ddodell@stjhmc.fidonet.org (David Dodell) (08/11/90)
AIDS TREATMENT NEWS Issue #108, August 3, 1990
Mycoplasma: CRI Plans Doxycycline Treatment Study
New Law Would Allow Property Seizure for "Health Fraud";
Hearing August 7
Sixth International Conference, Part III: Toxoplasmosis
Sixth International Conference: Treatment of CMV Infections
CPFs: Researchers Design New Anti-HIV Compounds
Announcements:
ACT UP/New York Treatment and Data Digest; Quan Yin
Herbal Program; CONTINUUM; Research Nurses Needed
Mycoplasma: CRI Plans Doxycycline Treatment Study
by John S. James
New York's Community Research Initiative (CRI), one of the
pioneers of community-based AIDS research, is developing a trial
to see whether the antibiotic doxycycline can help certain
patients with an ARC diagnosis -- and whether a blood test for
mycoplasma infection can predict who might benefit. This trial
will test the hypothesis of Luc Montagnier, M. D. -- one of the
discoverers of the AIDS virus -- that mycoplasma infection might
be an important cofactor in the development of AIDS.
Background
Mycoplasmas are organisms between viruses and bacteria in
complexity. They are known to cause some human diseases, and
they can be controlled with certain antibiotics. During the last
several years, Shyh-Ching Lo, M. D., and other researchers at the
U. S. Armed Forces Institute of Pathology found a mycoplasma
which appeared to be a previously unknown species in organs of 22
of 34 persons who had died of AIDS, and reported evidence that
this mycoplasma may be causing organ failures. (For more
information on this work, see AIDS TREATMENT NEWS #95, January
19, 1990.) In laboratory tests, the antibiotics most active
against this mycoplasma appear to be doxycycline and
ciprofloxicin (see Lo, SC and others, Sixth International
Conference, abstract #Th.B. 536).
At a special meeting organized at the Sixth International
Conference on AIDS last month in San Francisco, Dr. Montagnier
reported laboratory studies supporting a hypothesis that
mycoplasma might be a major cofactor in the development of AIDS
-- not just an opportunistic infection. His team found
mycoplasma in the blood of about one third of AIDS patients; the
organisms are hard to detect, so they may be present in others,
too.
Also, the researchers found that antibiotics which inhibited
the mycoplasma prevented HIV from killing cells in the
laboratory, although the drugs did not affect HIV directly. Dr.
Montagnier speculated that HIV might become more destructive
later in the disease than early after infection, because of later
mycoplasma infection. An abstract by Dr. Montagnier and others
(#1072, accepted for publication-only at the Conference, without
a talk or a poster presentation) reported that doxycycline
protected cells against destruction by HIV, even though the virus
continued to multiply within the already-infected cells. HIV
cultures treated with tetracycline lost their ability to kill
cells even after the tetracycline was removed, suggesting that a
tetracycline-susceptible contaminant in the culture (probably a
mycoplasma) enabled the HIV to kill the cells.
Dr. Montagnier has given high priority to further
investigation of the possible role of mycoplasma in AIDS, and has
assigned 15 people, half of his unit, to work on it.
For more information on this research, see the interview
with Dr. Montagnier by Martin Delaney of Project Inform,
published in The Advocate, July 3, 1990.
The CRI Study
The treatment study now being planned by the Community
Research Initiative will randomize 150 patients with an ARC
diagnosis to one of three daily doses of doxycycline: 50, 100,
or 200 mg twice a day. Researchers will monitor patients'
clinical status and do the usual blood work; in addition, a
special laboratory will test blood samples for mycoplasma, at
baseline and at three-month intervals. Because clinical
evaluations can be subjective, the mycoplasma test results will
be blinded; a Data Safety Monitoring Board will examine the
unblinded data after six months, in order to halt the study if
the results are dramatic enough to justify that step.
The CRI has raised about half of the $300,000 required for
this study; it wants to have at least two thirds of the funding
before beginning, to assure that the trial can be completed.
Doxycycline is a generic drug, as its patent has expired;
therefore pharmaceutical companies have no incentive to fund
research. Federal agencies are not yet ready to conduct a
treatment trial for mycoplasma, although they may do a prevalence
study by analyzing blood and tissue samples.
This CRI study is important for several reasons:
* Even before mycoplasma became an issue, some physicians
have prescribed doxycycline empirically for people with HIV who
had unknown illnesses. The rationale is that many people with
AIDS have opportunistic infections which have not been diagnosed
(as has been shown by autopsy studies); doxycycline is fairly
safe, and effective against many disease-causing organisms, so it
could be worth trying when attempts to diagnose a problem have
failed. The doxycycline trial will provide the best available
data to guide empirical use of the antibiotic by persons with HIV
-- whether or not mycoplasma is important.
* The study will test Dr. Montagnier's hypothesis that
mycoplasma infection may be a major cofactor in AIDS. It will
show whether the available mycoplasma blood test is helpful in
guiding the use of doxycycline, and whether testing for
mycoplasma has prognostic value.
