                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                        January 26, 1996

               Opportunistic Infections (Part XVIII)

                      Cytomegalovirus (CMV)

[Harvey S. Bartnof, MD. Treatment for Opportunistic Infections.
AIDS Treatment Highlights from the 35th ICAAC Conference in San
Francisco. Headline Treatment News. BETA - Bulletin of Experimental
Treatments for AIDS. Published by the San Francisco AIDS
Foundation. October, 1995.]

     IV cidofovir (Vistide) prevented progression of CMV retinitis
for 115 days among patients failing or intolerant to the standard
IV therapies of ganciclovir and foscarnet.  The dose was once
weekly for 2 weeks, then once every other week (J. Lalezan,
abstract LB-9, University of California at San Francisco).  NOTE: 
Gilead Sciences has submitted an application to FDA for approval
of Vistide for first line IV treatment of CMV retinitis, both as
initial and maintenance therapy.  Vistide is currently available
free-of-charge through an expanded access program (treatment IND)
for people who fail either ganciclovir or foscarnet (call 1-800-
445-3235 for more information).
     Valaciclovir (Valtrex) primary prophylaxis for CMV decreased
retinitis by a third when compared with either of 2 doses of
acyclovir.  The 21-month study of 1,227 patients resulted in
retinitis among 18% of those treated daily with either 800 mg or
3,200 mg acyclovir, compared to 12% among those treated with 8
grams of valaciclovir daily (J. Feinberg, abstract I214, Johns
Hopkins University).
     Ganciclovir eye implants led to a 2.5 times longer time to
progression of CMV retinitis among 125 patients when compared with
IV ganciclovir.  Implant patients experienced progression after a
median of 194 days, compared with a median time of 72 days for IV
ganciclovir patients.  Treatable retinal detachments occurred in
12% and eye infections (endophthalmitis) occurred in 2%. (B.
Kupperman, abstract I215, Chiron Ganciclovir Implant Study Group).
     Fifteen months of oral ganciclovir (Cytovene), 1 gram 3 times
a day, did not lead to a statistically significant decrease in CMV
retinitis among high-risk patients.  The CPCRA 023 Study of 994
patients did find a non-significant 16% reduction in the disease
among those taking the drug.  These results conflict somewhat with
those of the Syntex 1654 oral ganciclovir study, although the 2
studies are not identical.  Syntex 1654 did find a significant 49%
decrease in the rate of CMV disease, leading to an early
discontinuation of the study.  Differences in the 2 studies include
patients' entry CD4 counts, study duration and study endpoints used
to define CMV disease (C. Brosgart, abstract LB-10, University of
California at San Francisco).

      Advances in Treatments for Cytomegalovirus Retinitis
                         by Mark Bowers 

(Mark Bowers is the Treatment Hotline Manager at Project Inform and 
a frequent contributor to BETA.)

[Bulletin of Experimental Treatments for AIDS (BETA), No. 26 -
September 1995, at p. 13; published by the San Francisco AIDS
Foundation, BETA Subscriber Services, Infocom Group, 1250 45th
Street, Suite 200, Emeryville, CA 94608-2924.]

     Cytomegalovirus (CMV) belongs to the same family as other
herpes viruses (such as herpes simplex and varicella zoster).
Herpes viruses can remain latent in humans for their entire
lifetimes, and are more active when the human immune system is
somehow impaired. CMV is usually only a problem for people who
undergo deliberate immunocompromise prior to organ transplantation
or for people with AIDS, particularly those with fewer than 100 CD4
cells/mm3. Seventy-five percent (75%) of CMV retinitis cases are
found in people who have fewer than 75 CD4 cells/mm3.
Statistically, nearly 55% of all Americans and almost 100% of all
gay men carry latent CMV. CMV is primarily a sexually transmitted 
virus, but it can also be transmitted congenitally (from mother to
child at birth), by close personal contact and through blood
transfusion and organ transplantation.
     The clinical manifestations of CMV and the drugs used to treat
them are very different from those of the other herpes viruses. The 
usuual diseases associated with CMV are retinitis, encephalitis,
esophagitis, colitis, polyradiculopathy (a kind of peripheral
neuropathy) and pneumonitis. Of these, the most common and most
dreaded is retinitis, which leads to blindness if untreated and
seldom strikes without some loss of eyesight. CMV disease is one
of the most common opportunistic infections (OI) in people with  
AIDS, affecting 25-40%. The greatest amount of clinical research
on CMV disease has been done on the prevention and treatment of CMV
retinitis, which affects up to 15% of all PWA's.
     New technologies have been tested and new drugs are finding
their place in the treatment of CMV retinitis. But while acyclovir
effectively controls herpes simplex outbreaks with comparatively 
few side effects, the drugs that are active against CMV require
careful evaluation of their toxicities before they can be used for
treatment or prevention. Such an evaluation includes carefully
weighing the disease management factors articulated by Mark
Jacobson, MD, of the University of California at San Francisco:
individualizing therapy, balancing side effects and different
routes of drug administration and considering the cost of
treatment.

