July 19, 2010

Reaction to Obama National AIDS Strategy (HCV)

from Jules: below are excerpts from many internet articles on the Obama plan. Here is a response by me. It's only been 30 years since HIV & AIDS was discovered & 15 years since the Ryan White Care Act was implemented HA, and we are still trying to learn how to deal with this problem. It's been NO mystery for many years that African-Americans need extra services because they do not do as well as caucasians on HAART. We've known for years patients are diagnosed late. We spend hundreds of millions on vaccine research & global HIV, yet patients in the USA are on waiting lists to get HAART and ADAP remains underfunded. For USA patients aging & HCV coinfection are key causes in morbidity & mortality and the future predicts this are key concerns that will increase death rates without adequate attention. Sure it's great Obama declared this new strategy, will it be adequately implemented, will it take years to move, what about HEPATITIS C and coinfection, where there is NO FEDERAL FUNDING: 5 million in USA have HCV, the patient population is aging and getting sicker, yet there is NO federal funding for screening, we need a HCV Testing Day!!! Is this new plan just another federal stall effort, the federal response to HCV has been just that for 12 years, with lots of talk saying they support efforts but absolutely no money yet.

The question, the president said, is whether the nation will fulfill its obligations, and devote the resources and political will to confront what he called a preventable tragedy.

Michael Weinstein is president of the AIDS Healthcare Foundation.

"Access to care for HIV is declining in this country," said Michael Weinstein. "You can't say this is a new strategy, if you don't intend to spend any money on it."

Show us the money

Resources to support such expanded efforts are in short supply, however. The administration has dedicated $30 million from the Patient Protection and Affordable Care Act (the recently passed health care reform legislation) for NHAS implementation, but new money is not on the agenda.

"This strategy is a day late and a dollar short," said Michael Weinstein of the AIDS Healthcare Foundation. "Fifteen months in the making, and the White House learned what people in the field have known for years. There is no funding, no 'how to,' no real leadership."

Others also were critical.

"The Obama administration is spending only 4 percent of the National Institutes of Health AIDS research budget to find a cure, they're leaving 2,000 people without AIDS drugs because of a $100 million ADAP shortfall, and they're cutting AIDS treatment in Africa," said AIDS Policy Project Executive Director Kate Krauss. "That isn't a plan, it's a disaster."

In the days leading up to NHAS unveiling, the administration announced that an additional $25 million would be allocated to cash-strapped AIDS Drug Assistance Programs. But advocates argue that the need is closer to $125 million. Nearly 2,300 people are now on ADAP wait lists, according to the National Alliance of State and Territorial AIDS Directions' latest July 9 ADAP Watch.

"It is imperative that this nation has a comprehensive approach to HIV care and prevention," said Randy Allgaier, a member of the Coalition for a National AIDS Strategy. "The current ADAP crisis is a prime example of what is wrong with our current response to HIV/AIDS; it is fragmented and seems to move from crisis to crisis rather than to think strategically."

Obama stressed that while the government must do its part, "our ability to combat HIV/AIDS doesn't rest on government alone. It requires companies to contribute funding and expertise to the fight. It requires us to use every source of information Ð from TV to film to the Internet Ð to promote AIDS awareness. It requires community leaders to embrace all Ð and not just some Ð who are affected by the disease."

As a first step, the White House issued a memorandum asking federal agencies Ð including the Department of Health and Human Services, Centers for Disease Control and Prevention, the Departments of Labor, Housing and Urban Development, and Veterans Affairs, and the Social Security Administration Ð to develop plans to implement the strategy and reallocate funding within the next five months.

"This creates a roadmap for other administrations so that politics doesn't dictate strategy," said Sorensen. "It demands all sectors of society contribute. Certainly we could make that happen if we choose to. If the business sector, the public sector contribute, we can make that strategy happen."

Focus on high-risk groups

The NHAS aims to reduce the number of new HIV infections by 25 percent, lower the rate of HIV transmission by 30 percent, increase the number of infected people who know their status by nearly 10 percent, raise the number of people accessing care within three months of diagnosis by 30 percent, and increase the proportion of gay and bisexual men, blacks, and Latinos with undetectable viral load by 20 percent.

A key theme of the strategy is allocating resources where the need is greatest. Gay and bisexual men make up a small percentage of the U.S. population Ð estimated between 2 percent and 10 percent Ð but account for more than half of all new HIV infections. Blacks make up about 13 percent of the population but nearly half of people living with HIV.

The administration's goal is to reduce the number of new cases, improve access to care, and give greater help to poor people who are less able to afford antiretroviral drugs.

Gay or bisexual men and African American men are two of the highest-risk groups for HIV, which causes AIDS. More than half of all transmissions stem from male-to-male sexual contact, and African Americans are seven times as likely to contract the disease as other races. Latinos are also named as a priority by the plan.

Experts said gay and African American men tend to live in communities with higher rates of the disease and engage more frequently in such risk behaviors as male-to-male intercourse and intravenous drug use.

