People living with HIV are invited to participate in an online survey on HIV and employment in Canada. The purpose of this survey is to learn more about the education, training, employment and health needs of people living with HIV. Our ultimate goal is a national network that will provide employment support, information and advocacy opportunities for people living with HIV whether in or out of the workforce. Your responses to the survey will inform us on the employment-related issues that matter to you most.

The survey is available electronically and will take approximately 25 minutes to complete. You will be able to save survey responses and then submit the final version at a later date. If you would like to request a hardcopy of the survey please send your contact information to the address below.

You do not have to give personal information and we do not plan to publish personal information. If this plan changes, we will only do so with your agreement. You have the right to opt out of any question(s) at any point throughout the survey. You may choose to provide us with contact information if you would like to be kept updated on the progress of this project.

The link to the survey is provided below. The survey will be open for responses through Friday, March 13. This opportunity is unique to people with HIV. We look forward to your response to the survey.

http://www.surveymonkey.com/s.aspx?sm=BxPMtNFSCtrk5n1CZTiWPQ_3d_3d

Then participate in a survey!

You can help BCPWA by participating in a research project to assess the changing treatment information needs of HIV-positive people in BC. The research examines the experiences that HIV-positive people have with access to HIV/AIDS treatment information and the quality of these experiences.

To access the questionnaire, go to:
http://infopoll.net/live/surveys/s33258.htm

February 18, 2009

Battling both the federal government and drug problems in their communities, B.C.'s medical health officers have quietly passed a resolution asking all health authorities to develop supervised injection sites where needed.

The resolution, passed at the officers' biannual council meeting in Prince Rupert and posted publicly last week, recommends that supervised injection sites should "now evolve from a current single research project into being integrated into community primary-care settings, addictions services, hospitals and other health care services" everywhere in the province.

The suggestion is controversial. While many health workers and social advocates support injection sites as a way to prevent HIV and hepatitis C infections or drug overdoses associated with injection-drug use, critics say the sites send a dangerous message that it's okay to keep using drugs.

At the same time, Health Minister George Abbott confirmed to The Globe and Mail this week that the province will intervene in the court case between the federal government and advocates for InSite, the current injection site in the Downtown Eastside. Last year, Mr. Justice Ian Pitfield of the B.C. Supreme Court ruled that the site is an important health service and is protected by the Canadian Charter of Rights and Freedoms, a decision the federal government is appealing.

Mr. Abbott sent a statement to The Globe, saying: "Our government appreciates the role of the Health Officers Council of British Columbia in advocating for preventative health services for British Columbians. We believe InSite is an important part of the continuum of care and look forward to a positive response from the courts so we can consider the further use of this service to British Columbia's health care system."

Medical health officers say they passed their resolution partly to make it clear where they stand in the federal appeal case, and partly because they are grappling with a skyrocketing rate of injection-drug use and infections in some B.C. communities, especially in the north.

"I don't understand why the federal government is appealing this decision, but we just wanted to say that many of us have looked at the science and it does have benefits," said Roland Guasparini, the chief medical officer for the Fraser Health Authority. "We don't want the public to be confused."

Dr. Guasparini said he doesn't think a site would be considered in his health region currently, because it is trying to get other services in place to deal with drug addiction. Surrey is seeking funding for a sobering centre, for example, that can handle people with addiction problems who now overwhelm emergency wards. As well, he said, the region doesn't have the kind of street scene Vancouver does, so an injection site would not be effective in preventing overdoses.

However, medical health officers in northern regions of B.C. are seeing an alarming spike in injection-drug use and infections.

David Bowering, the chief medical health officer for the Northern Health Authority that geographically covers 63 per cent of B.C., said there is no immediate recommendation for an injection site, but it is something Prince George and other northern communities might have to consider.

Dr. Bowering said there has been a steep increase in HIV and hepatitis C infections in Prince George in the past five years, especially among the native population. That city's needle exchange now gives out 100,000 needles a year.

"We're seeing a pattern in Prince George that's reminiscent of what happened in the Downtown Eastside in the '90s," Dr. Bowering said. The Downtown Eastside's infection rate was so high then that it exceeded that of some Third World countries and was labelled an epidemic. It has since dropped and levelled off.

By Frances Bula, The Globe and Mail

February 20, 2009

The Canadian AIDS Treatment Information Exchange (CATIE) is hosting a series of public forums in cities across Canada in March that will examine the criminalization of HIV nondisclosure. CATIE is paying for the events with grant money from the Public Health Agency of Canada.

“We talk about the politics of sex and sexual identity and gender in a way that courts and law doesn’t really understand and that people in society have only a sort of simpleton view of,” says Glenn Betteridge, forum moderator (except in Quebec) and legal and policy researcher working in health and human rights. “This tour is a good idea because people across Canada need information on what is happening around the criminal law and HIV.”

In 1998 the Supreme Court of Canada ruled that you could be charged with aggravated assault for failing to disclose your HIV-positive status to a sex partner before having unprotected sex. Since then an increasing number of HIV-positive people, including many gay men, are being charged and convicted of violent offences ranging from aggravated sexual assault to murder.

It is morally dubious to deliberately expose a sex partner to a potentially lethal virus but a growing chorus of activists and researchers are saying HIV criminalization is fraught with injustice. They argue variously that criminalization hampers HIV-prevention efforts, fans the flames of HIV stigma, is rooted in misinformation and hysterical fear, puts the responsibility to protect sexual health entirely and unfairly on the shoulders of people living with HIV, turns gay men against each other and serves only to further victimize poz people.

Click here to find out how you can take action

But Betteridge says there remain disparate viewpoints, even within gay communities, about the best way to handle failure to disclose allegations.

“We almost talk about those things in a utopian aspirational way,” he says. “The idea that people living with HIV can have unprotected sex and face no consequences because the other parties should be looking out for themselves, asserting that as a human right, is tenuous.”

Betteridge says there may also need to be some remedy for those who become HIV positive after having unprotected sex when they simply don’t believe they have the free agency to refuse. What about those who honestly don’t feel they can insist on safer sex?

To Betteridge’s mind there is a struggle between what ought to be and what is. So, he says, he hasn’t yet made up his mind about criminalization.

“I am not sure,” he says. “It’s an issue I struggle with. I need to have my viewpoint more informed by those people who are feeling this profoundly to decide where I think the truth lies in this.”

Betteridge says he hesitates to publicly share a complete picture of his personal view because he wants to function as an impartial moderator and facilitator in the forums.

“We still have assertions on both sides that criminalization is both good and bad for a range of reasons and not a lot of evidence,” he says.

What if you are personally caught in a nondisclosure conundrum? Betteridge advises anyone who has been charged with a violent crime because of failure to disclose allegations to get a good criminal lawyer.

“The Canadian HIV/AIDS legal network and the HIV/AIDS legal clinic Ontario have been working with lawyers on strategies and approaches to develop really strong defences,” he says.

Should you call the cops if you think someone may be deliberately infecting others with HIV?

Betteridge says you should contact public health authorities, but stops short of advising you not to call police.

“What goes around comes around,” he says. “There’s this tide of criminalization that seems to be rolling along and you might get caught up in it yourself. Sex and sexual relations are really complicated so you could see yourself at a certain point in life not disclosing. There are often criminal acts in the essence of HIV transmission. To criminalize all the complexity in all those acts, be careful what you ask for.”

Vancouver
Sunday, March 1
British Columbia  People With AIDS Society
(604) 893-2200 /1-800-994-2437
or e-mail at: info@bcpwa.org

By Matt Mills, http://www.xtra.ca

February 25, 2009

Galveston, Texas -- University of Texas medical scientists say they've found most prison inmates with HIV don't seek appropriate treatment immediately following release.

