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Past Issues
Volume 18, number 5/6
May/June 2004
Demanding Gender Equality
Stephen Lewis issues a challenge
ARV Progress in India
Interview with Khousalya Periaswamy
Immunology Report
Gareth Hardy on the Keystone Conference
What's in the Cards?
Few discounts found in new Medicare Card program
Abbott's Bad Medicine
How the Norvir price increase will hurt innovation
Drug News
Updates on drugs in and out of the pipeline
Scramble for Africa
Gregg Gonsalves on the future of NIH's AIDS research network
Gender Inequality and AIDS
By Stephen Lewis
UN Special Envoy for HIV/AIDS in Africa
There is one factor more than any other that drives me crazy in
doing the Envoy job: it's the ferocious assault of the virus on
women. We're paying a dreadful and inconsolable price for the refusal
of the international community, every member of the community without
exception, to embrace gender equality. And in so many parts of
the world, gender inequality and AIDS is a preordained equation
of death.
There's nothing new in that. It's irrefutably documented in encyclopedic
profusion. The culture, the violence, the power, the patriarchy,
the male sexual behaviour... it's as though Darwin himself had
stirred this Hecate's brew into a potion of death for women.
Just last Monday, February 2nd, 2004, I attended the first meeting,
in London, of the newly-constituted Steering Committee of the Global
Coalition on Women and AIDS, a Steering committee, I might add,
of undisputed intelligence, influence and reach; a Steering Committee,
several of whose members are women living with HIV and AIDS. The
heading on the press release to stir media interest read: "HIV
Prevention and Protection Efforts are Failing Women and Girls...
More young women are becoming infected by husbands and long-tem
partners — female-controlled HIV prevention methods urgently
needed". And then, during the presentations throughout the day,
the ritual ghastly litany of examples defining a socio-economic-cultural
gestalt that puts women at deadly risk.
Not in a million years would I challenge either the usefulness
or intent of the Global Coalition. My problem, entirely independent
of the Coalition, lies in the divide between the analysis and what's
happening on the ground. I read the superb studies produced by
Human Rights Watch, and I know that the gap between rhetoric and
reality can be tolerated no longer. In the last two and a half
years, traveling extensively on the African continent, I have seen
virtually no improvement in the status of women. Virtually none.
It's too painful for words. It makes me feel almost criminally
complicit. I have come to the personal conclusion — and I admit
it's personal — that it's time, truly and resoundingly, to take
off the gloves. It's time for the respected UN community, for example,
on the ground in countries, to join with the indigenous allies
and groups fighting for women's rights to demand the visceral changes
that are needed. It's time to abandon the fawning diplomatic deference.
It's time to swallow the insufferable jargon, like 'mainstreaming
gender' which serves to cement inequality by pretending that a
process somehow transforms the lives women lead. It's not working.
In Africa, of the ten million people living with HIV/AIDS between
the ages of 15 and 24, nearly two-thirds are women and girls. Please
explain to me what is working.
The time has come to confront Cabinet Ministers openly, and demand
that they promulgate or amend the laws on property rights and inheritance
rights. It's time to put people in jail, for a good long chunk
of life, for property-grabbing. If sexual violence leads to HIV
and death, then it's time to use the entire apparatus of the state
to enforce laws against rape; to stop putting the onus on the woman
to fight off predatory male sexual behaviour, and move in on the
oppressor with a vengeance. If male teachers molest young girls,
make a spectacle of them. If early marriage is a death sentence,
change the age of marriage and enforce it as though life depends
on it, because life depends on it.
It's time, in other words, country by country, to make the struggle
for gender equality the cause celebre of the land. Give no quarter.
Call press conferences, demand audiences with the political and
religious authorities, form coalitions, take a tactical lesson
from the Treatment Action Campaign in South Africa, demonstrate,
boycott, rail, risk the possibility of being declared persona non
grata by government, and if it happens, on this issue, wear it
as a badge of honour. And should it happen, the cause of women
will have been advanced.
It's all too much: too much sickness, too much sadness, too much
death. Women are the resilient force that sustains the continent,
and they are being eviscerated by a virus. And the world, there
and here, largely inert, is watching it happen. Shades of the genocide
in Rwanda.
You see, if we can make real gains in 3 by 5, and leverage the
money for the Global Fund, and raise the intensity of focus on
microbicides and vaccines, and understand that the pandemic has
a woman's face, then we can begin to break the back of this appalling
scourge. No one has to feel defeated. We just have to feel resolved.
Doubtless it will require superhuman intervention: so much the
better. It requires that level of magnitude to energize the world.
But even all of that said — and if it came to pass, it would
be incredibly exciting — there remains one issue, growing
inexorably, that is thus far intractable: the issue of orphans.
I don't want to drive the nail through the wall; I've spoken a
long time and must wind my way to the end. But it is important
to understand that the millions of orphans are perhaps the most
vexing inheritance of the pandemic. There are several African countries
now, with more than a million orphans: it is without historical
precedent; no one quite knows how to handle it.
In the last few months, I've had the enviable opportunity to accompany
both Graca Machel and Oprah Winfrey on trips to Africa, primarily
to assess the situation of orphans and vulnerable children. Graca
Machel, who is seen by everyone as "Mama Africa", and has a formidable
understanding of the continent was, I think it fair to say, overwhelmed
at times by the sheer numbers and festering predicament of the
orphans. Oprah, than whom it would be hard to find someone of greater
worldliness, was equally shaken to her core. African communities
are struggling valiantly to absorb the orphans as the families
fragment and die, but given the levels of impoverishment, it's
desperately, indescribably difficult.
And it's all becoming so strange. Now we have, pervasively, this
phenomenon which AIDS has brought, of grandparents burying their
children, and then living out their impoverished days looking after
the orphan grandchildren. I was in Alexandra Township in Johannesburg
in December, meeting with a large group of grandmothers heroically
networking through their anguish: they had all lost almost all
their children. It was a spirited if terribly mournful conversation.
There was one grandmother who refused to speak until the end. And
then, in a voice of wrenching and unendurable pain, she told us
how she had lost all of her adult children, all five of her adult
children, between the years 2001 and 2003. Five children in three
years. She was left with four grandchildren, all of whom I later
learned, are HIV positive. Two generations will disappear in an
historical blink.
And where they don't disappear, these millions of orphans wander
the landscape of Africa. These lonely youngsters are bewildered,
angry, sad, frantically seeking nurture and affection, often hungry,
homeless, significant numbers living with grandmothers or in child-headed
households, countless numbers unable to go to school, a school
being the single most valuable and supportive environment they
could possibly have... unable to go to school because they can't
afford the school fees or the uniforms or the books. And when you
lose your parents, who then hands down the knowledge and values
from generation to generation? The orphan crisis is a crisis without
parallel.
Somewhere, somehow, someday, the world has to understand what
AIDS hath wrought. The understanding is not yet in evidence.
This is an excerpt from a plenary address delivered at the
12th Retrovirus Conference in San Francisco, February 8, 2004.
Khousalya Periaswamy
Interview by Bob Huff
What is the situation for access to antiretroviral (ARV) drugs
in India now?
In April, the government started giving free ARV drugs in six high
prevalence states in India, but only a few people are getting them
so far. They are focusing on high prevalence states, but we need
access everywhere. A few people are getting treatment, but they
still don't have monitoring or education and the government workers
are still not comfortable working with people with HIV.
The organization, INP+ (Indian Network of People Living with HIV/AIDS)
is working nationally and within that we have an organization for
working with women and children, which is called Positive Women's
Network (PWN+), which I am in charge of. So INP+ and PWN+ are working
closely together.
Indian generic drug companies are manufacturing low-cost ARV
drugs for sale in Africa, but they are more expensive in India.