"For the Bay Area and San Francisco, the plan allows a more coordinated effort between communities and federal agencies," said Jason Riggs, deputy director of the Stop AIDS Project, a prevention group in San Francisco.

Some gay rights groups and AIDS activists said the strategy took too long to develop and should have more funding, given the 2,200 Americans who are on wait lists for antiretroviral drugs as states struggle to cover the costs of treatment.

The strategy calls for the lead federal agencies to re-evaluate prevention programs in high-risk areas and use social media campaigns to educate the public about risk behaviors and the importance of getting screened.

"Sixty to 70 percent of new infections come from people who don't know their HIV status, so by finding people, getting them into care and helping them live a normal life span, we also help reduce transmission person to person," Saag said. Michael Saag heads the Center for AIDS Research at the University of Alabama at Birmingham and is also president of the national HIV Medicine Association. He said the plan will help lower the rate of infection and improve care for HIV and AIDS patients nationwide and here in Alabama.

Key goals in the national strategy on HIV and AIDS:

25 percent Reduction in infection rates nationwide by 2015.

$30 million Funding from health care overhaul law to reduce infection rates.

85 percent Portion of infected people to be treated three months after diagnosis.

$25 million Funds to help states pay for drugs to treat HIV.

In December of 2009, the American Academy of HIV Medicine submitted a set of policy recommendations for the National Strategy to the White House. Included in that document, were recommendations to bolster the U.S. workforce through tuition incentives and training opportunities in HIV care, increased reimbursement rates for HIV providers services, better coordination among government bodies that oversee and fund HIV providers, encouragement of health technologies, innovative research, and routine HIV testing.

The Strategy echoes the need for initiatives such as health professional training grants and financial incentives to compensate for HIV care management, but stops shy of outlining actual plans for implementing these types of provider programs. Also, unlike many of the other sections of the Strategy, the workforce section does not list anticipated results for 2015.

"So much of this strategy depends on an adequate supply of well trained practitioners," Friedman said. "Yet the implementation plan contains no quantified targets for replacing the nearly 1/3 of HIV practitioners who plan to retire over the coming decade. It's our hope that all the excellent workforce ideas included in the Strategy will be well underway by 2015, bringing qualified care providers to HIV patients nationwide."

National HIV/AIDS Strategy
The White House

One of the President's top HIV/AIDS policy priorities is the development and implementation of a National HIV/AIDS Strategy (NHAS). ... www.whitehouse.gov/administration/eop/onap/nhas

µ Download the National HIV/AIDS Strategy (PDF) µ Download the National HIV/AIDS Strategy Implementation Plan (PDF)

National HIV/AIDS Strategy for the United States. July 2010.


Stem cells made by reprogramming hold onto their past

July 19, 2010

Adult cells that have been reprogrammed into induced pluripotent stem cells (iPS cells) do not completely let go of their past, perhaps limiting their ability to function as a less controversial alternative to embryonic stem cells for basic research and cell replacement therapies, according to researchers at Children's Hospital Boston, John Hopkins University and their colleagues.

The findings, published online July 19 in Nature, highlight a major challenge in developing clinical and scientific applications for the powerful new technique of making iPS cells, which, like embryonic stem cells, have the capacity to differentiate into any type of cell in the body. Similar findings were published simultaneously online in Nature Biotechnology by other Boston researchers.

"iPS cells retain a 'memory' of their tissue of origin," said senior author George Daley, MD, PhD, a Howard Hughes Medical Institute investigator and Director of the Stem Cell Transplantation Program at Children's. "iPS cells made from blood are easier to turn back into blood than, say, iPS cells made from skin cells or brain cells."

In contrast, another technique known as nuclear transfer creates pluripotent stem cells without apparent memory and equally adept at transforming into several tissue types, the paper reports. In iPS cells, the memory of the original donor tissue can be more fully erased with additional steps or drugs, the researchers found, which made those iPS cells as good as the nuclear-transfer stem cells at generating different types of early tissue cells in lab dishes.

The residual cellular memory comes in part from lingering genome-wide epigenetic modifications to the DNA that gives each cell a distinctive identity, such as skin or blood, despite otherwise identical genomes. In the study, the persistent bits of a certain type of epigenetic modification called methylation were so distinctive in iPS cells that their tissues of origin could be identified by their methylation signatures alone.

"We found the iPS cells were not as completely reprogrammed as the nuclear transfer stem cells," said co-senior author Andrew Feinberg, MD, MPH, director of the Center for Epigenetics at Johns Hopkins, whose group did systematic epigenomic analyses of the cells. "Namely, DNA methylation was incompletely reset in iPS cells compared to nuclear transfer stem cells. Further, the residual epigenetic marks in the iPS cells helped to explain the lineage restriction, by leaving an epigenetic memory of the tissue of origin after reprogramming."

Epigenetic memory may be helpful for some applications, such as generating blood cells from iPS cells originally derived from a person's own blood, the researchers said. But the memory may interfere with efforts to engineer other tissues for treatment in diseases such as Parkinson's or diabetes or to use the cells to study the same disease processes in laboratory dishes and test drugs for potential treatments and toxicities.