The researchers said they discovered approximately 80 percent of Texas prison inmates infected with the human immunodeficiency virus, the virus that causes AIDS, fail to fill an initial prescription for anti-retroviral therapy within 30 days of their release from prison. And that, said the researchers, potentially increases the risk of harmful health consequences due to treatment interruption.

The researchers blamed the failure to seek continued therapy on the fact that most former inmates don't have health insurance during the first several months following their release, so accessing anti-retroviral therapy in a timely manner is difficult.

"Those who discontinue (therapy) at this time are at increased risk of developing a higher viral burden, resulting in greater infectiousness and higher levels of drug resistance, potentially creating reservoirs of drug-resistant HIV in the general community," the scientists said.

The study, led by Jacques Baillargeon of the University of Texas Medical Branch, is reported in the Journal of the American Medical Association.

http://www.upi.com

February 25, 2009

GlaxoSmithKline's recent announcement that it plans to reduce drug prices in some low-income countries and share information on patented drugs is "welcome" but not a "radical departure from standard fare," Tido von Schoen-Angerer -- director of Medecins Sans Frontieres' Campaign for Access to Essential Medicines -- writes in an opinion piece in London's Guardian. According to von Schoen-Angerer, GSK should employ the "tried and tested way to drive prices down -- competition with multiple generic manufacturers, thanks to which the first generation of AIDS treatments has seen a price drop of close to 99% in the past decade."

According to von Schoen-Angerer, the "price-cut pledge is restricted to 'the 50 least developed countries,' excluding those nations where burgeoning middle classes live side by side with millions who cannot afford medicines." He adds that this situation -- such as the one occurring in China, where GSK's patent "allows the company to charge prohibitive costs for the AIDS drug lamivudine" -- is "not one that can be wished away: as patients across the world start to develop resistance to existing drugs, they will need access to newer, more expensive medicines. The price of AIDS treatment is set to skyrocket."

Von Schoen-Angerer continues that he welcomes GSK's "attempts to encourage research through a 'patent pool' for neglected diseases" but that a "pool should not be restricted to so few diseases, and we need concrete changes to boost innovation and access for HIV/AIDS too. Such a scheme is already being established by the international drugs agency UNITAID." According to von Schoen-Angerer, GSK CEO Andrew Witty's claims that there is "sufficient innovation for AIDS drugs" is "wrong," adding that more heat-stable drugs are needed, in addition to new fixed-dose combination drugs and child-friendly combinations. He concludes, "Patent barriers can stop this innovation [from] happening -- until GSK pools its rights on lamivudine, patients in China can't benefit from the three-in-one pills that have revolutionized treatment elsewhere. For GSK to back the UNITAID patent pool would be the 'radical' shift to address innovation and access problems -- not Witty's proposals for price discounts" (von Schoen-Angerer, Guardian, 2/24)

http://www.kaisernetwork.org

February 23, 2009

A public inquiry has condemned the failings that led to thousands of people being infected with HIV and hepatitis C from contaminated blood.

The independent privately-funded inquiry called the use of contaminated blood products to treat patients with haemophilia a "horrific human tragedy".

The report suggested UK authorities had been slow to react, but accepted it was hard to directly apportion blame.

In the 1970s and 1980s, nearly 5,000 people were exposed to hepatitis C.

Of these, more than 1,200 were also infected with HIV.

Almost 2,000 of those people have since died as a result.

Infected Patient:

Haydn Lewis, 52, from Cardiff, is a haemophiliac who became infected with HIV and hepatitis C from tainted blood. He is now on the waiting list for a liver transplant, and believes he infected his wife because doctors delayed telling him. He said the report should have been more critical of government, and recommended better compensation arrangements for those affected. "I want to wake up one morning and not have to think about this issue because that is how you lead a constructive life," he said. "This has been a ball and chain around my ankle for 20-odd years, trying to get it addressed once and for all with some closure."

Despite the death toll, successive governments have refused to admit any fault or hold an investigation, forcing this public inquiry to rely on private donors.

Haemophilia is a rare inherited bleeding disorder in which the blood does not clot normally.

There is no cure, but the condition can be managed using a clotting chemical.

From 1973, some blood products containing such treatment were imported from the US as UK suppliers could not keep pace with demand.

The two-year inquiry, led by Lord Archer of Sandwell, said the main responsibility for the tragedy rested with the US suppliers of the contaminated blood products.

He said commercial interests appeared to have been given a higher priority than patient safety.

Viruses

Much of the blood had come from down-at-heel "skid row" donors, such as prison inmates, whose risk of hepatitis C and HIV was much higher than that of the general population.

Blood products began to be heat-treated from the mid 1980s to kill viruses.

However, Lord Archer also criticised the government at the time for being slow to become self-sufficient with blood products - it would have been unlikely for UK-sourced treatment to come from such a population of donors.

He said there was "lethargic" progress, with England and Wales taking 13 years compared to just five in Ireland.

But he added: "It is a bit late to say who is to blame when little can be done about it.

"What the government ought to address is the needs of people now."

To do this, he recommended a government-administered and backed compensation scheme for those who were affected - money currently available to victims comes from charitable trusts.

And to improve the treatment and management of the condition, the inquiry called for a committee of specialists to be set up to act as official advisers to ministers.

Lord Archer also said a public inquiry should have been held earlier.

He said some witnesses were unable to fully recollect what had happened because of the passage of time.

And Lord Archer lamented the decision of the Department of Health not to give evidence publicly - there were several private meetings with officials - and with-hold certain documents.

"It is hard to say what we could have found out."

'Swift action'

Sue Threakall, from the campaign group from Tainted Blood whose husband died after being given contaminated blood, welcomed the report.

She said: "What we need now is to see some very swift action from the government.

"All we have ever wanted is the truth, and some justice."

Christopher James, chief executive of the Haemophilia Society, agreed.

He said the use of contaminated blood was the "worst tragedy in the history of the NHS", and the way victims had been treated to date had not been right. He urged ministers to make up for this.

He said: "It is absolutely shameful that successive governments have not held a public inquiry into this issue.

"We've said for some time that the current level of payments and the method of payment are inappropriate and not fit for purpose.

"It is now up to the government to look at the report.

"We want them to act on it urgently and significantly."

A Department of Health spokesman said: "We have great sympathy for the patients and families affected and will study the findings of Lord Archer's report in detail."

He added there was now "robust screening" of blood and blood products taking place.

The Scottish Executive has promised a full public inquiry.

Publication of the report follows the news last week of the first case of vCJD in a patient with haemophilia - discovered during a post-mortem after the patient died from other causes.

Up to 4,000 haemophilia sufferers have been warned they could be at risk of variant Creutzfeldt-Jakob disease.

http://news.bbc.co.uk

February 25, 2009



Cape Town - Congress of the People leader, Mosiuoa Lekota, refused to comment on whether HIV causes Aids, during an interview with News24 ahead of the April elections.

"Look I am not an expert on HIV and Aids and I don't want to venture an opinion on whether it does or not," he said.

Former president Thabo Mbeki famously denied the link between HIV and Aids, a stance his biographer Mark Gevisser notes he still stands by in private. He sided with a small group of dissident scientists whose findings were considered outside the realm of reasonable scientific thought by the majority of the scientific community.

"Mbeki's views on HIV are his personal views, they are not government views," Lekota said about the notoriously touchy subject for politicians close to Mbeki.

Yet despite accepting shared responsibility for failures while he was in government, he refused to denounce the ANC government's fraught history on HIV/Aids.

Lekota steered clear of any strong positions on the disease. "(Where mistakes may well have been committed) I cannot accept that we consciously took a decision so that people should die."

Blacks used as guinea pigs

"When it came to the question of the ARVs [anti-retroviral drugs] it was true that we were very insistent that only ARVs which are approved for human consumption could be distributed here," Lekota told News24.

