       Treatment Issues - Vol. 9, No. 7 - July 1995
       --------------------------------------------
       Published by Gay Men's Health Crisis, New
       York, NY
       --------------------------------------------

       Contents

       The Changing Treatment Options for CMV Retinitis
       Testing for CMV in the Central Nervous System
       Finding Support for AIDS-Related Vision Problems
       CDC Report on Waterborne Cryptosporidiosis
       Treatment Briefs
       New Developments in Kaposi's Sarcoma
       Liposomal Chemotherapies
       KS Virus Controversy
       X-Rays for Monitoring Opportunistic Infection
       Washington Watch
       CDC Recommends HIV Testing for All Pregnant Women

       ************************************************
       The Changing Treatment Options for CMV Retinitis
       by Dave Gilden

       Cytomegalovirus (CMV) is a major opportunistic infection of
people with advanced AIDS, affecting a fifth of those with helper
T-cell counts below 50. CMV's most common target is the retina --
the light-sensitive tissue at the back of the eyes that sends what
we see to the brain. If left untreated, CMV infection of the retina
("CMV retinitis") causes blindness in the affected eye 90 percent of
the time.

       The standard therapies for CMV retinitis are very burdensome
for patients. They involve expensive one- or two-hour infusions
through a tube (catheter) permanently inserted into a chest or arm
vein. The two medications used -- ganciclovir and foscarnet -- are
both very toxic. Ganciclovir suppresses the bone marrow's production
of red blood cells, neutrophils and platelets, leaving patients
prone to anemia, bacterial infections and bleeding. Foscarnet
commonly impairs kidney function, and this disrupts the body's
electrolyte balance. The consequent low calcium levels can provoke
nerve malfunction (tingling and numbness) and, occasionally,
seizures.

       There is also a danger of outside bacteria spreading along
the catheter and into the bloodstream. The rate of infection was 0.2
per 100 days on catheter in one survey.[1] During the first, or
induction, phase of therapy, infusions take place two or three times
daily. This suppresses but does not eliminate the CMV. A life-long
maintenance phase is then necessary, which involves once-a-day
infusions. But the CMV lesions in the eye inevitably start spreading
again after three or four months. The current medical response to
renewed CMV is to return to induction therapy, possibly switching to
the other drug.

       "Everybody pretends that we have therapies for CMV, but they
are not working. Despite ganciclovir, people are going blind. There
is progression within a few months," said Kevin Frost in summing up
the current situation. Frost, a long-time activist on issues related
to CMV retinitis, is director of the Community Based Clinical Trials
Network at the American Foundation for AIDS Research.

       This is the old paradigm, which is set to change radically.
Within the next twelve months, companies expect to file for FDA
approval of four new anti-CMV medications, and these will radically
alter the treatment landscape.

       Reflecting the new expectations, Claudette Lajam, trials
coordinator at a New York City ophthalmology practice, says, "If
your T-cell count gets near 100, go and get screened for CMV by an
ophthalmologist rather than wait until you notice visual
deterioration. Before there was no need to screen because all it
would mean is that you would be catheterized three months early for
some itty-bitty infection that wasn't sight-threatening. Now, no one
need go blind from CMV if we catch it early enough and control it.
We have new tools every day, and if one stops working, we can switch
to another."

       These therapies unfortunately have to work with less and less
help from the immune system and therefore threaten to be less and
less effective with passing time. Each therapy also brings with it a
set of specific issues ranging from side effects to drug resistance
that limit its usefulness and can interfere with succeeding or
concurrent treatments.

       What works in one patient may not work in another. The
evolving complex treatment mosaic will require skillful manipulation
by physicians and people with AIDS. Below, we examine the pros and
cons of the new developments in CMV and see how they fit together.

       Ganciclovir Implants

       One of the inherent problems of systemic therapy for CMV
retinitis is that the blood-retina barrier, which is similar to the
blood-brain barrier, allows only a small amount of medication to
attain its target in the eye. One study examining how much
ganciclovir reached the eye after intravenous infusions[2] found
that the concentration in the eye's vitreous humor (the jelly-like
region between the retina and the lens) was below that needed to
inhibit CMV replication. This was true even with twice a day
infusions.

       The investigators commented that the suboptimal level of
ganciclovir in the eye may explain the drug's borderline efficacy.
It may also explain the frequent emergence of ganciclovir-resistant
CMV during treatment: In another study, 38 percent of patients
receiving ganciclovir for more than three months were found to have
resistant CMV.[3]

       The way to get more drug to the eye is through localized
therapy. Intraocular injections of ganciclovir directly into the
vitreous humor have been tried for some time, but their usefulness
is limited because they require a twice a week regimen likely to
irritate the eye. A better way is the time-release implant, which
Treatment Issues described in December, 1994 (page 1-2) and March,
1995 (pages 4-5). Chiron Vision, the implants' developer, filed for
FDA approval of the devices on July 5.

       In the trials, a single implant delayed CMV retinitis
progression (as defined by growth of the lesions on the
retina) by six to eight months, compared to a delay of only
two months for intravenous ganciclovir. Some recipients have
now gone for up to eighteen months without reactivation of
their CMV by receiving repeat implants. Until the implants
are approved, those who are failing or intolerant of the
traditional CMV therapies can obtain them through an open-
label protocol. For details, call Chiron at 800/244-7668.

       The implants seem like a great advance, but as more
experience is obtained through the open-label protocol, some of
their drawbacks have become more evident. Joseph Eviatar, M.D., a
New York City ophthalmologist with a large AIDS practice, commented,
"I hoped the implants would be revolutionary, but there are too many
complications. But we're using them 'on the late side,' with very
advanced patients."

       The first problem is that the implants do not work at all
with a few people, probably due to ganciclovir-resistant CMV bred by
prolonged exposure to intravenous ganciclovir. In more patients,
progression returns after only five or six months. The early relapse
may be due to the implants running out of drug earlier than
expected. Frequent eye exams are still necessary for individuals who
have implant. Possibly too, those with sight-threatening lesions
(near the center of the retina) should have their implants replaced
at intervals shorter than the current norm of eight months.

       The objection to earlier replacements is that the procedure
is a delicate operation. Installing an implant requires making a
small slit through the white part of the eye (sclera) and stitching
the plastic capsule onto the inside wall. The risk is that the
procedure might cause retinal detachment by disturbing the vitreous
humor's support of the retina. The implant trials did record a
number of such incidents (in eighteen percent of eyes with implants
during one study), but those with CMV retinitis frequently
experience spontaneous detachments due to the disease.

       According to one of the investigators, Daniel Martin, M.D.,
of Emory University in Atlanta, "The retinal detachment issue
remains unresolved." He holds out the hope that "the reduced CMV
progression may offset the risk of detachment from the implants
because a smaller surface of the retina will be diseased."

       The installation procedure nonetheless is a significant
insult to an already weakened eye, and the threat of retinal
detachment must be taken seriously, even though it is treatable.

       A more mild symptom of the disruption caused by the procedure
is the vision blurring that persists for several weeks
afterward. This blurriness makes it impossible to put
implants in both eyes at the same time.

       A longer-lasting (eighteen months to two years) version of
the implant is under development which presumably would minimize
many of these problems. As Dr. Martin put it, "Eliminating a
surgical procedure would be a kinder thing for the eye."

       Another issue would persist, though. That is the question as
to whether local therapy alone is enough to control CMV, which not
only can infect the other eye but also many other parts of the body.
For example, one recent paper noted that upon autopsy, half the
people with retinal CMV also have detectable CMV in their brains.[4]
In the largest study of the implant, extraocular CMV disease
occurred in twelve percent of the people receiving the implants
compared to none of the people in the intravenous comparison arm.[5]
There also was a high rate of CMV spread to initially uninvolved
eyes during the trial, with those on the implant tending to have a
worse experience than those on IV ganciclovir here too.

       Chiron Vision itself now warns that people receiving its
implants should have concurrent systemic therapy. But if systemic
intravenous therapy is needed to control breakthrough infections, is
there a point to the implants? Well, yes because the existing
retinitis is clearly better suppressed, but part of the quality of
life and economic advantages to the implants are nonetheless lost.

       Oral Ganciclovir

       An alternative to intravenous therapy is the new oral form of
ganciclovir, which was approved by the FDA last winter as a
maintenance therapy between courses of intravenous induction
therapy. "The implant plus oral ganciclovir would be an advance,"
said Dr. Eviatar.

       Indeed, there is just such a trial under way, comparing the
implant plus oral ganciclovir to the implant alone to intravenous
ganciclovir in people with stable, early (less than six months) CMV
retinitis in one eye. (This trial is still enrolling. Interested
parties should contact Roche Bioscience -- formerly Syntex
Laboratories -- at 800/526- 6367.)

       Oral ganciclovir faces the hurdle of reaching the bloodstream
from the digestive tract, which absorbs it very poorly. As a
consequence, blood levels are somewhat lower and time to CMV
progression is less than with intravenous ganciclovir. In the one
published trial6 comparing the oral and intravenous formulations,
mean time to progression was about twenty percent less for the oral
group. Interestingly, the incidence of extraocular CMV (almost zero
in this twenty week study) or CMV appearing in the uninvolved eye
(eleven to twelve percent) was about the same in both groups.

       Oral ganciclovir alone might be worthwhile therapy only in
those with inactive, CMV outside the all-important central retina
zone, but it might be of greater use when combined with the
implants. (Oral ganciclovir might also be more effective at a higher
dose, if the digestive tract can tolerate it. Such studies are now
underway. One, a European study comparing daily doses of three grams
and six grams, is now having its data analyzed.)

       In May, Syntex (now Roche Bioscience) submitted a
supplemental application to the FDA for clearance to market oral
ganciclovir as a CMV preventive for people with AIDS. To support
this prophylactic indication, Syntex submitted results from a trial
that found that over eighteen months, oral ganciclovir reduced the
rate of CMV retinitis from 39 percent to eighteen percent. (The
detected occurrence of other CMV disease was only a few percent, and
the effect of oral ganciclovir on the rate of extraocular infection
was not statistically significant. See Treatment Issues, October
1994, page 9 for details on this trial and a related,
problem-plagued trial sponsored by the Community Programs for
Clinical Research on AIDS (CPCRA), which found no difference between
oral ganciclovir and placebo in preventing CMV retinitis.)

       Why so many trial participants on oral ganciclovir developed
CMV retinitis is a matter of debate. Many observers are afraid that
suboptimal blood levels of the drug are encouraging the evolution of
resistant virus. Kevin Frost is probably most opposed to the use of
ganciclovir as prophylaxis. He said, "Oral ganciclovir is my worst
nightmare. It is a resistance breeder. Only 20 percent in trial got
a benefit from drug. Why treat everybody then? Widespread CMV
resistance will be a devastating problem for HIV and organ
transplant communities."

       Physicians such as Daniel Martin are worried that popular use
of prophylactic ganciclovir will reduce the effectiveness of
ganciclovir implants. Lawrence Drew, M.D., a San Francisco
investigator who contributed to the Syntex trial, grants that drug
resistance is a real concern with oral ganciclovir. Drug resistance
data from the trial are now being analyzed and may be presented at
the annual Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC) this September. Dr. Drew argues, though, "The
breakthrough infections were most likely due to either lack of
compliance on the patient's part or poor absorption. Resistance was
probably not the reason."

       (Since February, Syntex/Roche Bioscience has made available
an open label safety study that provides free oral ganciclovir for
preventing CMV in HIV-positive, CMV-positive individuals with CD4
counts less than 50 and no active CMV disease. Enrollment has been
very slow. As of July, just 132 of the 5,000 allotted slots had been
filled. Oral ganciclovir is available at pharmacies, officially only
for maintenance therapy, and physicians apparently prefer simply to
prescribe the drug for prophylaxis and avoid the study's paper work.