"These findings cut across all clinical applications people are pursuing and whatever disease they are modeling," said Daley, also a member of the Harvard Stem Cell Institute and professor of biological chemistry and molecular pharmacology at Harvard Medical School. "Our data provide a deeper understanding of the iPS platform. Everyone working with these cells has to think about the tissues of origin and how that affects reprogramming."

iPS cells became a focal point of stem cell biology four years ago when a Japanese team led by Shinya Yamanaka created the functional equivalent of embryonic stem cells from adult mouse skin cells with a cocktail of four molecular factors. A year later, Yamanaka's team, Daley's team and a University of Wisconsin group all independently reported creating human iPS cells from adult skin cells, raising hopes for future clinical and research applications. Earlier this month, Daley's team and two other groups reported making human iPS cells from adult blood cells, a faster and easier source. In that study, iPS cells from blood were also better at differentiating back into blood cells than into other tissue types.

In the current study, first author Kitai Kim, PhD, postdoctoral fellow in the Daley lab, tested mice iPS cells head-to-head with pluripotent cells made through somatic cell nuclear transfer. Best known as the cloning method that created the sheep Dolly fourteen years ago, nuclear transfer reprograms an adult cell by transferring its nucleus into an unfertilized egg cell, or oocyte, whose nucleus has been removed. The process of transferring the nucleus immediately reprograms it epigenetically, replicating the same process that happens to sperm upon fertilization, Kim said.

"Stem cells generated by somatic cell nuclear transfer are on average, closer to bona fide embryonic stem cells than are iPS cells," Daley said. "This has an important political message--we still need to study the mechanisms by which nuclear transfer reprograms cells, because the process seems to work more efficiently and faithfully. Learning the secrets of nuclear transfer may help us make better iPS cells."

Kim began the study with older mice (ages 1 to 2), aiming to emulate the future human clinical scenario, which is likely to involve older people. Older cells are set in their ways and harder to reprogram, Kim said. Kim originally wanted to compare the transplantation success of blood cells made from three different pluripotent sources: iPS cells, embryonic stem cells (the gold standard), and nuclear transfer stem cells.

He did not get as far as transplantation. "Even in vitro we observed strikingly different blood-forming potential," he and his co-authors wrote in the paper. "We focused instead on understanding this phenomenon."

iPS cells from blood were best at making blood, and fibroblasts were best at differentiating into bone, a closely related tissue, Kim and his colleagues found. The researchers could reset the iPS cells more fully by differentiating them first into blood cells and then reprogramming them again, or by treating them with drugs that change their epigenetic profile.

In contrast, nuclear transfer stem cells from the same sources -- blood cells and skin - were equally able to differentiate into blood and bone, Kim and his colleagues found. Like iPS cells, the nuclear transfer technique also creates patient-specific cells, but has not yet proven successful with human cells.

"This paper opens our eyes to the restricted lineage of iPS cells," said Feinberg "The lineage restriction by tissue of origin is both a blessing and a curse. You might want lineage restriction in some cases, but you may also have to do more work to make the iPS cells more totally pluripotent."

Another study published online simultaneously in the journal Nature Biotechnology reports similar findings. "Our paper comes to a similar conclusion that a retention of memory reflects the cell of origin and affects the capacity of the iPS cell to differentiate into other cell types," said senior author Konrad Hochedlinger, PhD, a stem cell biologist at the Massachusetts General Hospital Center for Regenerative Medicine and, like Daley, a member of the Harvard Stem Cell Institute, who demonstrated another method to more fully reprogram iPS cells. "When we let the cells go through a lot of cell divisions, they lose the memory," he said.

Provided by Children's Hospital Boston


Reprogrammed cells 'remember,' retain characteristics of their cells of origin

July 19, 2010

(PhysOrg.com) -- Investigators at the Massachusetts General Hospital (MGH) Center for Regenerative Medicine have confirmed that induced pluripotent stem cells (iPSCs) retain some characteristics of the cells from which they were derived, something that could both assist and impede potential clinical and research uses. In their report that will be published in Nature Biotechnology and has received early online release, the researchers also describe finding that these cellular "memories" fade and disappear as cell lines are cultured through successive generations.

"How faithfully iPSCs can be reprogrammed into a truly embryonic state has been a longstanding question, and we have found that the cell of origin does affect the capacity of iPSCs to differentiate in vitro into particular cell types," says Konrad Hochedlinger, PhD, of the MGH Center for Regenerative Medicine who led the research team. "But when cultured iPSCs go through many rounds of cell division, they lose that memory."

