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Past Issues
Volume 17, number 6
June 2003
Contents
Researching Alternatives:
A Talk with Donald Abrams
"Alternative"
Treatment Activism
Moving Forward with Integrative
AIDS Research
HIV/AIDS and People
with Disability
Reyataz Dosing Options
Discussed
A Space and Time for Healing:
The Importance of the Abundance Paradigm
Researching Alternatives
A Talk with Donald Abrams
By Bob Huff
You have a reputation as being a rigorous clinical researcher
and tough advocate for making evidence-based treatment decisions.
Yet you've also been very open to studying a number of alternative
and complementary therapies that have been used in the HIV patient
community. How did all these concerns come together and what are
you involved with these days?
I was training in oncology at UC San Francisco just as the first
AIDS cases were reported. I helped found the AIDS program there
and I've been participating in academic clinical research for over
20 years. More recently I've become an associate fellow of the Program
in Integrative Medicine at the University of Arizona that was founded
by Andrew Weil. This is a two-year program, mostly online, that
is increasing my training and background in integrative medicine,
including things like botanical medicine, manual medicine, and spirituality.
It's been a stimulating experience so far and I'm really enjoying
it.
I've been interested in complementary medicine since the very beginning
of my career, so one of the reasons I'm doing the fellowship is
to learn more that I can integrate into my own healthcare discussions
with my patients. Of course another impetus is to see what other
things we might want to do clinical research on. My intention is
to continue to investigate the complementary and alternative approaches
that our patients are using. We want to determine whether or not
they may be beneficial, but also determine whether or not they may
be harmful, particularly in how they interact with the conventional
medications that patients are taking.
In the earliest days of AIDS we didn't have any treatment for this
new disease; people were dying and everybody was frightened. Being
here in San Francisco, we were near the Linus Pauling Research Institute
in Palo Alto, so there were a number of people in the city who were
proponents of high doses of Vitamin C. One of the first responses
we saw in the early 80s were storefront clinics opening up where
people went to receive intravenous injections of very high doses
of Vitamin C. At that point in time we didn't even know that it
was a virus causing the disease. So I used to go around on the lecture
circuit with someone who would talk to audiences of concerned people
who listened to him while hooked up to intravenous infusions of
Vitamin C. Then I would speak as the academician who cautioned people
that we really don't know if this is beneficial and there may be
some dangers to being hooked up to intravenous vitamin C, and so
on. Ultimately, this led to me to write a grant proposal in collaboration
with the Linus Pauling Institute. It was right about the time we
learned that HIV was the cause of AIDS so we wrote a proposal to
the NIH to study the in vitro effects of Vitamin C on HIV. That
grant didn't get funded.
In San Francisco at that time there were also a number of DNCB
proponents. DNCB, dinitroclorobenzene, is actually a photographic
chemical used for developing pictures, but it is also a skin sensitizer
that had been used to test for delayed hypersensitivity reactions.
There were people who believed that somehow it might be useful in
restoring some of the T cell immunity that patients with this new
disease were lacking. So there were people who would paint themselves
weekly or so with DNCB until they developed these skin reactions,
thinking that the skin reaction was some sort of improved T cell
immune response that would help combat the virus. And again, seeing
that people were using this and seeing that we really didn't have
much else happening, I worked with some of the DNCB proponents,
as well as some experts from the University of California —
I remember Jay Levy was involved, as was Marcus Conant and others
— and we wrote a protocol that we submitted to the FDA for
funding. That also was rejected.
Around the time that AZT first became available in 1986, I went
to a conference in Japan where I was introduced to some investigators
from the Ueno Fine Chemicals company who told me that they had the
cure for this disease. They said it was something that was very
commonly used in Japan but they couldn't tell me about it until
I signed a confidentiality agreement. That turned out to be dextran
sulfate. Not long after I was going through the process of filing
the paperwork to get approval from the FDA to do a phase I study
of dextran sulfate in the United States when evidently some people
heard about it. They realized that it was a product that was widely
available in Japan — I believe it was used for lowering cholesterol
— so they started an importation scheme similar to what had
happened in earlier days with isoprinosine and ribaviran, which
were brought across the Mexican border. But people had now become
more sophisticated in their methods and began to import dextran
sulfate from Japan to sell in the underground AIDS therapy market.
I remember that activists stormed the offices of a Japanese drug
distributor in New York for refusing to make dextran sulfate more
widely available. Ultimately it became such a political issue that,
even though my clinical trial here in San Francisco didn't show
much benefit, Congress got involved and the AIDS Clinical Trial
Group (ACTG) was asked to do a study of dextran sulfate through
the NIH-funded mechanism. It turned out the drug was not even absorbed
into the blood.
Another Japanese product I worked with was lentinin, which was
an intravenously administered extract of shiitake mushroom. In Japan
it was felt to be an immune booster for patients with cancer. Although
it was being used by mainstream doctors in Japan, it was an alternative
therapy here because it was not something that we had ever learned
about or used in hospitals in the U.S. That's David Eisenberg's
description of what an alternative therapy is — that it's
not taught about in medical schools or widely available in U.S.
hospitals — and certainly shiitake mushroom extracts qualified.
Again, that's another study we did that had negative findings; there
was no benefit to the intravenous infusions of lentinin. Since I've
learned more about botanicals, it would seem to me that if there
were immune enhancing benefits to shiitake mushrooms then they are
more likely to be obtained by eating them rather than by injecting
an extract intravenously.
