Local & National News
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New HIV-AIDS Program Targets Aboriginals
February 26, 2008
Prince George - A new program debuted Monday in Prince George to reduce the
number of HIV-AIDS cases and sexually transmitted infections in B.C.'s aboriginal
community.
It's called the Chee Mamuk Aboriginal HIV-STI program and is designed by
the B.C. Centre for Disease Control to link health professionals with vital
HIV-AIDS and sexual health services in First Nations communities.
The launch of the program in northern B.C. is important because statistics
indicate aboriginal people represent about 17 per cent of the population
and over 78 per cent of all new HIV infections.
"The burden of HIV disease has been extremely high for the aboriginal population
in B.C.," said Melanie Rivers, acting manager of Chee Mamuk.
"Although aboriginal people only represent about five per cent of the total
B.C. population they represented just over 15 per cent of all new HIV infections
in 2006, with this overrepresentation being more pronounced for aboriginal
women, who accounted for 37 per cent of the new cases."
It's hoped the five-day course will foster greater community-based solutions
to the growing problem of HIV-AIDS and build new networks among participants.
The course runs until Feb. 29, with two more sessions planned in the coming
months.
In 2006, there were a total of 54 new aboriginal HIV cases reported in B.C.,
averaging more than one aboriginal person testing positive for HIV every
week.
Poverty, unemployment and a high percentage of alcohol and drug addiction
make aboriginal people more vulnerable to HIV-AIDS, said Chief Ron Mitchell,
from the community of Moricetown near Smithers.
By The Canadian Press, http://www.princegeorgecitizen.com |
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No Funding for AIDS Groups in Federal Budget
Liberals prop up minority Tory government
February 27, 2008
After a year of deep funding cuts, AIDS service organizations found no relief
in yesterday's federal budget.
"The 2008 budget is all about numbers and securing votes, with little focus
on helping people," says Monique Doolittle-Romas, executive director of the
Canadian AIDS Society.
With a $1-million cut to Ontario groups announced last year, it appears that
AIDS groups are the latest victims of the Harper government's shifting priorities.
This year's budget makes no mention of Canadian AIDS initiatives.
In no rush to face an election, the Liberals announced that they would support
the budget, as they continue to prop up the minority Conservative government.
Doolittle-Romas calls on the government to live up to its commitments.
"We've seen no reassurance to date that the $84.4-million promised to community-based
AIDS organizations in 2004... will be maintained, which could leave thousands
of Canadians living with HIV/AIDS without the services and programs they
so desperately need," she says.
Although the country's economy remains uncertain, the Tories are using that
fact as an excuse to justify inaction on major issues facing the nation,
says the Canadian Centre for Policy Alternatives.
"The Conservatives have the audacity to claim they are prudent fiscal managers
but for the first time in more than a decade, this country is facing a potential
deficit because of their $190 billion tax cut bonanza," says CCPA senior
economist Armine Yalnizyan.
Still, AIDS service groups vow to fight for adequate funding.
"We're not backing down," says Gail Flintoff, the Canadian AIDS Society chair.
"While the Finance Minister chooses to cut spending and show prudence while
forecasting tough times ahead, for us and people living with and affected
by HIV/AIDS, they're already here."
Brent Creelman, Xtra.ca |
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Superbugs Face A New Foe
February 28, 2008
A few weeks ago, the Journal of Clinical Microbiology published a paper about
the prevalence of a superbug on Vancouver’s Downtown Eastside. Six Vancouver
researchers studied a sample size of 301 intravenous-drug users. The superbug
MRSA—known in the scientific world as methicillin-resistant Staphylococcus
aureus—was present in 18.6 percent of them. That was up from just 7.4 percent
of intravenous-drug users testing positive for MRSA in a similar experiment
conducted in 2000.
The more recent study helped focus national attention on antibiotic-resistant
bacteria, which, up until then, were primarily seen as a problem within hospitals.
But new research conducted at UBC offers some hope of defusing the power
of the so-called superbugs, both within hospitals and in the community. The
answer could come through the use of naturally occurring compounds called
peptides, which consist of two or more amino acids.
So what’s the problem with MRSA? According to Bob Hancock, a UBC professor
of microbiology and immunology, MRSA and other staphylococcus bacteria cause
infections of varying severity. They can range from a cut that won’t heal
to deep-seated bone infections that spread throughout the body. Hancock told
the Georgia Straight that it’s difficult to persuade drug addicts, who often
have compromised immune systems, to remain in hospital for a couple of weeks
for the "mainstay" MRSA treatment, a drug called vancomycin.
"Right now, there is literally only a couple of antibiotics that you can
use," he said. "Both of them are relatively expensive."
Last year, the Straight published a story about how Hancock and UBC microbiologist
Brett Finley were using peptides to stimulate the body’s "innate immunity"
to fight off infections. They published their findings in the journal Nature
Biotechnology, and they continue to work in this area with the help of a
US$8.7-million grant from the Bill & Melinda Gates Foundation. Hancock
suggested that peptides could one day be given to vulnerable hospital patients
to help prevent infections.
"There is no reason why it couldn’t work on any kind of disease, to tell
the truth, but we’ve got a long way to go before we can demonstrate that,"
he said.
Hancock also told the Straight that researchers in his UBC lab are now using
sophisticated computer programs to pioneer more targeted approaches to superbugs
like MRSA and VRE (vancomycin-resistant Enterococcus). This approach, he
said, involves using peptides as "straight antibiotics" rather than as immune
boosters.
Researchers in his lab have developed a very broad spectrum of peptides,
and some, he said, are demonstrating "really good activity against at least
most of the superbugs now".
"I’m talking about MRSA as one of them," Hancock said. He noted that his
lab’s research is now being reviewed, which occurs before the findings can
be published in a scientific journal.
This use of peptides as antibiotics raises the spectre of an entirely new
avenue being developed to fight infectious diseases. Scientists have known
for years that peptides can kill bacteria, but the difficulty came in figuring
out how to create amino-acid sequences to kill mutating pathogens that develop
resistance. Hancock praised Artem Cherkasov, a UBC assistant professor of
infectious diseases, for accelerating research in this area with the use
of artificial-intelligence systems. "It was really his contribution that
made the critical difference there," Hancock said.
He said Cherkasov helped create a program that uses days of computer time
to predict what new peptides need to be developed. "Literally, the computer
has been able to go from a couple of thousand peptides that we made to looking
at 90 million permutations of peptides—and telling us which ones are the
most likely to be successful," Hancock said. "And the computer is considerably
more accurate than our previous rational approaches were."
The Gates foundation insists that any discoveries from its funding must be
made available to developing countries, so there’s a good prospect that if
this approach proves to be successful, treatments will be available for the
world’s poor.
Hancock has already won numerous prestigious scientific awards, including
being named the 2006 Canadian health researcher of the year by the Canadian
Institutes of Health Research. The prize was named after UBC’s deceased Nobel
laureate Michael Smith.
When asked if Hancock foresees himself and other UBC researchers ever winning
the Nobel Prize in medicine for their research on peptides, he laughed it
off and said that no scientist ever expects that to occur. "For me, I’m really
excited about the fact that I think we have really come up with a new way
of treating infections," he said. "It’s exciting. I’m excited, believe me."
This may not come soon enough for those already suffering the ravages of
antibiotic-resistant bacterial diseases. But it provides some reason to hope
that scourges such as tuberculosis, syphilis, and MRSA might not claim quite
so many victims in the future.
By Charlie Smith, http://www.straight.com |
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When Science Runs Into an Ideological Wall
The Canadian government has been taken to task for its lack of support
for, or knowledge of, scientific research
March 1, 2008
While it's usually a badge of distinction to have your work cited in a top-flight
academic journal, the federal government wasn't exactly in a celebratory
mood after two recent journal editorials discussed the feds' attitude toward
science.
That's because the journals had little good to say about the government's
lack of support for, or knowledge of, scientific research. As far as lack
of support is concerned, Nature magazine cited the government's recent decision
to eliminate its science adviser position, its muzzling of Environment Canada
scientists, and its putative failure to adequately fund research as evidence
of "the government's manifest disregard for science."
And as for a lack of knowledge, scientists at the B.C. Centre for Excellence
in HIV/AIDS took Health Minister Tony Clement to task in The Lancet Infectious
Diseases for Clement's apparent inability to distinguish between peer-reviewed
medical literature and an opinion piece appearing on the website of a lobby
group.
The Lancet Infectious Diseases article followed an earlier editorial published
last year in the online journal Open Medicine. That editorial, written by
University of Toronto medical professor Stephen Hwang and endorsed by more
than 130 scientists, argued that the government's approach to Vancouver's
supervised injection site reveals "that scientific evidence is about to be
trumped by ideology."
These are damning charges. And there is no question that the government has
been less than supportive of any scientific evidence that conflicts with
its ideology. This is a serious problem, since preferring to see the world
as you think it ought to be (ideology) instead of the way it is (the scientific
evidence) can be fatal, not just for governments, but for everyone.