* Doxycycline is readily available, very well known in human
use, and inexpensive. Therefore if the study does find a
positive result, it could have rapid impact on AIDS treatment in
the United States and elsewhere.
If you can help in the fundraising or otherwise in the
development of this study, call Bernard Bihari, M. D., Executive
Director, Community Research Initiative, 212/481-1050.
New Law Would Allow Property Seizure for "Health Fraud"; Hearing
August 7
by John S. James
A bill to expand "war on drugs" property seizure to cases
involving unapproved medical treatments has passed the California
State Senate, and could soon become law. The last chance for
public input may be early next week. While this law would only
affect California, it has national importance because other state
legislatures often follow California's example, and because of
the extensive medical research conducted here.
The proposed law, SB 2872, would allow seizure and
forfeiture proceedings against property -- including entire
companies -- in some cases even before conviction of a crime.
After expenses were paid, proceeds would be split 50-50 between
State and local prosecutors -- financing more health-fraud
investigations, and creating an organizational incentive for
prosecution against unapproved medical treatment, apart from any
public-policy objective.
Arguments For and Against
SB 2872 was introduced by Senator Marian Bergeson at the
request of the California Department of Health Services. The
initiative did not come from industry, the professions, or the
public; in fact, as late as April 17, when the bill was
considered by a Senate committee, not one person or organization
had contacted the legislature to support it.
By July 27, there were three supporters: the American
Cancer Society, the American Council on Science and Health, and
the Cancer Advisory Council of the State Department of Health
Services. The American Cancer Society could only give us its 91-
word letter to the legislature. This letter does not address the
merits of this particular bill, and shows no evidence that anyone
in the organization examined the bill's specifics.
The American Council on Science and Health could give us
even less. Its president was on vacation, and no one in the
office knew that the organization had taken any such position.
The short letter from the Cancer Advisory Council said that
the bill had been discussed briefly at its last meeting, and it
did give an argument in support. It praised California's
existing laws against unorthodox cancer treatment, but said that
"funding is not readily available for enforcement activities, and
thus some of our very effective laws tend to have a hollow ring
to them. The Bergeson Bill will help to rectify this."
As of July 27, two organizations were listed as opposing the
bill: the pharmaceutical company Genentech, Inc., and the
California Attorneys for Criminal Justice. The two and a half
page letter from Genentech's lawyers did provide a detailed
critique:
"Under the provisions of SB 2872, a pharmaceutical company
such as Genentech could have its entire manufacturing and
research facility seized and made subject to forfeiture
proceedings, even if a conviction has not yet been won. In
addition, the bill allows for the entire forfeiture of a
company's facility if intent is proven in even minor violations
of the instances enumerated in Division 21."
Division 21 (of the Health and Safety Code) covers "no fewer
than thirty activities which may be violated," Genentech's letter
explained. "The following list is just a sampling of those
activities which, if violated, would cause a pharmaceutical
company operating in California to become subject to forfeiture
proceedings," if there was a second violation, or any violation
"with intent to defraud or mislead." The list of 14 items
summarized in the letter mostly concerned drug labeling
deficiencies, prescribing or administering an experimental drug
in violation of State requirements, claiming that a new drug is
effective, or failing to maintain adequate records. A company
could also be seized if a product label failed to carry a warning
message required by California's Proposition 65. Inadequate
filing of paperwork with the State could also lead to a company's
seizure.
Another problem mentioned by the letter is that it is common
practice for a pharmaceutical company to make claims for a drug
which may later be contested by the FDA, based on a different
interpretation of the data. In such a case, SB 2872 would allow
the State to "arrest an appropriate company employee and thus
cease the operations of the company until the FDA matter is
settled."
The other letter opposed to SB 2872, from the California
Attorneys for Criminal Justice, said that the current forfeiture
law, in effect now for about one year, was "the result of careful
and lengthy negotiations by all parties and interests concerned.
It was generally agreed that the new law would be in effect for a
period of five years, at which time it could be closely evaluated
before it was expanded to other areas or eliminated."
An April 17 legislative analysis by the Senate Committee on
Judiciary pointed to other possible problems:
* Bounties could cause district attorneys to unduly
emphasize crimes which provide financing to their offices, to the
neglect of other serious crimes, such as rape, which do not.
* Increased prosecutions due to bounties could strain
courts, jails, or other parts of the criminal-justice system.
* Expenses could be recovered from persons not convicted of
or even charged with any crime. And the debt for such expenses,
unlike other debts, could not be discharged in bankruptcy.
Comment
Our concern is that funding law-enforcement agencies through
seizure of property could lead to enforcement actions conducted
primarily for generation of revenue, reducing patients' treatment
options and slowing the pace of research. People may believe it
is impossible that a major company like Genentech, capitalized at
four billion dollars, could be seized and sold as a result of
minor or technical law violations. But SB 2872 creates strong
incentives for prosecutors to build their budgets by seizing
assets. This kind of bounty hunting happens routinely in the
"war against drugs"; under SB 2872, it could happen in
pharmaceuticals, too, threatening California's industry and its
leadership in research.