Yes, we are selling the drugs for $150 per year in African countries,
but for $50 a month in our country. We have submitted a treatment
proposal to the Global Fund, so if we get it then maybe we can
interest our government in talking to the drug companies to get
the cost down.
So far, around the country, 1,000 people are receiving the medicines
for free from the government. They are planning that 100,000 people
will get ARVs within a year, so we hope that that will be fulfilled.
But we don't have all the money we need. So we are hoping that
we will get money from the Global Fund, we are hoping for more
outside money, and we are hoping that our government will also
put some money towards treatment.
The government has recently changed and we want the new politicians
to understand the importance of the free program and continue it.
So, we are planning to go to the politicians and show them what
is going on here and help them understand.
What drugs are the 1,000 people getting in the government
program?
One of our pharmaceutical companies, Cipla, is providing a three-drug
combination with nevirapine, lamivudine and zidovudine and another
one with nevirapine, lamivudine and stavudine. These are three
drugs in one pill. I can show you the medication that I take — It's
by Cipla; three together. The separate drugs are also available,
for children who need separate drugs. We don't have resistance
tests and we don't have many CD4 tests and viral load tests because
they are costly in our country. But we are hoping the Clinton Foundation
will help us to get CD4 and viral load testing for high prevalence
states. That may begin to happen in the next few months.
Where do people go to get treatment now?
The government is giving training for the government doctors. But
the country is big and the state is big — I am from the
Tamil Nadu state, and we have 30 districts in our state, but
we have only one treatment center. That means in Chennai we are
getting drugs in only one clinic and not in the other clinics.
We hope that the other clinics will be getting the drugs too,
but they don't have the proper resources in the hospital and
they don't have doctors who are trained. The training is now
going on for doctors and other healthcare providers.
The CDC is helping train the government doctors and staff in our
state. Before, we were seeing a lot of discrimination going on
in the hospital, but now they are taking better care of the people.
People from the positive networks are also there for counseling
at the clinic, so there are many changes now. But most people don't
have a doctor. There are only three doctors treating about 200
people, and there is no sharing of information between the government
doctors and the private doctors.
People with HIV from the IPN+ state level network and the district
level network are providing counseling, education and training
for people living with HIV. At the state level network they are
doing DOT training, care training, advocacy training and speaking
out as positive people. It is peer education. Before the programs
there was a lot of discrimination in the districts but now there
are a lot of changes with the community people giving care to people.
And the government is also supporting the Network, by giving space
for their meetings.
We have separate support group meetings for women and children
and then groups for men and women together. We have support group
meeting where they can share their own experiences. And we have
nutrition education programs and health education programs. And
we have separate meetings for people who have started ARVs. We
started a treatment education program about eight months ago. People
in the government ARV programs in the high prevalence districts
are getting information about ARVs and how to take care of themselves.
And we have some money for children's education.
What is the situation for women with HIV?
Women are vulnerable, but that is a global problem. In India, many
women are not getting care and there are many orphans now. So
many of the people infected in India are women — maybe half and
half. Many are mothers. Most are between the ages of 19 to 30.
In our culture they can marry at early ages; at 16 and 17 they
can marry and have children.
We don't have many doctors who are women's specialists. For example,
when the mother-to-child transmission prevention (PMTCT) program
started in our country there was a lot of discrimination in the
hospitals. Now that has changed a little bit, but the hospitals
are still not providing full information and they are not giving
women any help to take care of their children. They will give them
the medicines while they are in the hospital, but after, the women
are not coming back to the clinic.
The government program started in the STD clinics — the sexually
transmitted diseases clinic, but there is a lot of stigma attached
to that.
All pregnant women get HIV testing at the hospitals — not
only government hospitals, but all the hospitals. But at the private
hospitals they get no information and no counseling. And many in
the private hospitals are tested without informed consent. Then
if they have HIV, many private hospitals will discriminate against
the women. Maybe they turn them away or maybe they refer them somewhere
else. Some government hospitals have the PMTCT programs available
and women may be referred there. But some women don't know their
status and come in late at the time of delivery. After that they
don't get follow-up.
Do they give these women who come in late nevirapine?
PMTCT treatment with nevirapine is available in some of the government
clinics but not all of them. Information and counseling is available
in some of these clinics but not all of the clinics.
Then why do they test if they don't treat to prevent transmission
to the baby?
The doctors want to prevent themselves from becoming infected.
So children are still being born infected?
Yes. The government clinics have PMTCT treatment but the women
don't know to go there or if they are sent there they don't know
why they are being sent to that clinic.
They get no information or education in the private hospitals.
In the government hospitals, the counselors talk to people and
say they can provide free testing. If interested, the women get
an HIV test, but if they are not interested, the doctors in a government
hospital will test them anyway. That has happened. If they were
less than one or two months pregnant, they were told that they
can abort the baby. We didn't have a choice to carry the baby.
Now there have been some changes, and we can hope that more changes
will come.
We don't have child specialists to take care of a child on ARV.
That is another big task for us, to take care of the children.
There are only two or three trained doctors taking care of children
in all of India.
Are any public figures speaking out to help ease the stigma
about HIV in India?
Previously some movie stars have spoken out on the prevention aspect
but not on care and support. They are now making a Hindi movie
where an actor plays an HIV positive person. Maybe that will help
with discrimination. Before, though, movie actors would make HIV
into a horrible joke. But we don't have anyone monitoring the media.
They can do what ever they want and no one complains.
When did you start taking ARVs?
I started three years ago. My CD4 was 24 and I had a lot of diseases
and TB and then Cryptococcus, but now I'm okay. My CD4 increased
and I'm living! At that time the medicine was costly, but now
it is less because of our advocacy at INP+. In our state, the
state tax is waived on ARVs. Also, the AIDS Control Society has
a medical shop with better prices; an outside medical shop would
charge 20 percent more. Within our clinic in Chennai they are
also 20 percent less; about $50 a month. I'm lucky because I
can afford it, but not everybody can.
Khousalya Periaswamy is President of Positive Women's Network
(PWN+) and Board Member of INP+
Women with HIV in
India Speak Out
In March of 2002, a national consultation on women living
with HIV/AIDS was organized by the Positive Women's Network
(PWN+), Chennai, India in preparation for a study of the
gender dimensions of HIV within a human rights context. The
study produced a book entitled, "Positive Speaking: Voices
of Women Living with HIV/AIDS" published by the United Nations
Development Fund for Women (UNIFEM), South Asia Regional
Office.
Despite a clearly enunciated commitment to women's equality
in the Indian constitution, women, and especially women with
HIV, remain marginalized. The purpose of the study was to
make women's voices heard, since "what matters is women's
capacity to speak up, demand that they be heard and succeed
in motivating everyone concerned to take responsibility..." The
study is based upon 21 testimonies of individual women's
experiences, each with an analysis of the rights that had
been violated, the consequences of those deprivations and
discussions of specific opportunities to assert those rights,
seek redress and better their situations.
Here is one excerpt from the story of Arti, age 26:
"During the pregnancy of my second child, the hospital took a test in the seventh
month. They found I was positive so they told my husband that I should go to
another hospital. I went to the doctor who had handled the delivery of my first
child. He referred us to another hospital. When we went there for delivery we
did not disclose our status, because we feared rejection and the hatred that
would follow."
"At first my son was fine. One day he developed fever and
started vomiting. We took him to the hospital and kept him
there for 22 days. He had symptoms of epileptic fits also,
so they gave him an injection and after 22 days he was discharged.
He was fine for a week and after that he again developed
dysentery. He died the same night. We had not revealed his
status. But after his death we decided it was better to reveal
my elder son's status so that he could get proper treatment.
The doctor provided him with good care even after his status
was known. But the fever did not stop and he was admitted
to the government hospital for pneumonia."