In 1999, Mbeki claimed that AZT - the most suitable ARV at the time - was toxic and refused to make treatment available, despite offers of discounts from pharmaceutical companies and UN aid.

"We had to do it, given the history of pharmaceuticals in this party under apartheid, where many chemicals were distributed in this country using black sections of the public as their guinea pigs," said Lekota.

Botswana versus SA

About the same time, Botswana started a Preventing Mother-To-Child-Transmission (PMTCT) programme and its president launched a national ARV programme in December 2001. By 2005 there was an 85% ARV rollout in Botswana.

In contrast, Mbeki refused offers of cheaper and even free Aids drugs, blocked a $72m grant to KwaZulu-Natal and only began a national PMTCT programme in 2003 - after being taken to court by the Treatment Action Campaign (TAC). By 2005 there was only a 23% ARV rollout countrywide.

Experts say the delay in treatment cost thousands of South Africans their lives.

In a damning study published in 2008, Harvard researchers found that 330 000 South Africans died prematurely between 2000 and 2005 due to the lack of proper Aids treatment. An estimated 35 000 babies born with HIV during that time also perished because a PMTCT programme was not implemented.

In 2000 Mbeki's health minister Dr Manto Tshabalala-Msimang rejected the offer of free Nevirapine from its German manufacturer, despite the drug being cleared by the US's Food and Drug Administration and the WHO.

Grave clothes of HIV/Aids

But Lekota stood fast by Mbeki's decisions.

"We had a reason initially to say why we had to be cautious about it, not just to give it," he said, referring to the supposed toxicity of the drugs again. Asked about Cope's policy on HIV Aids, Lekota said the party would take a "multipronged" stance on Aids involving both medication and nutrition. He also highlighted the importance of awareness campaigns.

But the party itself has no reference to HIV/Aids in its policy framework on health. A mention of the implementation of an HIV and Aids strategy in its manifesto - which will encompass "prevention, treatment, care and support for those who are affected and infected, including the provision of antiretroviral treatment and the prevention of mother to child transmission" - is fleeting

However, newly selected Cope presidential candidate, Bishop Mvume Dandala, has been vocal about the disease in the past. In September last year he voluntarily tested for HIV/Aids in Nairobi, encouraging others to do the same.

He also spoke on the subject at Nelson Mandela's son, Makgatho Mandela's funeral, saying: "Africa has to be freed of the grave clothes of HIV/Aids".

Lekota was national chairperson of the ANC from 1997 until 2007 and minister of defence from 1999 till he quit late last year.

Read a transcript of News24's interview with Lekota here.

By Verashni Pillay, http://www.news24.com

February 21, 2009

Two separate surveys, when compared together, indicate that single Baby Boomers are putting themselves at risk for acquiring AIDS/HIV.

The surveys, courtesy of AARP, indicate two trends:

1. There are a lot of single Baby Boomers out there dating around;
2. More Baby Boomers than ever have the AIDS virus.

Here are the AIDS/HIV stats, according to an AARP article that cited the Centers for Disease Control and Prevention:

"115,000 of the 475,000 people living with HIV/AIDS in the United States are 50+. That’s nearly double the number in 2001. The real numbers are likely higher because many people with HIV/AIDS remain undiagnosed, according to the CDC."

Part of that stat is attributable to the fact that these 50-plus Baby Boomers contracted the virus when they were younger and have lived into the 50s and beyond because of the so-called "cocktail" of antiretroviral drugs and improved treatments.

But what alarms health care professionals is that nearly one of every six new diagnoses of HIV is in someone aged 50 and older, according to the AARP article.

Many of these health care professionals agree that the 50-plus Romeos and their female counterparts need a lesson in safe sex as a way to reduce the transmission of the virus.

It's a timely need because, according to another study cited by another AARP article, the high divorce rate means a lot of older singles are on the prowl.

The article -- which focused on Cougars (older women who date younger men) -- cited an AARP poll that surveyed several thousand people age 40 to 69: "56 percent are currently separated or divorced from a spouse, 31 percent have never been married, and seven in 10 (74 percent) of formerly married singles in their 50s have been single for five years or more."

While older adults remain sexually active they have to remember they are not immune from contracting the AIDS virus.

According to AARP, older adults are less likely to use protection because pregnancy is not an issue post-menopause and doctors do not always test older people for HIV/AIDS.

By Paul Briand, Baby Boomer Examiner

February 22, 2009

Two studies presented at the recent 16th Conference on Retroviruses and Opportunistic Infections in Montreal showed no benefit for HIV patients given a cancer drug designed to create immune cells.

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While earlier results showed promise, patients treated with Novartis’s interleukin-2 (Proleukin) fared no better than patients who did not receive the drug. “As far as I’m concerned, this is the end of interleukin-2 for HIV,” John Bartlett, a Johns Hopkins University AIDS researcher who was not involved with the studies, told Bloomberg News.

Interleukin-2 is a cytokine, a chemical that occurs naturally in the body and activates the immune system. It is approved to treat skin and kidney cancers. The two trials examined whether it would be of benefit to patients on antiretroviral regimens.

A $65 million National Institutes of Health–funded study looked at interleukin-2’s effect on 4,011 people who began treatment with CD4-cell levels higher than 300 per cubic millimeter of blood. The second study involved 1,695 patients who started with CD4-cell counts of 50 to 299. U.S. guidelines recommend that antiretroviral treatment begin when CD4 levels drop below 350.

While the drug raised immune cell levels in both trials more than researchers expected, death and illness rates were the same in treated and untreated groups, Marcelo Losso of the Hospital Jose Maria Ramos Mejia in Buenos Aires, who presented the results, told Bloomberg News. In the study of people who began with CD4-cell counts of more than 300, serious side effects were more common among those who received interleukin-2, he said.

“We could increase CD4-cell levels with the treatment but not improve the outcome,” Bartlett told the news agency. “Maybe getting them to the highest level possible isn’t as important as we thought it was.”

Carl Dieffenbach, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, said interleukin-2 may encourage the body to make CD4 cells that respond to illnesses other than HIV. “There’s something significantly different about the cells that get boosted with interleukin-2,” he told Bloomberg News. “Interleukin-2 is effective in cancer, and that may tell us something about HIV as a disease and cancer as a disease.”

http://www.hivplusmag.com

February 23, 2009

London - The development of gels that can protect people against HIV is to receive more than £90 million of funding, after work by British scientists suggesting that it has the best chance yet of controlling the spread of AIDS.

The field of microbicides, involving gels designed to block HIV from entering the bloodstream, is to be supported with the huge grant from the Government and the Bill & Melinda Gates Foundation, The Times has learnt.

A number of world-leading British research teams, including those at Imperial College London, St George’s, University of London, and the Medical Research Council, are expected to be recipients.

The grant follows results from a preliminary trial, released this month, which suggest that a new gel, applied inside the vagina, may reduce the chances of women contracting HIV by a third. The findings raise the prospects of success for a second, larger, trial of the same drug, run by Imperial, which is due to finish in August.

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Multimedia
GRAPHIC: how microbicides can protects against HIV

Scientists described the microbicide work as very promising, adding that a consensus was now growing that, with an AIDS vaccine still decades away, it was the most realistic drug strategy to protect people against HIV infection.

The condition has claimed more than 25 million lives to date. Of the 16,000 people around the world contracting HIV every day, the majority are infected by unprotected sex, with the greatest incidence in sub-Saharan Africa and India.

Microbicides are formulated as gels or creams designed to destroy bacteria and viruses or to reduce their ability to establish an infection.

The gel concept works by being applied to the vagina or rectum before sex to kill HIV, prevent the virus entering human cells and inhibiting HIV replication. It shares many of the advantages of a vaccine, including being undetectable when used by women, who might be unable to persuade their partners to use condoms.

