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Past Issues
Volume 17, number 1–2
January/February 2003
Contents
Our Biology is Social
Richard Levins discusses science, power and surprise
In Their Own Words: The Current
State of Women and HIV
Unique problems, recurring themes
Salvage Strategies and STI at
the 10th Annual Retrovirus Conference
STI in the salvage context
Global Treatment Update
TAC on the march and more
Boulder Blues
Lei Chou seeks the Rocky Mtn. source of T-20
Notes on HIV Drugs in Development
News from Retrovirus and elsewhere
You Can't Always Get What You
Want (And Sometimes You Can't Even Get What You Need)
Gregg Gonsalves on the coming catastrophe here at home
Our
Biology is Social
A Talk with Richard Levins By Bob Huff
Um outro mundo é possível — Another world is
possible.
You're a professor of population sciences; so, what‘s
up with us humans?
We can describe the present plight of our species as an eco-social
distress syndrome. It pervades everything: The relations to the
microbial world, to the physics of the atmosphere, to breathing
in the chemosphere, to nutrition and food production — even
our own biologies have been transformed.
Human biology is a socialized biology. For instance, one of the
constants of human physiology has been the belief that blood pressure
increases with age. Well, it does in our society; it does not among
hunter/gatherers and pastoralists. Our posture is very much determined
by class position and gender relations: whether you're willing to
be noticed or trying to avoid being noticed, and under what conditions.
Even breathing — the question of whether you breathe deeply
or shallowly, depends on stress patterns. Our eating habits have
certainly changed body size. The fact that we have electric light
in this country means that people sleep less; serotonin and melatonin
cycles are undoubtedly altered. We know that there are class differences
in cortisol behavior. So our biology is social. Our human biology
has been transformed. We are living in an environment that we've
created, and a lot of that environment is social and emotional.
And the emotional factors are as real as chemical ones.
A lot of these changes have been made possible by science.
Science does good things too. How could it work differently?
Science has a dual nature. On the one hand it's part of a long historic
increase in our understanding of the surrounding world. On the other
hand it's the product of a knowledge industry. And that knowledge
industry recruits, takes its agenda, and decides what's a problem
and what's a good solution, on the basis of the needs of the owners
of that industry. In an earlier time the owners of science were
the princes, who kept scientists around as decoration. Now they
are the trans-national corporations, so that ownership determines
the patterns of knowledge and ignorance.
In the areas that are closest to my own knowledge, we know a lot
about controlling pests with pesticides because they are commodities.
That's a way in which knowledge can be turned into a marketable
commodity. We know so much less about controlling pests by simply
having the right mixture of crops or by creating good conditions
for spiders, because you can only publish that knowledge as a column
of advice in Farm and Garden.
So you have a pattern of knowledge and ignorance and the first
thing a scientist has to ask is, "Is the agenda of my science
really where it should be? Do I want to join in the cutting edge
of that science or do we need a very different kind of cutting edge
coming from a different source?"
To really be able to do this, you have to have one foot outside
of the academy. Science is very good at picking up idiosyncratic
mistakes, like having dirty glassware or dividing by zero or having
confounding factors, but it's no good at all at identifying the
shared biases of the whole community. That's simply described as
"mainstream" or "common sense" or "cutting
edge." People who evaluate research are the ones who've created
the way it is now, so they tend to be very good at guaranteeing
that the worst kinds of errors aren't made but not at really advancing
science where it's needed.
There are different actors in the development of knowledge and
they each have their areas of blindness as well as insight. So,
for instance, in the international work I do with agriculture, it's
very often the case that people living in the country feel a desperate
urgency to guarantee that there will be beans available in three
months. And this creates a great demand for pragmatism, which sometimes
is unwilling to take the detours necessary to understand what's
really going on. On the other hand, people coming from the outside
very often have the luxury of looking at a longer time range, but
are also less sensitive to the needs of the population. And the
scientists from the country they are visiting are caught in between
a concern for their own people but also with looking for validation
from the international scientific community.
There's a tremendous urgency to get grants from the outside, to
publish in foreign journals, to be invited to international meetings,
to have a degree from one of the big places, and the problem is
you then get a kind of intellectual colonialism. It's interesting
that the great schools of tropical public medicine are not in the
tropics. It's Walter Reed Hospital, the Pasteur Institute, the London
School of Hygiene, and each of them is related to colonial expansion.
So they focused on the diseases that interfered either with the
safety of the troops, or the health of the colonial administrators,
or with the extractive industries.
Yet this doesn't mean one takes an anti-science attitude, but rather
a critical view: that science is a social product, and has to be
understood in its time and place. And, therefore, with this critical
view we can look for the kinds of biases that occur within the content
of the science as well. Critics of science began by worrying about
the application of science. In the sixties we had the research strike
at MIT, which was an anti-war gesture; they were concerned with
the misuse of science for war. Then they saw that science was also
being misused for profit. Then it was recognized that not everybody
had access to science, that there were questions about who was allowed
into the club. So gradually the critique spread out until it began
raising questions also about the content of science.
For a variety of reasons, science, coming from a long history of
growing up as kind of a little brother of capitalism, shares the
euphoria, the arrogance, the pragmatism, and the fragmented-ness
of capitalism. So you have a preference towards a reductionist science
— they recommend subdividing a problem into the smallest pieces
and so on — because the dominant view is a fragmented, atomistic
view of the world. The dialectical critique of science looks at
that science both in its strengths and in its weaknesses. Answers
to the classical problems, "What is this? What is it made of?"
are descriptive and science has been very successful at getting
those answers. The tools for answering those questions have become
more and more sophisticated — but the questions haven't.
Increasingly we see that the great successes of science have been
in answering the classical questions. But the great failures have
been in applying a fragmented science to a fragmented, complex reality.
So pesticides create more pest problems, antibiotics give us new
germs, hospitals are the focus of infection, the Corps of Engineers
produces flooding — and you start asking the question, "Well,
why?" The people who made these mistakes were just as smart
as we are, so why is it that what they did seemed so reasonable
at the time? And, again, it's the combination of the economic constraints
on science — what gets supported, what gets published, what
gets reviewed — with the prevailing philosophy.
So the critique of science is needed, but you have to go outside
of the scientific community to look at that critique. Very often,
farmers, patients of all sorts — the victims of science —
have a much deeper understanding than the professionals do. For
instance, Black Lung disease was recognized in England fifty years
before it was adopted in the United States. And the only reason
for that is not that English doctors are smarter, but that the English
working class had their own political party. Love Canal was discovered
by the people who were living there, while the scientists were saying,
"It's a random blip in the data, it's a cluster, it's not proven,
it's anecdotal."
In AIDS activism the slogan was, "We are the real experts."
And it's interesting in retrospect, in which ways you were and
which ways you weren't. If the element of desperation is missing
among the scientists, it means that they'll demand a higher degree
of evidence before allowing meaning. They'll also lack the subtlety
of the experience. That means that when you design intervention
programs, you miss a lot about what people really do.
For instance, there's now an insecticide-impregnated bed net program
in Africa. I was just talking to a Cuban friend, who works in Cameroon,
and she was telling me that, in Cameroon at least, it's too hot
to sleep under a net at night; people would rather sleep on the
floor. The bed net costs six dollars in a place where the average
income is about $250 a year; then you have to impregnate it for
eleven dollars, and redo this several times; so in the end it's
not economical, and it makes you miserable, so people will use it
occasionally, but not consistently.
