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Fortovase Approved: New Saquinavir Formulation
by John S. James
On November 7 the FDA approved Fortovase, the new "soft gel"
formulation of saquinavir, for treating HIV infection in
adults, in combination with other antiretrovirals. The new
formulation delivers much more of the drug to the blood than
the older version, Invirase® (saquinavir mesylate). The
main problem with Invirase has been that the amount
provided by the approved dose is too low.
Fortovase, which is taken three times a day with meals (or up
to two hours after a meal), should be on pharmacy shelves
within a week. The old saquinavir (Invirase) will remain in
pharmacies for six months; after that, it will still be
available on a limited basis to patients who want to continue
using it, through a special distribution program.
Fortovase has been priced to cost the same as Invirase, with
a wholesale acquisition cost of approximately $5,700 per
year. Developer Hoffmann-La Roche has a patient assistance
program, for persons unable to pay for the drug. This program
can also help patients who want to convert to Fortovase
before their health plan approves it for reimbursement.
A safety study with 442 patients who received Fortovase in
the approved dose, for a median of 52 weeks, found that the
main side effects were diarrhea, nausea, and abdominal
discomfort. Eight percent of patients had to discontinue the
drug due to side effects, mainly gastrointestinal; fewer than
one percent discontinued because of laboratory toxicities.
A large U.S. Fortovase trial now recruiting is comparing
Fortovase in a three times a day vs. a twice a day dosing
schedule (combined with other antiretrovirals), vs. Fortovase
plus VIRACEPT plus a new reverse transcriptase inhibitor.
This may be an attractive trial since everyone will receive a
credible treatment; there is no "loser" arm which must do
worse for the study to fulfill its purpose. For more
information about this trial, call 800-TRIALS-A.
Hoffmann-La Roche has established the following sources for
information about Fortovase:
Healthcare professionals, call 800-526-6367.
Patients (outside of the Washington D.C. area), call 800-
910-4687.
Patients in the Washington D.C. area, call 202-442-2437.
For the Roche HIV Therapy Assistance Program, call 800-282-
7780.
Plans for a larger 1592 expanded access program, projected to
start early in 1998, were discussed at an October 13 meeting
attended by several treatment advocates and Glaxo Wellcome
representatives. After the meeting, some community groups
called off a boycott of Glaxo Wellcome products, which had
been organized to protest serious difficulties in gaining
access to the drug.
Community representatives proposed the following design for
the 1998 program:
No Arbitrary Limitation on Program Size. As neither the
company nor community representatives could estimate the
actual need for the drug, it was agreed from the outset that
there should be no pre-established numeric limit on the total
number of patients served by the program. Every effort should
be made to allocate all available drug, not used for clinical
trials, to the program.
Principle of Expanded Access/Eligibility Criteria. The
underlying principle of the expanded access program should be
to allow patients to construct a viable treatment regimen
based on the current treatment guidelines. Unless required by
the FDA, community representatives felt this definition
eliminated the need to set arbitrary entry criteria such as
viral load, CD4+ counts, or failure of specific drugs. (See
"Expanded Access to Experimental Drugs: Activist Seek More
Open Programs" in our last issue, AIDs Treatment News #282.)
Initiation of Program. Glaxo agreed to make every effort to
initiate a broader expanded access program as soon as
possible in the 1st Quarter of 1998 -- without committing to a
date certain.
Traditional Distribution. The new program should not be
restricted to a small number of centers or physician
practices, but should be a more traditional expanded access
which would permit registration through a patient's primary
care physician.
Flexibility. The program should be designed with enough
flexibility that patients who need the drug as a treatment
option will have access.
Community Meetings. Glaxo representatives should continue
to meet with community treatment advocates and with
physicians by holding future meetings in various cities to
solicit feedback on the proposed framework for a wider
program in 1998.
Glaxo recently reported a total of 615 patients enrolled in
the 1592 adult program, but as of October 10 only two
children had been enrolled in the pediatric program. At the
meeting concerns were raised about the pediatric viral load
criteria being too restrictive. It was agreed this limit
should be lowered, subject to FDA approval.