A problem is that while many chemicals can kill HIV — undiluted household bleach included — their toxicity is such that they risk causing tissue damage that actually hastens any infection.

The findings released this month from the phase II/III clinical trial of PRO 2000 microbicide, which is being developed by the pharmaceutical company Indevus, suggest that this particular battle may be being won.

The preliminary study of 3,100 women whose husbands were HIV-positive showed a significant cut in transmission rates. While not conclusive — the difference was not great enough to make it statistically significant, meaning that it could still have been the result of chance — the findings have been welcomed with a confidence rarely seen of late in the Aids science community, which promotes the rapid development and delivery of a safe and effective microbicide product.

It will support ten new clinical trials investigating new and more sophisticated versions of the PRO 2000 drug, such as longer-acting gels and those made with specific antiretroviral drugs, over the next five years.

Renee Ridzon, senior programme officer in global health for the Gates Foundation, said that the organisation recognised the contribution that microbicides could make, particularly the “next generation” of more targeted drugs.

Zeda Rosenberg, the partnership’s chief executive, described the PRO 2000 trial as an “important milestone” and said the support of the Government and the Gates Foundation added “crucial momentum to delivering on the promise of microbicides”.

Michel Sidibe, head of the United Nations’ Aids programme, told The Times that further positive findings in August would prompt a major initiative to introduce the gel to countries worst affected by AIDS.

By Sam Lister, http://www.timesonline.co.uk

February 23, 2009

According to a new study, eating a one-half ratio of sodium to potassium can halve a person's chances of dying from heart disease.

People who consume high-sodium diets can improve their health by increasing potassium intake to match salt.

Paul Whelton said that potassium and sodium are like peas in a pod, and that this is the first study to show that eating the two nutrients together, more than either one by itself, can benefit people.

Due to high amounts of sodium in processed foods and in food prepared in restaurants, many people eat far too much of it, increasing their chances of dying from heart disease.

Excess sodium causes the body to retain fluids and raises blood pressure, putting the body at risk of strokes and heart attacks.

The link between heart health and potassium has also been studied, and in 1997, a study found that people taking dietary suppliments of potassium decreased their blood pressure by 3/2 mm Hg.

This is the first time that research has confirmed some scientists' suspicions that the ratio of sodium to potassium in the diet is important.

Researchers used data from two large trials designed to link blood pressure, diet, and weight loss.

The trials studied the effect of dietary sodium in thousands of people over spans ranging from two and a half to three years.

Some of the people reduced their sodium intake by 35%, which gave them a reduced likelihood of heart disease.

Among those who continued to eat high sodium diets, people who ate more potassium had a slightly lower risk of dying from heart disease.

Those with the lowest risk of cardiovascular disease were those who ate the lowest amounts of sodium and the highest amounts of potassium, and controlling the ratio of the two nutrients to each other turned out to be more important even than their respective amounts.

While the physical mechanism responsible for these effects is unknown, it is possible that potassium prevents the body from absorbing as much sodium.

It could also be because people who attempt to eat more potassium are bound to go for fruits and vegetables, and benefit from their fiber and antioxidants.

High-potassium foods include raisins, bananas, and oranges.

Two of the highest potassium foods are spinach and potatoes, with 950 mg per cup of spinach and 900 mg per potato.

http://www.hc2d.co.uk

February 19, 2009

People with HIV are at an increased risk for brain inflammation and damage, similar to problems typically seen in older members of the general population, according to a series of studies presented Wednesday, February 11, at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal. The latest research also indicates this damage may not be completely halted or reversed with the use of HIV treatment.

A great deal of attention has been paid recently to the effect of HIV on the aging process, with a number of studies reported in the past year showing that people with HIV are more likely to have heart, kidney, bone and other problems at a younger age than HIV-negative people. One possible reason for this: HIV exacerbates cellular damage and further inhibits the body to heal itself, both considered to be natural consequences of growing older.

Research presented at CROI also suggests that HIV can speed up the aging process in the brain, sobering findings in light of other data presented in Montreal indicating high rates of peripheral nerve damage in people infected with the virus.

The Lower the CD4s, the Higher the Risk

Igor Grant, MD, from the University of California in San Diego (UCSD), shared data involving 1,555 HIV-positive patients enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study. Eight-five percent of those enrolled were on antiretroviral (ARV) therapy at the beginning of the study, and 63 percent had a history of an AIDS diagnosis. The average lowest-ever CD4 count was 174. At the first study visit, 47 percent of the patients had normal cognitive functioning, 21 percent had mild impairment, 30 percent had moderate impairment, and only 2 percent had severe impairment.

Although Grant and his colleagues found, to their surprise, that the rate of cognitive problems in the CHARTER study participants had not improved significantly since the early days of the epidemic, they did find a strong connection between lowest-ever CD4 count, called the nadir, and the likelihood of cognitive impairment. People who’d never had a CD4 count below 200 and who kept their virus levels under 50 copies were much less likely to have cognitive impairment.

One disturbing finding by Grant’s team was that when they used an ultra sensitive viral load test on cerebrospinal fluid—a measure of what’s going on the brain—they found that 41 percent of people with an undetectable viral load in the blood did have very low levels of virus in the brain.

Grant surmised that waiting to start ARV therapy until CD4 cells drop below 200 could initiate a cycle of brain injury that subsequent treatment with HIV drugs cannot fully shut down.

Damage Without Symptoms

Signs of brain inflammation—a potential brain damage prerequisite—is very common in people living with HIV, according to findings presented by Bradford Navia, MD, PhD, from Sackler School of Biomedical Sciences at Tufts University in Boston. His group shared data on 263 HIV-negative and HIV-positive patients, all of whom were assessed using brain imaging technology that included magnetic resonance spectroscopy (MRS). The patients were on the older end of the spectrum, with the average age being 47, and more than one third being older than 50.

Most of the HIV-positive patients have been infected for at least 12 years, and the average nadir CD4 count was less than 50. One hundred twenty-two had no neurological symptoms at baseline, 64 had very mild symptoms of dementia, and 49 had moderate to severe dementia.

Navia and his colleagues found that all of the HIV-positive patients, including those with no symptoms, had increased levels of brain inflammation proteins. However, further analysis revealed that only elevations of proteins in the basal ganglia—which connects several parts of the brain and is involved in motor control, thinking, learning and emotions—were associated with having nuerological impairment. When combined with older age, basal ganglia inflammation was a significant predictor of reduced brain functioning.

Navia’s results were similar to those presented by Beau Ances, MD, PhD, from the Washington University School of Medicine in St. Louis. Ances showed the results of functional brain images, in which the researchers took an image of a person’s brain while at rest and again while attempting to perform a mental task. Ances and his team looked at the level of blood flow to the brain in 35 HIV-negative and HIV-positive people—half of those living with HIV were receiving ARV therapy—to determine what influence HIV and aging may have on brain function.

Ances and his colleagues found that at baseline, people with HIV at rest had a reduction in blood flow that was similar to an HIV-negative person who was 10 years older. When they conducted imaging on people as they sought to perform tasks, they found that the degree of reduced blood flow to the brain was even more pronounced, with HIV-positive patients having the blood flow of a person 15 to 20 years older.

Reduced blood flow to the brain can lead, in the short term, to reduced brain function, and over time, to brain injury. Though Ances did not look specifically for the underlying causes of the reduced blood flow, he speculated that it could be from increased inflammation in the blood vessels and changes to blood platelet functioning, which could lead to reduced blood flow throughout the body. He commented that although there was no difference in blood flow based on the type of ARV treatment a person took, being on treatment with an undetectable viral load did result in higher blood flow to the brain.

By David Evans, http://www.aidsmeds.com

February 23, 2009

Scientists at Duke University Medical Center have for the first time isolated an important antibody in human serum that could potentially play a key role in the design of an AIDS vaccine.