So one of the things we're studying now is consistency. We find
that when a health problem presents itself people get all excited
and committed to doing something about it, but as soon as you start
getting success, the threat is no longer as visible. As long as
everybody knew somebody who died of AIDS, education worked. When
the education works well enough and a new cohort comes along which
doesn't have friends who've died of AIDS, then the education becomes
abstract. And then the social gap between providers and patients
becomes more visible, more palpable, and more likely to create skepticism.
The bed net is the condom of malaria, a disease that, by the
way, is a tremendous, overlapping problem with HIV in Africa. How
goes that struggle?
Most of the time, malaria is being discussed now in terms of drug
resistance. It is being treated as a biochemical and genetic adaptation
problem. The broader issues involve what affects the abundance of
mosquitoes. For instance, irrigation is one of the things that have
allowed mosquitoes to become endemic in places where they were only
sporadic. The Aswan Dam is one of the big offenders there. Another
issue is the destruction of the ecology of wetlands such as the
eutrophication of lakes through nutrient pollution. Lake Victoria
has its margin now covered with heavy growths of water hyacinth.
So fish can't get in there to eat mosquitoes. There are big algal
blooms from the runoff from human waste and from agricultural fertilizers.
The algae die and sink to the bottom and absorb oxygen. So this
means that the dragonfly larvae and the midges and other things
that live at the bottom and threaten mosquitoes, are not there.
In other words, the exposure to mosquitoes is not just a natural
phenomenon. Every change in land use, when forests are cleared and
so on, also causes changes in the mosquitoes that are around, and
therefore in the exposure to malaria.
When you deal with diseases like encephalitis or West Nile, you're
dealing with the relation of birds to their habitats. And one of
the big things happening now is that birds that don't normally meet
are meeting, because there are so few habitats available for them.
The migrating birds will all gather in the few places that are still
around. And there they can trade viruses. Then some of these birds
move out into human areas, and then the mosquitoes transmit the
virus from birds to humans. Part of the West Nile issue is that
the cycle that had been maintained in bird populations is spilling
out into horses and other animals and into the human population.
So, backyard bird feeders are avian bathhouses?
Each one of these diseases has its own special history. The rodent-borne
diseases in Latin America, like Venezuelan hemorrhagic fever and
Bolivian and Argentine hemorrhagic fever, are all involving changes
in the agricultural pattern. In Venezuela, what happened was that
the plains were plowed up to plant grain, and two things came from
this. First of all, grain is mouse food, and secondly, farmers don't
like to have snakes and jaguars around, so the mice got more food
and fewer enemies. The mice were the reservoir for the virus, and
so it increased its contact with people. In Panama, I think it's
the changing agricultural season, relating to the adoption of different
crops. In Argentina it was the cultivation of the Pampas. And there
what happened was when they started growing corn there were weeds,
so they brought in herbicides. The herbicides were aimed at the
weeds that grow in the very beginning of the season when the corn
is short. Once the corn gets up high, it doesn't matter what's growing
there. And so the herbicides shifted the balance among weed plants
to the ones that come along a little bit later and grow underneath
the corn. And they happened to be the ones that were liked by a
different kind of mouse. And it just happens that this different
kind of mouse carried the virus of Argentinean hemorrhagic fever.
In the African forests, Ebola is, I think, related to the fact
that big mammals were being exterminated, so small mammals increased
and those were the ones that came into contact with people going
into the bush for bush meat. So the lesson of all of this is that
every time we change land use in any way, we're also changing the
epidemiology. And therefore there has to be a health impact statement
as well as an environmental impact statement, asking, what will
any development scheme do to mosquitoes, to ticks, to snails, to
mice, at least.
Anytime there are new overlaps there will be new blooms of viruses
or whatever. And they are always surprises. We do our best, but
then, for instance, it turns out that corn pollen is very good for
the Anopheles mosquito that transmits malaria. And people have been
growing corn a lot lately. In every backyard, every vegetable plot
has some corn. So if there's standing water within about 60 to 100
meters of your corn, then there'll be Anopheles mosquitoes developing
rapidly, coming out robustly and looking for a blood meal. So those
are the things you couldn't have guessed. Except to know that bugs
eat, and when you affect their array of plants, you're affecting
their feeding. So there's always a kind of guessing you have to
do.
One simple rule is that it's important to maintain biodiversity.
When you reduce diversity, you lose a lot of species, but the ones
that remain are not kept in check and you can have explosions of
these nasties. So it's good to maintain biodiversity rather than
get caught up in the economic rationale that only tells you to go
for the most profitable land use.
How do activists and advocates affect the balance of political,
social and economic interests?
One of the general perspectives we have is that in a very complicated
world, every situation is different. And sometimes this is used
to say that you can't really understand what's going on. But another
approach is to say, first of all, that our knowledge has to be to
understand patterns of difference, say in the form of behaviors.
And secondly, because each place is different, and because there'll
never be enough scientists to characterize each place, you have
to link the knowledge of professionals and non-professionals. It
takes a much bigger mobilization of collective intelligence to solve
these problems — and this will only work when the two can
meet as equals. So there's been a lot of non-professional invasion
of scientific turf, for example, the women's cancer movement, particularly
the Women's Community Cancer Project, which has been insisting on
the environmental causes of cancer; the River Watch network; the
environmental justice movement; the Black Panther Party, which initiated
a study of sickle cell; and the AIDS activist community. The intellectual
resources exist; we have a well-educated country, and there is the
possibility of tapping this knowledge and then demanding that science
be directed toward answering the questions of the community, rather
than responding to the grants of the pharmaceutical industry. A
women's cancer group in Long Island organized a scientific conference
where they brought the scientists together, but the women were the
ones who asked the questions. It worked very well.
Which scientists are studying understanding patterns of difference?
The ecologists. The work of protein research can be pretty much
done the same way in any lab in any place — if you have the
equipment. And so the differences are, who has the equipment and
skill? But when you're dealing with epidemics, the social context
of disease is an important ingredient. So in the health movements
and the ecology movements, you get people who are able to link the
particular to the global. And that's where the exciting knowledge
is going to be emerging in these fields. Also, the intellectual
independence that people develop in order to crack these problems,
will, I hope, lead to political independence, creating an independent
political structure, so they can play an independent role rather
than simply lobbying the ones that are already in power.
What do you make of the recent Bush Administration proposal
to treat people with HIV in Africa and the Caribbean?
I haven't studied the proposal, but I have studied the proposer.
So it's clearly not out of concern for the health of people, but
it's a political move to show his compassion and the compassionate
side of conservatism. I'm sure there's a lot of fine print about
what kind of help will be provided. For example, I doubt whether
there'll be any of it going to reduce poverty. Now, the impact of
HIV in Africa is not only on the patient with AIDS, but on the caretaker
and on the other members of the family. What's happening in a lot
of places is that as the disease progresses, less and less time
can be put into the farm. Eventually you can fall below the threshold
where the farm is no longer sustainable and you either sell off
your cattle or rent out the land, and depending on the rules of
landholding and land use, the poorer farmers who are infected can
lose their land and lose their livestock; if both parents die and
teenagers inherit the farm, they may not be able to hold onto it;
it may revert to more distant kin. So we have to look at AIDS and
the epidemic as a crisis of survival, which in some people will
be the AIDS symptoms themselves, in other people it will be hunger,
through the failure of the farm, or it will be neglect of children
through lack of parental care. You have to see it as a social as
well as biological epidemic.