Much of the current delay in access to 1592 and other
experimental drugs is primarily due to local IRBs
(institutional review boards), which often meet only monthly
and do not understand the disease or the drug; they may make
vital access programs wait in line behind more routine
research projects. Glaxo set up a national IRB for the 1592
open label program, but when hospitals have their own IRB,
they often require their physicians to use it instead of a
national one. As of the October meeting ten sites had not
enrolled any patients, as their own IRB approvals were still
pending.
Community representatives in attendance were encouraged by
the general tenor of the meeting; they felt that a more
constructive dialogue and spirit of working in cooperation
had begun. They remain hopeful that Glaxo will use best
efforts in its 1998 program to adequately address access for
all patients who need the drug.
HIV Resistance Testing: More Questions Than Answers
by Bruce Mirken
Since the advent of Highly Active Antiretroviral Therapy
(HAART) in early 1996, increased attention has been focused
on the subject of HIV's ability to develop resistance to
antiretroviral drugs. If a person's virus is already
resistant to two of the drugs in a three-drug combination,
his or her treatment is effectively reduced to monotherapy
and is likely to fail. Given the large number of PWAs who
have been treated with nucleoside analogs such as AZT and ddI
prior to the introduction of protease inhibitors and non-nucleoside reverse transcriptase inhibitors, along with the
possibility that some people might become newly infected with
resistant strains, choosing an effective regimen can be
difficult. Still, making the right choice means a greater
chance of long-term success and a reduced possibility of
developing resistance to the new drugs.
One obvious answer to the problem would be a test that
doctors could use before starting treatment to determine if a
patient's virus is resistant to any drugs and again in the
case of viral rebound to see if resistance has developed.
Tests that seek to do just that have been available for some
time, but serious questions remain as to their usefulness in
day-to-day clinical practice. There are two broad types of
tests that can be used to look at HIV drug resistance:
phenotypic and genotypic assays. Phenotypic assays test the
actual ability of the virus to replicate in cell culture when
a drug or drugs is added. Genotypic tests, on the other hand,
identify specific genetic mutations in the virus which
correlate with phenotypic resistance. Both types of tests are
used in research, but because today's phenotypic tests are
cumbersome, time-consuming and expensive, there has been
little effort as yet to make them commercially available for
clinical use. The faster and less expensive genotypic tests
have been available to doctors since last year, but their
usefulness remains controversial.
"When [genotypic resistance tests] started becoming available
we ordered quite a few," comments San Francisco AIDS
specialist Dr. Virginia Cafaro. But, she says, "they were not
matching up clinically with what we found, so they were not
all that useful." Cafaro still orders the tests occasionally
as a source of additional information in particularly
difficult or puzzling situations, but overall considers the
tests "just not good enough" at this point for use as a
regular part of clinical decision-making.
New York AIDS physician Dr. Paul Bellman agrees, calling
genotypic testing "disappointing" thus far.
One problem is that although researchers have identified
numerous specific HIV mutations associated with drug
resistance, the exact interplay of those mutations remains
somewhat unclear. This was underlined by several
presentations at the June, 1997 International Workshop on HIV
Drug Resistance, Treatment Strategies and Eradication, held
in St. Petersburg, in which the associations between known
mutations and real-world drug failure were not found to be as
clear-cut as might have been expected.
For example, two mutations, G48V and L90M, have been
associated with resistance to saquinavir. But when Stanford
researchers analyzed the virus from 40 patients who had
experienced treatment failure on long-term saquinavir
treatment, one or both of those mutations was seen in just 58
percent of them, and 35 percent had mutations typically
associated with resistance to other protease inhibitors.
Strikingly, all who developed the G48V mutation -- some of whom
remained on saquinavir and some of whom switched to indinavir
or nelfinavir -- eventually went on to develop a second
mutation associated with resistance to ritonavir and
indinavir. What this suggests, the researchers wrote, is that
resistance to saquinavir "may provide a genotypic foundation
for the development of resistance to other protease
inhibitors." In other words, mutations that arise during
saquinavir use may not directly cause resistance to other
protease inhibitors but may increase the likelihood of future
mutations that do cause resistance to those drugs. Numerous
other presentations at the St. Petersburg meeting suggested
similarly complex patterns -- all of which are not fully
understood as yet -- by which resistance to various protease
inhibitors develops.