Intravenous Ganciclovir and Foscarnet

     The 2 drugs that are currently licensed by the Food and Drug
administration (FDA) for the treatment of CMV retinitis are
ganciclovir (Cytovene) and foscarnet (Foscavir). For this
indication, both drugs require intravenous (IV) administration for
initial treatment, usually through a surgically implanted central
access catheter in the chest.
     After initial treatment (called induction) to stop the
progression of retinal deterioration, a maintenance treatment
period follows. Maintenance therapy continues for life. The
FDA-approved choices for maintenance are continuing the IV drug or
switching to oral ganciclovir.
     The choice of induction therapy is individualized. Ganciclovir
is infused for one hour at 5 mg/kg every 12 hours for 2-3 weeks,
then maintenance is given indefinitely at 6 mg/kg a day 5 days per
week. At the maintenance therapy dose, the half-life of ganciclovir
allows 2 days per week to be skipped; this is not true for
foscarnet, which must be infused 2-3 times daily.
     The normal intravenous dose for induction treatment with
foscarnet is 60 mg/kg every 8 hours or 90 mg/kg every 12 hours for
2-3 weeks at a constant rate over 2 hours, requiring the use of an
infusion pump. Renal toxicity must be constantly monitored, and
adequate hydration using saline solution is important to protect
the kidneys from damage by the drug. Maintenance therapy is usually
at 90 mg/kg daily. 
     Ganciclovir and foscarnet interact with many drugs commonly
used in the treatment of HIV disease or associated opportunistic
infections. Ganciclovir is bone marrow suppressive. About 30% of
people receiving ganciclovir experience significant neutropenia
(fewer than 1,000 neutrophils/mm3). Neutrophil and platelet counts
should also be closely monitored. Neutropenia can be corrected by
using colony-stimulating factors (G-CSF [Neupogen] or GM-CSF     
[Leukine]). Clinicians at San Francisco General Hospital recommend
300 mcg (one vial) of Neupogen 3-7 times per week until counts rise
above 1,000 cells/mm3. Other drugs that are bone marrow suppressive
are often discontinued when ganciclovir is being used, including
AZT (Retrovir), trimethoprim-sulfamethoxazole (Bactrim or Septra)
and pyrimethamine (Daraprim), all commonly taken by people with
AIDS. Normal neutrophil production usually returns within 22 days
of stopping ganciclovir therapy or switching to foscarnet.
     Foscarnet is potentially nephrotoxic (damaging to the
kidneys). This is why patients are pre-treated with 1 liter of
normal saline solution before being infused with foscarnet, and
also why an infusion pump is needed to control the rate of
infusion. Other nephrotoxic drugs may interact with foscarnet,
including amphotericin B, aminoglycosides and pentamidine.
Foscarnet leaves the body exclusively through the kidneys.
Creatinine, a test of kidney function, must be monitored when
foscarnet is in use. Concentrated foscarnet in the urine can cause
ulcers on the genitals (penis, vulva) if excess urine is not
blotted from the skin.
     The use of IV pentamidine and foscarnet at the same time
increases the risk of hypocalcemia (abnormally low levels of
calcium in the blood), which may have fatal consequences. 
Foscarnet and AZT used together increases the risk of anemia.
Foscarnet has anti-HIV effects of its own, so the discontinuation
of AZT may not be as problematic with foscarnet as it may be with
ganciclovir.

Alternating Foscarnet and Ganciclovir

     The Studies of the Ocular Complications of AIDS (SOCA) is a
network of 11 university research sites with resident
ophthalmologists, set up to conduct clinical research on CMV
retinitis. SOCA recently completed a retreatment study designed to
see if the combination of ganciclovir and foscarnet was better at
preventing CMV disease progression than either drug alone. All
participants had previously relapsed while on one therapy or the
other. A total of 271 people received 1 of 3 treatments: (1) IV
foscarnet (90 mg/kg twice daily for 2 weeks followed by maintenance
at 120 mg/kg once daily); (2) IV ganciclovir (5 mg/kg twice daily
for 2 weeks followed by maintenance at 5 mg/kg once daily); or (3)
the combination (continuation of previous therapy with the addition
of induction with the other therapy for 2 weeks followed by
maintenance at 5 mg/kg daily of ganciclovir and 90 mg/kg daily of
foscarnet).
     The standard of comparison in most CMV retinitis studies is
time to disease progression, defined as a 750 micron advance on the
retina of the area affected by CMV. The median time to progression
was 4.8 months on the combination, compared to 1.6 months for those
on only foscarnet and 2.1 months for those on only ganciclovir. A
significantly longer time to progression for those on the
combination must be weighed against the associated decrease in
quality of life, in part because of long daily infusion times and
in part due to the combined toxicities of the 2 drugs. No study
group enjoyed any survival advantage over any other.