During that time I was also involved with studies of conventional
therapies. Even in the days of early AZT monotherapy, which I was
not a big supporter of, I was involved in trying to put some evidence
behind the claims of the proponents for these various agents. And
since that time, I've had a constant history of investigating conventional
therapies through the federally-funded CPCRA (Community Programs
for Clinical Research on AIDS), and more recently through the ESPRIT
study of interleukin 2, as well as in other, sometimes pharmaceutical
industry-sponsored trials. But always ongoing with those studies,
I've been involved with clinical trials of complementary and alternative
interventions.
When we first became aware of immune thrombocytopenic purpora (ITP)
in AIDS, I worked with a nurse who was very interested in therapeutic
touch and we studied men with low platelet counts to see if therapeutic
touch could decrease their stress and increase their platelet counts.
That was another study that turned out to be fairly negative.
I then became interested in traditional Chinese medicine (TCM)
and, in fact, one of the colleges of TCM here in San Francisco sent
me to China in 1989 just to learn about Qigong (Chi Kung) —
that exercise that's felt to improve the immune system — to
see if it was something that I wanted to study here. Although I
never studied Qigong I collaborated with Misha Cohen from the Quan
Yin Healing Arts Center here in San Francisco. We did three studies
of traditional Chinese herbal interventions for, first, symptomatic
HIV, then for patients with diarrhea without a pathogenic source,
and then another study for patients with anemia. The last two were
hindered by the fact of being initiated about the time that HAART
became available, so patients with diarrhea as well as anemia became
scarce. There were also a lot of pills that needed to be taken in
these Chinese herbal investigations and patients at that time were
taking huge amounts of pills with their antiretroviral regimens,
so the studies weren't very attractive. None of these studies had
spectacular results and the anemia study was terminated for poor
enrollment.
Have "soft endpoints" such as life satisfaction created
a problem for designing and conducting credible studies?
The TCM herbal study that we published in 1996 investigated herbs
versus placebo in symptomatic HIV infection. At the time of the
study in 1993, we had patients with about 14 symptoms on average
and we found that there was a significant decrease of symptoms in
the herb-treated group — they decreased from 14 to 12 —
whereas the other group still had 14 symptoms. We also found that
they had improved "life satisfaction" which improved by
a factor of +0.86 or thereabouts. Yet, if you look at the rest of
the results, the Chinese herbal patients actually lost weight over
12 weeks compared to the placebo group, and their CD4 counts also
dropped — not statistically significant, but it was a trend.
So that was an example of where their symptoms improved and their
life satisfaction increased, but the parameters that we would normally
look at to see if a patient is doing well, i.e. weight and CD4 count,
went in the wrong direction. So, although I was also first author
on a study that showed that epoetin alfa improves quality of life
in HIV patients who are anemic, I'd have to say that a study whose
main endpoint is quality of life is something I would find difficult
to interpret.
The CPCRA actually did a large study of acupuncture for patients
with HIV-related peripheral neuropathy that was published in JAMA.
That was a landmark, having the NIH support an acupuncture study,
although, again, it turned out to have negative results; acupuncture
didn't appear to be effective in treating peripheral neuropathy.
About this time I began trying to study another botanical, which
has consumed my efforts for the past decade, and that would be cannabis,
or marijuana. Starting in 1992 I began proposing and developing
clinical trials to investigate first the effectiveness — but
then I realized that that wasn't going to happen — so subsequently,
the safety of smoked marijuana in patients with HIV. We finally
completed a study in the year 2000, that we hope will soon be published,
that looked at the safety of marijuana in patients taking protease
inhibitor regimens. And since that time we have obtained funding
from the State of California that allows us now to conduct clinical
trials to look at the potential effectiveness of smoked marijuana
in patients with various syndromes. We have also just completed
a pilot study in patients with HIV peripheral neuropathy, which
allowed us to ascertain that there was some effectiveness of marijuana.
But an open-label pilot study is not going to prove that, so we're
now in the process of continuing on with a randomized, placebo controlled,
double-blind trial in patients with HIV-related peripheral neuropathy.
We're also doing marijuana studies in patients with cancer who have
pain who are on opioid analgesics, and another study to look at
the effect of smoked marijuana in patients who have delayed nausea
and vomiting from breast cancer chemotherapy.
It was working with marijuana and all the problems that are inherent
in studying a plant as a therapy that has led me to a broader interest
in botanicals and the use of substances that come from nature as
medicinal agents. Certainly, for thousands of years, people have
depended primarily on these things. Whether or not they worked is
unclear, but as an oncologist I know that many of my most potent
chemotherapeutic agents were derived from plants. So right now we
are waiting to hear if a protocol we submitted to the National Center
for Complementary and Alternative Medicine (NCCAM) to investigate
the lipid lowering effects of oyster mushrooms in patients on Kaletra
is being funded. There's good evidence that mushrooms, including
oyster mushrooms in particular, have some activity for lowering
blood lipids and cholesterol.
We're also just finishing a three-year NCCAM grant studying the
effects of DHEA, dehydroepiandrosterone, which is an over-the-counter
adrenal steroid that people are taking for many reasons. We received
a grant to investigate it as an antiviral and to see what impact
it has on the immune system. Hopefully that data will be available
by the end of the year and we will know if DHEA had any impact,
positively or negatively, in our patients.
The goal, ultimately, would be to submit a center grant to the
NCCAM, to allow us to establish a center here for the study of botanicals
in HIV because there are still a number of herbal preparations and
mushroom extracts that warrant further investigation for their potential
benefit — and to make sure that they're not harmful in our
patients.
Safety keeps coming up again and again as one of the inarguable
justifications for doing this research.