So even though testing can now give doctors a print-out
identifying particular mutations, we may not have enough
information yet to truly understand what those mutations
mean. Ed Hurwitz, vice president and chief financial officer
of Affymetrix, whose GeneChip genotyping system is presently
being marketed only to researchers, says, "I guess our
opinion is it's going to take two to three years of research"
before the tests can be effectively used in "day-to-day
disease management."
The same concern was voiced in a May 24, 1997 commentary in
The Lancet by San Francisco General Hospital AIDS researchers
Drs. Steven Deeks and Donald Abrams, who argue that "there is
little consensus among experts on the significance of most
mutations." In a recent interview Deeks confirmed that his
views on the subject "have not changed a bit."
Another concern Deeks and Abrams raise is the sensitivity of
the tests. According to Dr. Terry Robbins, director of
clinical molecular biology for Specialty Laboratories, a Los
Angeles firm now marketing genotypic testing to physicians,
his company's assay can identify "the majority species of HIV
present in an infected individual... If it was present at 25
percent [of a person's total virus population] we would see
it." But Deeks and Abrams argue that "since drug-resistant
strains can be rapidly selected by antiretroviral therapy,"
mutants present at much lower levels are likely to be
significant.
Robbins notes that there is an opposite danger as well: A
too-sensitive test could "pick up random mutations" that are
clinically irrelevant. Indeed, data from the St. Petersburg
meeting suggested that such random, occasional mutations did
not appear to have an influence on the outcome of treatment.
The ideal level of sensitivity for genotypic resistance tests
remains uncertain at this point, but in discussions at the
recent Interscience Conference on Antimicrobial Agents and
Chemotherapy some physicians argued that it will be necessary
to detect mutants representing less than 10 percent of a
person's virus population.
Robbins, not surprisingly, is more upbeat than Deeks and
Abrams about the current use of genotyping as a clinical
tool. He argues that one key use of such tests, to determine
if an increase in viral load is due to the development of
resistance as opposed to other factors, doesn't depend on the
ability to detect minor populations. Still, though he
believes genotyping can be useful to physicians now, Robbins
cautions that it shouldn't be the sole basis for treatment
decisions: "If a physician is basing therapeutic changes on a
genotypic pattern, it needs to be done in conjunction with
the patient's past history. A therapeutic decision should not be based on a single test."
Meanwhile, research and development of HIV resistance testing
is continuing at a fairly rapid clip. Robbins notes that
Specialty Laboratories is developing a multicenter clinical
trial it hopes will validate clinical use of its test, while
the CPCRA is also mounting a genotyping trial. At ICAAC a
Canadian firm called Visible Genetics unveiled a new
genotypic test -- available only to researchers for the time
being -- which it claims can identify mutations others miss,
and for which it is planning several clinical trials. South
San Francisco based ViroLogic presented initial data on a new
phenotypic assay that can produce a result in 8-10 days,
nearly as fast as the genotypic tests. The ViroLogic test can
detect mutants at "about 10 percent of the population,"
according to researcher Chris Petropoulos.
That such research and development is moving ahead
energetically is a positive sign, and there seems little
doubt that HIV resistance testing will get increasing
attention in future years as both the technology and
scientists' understanding of how to use it improve. For now,
though, the only clear consensus is that it represents an
area with great potential and many unanswered questions.
Drug-Resistant Herpes: Cidofovir Gel in Limbo.
Interview with Jay Lalezari, M.D.
by John S. James
Cidofovir, a drug active against many herpes viruses, has
been approved for over a year in intravenous formulation
(VISTIDE®) for treatment of CMV retinitis in patients with
AIDS. Developer Gilead Sciences has also produced a 1%
cidofovir gel called ForvadeTM, to test as a topical
treatment for acyclovir-resistant herpes lesions, and perhaps
also for warts or other viral skin infections. A multicenter
study tested Forvade for treatment of acyclovir-resistant
herpes, but in May 1997 the FDA found the data insufficient
and turned down the drug for marketing. The study results
were published in October.1
Forvade -- very important for a small number of patients -- now
faces an unclear future. It would be difficult to enroll
another trial today, since improved antiretroviral therapy
has greatly reduced the number of opportunistic infections,
including cases of drug-resistant herpes.