Oral Ganciclovir Maintenance and Expected Approval for Prophylaxis

     Oral ganciclovir was approved for maintenance therapy
(following IV induction) in January 1995. A Phase I/II safety and
efficacy study of oral ganciclovir for maintenance was conducted
by the AIDS Clinical Trials Group (ACTG) and the Cytomegalovirus
Cooperative Study Group (CCSG). Oral bioavailability, a measure of
how much drug taken orally gets into the bloodstream compared with
intravenous administration, ranged from 2.6% to 7.3%. The data
suggest that oral absorption is prolonged at higher doses and that 
serious adverse events are rare. (Current European studies of high
dose oral ganciclovir are expected to confirm these observations.) 
Time to disease progression was compared for 50 people on 4
different doses: 62 days for those taking 1g every 8 hours, 148
days for those taking 500 mg every 3 hours, 75 days for those
taking 750 mg every 3 hours, 148 days for those taking 1 g every
3 hours, and 139 days for those taking 2 g every 8 hours. Nineteen
(19) people who had positive cultures for CMV but no evid ence of
disease or prior anti-CMV treatment were also given oral
ganciclovir as prophylaxis. A Roche Bioscience (formerly Syntex)
study of oral ganciclovir was stopped by its Data Safety and
Monitoring Board (DSBM) because of the significant benefit
experienced by the group treated with oral ganciclovir. All study
participants taking placebo were offered the drug. A new drug
application for prophylaxis was filed in May and FDA approval is
expected this year.

Cidofovir (Vistide)

     Cidofovir has been evaluated for use in treating retinitis by
2 groups using 2 different formulations. Gilead Sciences holds the
license for the development of cidofovir in the United States.
Recently published data from a study at the University of
California at San Diego (UCSD) show that single injections of
cidofovir into the eyes of 65 people with CMV retinitis results in
a delay of disease progression similar to that seen with IV drugs.
Although the study was uncontrolled, the results indicate that
retinitis was controlled for 6 to 8 weeks. Some community
ophthalmologists who are familiar with intraocular infections
caution that side effects of the procedure, such as retinal
detachment, are an increased risk.
     Gilead Sciences will offer intravitreal injections of
cidofovir to people who have failed or who are intolerant to
ganciclovir and/or foscarnet beginning in August, 1995 (call Gilead
at 415-476-6356). For more information see the June 1995 issue of
BETA, pages 52-55.
     Intravenous cidofovir offers an advance over IV ganciclovir
and foscarnet, in that dosing is needed only once weekly or less.
The most important adverse side effect of cidofovir is kidney
damage, which can be minimized by IV hydration similar to that
required prior to the administration of foscarnet. The use of the
drug probenecid increases the concentration of cidofovir and allows
for less frequent dosing while protecting agaist kidney damage.
(For an in-depth discussion of recent studies of IV cidofovir, see
BETA, June 1995, pp. 54-55.) Gilead has filed for Treatment
Investigational New Drug (TIND) status for IV cidofovir for the
treatment of CMV retinitis. TIND status would provide the drug free
to qualified patients under the supervision of their physician(s).
Call Gilead after October 1 for more information.

Ocular Implants

     Implants of a small device that releases ganciclovir into the
vitreous humor of the eye continuously for 6 months have been
clinically tested in a Phase I study at the National Eye Institute
(NEI). Thirty eyes (belonging to 26 volunteers who had
non-sight-threatening CMV retinitis) were either implanted with the
devices or received deferred therapy. The time to disease
progression was 15 days for the deferred therapy group and 226 days
for the implanted group. Participants experienced no systemic
toxicities nor any catheter-related toxicities, which are a risk 
when receiving infusions. There are risks from the implanting
procedure, including bleeding and reduced vision.
     A second study of the ganciclovir implants, manufactured by
Chiron Vision, compared the effectiveness of 2 different release
rates of the implant to IV ganciclovir in 180 people with
previously untreated CMV retinitis. The median time to progression
for the IV group was 72 days compared to 186 days for the implants.
No difference was seen in time to progression between the 2 release
rates. Those in the IV group who experienced disease progression
were given implants. There was no difference among the groups in
the rate of development of CMV disease outside the eye. Chiron   
Vision has applied for approval from FDA.
     Implants offer a true advance in the treatment of retinitis:
time to progression is 2-3 times longer than with currently
approved therapies. The operation to implant the ganciclovir device
is performed under local anesthesia on an outpatient basis, and
surgical complications are not common. No central venous access is
needed, and any extraocular disease that develops might be treated
(off-label) with oral ganciclovir.
     An expanded access program is open only to those who have
failed or cannot tolerate IV ganciclovir or foscarnet. Chiron
Vision can be contacted at 800-244-7668. Roche Bioscience,
manufacturer of ganciclovir, is currently sponsoring a study to
compare implants to implants plus oral ganciclovir and to IV
ganciclovir alone. The study recruits both newly diagnosed and
previously treated individuals who have CMV retinitis. For more
information, see the March 1995 issue of BETA, page 73.