       Third-party payers are reimbursing for this off-label use
even though the price is a hefty one -- $39 a day wholesale. Those
who cannot afford this expensive product can call the Roche
Bioscience Study Center at 800/569-4630 for information on enrolling
in the open-label study, which will continue until ganciclovir is
approved for primary CMV prevention.) Cidofovir (HPMPC)

       One way to avoid ganciclovir overuse is to try another drug.
William Freeman, M.D., of the University of California San
Diego believes that he has found just such a method using
intraocular injections of the highly active experimental
antiviral drug cidofovir (HPMPC).

       Dr. Freeman has pioneered this field by himself. He now
injects tiny amounts -- twenty micrograms -- of the long- lasting
cidofovir every six weeks into the vitreous humor of patients' eyes.
The results, he says, "are unbelievably good." Freeman claims that
he has seen no progression of CMV retinitis in his patients, now
numbering more than 70 persons who have received a total of 223
injections. The patient treated the longest has had ten injections,
amounting to 60 weeks of treatment.

       Originally there were problems with eye irritation (vitritis)
and loss of pressure in the eyeball (hypotony), but Dr. Freeman
reports that the present low dose avoids most of these events. There
remains the issue of cidofovir-resistant CMV -- and this resistance
could be due to foscarnet as well as previous exposure to cidofovir.
Strains with mutations rendering the virus cross-resistant to
foscarnet and cidofovir occur, so prior foscarnet therapy might
sometimes make the cidofovir injections ineffective.

       Dr. Freeman says that he has not had any problem with
resistance. In the eye, "we hit the virus with an overwhelming
amount of drug," he claimed. While Dr. Freeman waxes enthusiastic
over his discovery, other experts are more cautious. The words
"little data" come quickly to everyone's lips. Dr. Freeman is the
only person in the world now treating CMV retinitis with intraocular
cidofovir. He has just published the results from the first 52
injections in 33 patients.[7,8]

       The lack of available data is hardly Dr. Freeman's fault. The
owner of U.S. rights to cidofovir, Gilead Sciences, located south of
San Francisco, has consistently refused to support the San Diego
research. (Freeman's supply of cidofovir comes from an independent
European source.) Now, in the aftermath of the published articles,
Gilead says it will undertake a preliminary dose-ranging trial of
intraocular cidofovir.

       Dr. Freeman, meanwhile, is scrambling for funds to launch a
pivotal randomized trial with 30 to 40 volunteers, which would
provide enough data by itself, he says, to apply to the FDA for
marketing clearance. Dr. Freeman is also working on a more stable
version of the therapy in which the cidofovir is encapsulated in
liposomes (fat globules). Such a formulation might allow for thrice
yearly injections and be clearly superior to the present ganciclovir
implants.

       Gilead in the past few years has preferred to concentrate on
investigating cidofovir's use as a systemic, intravenous
therapy. Howard Jaffe, M.D., Gilead's director of research,
says, "We are a small company with no revenue. Our
intraocular studies were delayed because we gave priority to
developing a systemic drug for the systemic aspect of CMV."

       Cidofovir lasts so long in cells that infusions for systemic
therapy can be relatively infrequent. Intravenous cidofovir is
infused once weekly for the first two weeks and every other week
thereafter. Doses used are on the order three to five mg per
kilogram of body weight. (The total intravenous dose of several
hundred milligrams is easier than the intraocular version's mere
twenty micrograms to market at a profitable price, note the cynics.)

       Systemic therapy may be important, but intravenous cidofovir
turned out to have life-threatening kidney toxicities that
delayed research. This spring, two reports demonstrated that
intravenous cidofovir could be more safely administered along
with probenecid, which modulates kidney function but has its
own side effects, and intravenous prehydration.[9,10] These
measures did not interfere with cidofovir's dramatic
reduction of CMV shedding in the urine, the investigators
said.

       Right now, intraocular cidofovir is only available through
Dr. Freeman's clinic in San Diego. His patients must be off systemic
therapy and come in every two weeks for evaluation. Dr. Freeman
argues these restrictions are necessary to clearly document the
injections' effect, but they represent a serious obstacle to those
desiring the injections for their personal treatment.

       In a month or two, Gilead finally will commence an
intraocular dose-ranging trial, largely repeating Dr. Freeman's
work. It will take place at five sites: three University of
California campuses (Irvine, Los Angeles and San Francisco), Emory
University in Atlanta and Georgetown University in Washington, D.C.
Once again, participants may not have extraocular CMV and will not
receive systemic therapy.

       Gilead expects to apply to the FDA for marketing approval of
intravenous cidofovir by the end of the year. At present, the IV
formulation can be obtained in three ways. There are two on-going
randomized trials: the government-sponsored ACTG 281 and Gilead's
own phase II/III trial. Both of these trials are for people with
early CMV retinitis without prior therapy and include a comparison
arm whose treatment is deferred until the CMV retinitis lesions
progress. The trials' goal is to measure the extent to which
cidofovir delays progression.

       There is also a study for people with relapsing CMV retinitis
who have failed or are intolerant of ganciclovir and/or foscarnet in
which everyone receives immediate cidofovir. The company is also
working with the FDA to initiate a TIND (expanded access) program
for cidofovir in people who have failed the standard treatments and
cannot participate in a clinical trial.

       More information on access to cidofovir can be obtained by
calling Gilead at 415/573-4700. The company also will soon
commence trials on a less toxic variant of cidofovir, and an
oral version of this variant is under development, too.

       ISIS 2922

       Another new intraocular option is ISIS 2922, produced by the
Isis Pharmaceuticals outside of San Diego. 2922 is a novel sort of
drug that involves "antisense" RNA technology. It consists of RNA
made of sequences complementary to those produced by the CMV genes
integrated into an infected cell's genetic material. CMV messenger
RNA directs the cell's metabolic machinery to produce new virus
particles, but 2922 locks onto a specific portion of that RNA,
rendering it inoperative. ISIS 2922 is given by intraocular
injection once per week for the first three weeks and then biweekly
thereafter.

       A year ago, Isis reported the initial successful results with
its drug (see Treatment Issues, May, 1994, page 5), and the company
seemed to be charging ahead, with ISIS 2922 set to become the first
commercial antisense medication. Phase III trials commenced last
December, and Isis had hoped to file for FDA approval sometime in
1996.

       Unfortunately, the development of 2922 has hit a snag. As
many as five of the participants already enrolled in trials have
developed a stippling, or spotting, on their retinal surface. Four
of 23 treated eyes also suffered losses in peripheral vision. These
effects could be due to some previously unnoticed drug toxicity.
Isis temporarily halted enrollment in two of its trials while it
reviewed the situation. A third trial has remained open. It is an
open- label protocol for people who have failed on previous
therapies.

       In July, the company announced that it was preparing to
resume its trial in people with early CMV retinitis without prior
treatment. The biweekly injections of ISIS 2922 were being reduced
to 75 micrograms from 300 micrograms and would be increased as the
drug's safety was established. The company also was considering
redesigning a second trial, which tested ISIS 2922 in combination
with ganciclovir in more advanced patients, to also include a
gradual dose escalation -- and the use of oral ganciclovir as well.
The company reportedly is betting heavily on the effectiveness of
the combination of intraocular 2922 and systemic oral ganciclovir in
preventing CMV relapse.

       Further information on the trials' status may be obtained by
calling the Isis hotline at 619/929-3898. (Note that a call
to this number produced a response that there is no
"compassionate use" program for ISIS 2922. Ask about trial
CS7 for treatment failures with advanced disease.)

       ISIS 2922 has been a particularly interesting drug because it
attacks CMV by a wholly different method than other CMV treatments
(which attempt to terminate replication of the viral DNA gene set
within infected cells). Because of its unique character, the Isis
compound is not subject to the same type of resistance as the other
drugs. CMV resistant to 2922 has not emerged in laboratory tests,
although it is possible in principle.

       Claudette Lajam says that her office has seen real vision
improvement in some, but not all, patients on the drug. This
clinical improvement may be due to reduced nerve membrane
swelling as the CMV infection subsides or perhaps new
synaptic connections that compensate for dead tissue. She
says that the drug is "best for smoldering CMV [i.e., not too
advanced and only very slowly progressing]. It is very
promising, especially as an adjunct therapy. There is
probably a need for systemic treatment. We haven't had enough
follow-up yet to see how it works on its own."

       Another Type of Systemic Backup

       ISIS 2922 is not a candidate for systemic therapy because of
the compound's cost and instability in the bloodstream. Cidofovir
would seem a better candidate, but its present form, at least, has
some serious side effects that make many people hesitant. There is
also a risk that CMV resistant to either therapy will emerge,
ruining that drug's usefulness for local therapy. To have a more
complete arsenal against CMV requires a relatively nontoxic systemic
drug that preferably acts in a different manner than the localized
therapy.

       An attractive alternative systemic treatment under
development is MSL 109, a human monoclonal antibody against
CMV. Monoclonal antibody treatment consists of a purified
concentrate of a single human-type antibody that has strong
neutralizing activity against a particular virus. It is
produced in laboratory culture by a special hybrid cell fused
with a human B lymphocyte found to produce an antibody with
the desired properties.

       MSL 109 is about to undergo testing in two extensive human
trials (ACTG 266 and ACTG 294) involving a total of nearly 500
persons. These trials will try out the antibody in combination with
approved CMV treatments, i.e., ganciclovir, foscarnet and, when
approved, ganciclovir implants. Observation of participants will
continue for a year. (For more information, call the government
trials hotline at 800/TRIALS-A.)

       Decisive data on MSL 109 will not be available for several
years. This wait may be unavoidable, but it represents yet
another holdup in the long development of the antibody, which
was originally created by Sandoz Pharmaceuticals back in the
eighties. Sandoz sponsored initial human trials of MSL 109
some six years ago. It then decided to get out of this area
of research and eventually sold its experimental line of
antiviral monoclonal antibodies to Protein Design Labs, a
small company located south of San Francisco, in April of
1993. Protein Design Labs has spent the last two years
revamping the manufacturing process for MSL 109 in
preparation for further human testing. Four years have been
lost because of Sandoz's pullout.

       In one Sandoz trial conducted in 1991,11 seventeen persons
received a combination of MSL 109 and either foscarnet or
ganciclovir as maintenance therapy. The time until recurrence of CMV
progression was 200 days or twice as long as historically observed
with either ganciclovir or foscarnet monotherapy. MSL 109, which was
administered intravenously every two weeks, was well tolerated, and
it did not seem to provoke any immune response against it (this was
a problem with earlier versions of monoclonal antibodies, which were
mouse- rather than human-based).

       The 200-day delay in CMV progression was achieved despite the
fact that the MSL 109 was discontinued after at most 112 days. The
effect of prolonged therapy, to be evaluated in the current trials,
remains unknown, but according to Richard Pollard, M.D., the
principal investigator for ACTG 266, MSL 109-resistant strains of
CMV have not appeared in his extensive laboratory attempts to breed
such a viral strain (although one other lab did find reduced
sensitivity to the drug after exposure). Dr. Pollard, who works at
the University of Texas at Galveston concluded, "If there is no
escape mutant and the agent is nontoxic, it will be a good candidate
for long-term systemic therapy," at least in combination with other
compounds.

       Monoclonal antibodies' ability to cross from the blood to the
retina and the brain remains undetermined and may be
relatively poor due to their large molecular size. But their
lack of toxicity and unique mode of action make them seem a
potential candidate for supplementing localized eye therapy
so as to prevent breakthrough CMV infections elsewhere.
Whether a monoclonal could be used without ganciclovir or
foscarnet also remains to be determined.

