Saskatchewan Doctors Most Open to New Patients: Report

March 19 2008

Toronto - Canadians who are looking for a family doctor might have better luck in Saskatchewan, the birthplace of medicare, than elsewhere.

A national survey of doctors found that 45 per cent of the family doctors who responded in the province are accepting all new patients who come to them, compared to 41 per cent in Newfoundland and Labrador, 32 per cent in Manitoba and 28 per cent in Alberta.

British Columbia and Nova Scotia came in at 21 per cent, with Quebec not far behind at 19 per cent.

Only 14 per cent of the family physicians surveyed in Ontario and New Brunswick said they are taking all new patients. The situation appeared to be most dire in Prince Edward Island, where only two per cent of doctors surveyed said their doors are wide open to all new patients.

Dr. Tom Gabruch, head of the Saskatchewan chapter of the College of Family Physicians of Canada, said the province has a higher proportion of rural physicians than many other provinces.

"In rural areas, you don't have the luxury as a physician of not accepting patients," he explained.

"It's expected or anticipated you need to take on all the members of the community, so they can't say 'no' out in small-town Saskatchewan."

Initial details from the National Physician Survey were released in January and this regional breakdown was distributed Tuesday.

The survey was funded by the Canadian Medical Association, the College of Family Physicians of Canada, the Royal College of Physicians and Surgeons of Canada, the Canadian Institute for Health Information and Health Canada.

Seventy-two per cent of the P.E.I. family doctors rated their patients' access to an ophthalmologist as fair to poor.

"It is a problem and has been for a little while," Dr. Alfred Morais, head of the P.E.I. chapter of the College of Family Physicians of Canada, said from Charlottetown.

"It's one of the specialty areas where there can be quite a delay," he said, adding that these delays are not for anything that's urgent or critical.

Morais said he was surprised to see the statistic suggesting that only two per cent of P.E.I doctors are taking "all new patients."

Another question that was posed found that 27 per cent were not taking any new patients.

"So the converse of that would suggest that 73 (per cent) are taking some new patients in some capacity," Morais explained. "I think that's probably more accurate of what's happening."

"What I'm seeing in a lot of practices is they will end up taking new patients, but it's usually in a different way. Maybe it's a family member or a relative or a connection of someone they're currently looking after."

Some doctors will take new people moving to the province even though their practice is technically not open for all comers, he added.

In Ontario, 71 per cent of GPs surveyed said they felt their patients' access to a psychiatrist was fair or poor.

In Saskatchewan, 30 per cent of the doctors surveyed said access to cancer care was poor to fair, while only three per cent of the P.E.I. doctors said the same.

"We have a very good oncology unit that's well staffed and it seems to be well functioning because our accessibility seems to be pretty reasonable," said Morais.

In Saskatchewan, Gabruch said he suspects there's a longer waiting time to see an oncologist.

"I think that would go back to recruitment and retention of physicians and that might tie in with remuneration also. I know the cancer clinic struggles to maintain a full complement of oncologists."

In a statement, Dr. Brian Day, head of the Canadian Medical Association, said workforce planning in the health-care sector must be addressed to improve access to health care for patients "no matter where they live."

By The Canadian Press, www.ctv.ca

Cutting Funding Equals Cutting Lives

A statement by AIDS Service Organizations in Alberta, Quebec and Ontario

March 19, 2008

Toronto - A life saving post card campaign is being launched by people living with HIV/AIDS, their friends, families and service organizations in Alberta, Ontario and Quebec after the Federal government slashed community HIV funding across the country.

This HIV funding is used to provide direct services to the 62,000 Canadians living with HIV/AIDS and for implementing education programs designed to prevent new HIV infections. 2,508 Canadians were diagnosed with HIV in 2006, 14% more than were diagnosed in 2001. It is estimated that approximately 4,000 Canadians are actually newly infected with HIV each year. There still is no cure for AIDS; it continues to be a debilitating and fatal illness.

Ontario alone lost 30% of its promised federal funding with a $1 million cut in funding for programs to prevent HIV and to provide support services for people who are already infected. Quebec lost 24% of its funding and Alberta AIDS Service Organizations still have no commitment from the federal government to continue their funding which expires March 31, 2008.

AIDS Service Organizations in Alberta, Quebec and Ontario are united in urging Canadians to send a message to Prime Minister Stephen Harper and to their Members of Parliament that, Cutting Funding=Cutting Lives.

"Given a commitment by all of Canada's major political parties to double the funding by 2008 we were shocked when we learned of the cuts" said Sue Cress, Chair of the Alberta Community Council on HIV. "Alberta AIDS Service Organizations have not received an increase in funding since 2004. Instead of an expected increase this year, we will have a decrease from last year's amounts."

The Federal Initiative on HIV/AIDS promised to increase funding from $42.2 million to $84.5 million by 2008-09. The government's own figures show that $7 million will be cut from front-line service organizations at the national and regional levels over a 5 year period. These cuts are occurring as HIV/AIDS-related programs and services are experiencing dramatic increases in demand both because of the number of new infections and because people with HIV are living longer. In fact there was a 43% increase in demands for service between 1993 and 2003.

Lyse Pinault, General Director of Quebec's Coalition des Organismes Communautaires Quebecois de Lutte Contre le SIDA(COCQSIDA) stated, "Quebec has never before received a funding cut to our HIV/AIDS prevention and support services from any previous Federal government. The cost of preventing HIV is much cheaper than the cost of expensive medications to treat it."

Every HIV infection that is prevented saves approximately three quarters of a million dollars in direct and indirect costs.

On July 31, 2006, Minister of Health Tony Clement stated in a press release "...HIV/AIDS remains an issue of significant concern for Canada". Despite this assurance AIDS organizations were not given any notice that cuts were coming or a clear explanation as to why these cuts were needed. Information on the Public Health Agency of Canada's website advises that funds have been diverted to a new HIV vaccine program announced by the Prime Minister and Bill Gates on February 20, 2007.

According to Rick Kennedy, Executive Director of the Ontario AIDS Network, "Vaccine research is important for our future, but it should not come at the expense of people who are infected with HIV/AIDS. Our lives should not be any more expendable than people living with other serious health conditions. It is hard to imagine the government cutting support services for people with cancer or other very serious diseases to invest in research that may or may not prove life saving. An AIDS vaccine is many, many years into the future. What happens to our health now?"