Options for medical care not explicitly approved by the FDA
would be at even greater risk. California's existing laws
against unorthodox treatment acknowledge no right of patients to
make their own choices. Advertising that any kind of non-
approved treatment has any effect on AIDS or ARC is illegal; the
fact that the claim is true, and the person making it can prove
it, is legally irrelevant. Other laws allow astronomical fines
for even minor violations. SB 2872 would provide incentives for
prosecutions which could reduce accepted treatment for AIDS to
little more than giving patients AZT until they die.
Until recently, U. S. law has minimized seizure of property
as a way to fund prosecution. Historical examples show the
danger of creating such monetary incentives for prosecution which
otherwise would not need to occur. In the Middle Ages,
witchcraft trials became prevalent only in countries which
allowed seizure of property, which could be shared by religious
authorities, civil authorities, and accusers. Generation of
revenue -- not popular hysteria, as commonly assumed -- was the
real engine of the witch-hunts. So much property was transferred
in this way that after a century of the trials, one inquisitor
lamented that there were "no more rich heretics," and therefore
the future of his office was in doubt.
No one can guarantee a monopoly on truth. Law enforcement
should compete for funding with other public priorities, not fund
itself through seizures to expand prosecution without regard to
real needs.
How to Be Heard
SB 2872 has already passed the California Senate.
Legislators do not have time for the details, but want to look
"tough on crime," and not be portrayed as supporting quack cures
and other health fraud. Few people knew about SB 2872 until it
was almost too late to affect it.
The last chance to address the substance of the bill may be
next week, at hearings scheduled August 7 in the Assembly
Committee on Public Safety. Comments must arrive by mail or fax
before then, and should be addressed to:
Assembly Member John Burton
Chair, Assembly Committee on Public Safety
State Capitol -- Room 2179
Sacramento, CA 95814
Organizations can also send someone to testify in person at
the hearing. Anyone planning to testify should call the
Committee on Public Safety in advance.
It is a courtesy to also notify the legislator who
introduced the bill of any opposition, so she can be prepared
before the hearing. Send a copy of the letter to: Senator
Marian Bergeson, Member, California State Legislature, State
Capitol, Sacramento, CA 95814.
Sixth International Conference, Part III: Toxoplasmosis
by Denny Smith
The Conference news on Toxoplasma gondii infections largely
consisted of refinements in diagnosis and a growing
acknowledgement of the value of prophylaxis for people at risk
for toxoplasmosis. Although the Conference published abstracts
of more than twenty studies of this infection, no truly new
therapies available for use were among them.
Jack S. Remington, M. D. of Stanford University presented
the Conference's oral session on toxoplasmosis management, and
opened his discussion by commenting on the low priority assigned
thus far to combatting this major problem. Following is a survey
of his remarks and selected studies from the Conference
abstracts.
Toxoplasmosis usually, but not exclusively, presents as
symptoms of encephalitis or neurologic difficulties. Computerized
tomography (CT) scans are often used to screen possible causes of
neurologic symptoms, but they are not always reliable for
distinguishing the lesions of Toxoplasma from those of lymphoma,
Kaposi's sarcoma, PML, CMV or herpes. Magnetic resonance imaging
(MRI) is more useful, and brain biopsy or aspiration the most
conclusive.
To avoid losing critical time until a diagnosis is
absolutely certain, treatment for cerebral masses is often
initiated under the presumption of toxoplasmosis; a good response
to the treatment becomes a marker for an accurate diagnosis. But
not every case responds, and meanwhile some other cause of the
symptoms may have progressed untreated. An example of lymphoma
misdiagnosed as toxoplasmosis was mentioned in AIDS TREATMENT
NEWS #104. A Conference abstract from Rio de Janeiro described
how an increase in the number of presumptive toxoplasmosis
diagnoses for cerebral masses was accompanied by an increase in
deaths of patients who did not respond to toxoplasmosis
treatment. The authors cite the need for better criteria for
presumptive diagnosis of this infection (abstract #2115, Sohler,
MP and others).
Dr. Remington pointed out that the retina, GI tract,
pancreas, heart and lungs have been reported as sites of
infection as well, so toxoplasmosis must be approached as a
possibly disseminated infection. He added that he and American
and French colleagues have developed better methods (differential
agglutination) of testing Toxoplasma titers, but they can only
wait for private industry to make these widely available.
A study from the University of Miami and New York University
reported four instances of congenital Toxoplasma infections in
infants born to mothers who were seropositive for both HIV and
toxoplasmosis (abstract #F. B. 476, Mastrucci, M and others).
This information could be helpful for pediatricians trying to
diagnose encephalitis in newborns, since two of the mothers in
the study had no history of active toxoplasmosis. The infants
were born with HIV as well.
The treatments discussed in the oral session included the
standard regimen combining pyrimethamine with sulfadiazine, as
well as agents under study: clindamycin, dapsone, doxycycline,
566C80, gamma interferon and a class of drugs called macrolide
antibiotics, which include roxithromycin, azithromycin,
spiramycin and clarithromycin. (An important note for
researchers regarded the importance of different strains of
Toxoplasma. Since this variable often determines the agents to
which the protozoa will be susceptible, a number of strains
should be subjected to a given compound, in research studies.)