       Towards Better Medical Management

       The outlines of a "kinder, gentler" combination treatment
regimen that effectively manages CMV in people with AIDS is
gradually emerging. It would include some type of direct therapy for
the eyes that requires only occasional reapplication. Meanwhile, a
systemic therapy would protect against infection outside the
affected eye, and that therapy should be less onerous and more
effective than the present ganciclovir and foscarnet intravenous
regimens.

       But the path of research is never a straight one. Corporate
strategies (ganciclovir, cidofovir, MSL 109) as well as scientific
mishap (ISIS 2922) are impeding achievement of optimal therapeutic
strategies.

       The only treatment now easily obtainable for people with
refractory CMV is intravenous ganciclovir and foscarnet combined.
Administering both these drugs requires that patients spend most of
their day connected to an infusion pump and suffer the combined side
effects of both drugs. This unpleasant but more active therapy is
now the subject of ACTG trial 228.

       In the next article Gary Ranum describes what the delays in
developing better CMV treatments mean in personal terms.

       1 Stanley HD et al. Journal of Acquired Immune Deficiency
Syndromes. Mar 1994; 7(3):272-8.

       2 Kupperman BD et al. The Journal of Infectious Diseases. Dec
1993; 168(6):1506-9.

       3 Drew WL et al. The Journal of Infectious Diseases. Apr
1990; 163(4):716-9.

       4 Blysma SS et al. Archives of Ophthalmology. Jan 1995;
113(1):89-95.

       5 Chiron Vision/Hoffmann La Roche press release. July 5,
1995.

       6 Oral Ganciclovir European and Australian Cooperative Study
Group. AIDS. May 1995; 9(5):471-7.

       7 Kirsch LS et al. Ophthalmology. Apr 1995; 102(4):533-43.

       8 Kirsch LS et al. American Journal of Ophthalmology. Apr
1995; 119(4):466-76.

       9 Lalezari JP et al. Journal of Infectious Diseases. Apr
1995; 171(4):788-96.

       10 Polis MA et al. Antimicrobial Agents and Chemotherapy. Apr
1995; 39(4):882-6.

       11 Toplin M et al. Ninth International Conference on AIDS.
Jun 6-11 1993; I(abstract WS-B11-2):54.

       *********************************************
       Testing for CMV in the Central Nervous System

       CMV can involve both the brain (encephalitis) and the spinal
nerves (polyradiculopathy). Two European studies recently reported
that using polymerase chain reaction (PCR) to measure CMV's DNA in
the cerebrospinal fluid (CSF) was helpful in making the diagnosis
and following the response to treatment in patients with CMV
neurological disease.

       In a French study, the presence of CMV DNA in the CSF
correlated with a clinical diagnosis of CMV neurological disease and
was associated with an increased risk of death (J. Gozlan et al.
AIDS. March,1995; 9(3): 253-60). In the second study, conducted in
Sweden, seven AIDS patients with CMV disease of the central nervous
system were treated with ganciclovir for three weeks (P. Cinque et
al. The Journal of Infectious Diseases, June, 1995; 171(6): 1603-6).

       After treatment, all the Swedish patients had either a
reduction or disappearance of CMV DNA viral load in the CSF. Four
had neurological improvement. Three of four patients who had
autopsies done were found to have other pathogens in the brain. All
four had evidence of CMV brain infection. The authors concluded that
despite the reduction in CMV viral load in the CSF after ganciclovir
therapy, the treatment was unable to completely suppress replication
of the virus in the brain, possibly because of the low levels of the
drug reaching brain tissue.

       The Swedish investigators also felt that quantitative PCR
assay could be used reliably to monitor the response to therapy of
CMV infections of the central nervous system and to evaluate the
severity of the disease. -- GT

       CMV Drugs: Why They Work and How the Virus Evades Them

       Drug: Ganciclovir

       Mechanism of Action: A nucleoside analog, a defective copy of
the DNA building block guanine. It requires activation
through addition of a phosphate group by a viral enzyme
within infected cells. This phosphorylated ganciclovir is
taken up by a viral DNA polymerase that builds DNA replicates
of the CMV gene set. Ganciclovir prevents further extension
of the DNA chain, blocking creation of a new virus.

       Resistance: 1) A single mutation in the UL97 gene, which
governs the structure of the viral enzyme that phosphorylates
ganciclovir. This prevents creation of the active ganciclovir
molecule.

       2) Rarely, a mutational change in the viral DNA polymerase
enzyme reduces ganciclovir incorporation into viral DNA. This
change creates moderate resistance to ganciclovir. There is
potential cross-resistance to cidofovir.

       Drug: Foscarnet

       Mechanism of Action: An analog of the phosphate groups added
to nucleosides before they link up to form DNA. It binds to
CMV's DNA polymerase within infected cells and blocks this
enzyme's role in CMV replication.

       Resistance: A mutational change in the viral DNA polymerase
obstructs binding with foscarnet. Foscarnet-resistant CMV may
also be resistant to cidofovir.

       Drug: Cidofovir

       Mechanism of Action: Nucleotide analog, differs from
nucleoside analogs in that it is pre-phosphated and does not
depend on phosphorylation by a CMV enzyme. It is taken up by
CMV's DNA polymerase, and prevents further extension of the
DNA chain forming the new viral DNA.

       Resistance: A mutational change in CMV's DNA polymerase
reduces cidofovir incorporation into viral DNA. Cidofovir-
resistant CMV may be cross-resistant to foscarnet.

       Drug: ISIS 2922

       Mechanism of Action: An antisense sequence of nucleotides
complementary to a messenger RNA sequence produced by the CMV
genes in an infected cell. CMV's messenger RNA coordinates
the production of new viral protein in the infected cell's
cytoplasm. ISIS 2922 binds to a messenger RNA from CMV's IE2
gene, which produces proteins that regulate expression of
other viral genes.

       Resistance: None observed so far. In principle, a simple
change in the IE2 gene sequence would protect its messenger
RNA from binding with ISIS 2922. Because of ISIS 2922's
unique mechanism of action, CMV resistant to this compound
would not be cross-resistant to other medications.

       Drug: MSL 109

       Mechanism of Action: A laboratory-produced monoclonal
antibody that binds to a surface protein on a CMV virus
particle. It neutralizes the virus, probably by preventing
entry of the virus into uninfected cells. MSL 109 may also
bind to the viral protein on the surface of CMV-infected
cells, signaling the immune system to kill them.

       Resistance: Changes in CMV surface protein could reduce the
virus's susceptibility to MSL 109, but the extent of
resistance seems low from laboratory tests. There would be no
cross-resistance to other CMV treatments.

       ************************************************
       Finding Support for AIDS-Related Vision Problems
       by Gary Ranum M.A., M.Ed., Ed.D.

       People do not realize that getting a drug for CMV will not
make the disease go away. The drugs just hold the line for a little
while, then your vision continues to decline as your immunity
worsens. I first had CMV in my colon two years ago, and six months
later, the virus struck one of my eyes. I have had intravenous
infusions of ganciclovir for these last two years. Now, I am legally
blind in one eye and have one sight-threatening CMV lesion in my
other eye. I currently get infusions of foscarnet and ganciclovir
each day and I get weekly injections of ganciclovir in each eye. I
also had ganciclovir implants installed in both eyes this spring and
now all the old lesions in both eyes are dormant, but there is that
new and growing sight-threatening lesion in the central area of my
good eye's retina. As I write this, I am planning to up the dose of
my Tuesday ganciclovir intraocular injection and add a Thursday
injection of foscarnet.

       Unfortunately, the number of pages devoted to support
services for those of us who are becoming blind, or those of us who
are already blind, is limited indeed. Most articles published in the
AIDS community are about the medical conditions of vision loss
rather than the psychological or sociological aspects -- what does
one do, and where does one go, when vision loss is inevitable?

       In Manhattan, where I live, there are three agencies
specifically designed to help the blind and those becoming blind.
They are: The Jewish Guild for the Blind, The Lighthouse Inc. and
The Helen Keller Institute. At the Jewish Guild, for example, there
are case workers who work only with AIDS-related blindness. After
receiving information about the medical condition of vision loss,
these case workers help the person fill out the necessary paperwork
to submit to the city's Commission for the Blind and Visually
Handicapped (CBVH) to see which services are appropriate and
available for that individual.

       One needs to establish relationships with agencies early on
with vision loss, so that services will already be in place when
your impairment increases. It will be more difficult psychologically
to make the necessary connections after the vision loss has become
severe.

       Another step is to involve oneself in a support group. For
me, it has been the one thing at GMHC that got me through retiring
and going on disability. It also was the first place I could discuss
my vision impairment, but sighted people have a different
perspective than we do. My vision loss required a different kind of
support. Encroaching blindness causes extreme anxiety, fear,
depression and isolation more than AIDS by itself. AIDS plus
blindness is a doubly difficult diagnoses to cope with.

       We have different issues than just dealing with AIDS and
particular opportunistic infections. We are faced with a multitude
of questions: Who can sit with us? Who will maintain care of medical
matters, such as the infusions, injections and pills we are taking?
Who will go to the doctor's with us and fill out the paper work?
What happens if we are home alone and need help -- and cannot find
the phone? What about daily life -- preparing meals, bathing,
shaving, buying food, going out to eat, enjoying spare time,
transportation, bad weather, losing something in the apartment, to
name just a few.

       In May of 1994, I submitted a proposal to GMHC outlining the
rationale for establishing a support group to assist those with
vision problems. This would be the agency's first program for its
visually impaired clients. GMHC listened, and understood, and now
there are fliers posted around the agency giving the details about
the group. (Further information about the GMHC group may be obtained
from Mark Thomas, the group's facilitator, at 212/337-3515.)

       But the first support has to be you. People going through the
experience have to reach out and educate themselves. After I
realized the inevitable, it became apparent that there are things
one can do when one loses vision. There are computers designed to
assist blind people; there are books on tape; there is a radio
station at the Jewish Guild which broadcasts readings of daily
newspapers. Last but not least, in New York the Metropolitan Museum
of Art has a collection of art objects specifically for the visually
impaired. One of the curators will take you to the collection and
allow you to touch the various objects. Being blind is not the end
of life, there are still things we can do. Even though we are losing
vision, we can still "see," and the business of life continues.

       Because of the interventions in my case, and because I have
sought help, I am coping with my progressive loss of vision. I could
not have made it this far without my wonderful partner, though, who
stands by me as I confront my condition. My going blind is very
different for the two of us, as he becomes more and more "my eyes."

       As people with AIDS live longer, more and more will lose
sight. Here are some tips for those of you who are suddenly called
upon to be the eyes for someone who is visually impaired or blind:
1) if the person asks for help across the street, let them grab your
arm, please do not pull them around; 2) when entering a room,
introduce yourself to the person and tell them where you will be
sitting if necessary; 3) never leave a sightless person standing in
a room without guiding him or her to a chair or table (a safe area);
4) describe the room to let the person know what is in the room; 5)
avoid "throw rugs," as they can trip those with limited vision.

       ******************************************
       CDC Report on Waterborne Cryptosporidiosis

       This June, the Centers for Disease Control and Prevention
issued a report based on a meeting of outside experts to examine the
safety of public water supply in regards to cryptosporidiosis. This
parasitic disease causes life- threatening diarrhea in people with
AIDS.