Twenty-two years ago on December 10, 1986 a World Health Organization specialist announced that human testing of an AIDS vaccine would begin the following year. A vaccine for AIDS is still decades away. We need more vaccine research and ultimately a cure. However, Canada must not regress and reduce its efforts to prevent new HIV infections and save lives now, before a vaccine is found. Cutting Funding=Cutting Lives. Funding must be restored to the levels promised in the Federal Initiative.

We are calling on all Canadians to join us in letting the Prime Minister and his government know that these cuts are hurting Canada's ability to stop AIDS.

Send a message to the Prime Minister and Members of Parliament that HIV prevention, education and support services are important. Postcards for the "Cutting

Funding=Cutting Lives" campaign can be obtained in French or English at www.increaseaidsfunding.ca

For further information: AIDS Calgary Awareness Association, Susan

Cress, Executive Director, Tel) (403) 508-2500 ext 118,

scress@aidscalgary.org, www.aidscalgary.org; Quebec's Coalition des organismes

communautaires québécois de lutte contre le sida (COCQSIDA), Lyse Pinault,

General Director, Tel) (514) 844-2477, www.cocqsida.com ; Ontario AIDS Network,

Rick Kennedy, Executive Director, Tel) (416) 364-4555 ext 308,

rkennedy@ontarioaidsnetwork.on.ca , www.ontarioaidsnetwork.on.ca

http://www.cnw.ca

HIV Vaccine Volunteers Need More Support From Researchers

March 20, 2008

Toronto, Ontario - When it comes to developing a safe, effective vaccine to stem the global AIDS pandemic, researchers agree there is one component they can't do without - volunteers willing to become human guinea pigs for testing the experimental serums.

Tens of thousands of participants will be needed for clinical trials of vaccines aimed at preventing HIV infection, yet one study has found lots of reasons why people might be wary of offering up their bodies to advance this particular cause of science.

That's likely even more the case since the field suffered a major setback last fall, when a promising vaccine developed by pharmaceutical giant Merck not only failed to work in what was known as the international STEP trial, but actually increased the risk of infection in some volunteers.

A group led by Peter Newman, a professor of social work at the University of Toronto, decided to interview a number of people who had volunteered for the Toronto portion of STEP, but decided not to take part after going through the initial enrolment process.

Their reasons, he said, should be a cautionary tale for researchers in any future vaccine-testing endeavors.

``Pretty much, they all had altruistic intentions, that's why they did this in the first place,'' Newman said of would-be volunteers in Toronto, most of them gay men. ``They said they wanted to help find a cure or find something that would prevent this disease ... they had a friend who was ill or had died in the past and they wanted to do their part.''

``That was really across the board. So it's the issue that even despite that and the fact that they came in and said, `Hey I'll do whatever tests I need to do to see if I'm eligible,' they said, `When push comes to shove, I really don't want to do this.'''

In questionnaires and interviews, 13 decliners in Newman's study cited a number of reasons for pulling out, chief among them concerns about coming up positive on an HIV test (even if they weren't actually infected) due to antibodies produced in response to the vaccine.

Respondents saw all kinds of possible repercussions from such a false-positive result, he said. As one explained:

``This could change your life. We are not talking about getting little round spots on your hands or something. We are talking about showing up positive. How can you tell your doctor, your insurance company? Like, how do you deal with that? Because this has a huge stigma for people.''

A couple of subjects who decided against enrolling in the trial had contacted private medical insurance providers and were told they would not be eligible for some coverage if they took part, he said.

Some worried that a false positive might hurt their ability to get life insurance; others feared being denied entry to the United States (non-citizens with HIV are inadmissible by law) to work or visit friends and family.

Still others were concerned about their relationships, Newman noted. ``They said, `How am I going to explain to my partner? How am I going to explain to some guy I might meet and really like, you know I'm positive but I'm not really?'''

His study, recently published in the journal Vaccine, found that fears about possible side-effects from taking an investigational vaccine, inadequate remuneration and committing several years to a particular trial also tipped the balance against participating.

Jose Sousa, chair of the community advisory committee for the Canadian HIV Trials Network, called the concerns raised by the Toronto respondents ``pretty right on,'' and said they are surprisingly representative of the broader community of people at elevated risk for HIV and thus candidates for vaccine trials.

``The big thing is being antibody-positive afterwards and insurance,'' Sousa said from Montreal. ``You don't know it's a false positive until it's double-checked and insurance (companies) don't do that.''

Newman suggests future trials should be set up to provide more support for those people willing to roll up their sleeves for experimental inoculations, including free psychosocial counseling; an ombudsman to deal with insurers and other institutions; and reasonable payment for time, effort and risks involved with the research.

They are suggestions that scientists should not ignore, advised Sousa. ``If they want their studies completed, they better listen to the community.''

Addressing such concerns will be critical for future vaccine research, agreed Dr. Alan Bernstein, executive director of the Global HIV Vaccine Enterprise in New York, especially since the STEP trial results may have made potential volunteers gun-shy about coming forward.

``So if volunteers think the next trial is either not going to work or fail, then they're going to be increasingly resistant to volunteer for trials because they'll figure the scientists have lost their way and don't really know which way to go.''

Yet Bernstein doesn't view the STEP trial as a failure _ as many have called it _ but a learning experience that will help researchers refine the next generation of test vaccines.

``I think the failure has been our expectation that one vaccine trial would be a home run, would give us a vaccine ... So I think we have to convey to the communities who are potential volunteers that this is a long, incremental journey and a learning journey _ and we need their help.''

Dr. Rafick-Pierre Sekaly, a vaccine researcher at the University of Montreal, agreed that the STEP trial may mean some people will be leery of getting involved in subsequent research.

Yet, even with pre-testing in laboratory animals, scientists cannot foretell how a person's immune system will react to an inoculation, Sekaly said. ``The primate model is not a predictor, the mouse model is absolutely by no means a predictor.''

``The only way to know if a vaccine is going to work or not is by going into humans.''