When sulfa drugs cannot be tolerated, recent clinical
practice has been to replace sulfadiazine with clindamycin. Dr.
Remington said that the combination of clindamycin with
pyrimethamine is generally considered effective, but no evidence
yet proves it equal or superior to pyrimethamine with a
sulfonamide. IV clindamycin offers more data so far than oral
clindamycin.
Doxycycline, which has shown positive results against
Toxoplasma in animal data, did not control toxoplasmic
encephalitis in humans, according to doctors at Elmhurst Hospital
Center in New York. Their abstract was a chart review of six
patients who had shown intolerance to treatment with sulfadiazine
and pyrimethamine, and who were then given doxycycline for at
least one month. Five of the six experienced a return of lesions
during therapy. Three of those five responded to retreatment
with the standard drugs (abstract #TH. B. 479, Turett, G and
others). We were hoping for more success with doxycycline,
perhaps in some combination therapy if not by itself, for people
who cannot continue with sulfadiazine. A related study from
Sidney described the successful desensitization to sulfadiazine
in some people known to have sulfa allergies by giving gradually
increasing increments of the drug over several days. Of sixteen
patients with toxoplasmosis, ten were reported to be desensitized
(abstract #TH. B. 480, Tenant-Flowers, M and others).
Of the macrolide antibiotics, azithromycin looks the best in
mice studies. To control Toxoplasma, a drug must reach
significant concentrations in body tissues and not just blood.
Azithromycin is exceptionally effective in this regard. Dr.
Remington pointed out that azithromycin's strong potential as a
toxoplasmosis therapy has been common knowledge for over two
years, and not a single controlled human trial of the drug has
yet been conducted.
566C80 is a new agent from Burroughs-Wellcome with strong
activity against Toxoplasma, perhaps including the capacity to
kill the parasite's cysts. This compound is also under study to
treat Pneumocystis infections. Clinical studies of this drug are
planned by the NIH.
Gamma interferon, which is probably the body's prime natural
defense against Toxoplasma, has been shown to have additive or
synergistic effect with some antibiotics -- namely clindamycin,
roxithromycin and pyrimethamine. (On the other hand, AZT may
block the activity of pyrimethamine in mice, underscoring the
need for access to more than one anti-HIV drug for people
requiring treatments for opportunistic infections.) ACTG trials
of gamma interferon to treat toxoplasmosis are being developed.
An abstract from the University of Genoa described Septra as
an effective alternative to pyrimethamine and sulfadiazine for
treating toxoplasmosis (abstract Th.B. 477, Canessa, A and
others).
Trimetrexate, under investigation to treat Pneumocystis
infections, also has strong in vitro activity against Toxoplasma.
Authors of a Belgian abstract emphasized the importance of
environmental precautions for people who are HIV+ but who test
negative for toxoplasmosis. They advise their patients to avoid
gardening, exposure to cat feces, and eating raw meat or uncooked
vegetables (abstract F. B. 426, Liesnard, C and others). People
whose blood tests show evidence of a latent Toxoplasma infection
could of course also benefit from those precautions, as well as
the use of some preventive therapy to thwart a reactivation. Dr.
Remington mentioned that there are no data solidly supporting a
particular toxoplasmosis prophylaxis.
But recently, Septra, clindamycin and pyrimethamine have
been suggested as candidates for clinical prophylaxis trials. A
study from Spain described success with Fansidar in lowering the
incidence of toxoplasmosis (abstract #2116, Iribarren, JA and
others). Fansidar may have unacceptable risks, however, since it
has been linked to some fatal allergic reactions. Another chart
review at Elmhurst Hospital found that patients who were taking a
double-strength tablet of trimethoprim-sulfamethoxazole (Septra
or Bactrim) twice a day to prevent Pneumocystis pneumonia
experienced a lower incidence of toxoplasmosis than patients on
aerosol pentamidine (abstract Th.B. 482, Nicholas, P and others).
After an episode of toxoplasmosis is treated, some
suppressive therapy must be continued since no drug tested in
humans has been able to kill the oocysts (resting forms of the
organism) which can produce live parasites again in people with
compromised immunity. Researchers in Barcelona have found that
pulse-dosing, or intermittent maintenance treatment, of
pyrimethamine and sulfadiazine twice a week effectively prevented
relapses of active infections in fifteen patients. (A similar
finding was presented last year at the Montreal conference).
This could help many people who cannot tolerate the toxicity of
daily dosing. However, other experts have cautioned that the
half-life of pyrimethamine can vary from person to person, so
pulse-dosing may be reliable for persons whose bodies retain such
a drug long enough, and not for others. Incidentally, in the
comparison groups of the study's participants who could be
followed, fifteen patients decided, against medical advice, to
not continue with any maintenance therapy. Eight of those
developed a relapse of toxoplasmosis between two to fifteen
months after their first episode. Ten other participants tried
intermittent treatments of pyrimethamine with clindamycin,
instead of sulfadiazine. Unfortunately, four of them experienced
a relapse after two to nine months (abstract TH. B. 483,
Gonzalez-Clemente, JM and others).