A similar study from researchers at Children's Hospital Boston, published simultaneously in the journal Nature, also finds that cellular "memory" affects the differentiation potential of iPSCs. That report compared iPSCs with cells generated by somatic cell nuclear transfer (NT) - the technique used to clone animals - and finds that NT cells are closer to embryonic stem cells than iPSCs. "We still need to study the mechanisms by which nuclear transfer reprograms cells, because that process seems to work more efficiently and faithfully and may teach us how to make better iPS cells," says George Daley, MD, PhD, who led the Children's study. Both Hochedlinger and Daley are faculty members at the Harvard Stem Cell Institute (HSCI).

Generated from adult cells, iPSCs have many characteristics of embryonic stem cells but are also known to have important differences. Earlier studies found differences in function and gene expression between iPSCs that appeared to echo characteristics of the original adult cells. To discover whether donor cell patterns of gene expression truly persisted, the MGH team studied cells from genetically identical mice originally generated from iPSCs.

They indeed found differences in gene expression between iPSCs generated from different types of cells - skin cells, two type of immune cells, and muscle progenitor cells - from the same animal. Examining iPSCs generated from different animals revealed that differences based on the cell of origin were even greater than differences based on the animal of origin. There were also significant similarities between iPSCs and cells of origin in factors related to the epigenetic control of gene expression. In addition, the potential of iPSCs to differentiate into particular cell types varied, with those originating from either immune cells or muscle precursions being much easier to coax into forming blood progenitors than were iPSCs derived from skin cells.

Long-term culturing of any type of cell requires regularly splitting cultures into smaller populations and transferring them into new dishes or plates, a process called passaging. Because previous studies had suggested that repeated passaging could strengthen iPSC's similarities to embryonic stem cells, the research team investigated whether the process might help erase the cellular memory. Their experiments confirmed that cell-of-origin-based differences - both transcriptional and epigenetic - became less pronounced with subsequent passaging and totally disappeared by the 16th passage.

"Completely reprogramming cells appears to be a gradual process that continues beyond the iPSC stage, which may explain many of the reported differences between iPSCs and embryonic stem cells," says Hochedlinger. "The propensity of early-passage iPSCs to regenerate specific cell types could have clinical advantages, but there also are implications for the use of iPSCs to model diseases, since we'll need to make sure that differences between cells derived from patients and from healthy controls really reflect a disease process and not this cell-of-origin memory."

Hochedlinger is an associate professor of Stem Cell and Regenerative Biology at Harvard University and Harvard Medical School. Lead author of the Nature Biotechnology paper is Jose Polo, PhD, of the MGH Center for Regenerative Medicine and HCSI.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

Provided by Massachusetts General Hospital


The novel immunoregulatory molecule FGL2: A potential biomarker for severity of chronic hepatitis C virus infection

Katharina Foerester 1, Ahmed Helmy 1, Yi Zhu 1, Ramzi Khattar 1, Oyedele A. Adeyi 2, Kit Man Wong 1, Itay Shalev 1, David A. Clark 1 5, Pui-Yuen Wong 3, Elizabeth J. Heathcote 4, Melville J. Phillips 2, David R. Grant 1, Eberhard L. Renner 1, Gary A. Levy 1, Nazia Selzner 1

Received 23 September 2009; received in revised form 8 April 2010; accepted 12 April 2010. published online 24 June 2010. Corrected Proof

Background & Aims

This report describes the use of a novel sensitive and specific ELISA for the measurement of human fibrinogen-like protein 2 (FGL2/fibroleukin), a novel effector of natural regulatory T (Treg) cells, to predict the course of chronic hepatitis C viral infection (HCV).


Plasma levels of FGL2 were measured in HCV patients and compared to healthy controls and to patients with alcoholic liver disease.


FGL2 levels were significantly higher in HCV patients (84.3±89.1ng/ml, n=80) compared to healthy controls (36.4±21.9ng/ml, n=30, p<0.001), to a subset of patients who cleared HCV following anti-viral treatment (16.6±19.7ng/ml, n=32, p<0.001), and to patients with inactive alcoholic liver disease (18.8±17.4ng/ml, n=24, p<0.001). Among HCV patients, plasma levels of FGL2 correlated significantly with the stage of fibrosis (p=0.001) and were significantly higher in patients with cirrhosis (164.1+121.8ng/ml, n=60) compared to non-cirrhotics (57.7±52.8ng/ml, n=20, p=0.001). Genotype 1 patients had significantly higher levels of FGL2 (98.1±100.3ng/ml, n=60) compared to patients with genotype 2/3 (41.5±38.6ng/ml, n=20, p=0.0008). Patients with genotype 2/3 had FGL2 levels similar to healthy controls (41.5±38.6 vs. 36.41±21.9ng/ml, p=ns). Infiltrating lymphocytes in liver biopsies of HCV patients were positive for either FGL2 or FoxP3 (a marker of Treg cells) or expressed both markers.


This report documents the development of a sensitive ELISA for measurement of plasma levels of FGL2 an effector Treg cells, which correlates with the severity of HCV infection.