"Though the doctors provided treatment, there was some problem
when one doctor at the pediatric ward questioned why an 'STD
case' was being kept in that ward. Previously when he was
admitted the doctors used to treat him well. I feel that
if right treatment had been given on time he would have lived
longer. When my son was serious, the doctor was refusing
to admit him. But the network members helped me. They got
all the gloves and things like that and gave them to the
doctor and asked her to admit my son. I was able to get treatment
for him because we fought for it."
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ARV Drug Procurement
in India
Excerpts from a Letter to India's Minister of Health
and Family Welfare
The Affordable Medicines and Treatment Campaign (AMTC),
is a national campaign aimed at creating an environment that
will ensure sustained accessibility and affordability of
medicines and treatment for every individual in India.
We are writing this letter to seek your immediate attention
and intervention to ensure adequate and sustained supply
of antiretroviral (ARV) drugs for the free antiretroviral
therapy (ART) programme. As you know, on 1st of April of
this year Government of India initiated a free ART programme
for people living with HIV/AIDS (PLHA) in the six high prevailing
states (Andhra Pradesh, Karnataka, Maharashtra, Manipur,
Nagaland and Tamil Nadu) and New Delhi. Even though, the
first phase of the programme envisaged 15 delivery points,
the present number of ARV delivery points is only seven (one
hospital in each state). We estimate that at this pace the
treatment plan will cover less than 1,200 PLHAs in the first
phase. This is a minuscule number of the PLHA population
currently in need of ART in these six high prevalence states.
Further, this number is far below the overall target of providing
treatment to 100,000 PLHAs within the first year of the programme.
We understand that the inadequate procurement of drugs is
the main reason for the inadequate intake of the ART programme.
As you are aware, the programme was launched with limited
stock of drugs received from WHO, which is inadequate to
meet the demand. We feel that only large-scale procurement
of ARV drugs can address this issue. As you know, it is the
Indian pharmaceutical companies that supply ARV drugs to
majority of African and Latin American countries. Indian
companies shook the international pharmaceutical industry
and civil society by announcing the supply of ARV drugs for
$340 per annum against the then international price of $12,000
per annum. These companies went further and are presently
supplying ARV drugs for $140 per annum. However, the paradox
is that ARV drugs are still not accessible to vast majority
of Indian PLHAs. We seek your urgent intervention to end
this inequity.
We also have information that the current stock of ARV drugs
will be exhausted in July. Any discontinuance in the supply
of drugs will have life threatening consequences to those
people benefited under the programme.
Against this background, we request you to take necessary
steps to achieve the following: To ensure the immediate procurement
of ARV drugs before the exhaustion of current stock under
free ART programme; to scale up the procurement of ARV drugs
to meet the needs of those PLHAs who require immediate treatment;
and to engage with the Indian pharmaceutical companies to
bring down the price below $140 per annum to increase the
accessibility of ARV drugs.
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Keystone HIV Pathogenesis and Vaccine
Development Report
By Gareth Hardy, PhD
This year's Keystone Symposia on Molecular Mechanisms of HIV Pathogenesis
(X7) and HIV Vaccine Development (X8) was held in British Columbia's
Whistler Resort, Canada, from 12 – 18 April 2004.
This highly specialised and relatively small annual meeting is
often not attended by community activists or press. The focus on
basic science means that much of what is presented and discussed
has little, if any, direct implications for clinical practice.
However, the meeting attracts some of the world's experts on HIV
immunology and pathogenesis as a forum to exchange and discuss
ideas and data. From year to year, the feeling of these meetings
can shift from optimism and excitement, to a mundane business-as-usual
mood, to an urgent knuckle-down and crack-on intensity. This year's
meeting was somewhere between the latter two.
Of significant interest was a presentation entitled "Evolution
of HIV is focused in HIV-specific CD4+ T cells" by the group of
Dean Hamer at the National Cancer Institute together with the group
of Daniel Douek at the Vaccine Research Center, both at the NIH
in Maryland [1]. Douek has previously shown that HIV-specific CD4+
T cells harbour a large proportion of the pro-viral DNA that makes
up the latent reservoir of virus in infected individuals. In this
presentation Hamer not only showed that HIV-specific CD4+ T cells
are infected, but that they are also activated by HIV itself. CD4+
T cells from patients treated with HAART early in infection (i.e.
before any major loss of CD4+ count) were stimulated with HIV antigens
p24 and gp120, with CMV antigen, or anti-CD3 (which stimulates
all T-cells regardless of specificity), and the replication competent
virus induced was sequenced. In addition pro-viral DNA was also
sequenced from purified HIV-specific CD4+ T cells.
The sequences of HIV-1 envelope genes from viruses infecting HIV-specific
CD4+ T cells was found to have an 8-12% divergence from the envelope
sequences of viruses infecting CMV and anti-CD3 stimulated CD4+
T cells. Phylogenic tree analysis showed that these viral variants
were diverse and distinct from viruses populating other CD4+ T
cells. In general polyclonal (anti-CD3) stimulated CD4+ T cells
appeared to have very homogenous sequences representing the original
infecting strains, though during untreated chronic infection virus
sequences were found to be highly heterogenous both in HIV-specific
and polyclonal (anti-CD3 stimulated) CD4+ T cells. Hamer explained
that the HIV present in HIV-specific CD4+ T cells continues to
evolve even in individuals who initiated antiretroviral therapy
shortly after they became infected.
Mathematical modeling based on these findings suggested that boosting
HIV-specific CD4+ T cell frequency could increase viral load and
decrease T cell functional help. The argument here is that while
highly active anti-retroviral therapy may inhibit 99.9% of viral
replication, the remaining 0.1% of virus that is replicating, is
doing so in HIV-specific CD4+ T cells. The reason for this is logical
enough: the population of CD4+ T cells that are most likely to
be continually activated in HIV infection are HIV-specific ones,
even in the presence of antiretroviral therapy, due to the ongoing
presence of HIV antigen which stimulates them. Such activation
of these cells subsequently leads to high turn over of the virus
they harbour.
Though not particularly surprising, the implications of this data
are profound. This may explain why one HIV therapeutic vaccine
after another cannot induce sustained HIV-specific CD4+ T cell
proliferative responses. Yes, we can induce those responses, but
time and time again, they emerge as a transient phenomenon only
to mysteriously disappear again. Such short-term responses are
the hall mark of short-lived effector T cells which have a half
life of 12 days, and not central memory T cells which should live
for many years. The lack of generation of HIV-specific central
memory T cells has been a perplexing mystery for a long time. These
are the kind of T cells which protect us from re-infection with
measles for example, or from any of the organisms we have been
vaccinated against, years after inoculation. Although the jury
is still out on the precise origin of central memory T cells, one
popular current theory is that a small proportion of activated
effector T cells will always survive to subsequently become resting
(non-activated) long lived central memory T cells. The fact that
this does not seem to happen to HIV-specific CD4+ T cells could
be a very important component of why our immune systems fail to
control and ultimately eradicate HIV. Indeed Hamer explained that
the half-life of HIV-specific CD4+ T cells, once activated, was
less than 1 day, suggesting that all HIV-specific effector CD4+
T cells suffer the same fate. Hamer concluded that "The ability
of HIV-specific CD4+ T cells to serve as a distinct reservoir for
HIV growth and variation suggests that vaccines and treatments
aimed at augmenting HIV-specific CD4+ T cell responses should be
undertaken with caution." However many immunologists argue that
we need to ensure preservation of these responses, perhaps by using
more effective HAART regimens, which fully penetrate all anatomical
and cellular compartments, thus preventing the small amount of
virus replication that is taking place in HIV-specific CD4+ T cells.
Indeed these responses need to be expanded in a manner in which
they can be sustained, in order to help achieve long-term control
of viral replication in the absence of anti-retroviral treatment.