The research appears as a highlighted feature online in the Journal of Virology.

"The 2F5-like antibody is one of the gold standards for what an HIV vaccine needs to induce, but no one had ever found it before circulating in the blood of infected patients," says Georgia Tomaras, PhD, associate professor of surgery, immunology and molecular genetics and microbiology in the Duke Human Vaccine Institute and the senior author of the study.

The 2F5 antibody is especially valuable because previous research has shown it can successfully neutralize 80 percent of transmitted HIV viruses.

Now that researchers have found the antibody in circulating blood, Tomaras says they might be able to find ways to duplicate or enhance it, thereby boosting the body's defense system.

2F5-like antibodies belong to a class of immune cells called broadly neutralizing antibodies, one of the body's most powerful responses to infection. Only a small fraction of patients with HIV make these antibodies and they typically appear many months after initial transmission of the virus -- at a point when scientists feel it is too late to do much good.

Tomaras, working closely with lead author Xiaoying Shen, led a team of researchers who examined the antibodies present in 300 patients infected with HIV-1. They found only one patient who had developed 2F5-like antibodies, supporting the notion that they are, indeed, very rare.

Researchers discovered that the 2F5-like antibody was potent enough to block multiple strains of HIV in the laboratory, but researchers say they are not entirely clear if it played any part in controlling the virus in the patient who carried it.

The scientists were also struck by another discovery: The 2F5-like antibodies arose concurrently with particular autoantibodies that may be a clue as to why these antibodies developed in this person and not in others.

"Tomaras and her team have created the opportunity for us to isolate and study the immune cells that enabled the production of this very rare antibody," says Barton Haynes, M.D., director of the Duke Human Vaccine Institute. "Our goal will be to understand how to trigger these cells to routinely make these kinds of antibodies before infection occurs."

The research was funded by the National Institutes of Health and the Duke Center for AIDS Research.

Co-authors from Duke include Robert Parks, David Montefiori, Jennifer Kircherr, Feng Gao, Kent Weinhold, Charles Hicks, Michael Greenberg and Barton Haynes. Additional co-authors include Brandon Keele, Julie Decker, Beatrice Hahn and George Shaw, from the University of Alabama at Birmingham; and William Blattner, from the University of Maryland.

http://www.thebody.com

One of the pioneers of AIDS research, former Harvard retrovirology professor William Haseltine, said today that universal testing and treatment now offers the best hope of controlling the HIV pandemic.

Writing in the news magazine The Atlantic, Haseltine said that three other authorities involved in the discovery of HIV – Robert Gallo, Max Essex and Robert Redfield – have reached the same conclusion.

“History has shown that epidemics can be controlled, even in the absence of a vaccine,” he says. “Both syphilis and tuberculosis were pandemic at the end of the nineteenth century, and both epidemics were controlled by effective diagnosis and treatment.”

“I recommend that WHO, PEPFAR and the Global Fund begin studies to assess the effectiveness of universal testing and early treatment for the prevention of HIV transmission,” he urges.

At a recent seminar on global governance challenges at the James Martin 21st Century School at Oxford University, Professor Jonathan Weber of London’s Imperial College said that after 27 years in HIV research, he no longer believes a vaccine to be achievable. Instead he believes that population-based antiretroviral therapy (PopART) is the only strategy currently available that holds out the prospect of HIV eradication.

Population-based treatment, or universal testing and treatment, is a subject of growing interest to researchers. Last November the World Health Organization published details of a mathematical modelling exercise which suggested that if all people in South Africa could be diagnosed and begin antiretroviral treatment within a year of infection, the incidence of new infections could be reduced by 95% within ten years, assuming that treatment reduces the risk of transmission by 99%.

At the Sixteenth Conference on Retroviruses and Opportunistic Infections earlier this month, two studies of transmission risk in HIV-discordant couples were presented. One showed no cases of transmission in couples where the HIV-positive partner took antiretrovirals, while the other showed an 80% reduction in transmission risk.

Christophe Fraser, an epidemiologist from Imperial College, London, warned the confererence that the striking effect of universal treatment in mathematical models might not be replicated in real life if it proved less than 99% effective, and called for careful examination of the assumptions in the WHO models by other epidemiologists before policy is made.

By Keith Alcorn, www.aidsmap.com

A combination of two antiobiotics already in use to treat other bacterial infections could potentially treat extensively drug-resistant tuberculosis (XDR TB), scientists from New York’s Yeshiva University report today in the February 27 edition of Science.

If the results are replicated in human studies due to begin later this year in South Africa and South Korea, “this discovery could be one of the most promising developments in TB research since the discovery of isoniazid – it is very exciting,” said Professor William Jacobs of Yeshiva University’s Albert Einstein College of Medicine.

At present the treatment of multi-drug-resistant forms of TB is lengthy and toxic and often results in confinement for the patient. Some treatment courses can last two years. In cases of extensively drug resistant TB the situation is even more difficult. Patients with XDR TB have either developed or acquired a form of TB that is resistant to the majority of second-line TB drugs, and the chances of a cure are less good than for TB that is resistant only to isoniazid and rifampicin (the standard definition of multi-drug resistance).

In recent years extensively drug resistant TB has been reported in 45 countries, with the highest rates reported in Eastern Europe, Asia and South Africa.

The outbreak in South Africa has caused particular concern due to its emergence in people with HIV and the health professionals caring for them.

The study carried out by Albert Einstein College of Medicine set out to determine whether it was possible to make Mycobacterium tuberculosis susceptible to an antibiotic from the β-lactam class. This class of antibiotic, which includes penicillin has not proved active against Mycobacterium tuberculosis because mTB contains an enzyme called a β-lactamase that blocks the activity of β-lactam antibiotics.

β-lactamase inhibitors were developed to overcome the effect of this enzyme, which is found in many bacteria and which has been noted to spread since the introduction of antibiotics. The β-lactamase of Mycobacterium tuberculosis is particularly difficult to overcome; two β-lactamase inhibitors are ineffective against it.

However clavulanic acid, the only FDA-approved β-lactamase inhibitor, irreversibly inhibits the enzyme, so the researchers looked at the activity of the β-lactam antibiotic meropenem in combination with clavulanic acid against 13 strains of XDR TB and laboratory strains of mTB without drug resistance.

Meropenem was selected after extensive testing of β-lactam antibiotics as the drug with the best potential for inhibiting mTB growth, and tested in cell cultures with clavanulate. A sterilising cure – complete eradication of mTB – was achieved within 9-13 days, and the combination was equally effective in drug-susceptible and drug-resistant strains.

If the findings are replicated in humans, the use of these two drugs has the potential to simplify drug-resistant TB treatment from four to six drugs down to two drugs, said Professor John S. Blanchard of Albert Einstein College of Medicine.

The US National Institute of Allergy and Infectious Diseases, which co-sponsored the study, is now talking to manufacturers to provide clavanulate in a formulation suitable for studies (it is currently available only as a coformulation with amoxicillin). The first trial is planned in South Korea later this year in 100 patients. Meanwhile Albert Einstein College of Medicine will conduct a second study, in collaboration with the Nelson Mandela School of Medicine in Durban, South Africa.

Current efforts to find better treatments for drug-resistant TB focus on the development of antibiotics in new classes, with several agents with novel mechanisms of action against TB already in phase II trials.

However researchers are also keen to shorten the length of first-line TB treatment. At present patients must take four drugs for two months and then two drugs for a further four to six months.

“We see tremendous potential for treating not only XDR-TB cases, but also routine TB cases,” said Professor Brian Currie of Albert Einstein College of Medicine, who will lead the planned studies in South Africa.

Reference

Hugonnet JM et al. Meropenem-clavanulate is effective against extensively drug-resistant Mycobacterium tubeculosis. Science 323: 1215-1218, 2009.