       The experts concluded that the magnitude of the risk of
cryptosporidiosis remains uncertain. Whether or not a waterborne
crypto outbreak is occurring in a given locality, people with immune
deficiencies such as AIDS can protect themselves by consistently
drinking only water that has been: 1) boiled for one minute, or 2)
filtered with a one micron microstraining filter meeting industry
standards or 3) bottled by a commercial firm that has passed it
through such a filter or treated it by distillation or reverse
osmosis. For more information on this issue, see Treatment Issues,
September, 1994, pages 5-6 and October, 1994, page 15. -- DG

       ****************
       Treatment Briefs
       by Gabriel Torres, M.D., and Theo Smart

       Merck's Protease Inhibitor Expanded Access Program Now Open
Phone registration is now underway for the expanded access program
of Merck's protease inhibitor, indinavir sulfate (Crixivan) --
formerly known as MK-639 and L-735,524. The program will offer drug
to 1,100 selected with less than 50 CD4 cells who will be selected
in a lottery. To participate in the selection process, patients or
their care providers must call 800/497-8383 before 11 p.m. on August
11, 1995. Callers will be sent a one page "qualification form" which
must be filled out and returned to the company before September 8,
1995. The earlier these forms are returned to the company the
better, since drug recipients will be chosen on August 15. People
who aren't in the first 1,100 selected will be placed upon a waiting
list and may receive drug should more become available.

       3TC Compassionate Use Protocol Improved

       By the end of August, Glaxo Wellcome plans to increase the
weekly quota for its 3TC compassionate use protocol from 300 to 650
new enrollments. Although patients with fewer than 100 CD4 cells
will be given priority, anyone with less than 300 CD4 cells may now
apply for the program, which now distributes the experimental drug
3TC to 24,000 people. In April, Glaxo Wellcome reduced access to 3TC
through its compassionate use program because demand had outstripped
drug supply. This move followed wide publicity concerning the
improved CD4 and viral load responses seen when combining 3TC with
AZT. Glaxo limited the weekly enrollment and lowered the entry
criteria from 300 to 100 CD4 cells.

       This announcement follows Glaxo Wellcome's June 30 filing for
FDA approval of 3TC in combination with AZT as a first line therapy
in people with HIV and less than 500 CD4 cells. Call for
information: Treatment Issues would like to hear from any people
with HIV or their doctors who have observed unusual declines in
white blood cells, lymphocytes or CD4 cell counts while on 3TC. We
have heard of several cases in which people starting the AZT/3TC
combination have experienced such drops, at least temporarily
(although they may also have had concurrent reductions in viral
load). Glaxo Wellcome claims that it has received no reports of this
phenomenon.

       New Non-nucleoside Reverse Transcriptase Inhibitor

       Eli Lilly Co. has announced that LY30046-HCL, the first of a
new class of non-nucleoside reverse transcriptase inhibitors
(NNRTIs), has entered phase I clinical trials. The new class of
inhibitors, called the PETT series, were discovered when Lilly
researchers dismantled TIBO derivatives (another class of NNRTI)
into simple structural elements, and screened their organic compound
library to find substances with similar structures.

       Viral resistance is the biggest obstacle to an NNRTI. HIV
resistant to the NNRTI nevirapine also exhibits reduced
susceptibility to the PETT compounds. However, the company reports
that LY30046-HCL is more potent than nevirapine and that elevated
concentrations of this new compound should be able to inhibit
nevirapine-resistant virus. When exposed to LY30046-HCL in the test
tube, HIV develops resistance by making multiple mutations different
from the mutations that confer resistance to nevirapine.

       Lilly's announcement comes as a surprise. A year and a half
ago, Carlos Lopez, the company's Executive Director of Infectious
Disease Research, announced that Lilly had halted in-house research
on HIV treatments, as part of their plan to "focus resources in
areas where we feel we have a competitive advantage." Subsequently,
the company dropped out of the Inter-Company Collaborative on AIDS,
a network of pharmaceutical companies involved in developing
treatments for AIDS.

       Plasma Viremia Predicts Clinical Outcome

       A recent French study suggests that plasma HIV viremia may
predict clinical outcome during AZT therapy (A. Ruffault et al.
Journal of AIDS. April, 1995; 9(4): 330-4). Plasma viremia is a
measurement of culturable virus in the fluid of the blood, it is not
to be confused with viral load.

       The study involved 28 asymptomatic or mildly symptomatic
people with HIV and CD4 counts below 350. Their plasma viremia, p24
antigen levels and CD4 counts were measured before and during the
course of treatment. "Responders" were defined as patients who had
positive plasma virus cultures that turned negative during treatment
or that were negative at the outset and remained so during therapy.

       During the mean follow-up period of 21 months, 73 percent of
the non-progressors were "responders," whereas all of the thirteen
patients who progressed in their illness were plasma viremia
"non-responders." A significant and stable decrease in plasma
viremia was observed only in the nonprogressors.

       The persistence, increase or reappearance of viral
replication appeared to be an important predictor of poor clinical
outcome in this small group of patients undergoing AZT therapy.
There were significant discrepancies between clinical outcome and
the response rates in terms of p24 antigen levels and CD4 counts.
The authors concluded that plasma viremia is a more sensitive
surrogate marker, and may precede the decline in CD4 counts,
predicting disease progression earlier.

       Thalidomide for Microsporidiosis

       A small British study has reported positive effects using
thalidomide for the treatment of gastrointestinal infection with
Enterocytozoon bieneusi (microsporidiosis), one of the most common
causes of diarrhea in persons with AIDS. (D. Sharpstone et al. AIDS.
June 1995 9(6):6589) The rationale for the use of this agent comes
from its effects against tumor necrosis factor, a cytokine that has
been found at high levels in the stool of persons with
microsporidiosis.

       Twelve gay men with microsporidiosis and chronic diarrhea
were treated with thalidomide (100 mg per day for three weeks). All
had previously been treated with albendazole, but had failed to
improve. Following the first three days of thalidomide treatment,
all the men had improved, with a decrease in bowel movements and
decreased utilization of antidiarrheal agents. Stools became
semi-solid. After three weeks of therapy, the patients had gained an
average of 1.2 kilograms of body weight. The only reported side
effects were a generalized rash in one patient and drowsiness in
three, requiring a dose reduction to 50 mg per day. One week after
the dose was lowered, one patient relapsed. These encouraging
results indicate that an expanded trial, possibly including
albendazole, should be set up immediately.

       Rifabutin Induces Rifampin-Resistant TB

       The first case of tuberculosis resistant to the antibiotic
rifampin has been reported in an HIV-positive patient using
rifabutin for Mycobacterium avium complex (MAC) prophylaxis (A
Weltman et al.The Lancet. June 10, 1995; 345:1513). Rifampin and
rifabutin come from the same family of antibiotics and there has
been a growing concern that the widespread use of rifabutin for MAC
prophylaxis would result in emergence of Mycobacterium tuberculosis
resistant to rifampin, one of the most important drugs in the
treatment of TB.

       The case was in an HIV-positive prison inmate who had a CD4
count under 100 and negative results on three skin tests for TB (PPD
skin tests). He had been placed on rifabutin for MAC prophylaxis
seven months prior to the onset of symptoms of TB (cough, fever,
night sweats).

       A sputum analysis revealed a strain of TB mycobacterium
resistant to both rifampin and rifabutin. The resistance was
documented by genetic analysis of the bacterial DNA through a
technique called restriction fragment polymorphism (RFLP)
analysis.

       This case raises concern about use of rifabutin in
populations such as prisoners, homeless persons and injection drugs
users that have a high rate of latent TB and yet do not react to the
PPD skin test. Such "anergy" makes the diagnosis of the latent TB
impossible. Persons to be placed on rifabutin should first have
active TB ruled out by a chest x- ray and three negative sputum
analyses prior to starting the drug.

       Clarithromycin-Induced Mania

       The antibiotic clarithromycin is commonly used in people with
AIDS to treat or prevent disseminated Mycobacterium avium complex
(MAC) infections. A report from New Mexico described two patients
with AIDS who became psychotic possibly due to therapy with
clarithromycin (S. Nightingale et al. Clinical Infectious Diseases,
June 1995; 20(6):1563-4).

       Both became agitated and psychotic within 48 to 72 hours
after starting the drug at a high dose (1000 mg twice daily) to
fight MAC. Symptoms included anxiety and delusions of grandeur,
which resolved after the drug was discontinued but recurred when the
drug was restarted. One patient also was taking fluconazole, which
can interact with clarithromycin. A drug-drug interaction phenomenon
could not be excluded. The relatively high doses of clarithromycin
in these underweight individuals nonetheless is thought to have
contributed to this reversible alteration of mental status.

       ************************************
       New Developments in Kaposi's Sarcoma
       by Theo Smart

       Kaposi's sarcoma (KS) was one of the earliest, most visible
manifestations of AIDS in the gay community. Although a number of
debatable studies have claimed that the percentage of gay men
contracting KS is declining, the total number of cases is definitely
increasing. Also, now that treatments and prophylaxis for life
threatening opportunistic infections have improved, KS, which
normally progresses slowly, has the opportunity to cause greater
suffering and death. Meanwhile, efforts to explain why KS develops
and to find more effective regimens for KS have lacked direction and
support from the National Institutes of Health.

       One year ago, the Treatment Action Group (TAG) published a
report on treatment and research policy issues pertaining to KS.
Largely at TAG's prompting, the National Cancer Institute (NCI)
sponsored the first conference devoted to KS this past June. It was
an opportune time to hold such a conference since there have been a
number of major advances recently in our understanding of what
causes the KS disease process and how to treat it. We summarize here
some of the major findings presented at the conference.

       Clinical Features

       A number of speakers focused on the features and causes of
Kaposi's sarcoma. AIDS-related KS is much more aggressive than other
subtypes such as classical KS. Its lesions start as small purple or
reddish marks (macules), frequently on the tip of the nose or soles
of the feet, and become papules, nodules or plaques that can be
scattered across the body, commonly in mucosal tissues. In about 50
percent of people with AIDS-related KS, lesions form in the lungs
and gastrointestinal tract. KS in the lungs is most life-
threatening, causing pulmonary fluid buildup, obstruction of
airways, bleeding with resultant coughing and difficult breathing.
Wherever, and whenever KS occurs, it can be compounded by
inflammation, ulceration and secondary infections of the surrounding
tissues. KS involvement of the lymph tissues leads to a particularly
poor prognosis as the disease rapidly spreads to other organs.

       It is still undecided whether KS is a true cancer or merely a
skin growth in reaction to infection by an unknown agent. Cancers
are generally characterized by one type of cell that mutates and
begins to proliferate without control. Although many of the cells
that compose a KS lesion are spindle shaped like fibroblasts, they
are derived at first from various cell types. But as the lesion
advances, one cell line might become dominant, making the KS growth
resemble a cancerous tumor.

       Steven Miles, M.D, of the University of California Los
Angeles, has proposed a simple working model for the development and
spread of KS. He believes that cells are initially transformed
somehow, perhaps by a virus. When these transformed cells are
exposed to certain molecules present in abundance during HIV
infection -- immune system cytokines (especially IL-6), various
other growth factors that promote cell growth and HIV's tat protein
-- they replicate and spread. Eventually, the cells begin producing
their own growth factors, some of which stimulate angiogenesis --
the development of new blood vessels that help feed the growing
lesion.

       Kathryn O'Connell of Johns Hopkins University presented data
at the conference that seemed to support this model. By infecting
endothelial cells from nude mice with a virus (SV40), she was able
to produce tumors quite similar to KS. These lesions were easily
stimulated by many of the growth factors common in AIDS-related KS.

       Yuan Chang gave the conference an update on the data behind
her theory that KS is caused by a previously unknown herpes virus
popularly, and perhaps prematurely, referred to as KSHV (see page
17). There is as yet no definitive proof that KSHV (also dubbed
HHV8) causes KS, though.