Bruce Walker of Massachusetts General Hospital, Boston, Massachusetts,
presented an update on his structured treatment interruption study
in primary HIV infection. [2] Fourteen patients underwent up to
three structured treatment interruptions. Treatment was restarted
if the viral load increased to more than 5,000 copies/mL for more
than 3 weeks or if the viral load increased to more than 50,000
copies/mL on any single occasion. Following interruption, 11 patients
(79%) maintained control of viraemia for more than 90 days, despite
lack of tissue types associated with protection. 57% achieved control
of viraemia for 180 days, 43% for 369 days and 21% for 720 days.
However over time there was a gradual decrease in CD4 counts and
increase in viral loads. The total magnitude of CD8+ T cell responses
increased 3.5, 2.1 and 1.78 fold at the first, second and third
interruption and transiently detected HIV-specific CD4+ T cell
proliferative responses declined with recurrence of viraemia. Walker
concludes that "despite initial control of viraemia, durable immune
control in persons following treated acute infection occurs infrequently".
In response to this, Dean Hamer made a passionate request to Walker
that he would now denounce the practice of treatment interruptions,
acknowledge the potential risks of drug resistant evolution within
them, and agree that they offer limited real clinical benefit.
However there was little agreement on this and Walker did not seem
to share Hamer's view that structured treatment interruptions were
dangerous.
One particularly interestingly element of Walker's data was his
finding that CD8+ T cell responses measured by the release of the
T cell cytokine interferon (IFN)-gamma in the ELISpot assay did
not correlate with protection from viraemia in his patients. In
contrast, measurement of HIV-1 specific CD8+ T cell proliferation
revealed a very impressive correlation with protection from viraemia.
Walker used a florescent dye called CFSE to stain CD8+ T cells,
which binds to the cell membrane. With every round of division
undertaken by proliferating cells the membrane bound concentration
of CFSE halves. This assay is increasingly being used to measure
cell proliferation in different laboratories. Walkers data using
this assay concurs with previous data published by Migueles et
al, [3] demonstrating that HIV-1 specific CD8+ T cell expression
of the molecule perforin, which kills virus infected target cells,
and is known to be deficient in HIV chronically infected individuals,
correlates with CD8+ cellular proliferation. Thus while proliferation
is coupled to effector function such as perforin production, what
we are now experiencing is a gradually dawning understanding that
IFN-gamma expression is not part of this picture. In fact we have
known for some time that IFN-gamma expression is not linked to
cellular proliferation, in the way that other cytokines, particularly
interleukin (IL)-2 are. The implication here is that the commonly
used IFN- gamma assay, now the assay of choice in many immunotherapy
and vaccine trials, may not be telling us the correct information
about functional T cell responses in HIV infection.
Brigitte Autran of the Hôpital Pitié-Salpétrière,
Paris, France, presented the results of the first international,
randomised, double blind, placebo-controlled, phase-I therapeutic
vaccination trial: QUEST. [4] Here 79 individuals with primary
HIV-1 infection were treated with HAART >72 weeks before being
randomised to one of three immunotherapy arms. Group A continued
to receive ART alone, group B received the ALVAC-HIV(vCP1452) therapeutic
vaccine in addition to ART and group C received both ALVAC-HIV(vCP1452)
and Remune therapeutic vaccines in addition to ongoing ART. ALVAC-HIV(vCP1452)
was given I/M at weeks 8, 12, 16 and 20 following randomisation
in groups B and C and Remune was given I/M at weeks 0, 4, 12 and
20 following randomisation in group C. In all groups ART was discontinued
24 weeks following randomisation and patients were followed up
for an additional 24 week period. The primary endpoint was a viral
load <1000 copies/mL at week 48 (24 weeks after stopping ART)
without restarting ART. Secondary endpoints were maintenance of
viral load <400 copies/mL throughout the 24 week ART interruption
and time to reaching viral load above 1000 copies/mL after stopping
therapy. In all cases restarting HAART was considered failure in
the intention to treat analysis.
Preliminary analysis of the data (vaccinated patients in groups
B and C have not been unblinded) reveals that while vaccination
successfully induced T cell responses measured by IFN-gamma ELISpot,
the virological endpoints of this study all failed. In vaccinated
patients the median p24 specific CD4 ELISpot response was 180 IFN-gamma
responding lymphocytes per million peripheral blood mononuclear
cells (PBMCs) (n=32) versus a median of 0 for the ART alone treated
group (n=18) (p=0.006). The median CD8 IFN-gamma response to gag
was similarly high for the vaccinated patients at 275 IFN-gamma
responding lymphocytes per million PBMC (n=34) compared to 0 for
the ART-alone treated group (n=18) (p=0.002). Of the 52 vaccinated
patients, 15.4% reached the primary endpoint of a viral load <1000
copies/mL plasma at the end of the 24-week treatment discontinuation
period. Of the 27 ART-alone treated patients 22.2% reached this
endpoint. There was no statistically significant difference in
these values. There was also no statistical difference in the number
of patients achieving viral load <400 copies/mL during the
ART discontinuation period or the median number of days to a viral
load more than 1000 copies between the ART alone and vaccinated
groups.
The fact that vaccination here proved immunogenic in terms of
T cell IFN-gamma responses, but yet failed to translate into any
discernable clinical benefit further adds credence to the notion
postulated by Bruce Walker that IFN-gamma is perhaps the wrong
marker of immune function to be measuring in our immunotherapy
trials. It is becoming increasingly clear from the published literature
that IFN-gamma production is not tied to T cell function in the
manner perhaps we once thought it was. Indeed it is possible that
because of this, assays measuring IFN-gamma release tend to churn
out lots of positive results. These are popular as everyone likes
to show positive results. Thus IFN-gamma production assays validate
the immunogenicity of various strategies tested, while these responses
yield very little clinical benefit because they have limited or
no functional impact that could affect long-term clinical outcome.
Walker advocates the CFSE dye dilution assay as an accurate measure
of HIV-specific CD8+ T cell function. Functional assays for measurement
of HIV-specific CD4+ T cells that offer clinically relevant alternatives
to singly evaluating IFN-gamma production in the CD4 subset have
previously been shown by other groups. Anna Vyakarnam's group at
Kings College Hospital, London, demonstrate the superiority of
IFN-gamma and IL-2 double positive intracellular staining by flow
cytometry [5] and Frances Gotch's group at Chelsea and Westminster
Hospital also in London demonstrate the superiority of the traditional
lymphocyte proliferation assay which measures incorporation of
radioactive labeled thymidine into the replicating DNA of proliferating
cells [6].
If we are to get a handle on useful immune responses that candidate
vaccines or immunotherapies should be inducing, we need to be using
assays which correlate with clinical outcome. This means that immunology
laboratories and investigators need to be a little more adventurous
in terms of the assays with which they choose to evaluate their
immunotherapy trials. Hopefully the work in this area already laid
out by some groups will be verified in larger immunotherapy studies
and by other groups in the not too distant future. But until then
the incremental acquisition of failing immunotherapy data continues
to generate a business-as-usual feel to not really understanding
why our chosen immune-based interventions are not working. To this
end I returned from British Columbia back home to England and to
my London Immunology Lab, with a whole set of new plans for the
way ahead, while the bars of the Whistler resort roared to the
opening matches of a strange local game called "ice hockey" that
was way beyond my comprehension.
References
- Dean Hamer et al. HIV-specific CD4 T cells are a hot spot
for viral evolution. X7, Abstract 227.
- Daniel Kaufmann et al. Limited durability of immune control
following treated acute infection. X8, Abstract 081.
- Migueles SA. et al. HIV-1 specific CD8+ T cell proliferation
is coupled to perforin expression and is maintained in non
progressors. 2002. Nat Immunol. 11: 1061-8.
- Brigitte Autran of the Hôpital Pitié-Salpétrière,
Paris, France. Results of the first international, randomised,
double blind, placebo-controlled, phase-I therapeutic vaccination
trial: QUEST.
