considered
equally effective in treating CMV disease. The main side effect
of ganciclovir is decreased white blood cell count; the primary
side effect of foscarnet is decreased kidney function. A
recently published study of ganciclovir vs. foscarnet in CMV
disease found that those who received foscarnet survived an
average of four months longer, suggesting foscarnet may have
significant intrinsic anti-HIV properties (Jabs, USA, PoB3193).
The combined use of foscarnet and ganciclovir has also been
studied. Although it appears to be quite effective, it does have
toxicity. In one study presented, all six of the participants
developed penile ulcers, and leukopenia (decreased white blood
cells) was seen in four of the participants (PoB3253). New
drugs on the horizon for CMV include HPMC, FIAC, FIAU, and BW256
(Katlama, France, Session 85).
Use of G-CSF.
Ganciclovir decreases the white blood cell count in 30 to 50
percent of those receiving the drug. One study reviewed the
concurrent administration of a drug GM-CSF
(Granulocyte-macrophage colony stimulating factor) to prevent
decreases in white blood cells during the treatment of CMV
retinitis with ganciclovir. Eighteen percent in the group
receiving both GM-CSF and ganciclovir group, vs. 45 percent in
the group receiving ganciclovir only, developed a decrease in
white blood cell count. The group not receiving GM-CSF missed
more days of ganciclovir therapy because of low white blood cell
count, and as a consequence, this group had a higher incidence
of progression of CMV retinitis compared to the group receiving
both drugs. Since the study began, it has been found that
GM-CSF stimulates HIV replication in the laboratory. The
current standard of care for treatment-related low white blood
cell count is use of a closely related drug, G-CSF (granulocyte
colony stimulating factor) which has not been found to stimulate
HIV. In this particular study, however, GM-CSF was not
associated with increased HIV replication in the patients under
study (Hardy, USA, MoA0005).
A study of CMV neutralizing antibody levels in patients with
retinitis showed that those patients whose retinitis progressed
slowly had significantly higher neutralizing antibody levels
than patients with repidly progressing retinitis. All patients
were treated with foscarnet. This may have implications for
treatment of patients with antibody therapy in progressive or
relapsing CMV disease (Davies, USA, WeB1053).
Data was presented from a study using anti-CMV human
immunoglobulins to prevent CMV disease in individuals with AIDS.
This study, which is still in progress, is administering 0.25 mg
of anti-CMV human immunoglobulins intramuscularly every four
weeks. So far they have seen no illnesses caused by
reactivation of CMV. Additionally, they have seen increases in
CD3 and CD4 lymphocytes, increases in the ratio of CD4/CD8,
activation of natural killer cells, and significant increases in
the blood level of anti-CMV immunoglobulins (PoB3267).
A different approach to maintenance therapy, alternating
ganciclovir and foscarnet therapy every other day, was
presented. The aim of this open- label trial was to determine
if this mode of therapy would decrease side effects of either
drug. One of 10 patients on this regimen discontinued the trial
because of decreased kidney function. Although this group was
not randomized and no control arm was used, this data suggests a
possible alternative to maintenance therapy for patients who are
intolerant of standard maintenance regimens (Malte, Germany,
The most attractive treatment options on the horizon remain the
development of drugs that can be taken by mouth for CMV disease.
Oral forms of ganciclovir and foscarnet are under investigation.
Data was present from a study of adrenal insufficiency.
CMV infection of the adrenal glands is seen in 15 to 80 percent
of people with AIDS, but is often not detected until after
death. In this study, the investigators evaluated individuals
with fatigue, weakness, and loss of appetite, which are the
cardinal symptoms of adrenal insufficiency. They found 14
individuals with insufficient adrenal production of cortisol.
All of these people also had other signs of CMV disease, such
as CMV retinitis. After initiating treatment with 37.5 mg of
hydrocortisone a day, weakness, fatigue, and appetite improved
dramatically in all individuals. Adrenal insufficiency can be
easily detected through laboratory tests and should be
considered in individuals with these symptoms, especially if CMV
disease is present (PoB3836).
Acyclovir resistance. Most of the presentations regarding HSV
disease in HIV infection centered on new drugs for the treatment
of acyclovir - resistant HSV. Patients with chronic HSV
infections are at risk for developing acyclovir-resistant HSV,
especially if their HIV disease is advanced, if they have taken
repeated cycles of acyclovir for recurrent HSV disease. To be
effective, acyclovir needs to be activated by the enzyme
thymidine kinase, produced by HSV. The main mode of acyclovir
resistance is mutation of HSV to produce low levels of thymidine
kinase, thus preventing activation of acyclovir.
Acyclovir-resistant HSV lesions are sometimes apparent simply by
physical exam: these lesions are usually around the buttocks
(but may be anywhere on the body), are much larger and deeper
than acyclovir-sensitive HSV lesions, and are exquisitely
painful. The severe effect on these patients has stimulated a
search for effective therapies.
New agents for acyclovir viral resistance. Because of their
chemical structures, the drugs FIAC, FIAU and FMAU, which have
all been candidate alternative therapies in the past, are not
effective against acyclovir- resistant HSV due to
cross-resistance. The alternate treatment of choice is
currently systemic administration of foscarnet, which acts
through a different mechanism on HSV (other than the thymidine
kinase enzyme), and does not exhibit cross-resistance. Also in
this group of alternate therapies are Trifluridine (TFT) and
Vidarabine (ARA-A). TFT holds promise as a topical therapy for
acyclovir-resistant HSV as shown in preliminary open- label
trials (Pottage, USA, PoB3238). In one small open-label trial,
TFT topical cream completely healed six of 12 patients'
acyclovir-resistant HSV lesions (Kessler, USA, Session 85).
Other new agents.
A report was presented on a drug called 256U87. It is an
acyclovir pro- drug, meaning that it is converted to acyclovir
inside the body. It is well absorbed and rapidly converted to
acyclovir, resulting in acyclovir bioavailability equal to three
to four fold greater than oral acyclovir. Side effects were
minimal and included nausea, diarrhea, and abdominal pain
(PoB3885). It is being studied in phase II/III trials. The
AIDS Cinical Trials Unit here in Seattle is conducting one of
the studies. There are also trials underway studying the use of
256U87 as an agent for CMV prevention.
Copyright (c) 1992 - Seattle Treatment Education Project. Non-
commercial reproduction encouraged.