Ocular Injections

     In addition to the injections done with cidofovir,
ophthalmologists have been injecting either ganciclovir or
foscarnet directly into affected eyes for many years. One French
study highlighted the drawbacks to such injections: 141 of 151 eyes
that were injected experienced some scarring. There are no
controlled data to indicate that the incidence of retinal
detachment with injections is higher than the statistical average,
but this is nonetheless a concern.

Antisense Drug

     Isis Pharmaceuticals has been clinically testing an antisense
drug for CMV. An antisense drug is designed to bind the messenger
RNA made by CMV. If the RNA is bound and degraded, the virus cannot
replicate. Twenty-two volunteers who had failed intravenous
foscarnet or ganciclovir received injections every 2 weeks in a
safety study. Last December, Isis began 3 larger efficacy studies,
one of which is still open to volunteer participants. Two of the
studies were halted because 4 of 23 eyes treated with ISIS 2922
developed stippling (retinal spots), possibly due to a previously
undetected toxicity of the antisense drug. The study that remains
open offers weekly injections of ISIS 2922 followed by injections
every other week to people who have failed other CMV treatment
options. Contact ISIS at 619-929-3898 and ask about study CS7.
     This has been a watershed year for advances in the treatment
and prevention of CMV retinitis. More options are available than
ever before, and the drugs now available offer a longer period of
time without advancement of retinitis. Cidofovir can be
administered less frequently by the IV route than currently
approved drugs, and its protection is longer lasting. Oral
ganciclovir will soon be approved for primary prevention of
retinitis, which will allow those who are already using the drug
to be reimbursed by insurance plans.
     Eye implants offer longer lasting protection from advances in
retinitis than any other treatment to date. Finally, combination
strategies will be available that may be better than previous
combinations (IV ganciclovir and IV foscarnet) and will have fewer,
more tolerable side efects.

Sources

     Jacobson MA and others. Current management of cytomegalovirus
disease in patients with AIDS. AIDS Research and Human Retroviruses
10: 917-22, 1994.

     Jacobson MA and others. Randomized Phase I trial of two
different combination foscarnet and ganciclovir chronic maintenance
regimens for AIDS patients with cytomegalovirus retinitis: AIDS
Clinical Trials Group protocol 151. Journal of Infectious Diseases
170: 189-93, 1994.

     Kirsch LS and others. Intravitreal cidofovir (HPMPC) treatment
of cytomegalovirus retinitis in patients with AIDS. Ophthalmology
102: 533-42, 1995.

     Martin DF and others. Treatment of cytomegalovirus with an
intraocular sustained-release ganciclovir implant: a randomized
controlled clinical trial. Archives of Ophthalmology 112: 1531-39,
1994.

     Reese RE and others. Handbook of Antibiotics. Little, Brown
and Company, Boston. 1993.

     Spector SA and others. Pharmacokinetic, safety, and antiviral
profiles of oral ganciclovir in persons infected with HIV: a Phase
I/II study. Journal of Infectious Diseases 171: 1431-7, 1995.

     Copyright (c) 1995 - San Francisco AIDS Foundation. Reproduced
with permission.  Reproduction of this article (other than one copy
for personal use) must be cleared through BETA, email
beta@sfsu.edu. 

          Chiron Vision Files FDA Application to Market
              Intraocular Implant for CMV Retinitis