The published study tested Forvade, vs. a weaker formulation
(0.3% gel), vs. placebo, in 30 patients treated once a day
for 5 days. Half of those who received drug had either
complete healing or a partial response; none of those on
placebo did. Herpes virus shedding stopped in 87% of those
receiving treatment, vs. none of those on placebo. All
measurements used -- lesion healing, viral cultures, and pain
relief -- were consistent, and statistically significant
compared to placebo. Side effects were minor, and no drug (or
almost none, in patients who had the largest lesions) was
absorbed into the circulation.
We interviewed Jay Lalezari, M.D., who has an HIV practice in
San Francisco and is director of Quest Clinical Research. Dr.
Lalezari is one of the most experienced physicians in the
country in treating acyclovir-resistant herpes.
AIDS Treatment News: Why is Forvade (cidofovir gel)
important?
Dr. Lalezari: This was a double-blind randomized placebo-
controlled study, and all of the measured efficacy parameters
including healing, pain relief, and virologic outcome point
to a clear, consistent, and statistically significant benefit
of this drug.
In my experience, these lesions are among the most painful,
disabling, and difficult to treat complications of AIDS. For
such patients the pressing issue is pain relief, and the
clear benefit in this trial has been one of my most
gratifying experiences in AIDS research. Although the
infection has become less common, cases continue to occur,
and treatment options are urgently needed.
What is surprising is how much benefit we saw with only five
days of once-daily topical therapy. Cidofovir is one of the
most potent antiviral drugs that has ever been developed. Its
long tissue half life may also help explain why it worked as
well as it did.
And there was no down side. The drug is not absorbed into the
circulation, and therefore there was no systemic toxicity.
There have been reports about local toxicity using a higher
concentration of the gel, 3%, in treatment of warts; it has
been associated with some local ulcerations. But we did not
see any in this study.
ATN: What happens now?
Dr. Lalezari: Gilead is working with the FDA to determine
what additional studies it wants. But the bottom line is that
this condition is so infrequent that it would be extremely
difficult to accrue a new study.
It took us two years to enroll 33 patients in the original
study -- in the era before protease inhibitors, so there was
still a small but significant number of patients who had
acyclovir-resistant herpes who were desperate for treatment.
Therefore it was possible to enroll the study; we enrolled
half the patients in this office. But to do that now would be
extremely difficult -- not because there are no patients, but
because they are very spread out.
So I think that if the FDA insists on additional studies, it
effectively kills the development of this drug. What is not
clear is what are the politics behind that decision, at the
FDA and in turn at Gilead.
Fortunately, Gilead has said that it will continue its
compassionate use program. But no company can do that
indefinitely if the drug is not being developed.
This is not a make-or-break issue for thousands of patients,
but there are probably at any given time in this country ten
to 50 patients with this problem.
ATN: There was a dose response in viral culture negativity,
but the high dose was not better than the low dose in lesion
healing or pain relief. Do you know why?
Dr. Lalezari: It appears that patients in the low-dose group
took more pain medications, which tended to mask the pain
response.
Tissue healing is very complex. It involves many factors,
including nutritional status -- not just eradicating the virus.
What is important is that there was clinically significant
tissue healing (50 percent or better reduction in lesion
size), in half of the treated patients, vs. none of those on
placebo. And there were more patients on the high-dose group
who had complete lesion healing.
The results we saw were statistically significant, and were
clinically meaningful, in a disease for which there are very
few other treatment options.
ATN: Could the IV formulation (VISTIDE) be used topically?
Dr. Lalezari: I doubt it. You need something to keep the drug
on the lesion, to allow for gradual absorption. If you just
pour on the IV fluid, it runs off.
ATN: Why do you think the FDA denied permission to market the
drug?
Dr. Lalezari: I do not know. There was just one study with a
fairly small number of patients. But this is a very benign
treatment intervention, with positive, believable results, in
patients who have very limited options.