By Keith Alcorn, www.aidsmap.com

February 9, 2009

There's nothing like hearing the results of studies directly from those who actually conducted the research. In this interview, you'll meet two of these impressive HIV researchers and read their explanation of studies they presented at CROI 2009. After their explanation, they will answer several questions from the audience. This discussion was moderated by John Mellors, M.D.

John Mellors: Since the discovery of potent HIV protease inhibitors [PIs], a common theme of that class has been rapid metabolism and clearance from the bloodstream, requiring twice-daily or three-times-daily dosing. The use of ritonavir [RTV, Norvir] as a metabolic inhibitor of protease inhibitors caused a major advance in protease inhibitor-based therapy by allowing greater exposure with less-frequent dosing. That strategy has been dependent on one molecule, ritonavir, that is the intellectual property of Abbott Laboratories. It is only co-formulated with Abbott's protease inhibitor, lopinavir [LPV], and has been a bottleneck in efforts to co-formulate medications.

There has been a hewing cry and various protests about the availability of only one boosting agent. Also, there's been concern at a regulatory level and among clinicians about the effects of a boosting agent, such as ritonavir, used without a protease inhibitor -- let's say, used with an integrase inhibitor like elvitegravir [EVG].

So we applaud the efforts of Gilead Sciences and Sequoia Pharmaceuticals, who have some exciting news to tell us about inhibitors of the metabolism of protease inhibitors and other agents potentially used in a wide range of therapeutic areas. We're going to hear about those from Brian Kearney at Gilead Sciences and from Robert Guttendorf from Sequoia Pharmaceuticals.

Brian Kearney, Pharm.D.

Brian Kearney: Good morning. My name is Brian Kearney. I'm senior director of clinical research at Gilead Sciences located in Foster City, California.

This morning we presented data on GS-9350,¹ our pharmaco-enhancer. It shares with ritonavir a mechanism-based inhibition of cytochrome P450, which is critical in terms of being able to administer a low dose, as infrequently as once a day -- to provide not only boosting of bioavailability, but slowing of systemic clearance, to allow for optimal pharmacokinetics of the drugs that we choose to boost.

As John mentioned, the anti-protease activity that molecule has raises certain questions about its ability to select resistance even at a low boosting dose. In our development program we specifically sought to have the mechanism-based inhibition that ritonavir has and remove the anti-HIV activity -- and we were able to successfully do that.

Then there were other factors that we considered in ultimately choosing GS-9350. These included, broadly speaking, improvements in other areas of its DMPK profile -- drug metabolism and pharmacokinetics. That includes more specific inhibition of cytochrome P450 3A [CYP3A] relative to competitive inhibition of other enzymes; the 2C family and 2D6 are also inhibited by ritonavir.

Also, ritonavir has a certain amount of liability in terms of being able to reduce metabolism: Whereas it boosts effectively in the background, it can cause induction. We've removed the induction liability as well by removing [GS-9350's] activity in terms of activation of nuclear receptors. And that induces a number of drug metabolizing enzymes as well as drug transporters.

Other aspects that we focused on included reduced effects on adipose sites in vitro. We focused on this in particular because elevations in triglycerides and cholesterol, as well as insulin resistance, are sometimes seen in patients receiving boosted regimens. We were able to show GS-9350 has less effects in vitro.

The last, and one of the key, aspects of selection of GS-9350 was its high aqueous solubility. What that allows us to do is formulate it in a solid dosage form; it also allows for a co-formulation potential.

When all of those attributes were met, we moved into the clinic and conducted two clinical studies. The first clinical study was for safety and tolerability. It was a single- and multiple-dose study, and we looked to also establish proof of concept in terms of its ability to boost CYP3A substrates. In our study, we chose to use the validated probe midazolam. We showed that GS-9350 was able to reduce metabolism of midazolam, this 3A substrate, to the same extent that ritonavir is able to do at its boosting doses.

After that proof of concept was met, then we moved into a co-formulation study where we co-formulated GS-9350 with our integrase inhibitor, elvitegravir, as well as tenofovir/FTC [tenofovir/emtricitabine, Truvada]. The long and short of that story was the quad formulation -- GS-9350 had 150 milligrams, co-formulated with elvitegravir and tenofovir/FTC -- reached the desirable concentrations that we had set out to reach.

Based on those data, we'll move forward into Phase 2 with this quad tablet in a head-to-head study versus Atripla [efavirenz/tenofovir/emtricitabine, EFV/TDF/FTC] in treatment-naive patients. Our intent is to start that study in the second quarter of this year.

We're also in the process of completing a study of the standalone GS-9350 tablet to boost atazanavir [ATV, Reyataz]. It's a dose-finding study to see what dose is necessary to boost atazanavir, similar to what ritonavir does in the boosted state. When those data come through, we plan to conduct a head-to-head study with the GS-9350 standalone tablet versus ritonavir to boost atazanavir -- both of those regimens, with Truvada, also on treatment-naive patients. Our goal is, pending favorable data on that PK [pharmacokinetic] study, to also start that Phase 2 study in the second quarter of this year.

John Mellors: Thank you. Robert?

Robert Guttendorf, Ph.D.

Robert Guttendorf: My name is Robert Guttendorf from Sequoia Pharmaceuticals. I head up the pharmacology and experimental therapeutics group there.

I'm very happy to have this opportunity to talk with you about our PKE [pharmacokinetic enhancer] program.² As described, we are seeking to come up with an alternative to ritonavir as a booster in HIV therapy -- particularly with PIs, but also with potential application to other classes of antiretrovirals, and perhaps beyond.

We set out to try to address the limitations that ritonavir has, including its propensity to elevate certain lipids and its protease inhibitory activity, which could be associated. There's a risk [with ritonavir] of association with generating protease-resistant mutants, and also its GI [gastrointestinal] intolerability. We succeeded in those goals, in coming up with our lead compound, SPI-452.

It's probably worth mentioning that, if you aren't familiar with us: Sequoia Pharmaceuticals is a small, young company of only about 30 people, but we have a wealth of talent and experience at our disposal within the company, starting with our founder and CSO [chief scientific officer], Dr. John Erickson, with whom many of you are probably already familiar and who is here in the audience. Beyond that, we have breadth of experience and depth of experience across all stages of drug discovery and development and many different therapeutic elements. That allowed us to take this project from the initial inception of the PKE [pharmacokinetic enhancement] program to the full proof-of-concept demonstration in the clinic within only about three years.

As I mentioned, SPI-452 did have the profile that we were looking for in a lead candidate [according to the results of] in vitro and in vivo in animal studies. Pre-clinically, it demonstrated itself to be a very potent PK enhancer; it was on par with ritonavir. Our goal was to come up with something that was at least as good a booster as ritonavir, but which didn't have as many of the adverse aspects of the profile that ritonavir has.

It showed pre-clinically, and with that, we went into our clinical studies. We've conducted two so far: a single, rising-dose tolerance and a multiple, rising-dose tolerance, in which we showed that, indeed, SPI-452 does have a very safe and tolerable profile. It does not have any substantial GI side effects, andat least in the multiple-dose studies, it showed no statistically significant differences in triglycerides and LDL [low-density lipoprotein] compared to placebo.

In addition to that, we also built into each of these two studies an arm that would evaluate the ability of SPI-452 to enhance directed potential partner PI drugs -- saquinavir [SQV, Invirase] in the first study, atazanavir and darunavir [TMC114, Prezista] in the second study. The boosting that we saw for each of these compounds was quite remarkable and showed us beyond a shadow of a doubt that we were, in fact, hitting our molecular target and enhancing these PIs as we had hoped to do. These were on par with ritonavir, based on literature data.