Abbreviations: DC, dendritic cells, FGL2, fibrinogen-like protein 2, HBV, hepatitis B virus, HCV, hepatitis C virus, MHV-3, murine hepatitis virus strain 3, SVR, sustained virological response, Treg, CD4+CD25+ regulatory T cells

Keywords: FGL2, HCV, Treg cells


IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV

Scand J Infect Dis. 2010 Jul 7. [Epub ahead of print]

Falconer K, Askarieh G, Weis N, Hellstrand K, Alaeus A, Lagging M.

Department of Medicine Solna, Infectious Diseases Unit, Karolinska Institutet, Sweden.


Abstract The aim of this study was to investigate the utility of baseline plasma interferon-gamma inducible protein-10 (IP-10) levels in human immunodeficiency virus (HIV)-hepatitis C virus (HCV) co-infected patients. Baseline IP-10 was monitored during HCV combination therapy in 21 HIV-HCV co-infected patients (HCV genotype 1 (n = 16), 2 (n = 2), and 3 (n = 3)). Lower baseline IP-10 was significantly associated with a rapid decline in HCV RNA, in particular with the first phase reduction, and similar cut-off levels (<150 and >600 pg/ml) as in HCV mono-infected patients apply. In conclusion, baseline IP-10 <150 pg/ml is predictive of a favourable viral response to HCV therapy in HIV-HCV co-infected patients, and may thus be useful in encouraging such difficult-to-treat patients to initiate therapy


Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults.

Vaccine. 2010 Jul 6. [Epub ahead of print]

Frey SE, Houghton M, Coates S, Abrignani S, Chien D, Rosa D, Pileri P, Ray R, Di Bisceglie A, Rinella P, Hill H, Wolff MC, Schultze V, Han JH, Scharschmidt B, Belshe RB.

Saint Louis University School of Medicine, Division of Infectious Diseases and Immunology, St. Louis, MOUnited States.


BACKGROUND: Hepatitis C virus (HCV) causes chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. In animal studies, chimpanzees were protected against chronic infection following experimental challenge with either homologous or heterologous HCV genotype 1a strains which predominates in the USA and Canada. We describe first in humans clinical trial of this prophylactic HCV vaccine. METHODS: HCV E1E2 adjuvanted with MF59C.1 (an oil-in-water emulsion) was given at 3 different dosages on day 0 and weeks 4, 24 and 48 in a phase 1, placebo-controlled, dose escalation trial to healthy HCV-negative adults. RESULTS: There was no significant difference in the proportion of subjects reporting adverse events across the groups. Following vaccination subjects developed antibodies detectable by ELISA, CD81 neutralization and VSV/HCV pseudotype neutralization. There was no significant difference between vaccine groups in the number of responders and geometric mean titers for each of the three assays. All subjects developed lymphocyte proliferation responses to E1E2 and an inverse response to increasing amounts of antigen was noted. CONCLUSIONS: The vaccine was safe and generally well-tolerated at each of the 3 dosage levels and induced antibody and lymphoproliferative responses. A larger study to further evaluate safety and immunogenicity is warranted. Copyright © 2010 Elsevier Ltd. All rights reserved.


Many False-Positive HIV Test Results for Those in AIDS Vaccine Trials

Almost half get the erroneous result, causing stigma and hampering trial enrollment, experts say

SUNDAY, July 18 (HealthDay News) -- Almost half of HIV-negative people who participate in clinical trials for HIV vaccines end up testing positive on routine HIV tests -- even though they're not actually infected, a new study shows.

The reason: They underwent what experts call "vaccine-induced seropositivity/reactivity" (VISP), meaning that they possess immune system antibodies to the virus but not the virus itself. That's an important distinction, since routine HIV screening looks for virus antibodies only.

Experts pointed out that the results are not new or surprising, but simply underline the delicacies of conducting trials into HIV/AIDS.

"You need to make sure to use other forms of testing for HIV, for example, viral load or p24 antigen, not just HIV antibodies. And people who've been in trials need to know their antibody status by the end of the trial," said Dr. Michael Horberg, director of HIV/AIDS at Kaiser Permanente in Santa Clara, Calif. "If it is a false positive but they do not have HIV infection, that would be very important for them to know, especially if they do repeat testing as part of good preventive health."

But a positive test can still carry stigma as well as insurance repercussions, noted Dr. Jerome F. Levine, an infectious diseases specialist with Hackensack University Medical Center in New Jersey, adding that "trials have had trouble recruiting people for this very reason."

The findings are simultaneously being presented Sunday at the International AIDS Conference in Vienna and published in the July 21 issue of the Journal of the American Medical Association (JAMA).

In this study of almost 2,200 people -- all participants in HIV vaccine trials -- 41.7 percent underwent VISP and tested positive for HIV antibodies. And those rates differed depending on the type of vaccine administered, ranging from 6.3 percent to 86.7 percent.

A second study, also being presented at the conference and published in JAMA, found that a screening program used in emergency departments where patients can "opt out" did not turn up very many new cases of HIV. These types of screening programs routinely test people entering the emergency room, regardless of their suspected level of risk or the presence or absence of symptoms.

The study compared the effectiveness of the test in turning up new cases of HIV infection versus tests ordered directly by a doctor.