In spite of the good efforts and intentions evident in all
of these studies, people are still dying of toxoplasmosis.
Survival is better with early diagnosis and concurrent anti-HIV
therapy, but even given these advantages something less toxic and
more effective than pyrimethamine with sulfadiazine is needed.
Dr. Remington spoke for many when he expressed frustration with
the static situation of treatment research for this infection.
For example, more than a year ago an update on toxoplasmosis in
AIDS TREATMENT NEWS (#79) included a report on arprinocid, at
that time considered one of the most promising compounds to be
laboratory tested against Toxoplasma. We could find no mention
of arprinocid at this Conference, nor of trimetrexate, nor of any
human experience with azithromycin, as Dr. Remington noted.
If arprinocid, azithromycin, 566C80, gamma interferon, or
trimetrexate are not safe or useful in humans, we need to know.
And if they are safe and effective, we need to know that too, as
soon as possible.
Sixth International Conference: Treatment of CMV Infections
by Michelle Roland
CMV (cytomegalovirus) is responsible for several serious
opportunistic infections in people with AIDS. It most commonly
infects the retina of the eye (CMV retinitis), resulting in
blindness if untreated. CMV can also cause colitis and pneumonia
and can infect other organs, including the spleen. The one
approved treatment for CMV retinitis in the U. S. is intravenous
ganciclovir (also called DHPG). Because of its limited long-term
effectiveness, often serious side effects, and the inconvenience
of the intravenous formulation, alternative treatments for CMV
infections are urgently needed. In addition, very little is
known about the safety and effectiveness of ganciclovir or any
experimental treatment for other manifestations of CMV infection,
e.g. colitis and pneumonia; increased research attention in this
area is also crucial.
This article will cover the information presented at the
Conference on the use of ganciclovir by itself and in combination
with the experimental drugs ddI and GM-CSF. In addition, we will
discuss the unapproved drugs foscarnet (which is furthest along
the U. S. regulatory pipeline), oral ganciclovir, and TI-23
(anti-CMV monoclonal antibodies). Preliminary results of a study
on high dose intravenous acyclovir, which is FDA approved for
herpes infections, will also be summarized. Finally, we will
suggest some research directions which should be pursued
immediately to maximize the effectiveness and minimize the
toxicity of currently and soon to be available treatments for CMV
retinitis. (Note: for our last CMV update, see AIDS TREATMENT
NEWS #96, February 2, 1990.)
Intravenous Ganciclovir
Patients and health care workers familiar with ganciclovir
know that, although ganciclovir is quite effective in initially
stopping the progression of CMV retinitis, its long term
effectiveness is often limited, either by time, or by its serious
side effects. Data presented at the Conference shows that CMV
cultured from some patients develops resistance to ganciclovir
after three months of treatment, offering at least a partial
explanation for the time-limited effectiveness of this treatment
in many people with CMV infections. The amount of time for which
this drug is effective varies among patients. In a large study
of over 700 patients, almost half had experienced progression of
their retinitis in a mean of approximately 97 days (with a range
of 4 to 220 days); the other 56% had not experienced any
progression at the time the data was presented. (References to
this and other studies are listed at the end of this article.)
Although ganciclovir's effectiveness is often time-limited,
it is the only drug currently available in the United States for
use by people with CMV infections; it is important to learn how
to use it as safely, effectively and conveniently as possible
until better treatments are available, either by combining it
with other drugs and/or by altering the frequency of its
administration.
Ganciclovir with GM-CSF
Ganciclovir's most serious side effect is its depression of
the development of a type of white blood cells called
neutrophils. These cells are important in fighting off bacterial
infections. Many scientists and activists have believed that a
drug called GM-CSF (granulocyte macrophage colony stimulating
factor), which stimulates the growth of some types of white blood
cells in the bone marrow, might counter the neutropenia
(depressed neutrophil count) experienced by many people using
ganciclovir.
Preliminary results from a small study comparing one
patients treated with GM-CSF with others who received only
ganciclovir suggest that neutropenia severe enough to require
discontinuation of ganciclovir may be reduced with the use of
GM-CSF, although the differences between the two groups were not
outstanding.
What is the clinical significance of the small decreased
incidence of severe neutropenia? It is believed by many that
temporary or permanent discontinuation of ganciclovir contributes
to progression of CMV retinitis. Although the difference in
percentage of patients in the two groups who experienced
progression of their retinitis was not statistically significant,
the mean time to progression was 102 vs 156 days. There were
also fewer bacterial infections in those patients who received
GM- CSF (47%) than in those who did not (62%).
The preliminary results of this study appear to many to be
encouraging. There were some side effects, including more muscle
aches in the GM-CSF group, and an increase in the number of
another type of white blood cell called eosinophils. However, the
overall trend seemed to indicate that GM-CSF may help reduce some
of the adverse effects of ganciclovir and should be available to
patients who wish to use it. GM-CSF has long been one of the
drugs that treatment activists have advocated for immediate
expanded access before FDA approval.
Ganciclovir with ddI
Because ganciclovir and AZT have similar toxicities with
respect to bone marrow suppression and a decrease in the white
blood cell count, it was believed until recently by most doctors
and researchers that the two drugs should not be used together.