With that, we believe that SPI-452 has great potential. We see it as potentially being developed as a stand-alone agent or as a fixed-dose combination. And it has potential applications not only within HIV as a PI booster, but also in HIV for other types of classes of antiretrovirals, and in HCV [hepatitis C virus] for some of the development compounds that are out right now -- it would be a very good adjunct for that. In addition to that, there are also opportunities for either 452 or our general PKE platform to be applied outside of the antiviral space.

John Mellors: Thank you very much. These are two exciting developments in the treatment field. Questions?

Reporter #1: Would you be nicer than Abbott and license your compound to other companies so that they can manufacture a combo pill?

Brian Kearney: I'd say we're currently doing work with atazanavir and are engaging in conversations with other companies to conduct pharmacokinetic studies to see if our drugs can work together. I think we've shown, with our collaboration with BMS [Bristol-Myers Squibb Company], that we're more than willing to work with other companies.

John Mellors: Dr. Guttendorf?

Robert Guttendorf: Yes, I would echo that. We, as well, are looking at the possibilities of fixed-dose combinations with this compound and are in discussions with a number of potential large pharma partners to look at directed fixed-dose combinations for development.

Reporter #2: The grade 3 adverse event of "discoordination" -- could you define discoordination for us?

Brian Kearney: This [refers to] a subject in our study who came to the investigator in the study and said that she felt like she was having a hard time engaging in juggling, which was one of the [things] she did to pass the time when she was in the clinic, and felt that [the drug she was taking in the study] impaired her ability to do that. Per the toxicity grading criteria, this was considered discoordination. It was a grade 3 event per her report, and she was discontinued from the study because we had predefined stopping rules: Anybody who had a grade 3 adverse event would be discontinued.

Reporter #2: Do you have plans to do a parallel track for releasing this as a booster on its own, or is it only in co-formulation?

Brian Kearney: No, we intend to bring forward a stand-alone tablet of GS-9350 as well as the co-formulation.

Reporter #2: Would that be around the same time?

Brian Kearney: Yes.

Reporter #3: After 20 years in this field, I am very suspicious of the phrase "safe and well-tolerated." Could you run down the side effect profile of your enhancer? What were the most common side effects?

Robert Guttendorf: Sure. I probably should qualify that, if I didn't, as generally safe and well-tolerated. I agree there is no drug out there that is absolutely safe; it is all in relative terms. In the single-dose study, the predominate adverse events were four episodes of headache and four episodes of pharyngitis -- not strep pharyngitis, just general sore throat. These are fairly typical in this type of a study, particularly as people are being withdrawn from caffeine for the study and that sort of thing; headaches tend to be pretty prevalent.

In the second study, the multiple-dose study, there were an additional number of headaches -- remember, again, this was over 15 days of dosing with four or five, plus a couple of extra days for the PI dosing before, during and after the SPI-452.

All told, with the number of subjects, we had over 1,000 dosing events, during which time there were about 35 reports of headache in 17 people. Eleven individuals reported nausea or emesis [vomiting] a total of 13 times among those 11. It was interesting that a majority of those tended to occur right before a subsequent dose was given, and it tended to be related to the fact that that's when they were getting their breakfast. As it turns out, I guess not everybody's as big a fan of French toast as I am, because that tended to be one of the prevalent findings and the timing of that finding. There were a few scattered episodes of loose stools as well.

Reporter #3: What was the maximum duration of SPI-452 dosing in your studies?

Robert Guttendorf: It was 15 days.

Reporter #4: What is known, if anything, about the interactions of your compounds with other drug classes that are metabolized by the CYP3A4 isoenzymes, like statins, macrolytes and rifamycins?

Robert Guttendorf: We have conducted several drug-drug interaction studies in vitro and, insofar as we are intending to modulate CYP3A activity, we anticipate that there will be a fair number of drug-drug interaction studies that we'll have to elucidate in the clinic. Obviously, in the HIV area, that's a risk-benefit decision that's pretty well accepted at this point in time. We will evaluate those in further studies. Our study to be done will be a CYP cocktail study, which will evaluate the direct effects of 452 on specific CYP isoforms. That will help guide us, along with additional in vitro studies, on the specific types of drug-drug interaction studies that we'll have to do to support our label.

Brian Kearney: We would expect [GS-9350] to have the same type of 3A-mediated interactions with drugs that metabolize by that pathway. We also intend to do these cocktail studies, which are now recommended by guidance to look at the different specific isoforms.

Reporter #4: In your talk, you said that [with SPI-452] there was a propensity to enhance the concentration of at the end of the dosing interval. That seems kind of unique. What kind of implications would that have?

Robert Guttendorf: The main advantage of that would be that you can enhance the levels and maintain the duration of the drug above its targeted levels. As you know, in order to maintain efficacy, you have to keep levels above this certain target level through the duration of the dosing period. As I think I've said, it has a predilection for doing that as opposed to enhancing the entire profile. In a sense, it's almost like a hinge: If you increase the back end without doing much to the front end, then we're increasing the extent of the efficacy window and not at the same time commensurately increasing the [Cmax?], which would lead to potential additional side effects.

Reporter #5: Dr. Kearney, you had indicated there's a trial [of GS-9350] starting in second quarter this year. My assumption is that you've talked with the FDA [U.S. Food and Drug Administration] and this is headed toward approval. Given that this drug is not a drug per se -- it's a little different than most others -- what are they going to be looking for in terms of duration and size of trial? What are you going to need to prove to them in order to get approval for this compound?

Brian Kearney: To answer the first part of your question, our intent is to start two Phase 2 studies in treatment-naive patients in the second quarter. One will be the quad-tablet compared to Atripla. The second, pending the pharmacokinetic data boosting atazanavir, is a study of 9350 versus ritonavir to boost atazanavir -- each of those combinations taken with Truvada, also in treatment-naive patients. We have had discussions with the FDA and plan to move forward with that in the United States in the second quarter.

Your second question: It is a new chemical entity and it is a drug by definition. Therefore it would be expected to have the same type of data as if you were developing a new antiviral. We worked with the agency and the expectation is that we will provide a safety database, as was mentioned by Dr. Kim [inaudible], who was one of the moderators of the session from FDA. We would seek to comply with that expectation that we would have a sufficient number of subjects studied for over a year -- this tends to be in excess of 500 subjects -- and a larger number of subjects studied for a shorter period of time. Our development program is based on that.

John Mellors: Just to hone in on this a little bit: Will it be sufficient to show that there is safety and equivalent exposure to elvitegravir as that which would be achieved with ritonavir boosting, or do you have to show efficacy as a quad-containing tablet that you would for any new first-line therapy?

Brian Kearney: A lot of the numbers, when you're talking about specific numbers required for approval, go into discussions about the size of the database characterizing the safety of the molecule. As you probably all know, that can be generated from multiple, different clinical studies in different combinations of drugs. That would be the case here as well.

One of aspect of the safety database will be from Phase 3 studies of the quad compared to different regimens that we would consider standard of care, one being Atripla. It's not that you have to show efficacy against all specific other combinations.

What is the definition of efficacy? It'll be defined by the individual Phase 3 studies, which will be designed in concert with the regulators.

Reporter #5: GI symptoms are a big concern for people taking ritonavir, especially diarrhea. In your proof-of-concept study, Brian, when comparing different doses of the compound with ritonavir and placebo, did you collect any data on GI symptoms? Is there any difference?

Brian Kearney: The overall rates of adverse events in those studies were low from single doses to multiple doses. There's no evidence of any dose dependence, between 50, 100, and 200 milligrams, in those studies. Not a lot of GI adverse events.

Reporter #6: Primarily for Robert, I'm wondering if you can maybe say a little bit about what your plans are to combine your drug or use it with boceprevir for hepatitis C. And Brian, if Gilead's also planning anything. Are there other disease models in which pharmaco-enhancement using this kind of compound might be useful?