     Chiron Corporation and Hoffmann-La Roche announced on July 5,
1995, that Chiron's ophthalmic business, Chiron Vision, has filed
a New Drug Application (NDA) with the US Food and Drug
administration (FDA) to market Vitrasert, its intraocular implant
which delivers ganciclovir directly to the eye for treatment of
cytomegalovirus (CMV) retinitis.
     The NDA filing is based on results of two independent phase
III clinical trials conducted by Chiron Vision and the National Eye
Institute (NEI).  The studies demonstrated that the Vitrasert
ganciclovir implant offers a clinical improvement versus
intravenous ganciclovir in further delaying progression of CMV
retinitis in the treated eye.
     Chiron Vision and Hoffmann-La Roche, Inc., will collaborate
on the marketing of Vitrasert, Chiron Vision developed the
Vitrasert implant technology and Hoffmann-La Roche currently
markets Cytovene (ganciclovir), the drug used in the implant. 
Roche will provide ganciclovir, which was discovered and developed
by Roche Bioscience (formerly Syntex), another member of the Roche
Group, on an exclusive, worldwide basis for use in the eye implant. 
In the collaboration, Chiron Vision will develop, manufacture, and
sell the Vitrasert for CMV retinitis.  The two companies will co-
promote the Vitrasert, with Chiron Vision focusing on the
ophthalmic surgeon and Hoffmann-La Roche focusing on the primary
care and infectious disease physicians.
     Data from a planned interim analysis of the multicenter,
controlled, randomized Chiron Vision study, testing the implant in
188 AIDS patients with newly diagnosed CMV retinitis, were reported
January 31, 1995, at the National Conference on Human Retroviruses
and Related Infections in Washington, DC.  The study demonstrated
that the median time to progression of CMV retinitis was 186 days
for eyes receiving Chiron Vision ganciclovir intraocular implants
compared to 72 days for eyes receiving intravenous ganciclovir
therapy (P less than 0.0001).  The incidence of extraocular CMV
disease was 12 percent in the implant arms versus 0 percent for IV
ganciclovir.  There were few serious surgical complications.  The
firms' complete analysis of the data, upon which Chiron Vision's
FDA submission is based, confirmed these results.
     Study participants were assigned randomly to an IV ganciclovir
group or one of two implant groups (1 microgram/hour or 2
micrograms/hour), and were followed for eight months or until
progression of retinitis or death.  Progression of retinitis was
determined by a central masked Fundus Photograph Reading Center at
the University of Wisconsin.
     Results of the NEI study, published in the December 14, 1994
issue of Archives of Ophthalmology, showed that AIDS patients had
no progression of newly diagnosed, peripheral CMV retinitis for
about eight months using the ganciclovir implant.  Among those who
received no immediate treatment, the eye infection worsened in
about 15 days.  The study evaluated 26 patients, of which 30 eyes
were randomly assigned to either immediate treatment (patients
received an implant within 48 hours of study enrollment) or
deferred treatment (patients were evaluated until progression of
CMV retinitis was noted).
     The study found that in people who received immediate
treatment (within 48 hours of enrollment), the ganciclovir implant
eliminated all signs of active infection for a median of 226 days,
or about eight months.  Among study participant in the deferred
treatment group, the median time to CMV retinitis progression was
15 days.  During the study, most participants enjoyed good vision
with the implant.  By the final follow-up eye examination, 34 of
the 39 eyes treated with the implant had nearly perfect vision
(20/25 or better).  However, nearly all affected eyes had blurred
vision immediately after receiving the ganciclovir implant, and 18
percent of the eyes experienced retinal detachment, a common
problem for people with AIDS with CMV retinitis.
     Chiron Vision's intraocular implant contains ganciclovir
embedded in a polymer-based system that slowly releases the drug
into the eye for up to eight months.  The implant is placed into
the posterior segment of the eye through a 5 to 6 mm incision
during a one-hour surgery performed under local anesthesia.  The
implant can be removed and replaced when depleted of drug.
     Chiron Vision is preparing applications to market Vitrasert
in additional countries.  At the Journal's press time, the company
plans to file such an application in the first of these countries,
Canada, in July, followed by applications in several European
countries this fall.
     Currently, two additional clinical trials are underway to
further evaluate the ganciclovir implant for CMV retinitis. 
Enrollment in these studies is limited to patients who meet certain
eligibility criteria.  For more information on these studies,
contact the Professional Services Group at Chiron Corporation.  The
number is 1-800-244-7668, select 2. (Journal of the International
Association of Physicians in AIDS Care. 1995 July;1(6):37.)

[Editor's Note:  See also, Martin DF et al. Treatment of
Cytomegalovirus retinitis with an intraocular sustained-release
ganciclovir implant: A randomized controlled clinical trial. Arch
Ophthalmol. 1994;112:1531-1539.]

   New Chiron Method for Treating AIDS-Related Illness Wins OK

     An advisory panel to the U.S. Food and Drug Administration
recommended on Friday the approval of Chiron Corp.'s Vitrasert, an
implant that would directly administer to the eye drugs for a
potentially blinding disease in AIDS patients.  Cytomegalovirus
(CMV) retinitis affects as many as 40 percent of all AIDS patients,
often when they have less than one year to live. Vitrasert would 
deliver Roche Holding AG's Cytovene (ganciclovir) via a
time-release delivery system implanted in the eye.  The panelists
recommended that Chiron undertake further studies to determine how
the implant might be used with other drugs to treat CMV symptoms
throughout the body.  They also voiced concerns about a side
effect, which caused some patients' retinas to detach from their
eyes.  Related Stories: Wall Street Journal (12/11) P. B6; Boston
Globe (12/09) P. 40 (Investor's Business Daily (12/11/95) P. A17.)