There's not a huge amount that we know about some of these botanical
products and how they're metabolized, but there's probably more
than people think. There are a number of textbooks available that
talk about herb-drug interactions. That was the question in our
marijuana study: is there an interaction between cannabinoids and
protease inhibitors, which are both metabolized by cytochrome P450
enzymes in the liver, that may alter the activity of the protease
inhibitors such that patients lose their viral suppression when
they mix cannabis with their treatments? And in fact, in our article
that was already published in AIDS, we saw no such effect. We've
all heard about garlic and St. John's Wort and their interactions,
and I think there are many other agents that we would like to study
to make sure that they are not having significant interactions with
protease inhibitors. We don't want people to either lose control
of their viremia (through underdosing) or experience toxicity (through
overdosing) because of antiretroviral concentrations that have been
affected by herb-drug interactions.
You had to be enormously persistent to accomplish your marijuana
study. In the current political climate, is it going to be more
difficult to do marijuana studies?
I think we're blessed to live in the State of California, which
is somewhat of a freestanding republic in and of itself. In 1996,
the people of California voted to allow physicians to talk to their
patients about the medicinal use of cannabis. Then, through the
work of Senator John Vasconcellos, one of our state senators, appropriations
were made to the University of California that established the Center
for Medicinal Cannabis Research (www.cmcr.ucsd.edu).
And that Center has had funds for the past three years that allows
it to support clinical trials to investigate the use of marijuana
for medicinal purposes. Whereas the NIH and NIDA, via their congressional
mandate, could only give marijuana to clinical trials that show
that it was harmful (they are the National Institute on Drug Abuse,
not for Drug Abuse, as NIDA's director Alan Leshner always reminded
me), they were not really able to provide us with marijuana to study
the benefits. But now, they have modified their system so they can
provide marijuana for peer reviewed clinical trials that will look
at its effectiveness as a therapeutic agent — as long as they
are not funding it. So they have now created this ability for us
to obtain government marijuana.
Is there a need to increase provider knowledge about these
issues?
I think a part of the problem is a lack of communication from both
sides. Patients don't really perceive that these substances are
something that they need to tell their doctor about — in fact
many studies show they don't want to tell their doctor because they're
afraid they're going to be reprimanded or told that they're wasting
their money. And many physicians never even think about asking about
these things as potential confounders or as things that are causing
clinical symptoms. There also may be a variable of where in the
country you are. I know many surveys show that we in the West have
the highest percentage of people in the population who are using
complementary and alternative interventions. So many of my colleagues
here might be more familiar with how to ask the question and what
to be looking for.
I remember once seeing a patient at our drop-in clinic who clearly
had a drug rash. I looked through his chart — this was when
we had paper charts — and he had a high CD4 count and a low
viral load but he wasn't taking any medications.
So I said to the guy, "You're not taking any medications,
huh?" And he said, "No."
"Are you taking any vitamins?" And he said, "Yeah."
So I asked him what he took and he listed about four or five vitamin
preparations.
Then I asked, "Do you take any herbs?" And he said, "Sure."
And so I listed the three or four herbal substances that he took.
"Do you take any minerals?" And he said, "Yeah."
By the time I finished I had a list of 12 different things he
was taking.
So I asked, "Well, how come everybody else wrote down that
you don't take anything?" And he said, "Well, nobody ever
asked me before."
"Alternative"
Treatment Activism
By Jon Greenberg
A version of this article originally appeared in Treatment
Issues in the Winter of 1993/94. It was edited posthumously from
the writings of Jon Greenberg, who died of AIDS on July 12, 1993.
Since the beginning of the AIDS crisis, a number of "alternative"
medical treatments have been proposed and used with unknown success,
such as herbal compounds, nutritional supplements, traditional Chinese
medicine, as well as physical manipulation techniques and spiritual
approaches. Although these methods have all been lumped together
under the generic category "Alternative or Complementary Health
Care," they differ substantially in philosophy, modality, cost,
and other important ways. However, they all share one unfortunate
similarity — virtually nothing is objectively known about
their activity in the human body and their efficacy for treating
HIV/AIDS.
The AIDS community tends to fall into two separate camps regarding
alternative therapies. Some dismiss all alternative treatments,
regardless of evidence that demonstrates efficacy, while others
defend all alternative therapy, regardless of evidence suggesting
toxicity or lack of benefit. The reality probably lies somewhere
between these two extremes; some alternative therapies may be effective,
some are clearly ineffective, and most possess some potential for
toxicity. The chief difficulty with using alternative therapies
is a lack of empirical data and an absence of commercial scientific
interest in these compounds. Presently, there is no research infrastructure
to systematically address the potential benefits and risks of alternative
treatments using controlled experiments, the most rigorous known
method of producing convincing data about a treatment's effects.
Every FDA approved medicine for HIV has gone through this process.
Why not study all the treatments that people with HIV use in the
same way?
Obstacles to Testing Alternative Therapies
One goal of alternative therapy activists should be to advocate
for controlled clinical trials of alternative treatments, so that
people can make informed decisions about using them and that wider
acceptance can be gained for those treatments that are found to
be effective. Our goal should be to make the term "alternative"
obsolete. At present, very few alternative treatments are ever studied
in a government- or university-sponsored clinical trial. They have
never gone through a process that details their toxic effects in
humans; assesses bioavailability, pharmacokinetics, safety and efficacy;
or determines their impact on the immune system.
Since toxicity studies on most alternative therapies have not been
conducted — and since some alternative treatment practitioners
may recommend these therapies at very high doses — it must
responsibly be asserted that toxicities may occur. Yet, for the
most part, if a proponent of a specific alternative therapy has
observed negative side-effects, there is no mechanism, no mandate,
no regulation, and therefore no institutionalized reason to disclose
such information. And, of course, profit can be as big a motive
for the "alternative" medical community as it is for the
conventional pharmaceutical industry.