Now, it operates differently in each society because of the rules
of landholding and the kinds of mutual aid that are available, and
I'm sure that the Bush program is not going to deal with that. I
think that a lot of it will be pharmaceutical, and that his drug
company buddies will be able to cash in on it. So I'm skeptical
because it seems to be part of his war for hearts and minds.
Some U.S. government officials acknowledge the potential for
social destabilization in Africa arising from AIDS but they tend
to frame it as a national security problem for the U.S.
You'll find that in all those reports, social unrest is regarded
as a problem. Well, some of us would see it as a great advantage.
There are places that should not be tranquil. The message of Porto
Alegre* is that another world is possible if you do things differently;
we can break out of the constraints imposed by the rulers.
Richard Levins is a professor in the Department of Population
and International Health at the Harvard School of Public Health.
He is an ex-tropical farmer turned ecologist, biomathematician and
philosopher of science whose central intellectual concern has been
the understanding and influencing of processes in complex systems,
both abstractly and as applied to evolutionary ecology, economic
development, agriculture and health.
* The theme of the 2003 World Social Forum, held in Porto Alegre,
Brazil was: Another World is Possible.
| Dear President
Mbeki,
It saddens our heart to hear that you have still not decided
to let your people live. We who write this letter love you
so much and you are a hero to us.
We are a small group of People Living With AIDS in Nigeria
who would all have died a long time ago but our President,
Chief Olusegun Obasanjo gave us anti-retrovirals and we are
all living our normal lives. The medicines do a great wonder
in the fight against AIDS. For example our friend Mr. Nasko:
he was carried on a stretcher into the doctor's office and
given these medicines; yesterday he took the stairs two at
a time and came to visit us. He had returned to his job as
small-time trader. So also Mr. Ambursa, he was taken for dead
and wheeled into the doctor's office, but just six months
after, he too is back at his job.
The medicines are so easy to take and have no side effects
that have made any of us uncomfortable whatsoever.
About two hundred of us here in this poor, illiterate North
of Nigeria are taking these medicines very easily. Just three
in the morning and three in the evening. They are subsidized
for us and we all can afford the 10 dollars every month that
we are required to pay. Families have been reunited, even
Lami and Rueben have got married. Lami wrote her will a few
months before getting the medicines.
You are a good man, President Mbeki, just save the lives
of your people and be the "Best Man."
Our best regards,
Samaila Garba
Kebbi Alliance Of Positive People (KAPOP)
Birnin-Kebbi
Kebbi State, Nigeria
|
In Their Own Words: The Current State of Women
and HIV By Leslie Hanna, reprinted from BETA, Winter
2003
BETA, the Bulletin of Experimental Treatments for AIDS, asked
women with HIV, clinicians, and researchers a single question: What
do you consider to be the most important treatment or health issues
facing women with HIV today? BETA can be viewed online at www.sfaf.org/beta
Amy Justice, MD, PhD
Associate Professor of Medicine, University of Pittsburgh
School of Medicine
I think there are two major issues: helping women start and continue
taking appropriate multidrug, multiclass anti-retroviral therapy,
and doing research to determine the degree to which treatment recommendations
for men should be adjusted for women.
Access continues to be a huge issue. Women in 2002 still enter
care later than men and, as a group, adhere less well to treatment
than men. Today, it's not so much that providers will not or do
not treat women, it's that women have real trouble with the basics
of regularly accessing health care—they have trouble making
and keeping appointments. Access is not something that is barred
for women, but it is something that needs to be facilitated.
Drug toxicity is a huge issue we're only beginning to understand.
Clearly it's a huge issue for men, too, but men and women may have
different susceptibilities to many side effects. Diabetes is a good
example. Women tend to have more body fat, and body fat is a predisposing
factor for diabetes in the general population. What do HAART and
HIV do to the picture for women? These and other questions, if answered,
could improve routine monitoring—for instance, by informing
better ways to use glucose and liver tests.
Liver health is a real concern. Women's livers work differently
than men's. For example, we know that women are more susceptible
to cirrhosis (liver scarring) when they consume the same amount
of alcohol over the same amount of time, matched for weight—pound
for pound—with men. We don't really know why, but the fact
has been well demonstrated. Today, in HIV disease, a major cause
of death is hepatitis and liver failure. Women with HIV are likely
to be ethnic minorities and younger, inner-city residents with a
high risk of smoking, alcohol use, and injection drug use. It's
reasonable to ask whether these women might not be particularly
susceptible to liver injury. This really needs to be studied.
Priscilla Abercrombie, RN, NP, PhD
Assistant Clinical Professor, Department of Family
Health Care Nursing, University of California at San Francisco (UCSF)
I've been following women with abnormal Pap smears for many years.
Nothing's changed; HPV (human papillomavirus) is still a huge problem.
We're still treating it the same way, and following women very carefully
over time. We're not yet sure if HAART is helping to decrease the
number of abnormal Pap smears or if it's improving the status of
women with cervical dysplasia (abnormal cells). But the majority
of women—at least 50%—will have an abnormal Pap smear
at some point, and for most women
HPV is a recurrent, persistent disease. The rates of cervical cancer
have not changed, though.
Some women we've been treating for years are now entering menopause.
While the signs and symptoms of menopause in HIV positive women
are similar to those in HIV negative women, there are some unique
treatment complications (mostly liver complications), and there
are concerns about antiretroviral drug interactions and hormone
replacement therapy. We need to learn more about how best to manage
menopause in women with HIV who are taking HAART.
Eve W.
HIV-positive woman
I am very concerned about the long-term toxicity of the antivirals.
As a woman on treatment for close to ten years, I've had a hard
time dealing with the side effects. Although none have been life-threatening,
they started to really wear me down and scare me. On top of this,
adherence became more difficult over time. I just got sick of taking
the medications day after day. I felt I was pushed to start treatment
all those years ago. Hopefully things are different now.
Another thing that is important to me as an HIV positive woman
is that HIV did not take away my right to have a child. Women should
not give up on having a family if that is what they want.
Maureen Shannon, MS, FNP, CNM
Associate Clinical Professor, Department of Family
Health Care Nursing, UCSF
There are multiple issues because there are so many different
women with HIV disease who have acquired the virus in different
ways, and because it's a very complicated disease. There are some
major themes, though.
First, although things have changed, there is still a strong stigma
associated with this disease, especially for women. It's still so
shameful to have HIV/AIDS that some women delay seeking services
or treatment just for that reason. By trying to conceal their status,
they'll end up receiving suboptimal care. Even in the San Francisco
Bay Area, let alone the rest of the world, there's a prevailing
attitude toward women of, "What did you do to get this disease?"
Many women today do not tell their families or their coworkers or
neighbors. Stigma may be subtler in the U.S., but I've known positive
women who give birth to babies they hope are HIV negative, who then
have to go to a pediatrician— and the judging begins, or so
it's perceived. Just having to discuss the babies' HIV-related concerns
reflects on the mom, and it's not like discussing diabetes or herpes.