       Other researchers, such as Barbara Ensoli and colleague
Valeria Fiorelli (visiting Italian scientists at the NCI), argued
that no one agent, viral or otherwise, is necessary for the
development of KS. Instead, the presence of HIV's tat protein plus
the inflammatory cytokines and, in particular, basic fibroblast
growth factor (bFGF), may by themselves transform normal cells and
lead to the formation of lesions. In cell cultures, they have
induced normal endothelial cells (from umbilical cord tissue) to
acquire spindle cell characteristics by exposing them to both bFGF
and tat. These cells cause KS-like lesions after injection into
mice. According to the Ensoli model, the synergy between tat and
bFGF is responsible for the virulence of AIDS-related KS. If there
is no contagious microbe involved, why is AIDS-KS more common in gay
or bisexual men than in other HIV-positive populations? Valerie
Fiorelli thinks that there may be a number of environmental factors
to blame -- for example, the immune cytokine profile in gay men may
be somewhat altered. Gay men's immune systems are more activated,
Fiorelli claims, perhaps because they are exposed to a greater
variety of infectious agents.

       Potential Therapeutic Approaches

       Whatever the initial cause, everyone agrees that cytokines
and other growth factors play a primary role in the development,
growth and spread of KS. The list of these growth factors is quite
long and, besides bFGF and tat, includes a host of other fibroblast
growth factors: PDGF (platelet derived growth factor), IL-1, IL-6,
TNF-alpha, oncostatin-M, scatter factor and others. Inhibitors of
any of these factors may hold potential as treatments for KS. Many
such therapeutic strategies were discussed at the NCI conference.

       Angiogenesis Inhibitors: Angiogenesis (new blood vessel
formation) is necessary for the growth and metastasis of tumors, so
it is not surprising that much current anticancer research concerns
angiogenesis inhibitors. James Pluda and David Roberts of the NCI
reported on the status of research with these compounds, which
include IL-12, TNP-470, recombinant platelet factor 4 (rPF4),
tecogalan (SP-PG), pentosan polysulfate (which failed in its
clinical trials) and thalidomide.

       IL-12 has been shown to inhibit angiogenesis and primary
tumor growth in mice with Lewis lung carcinomas. Plans for a phase
II study in patients with cancer are under consideration at the NCI.

       TNP-470 is in a phase I study at the NCI. It is administered
as a one-hour infusion every other day. The investigators
have seen very little toxicity, but no major responses yet at
the doses currently being studied.

       Thrombospondin is a naturally occurring glycoprotein that
plays a role in platelet aggregation. It appears to have the
capacity both to stimulate and inhibit cell motility and
proliferation. Generally, its expression is associated with
decreased metastic potential, and it may inhibit bFGF. Researchers
at the NCI have investigated the complex activity of thrombospondin
and have found a specific peptide sequence that appears responsible
for its anti-angiogenic activities. They are currently devising
analogs of these peptides that may work as drugs (peptides are
notorious for being metabolized too quickly).

       Phil Browning of Vanderbilt University's Cancer Center
presented data suggesting that depletion of a naturally occurring
protein that inhibits angiogenesis aids the development of KS.
Apolipoprotein E (ApoE) is a protein complexed with lipids in high
and low density lipoproteins that helps transport cholesterol from
blood plasma to tissues. Reduced plasma levels are associated with
arteriosclerosis. ApoE appears to play a role in the regulation of
vascular cell growth. Levels of the protein become depleted early in
the course of HIV infection and people with HIV have an increased
risk of arteriosclerosis.

       In the test tube, ApoE inhibits KS cell growth and migration
and lowers the permeability of blood vessels. It has blocked
angiogenesis in mice. This naturally occurring substance may be a
novel and safe way to inhibit angiogenesis as it has no known
toxicity in animals. Analogs of ApoE are currently being designed
for clinical development.

       Liposomal Anthracyclines: Two of these are very near FDA
       approval. (See box, page 13.)

       Cytokines: As noted before, many cytokines and growth factors
are involved both in the proliferation of KS spindle cells and the
vascular structures that support them. Many cytokine inhibitors may
also be angiogenesis inhibitors, and much of angiogenesis
inhibitors' activity may actually involve the inhibition of
cytokines and growth factors.

       Peter Polverini of the University of Michigan presented data
at the conference on "scatter factor" and its potential inhibitors.
Scatter factor is a cytokine that causes endothelial cells to become
spindle shaped and scatter or spread out. KS cells both produce it
and have receptors for it, setting up a potential endless loop of
auto-stimulation. Antibodies to scatter factor markedly reduce
growth of KS lesions in lab experiments, as does an inactive variant
of scatter factor, which probably competes with the active molecule
for receptor sites.

       Dr. Miles of UCLA presented clinical data on a dose ranging
study of IL-4. IL-4 may increase CD4 cells and suppress IL-6, which
Dr. Miles believes is one of the critical cytokines stimulating KS
proliferation. IL-4 does inhibit KS cells in tissue culture studies.
In nine patients at the lowest dose, of 0.5 mg/kg of body weight per
day, just one patient showed a partial transient response, and five
had progressive disease. In the six patients at the next dose level
of 1.5 mg/kg per day, there were three cases of neutropenia,
headaches and fever were common, and only two patients had a partial
response. Dr. Miles saw no effect upon IL-6 or TNF alpha levels, but
he did note a 72 percent reduction in HIV levels as measured by
bDNA. IL-4 may have an antiviral effect through its modulation of
the immune system. Its side effects, which are related to that
modulation, are severe, though.

       Georgia Vogelsang of Johns Hopkins gave a presentation on
thalidomide -- which not only reduces levels of TNF alpha,
one of the inflammatory cytokines that may stimulate KS, it
also inhibits angiogenesis due to bFGF and perhaps other
growth factors. Thalidomide has shown anti-tumor activity in
animal models. In one study, dogs treated with thalidomide
experienced a stabilization and shrinkage of tumors. Clinical
trials for KS are now under consideration.

       Barbara Ensoli presented work on an "antisense" compound that
locks onto the cellular RNA directing production of bFGF. This
compound inhibits bFGF production and KS cell growth in a dose
dependent manner. It appears to work in a mouse model without any
deleterious effects. Because of her belief that bFGF and the HIV tat
protein synergistically stimulate KS, she also argued in favor of
developing tat inhibitors to treat KS.

       Retinoids: Retinoids are derivatives of vitamin A that may
reduce IL-6 levels and have other immune stimulatory activity.
Robert Yarchoan of the NCI presented data from a small study (in
twelve evaluable patients) of oral all trans retinoic acid (ATRA),
one derivative of vitamin A. ATRA is absorbed erratically, and
continuous administration seems to produce ever decreasing plasma
levels. To circumvent the absorption problems, it was administered
every other week in the study. Even with this precaution,
researchers saw no benefit, and ten of the twelve patients had
progressive disease.

       Steven Miles reviewed data from an ongoing study of topical
ATRA in forty patients with KS. Each patient had to have at least
six previously untreated lesions. Three were treated with ATRA and
three served as controls. Dr. Miles' group is seeing some responses
in treated lesions. The time to response seems to be dependent on
size. They are seeing more improvement in patients who have received
previous systemic treatment. However, the big problems are that
local absorption appears erratic, responses seem to depend upon site
of lesion, and new lesions appear elsewhere on the body. So there is
clearly a need to use systemic therapy.

       Dr. Miles also believes that there may be better derivatives
of ATRA. 9-cis retinoic acid is one that has a high level of
activity in the test tube. It and derivatives of it appear to have
much less complex pharmacokinetics.

       Novel Mechanisms: Bill Thorpe of the University of Texas
Southwestern Medical Center may have improved on the angiogenesis
strategy by finding ways to attack the established blood vessels in
tumors and KS lesions, cutting off their entire blood supply rather
than simply the formation of new blood vessels that sustains tumor
growth. He has found at least one protein, endoglin, that is present
only in replicating endothelial cells in tumor vessels, but not in
normal resting tissues. Administration of TEC-11, a combination
antibody/toxin that binds to endoglin, kills cells containing the
protein, triggering massive blood clots in the vessels feeding the
tumor. Dr. Thorpe was able to essentially starve mouse tumors to
death with this strategy.

       It is too early to tell whether Dr. Thorpe's tumor-
eradicating strategy will work on human KS. There are also serious
safety concerns about causing strokes and heart attacks as a side
effect. Dr. Thorpe is quick to say that even if the present
antibody/toxin proves too dangerous, he has a better protein target
and antibody that he is fairly certain will be safe. He plans to
publish information on the alternative treatment scheme in the next
few months (as soon as it is patented).

       Bruce Dezube presented data from a small study of SCHAL-1, a
cream containing clotrimazole. Clotrimazole has been shown to be an
inhibitor of cell proliferation, probably by inhibiting the calcium
signals that bFGF and other growth factors use to induce cell
growth. In a mouse model, clotrimazole was able to decrease
metastases in SCID-hu mice with melanoma.

       Eleven patients with AIDS-related KS enrolled in Dr. Dezube's
study, and nine were evaluable through week four. Half of the
patients' lesions were randomized to treatment, half to placebo. The
treatment was very safe but after four weeks, there were no
differences between treated and untreated lesions. There was, in
fact, a slight increase in the size of all the lesions, except
perhaps in a subset of small lesions.

       The SCHAL-1 cream contains a very low concentration of
clotrimazole, and there did not seem to be much penetration into the
lesions. Dr. Dezube's team is presently working on a more potent
formulation. Clotrimazole is an established antifungal medication.
Since it is relatively cheap and safe, it represents an attractive
treatment possibility.

       Robert Yarchoan reported on clinical results from a study of
Taxol in 29 AIDS patients with advanced KS (six had KS in the lungs)
with a median CD4 count of sixteen (an interim analysis of this
study was published in The Lancet, July 1, 1995; 346(8966):26-8).
Taxol, derived from the yew tree, has established activity against
other cancers, although its mechanism of action is unclear (it may
affect the formation of microtubules -- the cellular skeleton -- in
proliferating cells). The drug was administered in one three-hour
infusion every 21 days, at doses of 135, 155 and 175 mg per square
meter of body surface. Patients were given anti-inflammatory
steroids before administration, (but no G-CSF -- a therapy that
helps alleviate low white blood cell counts due to bone marrow
toxicity). Fatigue, hair loss and fever were the most common side
effects, and rash, fever, psoriasis, bone marrow suppression and
high levels of eosinophils (a type of white blood cell) were also
seen. There was one case of cardiac dysfunction that led to death --
but that may not have been drug-related.

       As for the clinical response, one patient had a complete
response and nineteen had partial responses. It took eight months
for the KS to start progressing again in the responders. Of the 29
patients who entered the study, eleven have died -- the median
survival is only fifteen months, and there were fourteen concurrent
major opportunistic infections -- so these patients were severely
immune compromised. Future studies of Taxol will include longer
infusion times and co-administration with G-CSF.

       The Elusive Standard of Care

       Very little of the conference dealt with standard of care
treatments. This was disappointing given the absence of guidelines
on what treatments should be used and when. The one standard of care
treatment that was discussed was radiation therapy in a presentation
by Patrick Swift of the University of California San Francisco.
Radiation therapy may be particularly useful for cosmetic purposes
and for painful lesions that interfere with functions like walking,
or lesions that are associated with bleeding or pain. But these were
broad observations for one modality of treatment when there are many
types of treatment and many types of clinical presentations. When
people with KS have different types of lesions that progress at
different rates (and this is compounded by concurrent opportunistic
infections and different states of immune dysfunction) what is a
doctor to do? Much of the published clinical information is often
inconsistent and confusing.

       ABV (the chemotherapeutic combination of adriamycin,
bleomycin and vincristine) is probably the agreed-upon standard of
care for widespread systemic and internal disease. But Michael Marco
of TAG presented data that showed that over the years, the response
rates to ABV, reported in clinical trials, appeared to be dropping
dramatically, going from a response rate of 88 percent down to 30
percent. One explanation for this decrease would be that
participants in earlier trials had less severe disease, and were
therefore more likely to benefit.