By The Canadian Press, www.365Gay.com

Bill to Repeal HIV Immigration Ban Wins Key Committee Approval

March 13, 2008

Washington -The Senate Foreign Relations committee on Thursday approved legislation that would repeal a travel and immigration ban on people with HIV. The measure now moves to a full vote on the Senate floor.
The ban was originally enacted in 1987, and explicitly restated in 1993, despite efforts in the public health community to remove the ban when Congress reformed U.S. immigration law in the early 1990s.

The travel and immigration ban prohibits HIV positive foreign nationals, students, and tourists from entering the U.S. unless they obtain a special waiver that only allows for short term travel. Current policy also prevents the vast majority of individuals with HIV from obtaining legal permanent residency.

While immigration law currently excludes immigrants with any "communicable disease of public health significance" from entering the U.S., only HIV is explicitly named in the statute. For all other illnesses, the Secretary of Health and Human Services retains the ability, with the medical expertise of his department, to determine which illnesses truly pose a risk to public health.

The HIV Non-Discrimination in Travel and Immigration Act was attached to the President's Emergency Plan for AIDS Relief, known as PEPFAR by its Senate sponsors, Sens. John Kerry (D-Mass.) and Gordon Smith (R-Oregon).

A House version is sponsored by Rep. Barbara Lee (D).

Immigration Equality said it is confident the legislation will pass the full Senate when it comes to a vote.

"The United States has enforced this antiquated policy for too long with no public health rationale for discriminating against HIV-positive people in such a severe manner." said Victoria Neilson, Immigration Equality's Legal Director.

"We are confident that this vote by the full Senate will be successful and will move the United States one step closer to lifting the HIV immigration ban."

The administration has acknowledged there are problems with the current system but White House proposals to amend the law still present roadblocks.
There are 12 proposed requirements of visitors and immigrants to this country who have HIV. They would require disclosure of HIV status to consular officials in the individual’s home country; certification that the individual has in their possession all medication necessary for the duration of their stay in the U.S.; certification that no symptoms are being exhibited; and a commitment to avoid all high risk behavior while in the U.S.

In addition it is left to the discretion of the consular officers who often do not have the medical knowledge to make these decisions. No guidelines are given on how to make these determinations and there is no appeal process. If an HIV positive individual is given asylum in the United States, that person is not allowed to obtain a green card or become a U.S. citizen – even if their asylum was given because of their HIV status.

The United States is one of only 13 countries that have an HIV travel ban.

PEPFAR, the bill the measure is attached to provides for spending of $50 billion over the next five years to combat the health crises posed by AIDS and other diseases in Africa and elsewhere in the world.

www.365Gay.com

AP/Montgomery Advertiser Examines Debate over Segregating HIV-Positive Inmates from General Prison Population

March 19, 2008

The AP/Montgomery Advertiser on Monday examined issues surrounding the segregation of HIV-positive inmates from the general prison population. Regulations in two prisons in Alabama previously restricted HIV-positive inmates from participating in some activities -- such as eating, worshiping and visiting family members -- with other inmates. Prison officials in November 2007 announced that they planned to eliminate some of the restrictions.

However, space issues at one of the prisons have kept some of the regulations in place, according to Margaret Winter, associate director of the American Civil Liberties Union's National Prison Project. Winter said that inmates living with HIV/AIDS must visit with their families in a separate visiting area and sit in separate pews during chapel services. Alabama Prisons Commissioner Richard Allen said the segregation is a "security issue," adding, "One thing we don't want to do is put the [HIV-positive inmates] in a situation where other inmates want to retaliate against them."

Integration of HIV-positive people into the general prison population has "gone much more smoothly" at the second prison, according to the AP/Advertiser. In addition, Allen said the Department of Corrections has started classes to help educate prisoners about HIV/AIDS, as well as to address related stigma and misconceptions about the disease. Winter said ACLU is recommending that the department offer 90 days of "intensive HIV education," adding, "I think we feel strongly that without that, it could be another 20 years" of inmate segregation. ACLU is advocating for HIV-positive inmates in Alabama to be allowed to participate in work release programs. "It's going to take some time," Allen said, adding, "It may take several sessions. We're committed to getting the attitudes changed" (Hunter, AP/Montgomery Advertiser, 3/17).

http://www.kaisernetwork.org

U.K. Crown Prosecution Service Issues Guidelines to Clarify Law on Intentional, Reckless Transmission of HIV

March 18, 2008

The United Kingdom's Crown Prosecution Service on Friday issued guidelines to clarify a law on intentionally or recklessly transmitting HIV, London's Daily Mail reports. According to the guidelines, cases of intentional or reckless HIV transmission will only be brought against people who transmit the virus to a series of sexual partners or against people who have transmitted the virus to a partner during a period of regular high-risk sex.

The rules state that it will be necessary to prove a "sustained course of conduct" in order to find a person guilty of intentionally spreading HIV. They add that it will be unlikely that "the prosecution will be able to demonstrate the required degree of recklessness in factual circumstances other than a sustained course of conduct during which the defendant ignores current scientific advice regarding the need for and the use of safeguards" (Doughty, Daily Mail, 3/15). The rules also state that people associated with such cases should be treated sensitively and told about "special measures," which can be used in court to make the experience less traumatic, Metro.co.uk reports. "We appreciate too that those who are defendants in these cases may be seen as victims themselves, as they also have the infection that they are alleged to have transmitted to another person," the rules state.

Ken MacDonald, director of CPS' public prosecutions, said, "Although these types of cases are rare, we are publishing this statement because we recognize the importance of consistent decision-making," adding, "We hope that it provides clarity" (Metro.co.uk, 3/14). According to the Mail, 11 cases of intentional HIV transmission have been prosecuted in England, 10 of which resulted in convictions. David Green of the London-based think tank Civitas warned that the new rules could encourage risky behavior among HIV-positive people. An HIV-positive person "who has sex in those circumstances is subjecting the other person to a potentially deadly illness and to suffering over a long period of time," Green said, adding, "These rules are too lenient, and they will lead people to think they will not be prosecuted" (Daily Mail, 3/15).

The new rules are available online here: http://www.cps.gov.uk/publications/prosecution/sti.html

http://www.kaisernetwork.org

THT Launches Tests and Treatments by Post

March 20, 2008

Sexual health charity Terrence Higgins Trust (THT) is to offer a range of paid-for sexual health tests and treatments.