Even when alternative treatment proponents have no financial investment
in proposed therapies, the emotional investment in the therapy's
success is usually high. Many alternative treatment enthusiasts
have a strong desire to prove conventional Western medicine wrong.
This sentiment sometimes precludes objective evaluation. Very often,
claims of efficacy and recommendations for alternative therapies
are based on anecdotal reports or loosely designed observational
studies. Design flaws, poor execution, or too-limited sample size
prevent these studies from generating useful or reliable information.
Making Decisions in the Information Vacuum
It is tiresome and sometimes confusing to depend on other people's
stories in order to make treatment decisions. As we all know, these
stories are often colored by biases and histories that we may not
necessarily share. This is not to say that these personal experiences
are invalid for those who believe and promote them. But each of
us has a different biological, emotional, historical, psychological
and intellectual make up.
Every person with HIV uses a variety of methods to gather information
on treatment options. How much do I take? How often do I take it?
Is it a pure substance? What are the possible side effects? Will
it work? This decision-making process is complex and individual.
We are too often forced to make decisions without much information.
Unfortunately, getting the information we need may require a long
process. And even controlled clinical studies of alternative treatments,
although necessary to gather scientific information, may ultimately
yield little useful information. Quite frankly, results from controlled
clinical studies often raise as many questions as anecdotal reports
or personal histories do.
Health care practitioners who share questions, doubts, criticisms
about treatment (as well as beliefs in a particular therapy), can
help people with HIV most by encouraging patients' responsibility
for his or her own decision-making process. People with HIV also
need to know that doctors do not have all the answers and that much
of the information they use to make treatment decisions can be learned.
Believing that only doctors and orthodox medicine holds the answer
can also be an obstacle to the self-empowerment of people with HIV.
Ideally, the trust in a treatment decision should come from within.
Taking Action
It is important to identify through controlled clinical studies
those treatments that seem most promising for potential development.
We must make contacts among key researchers in pharmaceutical settings,
the federal government, research universities, and institutes across
the country. (In pursuing these issues, I've found it easier and
more expedient to speak the language of the researchers and the
scientific community than it is to force them to speak the language
of people with AIDS and alternative treatment activists.) We must
create an interest in the research establishment to address the
obstacles to research on alternative treatments. We must learn how
to write concept sheets, the blueprints for clinical trials designs,
to spark the interest of researchers. We must strategize the best
way to study the compound in question and the most politically efficient
manner to initiate study. This often involves writing letters, making
phone calls, and staging political actions to urge all the parties
involved to take action. We need to get their attention.
Controlled clinical studies may offer the only opportunity to directly
evaluate alternative treatment options using well-defined criteria.
We should not have to place extraordinary faith in one practitioner
or theory of disease and treatment, whether conventional or alternative.
We need answers to our questions.
Moving Forward with Integrative AIDS Research
By George M. Carter, Mark Kuebel and Evan Ruderman
The Foundation for Integrative AIDS Research (FIAR) is a
not-for-profit organization formed in October, 2001, to sponsor
and stimulate interest in clinical trials of herbal and nutritional
treatments for people with HIV, AIDS and chronic hepatitis.
The goal is to show whether or not these treatments can lessen
symptoms, delay the use of Western drugs, reduce side effects,
and are safe. FIAR is working to develop studies in developing
nations where indigenous treatments are used and Western drugs
are largely unavailable. FIAR also seeks to help bring affordable
Western drugs, education and prevention to such under-served
areas.
FIAR has been working on several studies in collaboration
with the Mt. Sinai Medical Center. Among these are a study
of milk thistle in people with HIV and hepatitis C, a study
of the Ayurvedic herb, Bacopa monniera for minor cognitive
motor disorder, and a proposed phase I study of a therapy
being used by Siddha practitioners in Southern India. Siddha
is an ancient traditional medicinal system of India. FIAR
has also started a pilot condom distribution program for men
who have sex with men in Kathmandu, Nepal, working with the
Blue Diamond Society. Groundwork is being laid for an STD/HIV
clinic there.
The goal in working with local communities is to design and
implement clinical studies that help establish and strengthen
local capacity by bringing attention and funding where it
is needed. FIAR's selection of clinical questions to be addressed
will be drawn first from the infected and affected community.
Such a grassroots based approach to generating study questions
will help promote a sense of cooperation and comradeship between
researchers and people living with disease. Of course, the
first duty to participants in such studies is to assure only
the highest standards for informed consent, patient protection
and careful monitoring are met.
It's time that people had better information to help guide
treatment choices. Many studies show that a high percentage
of people living with HIV/AIDS already use many of these interventions.
Yet many questions remain: How do they work? Can they help
to manage side effects of drug therapy? Can they slow the
rate of progression? FIAR, working with the HIV/AIDS and Hepatitis
communities, clinics, hospitals, practitioners and organizations
around the United States and elsewhere, intends to design,
fund and implement clinical studies to address some of these
questions and thus help people make better-informed treatment
decisions.
For more information about FIAR: E-mail: fiar@verizon.net.
Web: http://aidsinfonyc.org/fiar |
HIV/AIDS and People
with Disability
By Nora Ellen Groce
Reprinted from The Lancet, April 26, 2003
Although AIDS researchers have studied the disabling effects of
HIV/AIDS on previously healthy people, little attention has been
given to the risk of HIV/AIDS for individuals who have a physical,
sensory, intellectual, or mental health disability before becoming
infected. It is commonly assumed that disabled individuals are not
at risk. They are incorrectly thought to be sexually inactive, unlikely
to use drugs, and at less risk for violence or rape than their non-disabled
peers. Yet a growing body of research indicates that they are actually
at increased risk for every known risk factor for HIV/AIDS. For
example, in a recent article, S. Blumberg and W. Dickey analyze
findings from the 1999 U.S. National Health Interview Survey and
show that adults with mental health disorders are more likely to
report a medium or high chance of becoming infected with HIV, are
more likely to be tested for HIV infection, and are more likely
to expect to be tested within the next 12 months than are members
of the general population.