Yet there is substantial evidence that ideology influences our assessment
of scientific evidence, particularly when one's views are ideologically entrenched.
In one experiment, social psychologist Charles Lord divided students into
two groups -- one made up those who were the most ardent supporters of capital
punishment, and the other of the most ardent opponents of the death penalty.
Lord then gave half of the students in each group a set of studies showing
that the death penalty acted as a deterrent, and the other half in each group
received studies showing that capital punishment had no deterrent effect.
Now, were the students acting rationally, we would expect those who received
evidence contrary to their views to soften their positions somewhat. But
the opposite happened -- both the supporters and opponents of capital punishment
strengthened their views upon receiving contrary evidence.
In effect, the students explained away the contrary evidence -- and justified
their original positions -- by criticizing the methods of those studies that
failed to support their ideologies.
More recently, Donald Braman and Dan Kahan of Yale University, in a paper
titled More Statistics, Less Persuasion: A Cultural Theory of Gun Risk Perceptions,
found that people's positions on gun control are determined by their cultural
worldviews. Much as in the death penalty study, the researchers concluded
that "individuals can be expected to credit or dismiss empirical evidence
on 'gun control risks' depending on whether it coheres or conflicts with
their cultural values."
These are troubling findings because they suggest people behave in a manner
exactly the opposite of that prescribed by science, which dictates that we
test and modify our theories on the basis of the evidence, rather than interpreting
the evidence in light of our theories.
But given that this is how many people -- and many governments -- behave,
and given the importance of allowing scientific evidence to inform government
policy, it's essential that we find ways of developing a rapprochement between
researchers and policy-makers.
Fortunately, there is a wealth of literature on what is called "research
transfer" or "knowledge utilization." Much of this literature has been written
by Canadians, including many in the employ of the federal government.
In one important paper titled Connecting Research and Policy, Canadian Health
Services Research Foundation CEO Jonathan Lomas notes that many factors influence
government decision-making, including interests (how one would like the world
to work), ideologies (how one thinks the world ought to work) and beliefs
(how one thinks the world actually does work.)
Of these three, Lomas argues that beliefs are the only factor likely to be
changed as a result of information, and even then, information comprises
much more than just scientific research, as it also includes "anecdotes,
experience and even propaganda." Further, beliefs typically take a long time
-- often years -- to change, and then only after "repeated exposure from
competing sources of information."
Given this reality, how can we make governments more responsive to scientific
research? Perhaps most importantly, Lomas notes both researchers and policy-makers
must have a better understanding of each others' domains.
In particular, both scientists and decision-makers tend to view the others'
field as a product rather than a process. Government policy-makers, for example,
typically see science as a "retail store" that provides them with just the
product they need when they want it.
A good example of this view came from Tony Clement when he begrudgingly extended
the supervised injection site's lease on life, saying that he needed more
"facts" about the site's effect on lowering drug use and fighting addiction.
While science can provide such information, Clement's words reveal that he
sees science as a retail store rather than as an activity, a process.
The problem with this approach is that it virtually guarantees that researchers
and policy-makers will come into contact with each other only at the moment
a decision is made, and researchers will present their findings only after
the policy agenda "has been framed within a particular context . . . and
often after the limits have been set around feasible options."
And as the government's approach to the supervised injection site -- and
the study of students and the death penalty -- make clear, it's highly unlikely
scientific research will change the beliefs of policy-makers at such a late
stage in the process, particularly when the government holds ideologically
entrenched views.
If, on the other hand, policy-makers view science as a process, and maintain
regular contact with scientists, they can influence the "conceptualization
and conduct of a study" and are also more likely to allow the study's results
to inform policy.
Similarly, if scientists view policy-making as a process, and maintain regular
contact with policy-makers, they stand a much better chance of influencing
the policy agenda and framing the issues, which again increases the chances
that their results will inform policy.
For these reasons, the Canadian government has placed considerable emphasis
on research transfer, and has developed many linkages between researchers
and policy-makers. This close relationship might explain why many bureaucrats
within the government have been influenced by the research on the supervised
injection site.
The problem, of course, is that government policy is ultimately set by the
cabinet ministers and the prime minister, who continue to view science as
a retail store. And until that changes, the government will continue to make
the pages of academic journals, for all the wrong reasons.
By Peter McKnight, The Vancouver Sun |
International News
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Talking With Children about Sex and AIDS: At What Age to Start?
February 26, 2008
What age is the right age to have "the talk," not just about where babies
come from, but also about sex and AIDS?
How about, oh, 4?
A new documentary, "Please Talk to Kids about AIDS," raises this question
in a cute but discomfiting way. So far it has been seen only at film festivals
and at schools of public health, including those at Harvard and Johns Hopkins.
But the film will soon be available at www.eztakes.com/Talk-to-Kids. I saw
it last month at a Gay Men’s Health Crisis screening for AIDS counselors.
In it, two incredibly sweet and precocious sisters — Vineeta and Sevilla
Hennessey, ages 6 and 4 — accompany their parents, the filmmakers, to the
2006 International AIDS Conference in Toronto. They interview top AIDS experts,
gay activists, condom distributors, a sex toy saleswoman, a cross-dresser
playing Queen Elizabeth II and an Indian transgender hijra in a sari.
The startling aspect is that, as one childish question leads to the next,
they ask things like: "How does AIDS get into your body?" and "How come they
want to have sex with each other?"
For a reporter, it is a guilty pleasure to see some of the world’s leading
scientists squirm — or not — when grilled by a child.
Dr. Anthony S. Fauci, the nation’s instantly recognizable authority on everything
viral, seems as relaxed as he does on television or before Congress. People
get AIDS from each other, he explains in the documentary. "You know," he
says, "when a man and a woman have sexual relationships they get infected.
And also from injecting from a needle that is contaminated with the virus."
But, with children as with senators, Dr. Fauci glides casually away from
the tough follow-up, segueing to: "Do you know what a virus is?"
By contrast, Dr. Mark A. Wainberg, the conference’s co-chairman, dissolves
in nervous laughter.
"Well, AIDS gets into your body in ways that can — can be complicated to
explain to little girls," he says, fumbling to a finish with: "In the same
way that a mommy and a daddy have a relationship that . . . results in our
coming into the world. But you know what, you asked a great question. I’m
just not sure I’m qualified to answer."
The girls get straightforward answers about bodies conjoining, from Craig
McClure, the AIDS society’s director, and about trading sex for money, from
a prostitution-rights activist.
But the film is hardly a medical lecture. The hallway theatrics — flags,
puppets, dancing — give the conference a carnival feel. In fact, an unplanned
stop at the Condom Project’s table inspired the filmmakers, Brian Hennessey
and Radia Daoussi, to center the film on their girls.
Sevilla thought the bright packages were candy and loved the Cinderella ball
gown and tutus made of blue and pink condoms. She asked about them, and a
volunteer’s struggle to turn her boilerplate spiel into words simpler than
"destigmatize" made it clear that a child’s innocence would elicit good interviews.
But innocence — being fleeting — fled. At one point, Vineeta draws for the
camera a picture of two people in bed. "These are condoms," she explains
of the bowl beside them, "that you put in the boy’s penis, so they don’t
get AIDS with a woman or with a man. A man can do it with a man if you like
it."
Interestingly, only some interviewees checked to make sure that the producer
and cameraman were Mom and Dad. To me, that would have been crucial; after
all, I wouldn’t tell a child there is no Santa Claus or why I am an atheist
without a parent’s permission.
The woman at the sex-worker booth did, as she was decking out the girls in
feather boas for a make-believe evening on the street. "I was wondering why
you were bringing kids up here," she said to Mr. Hennessey.
Poor Dr. Wainberg said he had been swamped with running the conference and
was told nothing about the girls before meeting them. "I was a bit taken
aback," he later said in a telephone interview. "I wasn’t sure if this was
the time and place to go into a long explanation of the birds and the bees."
Dr. Fauci said he had been briefed by a press aide, and guided his answers
by watching the girls’ reactions. I wished I had seen more of those in the
film. Were they confused? Bored? Horrified?
When the screening was over, I lingered to meet them. Would they turn out
to be traumatized robots parented by publicity-seeking control freaks?
They did not. Mr. Hennessey and Ms. Daoussi are on a mission but with a sense
of fun. For example, to protest cluster bombs, which kill children who find
the bomblets, they staged a bomblet hunt near the last White House Easter
Egg Roll.
And the girls seemed self-possessed and at ease with grown-ups. Asked by
an audience member if she had any advice, Vineeta said, Yes; don’t share
too much. "It’s like what they say at my school," she explained. "Don’t share
a comb or a hat because you can get lice."
There is, Ms. Daoussi argues, no right age for the topic. "It’s when they’re
ready to ask," she said. "It’s our own discomfort that’s the problem, not
theirs. Kids don’t have taboos."
I left only partly convinced. It is possible to push very young children,
with so little grasp of which fears are realistic, into information that
scares them — into, for example, lying awake worrying that sex will kill
their parents.