- Boaz MJ et al. Presence of HIV-1 Gag-specific IFN-gamma+IL-2+
and CD28+IL-2+ CD4 T cell responses is associated with nonprogression
in HIV-1 infection. J Immunol. 2002;169:6376-85.
- Wilson JD et al. Loss of CD4+ T cell proliferative ability
but not loss of human immunodeficiency virus type 1 specificity
equates with progression to disease. J Infect Dis. 2000;182:792-8.
Medicare
Drug Card Analysis
An examination of three GMHC clients, whose regimens typify
the needs of people with HIV, shows that the discount card
program is not comprehensive, lacks choice, and offers uneven
savings.
Barry takes 4 prescription medications
for HIV and pain management. Of the drugs covered by the
lowest-price discount plan offered by Medicare, the following
price comparisons were found: |
| Drug Name |
Medicare |
Drugstore.com |
Canadadrugs.com |
| Celebrex |
$151.56 |
$76.99 |
$88.72 |
| Levaquin |
266.28 |
97.93 |
149.56 |
| Viracept |
603.08 |
635.97 |
565.97 |
| Zerit |
329.75 |
316.24 |
259.08 |
| |
__________ |
__________ |
__________ |
| Total Monthly Cost for Barry |
$1,350.67 |
$1,127.13 |
$1,063.33 |
| Barry's best bargain |
Most Expensive |
Less
Expensive |
Least
Expensive |
| Total number of Medicare plans that cover all
of Barry's drugs: 4 |
| |
|
|
|
Patricia takes 6 prescription
medications each day. Of the drugs covered by the lowest-price
discount plan offered by Medicare, the following price comparisons
were found:
|
| Drug Name |
Medicare |
Drugstore.com |
Canadadrugs.com |
| Epivir |
$264.45 |
$269.99 |
$244.90 |
| Hydro-chlorothiazide |
3.89 |
8.99 |
2.02 |
| Retrovir |
308.16 |
326.21 |
330.61 |
| |
__________ |
__________ |
__________ |
| Total Monthly Cost for Pat |
$576.50 |
$605.19 |
$577.53 |
| Patricia's best bargain |
Least Expensive |
Most
Expensive |
Less
Expensive |
Patricia can purchase more of her drugs at
one time through non-Medicare outlets.
Total number of Medicare plans that cover all of Patricia's
drugs: 0
Number of Medicare plans that cover some of Patricia's drugs:
5
|
| |
|
|
|
Jim has been on Medicare
for 9 years and takes 12 prescription medications daily for
HIV, high cholesterol, sleeplessness, and pain. Of the drugs
covered by the lowest-price discount plan offered by Medicare,
the following price comparisons were found:
|
| Drug Name |
Medicare |
Drugstore.com |
Canadadrugs.com |
| Elavil |
$15.38 |
$10.99 |
$2.86 |
| Famotidine |
25.30 |
19.99 |
86.12 |
| Lipitor |
67.33 |
62.99 |
46.48 |
| Naproxen |
13.00 |
17.99 |
12.82 |
| Reyataz |
756.94 |
775.51 |
665.99 |
| |
__________ |
__________ |
__________ |
| Total Monthly Cost for Jim |
$877.95 |
$887.47 |
$814.27 |
| Jim's best bargain |
Less Expensive |
Most
Expensive |
Least
Expensive |
Total number of Medicare plans that cover
all of Jim's drugs: 0
Number of Medicare plans that cover some of Jim's drugs:
2
Analyses were conducted using prices listed on CMS's
website www.medicare.gov,
Drugstore.com's website, www.drugstore.com,
and Canadiandrugs.com's website, www.canadiandrugs.com,
on Thursday, May 20, 2004. Only drugs that were available
from all three sources were compared. All prices in U.S.
dollars.
|
Medicare-Approved
Discount Cards Will Benefit Some Summary from
AIDS Treatment News
Patients who are on Medicare and have income under 135%
of Federal poverty level and are not on Medicaid probably
should obtain one of the new Medicare discount cards that
became available on June 1, 2004, because all these cards
include $600 annual credit for prescription drug purchases
for persons within that income limit. Unfortunately, this
program is complex, no one yet knows how it will work in
practice, and after choosing a card one is locked in until
November 15. The most difficult part of the choice of which
card to get may involve how it interacts with other programs,
including ADAP, and pharmaceutical company patient assistance
programs.
For the complete report, visit: www.aidsnews.org. |
Abbott's Norvir Price Hike is Bad Medicine
By Bob Huff
Statement at the NIH Public Meeting on Norvir
On May 25, 2004, the NIH heard public statements concerning
a petition to invoke the march-in provisions of the Bayh-Dole
Act on Abbott Laboratory's Norvir. The law says that patented
inventions developed in part with public funds can be reassigned
to other business entities if the patent holder does not make
the invention available on reasonable terms.
In the first part of December 2003, the HIV/AIDS treatment community
was shocked to hear that Abbott Laboratories was raising the price
of its HIV drug, Norvir, five-fold. The price per 100mg pill would
increase from $2.14 to $10.71 (average wholesale prices; $1.71
to $8.57, wholesale acquisition cost).
As you've heard, although Norvir was developed and approved by
the FDA as an anti-viral drug — an inhibitor of the HIV protease
enzyme — due to excessive toxicity, it is no longer used as such.
Instead it is now used for an off-label indication in much lower
doses to take advantage of one of its side effects, namely the
inhibition of a metabolic pathway in the liver that effectively
improves the concentration of other drugs in the blood. In current
clinical practice, most other HIV protease inhibitors are "boosted" by
Norvir, which increases their effectiveness. In other words, Norvir
enables other drugs to work better.
 |
Here is a before-and-after price chart that shows the eight approved
HIV drugs that can be boosted by Norvir, and how the price increase
has affected their overall cost. Note that the price of Norvir
in its approved dosage as an antiviral is far out of proportion
to the others. Also note that the price of the drug Kaletra, which
is also made by Abbott and contains a small boosting dose of Norvir
in each pill, did not change and is now the lowest price boosted
protease inhibitor on the market. It is clear that the practical
and intended effect of the Norvir price increase was to position
Kaletra in advantage to its competitors.
Here is another chart that shows a timeline for the development
of some HIV drugs that require Norvir boosting. It includes two
protease inhibitors that were approved last year (Reyataz and Lexiva)
and several currently in development. It seems clear to me that
the Norvir price increase was calculated to come just after these
two new drugs received approval.
But I'm more concerned about the drugs that are still on the path
to approval — and about potentially useful drugs that may now never
enter clinical development — because they would be at the mercy
of Abbott's monopoly on Norvir.
I would like to argue that Abbott's failure to make Norvir available
on reasonable terms will adversely affect the development of new
drugs that depend on metabolic boosting and will limit the amount
of research that will be conducted on existing drugs that require
boosting.
Abbott's abuse of their patent on Norvir will limit patient access
to drugs, limit research, limit options for doctors and limit the
innovation of new-generation drugs of this type. This is why we
are asking the government to protect the public against Abbott's
unreasonable use of the Norvir patents.
Before a pharmaceutical manufacturer decides to invest hundreds
of millions of dollars into bringing a promising compound along
the path to FDA approval, the company projects the market for the
drug over the entire expected life of the product. While this isn't
easy, given the rapid pace of change in HIV therapy, it is necessary
to forecast whether the drug will be competitive and will repay
the considerable investment in clinical development. For the makers
of Norvir-boosted drugs in the pipeline, Abbott's price increase
has thrown these forecasts into chaos.
In seeking to mitigate the impact of the 400 percent increase
in the price of Norvir, Abbott has announced it will make the drug
available at the old price for research purposes to companies that
are developing a drug that requires Norvir-boosting. However this
offer expires once the new Norvir-dependent drug receives FDA approval
and goes on the market.