It's just not.
Another important issue for women, and one that affects access,
is the amount of violence that so many women experience, especially
at the hands of intimate partners. This includes both psychological
and physical threats. HIV positive women also have a very high rate
of past child-hood abuse, including sexual assault and molestation.
As providers we're more aware of this today than we were earlier
in the epidemic, but clinicians still do not screen for violence
as much as they should. Yet doing so can make a huge difference
when making treatment decisions. For example, you have to be very
careful when interpreting depression in women—is it related
to HIV? To medication side effects? To current violence, or a childhood
history of sexual assault? Women living with violence or with a
history of violence often have a condition similar to post-traumatic
stress disorder, but since they're not often screened for any of
this, they don't often receive the appropriate care. Such women
often self-medicate, too, and it's important for us as providers
to know why. Violence also impacts women's entry into care and adherence
to care. We discuss safety plans on a regular basis with many of
our women clients— for instance, do they have a supply of
medications and a suitcase ready to go in case they need to leave
a dangerous situation in a hurry? Finally, women with so much violence
in their lives also may end up spending time in jail or otherwise
incarcerated, which has implications for access to medicines.
A somewhat related issue is the lack of mental health services.
Women with HIV have a high rate of depression and chronic stress,
along with abuse. In general, there aren't a lot of psychological
services available for anyone these days, but what does exist tends
to be focused on people with severe mental illness. It would be
great to have services available to women earlier in challenging
situations— during periods of new or significant stress—to
teach coping and problem-solving skills. Instead, we tend to throw
drugs at people and hope for the best, i.e., without providing counseling.
We don't hesitate to order an expensive CT scan, but we don't generally
support psychological needs and services.
Grace McComsey, MD
Assistant Professor of Medicine and Pediatrics, Case
Western Reserve University School of Medicine
Several things come to mind. The most important thing is probably
the fact that we need studies focused on women. If we want answers
to questions about women, we cannot get the data we need from men.
This is true whether you're talking about antiretroviral treatments
or side effects.
Here in Cleveland we are beginning a study that involves two months
of complicated treatment, requiring participants to be seen frequently,
to use study medications that need to be taken three times daily,
and at study's end to have muscle and fat biopsies. This is a study
that might have been difficult to enroll anyone in, yet we have
so far enrolled 60% women (18 of 30 total). We also have more women
than men on the waiting list.
How have we enrolled so many women? What works is not mysterious:
we simply spend the time necessary to explain and discuss what the
study is trying to achieve and why it's important. When women understand
that there are more complications in women than in men, and once
they understand the purpose and benefits of the study to themselves
and to HIV medicine, they are usually very interested in participating.
I also give talks at different community groups and forums, some
of which are focused on women. In the days following a talk, women
have tracked me down at the clinic, asking for more information
and how to enroll. So our efforts to educate about special issues
relating to women have sometimes yielded very good results.
Leslie Hanna is the former editor of BETA.
Salvage Strategies and STI at the 10th Annual
Retrovirus Conference By Bob Huff
Selected news from the 10th Annual Conference on Retroviruses
and Opportunistic Infections (CROI) in Boston, February 2003. First
of a series.
STI in the Salvage Setting
Two studies presented at the 10th CROI investigated use
of structured treatment interruption (STI) in populations of patients
with very advanced HIV disease and long treatment histories. Typically,
these individuals are very difficult to treat, having developed
resistance to most available antiretroviral drugs in each therapeutic
class (multiple drug resistance — MDR). Because of the potential
for serious consequences due to disease progression while off therapy,
especially in these advanced patients, clinical use of the technique
of STI has been controversial. One theoretical rationale for its
use in a salvage setting, however, is to allow drug-resistant HIV
species to become overgrown by drug-susceptible wild-type virus,
which might then be suppressed by available drugs. Another rationale
for STI in this population is to allow individuals suffering from
drug toxicity a period of drug-free time in which to recover. Although
two trials investigating these issues were discussed in Boston,
they showed contradictory results and aren't likely to settle the
controversy. Nonetheless, the larger of the studies produced compelling
evidence of the dangers of unsupervised STI for individuals with
advanced HIV disease.
CPCRA 064
Jody Lawrence, from the University of California, San Francisco,
and an investigator with The Terry Beirn Community Programs for
Clinical Research on AIDS (CPCRA), reported on study CPCRA 064,
a randomized trial in 270 individuals with multi-drug resistant
HIV. The study compared whether the strategy of using a four-month
treatment interruption prior to starting a new therapy would result
in fewer clinical events and deaths than changing to new drug regimen
without interruption. Sixty-three percent of the participants entering
this study had CD4 cell counts below 200 cells/mm3, a demarcation
point for increased risk of developing one of the serious illnesses
associated with AIDS; about a quarter of study patients had CD4
cell counts below 50 cells/mm3, and over half had previously experienced
an AIDS opportunistic infection. At the time of study entry, all
patients had virus levels uncontrolled by their medications and
had previously used, on average, 4 HIV protease inhibitors (PI),
5 nucleoside analog HIV reverse transcriptase inhibitors (NRTI)
and at least one of the non-nucleoside class of reverse transcriptase
inhibitors (NNRTI).
After nearly a year of follow up 16 patients had died, with 8 deaths
occurring in each comparison arm. Overall, 34 patients experienced
clinical disease progression or died while on the study, with 22
of those events occurring in the interruption group and 12 in the
continuing group. After noting that patients in the interruption
group were not likely to be protected from disease progression,
a Data Safety Monitoring Board overseeing the study halted new enrollments
into CPCRA 064 in June of 2002.
In addition to experiencing more clinical events, patients who
interrupted treatment before changing their regimens also had poorer
CD4 cell count responses and higher HIV RNA viral loads than those
who switched immediately, although these trends were diminishing
during a follow-up period out to one year. There were no benefits
for treatment adherence or quality of life with either strategy.
The study investigators recommend that patients with multiple drug
resistant HIV should be maintained on an optimized antiretroviral
regimen and should not undertake an interruption before switching.
(Abstract 67, 10th CROI)
GIGHAART
Another trial also investigated the strategy of using treatment
interruption in people with advanced HIV disease and multiple drug
resistant virus.
Christine Katlama, a clinical investigator from the Hospital Pitie-Salpetriere
in Paris, reported on a study of an intensive HIV regimen called
GIGHAART in highly treatment experienced patients. Sixty-eight participants
were randomized to either receive the GIGHAART regimen (containing
6 to 8 drugs) immediately or to wait for 8 weeks before starting
therapy. The median CD4 cell count of study participants was 26
cells/mm3, indicating the advanced stage of HIV disease in this
group. At the time of study entry, participants' HIV viral loads
were not being controlled by therapy and all had previously received
multiple drugs from each therapeutic class.
Twelve weeks after starting the GIGHAART regimen, patients in both
study arms had experienced reductions in HIV viral load, although
there was significantly improved reduction among those who had interrupted
treatment as compared to those who began their new regimen immediately.
The median decrease in plasma HIV RNA in the delayed treatment arm
at week 12 of therapy was -1.91 log copies compared to -0.37 in
the immediate arm. While only 15 percent of those starting GIGHAART
without delay had undetectable viral load after 12 weeks of therapy,
38 percent of the deferred treatment group were undetectable.