Sevilla did say she was scared twice — once by an African guerrilla theater
skit showing a village massacre and an orphaned girl forced into a sugar-daddy
relationship, once by learning what a sex worker did. "I know it’s a job,"
she said, "but it’s a weird job."
But the film is not really for children — certainly not in its present form,
even its makers say. For a parent, however (and I have a stepson Vineeta’s
age), watching someone else’s very young child — maybe even too-young child
— grapple with the topic is a powerful exhortation to begin thinking about
how to talk to one’s own.
By Donald G. McNeil Jr., The New York Times |
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Agreement Reached on AIDS Bill
February 27, 2008
Washington - A House committee on Wednesday voted to more than triple spending
for a global AIDS program that has proven to be one of the Bush administration's
most successful and popular foreign policy initiatives.
The Foreign Affairs Committee's voice vote on the plan to approve spending
of an average $10 billion annually over the next five years came hours after
lawmakers and the White House reached a compromise on some of the policy
issues, including spending on abstinence programs, that had held up action
on the legislation.
The bill extends the President's Emergency Plan for AIDS Relief, which authorized
spending of $15 billion total for five years for prevention and care programs
in sub-Saharan Africa and other regions hit by the epidemic. That act, passed
in 2003, expires in September.
Every day another 6,000 people are infected by HIV, said committee chairman
Howard Berman, D-Calif. "We have a moral imperative to act decisively."
While the program has wide bipartisan support, the White House and many Republicans
objected to the original Democratic-crafted draft because it removed a provision
requiring that a certain amount be spent on abstinence programs and bolstered
links between AIDS treatment and family planning. Some Republicans said that
would open the way for family planning groups to spend money on abortions.
The compromise worked out in late-night negotiations Tuesday does eliminate
the clause requiring that one-third of all HIV prevention funds be spent
on abstinence, instead directing the administration to promote a "balanced"
prevention program in target countries. The administration must issue a report
if programs focusing on abstinence and fidelity do not receive half of funds
devoted to the prevention of sexual transmission of HIV, a smaller pot.
The agreement also allows the use of AIDS funds for HIV/AIDS testing and
counseling services in those family planning programs supported by the U.S.
government.
Rep. Ileana Ros-Lehtinen, R-Fla., top Republican on the committee, said the
compromise maintained core values important to both sides. "Many of us in
this room concluded that a collapse of the political consensus on this issue
would do irreparable damage to what is arguably the most successful U.S.
foreign assistance program of the last half century."
President Bush was hailed during his recent trip to Africa for a program
that has resulted in 1.4 million people receiving drugs to fight the virus
and has cared for nearly 6.7 million, including 2.7 million orphans.
The bill was named after two former chairmen of the committee, Reps. Henry
Hyde, R-Ill., and Tom Lantos, D-Calif., Hyde, who died last November, and
Lantos, who died earlier this month, sponsored the 2003 bill. Lantos was
the sponsor of the new bill.
"This historic agreement will save millions of lives," said Dr. Paul Zeitz,
executive director of the Global AIDS Alliance. He welcomed the increase
in funds for tuberculosis and malaria while expressing concerns that the
compromise retains limitations on AIDS funding for family planning.
The White House on Wednesday also repeated that the president's proposal
to double spending to $30 billion, rather than the $50 billion in the House
bill, was more appropriate. "We believe ... that $30 billion is the right
amount of money that could be effectively used by these governments to tackle
the HIV-AIDS problem," White House Press Secretary Dana Perino said. "We
don't think it's smart to send additional American taxpayer dollars that
will sit there and not be used, or be used ineffectively."
But Josh Ruxin, assistant clinical professor at Columbia University and a
resident of Rwanda where he heads the Access Project, said that while the
first five years of the program have been "extraordinary... simply continuing
to implement the same policies and practices over the next five years will
be inadequate to address this tidal wave" that is engulfing Africa.
He noted that investing more in such areas as running water and electricity
for health centers and training medical personnel increases the capacity
of programs to spend more to combat the disease.
The new bill adds 14 Caribbean countries to the 15 mostly African nations
that have been the focus of the program. It also retains a provision in the
2003 act that requires organizations receiving funds to oppose prostitution
and sex trafficking.
The Associated Press, www.365Gay.com
Also: Catholics Reject Influence of US Bishops in Congressional HIV/AIDS
Funding Battle
February 27, 2008
Washington - As people of faith who believe in social justice, Catholics
around the United States will be very disappointed with the influence the
Catholics bishops invested in gutting practical, life-saving programs during
the drafting of the Lantos/Hyde HIV/AIDS Global Leadership Act, Jon OBrien,
president of Catholics for Choice, said in a statement today.
Despite increasing funding overall, the House Committee on Foreign Affairs:
-- decoupled vital family planning services that can prevent mother-child
transmission of HIV/AIDS;
-- retained the anti-prostitution pledge, further marginalizing an extremely
at-risk group; and
-- removed the current abstinence-only funding, but in its place imposed
a complex formula that requires balanced funding for Abstinence, Be Faithful,
Use Condoms (ABC) programs, rather than allowing experienced agencies to
decide how best to spend the funds depending on local circumstances.
US taxpayers need to be aware that all of these moves came about, in part,
as a result of lobbying by the United States Conference of Catholic Bishops.
The approach adopted by the US bishops, in partnership with Catholic Relief
Services (CRS), stems from a self-serving perspective that few Catholics
share, let alone those of other and no religious preference. Catholics in
the United States and elsewhere support aid for international family planning
and reject abstinence-only education. Studies show that properly directed
funding for international family planning programs saves women's lives and
the lives of their children when those women have HIV/AIDS. Many studies,
including some sponsored by the US Congress, show that abstinence-only programs
do not work. The bishops ignored this evidence to ensure that their own narrow,
out-of-the-mainstream beliefs held sway on Capitol Hill.
In the future, Congress must pay greater attention when religious organizations
such as Catholic Relief Services apply for funds and then seek to influence
how that funding is distributed using religion, not proven public health
outcomes, to determine prevention strategies. Federal funds must be appropriated
for services with a proven track record of doing the job for which they are
intended, such as the provision of family planning services to women with
HIV/AIDS.
For the complete statement, please visit http://www.catholicsforchoice.org
By David Nolan, Catholics for Choice, http://news.yahoo.com |
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UNAIDS And OHCHR Call For Greater Protection Of The Human Rights Of All Persons
Regardless Of Sexual Orientation Or HIV Status
February 27, 2008
The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the Office of
the United Nations High Commissioner for Human Rights (OHCHR) are alarmed
at recent reports of human rights violations committed against people on
the basis of their sexual orientation and their actual or presumed HIV status.
UNAIDS and OHCHR urge all governments to be vigilant in respecting and protecting
the rights of individuals in this regard, in particular the rights of all
to be free from murder, torture, violence, arbitrary arrest and vilification,
regardless of their HIV status or sexual orientation.
Among specific concerns that have arisen in national responses to HIV are
reports of forced HIV testing, arbitrary detention on the basis of HIV status
and disclosure of an individual's HIV status without consent. Such punitive
measures violate individuals' rights and make it more difficult to reach
those in need of HIV prevention, treatment and care services. Where it exists,
homophobia fuels the HIV epidemic, and must be addressed as a key part of
national HIV responses.
Experience has shown that effective responses to HIV are those based on respect
for human rights, tolerance, and unimpeded access to HIV prevention, treatment,
care and support.
http://www.unaids.org, http://www.medicalnewstoday.com |
Studies & Treatment News
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Statins May Interact To Damage the Mitochondria
February 24, 2008
Washington - A new panel of tests aimed at finding out how drugs may damage
cells has turned up a series of interactions that may explain some of the
serious side-effects of statin drugs, researchers said on Sunday.
Statins, the wildly popular cholesterol-lowering drugs, may interact with
at least one blood pressure drug to damage the mitochondria, the powerhouses
of cells, the researchers reported in the journal Nature Biotechnology.
Their study also may lead to the development of drugs to treat diabetes and
diseases of aging and better ways to screen for drug side-effects, the researchers
said.
Vamsi Mootha of the Broad Institute at Harvard University and the Massachusetts
Institute of Technology said they had made their new database freely available
to other scientists to use for screening drugs.
The mitochondria are structures in cells that make adenosine triphosphate,
or ATP, which helps power cells. Dr. Mootha's team tested more than 2,000
drugs on cells to see how they might interfere with this process.
Their test looks at gene function, ATP levels and other measures of how well
the mitochondria are working.
Many patients who take statins have reported side-effects that include muscle
pain and weakness. The cause is not well understood but Dr. Mootha has long
suspected the mitochondria are involved. The effects have been hard to pin
down because studies of different groups have produced conflicting results.
Dr. Mootha's team said their findings showed some statins lower ATP levels
and interfere with the mitochondria.
"Of the six statins present in our screening collection, three (fluvastatin,
lovastatin and simvastatin) produced strong decreases in cellular ATP levels
and (mitochondrial) activity," they wrote.