Such findings should not be unexpected for individuals with disability.
There are significant risk factors for disabled populations around
the globe. For example, despite the assumption that disabled people
are sexually inactive, those with disability — and disabled
women in particular — are likely to have more sexual partners
than their non-disabled peers. Extreme poverty and social sanctions
against marrying a disabled person mean that they are likely to
become involved in a series of unstable relationships. Disabled
individuals (both male and female) around the world are more likely
to be victims of sexual abuse and rape than their non-disabled peers.
Factors such as increased physical vulnerability, the need for attendant
care, life in institutions, and the almost universal belief that
disabled people cannot be a reliable witness on their own behalf
make them targets for predators. In some countries, parents of intellectually
disabled children now report rape as their leading concern for their
children's current and future well-being. Individuals with disability
are also at increased risk of substance abuse and less likely to
have access to interventions. It is estimated that 30% of all street
children have some type of disability and these young people are
rarely reached by safe-sex campaigns.
Furthermore, literacy rates for disabled individuals are exceptionally
low (one estimate cites an adult literacy rate of only 3% globally),
thus making communication of messages about HIV/AIDS all the more
difficult. Sex-education programs for those with disability are
rare, and almost no general campaigns about HIV/AIDS target (or
include) disabled populations. Indeed, where AIDS campaigns are
on radio or television, groups such as the deaf and the blind are
at a distinct disadvantage.
The future for disabled individuals who become HIV-positive is
equally grim. Although little is known about access to HIV/AIDS
care, disabled citizens receive far fewer general health services
than others. Indeed, care is not only often too expensive for impoverished
disabled persons, but it can also be physically inaccessible —
e.g., clinic steps bar the way for a wheelchair user and consultation
with a physician without a sign-language interpreter is meaningless
for most deaf persons.
Currently, little is known about HIV/AIDS and disability. Only
a few studies have estimated prevalence and no prevalence data exist
for any disabled populations from sub-Saharan Africa, Asia, Europe,
Central and South America, or the Caribbean. However, a growing
number of stories from disability advocates worldwide point to significant
unreported rates of infection, disease, and death. Over the past
decade there have be a handful of articles on HIV/AIDS pilot programs
and interventions for intellectually disabled adults or services
for deaf adolescents. Many of these projects are innovative but
almost all are small and underfunded. There is a real need to understand
the issue of HIV/AIDS in disabled people in global terms and to
design and implement programs and policy in a more coherent and
comprehensive manner. The roughly 600 million individuals who live
with a disability are among the poorest, least educated, and most
marginalized of all the world's peoples. They are at serious risk
of HIV/AIDS and attention needs to be focused on them.
| In January 2003, the World Bank and
Yale University, started a global survey on HIV/AIDS and disability
that seeks to better understand variables of the current epidemic
as well as to identify best-practice interventions and grassroots
efforts.
Organizations that serve people with HIV and disability are
invited to participate in the survey. International respondents
are especially welcome.
Contact: Nora Ellen Groce, Global Health Division, Yale School
of Public Health, Yale University, New Haven, CT 06520, USA;
e-mail: nora.groce@yale.edu. |
Reyataz Dosing Options
Discussed
Excerpts from the FDA Atazanavir Hearing
By Bob Huff
Atazanavir has been developed as a once-a-day (QD) protease inhibitor
to treat HIV infection in combination with other antiretrovirals.
Its approved dosage will be 400mg QD, taken with food. The convenience
of QD dosing is expected to enhance regimen adherence and contribute
to treatment effectiveness.
Atazanavir (ATV) is distinguished among protease inhibitors by
having little impact on blood lipid levels such as cholesterol and
triglycerides. Patients who had developed high lipid levels after
taking other protease inhibitors experienced normalization of lipids
after switching to atazanavir. Atazanavir also had a unique and
favorable resistance profile among protease inhibitor naive patients
in which resistance, when it occurred via the protease mutation
I50L, produced a virus with increased susceptibility to other protease
inhibitors. A dose limiting side effect is the development of jaundice
or yellowing of the eyes due to otherwise benign bilirubin increases
in a large proportion of patients.
In a head-to-head comparison for 48 weeks, atazanavir performed
as well as efavirenz for lowering viral load below the limits of
detection in a large phase III clinical trial in people beginning
their first anti-HIV regimens. However, in 24 week data from a trial
in people with prior protease inhibitor therapy, 400mg of atazanavir
QD did not perform as well as a standard dose of Kaletra. But when
blood levels of a 300mg dose of atazanavir were boosted by 100mg
of ritonavir (RTV), reductions of viral load after 24 weeks were
equivalent to those produced by Kaletra in the treatment experienced
population.
On May 13, 2003, an FDA antiviral advisory committee, a panel of
experts convened by the federal Food and Drug Administration, met
to discuss data submitted by Bristol-Myers Squibb (BMS) to support
the approval of atazanavir. The daylong meeting considered issues
ranging from possible cardiac effects to the type and quantity of
"food" that should accompany a dose of atazanavir. Although
data on the efficacy of ritonavir-boosted atazanavir for treating
protease inhibitor experienced patients was shown at the meeting,
it had not been received in time for evaluation by the FDA, and
was not officially considered part of the sponsor's application.