THT by Post offers testing and treatment for chlamydia and gonorrhoea, testing for HIV and treatment for genital herpes and non-specific urethritis.

The service also offers a free online consultation to assess a man's suitability for impotence treatment and follow-up postal impotence treatment if appropriate.

Peta Wilkinson, Executive Director of Services at Terrence Higgins Trust said:

"Some people find going to a sexual health clinic inconvenient or embarrassing so we wanted to make it easier for those people to test.

"This new service is easy and quick to use.

"We hope that by offering the choice of tests and treatment that you can use at home, we'll be able to bring down the number of people with undiagnosed infections."

Online medical service DrThom has teamed up with THT to provide the service.

The tests involve taking either a saliva or urine sample at home and posting it off to a lab to be analysed.

The results are given differently depending on the test but most are uploaded to a private, password protected web page, often within two days of the sample arriving at the lab.

Those who receive a positive result for chlamydia and gonorrhoea will be sent free antibiotic treatment through the post and can receive medical aftercare from DrThom.

The tests, treatment and other sexual health services can be ordered online from thtbypost.org.uk

By Tony Grew, http://www.pinknews.co.uk

Study: TB Vaccine via Inhaler Effective

March 17, 2008

Chapel Hill, N.C - A new dry powder tuberculosis vaccine administered using an inhaler is as effective as the TB vaccine commonly used worldwide, a U.S. study said.

Researchers at the University of North Carolina at Chapel Hill School of Pharmacy said the vaccine is spray dried instead of freeze dried. Spray drying is the process of spraying a liquid through a heated gas such as nitrogen to create a powder. Spray dried vaccines don’t need refrigeration or water to be used.

Traditional TB vaccines are freeze dried, requiring refrigerated storage and transportation, and a source of clean water to reconstitute the vaccine for injection, study leader Tony Hickey said.

"The real advantage is that this vaccine does not need to be refrigerated," Hickey said in a statement. "It also doesn’t require needles, syringes and water like the injectable vaccine, and administering it is as easy as breathing in, making it ideal for use in developing countries."

Hickey, an expert in the delivery of vaccines and medicines via dry aerosol, said that breathing in a TB vaccine is beneficial because inhalation is the way tuberculosis is contracted.

The findings are published in the Proceedings of the National Academy of Sciences.

United Press International

Genetic Switch: Two Studies

a. Zinc-Finger Proteins Promise New Treatment For HIV/AIDS

March 18, 2008

London - A kind of protein called zinc-finger proteins which can turn genes on and off permanently may transform treatment of HIV/AIDS, heart disease and diabetes, British newspaper The Times reported on Tuesday.

Sangamo BioSciences, a company in California, has already developed several drugs based on the zinc-finger proteins discovered and named in 1985 by Aaron Klug of the Laboratory of Molecular Biology in Cambridge, England, The Times said.

"We can use this technique to change the function of a single gene permanently. The beauty of zinc-finger nuclease lies in their simplicity. Where other methods are long, arduous and often messy, it is relatively easy to switch off genes using this method," Klug was quoted as saying.

The first Sangamo drugs designed to target genes have begun clinical trials in the United States on patients with arterial disease and diabetes-induced nerve damage.

The most advanced of the drugs uses a zinc-finger nuclease - an enzyme - to treat diabetic neuropathy, a common complication of diabetes that causes nerve damage and pain. The drug binds to a gene called VEGF-A, known to protect the nervous system, and switches it on to prevent nerve damage. Phase 2 trials of the drug are underway.

The same gene is also being targeted to treat peripheral arterial disease, which causes blocked arteries in the limbs. A zinc-finger drug that has started safety trials aims to stimulate VEGF-A activity, which can promote the growth of new arteries.

According to the report, a third trial for HIV is due to begin within months.

If the trial is successful, scientists predict that the technique could change the way many diseases are treated, making genetic therapies a routine part of medicine for the first time.

Klug said that in the longer term, a similar approach might be used to grow new blood vessels in the heart.

http://www.chinadaily.com

b. Researchers Find Promise in HIV 'Switch'

March 18, 2008

If the battle against HIV, the virus that causes AIDS, is a chess match, then new research gives new insight into one of the virus' most important moves.

The findings, by University of Tennessee, Knoxville, and Oak Ridge National Laboratory researchers Michael Simpson and Roy Dar, with colleague Leor Weinberger who led the research at the University of California, San Diego, reveal new information about how a critical genetic switch in the virus operates. They are published as a letter in the upcoming issue of Nature Genetics.

When HIV infects an immune cell, it can enter one of two states: activation, where the virus replicates and then destroys the host cell; and latency, where the viral genetic material continues to exist in the cell, but there is no production of additional virus.

"While latency is a ticking time bomb," said Simpson, "a possible therapeutic goal could be to stably maintain latency indefinitely."

Previous work by Weinberger found that the genetic circuit that controls whether HIV chooses to go active or latent is not a simple "on-off" switch, but instead is controlled by a type of genetic pulse -- when the pulse lasts a certain amount of time, the switch will activate replication of the virus.

Now the three researchers have demonstrated that it is possible to manipulate the lengths of the pulses in a way that would favor the selection of latency.

This is vital, said Simpson, because the switch is a definitive factor in whether the virus will become active. If the pulse does not last long enough, he said, the virus cannot become active.

"This is an early step, but an encouraging one," said Simpson. "HIV has evolved a very effective infection strategy, so the name of the game is understanding how that strategy operates in order to find a way to defeat it."

A challenge of the work, according to Simpson, is that the process involved in how the switch operates cannot be directly observed. Instead, the researchers had to rely on an analysis of the "noise" created within the cell by the process to determine how it worked.

Simpson and Dar conducted their work in the Center for Nanophase Materials Science at ORNL, a recently opened facility that Simpson says has made this type of analysis possible.

Moving forward, the next step in the research is to determine whether it is viable to attempt to control the switch as part of therapeutic treatment for HIV. The researchers also hope to apply the techniques they used to understanding the operation of other types of human cells.

http://www.medicalnewstoday.com

Researchers Develop Method to Rapidly ID Optimal Drug Cocktails

March 18, 2008

UCLA researchers have developed a feedback control scheme that can search for the most effective drug combinations to treat a variety of conditions, including cancers and infections. The discovery could play a significant role in facilitating new clinical drug-cocktail trials.