Fluvastatin is sold by Novartis under the brand name Lescol, lovastatin is
sold under the brand name Mevacor and simvaststin is sold as Zocor.
Three others -- atorvastatin, made by Pfizer under the brand name Lipitor,
pravastatin or Pravachol, made by Bristol Myers Squibb and rosuvastatin,
sold under the Crestor brand name by AstraZeneca -- had little effect, they
said.
"We asked what pattern of dysfunction they cause in the mitochondria," Dr.
Mootha said in a telephone interview. "Once we figured out what the pattern
was we asked what other FDA-approved drugs give rise to that same pattern
of mitochondrial dysfunction."
They found a few.
"We were struck by the fact that one of these nearest-neighbour drugs is
propranolol, a widely used antihypertensive agent," they wrote.
Propranolol is a so-called beta blocker drug sold by Wyeth under the brand
name Inderal and also available generically.
"That was a bit of a surprise," Dr. Mootha said. "And it is important because
so many patients are on a statin as well as blood pressure medication."
Other drugs that resembled statins in their activity in mitochondria included
amoxapine, cyclobenzaprine, griseofulvin, pentamidine, paclitaxel, propafenone,
ethaverine, trimeprazine and amitriptyline.
A similar process may be going on in diabetes, nerve degeneration and aging,
Dr. Mootha's team said. They found a number of drugs, including the cancer
drug vinblastine may counter this process.
Dr. Mootha cautioned that his group has worked only in batches of muscle
cells grown in the lab so far and that far more tests are needed.
By Maggie Fox, Reuters |
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Experimental Anti-HIV Gel Safe, Tolerable for Women: Study
February 25, 2008
Chicago - The quest to develop a vaginal gel to prevent HIV infection took
a step forward Monday when researchers announced that one such gel is safe
for women to use on a daily basis.
The announcement comes a week after researchers announced that the first
prototype to complete advanced clinical trials was ineffective in preventing
infection.
Microbicides are one of the most eagerly-sought avenues in the war on AIDS,
where at present there is neither a cure nor a vaccine and prevention depends
on the condom or abstinence.
Scientists are grappling for a means by which women, who are physically more
at risk from AIDS infection than men, can protect themselves without having
to rely on male consent to wear a condom.
A number of different gels are currently being tested around the world but
none have been proven to be effective and some have even increased the risk
of contracting HIV.
This latest attempt by researchers in the United States and India is still
in the early stages.
Researchers asked 200 sexually-active, HIV-negative women in New York and
Pune, India to apply the gel either daily or before intercourse for a period
of six months. They were also asked to use condoms in addition to the gel.
The researchers found no disruption of liver, blood or kidney function and
found a significant willingness among the women to follow the treatment guidelines.
More than 90 percent of the women said they would serious consider using
the gel if it were approved to help prevent HIV infection and more than 80
percent had followed the experimental regime.
"Based on what we have learned we can proceed with greater confidence on
a path that will answer whether tenofovir gel and other gels with HIV-specific
compounds will be able to prevent sexual transmission of HIV in women when
other approaches have failed to do so," said lead investigator Sharon Hillier,
director of reproductive infectious diseases at the University of Pittsburg
School of Medicine.
The findings were presented Monday at an international microbicides meeting
in New Delhi.
An estimated 33.2 million people, in a range from 30.6 to 36.1 million, are
living with AIDS or the human immunodeficiency virus (HIV) that causes it,
the specialised UN agency UNAIDS says.
AFP |
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Growth Hormone Boosts Thymus T-Cell Production
February 25, 2008
Recombinant human growth hormone (rhGH), manufactured as Serostim by Serono
Laboratories and approved for the treatment of AIDS-related wasting syndrome,
may also prove to be useful as an immune-based therapy in people living with
HIV. The drug, researchers reported in the March issue of the Journal of
Clinical Investigation, restores the ability of the thymus gland to produce
new CD4 cells.
CD4 cells are a type of immune system cell called a T-lymphocyte. They are
made in the bone marrow and then travel to the thymus to mature, hence the
T in their name. The thymus trains the T-lymphocytes to fight infections
in the body, sometimes in the form of "helper" CD4 cells.
The thymus produces the majority of CD4 cells the body needs within the first
few years of life and becomes filled with fat—a process called involution—and
almost completely inactive by adulthood. Scientists have long assumed that
involution of the thymus is permanent and that it is not possible to coax
the gland to produce new CD4 cells, even in people whose immune systems have
been badly damaged by HIV.
Laura Napolitano, MD of the Gladstone Institute of Virology and Immunology
(GIVI) and the University of California, San Francisco, and her colleagues
recruited 22 HIV-positive people who’d been taking antiretroviral therapy
for at least a year but who had not seen significant CD4 cell increases.
Dr. Napolitano’s team wanted to study the effects of rhGH, a drug that not
only helps the body build muscle but also break down fat. They theorized
that the injectable hormone’s ability to shrink fat in the body may also
help reverse involution of the thymus, thereby jump-starting the gland’s
ability to produce new CD4 cells.
The team followed its study volunteers for two years, conducting detailed
analysis of the participants’ immune function. During the first year, one
half of the group received rhGH, while the other half did not. In the second
year, the group who’d been receiving rhGH stopped taking it and the group
who’d not been taking rhGH started taking it.
Not only did rhGH decrease thymic fat mass, it increased patients’ CD4 cells
by 30 percent. What’s more, CD4 cells continued to increase for three months
after people stopped taking rhGH, and these gains were sustained for at least
a year after stopping treatment.
Dr. Napolitano cautions that their findings are preliminary and that, "[rhGH]
should not be used as a treatment for immune purposes in HIV disease or in
any other individuals at this time, unless this treatment occurs within a
research study. More research is needed to learn whether stimulating the
production of new T-cells actually provides a health benefit."
http://www.poz.com |
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Drug-Resistant TB at Record Levels
February 26, 2008
Multiple-drug-resistant tuberculosis cases in parts of the former Soviet
Union have reached the highest rates ever recorded and could soar even higher,
spreading the bacterial disease elsewhere, the World Health Organization
said on Tuesday in releasing findings from the largest global survey of the
problem.
The highest rate was in Baku, the capital of Azerbaijan, where 22.3 percent
of new tuberculosis cases were resistant to the standard anti-tuberculosis
drug regimen during the survey period from 2002 to 2006. That exceeded the
previous high of 14.2 percent, in Kazakhstan.
Studies in China also suggest that multiple-drug-resistant TB is widespread
in the inner Mongolia and Heilongjiang regions, W.H.O. said.
The new survey, the first in four years, shows that earlier predictions were
correct and that governments have lost control of tuberculosis in many areas.
The reason, health officials say, is that countries have failed to invest
enough to build, equip and staff the laboratories needed to detect the disease.
The countries also failed to assure sufficient amounts of standard drugs
and then to monitor patients to ensure that they complete a full course of
therapy.
Inadequate therapy often leads to development of multiple-drug-resistant
strains of the tuberculosis bacterium.
Drug-resistant tuberculosis, like drug-sensitive TB, can be transmitted from
an infected individual to a noninfected person in droplets through coughing,
sneezing, singing and other activities. The drug resistant form can take
two years to treat with drugs that are 100 times more expensive than the
first-line regimen, the health agency, a unit of the United Nations, said.
The survey also found alarmingly high rates in Moldova (19.4 percent), Donetsk
in the Ukraine (16 percent), Tomsk Oblast in Russia (15 percent) and Tashkent
in Uzbekistan (14.8 percent).
Those levels surpassed the highest levels that nearly all experts once thought
were possible, Dr. Mario C. Raviglione, who directs the health organization’s
Stop Tuberculosis program, said in an interview.
"We are seeing levels of multiple-drug-resistant TB that we never expected
— 20 percent is a very high level," Dr. Raviglione, said. The Global Plan
to Stop TB is a road map for reducing by half TB prevalence and deaths by
2015 compared with 1990 levels.
When W.H.O. started a drug surveillance project in 1994, he said, "the general
thinking was that multiple-drug-resistant TB would never be a real problem
since it was felt to be confined to immunosuppressed patients."
A decade ago, when W.H.O. first received reports of 9 to 10 percent rates
of multiple-drug-resistant TB in some areas, many scientists thought the
figure was inaccurate due to a misclassification that mixed new, previously
treated and chronic cases together. Experts also said higher rates were not
possible, Dr. Raviglione said, but "we see now it is possible, it tells you
they are really doing something wrong in places where this form of TB is
spreading."
Overall, about one in 20 new cases of tuberculosis in the world is resistant
to first line drugs, which translates into nearly 500,000 of the 9 million
new tuberculosis cases that are detected each year, according to the W.H.O.
survey, which involved 90,000 patients in 81 countries.
The World Health Organization says that there is a financial gap of $2.5
billion of the estimated $4.8 billion needed this year for overall TB control
in low- and middle-income countries.
For the first time, the survey included analysis of extensively drug-resistant
tuberculosis, or XDR-TB, a virtually untreatable form of the respiratory
disease because the causative bacteria are resistant to virtually all the
most effective anti-TB drugs.
