March 6, 2008
Local and National News
New HIV-AIDS Program Targets Aboriginals
No Funding for AIDS Groups in Federal Budget
B.C. Superbugs Face A New Foe
When Science Runs Into an Ideological Wall

International News
Talking With Children about Sex and AIDS: At What Age to Start?
Agreement Reached on AIDS Bill
UNAIDS And OHCHR Call For Greater Protection Of The Human Rights Of All Persons Regardless Of Sexual Orientation Or HIV Status

Studies & Treatment News
Statins May Interact To Damage the Mitochondria
Experimental Anti-HIV Gel Safe, Tolerable for Women: Study
Growth Hormone Boosts Thymus T-Cell Production
Drug-Resistant TB at Record Levels
HIV Persists in Gut CD4 Cells Even in The Presence of Effective Therapy
GeoVax Vaccine to Move Forward
Finding Could Pave the Way for Future AIDS Treatment, Scientists Say
Microbicides 2008
The HIV/AIDS eNews is published by the British Columbia Persons With AIDS Society. This publication is a compilation of various articles collected from various news sources. Opinions and information expressed are those of the individual authors and not necessarily those of the Society.
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This Week’s Topic: Your Kidneys and HIV

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The Face of AIDS
You are invited to attend a community forum on HIV associated lipodystrophy and facial lipoatrophy and learn about the treatments used for facial wasting.
When: Wednesday, March 26th at 6 pm
Where: Best Western Chateau Granville, 1100 Granville Street, Vancouver
Please rsvp by emailing zorans@bcpwa.org

Local & National News

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

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International News

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

[ Top ]
Studies & Treatment News

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

[ Top ]

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

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North Arm Capital Services
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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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