The "opt-out" program started being recommended by the U.S. Centers for Disease Control and Prevention in 2006, but only in locales where the rate of undiagnosed cases of HIV infection rose above 0.1 percent.

Most health care facilities in the United States still don't use the opt-out method, said Levine.

This study took place in a Denver emergency department that annually sees about 55,000 patients. The hospital alternated from physician-directed testing to opt-out testing every four months over the course of two years.

First of all, the study found that only 25 percent of patients in the opt-out group actually agreed to a test.

Furthermore, close to 7,000 people were screened but only 0.15 percent turned out to be HIV-positive. Only 1 percent of the more than 21,000 patients who opted out were screened later and only 2.2 percent of those were found to be HIV-positive.

The small number of people who underwent HIV testing -- only one-quarter -- is a big limitation to the study, said Horberg, but that doesn't mean that such programs don't have value.

"Just because someone has a negative test, that doesn't mean that that testing wasn't successful," he said. "It may have raised the awareness of the patient. It may be prompting them to change their behavior and to really do an analysis of what good preventive health they need to follow."

A third paper in the journal recommended that all cancer patients be screened for HIV. This might sway cancer treatment decisions, for instance, helping doctors and patients avoid drugs that suppress the immune system, the authors noted.

SOURCES: Michael Horberg, M.D., director, HIV/AIDS, Kaiser Permanente Health Plan, Santa Clara, Calif.; Jerome F. Levine, M.D., infectious diseases specialist, Hackensack University Medical Center, N.J.; July 21, 2010, Journal of the American Medical Association


Reinventing vaccines: New frontiers in prevention

Genetic engineering, increased understanding of the immune system and new immunization delivery technologies could make this century the golden age of vaccines, observers say.

By Christine S. Moyer, amednews staff. Posted July 19, 2010.

One night in 1961, William Schaffner, MD, was called to a New York City hospital to assist with an emergency lumbar puncture on a child critically ill with Haemophilus influenzae type b meningitis.

At the time -- before a vaccine was developed -- Hib disease was the leading cause of bacterial meningitis among children younger than 5. It infected about 20,000 U.S. children and killed nearly 1,000 annually.

In the nearly 50 years since Dr. Schaffner, an infectious disease specialist, saw that child with Hib disease, he has seen vaccine developments that have changed medicine and saved scores of lives.

"My comment used to be that pediatric residents read about [Hib] disease, but they don't see it anymore. Now they don't even read about it," said Dr. Schaffner, professor of medicine and preventive medicine and chair of the Dept. of Preventive Medicine at Vanderbilt University School of Medicine in Nashville, Tenn.

During the past two decades, the number of diseases that can be prevented by vaccines has doubled, according to the Centers for Disease Control and Prevention.

Since 1990, the Food and Drug Administration has licensed immunizations for Haemophilus influenzae type b, varicella, human papillomavirus, rotavirus and shingles, among others.
Experts say the 21st century holds even more promise for new vaccines.
Application of genetic engineering, an increased understanding of the immune system and new immunization delivery technologies have created what some call the golden age of vaccines.
Scientists are exploring new frontiers where vaccines can be developed in plants. Other possible advancements include using a patch to immunize patients, and treating drug addiction with a vaccine. But such advancements take years or, in some cases, decades to develop and be licensed.
The upswing in vaccine development, after a slowdown in the 1970s and 1980s, has not been without stumbling blocks. The advanced technology used to develop new vaccines has made them too expensive for some physicians to purchase, store and administer. Outdated manufacturing systems have struggled to keep up with demand.

And even the success of vaccines can have negative effects -- some parents choose not to immunize their children, in part, because they no longer think there is a need.

The anti-immunization movement has led to the resurgence of potentially fatal diseases such as mumps and pertussis. California, for example, is on pace to have its highest number of pertussis-related illnesses and deaths in 50 years, according to the state's public health department.

Vaccine developments

Dr. Schaffner views the HPV vaccine as one of the most exciting recent advancements because it demonstrates the potential for vaccine development in the 21st century. One reason is because of the role genetic engineering played in the vaccine's creation.

Research for the HPV vaccine, which was first licensed in 2006, began in the early 1990s, according to Douglas Lowy, MD, an HPV researcher for the National Cancer Institute. He said the NCI lab was the first to show that if a single HPV gene is expressed, it could self-assemble to create virus-like particles. GlaxoSmithKline's Cervarix vaccine and Merck's Gardasil are based on this development, he said.

Cervical cancer was considered a vaccine priority, in part, because of the high number of women diagnosed with the disease, Dr. Lowy added. The American Cancer Society estimated that 11,270 new cases of invasive cervical cancer were diagnosed in 2009. About a third of those women will likely die from the disease.
Underserved populations, particularly Hispanic and black females, are disproportionately affected because they often cannot afford cervical cancer screening.

"The HPV vaccine could be one way, in the long run, to try to address this disparity," Dr. Lowy said.