The best known use of drug cocktails has been in the fight against HIV, the virus that causes AIDS. Drug cocktails also have been used to combat several types of cancer. Often, drugs that might not be effective in combating diseases individually do much better in combination.

With the use of the new closed-loop feedback control scheme, an approach guided by a stochastic search algorithm, researchers at the UCLA Henry Samueli School of Engineering and Applied Science and UCLA's Jonsson Comprehensive Cancer Center have devised an invaluable means of identifying potent drug combinations fast and efficiently. Their findings appear in the March 17 online version of the journal Proceedings of the National Academy of Sciences.

It has long been a difficult challenge for clinical researchers to determine the optimal dose of individual drugs used in combination. For example, a researcher testing 10 different concentrations of six drugs in every possible arrangement would be faced with 1 million potential combinations.

"With the development of this optimization method, we've overcome a major roadblock," said study author Chih-Ming Ho, UCLA's Ben Rich-Lockheed Martin Professor and a member of the National Academy of Engineering. "There have always been too many choices and too many combinations to sort through. It was like finding a needle in a haystack."

In one test case, the research team examined how to best prevent a viral infection of host cells. Using the closed-loop optimization scheme, they were able to identify, out of 100,000 possible combinations, the drug cocktails that completely inhibited viral infection after only about a dozen trials. In addition, they found that total inhibition of the virus occurred at much lower drug doses than would be necessary if the drugs were used alone; in fact, the concentrations of the drugs were only about 10 percent of that required when used individually.

"Viruses grow very rapidly and change rapidly as well. Because of that, a virus can become resistant to a particular drug," said Genhong Cheng, a member of the research team at the UCLA Center for Cell Control and UCLA's Jonsson Comprehensive Cancer Center. "This is why it's so important to be able to use a combination of more than one drug. If the virus mutates to become resistant to one drug, it is still sensitive to the other drugs."

Drug combinations can also be used effectively to inhibit infectious diseases because resistance to a single drug is very common, according to Ren Sun, UCLA professor of molecular and medical pharmacology and a member of the research team.

"If we can apply multiple drugs against one infectious agent, it probably will prevent the occurrence of drug resistance," said Sun, who is also a researcher at the Jonsson Cancer Center. "But, of course, when you use multiple drugs, side effects will be strong. With this model, there is a way to optimize the combination to reduce the side effects while maintaining efficacy that will be very beneficial."

"What the search scheme does is it tries to detect trends for optimal output," said Pak Wong, a former UCLA graduate student who participated in the study and is now an assistant professor of mechanical engineering at the University of Arizona. "Basically, the algorithm sees a trend and a direction and drives the trend in that direction. It's like mountain climbing and finding a way to get to the peak. So you keep going, and soon you rapidly find the peak while being guided by a smart search scheme."

In an example used to illustrate the prevention of viral infection of host cells, researchers started with arbitrarily chosen dosages of the drugs. The percentage of non-infected cells under this initial drug-cocktail treatment was fed into the stochastic search algorithm, which essentially helps guide a random search process. The algorithm then suggested the next drug concentrations for producing a higher percentage of non-infected cells. This closed-loop feedback control scheme is carried out continuously until the best combination is found. Randomness is built into the search decision, preventing the trap at local optimum levels and allowing the search process to continue until the optimal drug cocktail is identified.

The model also provides an alternative approach to studying cellular functions. Molecular biologists can identify all the players of a particular regulatory pathway in order to decipher how to block or augment that pathway. Cells are complex systems with many redundant functions, and it is difficult to predict how a cell will respond to multiple stimulations at one time. The model overlooks these details and lets the system determine what works best for itself. If researchers are more interested in how the cellular network functions, this approach can provide an initial bird's-eye view, but it also allows them to home in on the important molecular activities controlled by the best drug combinations.

This search scheme is an extremely effective and versatile tool that can be applied to combat numerous diseases, including cancer, the researchers say, and its multidimensional properties will likely make it useful in a wide variety of additional situations.

The next steps are animal and clinical testing.-University of California - Los Angeles

http://www.huliq.com

Tenofovir Has Good Concentrations and Anti-HIV Effect In Semen

March 17, 2008

Tenofovir (Viread) rapidly suppresses HIV in semen and could help prevent the sexual transmission of HIV, according to a small study published in the March 1st edition of the Journal of Acquired Immune Deficiency Sydromes. Levels of tenofovir in semen were several times those seen in blood.

The risk of the sexual transmission of HIV is associated with the level of HIV in the male and female genital tract. There is also some evidence that the male genital tract acts as a “reservoir” for HIV, with the virus reproducing there independently to the blood . Therefore, anti-HIV treatment that gets into the genital tract could reduce HIV viral load and the risk of transmission, and also the help reduce the risk of drug drug-resistant HIV developing.

Tenofovir is a powerful anti-HIV drug that belongs to the nucleotide reverse transcriptase inhibitor family of antiretrovirals. It is contained in the combination pills Truvada and Atripla and is a popular choice for first-line antiretroviral therapy.

Laboratory studies involving monkeys have shown that tenofovir works against HIV in the female genital tract and studies are currently underway to assess its safety and effectiveness as a microbicide. The drug is used in post-exposure prophylaxis (PEP) regimes and is being invested as pre-exposure prophylaxis (PREP).

But little is known about the ability of tenofovir to get into the male genital tract and to reduce viral load in semen.

Investigators at the University of North Carolina therefore designed a small study involving nine HIV-positive men to measure concentrations of tenofovir in the genital tract after the first and then multiple doses, and to see the effect of the drug on viral load in both the blood and semen.

The study was conducted between 2003 and 2005. All the men had an HIV viral load above 200 copies/ml on entry to the study. Eight of the men were not taking any antiretroviral therapy. These patients were provided with 14 days of tenofovir monotherapy at a standard daily dose of 300mg and then started multi-drug anti-HIV treatment. The remaining patient added tenofovir to an antiretroviral regimen that was failing to suppress his viral load. The study lasted 28 days. Paired blood and semen samples were obtained from the men throughout the study.