XDR-TB has been reported in 45 countries, but because few countries have
the necessary laboratories to detect it, the data were limited.
The true extent of the problem remains unknown in some pockets of the world
because only six countries in Africa, the region with the world’s highest
incidence of TB, could provide drug resistance data for the report, Dr. Raviglione
said. Other countries in the region could not conduct surveys because they
lack the laboratory equipment and trained personnel needed to identify drug-resistant
TB.
Outbreaks of drug resistance are likely going undetected, Abigail Wright,
the principal author of the W.H.O. report, said.
Although the W.H.O. report highlights the extent of drug resistance, Dr.
Raviglione said there were successes where governments invested in control
measures. He cited the Baltic countries of Estonia and Latvia as "the model"
because they were the drug resistant tuberculosis "hot spots" 13 years ago.
Today, following a substantial investment and a sustained assault on multiple-drug-resistant
TB, rates in these two countries are stabilizing and rates of new TB are
falling.
By Lawrence K. Altman, The New York Times |
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HIV Persists in Gut CD4 Cells Even in The Presence of Effective Therapy
February 25, 2008
New evidence that CD4 cells in the gut may be a reservoir of HIV could impact
future treatment strategies, say researchers in an article published in the
online version of The Journal of Infectious Diseases. Their cross-sectional
study found relatively high levels of HIV among the depleted CD4 cell population
of the gut lymph tissue, even in the presence of effective antiretroviral
therapy. New drug regimens targetting these cells might one day lead to more
effective control of the virus, they propose.
Effective antiretroviral therapy is able to reduce HIV in the blood to undetectable
levels. However, current therapies do not completely eradicate HIV from the
body. Simply put, there is no cure for HIV. One possible reason for this
is that virus persists in areas of the body that are unaffected by current
drugs. These reservoirs could form a long-standing source of HIV-infected
cells.
The gut-associated lymphoid tissue (GALT) is a potential reservoir. It is
the largest lymphoid tissue in the body and contains the most HIV-susceptible
CD4 cells. It is associated with HIV replication early in infection, but
there are few investigations into its role in later infection. In the current
article, Chun and colleagues from the US National Institutes of Health provide
evidence that HIV persists in the GALT, even in the presence of successful
antiretroviral therapy.
The study recruited 8 HIV-positive individuals who had been on long-term
antiretroviral therapy (average 8.4 years). The group’s mean blood CD4 cell
count was 622 cells/mm3 and they had had an undetectable viral load (<
50 copies/ml) for an average of 5.6 consecutive years at the study's start.
The researchers first isolated CD4 cells from blood samples and from biopsies
of the terminal portion of the small intestine of study participants. They
found that the levels of CD4 cells were significantly lower in the GALT than
in the blood (p = 0.005), and much lower than what would be expected in a
healthy individual. While the percentage of CD4 cells in GALT is generally
lower than in the blood of healthy individuals (about 40% versus about 65%,
respectively), the mean CD4% in GALT of the study participants was 11.3%.
During the natural course of HIV infection, CD4 cell counts slowly drop as
the virus replicates. When a person starts antiretroviral therapy, viral
replication is suppressed and CD4 cell counts normally rebound, often reaching
values within the range found in HIV-negative individuals. Thus, the low
CD4 percentage found in GALT of infected individuals, the authors state,
suggests that the CD4 cells in the GALT never completely rebounded and that
the virus persists in GALT CD4 cells.
The researchers then determined the level of HIV genetic material in CD4
cells from blood and from GALT. Levels of HIV genetic material can give a
measure of frequency of infection. Researchers found that viral genetic material
was present in all cell types and was highest among CD4 cells of the GALT
at 4887 cells infected per million CD4 cells. Blood CD4 cells reported significantly
lower infection rates, 1083 cells per million cells (p < 0.001) for resting
CD4 cells and 1796 cells per million cells (p = 0.001) for activated CD4
cells.
Combining the findings of reduced presence of CD4 cells with high level of
infection, the researchers conclude that "CD4+ T cells in the GALT, even
when present in low numbers, may support low but readily detectable HIV replication
in infected individuals, despite their having received years of effective
antiretroviral therapy that resulted in sustained, undetectable levels of
plasma viremia."
Finally, the researchers tested whether CD4 cells were migrating between
the blood and the GALT. They did this by comparing the DNA sequences of HIV
taken from infected CD4 cells harvested from the two compartments. In this
type of analysis, a lack of cross-infection would lead to all the DNA sequences
from HIV in the blood being similar to each other and distinct from HIV DNA
from the GALT. Instead, the researchers found that sequences were sometimes
shared between blood and tissue compartments, suggesting that virus or infected
cells had migrated. This finding, they write, "may explain, in part, the
persistence of HIV in peripheral blood CD4+ T cells, possibly as a consequence
of new rounds of infection in the tissue compartment."
In an accompanying editorial commentary, Yuki and Wong support the researchers’
interpretation of the data and add, "The effect of treatment intensification
or novel treatment strategies on the reservoir of HIV cells in GALT should
be explored." Intensification of regimens by adding more drugs is known to
further decrease blood viral load among individuals with already suppressed
virus. They propose that a similar strategy, especially including new agents
such as integrase and entry inhibitors, might yield similar results in GALT
cells.
Reference
Chun TK et al. Persistence of HIV in gut-associated lymphoid tissue despite
long-term antiretroviral therapy. J Infect Dis 197 (online edition), 2008.
Yuki S and Wong JK. Blood and guts and HIV: preferential HIV persistence
in GI mucosa. J Infect Dis 197 (online edition), 2008.
By David McLay, www.aidsmap.com |
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GeoVax Vaccine to Move Forward
February 26, 2008
The HIV Vaccine Trials Network (HVTN), part of the National Institutes of
Health (NIH), has decided to proceed with a phase IIa safety study of an
HIV vaccine produced by the company GeoVax.
The GeoVax vaccine differs somewhat from the Merck vaccine that recently
proved to be ineffective in the STEP trial. The Merck vaccine used a modified
cold virus to deliver pieces of HIV’s genetic material to the immune system.
The GeoVax first primes the immune system by directly delivering pieces of
HIV DNA, followed by a booster shot of a disabled form of the smallpox virus,
called modified vaccinia ankara (MVA). The MVA boost is designed to amplify
the immune system’s initial response to the HIV DNA prime.
In animals, the GeoVax vaccine was protective against infection, and in early
human studies the vaccine appeared both to be safe and to elicit a strong
immune response.
http://www.poz.com |
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Finding Could Pave the Way for Future AIDS Treatment, Scientists Say
February 28, 2008
Researchers at the University of Alberta have discovered a gene that can
block certain forms of HIV and may perhaps one day be used to prevent the
onset of AIDS.
In lab studies, conducted with scientists at the University of Pennsylvania,
researchers at the Edmonton university identified a human gene called TRIM22
that can block HIV infection by preventing the virus from replicating.
When researchers prevented human cells from turning on TRIM22, the natural
defence system generated by the body when a foreign invader attacks, the
cells could not protect themselves against HIV.
"This means that TRIM22 is an essential part of our body's ability to fight
off HIV," Dr. Stephen Barr, a researcher in the department of medical microbiology
and immunology at the University of Alberta, said in a release issued Thursday.
Other genes in the TRIM family have also been shown to prevent viruses from
replicating. TRIM5a blocks the early replication of HIV-1 while RhTRIM5a
blocks late-stage HIV replication.
The scientists are now exploring how this gene can be turned on in people
who cannot defend themselves against the virus.
"We hope that our research will lead to the design of new drugs and/or vaccines
that can halt the person-to person transmission of HIV and the spread of
the virus in the body, thereby blocking the onset of AIDS," said Barr.
He acknowledged that such development could be decades away.
The study was published Thursday in the Public Library of Science journal
Pathogens.
www.cbc.ca |
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Microbicides 2008:
1. Accurate Adherence Reporting Essential for Microbicide Trials
2. First Hint of Efficacy In Rectal Microbicide Trial, Thanks To New Biopsy
Assay
3. Polydex Announces Ushercell Prevents Systemic HIV Infection in Rhesus
Macaques in New Clinical Trial
4. The Second Generation Is On Its Way
1. Accurate Adherence Reporting Essential for Microbicide Trials
February 26, 2008
Researchers need much better ways of determining adherence to candidate microbicides
in trials, and also of ways of determining sexual behaviour, the 2008 Microbicides
Conference heard today in Delhi, India.
Barbara Mensch of the Population Council told the Conference: "The inability
to prove effectiveness leaves the question of product efficacy unanswered."
Several trials of new prevention technologies have failed recently despite
excellent adherence to the intervention reported by participants. In the
recent Carraguard trial (run by the Population Council), 96 per cent of women
claimed to be using gel correctly. However when applicators were tested to
see if they had actually been used, only 44 per cent had. Similarly the figures
for women who claimed always to use condoms only, condoms plus gel, or gel
only, added up to more than 100 per cent.