There are, however, some ethical concerns with the immunization, said Ruth Faden, PhD, MPH, director of Johns Hopkins Berman Institute of Bioethics in Baltimore. Faden said the HPV vaccine is too expensive for many poor nations to purchase. That means the people who need the vaccine the most often do not get it.

A more immediate public health benefit has been experienced with the two rotavirus vaccines, Merck's RotaTeq, licensed in 2006, and GlaxoSmithKline's Rotarix, licensed in 2008. Before the development of the vaccines, rotavirus led to the hospitalization of 55,000 to 70,000 U.S. children each year and caused an estimated 20 to 60 deaths, according to the CDC.

During the 2008-09 rotavirus season, the number of positive rotavirus test results decreased 60% from the pre-vaccine period of 2000-06, the CDC reported in October 2009.

Vaccines of the future

AIDS is one area of focus for tomorrow's vaccines. Experts agree that greater research into the human immune system, and how it works, has contributed to recent advancements in the quest for an AIDS vaccine. HIV/AIDS infects about 50,000 new Americans each year, said James Kublin, MD, MPH, director of the HIV Vaccine Trials Network, an international collaboration of scientists and educators searching for an HIV vaccine.

Globally, about 33.4 million people were HIV positive in 2008, and an estimated 2 million died of AIDS, according to the World Health Organization's most recent data.

"It will be very difficult to treat our way out of this epidemic," Dr. Kublin said.
In 2009, a six-year HIV immunization study in Thailand showed the first evidence of efficacy from an HIV vaccine. Researchers found that participants who received the combination of a priming vaccine and boosting vaccine were 31.2% less likely to get HIV than those who received a placebo, according to a study in the Dec. 3, 2009, New England Journal of Medicine.

Dr. Kublin said an HIV vaccine could be licensed within the next decade.

In July, scientists led by a team from the National Institute of Allergy and Infectious Diseases Vaccine Research Center revealed their discovery of two naturally occurring antibodies that can stop more than 90% of known global HIV strains from infecting human cells in the laboratory. Researchers said the technique used to find these antibodies could be applied to vaccine design for many other infectious diseases.

Some infectious disease experts are heralding the discovery as a significant step toward developing an HIV vaccine. But scientists still have years of research and clinical trials before a safe and effective vaccine is developed.

Research into the immune system factored into advancements made in the development of a cocaine vaccine that is being readied for national multisite study. Principal researcher Thomas R. Kosten, MD, chair and professor of psychiatry, neuroscience and pharmacology at Baylor College of Medicine in Houston, has been working on a cocaine vaccine for about 15 years. The vaccine provokes the body to make antibodies that bind to cocaine and prevent it from leaving the bloodstream. The result is an inability to experience the drug's euphoric effects.

The ethical question, according to Faden, of Johns Hopkins, is whether people who get the cocaine vaccine would start abusing another drug. She said such questions need to be addressed as vaccines for drug abuse are developed.

Other research is looking at more ways to deliver vaccines beyond the needle.

Work is under way to administer the influenza vaccination, along with other immunizations, using a patch lined with tiny micro needles that would be essentially painless, according to Dr. Schaffner. Using a patch also would reduce costs by eliminating the need to refrigerate vaccines, and it would eradicate the safety issues that accompany health professionals handling needles and syringes, he said.

Researchers are also, in various forms, combining work on genetic engineering, immune-system research and new immunization-delivery technologies. For example, Dr. Schaffner said researchers are using recombinant genetics to find ways to include vaccine antigens in edible plants, such as tomatoes and bananas. The idea is that when people eat the food, Dr. Schaffner said, they would receive a vaccine boost.

"That would be an incredible way to administer vaccines to large populations, particularly in the developing world," Dr. Schaffner said. However, the possible introduction of such foods is a long way off, experts said.

Researchers also are developing a universal influenza vaccine, which would provide patients immunity against the flu for multiple years, said Frederick Cassels, PhD, SARS and Influenza Vaccine Program officer for the NIAID. He predicted it likely would take at least 10 years for it to be licensed.

Closer to becoming a reality: adding adjuvant to flu immunizations, which could stretch the vaccine supply and elicit a broader immune response from those who receive it, Cassels said. Also on the horizon are therapeutic vaccines that could extend the lives of cancer patients.

Infectious disease specialist Dr. Schaffner is among those closely watching studies being conducted on potential vaccines. Like others, he is confident that today's diseases will fall victim to tomorrow's vaccine, following the path of Hib and polio -- out of doctors' offices and into the history pages of medical textbooks.

Vaccine timeline
In the past two decades, the number of diseases that can be prevented by vaccines has more than doubled. Here is a time line of vaccine development from 1914 to 2010.

1914: Whole-cell pertussis vaccine licensed.

1923: Diphtheria vaccine licensed.

1924: Tetanus toxoid produced.

1945: Influenza vaccine first used.

1948: Tetanus, diphtheria and pertussis vaccines combined to make DTP vaccine for routine childhood immunization.