After the first dose, concentrations of tenofovir in semen were 4.4-fold higher than those in blood. After subsequent doses tenofovir maintained a higher concentration in semen than in plasma, this concentration being 5.1-fold higher at the end of the study.

But tenofovir could only be detected in the cells of three of these men. In these three patients intracellular concentrations of tenofovir in the genital tract were 9-fold higher than those in peripheral blood mononuclear cells after the first dose of tenofovir and 17.5-fold higher after the seventh dose.

After 14 days of treatment, median viral load was 866 copies/ml in blood and below 400 copies/ml (the lower limit of detection) in semen in the eight men who received monotherapy. The magnitude of the fall in viral load in blood and semen from baseline was comparable at approximately 1 log10 copies/ml.

The single patient who added tenofovir to his existing antiretroviral regimen had an undetectable viral load in his semen for the duration of the study. The viral load in his blood was 366 copies/ml on entry to the study and 709 copies/ml at the end of the study.

Resistance tests were conducted in the four patients who had a tenofovir viral load above 1000 copies/ml in blood (four patients) or semen (one patient). No patient developed the K65R mutation that confers resistance to tenofovir.

On the basis of these findings the investigators conclude that tenofovir may have the potential “to reduce the sexual transmission of HIV.”

Reference

Vourvahis M et al. The pharmacokinetics and viral activity of tenofovir in the male genital tract. J Acquir Immune Defic Syndr 47: 329 – 333, 2008.

By Michael Carter, www.aidsmap.com

Discovery of How HIV's Stealth Protein Gets Into Cells

18 Mar 2008

Scientists have known for more than a decade that a protein associated with the HIV virus is good at crossing cell membranes, but they didn't know how it worked. A multidisciplinary team from the University of Illinois has solved the mystery, and their findings could improve the design of therapeutic agents that cross a variety of membrane types.

A paper describing their findings appears this month in Angewandte Chemie.

The TAT protein transduction domain of the HIV virus has some remarkable properties. First, it is a tiny part of the overall TAT protein, containing only 11 amino acids. Second, and more important, it has an uncanny knack for slipping across membranes, those lipid-rich bags that form the boundaries of cells and cellular components and are designed to keep things out.

"TAT is extremely good at getting through cell membranes," said materials science and engineering professor Gerard Wong, who led the new study. "You can attach TAT to almost anything and it will drag it across the membrane. It can work for virtually all tissues, including the brain."

The TAT protein's versatility makes it desirable as a drug-delivery device. It is already being used for gene therapy. (TAT is not involved in transmitting the HIV virus; it only aids the passage of other materials across the membranes of infected cells.)

Because it has so many potential uses, scientists have long endeavored to understand the mechanism that allows the TAT protein to work. But their efforts have been stymied by some baffling observations.

Six of its 11 residues are arginine, a positively charged amino acid that gives the protein its activity.

Most membranes are composed of a double layer of neutral, water-repellent lipids on their interiors, with hydrophilic (water-loving) "head groups" on their internal and external surfaces. The head groups generally carry a mildly negative charge, Wong said. Since opposites attract, it made sense to the researchers that the positively charged TAT protein would attract the negatively charged head groups on the surface of the membranes. This attraction could deform the membrane in a way that opened up a pathway through it.

If a short, positively charged protein was all that was needed for TAT to work, the researchers thought, then any positively charged amino acid should do the trick. But when they replaced the arginine in the protein with other positively charged amino acids, it lost its function. Clearly, a positive charge was not enough to make it work.

To get a better picture of the interaction of TAT with a variety of membranes, the researchers turned to confocal microscopy and synchrotron x-ray scattering (SAXS). Although sometimes used in biological studies, SAXS is more common to the fields of physics or materials science, where the pattern of X-ray scattering can reveal how atomic and nano scale materials are structured.

The researchers found that adding the TAT protein to a membrane completely altered its SAXS spectrum, a sign that the membrane conformation had changed. After analyzing the spectrum, the researchers found that TAT had made the membranes porous.

"The TAT sequence has completely reconstructed (the membrane) and made it into something that looks a little bit like a sponge with lots of holes in it," Wong said.

Something about the TAT protein had induced a "saddle splay curvature" in the membrane. This shape resembles a saddle (like that of a Pringles potato chip), giving the openings, or pores, a bi-directional arc like that seen inside a doughnut hole.

The newly formed pores in the membrane were 6 nanometers wide, large enough to allow fairly sizeable proteins or other molecules to slip through. The pores would also make it easier for other biological processes to bring materials through the membrane.

Further analysis showed that the arginine was interacting with the head groups on the membrane lipids in a way that caused the membrane to buckle in two different directions, bringing on the saddle splay curvature that allowed the pores to form.

When another positively charged amino acid, lysine, was used instead of arginine, the protein bent the membrane in one direction only, forming a shape more like a closed cylinder that would not allow materials to pass through.

These findings will aid researchers hoping to enhance the properties of the TAT protein that make it a good vehicle for transporting therapeutic molecules into cells, Wong said.

Wong also is a professor of physics and of bioengineering.

Diana Yates, University of Illinois at Urbana-Champaign

Adapted by http://www.medicalnewstoday.com

SSRI Treatment Improves Adherence and Outcomes in Depressed HIV-Positive Patients

March 19, 2008

HIV-positive patients with depression have poorer adherence to antiretroviral therapy than non-depressed individuals, according to a US study published in the March 1st edition of the Journal of Acquired Immune Deficiency Syndromes. The study also showed that depressed patients were less likely to achieve good suppression of HIV with anti-HIV treatment than non-depressed patients.

But the study also showed that treatment with SSRI (selective serotonin reuptake inhibitor) antidepressants was of value, with their use improving adherence to treatment. Furthermore, SSRI treatment boosted the chances of depressed patients achieving good viral suppression and increases in CD4 cell count.

SSRI treatment for depressed individuals has recently been the subject of controversy, with suggestions that the drugs are only of value for patients with severe depression. The results of this study suggest that therapy with SSRIs may also be of value to the estimated 30% of HIV-positive patients diagnosed with depression.