The interruption strategy produced favorable results in other study
parameters as well. After nearly a year of follow-up, CD4 cell counts
were up by 69 cells/mm3 in the deferred arm compared to a median
increase of 7 cells/mm3 for those who started immediately. Overall,
in this difficult-to-treat population of people with advanced HIV
disease, an 8-week interruption before starting an intensive antiretroviral
regimen was associated with improved virological and immunological
results that were sustained out to one year.
During a discussion following her talk, Dr. Katlama speculated
that the superior potency of the GIGHAART regimen might explain
why these results differed from those in CPCRA 064. Commenting on
the shorter duration of STI in her study, Katlama also said she
didn't believe that it was necessary to wait for the wild-type virus
to come back completely as long as drugs could be found to keep
the virus down. (Abstract 68, 10th CROI)
Deeks Weighs In
A paper recently published in the journal AIDS by Steven
Deeks of the University of California, San Francisco, also addressed
the role of STI in salvage therapy. In a non-randomized observational
study, 24 patients who were experiencing virological failure despite
remaining on HAART elected to stop all ARV medications for at least
12 weeks. Following re-initiation of treatment, patients' viral
genotype, phenotypic drug susceptibility, viral load and CD4 counts
were monitored. In a previous study, Deeks had shown that during
a treatment interruption in patients with MDR virus, drug-susceptible
wild-type virus usually eventually outgrew the less replication
competent virus population that had been selected by drug pressure.
In an extension of that investigation, this study looked at the
long term effects of what happened when patients restarted their
various ARV regimens after STI.
Fifteen subjects (64%) maintained viral load below 200 copies for
up to 109 weeks of follow-up after restarting therapy. Twenty of
the subjects had a shift in viral phenotype from resistant to susceptible
during the period off drugs. After restarting therapy, 13 of these
20 patients were able to suppress and maintain viral load below
200 copies within the follow-up period. This durable viral suppression
did not occur in any of the 6 patients who restarted therapy without
adding at least one drug to which their baseline virus was phenotypically
sensitive. In contrast, all 9 patients who started a regimen with
at least one drug to which their baseline viral population was susceptible
achieved viral suppression. For 5 of the 9, the new drug was an
NNRTI. Finally, 4 of the 5 who restarted with a regimen containing
at least 2 drugs active against their baseline viral population
also sustained successful suppression through follow-up. (AIDS 2003;
17(3):361-370)
The theory behind this approach in the MDR patient population is
that after stopping drugs, the less-fit MDR virus will be overgrown
by a drug-susceptible wild-type virus that has been waiting quietly
in the viral archives. Once the drug-resistant strain has been sent
to the archive and the WT reestablished, therapy including several
recycled drugs is restarted and the dominant drug-susceptible population
is suppressed. As Deeks has demonstrated in previous studies, if
only recycled drugs are used, the MDR virus soon bounces back and
viremia blooms within weeks. But the new study suggests that, if
only one new drug is added along with the recycled meds, then this
may be sufficient to keep the less replication-capable MDR strain
from establishing a foothold. The key is the STI, which allows the
MDR strain to retreat to archival levels. If the MDR strain were
still actively replicating as the dominant strain when treatment
was switched, there might be a temporary lowering of viral load,
but resistance to the single highly active new drug would quickly
appear and the evolved virus would be all that tougher to treat.
The conclusion that adding only a single new drug may provide durable
viral suppression after an STI could be welcome news for people
with MDR virus who perhaps can't access more than one drug that
their virus is sensitive to. With Fuzeon waiting in the wings, this
finding, if confirmed, may have profound implications for the outlook
for salvage therapy. Conventional wisdom during the past couple
of years has held that to forestall resistance after changing regimens,
patients must add at least two new drugs to which their virus is
sensitive. This may still be true, especially when an STI is not
feasible or too risky, since, as the CPCRA trial warns, taking an
STI may not be such a good idea for people lacking the immunological
cushion to keep them from getting sick while off therapy. Finally,
if no new drug is accessible, earlier work by Deeks demonstrating
that drug resistant virus may be less replication competent and
perhaps less pathogenic suggests that it may be advantageous to
remain on a failing regimen for as long as tolerable until newer
drugs come along.
In an extension of his salvage STI paper in the journal AIDS, Dr.
Deeks also presented a poster at CROI on the selective interruption
of only one component of HAART. This non-randomized study in 20
patients applied a finer scalpel to the interruption strategy by
halting only the PIs and continuing NRTIs (or vice versa). It also
introduced a new acronym to the literature, PTI, for partial treatment
interruption. The study participants' median CD4 count was 336,
the median viral load was 3.9 log copies/mL, and all had been experiencing
persistent viremia despite good adherence. The decision whether
to halt PIs or NRTIs was based on each individual's toxicity profile.
For 15 subjects who interrupted all PIs and continued NRTIs, viral
load and CD4 counts remained stable, while triglycerides and cholesterol
were significantly reduced by week 12 of the intervention (TG by
-90mg/dL; non-HDL-C by -30mg/dL). Genotypic and phenotypic resistance
remained stable past week 16, although in 2 patients, drug susceptible
PI mutations began to dominate by week 24 and viremia increased
as viral replicative capacity improved. Overall, stopping PIs improved
lipid values and staying on failing NRTIs continued to provide some
virologic benefit. Larger, randomized studies are needed to confirm
this.
The 5 patients who stopped NRTIs but continued their PIs did not
fare as well, experiencing immediate and sustained viral load increases
of about 0.03 log copies per week. Three of the 5 eventually had
their M184V 3TC resistance mutation disappear, which was accompanied
by an up-tick in viral replication fitness. (Abstract 640, 10th
CROI)
Complete or partial treatment interruption as a tool to guide viral
resistance properties may have some promise in settings where close
monitoring is assured, but at this stage it remains a risky undertaking
best reserved as a subject for additional research.
Comparison of CD4 and Viral Load
Changes in STI Studies for People with
Multi-drug Resistant Virus |
| |
|
|
|
| |
CPCRA |
GIGHAART |
DEEKS |
| Study Type |
Randomized |
Randomized |
Observational |
| # of pts on STI |
135 |
34 |
24 |
| Baseline CD4 (cells/mm3) |
180 |
28 |
218 |
Baseline VL (log10 copies/mL)
|
5.0 |
5.4 |
4.6 |
| Duration off therapy |
16 weeks,fixed |
8 weeks, fixed |
Median 20 wks pt. choice |
| End of STI: |
|
|
|
| CD4 change from baseline |
-53 |
-10 |
-84 |
| VL change from baseline |
+0.31 |
+0.16 |
+0.76 |
| 48 weeks after restarting treatment: |
|
|
|
| CD4 change from baseline |
+7 |
+69 (40 wks) |
-3 |
| VL change from baseline |
-0.76 |
-0.79 |
-2.00 |
|
Global Treatment Update By Gregg
Gonsalves
Roche Drops the Price
After a sustained campaign, particularly by Medecins Sans Frontieres/Doctors
without Borders, pharmaceutical giant Roche has lowered the price
for nelfinavir (Viracept) for least developed countries and Sub-Saharan
Africa to $900 per patient year, a more than 80 percent reduction
off of the cost of the drug in the United States and Europe. For
middle income countries, Roche isn't offering much of a bargain
and is setting a cost of $3,000 per patient year. Roche is also
tacking on "shipping and handling costs" to this offer,
which could amount to a 20 percent surcharge for these developing
countries. One wonders why Roche was the last to the table in offering
differential pricing for their product, when most other big manufacturers
have already agreed on substantial discounts on their products for
poor countries.