As the standard dose of AZT is lowered, more physicians are
recommending that patients may continue to take low doses of AZT
with ganciclovir, as long as their blood counts are monitored
frequently. With the widened availability of ddI, and the
knowledge that ddI does not depress white blood cell counts when
used alone, there is much hope that ganciclovir and ddI can be
used together safely. This combination would provide patients
with anti-retroviral therapy in addition to their anti-CMV
treatment.
Preliminary results from an extremely small ongoing study
(five people) support the hope that ddI and ganciclovir can be
taken together without any additional toxicities. All of these
patients had taken AZT previously and four of them had had to
discontinue the AZT because of neutropenia. No one developed
decreased blood cell counts in the short time of the study (2-7
weeks). The initial findings are far from conclusive, but do
support the belief that ddI may well be a better anti-retroviral
than AZT for people who need to use ganciclovir.
Ganciclovir Three Times Per Week?
Ganciclovir is currently administered twice a day for 14
days (induction phase), followed by once a day, five days a week
administration as maintenance therapy. An Australian study
tested the use of ganciclovir three times per week in the
maintenance phase, at approximately twice the dose used in the
five days per week schedule. Although this study did not have a
control group with which to compare its results, it did find
rates of progression of CMV retinitis similar to those reported
in many other studies. 40% of the patients had experienced
progression of their retinitis at a mean of 4.1 months; 38%
continued to have inactive retinitis on maintenance therapy at a
mean of 6.1 months in the study. (As mentioned above, the large
ganciclovir study presented at the Conference reported 44%
progression at a mean of 97 days.)
Again, this study is not conclusive, but it does suggest
that ganciclovir may be used effectively less frequently than it
is being used now. Given the inconvenience of the intravenous
therapy, if this data were to be confirmed, it would be very good
news. We believe that this type of information is of critical
importance to people with AIDS and CMV infections and should be
seriously pursued by other researchers.
Ganciclovir for CMV Colitis
Very few studies have been conducted with treatments for CMV
infections other than retinitis. A single placebo-controlled
study of ganciclovir in colitis showed some improvement in weight
loss and significant improvement in progression to CMV retinitis
and laboratory assessment of infection as compared to the placebo
group. Unfortunately, although the incidence of diarrhea and
abdominal pain decreased in the ganciclovir group, the group
receiving placebo experienced the same degree of improvement in
these symptoms, suggesting that the drug was not responsible for
the improvements.
Ganciclovir appears to be useful in at least some aspects of
the treatment of CMV colitis; however no studies have been done
to answer such questions as whether treatment should be continued
indefinitely or just until symptoms resolve. Different doctors
and researchers have different opinions about ganciclovir
maintenance therapy in CMV colitis. Further investigation in
this area is certainly warranted.
Foscarnet
Given the limits of ganciclovir, the development of other
treatments for CMV infections is essential. Furthest along the
developmental and regulatory pipeline is foscarnet. Although
this drug also has serious limitations (can be toxic to the
kidneys; also requires daily intravenous infusion), it is
essential that more than one drug be available to treat this
viral infection. Data from the Conference continues to suggest
that foscarnet is effective in stopping CMV retinitis for a
limited time and delaying its future progression. The relapse
rates appear to be similar to those found with ganciclovir. In
addition, one study found a consistent decrease in p24 antigen
levels (in those who were initially p24 antigen positive); these
researchers concluded that due to it's potent anti-HIV and anti-
CMV activities, foscarnet may prove to be the treatment of choice
in CMV retinitis.
Foscarnet is not without its problems, however, and not all
scientists believe that it will prove to be superior to
ganciclovir. In addition to the already identified side effect of
reversible kidney toxicity, reversible penile lesions have also
been identified in a number of people taking foscarnet. These
lesions often require cessation of therapy to heal. Also, one
study found dose limiting neurotoxicity in 2 of 16 patients at a
seemingly more effective but higher dose of foscarnet. Finally,
another study demonstrated that, although calcium levels in the
blood were not altered, the two hormones involved in keeping
calcium levels steady in the body were elevated in people taking
foscarnet. The clinical implication of this observation is not
known at this time.
Comment
A note about the design of clinical trials for CMV
retinitis: Researchers do not like to design clinical trials
without a control group which receives either a placebo, no
treatment, a different treatment, or a different dosage of the
same treatment. In designing clinical trials for CMV, some
researchers have invented a new category which they call "non-
sight threatening CMV retinitis" based on the location of the CMV
lesions on the retina. They created this category of patients so
they could justify withholding treatment from one group to
compare against a treatment group. In their abstract, these
researchers write, "Data previously presented demonstrated that
[immediate treatment] was more effective than delay in postponing
progression of CMV retinitis." Any clinician treating patients
with CMV retinitis could have told them that. It is essential
that this dangerous distinction between non-sight threatening and
sight threatening retinitis not be used in any future clinical
trials of agents against CMV retinitis.
Ganciclovir vs Foscarnet...or Better Yet, Together?