       Ron Mitsuyasu of UCLA listed a number of reasons why it is
difficult to assess the clinical improvement reported in clinical
trials over time. For one, treatment has changed for primary
infection of HIV and for opportunistic infections. But the biggest
problems concern methodology: 1) there is no clear evidence that
improved survival is associated with tumor reduction; 2) there is no
agreed upon system of staging the disease; 3) different studies
assess responses differently -- for example, one study may define a
partial response as a 25 percent reduction in tumor size (even
though new tumors are cropping up everywhere), while in another
study, only a greater than 50 percent reduction in lesion size with
no new lesions qualifies as a partial response; 4) few studies
assess how treatments effect quality of life; and 5) there simply
have not been any large randomized comparative clinical trials.

       Michael Marco noted, too, that the availability of G-CSF and
improvements in antinausea medications make chemotherapy not as
horrible as in the past. Even so, as Susan Krown, M.D., of
Sloan-Kettering concluded, "The future treatment of KS will probably
rely on combination approaches that address all the various factors
that contribute to the development of KS." The focus is shifting
from the standard anti-cancer chemotherapies.

       ************************
       Liposomal Chemotherapies
       by Theo Smart

       Just two days after the KS conference concluded, the Food and
Drug Administration (FDA) Oncology Drugs Advisory Committee
recommended that the agency approve DaunoXome (liposomal
daunorubicin) for the treatment of patients with systemic KS. This
was the second time that Vestar had filed for approval of the drug.
The last time the company's data were so disputed that the drug was
rejected out of hand. Data from a large phase III trial were now
available, but it was a close call even so.

       "It was a relief -- five years of work came to a good end,"
said Parkash Gill who served as investigator on a number of the
DaunoXome studies. The phase III trial involved 227 participants
with advanced systemic KS (more than 25 lesions, visceral/internal
disease, or severe edema). Patients were randomized to receive
intravenous DaunoXome, (40 mg/m2 of body area) or a low dose
intravenous ABV (adriamycin ten mg/m2, bleomycin fifteen U, and
vincristine one mg) that permitted concurrent administration of
antiviral drugs. Earlier studies in people with AIDS have shown
low-dose ABV to be as efficacious as higher doses.

       The results were not remarkable. Overall the response rates
for both arms were lower than expected. By the FDA's assessment, 23
percent responded on DaunoXome and 30 percent responded on ABV. Time
to progression was slightly in favor of ABV, but not significantly,
while there was an insignificant trend to prolonged survival on
DaunoXome. Oddly, there also seemed to be a trend toward increased
opportunistic infections on DaunoXome.

       There were no fewer cases of neutropenia or cardiac
abnormalities, as was expected with DaunoXome. On the contrary,
there seemed to be slightly more neutropenia. There were differences
in toxicity, just not the types of toxicity that, according to Gill,
"seemed to matter to the review panel," (for example, the incidence
of hair loss, fatigue and neuropathy was significantly lower on
DaunoXome). Dr. Gill notes, "If there is no hair loss and people can
go back to work without everyone knowing they are on chemotherapy,
that makes a large difference to patients." Overall quality-of- life
scores were somewhat better on DaunoXome, and patients also could
continue treatment for a longer period of time.

       One other liposomal anthracycline, Doxil (liposomal
doxorubicin), has also been recommended for approval. Is one better
than the other? Doxil certainly has its promoters. Its developer,
Sequus (formerly Liposome Technology), claims that a component of
Doxil's liposome, PEG (or polyethylene glycol), makes that liposome
superior to other liposomes, because it increases the liposome's
life circulating in the blood stream. This does not, however, mean
that more drug gets into the tumor, and even if it does, doxorubicin
may not be the equal of daunorubicin. Of DaunoXome versus Doxil, Dr.
Gill says "it would be great to compare them head to head. It is
clear that liposomal delivery is going to make a difference in
quality of life."

       Human Chorionic Gonadotropin
       by Theo Smart

       The pregnancy hormone human chorionic gonadotropin, (HCG) is
one of the most intriguing experimental treatments for KS
(see Treatment Issues, August 1994, pages 4-5). Interest in
HCG stems from anecdotal reports of remission of KS in women
who became pregnant, and published reports of an anti-KS
effect in mice.1 A recent letter in The Lancet, and ongoing
clinical studies of HCG are likely to generate even more
interest in the compound.

       In the Lancet letter, Pamela Harris of Washington, D.C.
reported treating six of her AIDS-related KS patients with
HCG.2 Two patients had only one lesion; two had extensive
cutaneous disease; and two had cutaneous and internal KS. She
started them on a low dose of intramuscular HCG, and
escalated the dose to 150,000 IU (and higher), three times a
week. These doses are comparable to the extremely high ones
used in mice.

       The only side effects were a sensation of skin retraction
around the lesions and tolerable pain at the site of the
injections. Side effects seen in other studies of HCG include
phallic and testicular enlargement in boys. Breast
enlargement has also been observed, but safety of chronic use
is unknown.

       All the patients had significant tumor regression. When
treatment was delayed or if patients were treated with less
than 100,000 IU, the tumors started growing back. Regression
lasted until treatment was discontinued due to cost.

       These doses are expensive, particularly without insurance
reimbursement. At the 150,000 IU dose Harris is using, the
retail cost of Serono Laboratories' brand name version,
Profasi HP, is $10,800 per month ($60 per 10,000 IU vial).
The generic HCG is cheaper, at about $3,150 per month ($35
for one 20,000 IU vial).

       Meanwhile, Parkash Gill, M.D., of the University of Southern
California, has finished his 24-person dose escalation study
of intralesional HCG (250, 500, 1,000, and 2,000 IU). Dr.
Gill cannot yet release the results, which have been
submitted for publication. They apparently are at least good
enough to justify commencing a follow-up study of HCG.3
The new study tries out systemic HCG therapy. The hormone
will be injected subcutaneously, starting at a dose of 2,500
IU once a day, escalating to 10,000 IU and perhaps more.
Besides evaluating HCG's safety and anti-tumor effect, Dr.
Gill plans to monitor the patients' viral load as HCG has an
anti-HIV effect in the test tube. (This effect could be part
of the reason why so few HIV-positive infants are born to
HIV-positive mothers.4)

              1 Lunardi-Iskander Y et al. Nature. May 4, 1995;
       375(6526):64-8.

              2 Harris P. Lancet. Jul 8, 1995; 346(89667):118-9.

              3 Personal Communication. July 13, 1995.

              4 Bourinbaiar AS and Nagorny R. FEBS Letters. Aug 31,
       1992; 309(1):82-4.

       ********************
       KS Virus Controversy
       by Theo Smart

       The causal role of the new herpes virus (popularly known as
KSHV) in the development of KS was called into question by some
researchers, including Robert Gallo, M.D., at the KS conference. The
genetic footprints of this virus were discovered in tissue from
AIDS-related KS lesions by Patrick Moore and Yuan Chang, of Columbia
Presbyterian Hospital in New York. (See Treatment Issues, January
1995, pages 11-12.) Traces of the virus were isolated by comparing
genes present in diseased tissue to genes in healthy tissue. Since
then other researchers have duplicated and extended their findings.

       Yuan Chang reviewed her group's research to date at the
conference. The researchers have isolated sixteen genes from this
virus, fifteen of which bear striking similarities to genes from
herpesvirus saimiri, a monkey virus, and the Epstein-Barr Virus
(EBV). These are both viruses of the gamma herpes sub-family that
have been associated with tumors. "KSHV" also is detectable in body
cavity lymphomas (BCL), a rare type of non-Hodgkins lymphoma.

       In blinded case-controlled studies, Chang, Moore and other
investigators have found the virus in tissue from patients with all
subtypes of KS, but not in healthy tissues from these patients, and
generally not in other types of tumors or carcinomas other than BCL
(although there were exceptions to this rule in patients from
Africa). With the help of Alvin Friedman-Kien, M.D., of New York
University, the Columbia group has detected virus in the lesions of
HIV-negative gay men with KS.

       Dr. Chang feels that the group has nearly fulfilled the
epidemiological criteria for establishing KSHV as the cause of KS
because 1) the virus is found in KS lesions of all sub- types; 2)
the virus is not found in other tumors except for BCL; 3) there is a
biologic gradient since virus is found in the lesion and in tissues
close to the lesion, but not in tissues farther away; 4) there is a
temporal association -- the virus appears in the white blood cells
of some patients before they develop the lesions; 5) these findings
have been reproduced by several labs; and 6) there is a biologic
plausibility since the virus belongs to a family of organisms that
is thought to cause cancers.

       Other researchers criticized these conclusions. Dr. Gallo,
who calls the virus human herpes virus 8 (HHV8), claimed that his
lab has been unable to find the virus in one of his KS cell lines. A
recent article in Science reports that Parkash Gill, M.D., also has
had trouble finding the virus in some of his KS cell lines, but the
article adds that frequently when cell lines are grown for a long
time in culture, they begin to lose resemblance to the original
tissue.

       In one presentation at the conference, Robert Biggar, M.D.,
an epidemiologist from the NCI, cited a paper by Rady, et al. in The
Lancet1 which he believes indicates that this virus may not be the
cause of KS. The researchers reported finding KSHV in 82 percent of
33 lesions taken from four organ- transplant patients on
immunosuppressive drugs. The lesions included basal cell carcinomas,
squamous cell carcinomas, actinic and seborrheic keratosis and
verruca vulgaris -- the common wart. The researchers concluded that
the herpes virus may be involved in all sorts of proliferative
lesions in immune-compromised people. But Biggar thinks that this
research shows the virus is not specific to KS which weakens the
case for it being the causative agent. Could it be, mocked Biggar,
that this is "the cause of all cancers?" Dr. Friedman-Kien, in
contrast, is not so troubled by the idea that the virus may indeed
be involved in the development of many types of lesions. There is
precedent for this: the closely related EBV is also associated with
a number of tumors, for example. Dr. Friedman-Kien says that his lab
has also found the virus in a number of different neoplasms.
Accordingly, he agrees that the virus should be named HHV8.

       Foscarnet for KS

       If KS is indeed caused by a herpes virus, there is a
possibility that an antiviral drug may have a therapeutic effect.
Foscarnet may be the available treatment with the greatest potential
as it has activity against all known herpes viruses.

       Even before the discovery of HHV8, there had been anecdotal
reports that people taking foscarnet experienced remission in their
KS lesions. Dr. Friedman-Kien, of NYU, has reported on a few such
cases. His patients had remissions and developed no new lesions for
up to a year.

       One open-label study of five people with KS treated with
foscarnet was published last year.2 Three of these patients
experienced regression and even clearance of external (and in one
case, internal) lesions for more than a year after just one or two
brief courses of foscarnet. The authors noted that the two patients
who did not respond had advanced disease and concurrent
opportunistic infections.

       Also, a retrospective analysis of 20,228 patients with
HIV/AIDS found that patients who were treated with foscarnet for any
reason were 70 percent less likely to develop KS than people who did
not receive foscarnet.3 Ganciclovir and acyclovir had no effect, but
foscarnet has a different mechanism of action than these drugs.

       Some researchers remain skeptical of this approach. Robert
Gallo, M.D., who has conducted extensive KS treatment research at
the National Cancer Institute, in particular is unconvinced that
HHV8 is the cause of KS. In contrast, Dr. Friedman-Kien and others
contend that KS could become a malignancy in later stages as a
result of cellular changes induced early on as a result of infection
by the virus. Delaying antiviral treatment could rob it of its
benefit.