TAC on the March
The Treatment Action Campaign of South Africa marched on
Parliament on Valentine's Day, February 14, to demand a national
HIV/AIDS treatment and prevention program from their government.
TAC's struggles with the government of South African President Thabo
Mbeki represent the struggles and aspirations of people living with
HIV/AIDS all over the developing world: for access to antiretroviral
therapy and other AIDS care that have kept thousands of people in
the United States and Europe alive and healthy, and truly living
with HIV. GMHC in collaboration with Health GAP and the African
Services Committee, sponsored a demonstration in support of the
Treatment Action Campaign outside the South African Consulate in
New York on the eve of TAC's march.
Getting Religion: The Church and ART
Church World Service sponsored a roundtable on the Universal
Access to AIDS Treatment, February 19th and 20th in New York City,
bringing representatives of major protestant denominations and their
associated international health programs together with AIDS treatment
activists for the first time. The roundtable explored the potential
role for faith-based organizations in providing care for people
with AIDS in the developing world, where religious hospitals and
health centers provide a substantial portion of health care services
in general, and advocating for public policies in the U.S. and abroad
to improve access to treatment.
Presidential AIDS Initiative
President Bush unveiled a startling new AIDS initiative
in his State of the Union speech in January, which includes $15
billion to provide treatment and prevention services to 2 million
people in Africa and the Caribbean. The initiative, which includes
a request for $10 billion new dollars from Congress, represents
a sea-change in U.S. global AIDS policy. The devil is in the details
of course and the President's new plan relies heavily on a yet-to-be
created U.S. program through the State Department to manage this
effort, instead of funneling the needed resources to the already-up-and-running
Global Fund for AIDS, TB and Malaria (GFATM). The initiative is
also slow to get started, with the President asking only for $2
billion in the coming fiscal year. While praising the effort as
more ambitious and sweeping than anything proposed by his predecessors,
GMHC expressed disappointment that the President bypasses the GFATM
and doesn't offer more assistance in the near term for people living
with AIDS in the developing world.
Speaking of the Global Fund
In a piece of masochism or shrewd political maneuvering,
the Board of the GFATM elected U.S. Secretary of Health and Human
Services, Tommy Thompson as its Chairperson. With the U. S. shortchanging
the Fund in favor of its own unilateral initiatives and its championing
of moralistic approaches to HIV prevention, the appointment of Thompson
is a mixed blessing. Perhaps giving the U.S. a leadership role on
the Board may curry some favor with the Administration and lead
to increased funding down the line, but the price may be increased
pressure from the U.S. delegation on abstinence-only prevention
approaches, restriction of family planning options, and stigmatization
of drug users and sex workers. While the Fund also gave out $866
million in new grants at its last Board meeting, they also announced
that they don't have the cash to offer a new round of grants later
this year.
Boulder Blues
By Lei Chou
On Valentine's, Roche invited state ADAP (AIDS Drug Assistance
Program) directors and community activists to a meeting about Fuzeon
(T-20, enfuvirtide) pricing at its manufacturing plant in Boulder,
Colorado. Unfortunately, only the directors of four ADAPs were able
to attend, although these represented the country's largest programs.
Lanny Cross from New York, Michael Montgomery of California, Dwayne
Haught from Texas, and Paul Arons from Florida made the snowy trek.
Illinois could not attend since that program does not forsee any
possibility of adding this drug to their formulary, no matter the
price. Martin Delaney, Bill Arnold, and Lei Chou were present as
members of the Fair Pricing Coalition. Dani Bolognesi, Carol Ohmstede,
and Walter Capone attended from Trimeris and David Reddy, Kathy
Presto, Georges Gemayel, Eric Lodewijk, John Tayer, Archie Shew,
Arnie Doyle, Donny Moss and others from Roche were present.
Roche and Trimeris held a rehearsal meeting the night before and
it showed. Their presentations were well prepared and comprehensive.
Dani Bolognesi, the chairman of Trimeris, kicked off the meeting
with "The Fuzeon Story:" the history of the drug from
discovery through development. Their excitement about the pending
FDA approval was palpable. The chemical structure of Fuzeon was
flashed on screen several times to emphasize the SIZE of this thing
as compared to other ARVs. One does wonder how it will fit onto
the FDA package insert.
The resistance data presented at Retrovirus in relation to a related
drug, T-1249, was also discussed. Since it appears that the longer
someone is on Fuzeon, the less effective T-1249 will be, concerns
were raised about the slow pace in the development of T-1249. Dani
indicated that Roche is committed to expediting development of T-1249
and to bring it to market as soon as possible. David Reddy, who
oversees global development of HIV drugs for Roche, was asked and
confirmed that indeed, T-1249 development will be expedited.
Roche is positioning Fuzeon to be the therapeutic foundation for
treatment-experienced patients. Subset analysis from TORO trials
with OB (optimized background) suggests that using 2 OB ARVs is
just as effective as using 5 OB drugs. Additional details on the
cost effectiveness of this strategy will be presented at the next
Glasgow Conference. They are aiming for Fuzeon to replace the current
megaHAART approach, and are in talks with the VA and Kaiser Permanente
regarding that possibility. They are also continuing the development
of pharmaceutical peptides by looking at pegylation, pushing towards
eventual once-a-week dosing.
Next up were Eric Lodewijk, who runs the Boulder Plant, and Carol
Ohmstede of Trimeris. They went into considerable detail about the
manufacturing of the drug, from obtaining raw materials from around
the world, to retooling the factory and installing new equipment
(this was not a new plant built from scratch as previously indicated
by Roche), to hiring 300 employees (with half working on Fuzeon).
The molecule itself is built in 106 steps, assembled in three sections
using the Rosenmound von Braun process*, with numerous additional
steps required to get to the final product including lots of washing
and drying at low temperatures. The entire job takes 6 to 7 months
to complete.
David Reddy followed up the tech talk by diving right into the
pricing discussion. He presented Roche's pricing philosophy with
regard to Fuzeon.
- It takes 45 tons of raw materials to make 1 ton of Fuzeon;
- R&D has cost much more than that for the protease inhibitors;
- The $600 million in R&D breaks down as:
1% Research,
55% Development,
11% Manufacturing,
11% Phase IV patient support, and
22% in manufacturing investment.
It was revealed half way through his presentation that the price
has already been decided upon: "No, of course I can't tell
you what it is!" Reddy said.
He said these factors should be considered before reacting to the
price:
- The price is fair concerning the high cost of manufacturing.
- The drug is defining the future of salvage therapy.
- It will be cost effective (data under development).
- Roche is committed to work with all parties on access (They
will collaborate with BI on tipranavir trials, and will provide
drug for that purpose).
- The price has to be sustainable for the company. Reddy said
the price is based on an "adequate but not aggressive time
frame" for generating revenue and the profit margin for Fuzeon
will be significantly lower than for other ARVs.