Adherence is the single most important factor under a patient's control influencing the success of their antiretroviral therapy. Mental health problems can have a negative impact on adherence, and depression is considered to be a risk factor for non-adherence to anti-HIV treatment.

Depression is widespread amongst patients with HIV and has also been shown to be associated with earlier death.

Investigators wanted to see if treatment with SSRI antidepressants improved adherence to antiretroviral therapy amongst depressed patients. They also wanted to see if such treatment for depression had an effect on viral load and CD4 cell counts.

They therefore performed a retrospective study involving patients who received their HIV care from Kaiser Permanente and Group Health Cooperative facilities between 2000 and 2003.

A total of 3359 patients were included in the investigators’ analysis. This included 1398 patients (42%) who had a diagnosis of depression in their medical records, and 508 of these patients had received treatment with an antidepressant from the SSRI class.

Over twelve months, mean adherence for all patients was 81%. For non-depressed patients mean adherence was 83%, compared to 79% for depressed patients who did not receive treatment with an SSRI, a significant difference (p = 0.01).

But mean adherence was 81% for patients treated with an SSRI (comparable to that seen in non-depressed individuals), and was 85% amongst those patients who were also adherent to their SSRI treatment – significantly better than the mean adherence seen amongst non-depressed patients (p = 0.01).

The investigators then looked at the impact of depression and SSRI treatment in viral load and CD4 cell count.

They found that depressed patients without SSRI treatment were significantly less likely to achieve an HIV viral load below 500 copies/ml after a year of anti-HIV treatment than non-depressed patients (p = 0.02). However, depressed patients who received SSRI therapy were just as likely to achieve this virological outcome as non-depressed patients.

Mean CD4 cell count increased by 152 cells/mm3 for the entire cohort. Overall there was no difference in CD4 cell increases between depressed and non-depressed patients. But the investigators found that depressed patients who had good adherence to SSRI therapy not only gained more cells than other depressed patients, but 19 cells/mm3 more than patients who were not depressed, a significant difference (p = 0.01).

Finally the investigators looked at the effect of SSRI therapy on patients who changed antiretroviral therapy. None of these patients had taken SSRI therapy before changing therapy. Taking SSRI treatment with a new antiretroviral regimen was not associated with better adherence, or in better virological control or improved CD4 cell gains.

“We demonstrate that a diagnosis of depression is associated with significantly reduced adherence to HAART regimens”, comment the investigators, adding that “depression was associated with significantly decreased odds of achieving HIV RNA levels below 500 copies/ml.”

The investigators believe that factors other than adherence may affect viral load in patients with depression and suggest “depression itself may affect viral control. Viral control was improved among patients prescribed SSRI medication, even more so if SSRI adherence is considered.”

They also draw attention to the superior gains in CD4 cell count seen in the patients with good adherence to SSRIs. They write, “these results are particularly important, because depression has been associated with earlier mortality in HIV-positive patients.”

“Our results have clinical implications”, add the investigators. They recommend that patients should be screened for depression, and that depressed patients should be offered SSRI treatment, “because compliant SSRI medication use was associated with improved HAART adherence and HIV laboratory parameters.”

Reference

Horberg MA et al. Effects of depression and selective serotonin reuptake inhibitor use on adherence to antiretroviral therapy and on clinical outcomes in HIV-infected patients. J Acquir Immune Defic Syndr 47: 384 – 390, 2008.

By Michael Carter, www.aidsmap.com

Grape Skins Stop Diabetic Complications

March 19, 2008

Plymouth, England - Resveratrol -- found in grape skins -- can stop diabetic complications such as heart disease, kidney disease and blindness, a British study found.

Researchers at the Peninsula Medical School in Plymouth, England, say resveratrol -- also present in seeds, peanuts and red wine -- can protect against cellular damage to blood vessels caused by high production of glucose in diabetes.

Principal investigator Dr. Matt Whiteman says elevated levels of glucose that circulate in the blood of patients with diabetes causes micro- and macrovascular complications by damaging mitochondria -- the tiny power plants within cells responsible for generating energy. When they are damaged they can leak electrons and make highly damaging "free radicals."

"Resveratrol or related compounds could be used to block the damaging effect of glucose which in turn might fight the often life threatening complications that accompany diabetes," Whiteman said in a statement. "It could well be the basis of effective diet-based therapies for the prevention of vascular damage caused by hyperglycemia in the future."

The findings are published in the journal Diabetes, Obesity and Metabolism.

United Press International

Some HIV Subtypes May Carry Natural Resistance To Tipranavir

March 20, 2008

Certain subtypes of HIV may be more likely to have genetic mutations that confer resistance to tipranavir (Aptivus), even in people who have taken no anti-HIV drugs, according to a study in the March 12 issue of the journal AIDS. These findings, the study authors suggest, may have implications for treatment-experienced patients who are working with their doctors to find active agents to include in a new regimen.

The distribution of the different subtypes of HIV varies geographically. Subtype B is common in the developed world and is well studied. Meanwhile non-B subtypes make up a large proportion of cases in some areas. Little is known how resistance patterns in non-B subtypes.

The protease inhibitors (PIs) tipranavir and darunavir (Prezista) are important options for treatment-experienced patients. But their suitability will depend on a patient’s individual resistance profile. Researchers at Hospital Carlos III in Madrid hypothesised that resistance to the two drugs may vary with subtype of HIV, and to test this they undertook a retrospective analysis of drug-resistance assays performed at an HIV laboratory in the city.

The researchers analyzed anti-HIV drug resistance among a total of 1364 samples using both genotypic and phenotypic resistance testing. For genotypic testing, the IAS-USA list was used to identify and assess darunavir mutations, and three lists were consulted to assess tipranavir mutations.

For analysis, samples were grouped by subtype and as either being treatment-naïve or having already been exposed to PIs. Of the total, 1178 samples were subtype B. Of these, 285 were from treatment-naïve patients and 893 from patients who had taken a PI. Non-B subtypes accounted for the remaining 186 samples, with 137 being from treatment-naïve patients and 49 from patients who had received a PI.