       The reports cited above and other anecdotal accounts are
nonetheless cause enough to investigate foscarnet. And even if the
proposed mechanism of action turns out to be nonsense, there may be
other ways that this drug could have an effect, perhaps simply
through foscarnet's anti-HIV activity.

       For several months, Dr. Friedman-Kien has wanted to launch a
formal study of the drug in patients with early KS at the NYU
AIDS-Related Malignancy Clinic. He received approval from his
Institutional Review Board back in December, but he only just
received drug the first week of July. The hold-up? It took him
considerable time to convince Astra Pharmaceuticals in Sweden that
the study was worth running. Also, the FDA gave the him approval
only fairly recently.

       The study will be an open label trial for 25 people with
early KS, who seem to have the most chance of benefiting from
antiviral treatment. Trial participants will receive the standard
loading dose of foscarnet, (180 mg/kg in two divided doses -- twice
a day -- for fourteen days) in three two-week cycles separated by
two weeks off drug. Patients will be administered with treatment at
home, and all blood will be drawn in the home. Patients will need to
go into the clinic for baseline check-ups. Recruitment has already
begun (anyone interested should call Clare Kenny or Lorrie Jondreau
at 212/263-5244). If the trial goes well, a multicenter study
(probably placebo-controlled) will follow.

              1 Rady et al. Lancet. 345(8961);1339-40, May 27, 1995.

              2 Morfeldt L and Torssander J. Scandinavian Journal of
       Infectious Diseases. 26:749-52, 1994.

       3 Jones JL et al. Science. 267:1088-1089, February 24, 1995.

       *********************************************
       X-Rays for Monitoring Opportunistic Infection
       by David Pieribone, R.T.

       Regular diagnostic x-ray exams as well as specialized x-ray
procedures are routinely used in the diagnosis of secondary
infections and cancers associated with HIV infection. These
exams can give a physician a great deal of information about
a patient's condition, information that in many cases could
only be obtained otherwise with increased risk.
Some people worry about the harmful effects of x-ray
radiation, but the need for accurate diagnosis generally
outweighs the minimal risk of inducing cancer or damaging the
immune system. Modern x-ray technology provides detailed
images of the body while exposing the person to a relatively
small amount of radiation.

       Understanding what an x-ray exam entails and what, if any,
steps a patient should accomplish before or after an exam can
make the exam a success or a failure. While not much patient
preparation is necessary for a routine chest x-ray, a
gastrointestinal (GI) x-ray exam or a computed tomography (CT
scan) can be a complicated procedure.

       Gastrointestinal Exams

       X-ray examinations of the gastrointestinal (GI) tract are
used in the diagnosis of a number of complications associated
with HIV and AIDS. There are three basic GI tract exams: the
upper GI exam focusing on the esophagus and stomach, the
lower GI exam used for the small intestine and the barium
enema exam, which is used for the examination of the large
intestine or colon.

       All GI exams require the use of a contrast agent. A contrast
agent blocks x-rays and thereby silhouettes (outlines) the
body parts of interest, allowing their visualization.
Contrast agents used for the GI tract are usually composed of
a barium sulfate liquid suspension, but iodine and non-iodine
based contrast agents are also used. The barium mixture has a
thick milky consistency and is either swallowed or introduced
into the rectum by an enema while the x-rays are taken.

       The contrast agent and not the x-rays generally cause the
complications arising from the exam. Because constipation can
occur with barium sulfate, patients need to drink plenty of
water after the exam and if conditions allow, they should
increase the amount of fiber in their diet for the next
several days. Stools will be white or very light-colored
until all the barium is expelled. Some physicians will
prescribe a laxative to promote bowel movement. A dose of
mineral oil can help propel the barium through the bowels.

       A physician should be notified immediately if a bowel
movement does not occur within 24 hours after the exam or
there is any of the following: rectal bleeding, faintness,
weakness, abdominal pain, inability to pass gas, polyuria
(excessive urination), nocturia (excessive urination at
night) or abdominal distention (extension of the abdomen with
pressure). In rare instances, barium contrast agents can
obstruct the intestines. This blockage can be life
threatening if not caught in time.

       Upper GI Exams

       An upper GI exam, also known as a barium swallow, aids in the
diagnosis of candidiasis, herpes, cytomegalovirus (CMV) and
Mycobacterium avium complex (MAC) infections of the
esophagus. An upper GI exam can also detect ulcerations of the
stomach and other gastric (stomach) problems as well as Kaposi's
sarcoma (KS) of the throat and stomach.

       Individuals undergoing an upper GI exam should have nothing
to eat for the eight hours prior to the examination. Smoking and
chewing gum before the exam is discouraged because they stimulate
stomach secretions that can dilute the contrast agent. Most
medications are also restricted for eight hours prior to the
examination, but always consult with a doctor before stopping or
altering a medication regime. An upper GI exam requires that
patients drink the contrast agent (barium sulfate) while the x-rays
are taken. Often a second contrast agent, usually granulated like
Alka-seltzer, is added. These secondary agents are quickly swallowed
and produce a gas (carbon dioxide), which allows the radiologist to
better visualize the mucosal surface of the throat and stomach. When
both liquid and gas contrast agents are used, the procedure is
called a double contrast exam.

       Lower GI Exams

       A small bowel exam is used to visualize the small intestine.
This exam is generally combined with an upper GI exam but can be
done alone. It is needed for diagnosing CMV, Cryptosporidium, and
MAC infections as well as intestinal KS and lymphoma. As with the
upper GI exam, the patient drinks a contrast agent.

       A barium enema is used for x-ray images of the large
intestine, which are needed for detecting CMV colitis, aphthous
ulcers, and KS. Careful preparation is necessary for a barium enema.
If time allows, patients should eat foods low in residue for several
days prior to the exam. A low residue diet excludes fresh fruits,
and vegetables, fatty and fried foods, whole grain cereals and
breads. Increasing fluid intake for two to three days prior to the
exam also is recommended. This helps clear the large intestine of
waste before the examination.

       Twenty-four hours before the examination, a clear liquid diet
should be consumed. Clear liquids include coffee or tea with sugar
but no milk, clear gelatin, clear broth, and carbonated beverages.
The afternoon before the barium enema, a laxative is prescribed --
the type and amount governed by the patient's condition. A cleansing
enema is usually prescribed to remove any additional residue on
night or the morning before the exam. A barium enema exam will be
canceled if the lower bowel is not properly cleaned.

       The barium sulfate is given via an enema. The mixture is
administered through a tube placed in the rectum. Taking in short
breaths while the tip is being inserted will be more comfortable.
The exam can last up to 45 minutes and requires the patient to
assume a number of different positions while lying on the x-ray
table. Patients cannot evacuate their bowels (go to the bathroom)
during the exam period. It is often routine, though, to have a final
x-ray taken after the patient goes to the bathroom and evacuates as
much of the barium as possible.

       Because x-ray exam procedures vary from institution to
institution and from patient to patient, patients should ask their
doctors for specific instructions.

       CT Scan

       A CT scan is actually many x-ray images taken in rapid
succession. Each image is a thin slice very much like the way you
would slice a loaf of bread. Unlike standard x-ray machines, a CT
scan requires the patient to lie on a bed that is moved in and out
of a gantry with a hole in the center as the x-rays are being taken.
CT scan images provide a high degree of accuracy and detail not
obtained with traditional x-ray techniques.

       CT scans are used more and more to aid in a better diagnosis
of tuberculosis (TB), pneumocystis carinii pneumonia (PCP),
infections of the brain and spinal cord (i.e., encephalitis,
toxoplasmosis, meningitis and progressive multifocal
leukoencephalopathy (PML). CT scans are also used to guide needle
biopsies, allowing the doctor to accurately position the needle at
the desired site.

       Breathing in the course of some types of scans is very
critical, and the radiographer will instruct the patient when to
breathe.

       As with other special x-ray exams, contrast agents may be
used in CT scanning. The contrast agents normally used contain
iodine, though more expensive non-iodinated contrast agents are
available. The contrast agent is administered by way of an
intravenous (IV) drip but can be taken orally as in GI exams.
Special contrast CT scans involve the automatic intravenous
injection of contrast agent that is activated as the scan begins.

       Contrast Reactions

       Allergic reaction is a major consideration when using any
contrast agent. Allergic reactions are rare and usually consist of
mild itching, rash, hives and sometimes nausea. But reactions can be
severe enough to cause death if not caught in time.

       Patients should tell the radiographer (person performing the
x-ray exam) immediately if they feel sudden itching, see a rash
developing or experience any trouble breathing. Contrast reactions
happen more often with IV administered contrast. It is very
important that patients who have a history of asthma or have
allergies to seafood (which also contain iodine) or previous
contrast agents inform the doctor or radiographer of this before the
exam. The administration of drugs such as benadryl or epinephrine
are used to control allergic reactions. These drugs can be given
prophylactically (to prevent the reactions from arising) in persons
with known allergies to contrast agents.

       Special Note for Women

       Because x-radiation can be dangerous to a fetus, women should
tell their radiographers or doctors if they even suspect that they
are pregnant. If it does not interfere with the exam, shielding
should be provided, usually in the form of a lead apron.

       References

       Radiology of AIDS, Michael P. Federle, Alec J. Megibow, David
P. Naidich. Raven Press, New York 1988.

       Basic Medical Techniques and Patient Care for Radiographers,
Lillian S. Torres, J.B. Lippincott Company, Philadelphia 1989.

       ****************
       Washington Watch
       by Rich Lynn

       Reviewing the Research Agenda

       Until 1993, the federal government's AIDS research monies
were allocated to the various institutes making up the
National Institutes of Health (NIH). The institutes then
dispersed the money to programs of their choice. Many
community activists and even the National Academy of Science
called for more coordination. At the urging of a coalition of
AIDS organizations and researchers, the Congress overhauled
the way the NIH managed its AIDS research programs in the NIH
Revitalization Act of 1993. This legislation gave budgetary
and coordination authority for all NIH AIDS spending to the
Office of AIDS Research (OAR) at the NIH.

       Congress also mandated that the OAR conduct a comprehensive
review of the NIH's AIDS research programs to help determine the
Institutes' AIDS priorities. As this review was to be the
government's first overall analysis of the NIH's AIDS efforts, the
recommendations of the review committee were expected to have
far-reaching effects.

       The OAR was forced to spend most of its early months fighting
for staff positions and asserting its power with entrenched NIH
bureaucrats who resented the OAR's new role. The review finally
started this spring in preparation for the planning for fiscal year
1998 that will occur next year. The OAR was given no power over
funds that had already been committed, so the OAR only gains control
of funds when existing commitments expire. Since most grant and
contract awards last for multiple years, the first year in which the
OAR will control a substantial amount of funds is fiscal year 1998.
(The director of the OAR does have a modest discretionary budget
that he can use to fill in gaps identified by the review before
1998.)

       The OAR divided the work of the review amongst an oversight
and coordinating committee called the Evaluation Working Group and
six Area Review Panels. The panels have each been assigned one of
the following areas: 1) Drug Discovery, 2) Etiology and
Pathogenesis, 3) Natural History, Epidemiology and Prevention, 4)
Behavioral, Social Science and Prevention, 5) Vaccine Research and
Development, and 6) Clinical Trials. Each panel contains fifteen to
twenty members, with each member expected to devote a substantial
amount of time to the panel's work.

       Members of the panels include activists and community
representatives (this writer among them) in addition to prominent
researchers and industry representatives. There are some vocal
critics of government programs, too -- scientists who supported NIH
reform at a time when it was professionally risky for them to do so.
In addition, younger researchers are represented on the panels. Such
researchers would benefit the most from an intelligent, sweeping
redesign of government AIDS research.