We brought up our concern regarding the possible short life span
for Fuzeon in the market, given that other oral entry inhibitors
are being developed, and asked how that will impact the price. We
speculated that Roche must be patenting every single step along
the way and most likely has the market on polypeptides cornered.
Reddy seemed to indicate that they are treating this whole line
of R&D as one, so the profitability potential spreads into T-1249
and other compounds under development (possibly for other diseases
such as Alzheimer's).
Without knowing the actual costs, it was hard to tell from this
presentation what the final price will be. Roche seems to be signaling
that they are not expecting Fuzeon to be an instant blockbuster,
but the lengths they went to convince us of the high cost of bringing
Fuzeon to market kept us guessing. At this point in the meeting
they assured us that pricing discussions will continue and then
herded us out of the meeting room and onto a tour of the plant (in
hard hat and goggles). Half way through the tour, David Reddy apologized
that he needed to catch a plane due to security concerns at Heathrow
Airport. He did not get a chance to hear anything from the ADAP
directors, and community members did not get to the meat of our
arguments. NOTE TO ACTIVISTS: NEXT TIME THE BIG MAN IS IN THE ROOM,
GET RIGHT TO THE POINT! They seem to have this habit of slipping
out early. Kathy Presto promised to relay everything and Reddy said
he will contact ADAP directors individually.
On to the tour: They showed us giant tanks that hold the raw materials
and solvents used in production, different machines that do the
assembly of amino acids, and a myriad of dryers and washers, all
with little glass window you can look into and see churning whitish
liquids and powders. It's a factory, unlike what I had imagined
(pristine labs and glassed off walkways, robots and test tubes).
The place smelled like a gas station, with water leaking from ceilings,
and a little room with two computers and two workers overseeing
the entire process. However, it was quite amazing to see the transition
from funky Quicktime movies illustrating the molecular mechanism
of fusion to the large-scale production of tons of the drug.
After lunch, each ADAP director told those remaining about the
crisis facing their programs. It's heart breaking to hear the frustration
these guys feel in not being able to meet the needs of people they
serve. It's one thing to see the numbers, quite another to get a
view from inside the programs looking out and forward. Lanny Cross
announced that most ADAP directors have gotten together (covering
80% of U. S. clients) and have sent a letter to all the drug companies
requesting a meeting to discuss further lowering of prices. (More
on this movement and what you can do to help in the weeks ahead!)
Roche seemed amenable to further pricing discussions, including
possibly offering more discounts for ADAPs.
They also asked Roche to establish a medical criteria for access
administered through the central distributor so they won't have
to impose separate restrictions at the state level (those that can
afford it) since, despite capping the number of slots, this will
be the only way that Fuzeon can be covered. Roche's pharmacy distributor
will contact each ADAP individually to set up delivery details.
Roche said 65 percent of the first 15,000 slots available would
go to the U.S., based on HIV prevalence. We told them that European
countries are going to take at least a year for price negotiations,
and most likely the drug will only be available there to private
payers. This is perhaps one of the considerations for us stateside
as we think about price control; European countries pay lower prices,
but they also get the drug later.
With the Federal Budget allocating an $80 million increase for
ADAP, we are still $140 million short for this fiscal year. Fuzeon
will only come to most of those who need it at the cost of reduced
formularies and stricter financial eligibility criteria. With a
scary new Medicaid proposal coming out of the White House, most
states will wait until the dust settles before committing to anything
major. If the Bush proposals go through, optional services such
as prescription drug coverage may no longer be required and states
may drop them. Drug companies will no longer be able to count on
the automatic coverage for over half of the domestic HIV market.
This could have a huge impact on revenue and R&D investment
in future therapies. The price of Fuzeon will be the first test
of this new reality we live in. One hopes Roche will do the right
thing. They've certainly been informed.
Keep up with ADAP news at www.atdn.org
Notes on HIV Drugs in Development By
Bob Huff
Large Tipranavir Trials Open
Boehringer Ingelheim announced the start of two large Phase
III trials of tipranavir, a new kind of protease inhibitor (PI)
that binds to the enzyme in a different way than currently available
PIs. The U.S. study, dubbed RESIST 1, is aimed at people who have
developed resistance to existing protease inhibitors and is one
leg of the largest clinical research program ever launched for this
highly treatment-experienced population. In phenotypic assays and
early clinical trials, Tipranavir has shown activity against HIV
with multiple protease resistance mutations.
RESIST 1 will enroll more than 500 patients at more than 115 trial
sites in the United States, Canada and Australia. A similar 800-person
study, RESIST 2, will enroll in Europe and South America. Two companion
trials (study 1182.51 and RESIST 3) will be available for individuals
with extremely limited treatment options that do not meet entry
criteria for the two main trials. Finally, a very small emergency
access program should be available to supply drug to about 50 patients.
Overall, the suite of tipranavir studies will involve about 1500
people worldwide.
RESIST participants will be randomized to receive either tipranavir
(boosted with low-dose ritonavir) or an approved ritonavir-boosted
PI selected by the individual's physician on the basis of treatment
history and baseline resistance testing. Resistance testing will
also be used to help determine an optimal individualized background
regimen to backup the study drugs. Participants will be allowed
to use certain currently experimental drugs such as T-20 (enfuvirtide,
Fuzeon) and atazanavir. Eligible patients must have received at
least two PI regimens prior to the study. Patients also must have
received drugs from the NRTI and NNRTI classes, and must have at
least one primary PI mutation prior to enrollment. There is no CD4
cell count criteria for entering the study but viral load at study
entry must be over 1,000 copies/mL. U.S. trial sites for RESIST
1 can be located through: www.clinicaltrials.gov
Informed Access
Community representatives met with T-20 makers Roche and
Trimeris in New York in January to get a briefing on plans to distribute
the injectable fusion inhibitor as soon as it is approved (see Boulder
Blues for an account of a meeting with state ADAP directors). Due
to an initially limited supply and no reliable guess on how much
demand there will be, Roche is setting up the framework for a system
that would be able to fairly allocate supplies if required. They
will contract with a third-party pharmacy service corporation that
will deliver drug kits (either by mail or to selected pharmacies),
staff a patient assistance hotline and handle prescriptions for
patients unable to pay.
The patient support component of this system will be critical if
patients are to have good outcomes when using T-20. It's becoming
increasingly clear that T-20 is not an easy drug to take and the
decision to begin enfuvirtide therapy should be made in consultation
with a physician who has been trained in the correct preparation
and administration techniques. Resistance to T-20 can develop fairly
quickly if full doses are not taken on a consistent basis, so an
individual's informed commitment to making the regimen work is a
must.
If you believe you may be a candidate for T-20, be sure your doctor
and his or her staff have received the training offered by Roche.
It is especially important that Medicaid providers involved with
HIV care receive training so that this large segment of the patient
population has access to this potentially important new drug and
can enjoy the best possible outcome from it.
Although no price has been announced for Fuzeon, it is expected
to be a doozy. Roche has been spreading a PR cushion to soften the
blow, but there are signs that initial projections of $12,000 per
year may be far too low. People with private insurance will be covered,
as eventually will Medicaid recipients. But this leaves a large
gap in the middle, especially if state ADAP programs decide they
cannot afford to add this budget buster to their formularies. Roche
has promised to make Fuzeon available to any who cannot afford it
through a program administered by their third-party distributor.