Yet research on these drugs can not and must not end with approval.
Post-market research, so-called Phase IV studies, are important
to "fill in the blanks" about how a drug behaves in real-world
settings and to provide controlled data that helps physicians make
the most appropriate use of all the drugs in their armamentarium.
Much of this Phase IV research is mandated by the FDA and some
is initiated by the company for marketing purposes. For the recently
approved protease inhibitors, the 400 percent increase in the price
of Norvir means that the cost of post-marketing research has now
increased dramatically. One pharmaceutical executive estimated
that the cost of post-approval research could go up by $20 million
to $30 million. And this is for drugs that have already been approved,
with FDA-mandated post-market research already planned and budgeted.
The impact on drugs still in the pipeline is far more insidious.
A drug company's Phase IV research commitments are decided in
negotiations with the FDA. The FDA says it will grant accelerated
approval based upon available safety and efficacy data, but only
if the company will show a plan for continuing research on the
drug after entering the market. These research plans are negotiated
based on what the FDA would like to see and what the drug company
can afford. The simple fact is that after the 400 percent rise
in the price of Norvir, companies will not be able to afford as
much post-market research. And the high price of Norvir will effectively
tie the hands of the FDA in what they can ask of companies. This
is going to hurt patient care.
There are four Norvir-dependent drugs in the pipeline that this
will affect. Abbott's monopoly on Norvir means that there will
be less post-marketing research and, consequently, less important
real-world medical information produced on how to use these drugs,
for example, in women, in people of color, in prisons, in combination
with other drugs, in people with hepatitis infections or in people
with liver or kidney disease. Much of this research will become
too expensive.
But my main concern is with what Abbott's monopoly on Norvir means
for the future. One pharmaceutical executive I spoke to, in evaluating
the impact of Abbott's action, posed this as a rhetorical question: "Who
would risk developing a Norvir-boosted protease inhibitor after
this price increase?" What he meant was that, not only will the
high price of Norvir place any new Norvir-dependent drug into an
uncompetitive price stratum, but Abbott's unpredictable behavior
has made depending on them or their products an unsupportable risk.
It's difficult enough to project market conditions for new HIV
drugs that don't need Norvir; it's very unlikely that a corporate
market analysis will ever again justify investment in drugs of
this type. In the words of another pharmaceutical executive, after
the drugs currently in the pipeline empty out, "We've seen the
end of the line for boosted protease inhibitors."
And that is a shame, because we desperately need new protease
inhibitors to treat drug-resistant HIV. The so-called HIV salvage
population is the fastest growing market segment in HIV therapy.
Drugs with incremental benefits have continued to trickle onto
the market over the past few years, but in practice, this has resulted
in many patients simply adding the latest therapy onto a failing
regimen, which starts the cycle of resistance all over again. Unless
a person switches to multiple drugs that his virus is susceptible
to, the development of resistance seems inevitable.
For drugs in the protease inhibitor class — which are very durable
HIV therapies — Norvir has assumed a crucial, enabling role by
assuring that sufficient blood levels of the active antiviral drugs
are achieved. Looking ahead, we can foresee the continued need
for new protease inhibitors that will have novel resistance profiles,
that will have less toxicity, and that are more durable. Some of
the drugs in the pipeline have some of these qualities, but none
has all of them. Most observers expect the protease inhibitors
in the pipeline to continue towards approval because their sponsors
have already made substantial financial commitments to their development.
But how many important, useful, and desperately needed drugs will
now never see the light of day — because of Abbott's monopoly on
Norvir? Abbott's unreasonable terms for Norvir will inhibit innovation,
restrict research, limit medical options and hurt people with HIV.
Finally, the pricing issue aside, Abbott has not been a responsible
custodian of this drug. Although Norvir's usefulness is as a metabolic
booster and not as a protease inhibitor as they had hoped, the
company has not made the drug available in dosages that would optimize
the use of Norvir for this purpose. With only a 100mg pill of Norvir
available, many patients who would only require 50mg or less for
boosting are being subjected to unnecessary toxicity.
Furthermore, Abbott has not sought FDA approval for Norvir as
a metabolic boosting agent and continues to represent the drug
in medically misleading terms — all the while encouraging continued
off-label use.
Also, Abbott has, I have been told by several pharmaceutical executives,
been unwilling to offer reasonable terms for licensing Norvir for
co-formulation with other companies' drugs, even though a co-formulated
pill is widely considered to help simplify drug regimens and improve
patient adherence and therapeutic outcomes. Yet Abbott, in order
to protect its own, more toxic Kaletra product, continues to resist
this.
To sum up, Abbott has behaved unconscionably, and perhaps illegally,
in increasing the price of Norvir, and in doing so they have abused
the privilege of their patents.
- They have attempted to manipulate the market and restrict
patient access to competing drugs that have less toxicity.
- They have increased the financial burden their competitors
face in performing important post-market research.
- They have tied the hands of the FDA in how much post-market
research can be required of drugs approaching approval.
- They have stifled innovation and have killed the market chances
for any new drug candidate that would require Norvir.
- They have not been responsive to the medical need for safer
and more rational doses of Norvir.
- They have refused reasonable offers to license Norvir for
co-formulation into patient-friendly combinations with other
drugs.
With at least ten HIV drugs dependent on Norvir to achieve optimal
efficacy and minimal toxicity, I believe Norvir should be considered
a public amenity and be contracted to more responsible custodians.
I'd like to note that I think the case of Norvir is an exceptional
one, and that I fully support industry development programs that
build on government funded research. It seems clear that the intent
of the Bayh-Dole Act was to stimulate innovation, and in this it
has been incredibly successful. But it also seems clear that a
mechanism was provided to address abuse, and that, in Norvir, we
are confronted with that rare case.
Under Abbott's monopoly control of Norvir, drug access (both to
Norvir and to dependent drugs), patient care, innovation, research,
and medical options are being restricted. The public interest would
best be served by making this vital resource more broadly available
under much more reasonable terms.
FDA Issues Warning
Letter to Abbott over Norvir Pricing Spin
On June 10, 2004, the Food and Drug Administration issued
a Warning Letter to Abbott Laboratories about a "false and
misleading" cost comparison chart that Abbott had distributed
to community groups in an effort to counter public outrage
over the recent 400 percent increase in the price of their
HIV drug, Norvir. The cost chart purported to show that Norvir,
even at its new, higher price (the price for a single 100mg
pill increased from $1.71 to $8.57 each) was the lowest priced
HIV drug at its most commonly prescribed dosage. Although
Norvir was originally developed as an HIV protease inhibitor,
it is now used primarily at a much lower dose to "boost" the
blood levels of other HIV protease inhibitors. At 100mg,
Norvir is not active in on its own. Yet the chart implied
that this boosting dose of Norvir was comparable to several
full-dose antiretroviral drugs and even to one complete HIV
regimen.
The FDA's letter stated:
"The cost chart is misleading for two reasons. First, it
compares a subtherapeutic dose of Norvir (100mg once daily)
to the labeled dosing regimes of other antiretroviral agents.
Second, the chart implies that Norvir may be used other than
in combination therapy, when it is not labeled for such use.
Given by itself as a subtherapeutic dose, Norvir would likely
have no antiviral activity and would place patients at risk
for developing protease inhibitor resistance mutations."
"The cost chart misleadingly claims that Norvir has the
lowest daily cost of all antiretroviral drugs and minimizes
the risks of Norvir, and thus misbrands Norvir under 21 U.S.C.
352(a)." Abbott was to respond to the FDA by June 25.
|
Drug News
By Bob Huff
Fixed-Dose Combinations
The FDA has granted a fast-track approval to Gilead's new co-formulated
FTC/tenofovir pill. It should be approved by September 12. This
is sooner than had been expected but the company says it has
sufficient manufacturing capacity to begin shipping soon after
that date. The FDA speeded up approval after prodding by treatment
activists and a recognition that seemingly small advances, such
as co-formulation, are worthy of accelerated approval, because
it can mean a big difference in treatment outcomes for people
due to the improved adherence that comes with simpler regimens.