Similar problems may have plagued the recent HPTN 039 trial of aciclovir
for herpes prophylaxis, in which the reduction in genital ulcers was suspiciously
low despite reported 94% adherence amongst participants and pill counts.
Low adherence in itself may not jeopardise a trial as long as sufficient
participants are high adhererers and as long as we know which is which, Mensch
said.
"Poor adherence means that results of an intention-to-treat analysis will
be very different from a per-protocol one," she said, "but inability to measure
poor adherence biases effects towards the null." In other words, the inability
to even compare intention-to-treat analysis, in which results are viewed
as if all participants adhered to the trial medication, with per-protocol
analysis, in which only participants that took it as prescribed are counted,
is likely to lead to negative results even when the microbicide is highly
effective in those who use it.
What are researchers doing to try and establish true adherence and behavioural
data? One way is to use Automated Computer-Assisted Self-Interviewing (ACASI)
with participants instead of face-to-face interviews live researchers.
This technique worked well in a substudy of the Carraguard study. This was
a simulated three-month microbicide study in which 848 women were given placebo
gel but assessed as if they were taking a trial compound.
As well as using ACASI to assess adherence, researchers visited the women
to count off used applicators. The trial also used a PCR test to detect sperm
in vaginal fluids to assess the true levels of sexual activity.
Establishing the latter is also extremely important; microbicide researchers
are just beginning to understand the degree to which trial participants give
unreliable reports of their own sexual activity.
For instance, in the MIRA trial, which looked at the possibility of using
the female diaphragm in HIV prevention, the pregnancy rate was actually higher
in women who reported contraceptive use than in women who did not. In the
MTN 035 phase IIb trial of the microbicides Buffergel or 0.5% PRO-2000, at
one site participants reported more sex acts protected by a condom than the
total number of sex acts reported to investigators at that site.
In the simulated trial, 19% of women who reported no sex in the last 48 hours
tested positive for semen in the vagina.
Sex may be misreported for a variety of reasons, not all of them due to deception;
women may differ in their definitions of what ‘sex’ is, may fail to report
non-consensual experiences, or may simply tell the researcher what they want
them to hear: very few of us accurately report our sex lives, even to ourselves.
The ACASI technique proved particularly useful in assessing non-adherence
to the product. Fact-to-face interviewing (FTFI) consistently produced lower
figures for non-adherence than the ACASI technique, as in the following table:
Reason for non-use
"It might cause harm"
FTFI 3%
ACAS 13%
"I ran out of gel"
FTFI 5%
ACASI 14%
"I had no privacy"
FTFI 4%
ACASI 15%
"There was no time/sex was unplanned"
FTFI 18%
ACASI 39%
Researchers also had to take lessons from demographers and opinion pollsters
in how they phrased questions, Mensch added, for instance, asking "Were you
able to use the gel last time you had sex?" instead of the more direct "Did
you use the gel last time you had sex?"
Better still might be to ask about non-use rather than use: "In how many
sex acts were you not able to use the gel?"
Interviewers should be trained to use supplementary questions to establish
how participants arrived at answers ("When I just asked you how many sex
partners you’d had, how did you count them up?") and what their understanding
of terms was ("What counts as a sex partner for you?").
Mensch asked a list of questions microbicide trials had failed so far to
ask, or have answered. Are the highest-risk participants the most or least
adherent? Does adherence and sexual behaviour change over the trial? Under
what circumstances are microbicides most and least likely to be used? What
influence do partners and family have on women? Are trial populations really
representative of the target population and if not, does it matter?
Future trials will try and answer some of these questions with more sophisticated
monitoring. The MTN 035 trial site in Malawi, for instance, has started using
an ACASI system asking questions of participants in writing, in voice and
with graphics.
The CAPRISA 004 tenofovir-gel study, which has recently started in South
Africa, is considering issuing participants with modified Blackberry terminals
in which to record their gel use and behavioural data and transmit them to
the centre. And the International Partnership for Microbicides is considering
how to do the most direct-possible observation of women’s gel use in its
series of studies of dapivirine (TMC120) without endangering or stigmatising
participants.
In conclusion: the recent failure of the Carraguard trial to produce a positive
result has not dampened researchers’ and advocates’ enthusiasm or belief
in the concept of microbicides. It has instead highlighted the extreme complexity
of these large trials and the numerous social and behavioural influences
that need to be considered if researchers are to generate a meaningful result
for the millions of dollars spent on them.
Reference
Mensch B. Approaches to integration of behavioral research into regulatory
phase I II, and III studies of microbicides. Plenary presentation, microbicides
Conference, Delhi. 2008.
By Gus Cairns, www.aidmap.com
2. First Hint of Efficacy In Rectal Microbicide Trial, Thanks To New Biopsy
Assay
February 25, 2008
Preliminary, still blinded data presented to the 2008 Microbicides Conference
in Delhi today offered a strong hint that a rectal microbicide gel containing
a non-nucleoside HIV drug may prove to be effective at stopping infection
in humans.
The same preliminary analysis also seems to indicate that the drug may be
safe, at least if volunteer reports, and the results of a battery of tests
of inflammation marker chemicals, are reliable indicators of likely harm.
The trial
Peter Anton of the ‘U19’ rectal microbicide programme was presenting data
from the first 19 of 28 subjects enrolled into a phase I safety study of
two doses of a microbicide gel containing the NNRTI drug UC-781. This programme,
funded by the US National Institutes of Health, is the first series of studies
to trial rectal microbicides in human subjects. It involves a series of double-blinded
trials, currently comparing two doses of UC-781 (1% and 2.5%) with placebo;
as the programme progresses this may be narrowed down to one dose.
This initial study is primarily designed as an acceptability study. However
the use of some innovative inflammation markers and assays allows early educated
guesses to be made about toxicity and even eventual efficacy.
In this study 36 male and female volunteers were screened at the beginning
of the trial for exclusion criteria such as HIV and STI infection. Those
enrolled inserted a measured dose of the UC-781 gel with a rectal applicator
at two separate timepoints. At baseline and both times after gel application,
biopsies – small sections of rectal tissue – were taken for the safety and
drug efficacy assays – of which more below. At the same time samples of rectal
fluid/mucus were taken for evaluation of soluble proteins.
On the second week of the study volunteers applied a single dose of UC-781
gel or placebo under supervised conditions, and biopsies were taken immediately
afterwards (within 30 minutes).
After a rest period, volunteers were then issued with a week’s worth of gel
doses, again in applicators, which they used every day at home on the sixth
week of the study. At the end of this week they returned to the research
centre for more biopsies to be taken. Anton emphasised that each biopsy,
of which typically 15 were taken from each subject at distances of 10cm and
30cm into the rectum, were small and painless procedures.
Adverse events and toxicity
Anton was presenting data from the 19 out of 28 subjects who have completed
all visits. Importantly, all the data he was presenting was blinded: so we
cannot be sure whether results are due to the microbicide, the placebo, the
participants, or chance. However they do describe general changes within
the trial population over time.
In terms of safety there were no serious adverse events (grade 3 or 4). There
were seven minor events reported from four participants, but four of these
(diarrhoea, bloating and abdominal discomfort) were reported by a single
participant at the single-dose visit – and were probably due to his previous
meal.
There were also preliminary, blinded safety data available in terms of laboratory
markers of toxicity. The U-19 programme will use a whole battery of tests
to try and find any indication of cellular toxicity or inflammation in gel
recipients. Conscious that the rectum has been largely ‘unknown territory’
in terms of what constitutes a ‘normal’ immune picture, this had to involve
a lot of preliminary studies to assess benchmarks – see this report.
The early data also showed no difference between the trial groups in terms
of macroscopic or microscopic cell damage, nor any signal of an inflammatory
response in terms of the levels of a large number of different cytokines
and chemokines (soluble inflammatory proteins produced in response to injury).
A hint of efficacy, and a way of estimating it
The really innovative aspect of this trial is the way the biopsies are being
used as ‘surrogate markers’ for HIV seroconversion.
Microbicide studies have suffered from the huge disadvantage that up till
now there has been no early way of estimating their likely protective effect
in humans. Animal models can give unreliable results and there have been
no ‘correlates of protection’ such as the immunogenicity markers that have
been used in vaccine trials to select promising candidates (though those
are currently being called into question). The only way up until now has
been to put on a huge and expensive efficacy trial on the basis of results
in a handful of monkeys, or even in vitro data, and hope the candidate proves
to be effective.
The U19 Programme is getting round this by using an ‘in vivo-ex vivo’ HIV
infection model. In this, volunteers use the microbicide or placebo gel as
instructed, and biopsies are taken. These are then cultivated as cellular
explants – small pieces of tissue kept alive on gel rafts in a nutrient medium.
Two hours after being set up, the explants are then incubated with HIV. The
proportion that get infected with HIV is then determined by measuring the
amount of the HIV p24 protein in the culture medium over the next month (which
typically grows exponentially in cases of infection).
In this study, explants were infected with two different doses of HIV, one
containing 100 times more virus than the other. The stronger of the two doses
should in theory infect 100% of biopsies containing cells expressing the
CCR5 HIV co-receptor.