This created a quandary for the committee members who, while generally
convinced of atazanavir's efficacy in a treatment naive population,
felt that unboosted atazanavir for patients with prior PI mutations
would not be a wise choice. They felt they had no alternative but
to consider data about boosted atazanavir that had not been officially
presented to them.
The following are edited excerpts from the hearing that focus on
the issues of atazanavir blood levels at the end of a dose cycle
(Cmin; minimum concentration) and the question of whether to support
the approval of unboosted atazanavir knowing that in practice, it
will likely be boosted with ritonavir in treatment experienced patients.
Boosting with ritonavir improved Cmin considerably. There were also
a few questions about the compromising effect that adding ritonavir
to the regimen might have on the lipid benefits seen with unboosted
atazanavir.
Despite the apparent effectiveness of 400mg atazanavir in treatment
naïve patients, several committee members were concerned by
data from pharmacokinetic (PK) studies that revealed wide variability
in the Cmin at 24 hours. They questioned if subtherapeutic doses
at Cmin in some treatment naïve patients were responsible for
treatment failures seen in the Phase III study.
The significance of Cmin is acknowledged in this sentence from
the sponsor's briefing document: "The association of Cmin with
antiretroviral activity is consistent both with HIV being a continuously
replicating virus, and with drug needing to be present at all times
in concentrations that equal or exceed those concentrations required
to inhibit viral replication."
The lower range of Cmin in atazanavir PK studies at 400mg QD was
12 ng/ml. The EC90 of atazanavir, the drug concentration observed
to inhibit virion production by 90 percent in a cell-based assay,
after adjustment for protein binding, was about 75 ng/ml against
a laboratory strain of HIV. However, similar assays performed with
actual HIV isolates from treatment naive patients produced a median
EC90 of 14 ng/ml, with values ranging from 2.4 to 40.6 ng/ml.
It should also be noted that only 24 hour Cmins were reported.
Data on 48 hour Cmin, such as might result from a skipped daily
dose, were not presented.
Definitions:
Cmax: the
maximum concentration of a drug in the body after dosing. It
defines the peak level after dosing. Cmax is often associated
with side effects.
Cmin: the lowest concentration
of a drug after dosing. It defines the trough level at the point
when another dose is taken.
EC50: A point
half-way between a concentration of drug that produces 100%
suppression of HIV in a laboratory test and one that produces
no suppression. EC90 reflects 90% suppression.
Pharmacokinetics (PK): the study of the absorbtion,
distribution, metabolism and elimination of drugs in the body.
Therapeutic drug monitoring (TDM): measuring
blood drug levels so that the most effective dosage can be attained
with minimal toxicity. |
Discussion
Discussants: Antiviral Drugs Advisory Committee Chair: Roy
Gulick, MD, MPH; Members: Eugene Sun, MD, Rory Remmel, PhD, Courtney
Fletcher, Pharm.D., Wm. Christopher Mathews, MD, Janet Englund,
MD, Thomas Tephly, MD, Princy Kumar, MD. For FDA: Debra Birnkrant,
MD. For BMS: Michael Giordano, MD, Steven Schnittman, MD.
A complete transcript of the FDA hearing can be found under "Antiviral
Drugs" at: www.fda.gov/oc/advisory/acdrugs.html
On the Cmin in naïve patients:
DR. SUN (ABBOTT LABS): In your analysis of the virologic failures
from your various clinical trials, have you analyzed the pharmacokinetics
in those patients, especially given the fact that there is a fairly
large variability in PK, particularly around Cmin (see Table 1),
and that that might account for a substantial part of the failures
that you can't attribute just to phenotypic analysis?
| Table 1: Mean (Range) Steady-State Pharmacokinetic
Parameters of Atazanavir |
| |
ATV 400mg
Unboosted |
ATV 300mg/RTV 100mg
Boosted |
| Cmax (ng/ml) |
5358
(3166-7970) |
6450
(2829-11910) |
Cmin
(ng/ml) |
218
(12-840) |
1441
(214-3323) |
DR. SCHNITTMAN (BMS): We have not selectively analyzed the pharmacokinetic
parameters in those subjects who have failed. In fact, when one
goes back and looks at these patients, many of the reasons for failure
have to do with adherence, compliance or other issues that really
have no bearing on what the actual absorption of drug is.
DR. REMMEL: At the 400 mg dose, clearly, there was good effect
with atazanavir, but I am concerned about the pharmacokinetic variability
of the drug.
While the sponsor probably wouldn't want to encourage concentration
monitoring (TDM), this is a major issue in terms of many of the
protease inhibitors, especially because they are all CYP3A substrates,
and I think that we could see some benefit if it was to be done.
But I would like to see some sort of indication of how many patients
who fell at the low end for the Cmins or area under the curve were
actually failing, and what that component is in terms of the efficacy
of this drug.
DR. GULICK: Then, Dr. Remmel, you suggest maybe TDM would be an
interesting thing to think about for this drug?
DR. REMMEL: It is not something sponsors like to hear, but I think
that we can understand more about this drug (by doing TDM). (The
drug) does have a very large variability in the PKs when it is not
taken with a boosted ritonavir dose. Now, it may be overly burdensome
for certain patients and certain types of practices, but I think
from the company's standpoint, I would want to know where my trough
levels are.
DR. GULICK: Dr. Fletcher, anything to add?
DR. FLETCHER: I would agree. I think as a Phase IV study, (TDM)
would really be a worthwhile study to consider. It actually goes
to Dr. Sun's question about what was the incidence of pharmacokinetic
reasons for failure in patients, and if you look at the well-controlled
pharmacokinetic studies that the sponsor presented, the range of
trough concentration goes down to 12 nanograms per ml, which is
below the adjusted IC50, and I think that has to clearly put a patient
at risk of failure.