                   Cytovene Capsules Approved

     Cytovene (ganciclovir) capsules were approved by the Food and
Drug Administration on December 22, 1994 as an alternative to the
intravenous formulation for maintenance therapy of CMV retinitis
in patients with HIV disease.  The approved use of the drug is
further limited to patients whose retinitis is stable following
appropriate IV induction therapy, where the risk of more rapid
disease progression is balanced by the benefit associated with the
avoidance of daily infusion.  The FDA approval allows physicians
to prescribe the capsules off-label as a prophylaxis against CMV
retinitis.  (See JPAAC, November 1994.)
     In clinical studies comparing cytovene capsules to the IV
formulation, progression of CMV retinitis in patients on the oral
formulation occurred moderately faster.  The mean time to disease
progression was 5-12 days faster for patients on the oral
formulation.  As with the IV formulation, the major side effects
of Cytovene capsules are granulocytopenia, anemia, and
thrombocytopenia.  The most common side effects experienced by
clinical trial subjects taking the capsules, compared with those
on the IV formulation, were: diarrhea (41 vs 44 percent), fever (38
vs 48 percent), leukopenia (29 vs 41 percent), and nausea (26 vs
25 percent).
     The benefits of Cytovene capsules over the oral formulation
as shown in clinical trials included fewer serious incidents of
sepsis (4 vs 15 percent), fewer catheter-related infections (6 vs
22 percent), and a lower incidence of anemia (19 vs 25 percent) and
leukopenia (29 vs 41 percent). [Journal of the Physicians
Association for AIDS Care. 1995 January;2(1):15.]

[Editor's Note:  See also: The Oral Ganciclovir European and
Australian Cooperative Study Group. Intravenous versus oral
ganciclovir: European/Australian comparative study of efficacy and
safety in the prevention of cytomegalovirus retinitis recurrence
in patients with AIDS. AIDS. 1995;9(5):471-477.]

               Ganciclovir Approved to Prevent CMV

[Dave Gilden. GMHC Treatment Issues. 1995 Nov;9(11):3.]

     Hoffmann-La Roche received FDA approval last last month to
market its capsule form of ganciclovir for preventing CMV infection
in people with "advanced HIV infection at risk for developing CMV
disease." Oral ganciclovir (brand name:Cytovene) already had
approval as a maintenance therapy for CMV retinitis. It could be
taken after the infection had been brought under control by two to
three weeks of daily infusions with the older intravenous
formulation of ganciclovir.
     Approval of ganciclovir prophylaxis was based on an eighteen-
month study conducted by its manufacturer, Roche Bioscience
(formerly Syntex Laboratories). This trial found that oral
ganciclovir reduced the incidence of CMV retinitis by half (39
percent of participants on placebo contracted the disease compared
to 18 percent on oral ganciclovir). Countering the Roche Bioscience
trial was one conducted by the community Programs for Clinical
Research on AIDS (CPCRA), which found no benefit from oral
ganciclovir in terms of preventing symptomatic CMV. But critics
have complained that the CPCRA study was not sensitive enough to
detect a benefit within its alloted time period. (See Treatment
Issues, Octobver, 1995, page 10).
     The indication approved by the FDA is vaguely worded,
reflecting the unresolved question of who should take oral
ganciclovir prophylactically. The drug costs $47 a day wholesale
and can cause some serious side effects (in particular, suppression
of blood cell production by the bone marrow) while only cutting the
incidence of CMV by half for the first eighteen months (what
happens after that is unknown).
     CMV normally appears in people with very advanced AIDS. Only
those with CD4 counts less than 50 and positive CMV test results
may be appropriate for the drug. Alternatively, a history of other
opportunistic infections associated with severe immune suppression
may be useful in assessing riks. Those who had had mycobacterium
avium cmplex (MAC), for example, experienced a four-fold increased
risk of CMV in one study (presented last January at the Second
Annual Human Retrovirus Conference, abstract 290).

                 CYTOVENE (GANCICLOVIR CAPSULES)
      From Roche Laboratories (A Member of the Roche Group)

Indications:  An alternative to CYTOVENE-IV (ganciclovir sodium for
injection) for the maintenance treatment of immunocompromised
patients, including patients with AIDS, in whom retinitis is stable
following appropriate induction therapy and for whom the risk of
more rapid progression is balanced by the benefit associated with
avoiding daily intravenous infusions.

DOSAGE:  The recommended maintenance dose of CYTOVENE capsules is
1000 mg tid with food.  To maximize bioavailability, it is
important to take CYTOVENE capsules with food.

Reinduction:  For patients who experience progression of CMV
retinitis while receiving maintenance treatment with either
formulation of CYTOVENE reinduction treatment is recommended.

Follow-up examinations:  Patients should be advised to have
ophthalmologic follow-up examinations at a minimum of every 4 to
6 weeks while being treated with CYTOVENE. Some patients will
require more frequent follow-up.

How supplied:  CYTOVENE (ganciclovir capsules) 250 mg is supplied
in bottles of 180.