GlaxoSmithKline (GSK) expects to add a third co-formulated pill
to its line-up with a 3TC/abacavir combo that will likely be
approved in August. GSK pioneered the combo concept for HIV drugs
with their AZT/3TC pill, Combivir, approved in 1997, and followed
it with Trizivir (abacavir/AZT/3TC) in 2000.
The FDA acted after issuing a draft guidance document in May 2004
encouraging manufacturers to develop co-formulated regimens. Specifically
they were responding to a controversy about the co-formulated pills
produced by several Indian generic drug makers that are widely
used in treatment programs in the developing world. These medications
have been evaluated and "prequalified" by the World Health Organization
(WHO) for purchase by private and government sponsored treatment
programs. The generic all-in-one pills (nevirapine, AZT and d4T
is one common combo) are preferred by programs operating in resource-poor
regions because adherence is better, education and dispensing is
simplified, and procurement problems are minimized. Also, the generics
typically cost only about a tenth what their branded counterparts
do. But representatives of the multi-national pharmaceutical industry,
perceiving a threat to their markets, have been fostering the impression
that these drugs are of inferior quality and have convinced the
U.S. government to only buy drugs that have received FDA approval.
With $15 billion promised by President Bush for his international
AIDS program, known as PEPFAR (President's Emergency Plan for AIDS
Relief), the drug companies have a powerful motivation to keep
the generic makers out of the loop. But the practical result of
their obstruction will be far fewer people receiving treatment
and suboptimal outcomes for those who do benefit from the U.S.-sponsored
programs.
The FDA, to its credit, stepped into the middle of this argument
and has offered a fast track for generic makers to receive FDA
review of their products, even if they are not approvable in the
U.S. due to patent issues. While many feel that the WHO prequalification
process is sufficiently stringent and that FDA review is superfluous,
given the political climate and the power of the pharmaceutical
lobby, it is unlikely that U.S. dollars will become available with
out this extra step. Even so, the flap over prequalification of
generics may prove to have been a feint, and the U.S. will simply
continue to funnel money to the multi-national companies.
One significant byproduct of the FDA's shift in thinking is that
unprecedented collaborations between drug companies may now be
in the works to produce new co-formulated HIV regimens in the U.S.
and Europe. Simultaneous with the FDA statement, a joint press
release from Gilead Sciences, Bristol Myers Squibb and Merck announced
that they were in discussions to offer an all-in-one pill containing
efavirenz (Sustiva), tenofovir and FTC. Merck is involved because
they market efavirenz in certain parts of the world as Stocrin.
Another announcement from GSK and Boehringer Ingelheim suggested
that they were exploring a combination with nevirapine (Viramune),
AZT, and 3TC. This is an amazing step forward (after years of protest
that FDA regulations and anti-trust laws would make these collaborations
impossible) but in a perfect world we would see Sustiva hooked
up with Combivir and Viramune paired with Gilead's nukes, too.
One size doesn't fit all.
Abbott
Abbott is looking ahead to a new once-a-day version of Kaletra
and expects to show new data later in the year and file for FDA
approval in the following months. The company is also cautiously
excited about the early results from some small studies that
have used Kaletra as a solo antiretroviral agent — without nuke
backup. A company representative recently told investors that
this could "change the paradigm for HIV treatment." Hopefully
more data will appear at this year's ICAAC conference in October.
The company also says it is working on a new, more stable formulation
of ritonavir that will not require refrigeration. The new process
is said to employ Abbott's proprietary melt-extrusion (Meltrex)
technology, whereby drug molecules are stabilized in a solid dispersion
within a special polymer that dissolves at a controlled rate. This
could overcome one of the biggest limitations to using Kaletra
in resource poor settings, which has been the need for a cold distribution
chain. But don't expect this new product very soon. Typically,
pharmaceutical companies start to introduce new formulations only
when their patent protections begin to sunset. This allows them
extend the market life of their branded products. Abbott's Kaletra
patents don't begin to expire until 2012.
One dark cloud over the potential for using Kaletra in other parts
of the world: a recent report found resistance to Kaletra developing
fairly rapidly in a treatment naïve woman in South Africa who had
Subtype C HIV.
Trimeris
After a disappointingly slow start to the roll-out of their premier
drug, Fuzeon (T-20, enfuvirtide), following approval in March
of 2003, Trimeris is planning to make some improvements. Initially,
distribution of Fuzeon was restricted because of limited manufacturing
capacity and a desire by Trimeris' distribution partner, Roche,
to be sure prescribers and patients had been properly educated
about the techniques of reconstitution and injection. Its record
breaking price also slowed acceptance by some third party payers
(and even a year later it is not yet available through every
state ADAP program). But the biggest impediment to an enthusiastic
reception by patients is the need to inject the drug under the
skin of the abdomen or arm, twice-a-day, every day. A high rate
of injection site reactions has been reported, with symptoms
ranging from redness to "golf ball size" nodules. Yet for those
who can tolerate the routine, the drug has proven remarkably
effective, even in people with extensive drug resistance to other
classes of antiretrovirals.
Now Trimeris has announced that it is beginning studies of a needle-free
injection system for the current generation of Fuzeon, and is moving
forward with studies using the drug in a once-a-day regimen, although
these improvements may not become generally available until 2006
or after. Trimeris is also pressing forward with the search for
second-generation fusion inhibitors with better resistance profiles
and more convenient dosing (possibly once-a-week) and says it may
be able to announce a drug candidate by the end of 2004.
The company doesn't believe that the coming wave of oral CCR5
inhibitors will make Fuzeon obsolete. Since up to 40 percent of
people with advanced HIV disease will have an X4-using virus that
will not be susceptible to the new drugs, Trimeris thinks there
will continue to be a place for fusion inhibitors in this population.
They cite in vitro studies that show dramatic synergy between Fuzeon
and other entry inhibitors when used in combination, and suggest
that viral suppression could be achieved with only one tenth of
the current dose of the drugs when used individually — at one tenth
the cost. One needle-free shot, once a week, costing only $40 may
be just the thing to turn Trimeris' fortunes around.
CCR5 Blockers
There are several CCR5 blockers/entry inhibitors in development,
including Schering's SCH-D, Pfizer's UK 237, Glaxo's GW873140,
and Progenics' PRO140. These drugs are keenly anticipated by people
who have developed resistance to all drugs in the conventional
classes and the FDA has seemed to signal that they favor larger,
Phase III clinical trials in people with multi-drug resistant virus.
But there may be a hitch. People with few remaining treatment options
tend to be people with more advanced HIV disease. And the longer
people have had HIV, the more likely they are to have evolved virus
that is capable of using CXCR4, a development associated with accelerated
disease progression. These people won't be helped by a CCR5 blocker
and they may be put in danger if the drugs force a shift to X4-using
virus that speeds up immune deterioration. The possibility of this
risk would seem to favor first investigating the CCR5 blockers
in a more recently infected population, where the X4 virus will
be less common. To do this safely, though, a sensitive and reliable
screening test to detect low levels of X4-using virus must be developed.
All of this may call for a rethinking of how to test these new
drugs.
One fallback position (though it will likely slow enrollment)
may be to require Fuzeon for every trial participant as a "safety
net" to catch any virus that achieves coreceptor binding. A bonus
to this is suggested by a bit of recently reported data that found
Fuzeon may also block X4 coreceptor usage, in addition to mucking
up fusion.
Boehringer Ingelheim
BI is set to widen access to tipranavir, its salvage-oriented
protease inhibitor, by the end of summer. The drug is active against
HIV that has been exposed to most every other PI, which will be
welcome news to the growing number of people who are searching
among limited treatment options to cobble together some kind of "salvage" regimen.