It is believed by many researchers that foscarnet and
ganciclovir are approximately equally effective. A comparison
study of the two drugs under way in England has found that the
initial response of CMV retinitis may be a bit slower with
foscarnet than with ganciclovir. Although the mean time to
reactivation of the retinitis was about 4 months in both groups,
the British researcher stated that there may be a trend to later
and fewer reactivations with ganciclovir than with foscarnet.
Importantly, regardless of small differences in efficacy, most
patients on both treatments required an interruption or change in
their medication at some point during treatment; many of those
who did switch therapies responded to the second drug.
As expected, both drugs have their limitations. However,
because of their different toxicities, they may be more effective
if used concurrently or in alternation than when used alone.
Clinicians and researchers familiar with the two drugs find that
people respond differently to each, but that what is most
important is having an alternative treatment available if the
first one does not work.
Comment
What should be the next step in testing ganciclovir and
foscarnet? Researchers associated with the AIDS Clinical Trials
Group (ACTG), the government sponsored research group, are
currently designing a comparative study of ganciclovir and
foscarnet, to determine which one is a better treatment. But as
we already know (and the English study supports), neither of
these treatments is ultimately satisfactory on its own. People
often either experience a relapse of their retinitis or have to
discontinue treatment due to serious side effects. What seems
clear is that, given the reality at this time of two imperfect
drugs, the most important information we need now is how best to
use them together. This is the same question that is starting to
be asked about the use of the anti-retroviral drugs AZT, ddC and
ddI.
Instead of asking which one works better, we need to ask if
it would be more efficacious and less toxic to use the two drugs
concurrently or in alternation. (We have heard a report that one
or more doctors may be using them concurrently now.) If used
concurrently, how much of each drug should be combined? If used
in alternation, when should they be switched? Business as usual
in this case would be to compare the two drugs alone; business as
usual is a luxury that people with AIDS cannot afford,
particularly in this case. We believe that the next step should
be to design a trial which intelligently examines options for
using these two drugs together.
Note that activists have been pressuring foscarnet's
manufacturer, Astra Pharmaceuticals, to release the drug broadly
on compassionate use for about two years. In the United States,
foscarnet is still only available to those patients who qualify
for, and have access to, a clinical trial.
Other Treatment Possibilities: High Dose Intravenous Acyclovir
A very small study suggested that high dose intravenous
acyclovir, taken with AZT, may be an acceptable alternative
treatment for people who are intolerant of or have failed
ganciclovir or for those patients who cannot tolerate both AZT
and ganciclovir together but wish to continue taking AZT.
Patients were initially treated with ganciclovir and
switched to intravenous acyclovir plus AZT for maintenance. The
published abstract of this study states that 2 of the initial
eight patients treated experienced progression of retinitis at
weeks seven and eight after the completion of the ganciclovir
induction. This study is ongoing and is too small at this time
to allow us to draw any reliable conclusions.
TI-23 (CMV Monoclonal Antibody)
Results from a small, dose ranging study of intravenous TI-
23, a monoclonal antibody against CMV, suggested that this
approach may be a safe alternative to other anti-CMV drugs
currently available or being studied. Since this drug is a
foreign protein, it was important to make sure that the body
would not create antibodies against the drug as a normal immune
response. No such antibodies were detected and there were no
objective side effects observed in the CMV positive, asymptomatic
patients who were studied.
This study was not designed to determine if the drug is
effective; the second phase of the study, which is currently
ongoing in symptomatic patients with CMV infection, was reported
to be showing encouraging early results.
Oral Ganciclovir
Alternatives to intravenous treatment for CMV infections are
greatly desirable; preliminary data was presented at the
Conference on an oral form of ganciclovir. Although this study
was designed to determine safety rather than effectiveness, some
preliminary observations can be made. At the doses studied so
far in this initial dose-ranging study (designed to find the
maximum tolerated dose), all 11 of the patients had experienced a
relapse of their CMV retinitis in a median time of 62 days (range
of 3 to 131 days). There were no problems observed with
toxicity, although resistant strains of CMV were isolated in two
of the patients.
With the formulation of the drug which was tested, only 6-8%
of the drug was found to be active in the blood stream. It is
possible that if better formulations of the drug can be
developed, effectiveness will be improved.
Other Possibilities
Other oral drugs, such as FIAC and HPMPC, are also in
development but no data was presented on them at the Conference
(See ATN 94 for information about FIAC and ATN 76 and 96 for
information on HPMPC.)
References
Ganciclovir and GM-CSF: F. B. 92
Ganciclovir and ddI S. B. 474
Ganciclovir 3 times per week: Th.B. 433
Ganciclovir in colitis: F. B. 94
Foscarnet: Th.B. 434, Th.B. 435, Th.B. 436,
Th.B. 437, Th.B. 438*, Th.B. 439, Th.B. 440,
F. B. 96 *non-sight threatening
Foscarnet vs Ganciclovir: F. B. 95
Intravenous Acyclovir: Th.B. 441, TI-23, Th.B. 442
Oral Ganciclovir: F. B. 9
CPFs: Researchers Design New Anti-HIV Compounds
by John S. James
On July 20 researchers at the Dana-Farber Cancer Institute
at Harvard Medical School, and at the Harvard University
Department of Chemistry, reported the development of a new class
of anti-HIV chemicals, in an article in Science magazine
(Prevention of HIV-1 Infection and Preservation of CD4 Function
by the Binding of CPFs to gp120. Finberg RW and others, Science,
vol. 249, pages 287-291, July 20, 1990.) A brief flurry of news
reports followed. While these chemicals are not yet ready for
human tests, their development is important.