It took us two years to find all those patients. I cannot
imagine having done a study much bigger. And the size should
not matter as long as the results were statistically
significant.
There may also be concern about the adequacy of the
photographs. We took photographs of geographically complex
lesions, and did the best we could. There are different focal
planes, so not all the lesions are clear in all the photos.
Even if the photographs were not adequate, the virology data
is clear and objective. And there is no way to argue with the
fact that there was clinically significant resolution of the
lesions, and reduction in pain.
These patients have advanced disease, and do not generally
have a long life expectancy. All that really mattered was
improving their quality of life, by eliminating the herpes
virus, and reducing pain and lesion size. It made their
quality of life significantly better.
I do not know what the politics are between Gilead and the
FDA.
The other possible concern is potential carcinogenicity; a
study in rats found an increase in mammary tumors associated
with subcutaneous administration of cidofovir. This did not
prevent approval of the injected drug, but if the gel were
approved for acyclovir-resistant herpes, there may be concern
at the FDA that it might be used much more broadly. People
might start choosing it instead of acyclovir to treat less
serious herpes, and the FDA may have concerns about possible
long-term risk.
Drug-resistant herpes in advanced AIDS is a miserable
disease. For these people, going to the bathroom can be
excruciating. This drug works in drying up the lesions; in
some cases there was complete healing. You do not see that in
the natural history of this disease, or in the placebo group.
So the drug works. And since there was no down side, I cannot
imagine why it would not be approved.
It is a shame that the needs of these patients are not being
given appropriate consideration.
References
1. Lalezari J, Schackter T, Feinberg J. and others. A
randomized, double-blind, placebo-controlled trial of
cidofovir gel for the treatment of acyclovir-unresponsive
mucocutaneous herpes simplex virus infection in patients with
AIDS. THE JOURNAL OF INFECTIOUS DISEASES. October 1997;
number 176, pages 892-898.
Treatment in Developing Countries: New UNAIDS Pilot
Program
by John S. James
On November 5 the Joint United Nations Programme on HIV/AIDS
(UNAIDS) announced the UNAIDS HIV Drug Access Initiative, a
pilot program to develop ways of making AIDS-related
treatment more available to the 90% of people with HIV who
live in developing countries and have little or no access to
modern treatments today.
This program is a collaborative effort between pharmaceutical
companies (including Glaxo Wellcome, Hoffmann-La Roche, and
others) and health officials in developing countries. It was
designed with the realization that money is not the only
obstacle to effective treatment access, as there are also
major training and infrastructure issues. The current pilot
phase will operate in four countries -- Chile, Cote d'Ivoire,
Uganda, and Viet Nam -- to develop procedures and knowledge
that can then be used in many other countries.
In each country, two new entities will be created:
A national HIV/AIDS drugs advisory board, under the
Minister of Health. This board, which will include
representatives of local medical, public health, and HIV
communities, will devise a coordinated national policy for
the provision of HIV-related drugs.
A nonprofit company which will be a clearinghouse for
placing orders and receiving drugs on behalf of the
government. Drug price subsidies will be negotiated
separately between each country and the pharmaceutical
companies.
This initiative will include not only HIV drugs, but
antimicrobials to prevent and treat opportunistic infections,
and antibiotics to treat other sexually transmitted diseases,
which increase the risk of HIV transmission.
This effort will be funded from a variety of sources. UNAIDS
itself will provide $1,000,000 for oversight, evaluation, and
dissemination of the recommendations.
"This program will provide the information we need to
determine whether HIV/AIDS-related drugs can be obtained and
distributed effectively in developing countries," said Dr.
Joseph Saba of UNAIDS, coordinator of the initiative. "Armed
with this information, countries will then be able to
mobilize the necessary resources to treat infected
individuals, and to help control the global epidemic."
More information is available in a 12-page background
document distributed by UNAIDS, October 1997. A detailed
summary is available at http://www.unaids.org.
Geneva Conference Deadlines: Time to Start Planning
by John S. James
The 12th World AIDS Conference will be held at the Palexpo
Conference Centre in Geneva, June 28 - July 3, 1998. It is
important to begin planning early because:
(1) Conference deadlines start as early as February 2.