Details of the plan are yet to come. Expect approval by the end
of March.
Cool your Jets
T-1249, a follow-on compound to T-20 with activity against
HIV resistant to T-20, is now apparently on a slow track. Two years
ago Trimeris was saying that T-1249 was about two years behind T-20
in the pipeline. Now, the company says not to expect the next fusion
inhibitor until 2008, putting it 5 years behind its sibling. It's
not clear exactly why this is, although it's likely the company
wants to see how T-20 pans out before they sink another $500 million
into developing a similar product. The manufacturing process for
T-20 is famously difficult and expensive and there has been speculation
that Roche may want to explore producing their next long peptide
as a biologic product through gene expression instead of by the
step-by-step assembly process currently in use. Another theory holds
that the company would like to first perfect a pegylated form of
T-1249 that would allow weekly injections rather than multiple daily
shots. An effective pegylated T-20 would surely be welcomed by people
currently taking the drug who have been bothered by painful or troublesome
injection site reactions.
Another reason to speed T-1249 along emerged at the Retrovirus
Conference where data was shown that indicated while people failing
T-20 after one or two years of poking themselves responded to T-1249
during an 11-day activity study, only about half those failing with
more than two years of T-20 above their beltlines responded. This
may mean that if resistance mutations to T-20 continually accumulate
and begin to affect T-1249's activity, then, for the first wave
of those starting T-20 in the next few months, 5 years will be too
long to wait. Step it up, kids.
Longer Term Atazanavir Data
Bristol-Myers Squibb reported long-term efficacy and safety
results on their experimental, once-a-day, protease inhibitor, atazanavir
(ATV) during a poster session at the 10th Annual Retrovirus Conference
held in Boston. The trial was a follow up study to an earlier Phase
II trial that compared two doses of atazanavir with nelfinavir.
Results from the previous study, BMS 008, established that atazanavir
was able to produce viral suppression comparable to that of nelfinavir
without raising blood levels of cholesterol and triglycerides.
The new trial, BMS 044, either continued patients at their originally
assigned doses of atazanavir (400mg vs. 600mg, both once-daily)
or switched those who had been receiving nelfinavir to atazanavir
(400mg once-daily). All participants also continued stavudine (40mg
twice-daily) and 3TC (150mg twice-daily).
Results were presented on virologic response, lipid levels and
side effects with experience now out to 108 weeks of atazanavir
use. Virologic response, defined as the proportion of subjects having
a viral load less than 400 copies/mL, was sustained in those originally
assigned to atazanavir (80% on ATV 400mg and 82% on ATV 600mg).
At 24 weeks following the switch from nelfinavir to atazanavir,
86 percent of those switched had a virologic response, up from 71
percent at study entry.
Lipid profiles remained unchanged among those continuing on atazanavir,
but improved significantly in those originally assigned to receive
nelfinavir. Patients switched experienced median reductions in total
cholesterol from 202mg/dL to 169mg/dL; reduction in fasting LDL
(bad cholesterol) from 132mg/dL to 99mg/dL and reduction in fasting
triglycerides from 127mg/dL to 102mg/dL.
Adverse events were comparable among the study groups and the drug
was generally well tolerated. Elevated unconjugated bilirubin was
the most frequent laboratory abnormality and was associated with
symptoms of jaundice and yellowing of the eyes in as many as 22%
of patients. No association between elevated bilirubin and elevated
hepatic transaminase levels was observed which supports descriptions
of atazanavir-linked hyperbilrubemia as clinically benign. Bristol-Myers
Squibb has filed for U.S. and European approval of atazanavir. (Abstract
555, 10th CROI)
You Can't Always Get What You Want
(And Sometimes You Can't Even Get What You Need) By
Gregg Gonsalves
Well, the President's budget for the coming fiscal year arrived
on Capitol Hill at the beginning of February and except for an unexpected
spasm of largesse for global AIDS efforts, the news looks bleak
for domestic HIV programs, as well as Medicaid, which provides healthcare
to thousands of people with HIV/AIDS.
While reports from the 10th Annual Retroviruses Conference in Boston
warned that 25 states that track HIV cases are reporting an increase
in new diagnoses, the Bush Administration offers flat funding for
the Centers for Disease Control and Prevention's domestic prevention
programs. While scientists at the CDC have announced a goal of cutting
new infections in half by 2005, they're getting no help from 1600
Pennsylvania Avenue, except cries of "Just Say No!" (to
sex, to drugs, to condoms, to clean needles) from the arch-conservatives
that seem to be dominating White House policy making in this area.
AIDS treatment activists have been pushing hard for additional
funding for state AIDS Drug Assistance Programs, as thirteen ADAPs
have already either limited access to antiretroviral treatments
or closed enrollment to new clients. Let's pray that T-20, the new
fusion inhibitor from Roche, doesn't break the ADAP bank when it
receives FDA marketing approval and the price is announced, but
don't count on states being able to afford it if you're an ADAP
client with few therapeutic choices left. By the way, ADAP was the
lucky sibling among the family of other Ryan White programs: the
rest of them are looking at flat funding or even a slight decrease
in funding.
Medicaid is the principal source of government funding for HIV/AIDS
care and treatment in the United States, covering 40% of people
with HIV and 55% of people with AIDS. While state Medicaid programs
are reeling from the deepening recession and require immediate fiscal
relief, the Administration isn't offering additional funding to
states and, over time, is looking to cap the program. Capping Medicaid
would severely diminish the program's capacity to respond to the
HIV epidemic.
So, the future is grim for people with HIV/AIDS in the United States.
While the President is practically rabid about involving the country
in a multi-billion dollar assault on Iraq and cutting taxes for
the wealthiest of Americans, he's hacking away at programs that
serve the poor and the sick and is racking up huge deficits that
will curtail social spending for years to come. I exhorted TI readers
to get involved in AIDS advocacy last month based on the fiasco
that was 2002 for people with HIV living under Bush Jr. The coming
year looks no better.
Last Saturday, I participated in a demonstration against the coming
war in Iraq on a truly frigid day in New York City. I was joined
by about 200,000 others from all over the Northeast. Perhaps, activism
is coming back from the deep freeze and people are beginning to
wake up to the insanity of what's happening around them.
The AIDS community slumbered through the late 1990s and the grassroots
strength and policy expertise that it had built up over the previous
decade-and-a-half has withered and disbursed. We need to rebuild
our grassroots capacity by making a new commitment to community
organizing within our diverse AIDS community and by building new
partnerships with others working on behalf of the poor, the sick
and disabled, and "vulnerable" populations, including
prisoners, drug users and sex workers. We need to be able to rally
thousands to action to undo the damage of the past three years and
it's going to take a lot of time, effort and resources to do this.
We've also got to confront the "brain-drain" from AIDS
policy work. While there are still some great people working on
public policy in AIDS, we've lost far too many others to industry,
consulting firms or academia. Recruiting new, smart and practical
policy "wonks," while trying to re-engage the alumni who
were responsible for many of the advances during the first two decades
of the epidemic, needs to be another priority for us all.
Growing a stronger grassroots movement and public policy apparatus
is a recipe for success — it's been used effectively by political
parties to drive their agendas through Congress or their candidates
into the White House.
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