Ninety-six per cent of volunteers’ biopsies taken at baseline, before any
gel application, were infected with HIV (i.e. 18 out of 19 subjects – one
person’s biopsies stubbornly resisted HIV infection throughout, despite his
having CCR5-expressing cells).
At the three-week visit, one-third of the explants grown from biopsies taken
immediately after gel application (six subjects) resisted infection with
the higher dose of virus, while another third showed reduced p24 expression.
The final third were infected just as easily.
This pattern was not observed at week seven. This is probably, Anton commented,
because biopsies were taken the morning after the last day of gel use, in
other words anything between ten and 24 hours after the last possible exposure
to UC-781.
"It would be convenient to anticipate from this blinded data," said Anton,
"that the high drug dose group will turn out to be the ones whose cells showed
no response." And, he might have added, the lower dose group those with a
blunted response.
However, this being blinded data, with full unblinded results not available
until the end of this year, anything could turn out to be the case, ranging
from complete concordance with microbicide use to a worst-case perverse response
in which the lower rate of infections turn out to be in those who received
placebo. At the moment all we can say is that the 33/33/33 split in cellular
response is suggestive.
References
Anton PA. A phase 1 safety and acceptability study of the UC-781microbicide
gel applied rectally in HIV seronegative adults: an interim safety report
at 50% completion. Microbicides 2008 Conference, Delhi, abstract BO5-290,
2008.
Elliott JE. Ex vivo HIV-1 challenge of colorectal explants may be an important
predictor of micobicidal effectiveness invivo. Early, blinded results from
a phase 1 rectal microbicide trial of UC-781. Microbicides 2008 Conference,
Delhi, abstract BO4-241, 2008.
Cho DD. Stability of mucosal cytokine profiles and mononuclear lymphocyte
phenotype following rectal administration of UC-781 microbicide gel in a
phase I safety assessment. Microbicides 2008 Conference, Delhi, abstract
BO6-427, 2008.
By Gus Cairns, www.aidmap.com
3. Polydex Announces Ushercell Prevents Systemic HIV Infection in Rhesus
Macaques in New Clinical Trial
February 26 2008
Toronto - Polydex Pharmaceuticals Limited (Nasdaq:POLXF) reports that CONRAD,
a lead investigator of Ushercell, has completed a clinical trial using rhesus
monkeys. The results of that trial have today been reported at the Microbicides
2008 conference ongoing in New Delhi, India. Ushercell is a cellulose sulphate,
cotton based gel envisioned for use as a contraceptive and in the prevention
of sexually transmitted infections, including HIV.
This trial was undertaken after the Phase III human clinical trials were
halted in January of 2007, when an interim analysis of data revealed a higher
than expected seroconversion rate among participants at some, but not all
trial sites. This new trial was commenced with the objective to try and understand
why Ushercell had not shown effectiveness in the trials with women. Prior
to the commencement of the Phase III HIV trials, scientists had evaluated
data from 11 previous clinical studies done in Africa, India, the U.S. and
Europe. None of the data suggested that the product could increase the susceptibility
to HIV.
In this trial, two groups of 6 rhesus macaques each were treated intravaginally
with 2 ml of HEC-based "universal" placebo or 6% Ushercell gel (the same
clinical formulas used in the Phase III trials) and challenged 30 minutes
later with a mixture of R5 and X4 tropic simian-human immunodeficiency viruses
(SHIV<>><>><>>). The gel/virus exposures were
repeated at weekly intervals for up to 13 weeks and infection monitored for
24 weeks after the first exposure to the virus.
While 5 of 6 macaques were infected in the placebo group, none of the animals
in the Ushercell gel group were infected. This data suggested that consistent
vaginal application of Ushercell gel effectively reduced the infectivity
of the virus, significantly decreasing the rate of vaginal mucosal SHIV transmission
following repeated virus exposures.
There is not a clear explanation at this point for why Ushercell would demonstrate
effectiveness in monkeys and not in humans, however certain hypotheses are
plausible. According to CONRAD researchers, humans may not have consistently
used the gel with every act of intercourse. Another CONRAD hypothesis is
that they may have used the gels much more frequently than in the monkey
study, possibly irritating the vaginal mucosa or changing its microflora.
Although scientifically sound, the monkey model has not been clinically validated
yet and may differ from the actual human conditions of transmission in a
way that affects its predictive power.
High frequency of use may have been a factor in the enhanced HIV transmission
seen in certain groups of women. This may be due to a possible cervicovaginal
inflammation or disruption of the normal mucosal immune responses. If these
adverse events were induced by formulation ingredients other than cellulose
sulphate, the formula could be changed to prevent this from happening. For
example, the preservative in the Ushercell formulation, benzyl alcohol, is
thought to cause a slight tingling sensation amongst users and may also be
responsible for producing an irritative effect.
As reported on December 23, 2007, CONRAD has also commenced a Phase I trial
to assess the safety of several vaginal products, including Ushercell. The
safety study of 60 women is being done using existing and new methodologies
for evaluating candidate vaginal products, and includes new safety markers
that have not previously been studied in women using any microbicide candidate.
In addition to providing information about these products, the study will
look at the correlation between clinical and preclinical results, thereby
making it easier to use preclinical studies to eliminate products that may
have an inflammatory effect.
Polydex Pharmaceuticals Limited, based in Toronto, Ontario, Canada, is engaged
in the research, development, manufacture and marketing of biotechnology-based
products for the human pharmaceutical market, and also manufactures bulk
pharmaceutical intermediates for the worldwide veterinary pharmaceutical
industry. www.Polydex.com
The Polydex Pharmaceuticals Limited logo is available at http://www.primenewswire.com/newsroom/prs/?pkgid=3414
CONRAD is a cooperating agency of USAID committed to improving reproductive
health by expanding the contraceptive choices of women and men and by helping
to prevent the transmission of HIV/AIDS and other sexually transmitted diseases.
CONRAD is administered through the Department of Obstetrics and Gynecology
at Eastern Virginia Medical School in Norfolk, VA and headquartered in Arlington,
VA. www.conrad.org
Note: This press release contains forward-looking statements, within the
meaning of the United States Securities Act of 1933, as amended, and the
United States Securities Exchange Act of 1934, as amended, regarding Polydex
Pharmaceuticals Limited, including, without limitation, statements regarding
expectations about future revenues or business opportunities and developments
relating to Ushercell, partner relationships or other potential research
projects. These statements are typically identified by use of words like
"may", "could", "might", "expect", "anticipate" or similar words. Actual
events or results may differ materially from the Company's expectations,
which are subject to a number of known and unknown risks and uncertainties
including but not limited to changing market conditions, future actions by
the United States Food and Drug Administration or equivalent foreign regulatory
authorities as well as results of pending or future clinical trials. Other
risk factors discussed in the Company's filings with the United States Securities
and Exchange Commission may also affect the actual results achieved by the
Company.
News Releases and other information available at company website: www.Polydex.com
This news release was distributed by PrimeNewswire, www.primenewswire.com
Source: Polydex Pharmaceuticals Limited
North Arm Capital Services
for Polydex Pharmaceuticals Limited
Linda Hughes
1-877-945-1621
Linda@northarm.com
PrimeNewswire, Inc.
4. The Second Generation Is On Its Way
February 28, 2008
The next generation of microbicides designed to protect women against HIV
infection will rely on maintaining a high level of an antiretroviral drug
in the genital fluids and tissue rather than using a barrier gel, Sharon
Hillier, Principal Investigator of the Microbicides Trials Network, told
the Microbicides 2008 conference this week in Delhi.
She described the second generation of microbicides about to start major
trials, as ‘topical PrEP’ – pre-exposure prophylaxis with antiretroviral
drugs in the vaginal tissues and fluids. Although this approach may be potent
it could have drawbacks too – leakage of the drug into the bloodstream, with
a potential risk of drug resistance if the user becomes infected, and toxicity.
She also reported preliminary findings from the two remaining studies of
‘first generation’ microbicides, the HPTN 035 study of 0.5% PRO-2000 or Buffergel,
and the MDP 301 study of 0.5% PRO-2000, in which the arm using 2% PRO-2000
was stopped recently because of futility (meaning it would produce no meaningful
results). (These findings will be reported separately.)
The Trial Progammes
There are three major programmes of trials which will lead up to phase IIb/III
efficacy trials of antiretroviral-containing microbicides for vaginal use:
* First to report - if all goes well - will be the CAPRISA 004 (Centre for
the AIDS Programme of Research of South Africa) study of 1% tenofovir gel
in 980 women at two sites in KwaZulu Natal, South Africa, a collaboration
between CONRAD and Family Health International. This is the only study looking
at ‘coitally-dependent’ use, in which women are told only to use the gel
when they think they will have sex. CAPRISA 004 already has 566 women enrolled,
and may report by April 2010.