       Most of the area review panels have met at least twice. The
panelists have grappled with two issues in these early meetings:
what is the true mission of this committee and how are we going to
find the information we need to do our work? None of the scientists
had ever participated in an effort of this kind before. All the
participants have reviewed grant proposals or another's research and
some have even analyzed a department or a major program, but none
have been asked to dissect a billion dollar endeavor.

       Members of the committees are clearly intimidated by the
scope of their mandate. Uncovering which programs and
personnel are successful and which are failures or merely
redundant, and determining how to establish new programs and
attract new, more insightful investigators threatens to upset
well-established fiefdoms. Among these is the large in-house
effort at the National Cancer Institute's own laboratories,
which consumes one-tenth of the national AIDS research
budget.

       Participants have discussed the temptation to focus on
specific grants instead of the bigger picture. The purpose of
the review is not to critique individual research, but to
decide if suitable research is progressing in the right
areas. They must decide what mechanisms are needed to insure
that such research does get done. Without a set of mechanisms
for keeping research priorities and funding mechanisms
current, AIDS research will ossify as researchers compete
with each other to answer the same questions over and over.

       Still, nothing will happen if the committees have
insufficient information. Unfortunately, obtaining data from
the NIH is a logistical nightmare. All of the NIH's policies,
procedures and information systems have been designed to
support an arcane budgeting process, not to assist anyone
actually trying to analyze NIH spending. As one member of my
panel stated, "Government budgeting and accounting systems
are designed to provide reports that are crystal clear and
completely wrong."

       The majority of institutes can provide a summary of their
total spending and not much more. Congressional mandates have
made the situation with AIDS marginally better. We can obtain
listings of all grants in the area of AIDS research. But
these reports only include the title of an application, the
amount, the area of research and in some cases, the abstract
that accompanied the investigator's original application.

       As investigators realize that their abstracts will be a
matter of public record, they become extremely vague so as
not to provide competing scientists with specifics of their
research. Some of the abstracts are so unspecific, that it is
not even apparent how the proposed research relates to AIDS.

       Nonetheless, the starting material for all the committees
consisted of intimidating stacks of printouts of these grant
abstracts as well as some program summaries and requests that
were used to solicit applications. It took the NIH staff two
months to disgorge this disjointed muddle. Conspicuously
absent from the stack were investigator progress reports, the
specific objectives section from investigator applications,
and information about grants that went unfunded. Such
information would have provided a clearer sense of what the
NIH's priorities have been over the past years. But providing
information on individual projects would violate the
confidentiality of the grant review process, says the NIH,
which has deemed that data beyond the scope of the review.
Instead, the review panelists will be allowed only to
interview the various NIH officials who coordinate grant
reviews and funding initiatives. Having to resort to this roundabout
strategy will lengthen and complicate the review. If the program
officers turn out to be forthcoming, though, it may be more helpful
than trying to sort through piles of uncategorized information.

       The review will only be as good as the information available
to work with. And besides the challenge of finding the relevant
information, panelists will have to devise new ways to organize and
measure what they expose to enable them to reach some reasonable
conclusions. Many committees will find it difficult just to connect
specific initiatives with specific results. For example, the drug
discovery panel must determine the effectiveness of the NIH's drug
discovery programs when there is no clear way to figure out which
compounds were discovered with NIH resources.

       The obstacles to an effective review are formidable and many
in the research and activist communities have been quick to
criticize the review of research projects. Indeed, in its current
understaffed state, the OAR has not been able to move as quickly as
its supporters had hoped. But perpetually sniping at the OAR and its
review effort plays right into the hands of the right-wingers in
Congress who would just as soon strip the OAR of its power and then
defund AIDS research entirely as the institute heads bicker among
themselves. Our best defense against this onslaught is a coherent
plan that would lay out the research, drug discovery and prevention
efforts that must proceed for a cure to be found.

       The OAR review must produce this strategy for AIDS research
to continue. Without a strategy for researchers and our remaining
allies in Congress to rally around, it will be impossible to protect
AIDS research -- particularly if we are faced with a Republican
president as well as Republican Congress after 1996.

       Alert -- AIDS Research Budget in Danger!

       On July 11, the House of Representative's Subcommittee of
Appropriations for Labor, Health and Human Services took steps to
eliminate the OAR's authority to direct the NIH's AIDS research
budget. More importantly, the committee removed the budgetary
requirement that the NIH allocate a certain amount of its funds to
AIDS research.

       As Treatment Issues went to press, this measure had been
approved by the full House Appropriations Committee, but not the
House floor or the Senate, and its future is uncertain. The fact
that it has gotten this far, though, underscores the importance of
the need for strong leadership from the OAR to create a cohesive and
respected AIDS research agenda. The review process mentioned on
these pages is central to this effort. -- TS

       *************************************************
       CDC Recommends HIV Testing for All Pregnant Women
       by Dave Gilden

       On July 7, the Centers for Disease Control and Prevention
(CDC) issued new guidelines urging "voluntary" HIV testing
for all pregnant women. The agency report stated, "Because
specific services must be offered to HIV-infected women to
prevent perinatal transmission, PHS [the Public Health Service] is
recommending routine HIV counseling and voluntary testing of all
pregnant women so that interventions to improve the woman's health
and the health of her infant can be offered in a timely and
effective manner."

       Several factors have contributed to the CDC announcement.
Most immediately, several states and Congress are considering
proposals to institute mandatory HIV testing of all newborn babies.
At Treatment Issues' press time, the House Commerce Committee had
just defeated one attempt to impose such testing, the Coburn
amendment to the Ryan White CARE Act (which provides funding for
AIDS services). Nonetheless, some measure mandating HIV testing of
all infants seems likely to pass Congress this year.

       Testing of newborns is in reality testing of mothers: The
usual HIV test checks for antibodies against HIV, not the virus
itself. Babies carry their mothers' antibodies for up to eighteen
months. Although all babies born to HIV-positive mothers test
HIV-positive themselves, only about a quarter of them have actually
contracted the virus from their mothers. The CDC estimates that
7,000 HIV-infected U.S. women give birth annually, resulting in one
to two thousand babies with HIV. Based on scattered studies, the
agency also estimates that under the old 1985 guidelines, which
promulgated a testing strategy that targeted women who report high
risk behaviors, half or more of the HIV-positive pregnant women were
never identified.

       Until recently, more comprehensive testing of expectant
mothers would not have had much of an impact on the number or health
of babies with HIV. But the results of ACTG 076, a trial using AZT
during pregnancy and in the early weeks of a baby's life to impede
HIV transmission from mother to child, have wrought a sharp change
in official attitudes. The 076 regimen achieved a two-thirds
reduction in such "vertical" transmission. (See Treatment Issues,
March, 1994, pages 15- 16.)

       According to Martha Rogers, M.D., chief of the epidemiology
branch of the CDC's Division of HIV/AIDS Prevention and main author
of the testing guidelines, "The guidelines were sparked by the AZT
trial, which increased the need to test women who don't know their
HIV status before pregnancy." There are many limitations to the 076
study. Among them are: the women tested were relatively healthy
(half had CD4 counts over 500) and had not had extensive prior AZT
therapy; it is unclear what phase of the AZT treatment was effective
-- the capsules during the last two-thirds of pregnancy, the
intravenous AZT during labor or the syrup given to the baby for six
weeks after birth; and the treatment's long-term effects on the
children (including birth defects, cancer, damage to muscle and
heart tissue) will not be known definitively for several decades.

       Besides, there are several other potential treatments that
are probably safer and may be more effective. The wide range of
possibilities include the anti-HIV drug nevirapine, HIVIG
(concentrated HIV antibodies extracted from other people), vitamin
A, and vaginal cleansing (lavage) just prior to birth. There also
are studies suggesting that only women with relatively high HIV
levels transmit the virus to their babies. (See Treatment Issues,
March 1995, pages 2-3.)

       Pregnant women with high viral loads may be the only ones in
need of therapy to prevent transmission. Excessive use of AZT
increases the likelihood of needlessly breeding AZT-resistant virus,
making the drug useless to women when they might need it later on to
ameliorate their own medical condition.

       These lingering questions did not stop the CDC from issuing a
set of guidelines last August that strongly favored following the
076 therapy schedule as much as possible in all women with HIV.
Defending the AZT guidelines, Dr. Rogers of the CDC said, "AZT is
what we have right now. Other things are not proven, but sound
scientific study shows that women with the trial characteristics
were benefited by AZT. The AZT guidelines make clear that our
information is limited and that counseling should make clear the
risks and benefits." Changes in the standards for care for babies
exposed to HIV have also increased the urgency around the testing
issue.

       On April 23, the CDC issued a revised set of guidelines for
prevention of Pneumocystis carinii pneumonia (PCP) in infants
"exposed" to HIV. Citing the tendency for babies with HIV to
suddenly develop catastrophic cases of PCP accompanied by
precipitous drops in CD4 count, the CDC wants pediatricians to
institute PCP prophylaxis, primarily with Bactrim, in all infants
six weeks to a year old who are born to HIV-positive mothers and in
whom HIV infection cannot yet be excluded. Advances in testing
technology have made the PCP prophylaxis guidelines more practical
by making it easier to determine which babies really have HIV. This
fall, the Hoffmann-La Roche drug company plans to seek FDA approval
for using its diagnostic polymerase chain reaction (PCR) test in
newborns.

       The PCR test is a very sensitive one that directly detects
HIV, not antibodies. Still, it is not very accurate until the baby
is one month old. It is also rather expensive (about $200 per test).
For the purposes of ending needless PCP prophylaxis, the CDC
recommends performing two PCR tests on the baby, at one month and
four months. If both are negative, the baby is considered
uninfected.

       The three-part AZT therapy, the PCR tests, the Bactrim: this
all amounts to a complicated medical regimen with high
potential for side effects that require further medical management.
This is the reason why the testing should be voluntary, asserts Dr.
Rogers. "The women enter into a whole process for better health of
mother and baby. Women want what's best for the baby, but if you
take a mandatory approach, you set the wrong atmosphere," Dr. Rogers
said.

       Perhaps, though, the wrong atmosphere is already set by
focusing on women as carriers of babies. It is best to know that you
have HIV as soon as possible, regardless of whether you are pregnant
or not. Pregnancy, with all its other stresses, is a bad time to
find out you are HIV-positive, points out Marion Banzhaf, director
of the New Jersey Women's AIDS Network. "The shock and denial have a
particularly negative impact then," she observed.

       The obstetrics establishment is not known for its patience
with pregnant women. It is noteworthy that one of the biggest
proponents of mandatory infant testing on Capitol Hill, newly
elected Rep. Tom Coburn (R-OK) is an obstetrician by profession.

       If the health care system's entire approach to the HIV
testing issue is set up out of concern for the babies and not the
mothers, Banzhaf warned, "The pressure will build an antagonism into
the mother-child relationship. Women want to do what's best for
their babies, but this becomes an issue of state control of
reproduction."

       Many women will find reasons to reject the 076 regimen. All
pregnant women with HIV will be urged to follow the course of AZT
treatments even though it will make a difference in outcome in only
one out of six babies. The doubts about the treatment's safety have
yet to be resolved. And AZT's side effects, such as nausea, fatigue,
weakness and anemia, are likely to be especially intolerable to
someone already enduring the effects of pregnancy.

       If women reject their care providers' advice at any point,
they will find out how voluntary the system is. The HIV Law Project
in New York City says that it already has two clients whose doctors
reported them to child welfare authorities when they refused to give
AZT to their infants.

       The CDC advocates training medical professionals to be able
to counsel women in a more supportive and sensitive manner, although
the effectiveness of such training has yet to be established. Now
comes Congress (and several the state legislatures) trying to force
testing of babies whose mothers refuse HIV testing before their
birth. For women with HIV, such measures add to the threat of
coercive medical care without providing any protection at all
against abuse of power by medical practitioners.        

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