Important safety information:  The most serious side effects
associated with the use of CYTOVENE are granulocytopenia
(neutropenia), anemia and thrombocytopenia. CYTOVENE should not be
administered if the absolute neutrophil count is <500 cells per
milliliter or the platelet count is <25,00 cells per milliliter.
Transient elevation of serum creatinine levels were observed in
clinical studies of CYTOVENE. Careful monitoring for renal function
should be undertaken while patients are receiving CYTOVENE.
Patients receiving CYTOVENE capsules should be advised of the risk
of more rapid progression of CMV retinitis when taking the capsules
versus daily intravenous infusions.

    Preventing and Treating CMV Retinitis - Oral Ganciclovir

     Unlike previous reports, a new study has concluded that oral
ganciclovir does not significantly delay the onslaught of
cytomegalovirus (CMV) retinitis in HIV-infected individuals.  But,
"most people feel oral ganciclovir offers protection," said Henry
Masur at a recent staff conference at the National Institutes of
Health Clinical Center.  "Was it a careful study?," Masur
questioned.  The meeting focused on how sight can be preserved if
the infection is identified and treated before symptoms become
obvious.  Still, many of the newly-available laboratory tests are
limited, and oral prophylaxis is expensive and offers no long-term
survival benefit. (Lancet (10/28/95) Vol. 346, No. 8983, P. 1153; 
Rowe, Paul M.)

[Editor's note:  But see also, Spector S et al. A randomized,
double-blind study of the efficacy and safety of oral ganciclovir
for the prevention of CMV disease in HIV-infected patients. 35th
Interscience Conference on ANtimicrobial Agents and Chemotherapy,
San Francisco, 1995.]

               Cidofovir Available Under Treatment
                      IND for CMV Retinitis

FDA has designated the investigational drug cidovir (Vistide) for
use in treatment of HIV-infected persons with relapsing
cytomegalovirus (CMV) retinitis that has progressed despite
treatment.  the treatment IND program enables patients with serious
or life-threatening conditions who have exhausted existing
treatments or have no satisfactory treatment to be treated with
promising investigational drugs.  Further information on access
under the Treatment IND may be obatained from the sponsor, Gileas
Sciences Inc of Foster City, Calif.  Telephone:  (800-GILEAD 5 from
8:00 AM to 6 PM EST. [From the food and Drug Administration. JAMA.
1995;274(14):1109.]

                  New CMV Treatment - Cidofovir

     Gilead Sciences, Inc., announced in late August that it has
begun a Phase II study of an intravitreous formulation of cidofovir
for the treatment of relapsing cytomegalovirus (CMV) retinitis.
This randomized, controlled, multicenter study is designed to
deterine the safety, tolerance and efficacy of various dose levels
of cidofovir whlen administered locally by direct injection into
the vitreous or inner chamber of the eye. The study is designed to
enroll up to 90 patients with relapsing CMV retinitis that has
progressed despite treatment with a currently approved systemic
therapy.
     CMV retinitis occurs in approximately 15% to 40% of patients
with AIDS. CMV is a syustemic disease and the most common viral
opportunistic infection occurring in approximately 95% of AIDS
patients. CMV can infect several sites in the body and when it
invades the retina, lesions form on the light-sensitive layer of
cells at the back of the eye that transmits images to the brain.
As these CMV lesions progress, the patients's vision deteriorates.
     Currently approved therapeutics for CMV retinitis are
administrered as systemic agents. Some patients, however, may
benefit from local therapy administered directly to the eye.
Patients enrolled in this study will receive a single injection of
intravitreous cidofovir at one of three dose levels in each
infected eye. Patients may continue to receive one or more
subsequent injections as maintenance therapy.
     In April, results from two investigator-sponsored clinical
studies using intravitreous injections of HPMPC, the active
ingredient in intravitreous cidofovir were published. The data was
encouraging in that it suggests the intravitreous HPMPC may be
beneficial in delaying the time to progression of CMV retinal
lesions and that further investigation is merited. This is the
purpose of the Gilead-spnosored trials that are currently underway.
(NAPWA Medical Alert. 1995 Nov/Dec;3(5):5.)

----------------------------------------------------------------

             Information Sheet for Patient Education
                          June 16, 1995

[Editor's Note:  Belos is one of a series of Information Sheets
prepared by the National AIDS Treatment Information Project (NATIP)
with funding from the Henry J. Kaiser Family Foundation.  The
materials are designed for self-education by HIV-infected persons
and for counseling by community advisors, case managers, social
workers, and clinicians.  For more information about NATIP, call
617-667-5520 or write:  Helen E. Woods Wogan, Project Manager,
Libby 317, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA
02215.  Fax: 617-667-2885.  Internet:  hwoods@bih.harvard.edu]
What is cytomegalovirus?