Still, and this can't be stressed enough, a drug like tipranavir
will work best over the longer term only if it is paired with at
least one other drug that a person's HIV is susceptible to. For
many, if not most, this is likely to be Fuzeon. One bit of disappointing
news about tipranavir has surfaced: it seems to lower the blood
levels of other PIs, making them unreliable partners, despite ritonavir
boosting. Saquinavir in particular was seen to drop to sub-therapeutic
concentrations in the presence of tipranavir. This means that the
emerging salvage strategy of using dual boosted PIs may not be
possible with tipranavir.
Also, BI has announced that a clinical trial with alovudine (MIV-310),
an NRTI targeting multiresistant HIV has recently begun. Continuing
BI's foray into salvage therapy, alovudine (say it with a Cockney
accent) was licensed from Medivir in July 2003. The trial has been
designed to evaluate short-term antiviral activity and safety in
patients with HIV resistant to multiple NRTIs. The trial is a dose
finding study in patients infected with HIV resistant to multiple
NRTIs and with detectable viral load. They will be treated for
one month with alovudine added to their standard regimens.
Gilead
Gilead Sciences is working on a new prodrug technology that has
the potential to all but revolutionize HIV protease inhibitor
therapy. Prodrugs are "almost" drugs that are converted to their
fully active form once they are in the body. The best known example
is Glaxo's recently approved Lexiva, a prodrug of their earlier
protease inhibitor, Agenerase (amprenavir), which suffered from
poor solubility in the gut and required a large number of pills
to simply get a sufficient amount of drug absorbed into the body.
But Lexiva has a chemical modification that makes it much more
soluble in the intestines than Agenerase, so fewer pills are
needed to deliver an active dose to the bloodstream. Then, as
Lexiva crosses the intestinal wall, the chemical modification
is clipped by an enzyme there and the original, active drug goes
on its merry way. The same potency is delivered with far fewer
pills.
Now Gilead is working on a prodrug concept that goes one — if
not two or three — steps further. The company's scientists have
invented a chemical modification that specifically targets a drug
to lymphocytes — precisely the kind of cells that HIV infects.
The prodrug modification is clipped by an enzyme specific to these
cells and only turns into its active form once it is in or around
lymphatic tissue. Details of the enzyme involved and how all this
works have not yet been published. So far Gilead has tested its
prodrug concept with a modified form of tenofovir (Viread), which,
in a short term clinical trial, effectively lowered viral loads
with only a fraction of the usual dose required.
Gilead is also developing a new protease inhibitor that uses the
prodrug trick. The chemical modification is tailored to let the
prodrug be easily absorbed in the gut, and also let it dodge premature
clearance by the CYP 3A4 enzyme system in the liver, so no boosting
should be required. The active form of the drug would only get
down to business after it is modified in its target cells, where
it would be trapped. If this all pans out — and the PI version
has yet to be tested in people with HIV — protease inhibitor therapy
may take a quantum leap in terms of activity, tolerability and
pill burden. The inherent efficiency of the prodrug system means
that much smaller dosages are required, which could open the door
for a three-in-one, PI-based, single pill regimen. The specificity
for lymphocytes might mean that collateral toxicity to other cell
types could be greatly reduced. In lab tests, the PI appears to
have a similar resistance profile to that of tipranavir, which
is active against many HIV strains that are multi-PI resistant.
It is yet to be determined if the prodrug will reach infected cells
in reservoirs or sanctuary sites in the body. Despite the exciting
potential, it may be another year before we know if this prodrug
technology will survive the boot camp of Phase I trials, and then
another year or two until it becomes available, most likely in
a tenofovir version first.
Scramble for Africa
By Gregg Gonsalves
In 1884, German Chancellor Otto von Bismarck called together the
major western powers of the world to apportion control of Africa
amongst them. At the time of the conference, 80 percent of Africa
was still under traditional and local rule.
Now, 120 years later, the major clinical trials networks of the
western world — that is, the half a dozen or so of these groups
funded by the U.S. National Institutes of Health (NIH) — are set
to carve up Africa, Asia and much of the developing world for the
purpose of testing treatments, vaccines, microbicides and behavioral
prevention approaches.
Of course, both the NIH and the investigators involved will scream
that I am being singularly unfair: the new emphasis on clinical
research on HIV/AIDS in the developing world will be a partnership
between American investigators and their African, Asian, South
American, and Caribbean counterparts and will bring much needed
resources to these regions.
These clinical trials networks are getting ready to apply for
funding, or "re-compete," for their next five-to-seven year cycle
of federal support. Bureaucrats at the Division of AIDS are now
furiously crafting a Request for Application (RFA) to guide those
applying for the $400+ million in AIDS clinical research funding.
The networks have been in existence for well over a decade and
the scientists who lead them inhabit key positions in the world
of AIDS research. Despite earnest invocations of partnership, the
same group of U.S.-based researchers that has been in charge of
clinical research on AIDS for many, many years will still be pulling
the strings as their studies move to the global South (and they
will not share or relinquish control easily).
While this stands as a moral outrage, it is a scientific one as
well. There are key questions that need to be answered about treating
HIV in the developing world concerning how to best use antiretroviral
therapy in these settings, the impact of co-infections like tuberculosis
and malaria, and best ways to deliver treatment where little health
care infrastructure exists. All of these questions and the trials
needed to answer them are far from the kind of high-tech, university-based
studies that have been the focus of the American clinical research
establishment. In fact, the researchers best positioned to develop
a clinical research agenda for the developing world are those working
there now.
The re-competition of the NIH's clinical trials networks is set
to establish a new colonialism in AIDS research that is as unilateral
as the administration's foreign policy. After cries of outrage
from treatment activists, the Office of AIDS Research at NIH and
its director Dr. Jack Whitescarver responded by bringing in a set
of outside experts to draft some principles to guide their efforts.
Initial drafts of these principles look promising, but the real
problem lies at the Division of AIDS at the National Institute
of Allergy and Infectious Diseases (NIAID) where deep parochialism,
arrogance and lack of vision threaten to squander a precious opportunity
to revamp this huge clinical research system.
So what is to be done? First, whether it wants to or not, DAIDS
needs to ensure that researchers from the developing world have
control over the scientific agenda of studies to be conducted in
their countries. It simply isn't good enough to have "representation" from
the developing world on decision-making committees of the major
clinical trials networks — this is tokenism. Protocol design, administration
and evaluation for studies conducted in the developing world can
and should be conducted in the developing world — there is no reason
it has to happen in Denver, Seattle, Baltimore or Bethesda.
Second, DAIDS should sequester a quarter or more of its annual
clinical research budget for non-network-supported studies with
a rapid review process. This would allow outside groups to apply
for support to answer critical questions that the networks will
not or cannot address. Indeed, there are some kinds of studies,
particularly the operational research that will be vital to shaping
the AIDS treatment programs of many developing countries, which
standing networks are poorly suited to perform. This would also
allow smaller, key studies to be performed without the onerous
delays in protocol implementation that the existing networks are
notorious for.
Third, DAIDS needs to ensure strong, external oversight of its
clinical trials networks. The NIH Office of AIDS Research should
be entrusted to establish an AIDS Clinical Research Advisory Group
made up of leading researchers unaffiliated with funded networks
and with strong representation from developing countries to provide
guidance to the networks on a regular basis.
Clinical research on HIV/AIDS is one of the key engines for improving
the treatment and prevention of HIV infection — the way it is conducted,
by whom and what is studied have tremendous implications for the
millions of us living with HIV/AIDS and those at risk. There are
some momentous choices to be made in Bethesda this summer. Perhaps
the leaders at the Division of AIDS will finally wake up to the
enormous responsibility they now hold in their hands.
© 2004 Gay Men's Health Crisis
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