The best response is always to the first regimen. If there is an
opportunity to improve the rates of response in naive patients,
I would think that would be good for patients and good for the sponsor
to take a look at. So, I would encourage some serious look at whether
therapeutic drug monitoring could improve response of patients to
this drug.
What can the drug label say about atazanavir in treatment
experienced patients?
DR. FLETCHER: This would be a question to the FDA. Would the agency
consider, in the dosing recommendations, the use of the boosted
atazanavir/ritonavir dose (300/100 mg regimen), or does the dosing
really have to be constrained to the 400 mg, once daily, dose (supported
by available data)?
DR. BIRNKRANT (FDA): As of today, it would be restricted to the
400 mg dose. The date by which a regulatory decision has to be made
by law, is the 20th of June, so between now and then, there isn't
that much time to review that additional data that came in late.
DR. MATHEWS: There is a real dilemma, I think, facing the committee
and the agency because the agency has not reviewed the 16-week data
on the PK-boosted regimen, and yet the (unboosted) data that was
reviewed in experienced patients (leaves a physician) with the decision
of using a regimen which may have inferior virologic outcomes, but
has a lot of advantages in terms of simplicity, tolerability, and
so on.
Based on the data that is reviewed and reviewable at this point...
you could say that it's superior to placebo based on the comparisons
that were done in that trial, but inferior to a regimen containing
Kaletra.
DR. GULICK: It puts us, as a committee, in an awkward position
because we are seeing evidence of activity (in treatment experienced
patients), but it is not as good as a comparator arm; at the same
time, we saw preliminary activity which hasn't been reviewed by
the agency, which seemed to suggest similar virologic effects to
a Kaletra-based arm. In addition, (we also saw) pharmacokinetics
data to support better drug levels and a better Cmin, when boosted
with ritonavir, so I think that we are feeling a bit conflicted
about this point.
DR. BIRNKRANT (FDA): Well, it is a dilemma for us, as well, to
see snippets of data that look potentially promising, but given
that it was submitted so late, it is difficult to review all of
that data within such a short period of time.
DR. FLETCHER: Well, in my mind, (the boosted regimen data) is the
only data that would really make the case for using the drug in
the treatment-experienced patient. If you have to look at just the
400, once daily, regimen versus Kaletra, it wasn't as good as other
available agents.
DR. GULICK: Other thoughts on that?
DR. ENGLUND: But I also can sense at least from the people I work
with, and I know the FDA appreciates this, too, is the sense of
urgency. We have patients that are running out of alternatives.
DR. GULICK: Other opinions about this? Dr. Mathews.
DR. MATHEWS: Let me say that I think we would not be well advised
to take the extreme position of saying that because it's inferior
to a Kaletra-containing regimen, it shouldn't be approved for treatment-experienced
patients. I mean I have lots of patients who are having a lot of
trouble taking Kaletra or other PI-based regimens that are very
anxious to get to a simplified PI regimen. On the other hand, I
am going to have to tell them, "You are barely controlled right
now, and the small difference in efficacy between what you are on
now and this more simplified regimen may cost you long-term virologic
control. We don't know."
DR. GULICK: Clearly, the biggest need in the clinic right now is
not so much the early failure people where you may have several
options to choose from, but in the later stages where you want some
good options. (The drug's benefits) in a naive regimen — low
pill count, once a day, apply in the salvage setting, as well.
DR. REMMEL: There is, of course, another class of experienced patients
to consider, and those would be patients who already have disturbed
lipid profiles and who you want to switch to lower their cholesterol
or lower their triglycerides especially. That clearly would be advantageous
for many patients in addition to simplifying their regimen.
DR. TEPHLY: Exactly. We can't forget the advantage of the lipid-lowering
quality of this particular agent.
DR. GULICK: Other comments on the experienced? Dr. Kumar.
DR. KUMAR: I want to echo some of the comments that Dr. Mathews
had said. In the treatment-naive patient, I think it is an excellent
drug, it's a drug that I feel very, very comfortable with, but in
the treatment-experienced patient, using it by itself, with unboosted
dose, my concern is that failure begets failure, and in that setting,
despite its convenience, the dosing, that it may lead to the development
of more and more resistant mutants, so that is really what I am
concerned about, using it as a single dose of 400 mg without boosting.
DR. MATHEWS: I have a question about the (lipid) effects of boosted
atazanavir compared to unboosted: In one of the slides that Dr.
Grunfeld showed, in experienced patients, the proportion taking
lipid-lowering therapy on unboosted regimens was about 4 percent;
boosted, it was 7 percent, which is nearly twice as much. So, I
think it is relevant to know what the direct comparison is; how
much of (atazanavir's lipid) benefit is lost if it's boosted?
DR. GIORDANO (BMS): We don't have data which is a head-to-head
comparison of atazanavir boosted versus unboosted, so I can't answer
that specific question. Sorry.
DR. GULICK: Let's shift gears and talk about what the resistance
data implied about the use of atazanavir in experienced patients.
We saw lots of evidence for cross-resistance in the highly PI-experienced
patient. Maybe we could also think again about atazanavir by itself
versus boosted atazanavir.
Dr. Fletcher, why would a ritonavir-boosted atazanavir regimen
work better against a resistant virus?
DR. FLETCHER: Well, it's because of, to use the term from the sponsors,
the PK cushion. You have an inhibitor that is going to raise the
atazanavir levels, and in the case of viruses that have decreased
susceptibility, it will provide the more typical type of relationship
between the concentration of drug and the concentration that the
virus needs to inhibit it.