(2) Hotel rooms will be tight. Of the seven different zones
where conference hotels will be located, only one is in
Geneva; three are in France. Travel times to some of the
hotels can be as much as 90 minutes each way, although
average time is probably closer to 45 minutes. [However, our
travel agent tells us that there are rooms in Geneva
available at this time, without going through the conference,
starting at $115 per night.]
(3) The best way to get low-cost air tickets is usually to
buy them in sales which occur during the winter months.
When setting travel dates, note that community and other
satellite meetings usually occur before the international
AIDS conference, not after. The earliest meeting now in the
official schedule is the Community Rendez-Vous, starting
Friday June 26 at 5:30 p.m.; however, many events have not
been set yet, and some may be earlier. Since air and hotel
reservations may not be changeable, we like to arrive a
couple days early, giving time to rest and prepare for the
conference -- or to be available for meetings that otherwise we
could not attend.
Conference Deadlines
February 2 is the deadline for: Abstract submission (must be
received at the conference organizer in Stockholm, Sweden, on
the form provided, *not* by fax); Scholarship applications
(also not accepted by fax); Early registration fee; NGO booth
requests; and Satellite meeting requests.
April 1 is the deadline for accommodation requests (subject
to hotel availability after this date).
May 1 is the deadline for the standard registration fee, and
for child care requests.
June 1 is the deadline for late-breaker abstracts.
Early registration is advised. There might or might not be
onsite registration, depending on space available.
Costs
As this issue went to press, the cheapest regular fare from
the San Francisco area to Geneva was $1070 round trip;
however, there are charter flights to Paris for $398 round
trip, and the train from Paris to Geneva takes 6 hours and
costs $98 each way. Travel in Europe is crowded during the
summer, and expensive; if one is flying into another city and
taking a train to Geneva, it can help to go a day early to
rest, and leave time to assure connections. Another option is
a group fare, which a travel agent may be able to arrange if
you have enough people flying from the same city. [Thanks to
Tim James of Uniglobe Majestic Travel in Lafayette,
California for this information.]
Hotel prices for accommodations obtained through the
conference organizer are in six categories, ranging (in Swiss
francs) from CHF 80 to CHF 435 per day for a double room
($1.00 = CHF 1.35 in November 1997).
The regular conference registration fee is CHF 940 (CHF 590
student) before it goes up after February 2. For media
registration, see the Second Announcement and Call for
Abstracts (described below).
Miscellaneous
A valid passport is required for citizens of all countries to
enter Switzerland; a visa is required from residents of about
two dozen countries (not including the U.S. or Canada). No
vaccinations are required, and there are no HIV-specific
restrictions. Be sure to check travel requirements of other
countries you are traveling through -- and for France if you
are assigned to a hotel there. (U.S. citizens can enter
France as tourists for up to three months without a visa, but
"the expiration date of your passport must exceed by six
months the last day spent in France.") Documentation
requirements may change, so check with a travel agent or
other expert.
Geneva is in the French-speaking part of Switzerland. English
is widely understood.
The electricity is 220 volts, 50 cycles.
For More Information
For more information, see the Second Announcement and Call
for Abstracts, which has been widely distributed to AIDS
organizations and those who have attended previous
conferences. There is also a Web site, below, but most of the
information in the Second Announcement is not on the Web at
this time. Also, the Second Announcement includes the
abstract and other required forms.
The conference organizer (for participants, exhibitors,
media, scholarship applications, abstracts, and satellite
meetings) is:
There are also separate addresses in different cities for
program planning, accommodations and tours, and sponsorship
and corporate relations; these are listed on the inside cover
of the Second Announcement.
Media inquiries can be directed to Ogilvy Adams & Rinehart in
New York, 212-880-5231, ask for AIDS98.
ISSN # 1052-4207
Copyright 1997 by John S. James. Permission granted for
noncommercial reproduction, provided that our address
and phone number are included if more than short
quotations are used.
This article was provided by AIDS Treatment News. It is a part of the publication AIDS Treatment News.