Cytomegalovirus (CMV) is a virus that infects more than half of all
adults but rarely causes significant disease unless there is damage
to the person's immune system.  Health adults usually become
infected by CMV through close personal and sexual contact with
others.  After CMV infects a healthy person, the immune system
keeps virus from spreading and causing disease but never completely
eliminates CMV from the body.

How does it affect HIV-infected persons?

Since CMV is spread in a similar fashion to HIV, it often infects
persons with HIV disease.  After HIV infection has progressively
damaged the immune system over a period of years, your body may no
longer be able to control CMV, and the virus may cause disease. 
CMV disease is rare until the T-cell count is below 100.  In this
setting, CMV may cause disease in the eye (retinitis), the gut
(esophagitis, colitis), and occasionally the nervous system, liver,
and lungs.

What are the symptoms and signs of CMV disease?

The symptoms of CMV disease depend on the part of the body affected
by the disease, and similar symptoms can be caused by other
conditions.  People with CMV retinitis may have blurry or lost
vision, or they may see small moving spots called "floaters" or
shadows as if a shade is drawn over the eye.  Early retinitis is
often without any symptoms whatsoever.  CMV esophagitis usually
causes pain or discomfort in the mid-chest when swallowing food. 
People with CMV colitis may have fever, loss of appetite, abdominal
pain, and diarrhea.  CMV can also cause painful tingling or pain
in the legs, hands or feet (neuropathy), yellow eyes and skin
(jaundice), or pneumonia.

How is CMV disease diagnosed?

CMV retinitis has a typical appearance on examination with an
ophthalmoscope, an instrument which the doctor uses to look in the
back of your eyes.  Detection of early disease requires dilating
your pupils with eye drops.  To diagnose CMV disease in other parts
of the body, your doctor must perform a biopsy (take samples of
tissue), which is cultured (placing it in a laboratory container
to try to grow the virus) and examined under the microscope.  Small
numbers of CMV may be present in the body fluids even in persons
without symptoms, and the virus can often be detected by culture. 
A positive culture, however, means that CMV is present in the body
but does not prove that it is causing disease.

How is CMV disease treated?

There are two standard treatments for CMV disease: ganciclovir and
foscarnet.  Neither of these drugs will cure CMV, but they often
suppress the disease, improve symptoms, and prevent further damage
to the body.  High-dose therapy with one of the medications is
generally provided for 2-3 weeks, followed by a reduced daily dose
once the infection has stabilized.

Both drugs require a daily infusion, and they have to be given
through the vein (intravenously) every day for about 2 to 4 hours. 
CMV treatment is usually infused through a small tube called a
catheter (Hickman or Portacath) inserted into the chest or arm (a
PICC line) that makes it easier and safer to give the infusion. 
The catheter must be bandaged and kept clean and dry.  Because
drugs only slow down CMV but do not eliminate it from the body,
treatment must continue indefinitely.  You must also see your
doctor regularly to make certain that the CMV disease is not
getting worse and that the medicine is not causing serious side
effects.

It is possible that these drugs will not work well or have side
effects that make you feel sick and that your doctor will need to
change your regimen.  While there has been one study suggesting
that foscarnet therapy may be associated with slightly longer life
expectancy than ganciclovir, foscarnet can also have more serious
side effects and require a more lengthy daily infusion.  In
patients with CMV retinitis who are unable to tolerate either
medication, ganciclovir implants or injections have been used with
some success.

An oral form of ganciclovir is now also available, although it is
still unclear in what situations it might be useful.  Other
medications, which might be more effective and easier to take, are
also being evaluated in clinical trials.

What are side effects of the treatments?

The most common side effect from ganciclovir is low white blood
cell count (neutropenia), which generally does not cause symptoms. 
The neutropenia will usually go away if you stop taking the drug. 
Neutropenia can also be treated with a medication called G-CSF
(Neupogen), which is given by injection under the skin
(subcutaneous).  AZT can also cause neutropenia, and, because of
this, taking AZT and ganciclovir together is usually not
recommended.  Other side effects from ganciclovir may include
anemia, fever, rash, gastrointestinal disturbances (nausea,
vomiting, diarrhea), and abnormal liver function tests.  Foscarnet
can cause serious metabolic disturbances (low blood calcium,
magnesium, phosphorus, and potassium), kidney damage, and skin
ulceration.

Another very difficult side effect of both drugs is the possibility
of developing an infection from the catheter.  Symptoms may include
fever, redness or soreness at the catheter site, or difficulty with
infusing fluids.  It is very important to keep the catheter clean
and dry and to change the bandage that covers it regularly. 
Catheter infections can be very dangerous and should be treated
immediately by your doctor.

Can CMV disease be prevented?

There are no medicines proven to prevent CMV from causing disease
in HIV-infected persons, although oral ganciclovir is currently
being evaluated.  Regular eye examinations may be useful in
detecting early CMV retinitis in those at risk.

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