* The Microbicides Trials Network (MTN) is co-ordinating studies leading
up to the VOICE (Vaginal and Oral Interventions to Control the Epidemic)
study, an inventive trial which, as its name suggests, will directly compare
a tenofovir gel with oral tenofovir pre-exposure prophylaxis in 4,200 women
at 10 sites in South Africa, Malawi, Uganda, Zambia and Zimbabwe. This is
due to start in late 2008 and may report by 2011.
* The International Partnership for Microbicides (IPM) is co-ordinating a
series of studies largely in Africa but also in the USA and Belgium, using
the NNRTI dapivirine (TMC120) both as a gel and as drug infused into a silicone
vaginal ring which can be left in place for a month: the phase III gel study
(IPM 009) is at the planning stage, while the timing of the vaginal ring
studies depends on preliminary safety and formulation studies. Study 009
may report by 2012/13.
* In addition to these vaginal studies, there is the U-19 programme using
the NNRTI UC-781 as a rectal microbicide: see this report for more.
Further into the future, IPM has now negotiated licensing agreements with
drug companies to develop CCR5 inhibitors as microbicides: with Pfizer for
its drug maraviroc, and – just announced at the Microbicides Conference -
with Merck for a CCR5 inhibitor called MRK 167.
There were a number of preliminary results and presentations from the preparatory
safety and drug-monitoring studies for these large trials at the Microbicides
Conference.
Safety And Acceptability: Tenofovir Gel
Sharon Hillier herself reported on safety and acceptability findings for
a preliminary study on tenofovir gel in women that had both a coitally-dependent
arm (as in the CAPRISA study) and a regularly-dosed arm (as envisaged in
the VOICE study).
This, the HPTN 059 Study, gave tenofovir gel to 200 women aged 18 to 50,
randomised to use tenofovir or placebo either daily, or only when sex was
anticipated, for six months. The study results were widely reported in the
Indian press, as one of the sites was at Pune in southern India (100 women),
the others being at Birmingham, Alabama (52 women), and in New York City
(48 women) in the USA. Safety and acceptability assessments were done at
one, three and six months.
Retention of trial subjects was good, with 96% returning for their final
visit at six months. There was only one pregnancy in the study. This was
also good, as trial subjects have to drop out when pregnant and this has
led to low numbers and meaningless results in certain African studies where
pregnancy rates as high as 30 per cent have been recorded. Most future studies
will provide women with contraception for this reason.
There were interesting differences between the Indian and the American women.
They were about the same average age (33 and 31 respectively). However, in
a country where marriage is the highest single risk factor for HIV in women),
all but one of the Indian participants was married, compared to 28% of the
US women. Sixty-three per cent of the US women had had over twelve years
of education, whereas only 21% of the Indian women had had over ten years.
And there was a stark reminder of economic inequality in that the average
income of the US women was $1503 a month, compared with $55 a month in the
Indian women.
There was one new case of herpes infection in the study and three of chlamydia,
with no other STIs.
Self-reported adherence to the daily gel was good, and didn’t vary much between
sites, with 82% of the Pune women reporting use of the gel for at least six
of the last seven days and 75% of the New York women (though see this report
for the unreliability of self-reported adherence in microbicide trials).
The most common reason for not using the gel daily was because the woman
was having her period.
Adherence to the intercourse-dependent dosing was more variable, with the
Pune women reporting use 88% of the time and the Birmingham women only 58%
of the time.
There were 16 instances of cervical, vaginal or vulvar lesions seen in women
using the daily dose of tenofovir gel compared with six (all cervical) using
placebo, and ten in the sex-dependent arm, with none on placebo, indicating
some marginal toxicity of the tenofovir-containing gel, although only one
subject was withdrawn from the study due to adverse reaction to tenofovir
gel.
What was encouraging was the acceptability data. Forty per cent of women
said the gel was easy to use, and few found it difficult. No one said it
made sex less pleasurable, and 12% said it made sex better. Two African studies
also reported at the conference found that up to a third of participants
said that using the gels made sex better. However six per cent of the sex-dependent
users and 11% of the daily users said they’d had some opposition to the use
of the gel from their partners.
Safety: Dapivirine
Shanique Smyth of IPM presented data from a safety study of dapivirine gel.
Dapivirine gel was packaged into pre-filled applicators delivering 2.5 millilitres
of gel. Three concentrations were tested, ten micrograms per millilitre (mcg/ml),
20mcg/ml and 50 mcg/ml against a placebo gel (hydroxyethylcellulose or HEC,
an inactive ‘carrier’ gel which is becoming the standard placebo in microbicide
trials).
One hundred and eleven women in Rwanda, South Africa and Tanzania were instructed
to use the dapivirine gel twice-daily for 42 days. There were 32 women in
the 10mcg and 20mcg arms, 31 in the 50mcg arm and 16 in the placebo arm.
Safety was evaluated by adverse events (AEs), clinical laboratory tests,
and colposcopy (examination of the cervix), with a follow-up visit at Day
56.
No serious adverse events thought to be related to the drug were reported.
Four women had lesions to the vulva, the vaginal lining (epithelium) or the
cervix: two from the 10mcg group and one each from the 20mcg and placebo
groups.
Six women did develop neutropenia, a fall in white blood cells: two each
in the 10mcg and 20mcg arms, and one each in the 50mcg and placebo groups.
These were serious (grade 3 or 4), but thought unrelated to the drug and
certainly didn’t seem dose dependent.
Pharmacokinetics: Dapivirine
Systemic absorption – leakage of the drug from the vagina into the bloodstream
– is a crucial issue for ARV-containing microbicides, as the biggest safety
concern surrounding these compounds is whether women using them who are HIV-positive
but undiagnosed, or who catch HIV despite using them, could develop drug
resistance.
In a study of dapivirine drug levels, IPM’s Annalene Nel used the same three
doses of dapivirine in 18 women, who used the gel for ten days. Dapivirine
levels were measured in the blood after the first and last doses at six intervals
during the day then daily from two to five days after the last dose.
Despite dapivirine being very insoluble, and chosen for microbicide use precisely
because of its poor oral bioavailability, women did develop measurable levels
of dapivirine in their blood. After the first dose peak levels were 60 picograms
(trillionths of a gram) per millilitre (pg/ml) at the 20mcg dose and 80 pg/ml
at the 50mcg dose. At day ten drug levels were higher, with a peak level
of 500 pg/ml at the 50mcg dose twelve hours after application. Drug levels
tailed off extremely slowly, with levels halving every 65-88 hours. "Increasing
half-life at this level could indicate increasing accumulation of the drug
in tissues," commented Annalene Nel.
Pharmacokinetics: Tenofovir
Buildup in tissues could be good or bad depending on which tissues are affected,
and whether cells containing HIV are active in them. Jill Schwartz of CONRAD
reported on a similar pharmacokinetic study of tenofovir gel as part of the
studies leading up to the VOICE trial.
Twenty-one women used a single dose of four grams of tenofovir gel. Drug
levels were taken seven times in the 24 hours after the dose. Drug levels
were also measured in vaginal fluid and inter- and intracellular levels in
vaginal tissues were measured by biopsy. Once this was done the women then
took a single oral dose of tenofovir to compare levels.
Most tenofovir concentrations in the blood were below five nanograms (billionths
of a gram) per millilitre (ng/ml), though peak values of up to19.5 ng/ml
were measured in some women.
This is way below the dose seen when tenofovir is taken orally, and indeed
the study then gave an oral dose to the women to compare levels, and blood
levels 100 times greater were seen, at 296 ng/ml, after the oral dose.
Vaginal fluid levels were, as one would expect, a million times higher than
blood levels, at 1.5 to five milligrams per millilitre at eight hours, and
0.045 to 0.47 milligrams per millilitre at 24 hours.
Levels also built up in the tissues lining the vagina, to levels a thousand
times those seen in the blood, with levels at one hour after dose of 0.45
milligrams per gram of tissue and 0.015 milligrams per gram at 24 hours.
The tenofovir was mainly concentrated into the gaps between cells but low
but detectable levels were seen inside the cells of three-quarters of the
women. As long as this is localised to vaginal tissues, this is a good thing
as it should mean that tenofovir is being absorbed to a sufficient depth
to defend the immune cells vulnerable to HIV against infection.
References
Hillier SL. Safety and acceptability of daily and coitally dependent use
of 1% tenofovir over six months of use. Microbicides 2008 Conference, Delhi,
abstract BO12-655, 2008.
Smythe S. Clinical safety and tolerability assessment of an anti-HIV dapivirine
vaginal microbicide gel (Gel-002). Microbicides 2008 Conference, Delhi, abstract
BO9-546, 2008.
Nel A. Pharmacokinetic assessment of an anti-HIV dapivirine vaginal microbicide
gel (Gel-002).Microbicides 2008 Conference, Delhi, abstract BO10-563, 2008.
Schwartz J et al. Preliminary results from a pharmacokinetic study of the
candidate vaginal microbicide agent 1% tenofovir gel. Microbicides 2008 Conference,
Delhi, abstract BO11-610, 2008.
By Gus Cairns, www.aidsmap.com |
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