DR. REMMEL: Again, I think this is where sometimes a pharmacokinetic
evaluation could be helpful. If you had a 5-fold increase in resistance,
and you have a patient with a longer half-life, you might feel more
comfortable about raising the dose slightly to make sure that you
have a good therapeutic window.
For patients with shorter half-lives, you feel like you can't reliably
raise that window. Because of a 24-hour dosing interval, you could
go to a more frequent dosing interval or perhaps go to a boosted
regimen. We haven't really talked about giving the drug on a BID
(twice-a-day) schedule, but many patients could adhere to that schedule,
and that might solve some of those problems.
DR. MATHEWS: As I said earlier this afternoon, if you are trying
to trade off toxicity, simplicity and lipid (benefits) with virological
efficacy or effectiveness, having a more precise estimate of what
the pharmacodynamic response pattern is in experienced patients
is very important.
What post-approval studies should be considered?
DR. MATHEWS: I mentioned a study that I thought should be done:
a direct comparison of boosted versus unboosted for the lipid effect,
but perhaps that could be studied in the context of another naive
trial of boosted versus unboosted atazanavir to improve on the long-term
response rate, because, for whatever reason, 65 percent suppressed
at 48 weeks is not optimal.
Commentary
The outstanding rationale for developing atazanavir for the HIV
market has been once daily dosing. The clear consensus of the FDA
advisory committee was that 400mg QD will produce adequate drug
exposure for most treatment naive patients (resistance testing prior
to starting a first regimen is recommended to assess susceptibility).
For those with ARV resistance, that dosage was recognized as inferior
to a ritonavir-boosted dose. Yet there were also concerns that the
unboosted dose will not provide sufficient coverage in a minority
of naive patients. Higher doses produced unacceptable bilirubin
increases, and while boosting with ritonavir was effective at increasing
Cmin without increasing toxicity, the important lipid-neutral benefits
of atazanavir may be compromised — an unexplored issue for
experienced persons, as well.
There is a real concern among community activists that QD dosing
will be oversold in advertising for Reyataz. Since no information
about the efficacy of a boosted regimen will appear on the product
label, there will be a critical need for education to clarify the
limitations of 400mg QD in treatment experienced individuals. For
naive patients, discovering which are susceptible to low Cmin and
would benefit from boosting, higher doses or more frequent dosing,
may be a problem. Several committee members recommended TDM (therapeutic
drug monitoring) of drug concentrations in the blood, a complicated
assay that is not widely available in the U.S. Post-marketing studies
of TDM to determine the frequency of low Cmin in the patient population
should receive top priority.
A Space and Time for
Healing: The Importance of the Abundance Paradigm
By Ana Oliveira
November, 1981, 7:30 a.m.; clients line up in front of
an old Department of Health building in the Bronx — the acupuncture
building. It was there I learned the vital importance of healing;
of maintaining an environment that holds healing.
June, 2003, 12:30 p.m.; clients sit with eyes closed,
quietly, in The Corner, the acupuncture space at Gay Men's Health
Crisis. It is here that I learn the continued importance of long-term
healing; of maintaining a space that holds and integrates
healing.
The longer the AIDS plague continues, the more important it becomes
to integrate and multiply the opportunities for access to complementary
therapies in the lives of our communities. Whether through traditional
healing practices received from ancestors, or through desperation
and the need for alternative options, more and more individuals
are using complementary therapies to support and enhance the quality
of their lives. The increasing complexity of HIV medical management
and its side effects, the increasing limits on access to care, and
the growing toll of untreated mental health conditions compel us
to recognize and institutionalize effective complementary therapies
into all of our helping organizations.
Holistic and complementary therapies are increasingly being brought
into public health settings in the U.S. Urban and rural substance
abuse clinics, criminal justice and prison settings, emergency and
crisis-intervention settings have all benefited from the immediate
rewards and drug-free approach offered by holistic interventions.
From nutrition to acupuncture to herbal treatments, more and more
practitioners are motivated to practice in public health settings,
reaching the neediest and most complex clients. Schools are bringing
internships and off-site trainings to community-based organizations
that facilitate access to the practitioners, interventions, and
staff of holistic centers.
Complementary therapies use mostly non-verbal, non-intimidating
methods and work well alongside other interventions. They tend to
operate from a building, or re-building approach, as a teacher would,
strengthening the capacities that are present and opening up a receptivity
for change. They enhance, rather than decrease; they release, rather
than control; and they can create experiences that are critical
for the healing of individuals and of communities that are the most
depleted and vulnerable. They build towards, rather than fight against,
and in doing so generate the actual experience of hope and possibility
that is so critical for continuing the fight in this plague.
Complementary therapies are also, relatively speaking, much less
expensive than allopathic medicine. Because they attempt to integrate
the spirit, the body and the mind, they tend to be less fit for
simple marketplace solutions. The importance of the personal exchange
and the relationship between the practitioner and the client creates
an invaluable opportunity for energetic exchange and becomes a unique
aspect of the healing encounter. Vulnerable communities and individuals
often describe their access to complementary therapies as a strengthening
experience and a necessary one for the improvement of their health.
Some complementary approaches can be taught and can involve members
of the family network, thereby enhancing the sense of competence
and independence that is so critical for sustained healing.
Most importantly, complementary therapies work from a paradigm
of abundance, where the more an individual gives, the more he or
she gains — a critical and essential lesson for life and a
practical and spiritual approach for the resolution of the AIDS
plague, and, ultimately, for advancing the cause of human justice.
Ana Oliveira is the executive director of Gay Men's Health
Crisis (GMHC) and a licensed acupuncturist.
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