Researchers found that darunavir mutations were significantly more common among samples with subtype B (mean number of mutations, 0.4 ± 0.9) than those with non-B subtype (0.06 ± 0.3). Subtype B samples also had a higher mean number of PI mutations than non-B subtype samples (4.9 ± 3.7 versus 4.2 ± 1.8, respectively), and they had been exposed to more PIs (mean 2.5 ± 1.4 drugs for subtype B samples versus 1.2 ± 1.1 for non-B subtype samples).

Conversely, the mean number of tipranavir mutations was significantly higher in samples with non-subtype B (2.7 ± 1 to 3.1 ± 0.9, depending on list used) compared with subtype B (0.7 ± 0.9 to 1.6 ± 1.8). This difference remained when the researchers analysed the treatment-naïve samples separately from the PI-experienced samples.

When researchers evaluated 422 samples from treatment-naïve patients, they found that some tipranavir mutations were significantly more common in non-B subtype samples (range, 4.4% to 97.1%, depending on mutation) then subtype B samples (range, 0.7% to 28.1%). However, they noted that one subtype, a recombinant form of subtypes A and G, comprised 39% of their non-B subtype sample, which likely skewed their findings. In contrast, darunavir resistance mutations were rare among the samples and showed no remarkable differences between subtype B and non-B subtype subtypes.

Phenotypic testing of 29 treatment-naïve samples revealed two samples with resistance to tipranavir, seen as a 2.1 and 2.7 fold-change, respectively. Subsequent genotypic testing revealed that these two samples were subtype F and contained three known tipranavir resistance mutations. The sample with the higher resistance also contained a fourth known resistance mutation. All samples showed no phenotypic resistance to darunavir.

The researchers conclude that non-B subtype subtypes show a relatively high number of tipranavir resistance mutations, even in patients never exposed to PIs. However, only some subtype F subtypes may show reduced susceptibility to the drug. “Based on this observation,” they suggest “it might be worth performing HIV subtyping before considering TPV [tipranavir] in salvage therapy in countries where subtype F is prevalent, such as Brazil, Argentina and Uruguay.”

Reference

Poveda E et al. Evidence for different susceptibility to tipranavir and darunavir in patients infected with distinct HIV-1 subtypes. AIDS 22: 611 – 616, 2008.

By Michael Carter, www.aidsmap.com

Commentary

Let's Get Serious About Drug-Resistant TB

By Dr. Lee B. Reichman

March 22, 2008

It took a high-profile case of an American air traveler with tuberculosis last year to call America's attention to the threat of drug-resistant TB. But as Monday's World TB Day approaches, it appears the United States is finally getting serious about addressing this crisis.

Six years ago, I warned that drug-resistant TB was a ticking timebomb. Most recently, the World Health Organization reported that of the 9 million new TB cases in the world each year, about half a million are MDR-TB. Drug-resistant TB is spreading faster than ever before. Extensively drug-resistant TB (XDR-TB), the most dangerous form of the disease, has now been detected in 45 countries, including the United States. The actual number of countries with XDR-TB is almost certainly higher, since many countries lack the capacity even to make the diagnosis. One has to wonder whether the timebomb has already been detonated.

The key to controlling and halting the spread of drug-resistant TB is the ability to diagnose TB patients in a timely manner, and ensure that they take their full course of medicine. This way, it is ensured that the strain will not return as a more resistant, and therefore more difficult and expensive to treat, form of tuberculosis. With few resources, this can be difficult to manage in developing countries and wealthy countries like the U.S. But programs like our Global Tuberculosis Institute in Newark, N.J., show what is possible when the resources and the will are applied to help control TB.

Recently the World Health Organization's Web site featured Michael Berrian, a 42-year-old homeless man who has benefited from the vigilance of the Newark program. After being diagnosed with TB, he was placed under treatment and kept in isolation at a hospital until he was no longer contagious. Upon release from the hospital, the state branch of the American Lung Association arranged for his stay in a studio apartment for the duration of his six-month treatment.

To ensure Berrian completed his treatment, health worker Rebecca Stevens was assigned by our institute to bring him his medication each day. Stevens also delivered restaurant and grocery store vouchers to Berrian to ensure adequate nutrition during his course of treatment. Thanks to this comprehensive system of support, Berrian is making a complete recovery, and most importantly, his tuberculosis won't turn in to MDR-TB and won't infect anybody else.

With the political commitment and modest investments globally, we can make sure all patients have an uninterrupted drug supply and support to complete treatment. Not only could this save more than 1.5 million lives a year, but it can prevent further drug-resistance.

We have seen what is possible when we have the tools and the data necessary to combat TB, but there's a tremendous gap in resources. Many poor nations with high rates of TB -- especially in sub-Saharan Africa -- lack the capacity to ensure strong programs and lack the ability even to test for drug-resistant TB.

With weakened immune systems, people with HIV/AIDS are far more susceptible to getting sick with TB. With Africa -- where TB is the No. 1 killer of people with HIV/AIDS -- bearing the heaviest burden of the AIDS epidemic, health officials fear the region could become a flashpoint for an epidemic of MDR-TB and XDR-TB that could literally roll back the progress made in AIDS treatment scale-up.

Recognizing the link between TB and the survival of people living with HIV/AIDS, Congress wisely chose to include major funding for global TB efforts in the legislation reauthorizing the president's AIDS Initiative. The House Committee on Foreign Affairs and the Senate Committee on Foreign Relations have passed versions of the U.S. Leadership Against HIV/AIDS, Tuberculosis and Malaria Reauthorization Act of 2008, which would authorize $4 billion over the next five years in critical resources for TB treatment and prevention worldwide. Both bills also make provision to scale up life-saving TB-HIV efforts and allocate $2 billion for the Global Fund to Fight AIDS, TB and Malaria in 2009. As these bills move forward for a full vote by the Senate and House, it is critical that these TB provisions be included.

Years ago, I felt like a voice crying in the wilderness about the perils of drug-resistant TB. While it's gratifying to see that the message has finally gotten through, we must make up for lost time in the race to stop this catastrophe before it spirals beyond control. We may yet still have time to defuse the MDR-TB time bomb.

Lee B. Reichman, M.D., M.P.H., is executive director of the New Jersey Medical School Global Tuberculosis Institute, and is professor of medicine, preventive medicine and community health at the New Jersey Medical School of the University of Medicine and Dentistry of New Jersey in Newark.

http://www.heraldnet.com