The new substances, called CPFs, are chemical variants of
small peptides -- short fragments of amino acids, the building
blocks of proteins. CPFs contain only two amino acids. They
work like soluble CD4, binding to the gp120 molecules on the AIDS
virus -- the molecules which attach to T-helper cells and allow
the virus to enter. They may also protect the T-cells from being
damaged by free gp120 in the blood.
In laboratory tests, the chemicals already developed
required relatively high concentrations to protect cells against
infection -- 40 micrograms/ml or more. A good antibiotic would
usually work at lower concentrations -- suggesting that the CPFs
already studied might not become useful drugs themselves. But
the researchers have found that small changes in the molecule can
make big differences in effectiveness, suggesting that better
versions might be created in the future.
At this time, no one knows if humans can tolerate CPFs -- or
if they will be stable in the body. But mice given 20 to 50
times the dose expected to be effective showed no toxicity,
according to a UPI report based on a recent interview with one of
the researchers.
CPFs may be important because:
* They were rationally designed to block a specific part of
gp 120 which is essential for viral binding to T-helper cells
(and other cells with the CD4 marker, which HIV apparently uses
to gain entry into uninfected cells). Test after test has shown
that CPFs behaved as expected in laboratory cultures. The
existence of a clear rationale helps chemists design new versions
of the chemical which may work better.
* HIV binding to uninfected cells seems to depend on a
critical arrangement of molecules in the virus. Therefore,
scientists expect that HIV may not be able to develop resistance
to CPFs, as it appears to do with AZT-type drugs. If the virus
mutates so that its gp 120 cannot bind to CPFs, then it may also
be unable to bind to CD4 receptors and infect cells.
* Unlike soluble CD4, CPFs are easy and inexpensive to
manufacture. And they could probably be given orally.
Announcements
ACT UP Treatment and Data Digest Now Available
A weekly two-page newsletter from ACT UP/New York's
Treatment and Data Committee reviews the issues addressed each
week by this Committee, one of the leading treatment- activist
organizations anywhere. Each issue has several short articles
about treatments themselves, negotiations with companies, and
preparations for clinical trials or other access. The Digest is
published rapidly, providing the latest information on treatments
which activists are working on.
Over 45 issues have been published. The first ones were not
advertised, but now ACT UP is offering subscriptions; the cost is
$40.00 per year, and additional contributions are appreciated.
To subscribe, send your name, address, and a check to ACT UP/NY
to: Treatment Digest, c/o Richard Lynn, 155 E 31st Street, Apt.
20L, New York, NY 10016.
San Francisco: Quan Yin Herbal Program Starts August 8
The next Quan Yin Chinese herbal program starts August 8;
participants should register by August 3. The cost for the 12-
week program is $210. For more information, call 415/861- 4964.
This is the 13th similar program run by Quan Yin. Over 600
persons with AIDS or HIV have participated. A brief report of
results of the early programs appeared in AIDS TREATMENT NEWS
#93, December 15, 1989.
Quan Yin, a nonprofit organization, also runs a low-cost
acupuncture clinic for persons with HIV, HIV certification
programs for acupuncturists and for medical doctors, the San
Francisco AIDS Alternative Healing Project, and other programs.
Note: There has been confusion about Quan Yin after press
reports that it had closed. Founder Misha Cohen explained that
the main acupuncture clinic did close, due to tens of thousands
of dollars unexpected cost to move into its new offices, major
additional costs due to the October 1989 earthquake, and a recent
California decision to deny Medicaid reimbursement for
acupuncture. But other branches of Quan Yin remain open and are
expanding at this time.
San Francisco: CONTINUUM Day-Care Center Opens
California's first adult day-care health program for persons
with AIDS has been licensed and is now accepting referrals.
CONTINUUM HIV Day Services, a non-profit, community-based
organization funded by businesses, private foundations, and San
Francisco, California and Federal government agencies, will offer
nursing care, social services, counseling, support groups,
recreational and education programs, transportation if necessary,
and support for families and caregivers. CONTINUUM is intended
for persons who do not require hospitalization but do need care
during the day when their primary caregiver is away.
For more information about the program, call 415/241-5500.
Research Nurses Needed in Washington DC and Elsewhere
A continuing shortage of research nurses and other
professionals to run clinical trials is delaying research across
the United States. Qualified persons can work at the cutting
edge of the field testing new AIDS/HIV treatments, with good
salary and benefits and their choice of locations.
Recently we were asked to announce a position at the
community-based Whitman-Walker Clinic in Washington, DC. Persons
interested should call Basil Vareldzis, M. D., at 202/797-3534.
permission granted for non-commercial use.
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