Robert Guttendorf: At this point, we've shown proof of concept that we are able to enhance the levels of boceprevir [with SPI-452] in vitro, and we are conducting some animal studies now to help confirm that. Our ability to co-administer that with boceprevir is complicated a bit by the fact that it is also an NCE [new chemical entity] and in order to do that we would have to have some sort of collaboration and probably a new IND [investigational new drug application] in collaboration with the developers of boceprevir. However, we do look at that as a very good opportunity, as well as for other PIs in the HCV realm and some other HCV compounds as well.

Beyond the antiviral space, as I mentioned, our PKE platform is actually fairly broad-reaching. We have additional compounds in the pipeline that could come in as either stand-alone or fixed-dose combinations -- that have improved on some of the attributes of SPI-452 -- which could be used for HIV, HCV or elsewhere. In addition to that, we're also developing, additionally, selective PKEs for other CYP isoforms that may be able to be applied outside of the HIV space and antiviral space in general.

Brian Kearney: Our plans [for GS-9350] are most developed for the HIV program right now, but we are looking at opportunities in other therapeutic areas, including HCV.

John Mellors: Thank you very much.

This transcript has been lightly edited for clarity.

References

1. Kearney B, Mathias A, Lee M, et al. GS-9350: A Pharmaco-enhancer without Anti-HIV Activity. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 40.
2. Guttendorf R, Gulnik S, Eissenstat M, et al. Preclinical and Early Clinical Evaluation of SPI-452, a New Pharmacokinetic Enhancer. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 41.

http://www.thebody.com

February 8, 2009

While at CROI 2009, I had the opportunity to sit down with Robert Siliciano, M.D., one of the world's foremost researchers on the topic of HIV eradication. In August 2008 at the XVII International AIDS Conference, Siliciano offered evidence that modern HAART had essentially stopped viral replication in a patient's body. Here at CROI 2009, Siliciano presented further findings to suggest that residual viremia in patients with a suppressed viral load on HAART was caused by as-yet-known reservoirs of HIV. I asked him about these findings and other developments in his field.

How have things changed since the summer? Have there been any new understandings about eradication? There's been a lot of talk about the Swiss statement, there's a lot of talk about the cure -- the so-called "Berlin patient."

Robert Siliciano, M.D

The Berlin patient: Since that hasn't been published, I don't want to comment on that. But there is a big swing in interest in eradication. I think people are now realizing that we need to put some energy into this and try to do it.

It's going to be very difficult. To me, the most encouraging thing is the fact that the drugs will stop replication. This is still very controversial. But unless you can stop replication, it's never going to work.

Why is this controversial?

I think when virologists see a virus in the blood, they think it's got to be replicated. It's a different concept to say that the virus in the blood is coming from a cell that was infected 10 years ago, before the patient started HAART. It's conceptually very difficult for people to understand.

A virus has a very short half-life. You think it's being produced by a cell that just got infected, and the whole thing is a cycle that keeps going and going. So this is a very different concept, and I think people have a hard time understanding it.

I notice that at CROI there are going to be some studies about the detection in seminal fluid of HIV [despite an undetectable viral load in the blood], and about how that poses some risk for transmission. Can you talk about that?

There are latently infected cells, essentially, all over the body, and they pose in principle a risk for transmission even in a patient who's doing well on treatment. I think quantitatively the risk is very low, but it's still there.

But there seems to be a reluctance by medical professionals in America to discuss this. In Europe, they're more willing to talk about it.

Well, there are good studies of the relationship between viral load and the chance of transmission. Basically, it's just like you would think: the more virus, the more chance of transmission. When the viral load is very low, the chance is low, but you don't want to tell patients that there's no risk because, in fact, there is a risk.

I think it's a bit hard to quantitate, and that's not really my expertise. I think the safest thing to say is that it's a low chance but you should always take precautions. Right?

A lot of people get confused when you're talking about eradication versus "the cure." Is there any difference?

No. Eradication means that there's no more virus.

And it will not come back if you stop treatment. [Dr. Siliciano nods.] OK. So what are the steps that must be taken to reach that?

There are three steps. You have stopped the virus from replicating -- that's done, in my opinion. Second, you find all the reservoirs. We know at least two exist. And then third, you find a way to get rid of each one. Those are going to be very difficult to do.

How many reservoirs are there?

We don't know. But the one that we identified a long time ago in resting T cells is there in everybody. But there appears to be a second one, and there may be others, as well.

Is anyone currently doing that work?

A lot of groups are trying to target the latent reservoir in resting T cells with small molecules.

How close are we to this understanding?

We're not close because we don't even know how many reservoirs there are, and we don't know how to get rid of them -- any of them -- yet. I think one optimistic recent development -- not published yet by our group, but other versions have been published by others -- is that there are model systems in which you can generate these latently infected cells in a test tube. That makes a big difference, because now you can begin to use those to screen for drugs that might target these reservoirs. That's what we're doing and I think that's going to really help.

Have the reservoirs in elite controllers of HIV been studied, as well?

They are hard to study because they are much smaller. It's hard enough to study the reservoir in a patient who is not an elite controller. They probably have reservoirs, but they are extremely small.

You mentioned before why eradication is suddenly being talked about again. Could it also be because the antiretroviral pipeline is somewhat dry?

I think the pharmaceutical companies are realizing that they have very good drugs now, but they're never going to cure anybody. They're going to keep people healthy if they take the drugs, but they're never going to cure anybody. So now I think it's natural that people would say, "Well, the next step is to try and go after the reservoirs."

But it's a funny moment in time, because the pipeline is kind of dry, and we don't know what's going to happen when these patients become resistant to all these new drugs.

Yes, but I would say that resistance is not inevitable. There's this whole argument of whether HAART stops replication. If HAART stops replication, resistance will never arise if the patients [continue to] take the drugs. Now, of course, if the patients don't take the drugs, then all bets are off -- if they don't take them correctly.

Right. And that seems like an ongoing problem.

It certainly is a problem, but as John Mellors mentioned, resistance is decreasing, which is quite amazing, in the U.S. That's because the newer regimens are easier to take and they don't have so many side effects, so patients actually take them.

What will happen five years from now, who knows? Ten years from now? It's hard to say.

We have a new way of evaluating the antiviral activity of drugs, and it allows us to estimate how well the drugs are going to control replication in vivo. In this analysis, certain protease inhibitors have an extraordinarily high potential, on the order of 10 logs, 10 billion-fold inhibition.

But for two classes of drugs, the nucleoside analogs and the integrase inhibitors, there's an intrinsic limitation that keeps those drugs from reaching that same high level of inhibition. The rapid drop in viral load seen by patients on raltegravir [Isentress] is really just a consequence of the fact that the drug acts later in the life cycle. Drugs acting later in the life cycle automatically produce a more rapid drop in viral load, even if they're not any more potent than other drugs.

So how do you explain the head-to-head comparison between raltegravir and efavirenz [EFV, Sustiva, Stocrin]?

I think it's a consequence of the fact that the drug is used in combination and in both of those combinations, what we call the inhibitory potential is sufficient to completely stop replication. Once you stop replication, it really doesn't matter if you have a regimen that has the ability to stop, let's say, 14 logs of replication. If there's only 6 logs occurring, it doesn't really matter. Both of those combinations have reached the limit where they control all the replication that's occurring.

In terms of raw antiviral activity: All of the integrase inhibitors have this intrinsic limitation that puts them, in terms of raw antiviral activity, below the best protease inhibitors.

Do you think this has implications for care, then?

I think this is a basic science finding, the significance of which has to be explored.

This was published where?

We have a paper in Nature Medicine, and in PNAS.

Great, thank you.

This transcript has been lightly edited for clarity.

By Bonnie Goldman, http://www.thebody.com