1955: Inactivated polio vaccine licensed.

1961: Monovalent oral polio vaccine licensed.

1963: Trivalent oral polio vaccine and measles vaccine licensed.

1967: Mumps vaccine licensed.

1969: Rubella vaccine licensed.

1971: Measles, mumps and rubella vaccine licensed.

1982: Hepatitis B vaccine licensed.

1985: Haemophilus influenzae type b polysaccharide vaccine licensed.

1990: Haemophilus influenzae type b polysaccharide conjugate vaccine licensed for infants.

1991: Acellular pertussis vaccine licensed for use in children 15 months to 6 years old.

1995: Varicella and hepatitis A vaccines licensed.

1996: Acellular pertussis vaccine licensed for use in infants.

1998: First rotavirus vaccine licensed. It was withdrawn a year later due to adverse events.

2000: Pneumococcal conjugate vaccine licensed.

2003: Live attenuated influenza vaccine licensed for people age 5 to 49.

2005: Tetanus, diphtheria, pertussis vaccine licensed for adolescents and adults. A new meningococcal vaccine also licensed for people age 11 to 55.

2006: Vaccines against rotavirus, the human papillomavirus and shingles licensed. A new immunization that combined measles, mumps, rubella and varicella also licensed.

2008: A second rotavirus vaccine licensed.

2009: A second human papillomavirus vaccine and four vaccines against the 2009 A(H1N1) influenza virus licensed. A new high-dose inactivated influenza vaccine for people age 65 and older also licensed.

2010: A second conjugate pneumococcal vaccine licensed.

Source: Centers for Disease Control and Prevention


"Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand," New England Journal of Medicine, Dec. 3, 2009 (www.ncbi.nlm.nih.gov/pubmed/19843557)

Centers for Disease Control and Prevention on vaccines and immunizations (www.cdc.gov/vaccines)

HIV Vaccine Trials Network (http://www.hvtn.org/)

National Institute of Allergy and Infectious Diseases on 2009 H1N1, seasonal, avian and pandemic influenzas (www.niaid.nih.gov/topics/flu)

National Cancer Institute fact sheet on cancer vaccines (www.cancer.gov/cancertopics/factsheet/therapy/cancer-vaccines)


Foreign clinical trials need stricter controls, HHS study says

Requiring standardized electronic clinical trial data is among a new report's recommendations.

By Tanya Albert Henry, amednews correspondent. Posted July 19, 2010.

More than half of clinical trial subjects and sites for drugs and biologics were located outside the United States in fiscal 2008, a new study said. And 80% of the drug and biologic marketing applications that the Food and Drug Administration approved contained foreign clinical trial data.

Western Europe accounted for 58% of subjects enrolled at foreign sites and 60% of the foreign sites. Central and South America had a significant number, including the highest average number of subjects per site compared to other foreign regions, according to a June report by the Dept. of Health and Human Services Office of Inspector General.

The study also found that foreign sites did not have the inspections that domestic ones did. The FDA inspected clinical investigators at less than 0.7% of foreign clinical trial sites compared with 1.9% for domestic sites.

The report comes as critics have raised concerns that foreign trials, particularly those in developing countries, may not provide results generalizable to the U.S. population. Medical ethicists also have questioned whether local regulatory bodies and institutional review boards adequately monitor clinical trials to protect the rights and welfare of subjects and to ensure data integrity.

With reliance on foreign clinical trials expected to grow, the report recommended that the FDA should:

■Require standardized electronic clinical trial data and create an internal database.

■Monitor trends in foreign clinical trials not conducted under Investigational New Drug applications and, if necessary, take steps to encourage sponsors to file INDs.

■Continue to explore ways to expand oversight of foreign clinical trials, including developing inspectional agreements with foreign regulatory bodies, inspecting clinical trials in more countries and looking to implement new oversight models.

Overall, the FDA agreed with the OIG's recommendations.

"For each OIG recommendation, the agency either has ongoing efforts that will address the recommendation or has initiated development of new procedures that will incorporate the recommendation," the FDA wrote in response to a draft of the OIG's report.

The FDA said it has long recognized the importance of data from clinical trials conducted outside the U.S., as long as the studies meet regulatory standards and yield results applicable to American patients. But the agency said increasing clinical trial globalization has presented challenges.

"Resource constraints limit the number of foreign clinical trial site inspections that can be conducted," the FDA said. "In addition, inspections are usually conducted after a clinical trial is completed, too late to fix any problems."

The Assn. of Clinical Research Organizations, which represents companies that focus on clinical research, said in a statement that it supports the recommendations.

Pharmaceutical Research and Manufacturers of America Senior Vice President Ken Johnson said in a statement, "Is it ethical to conduct such studies outside of the U.S.? In a word: Yes. ... Regardless of the location, however, companies seeking U.S. approval must maintain the FDA's high standards for conducting the trial."

"For instance, any related trials conducted outside the U.S. must comply with FDA requirements covering good clinical practices, in addition to meeting the requirements mandated in these important emerging markets."