They will study mother-to-child HIV transmission in Malawi, malaria prevention in Ghana.

Danielle Wickman, UC Riverside

Three first-year students in the UCR/UCLA Thomas Haider Program in Biomedical Sciences at the University of California, Riverside, are headed to Africa next month to gain first-hand experience in working with patients with HIV and malaria. After spending a month there, the students — all women — will return to the United States, where they hope to apply the knowledge gained from working in African clinics to medically underserved areas, such as inland Southern California.

Danielle Wickman and Virginia Tancioco have been selected to participate in the UCLA Global Health Program in Malawi. They leave on June 4 and return on July 13. Judy Gbadebo was selected to participate in the UCLA Global Health Program in Ghana. She leaves on June 19 and returns on July 22.

Wickman, 23, was part of the University Honors program at UCR. She has not been to Africa before, and expects her trip to Malawi will increase her passion for working in women’s health issues. Along with Tancioco, she will work on a project that focuses on preventing mother-to-child transmission of HIV. Specifically, they will study, along with Dr. Risa Hoffman, an assistant clinical professor of medicine at the UCLA David Geffen School of Medicine, the effectiveness of antiretrovirals that are part of a World Health Organization treatment plan to prevent HIV transmission.

“HIV-positive pregnant women in Malawi are using — or are expected to be using — these medications,” said Wickman, a first generation college student, who plans to specialize in obstetrics and gynecology. “But a large number of them stop using them for reasons we would like to study. We want to understand the effectiveness of these medications, and look into how many women are able to follow up and take all the medication after the initial visit to the clinic.

“We will be working in Malawi’s capital, Lilongwe, with Partners in Hope, while using as our home base the main hospital in Nkhoma, where we will work with patients at the hospital and in outpatient clinics, in addition to conducting home visits in villages to evaluate access to care,” Wickman added. “We will also investigate male partner involvement, meaning how many male partners are involved in the treatment process. A good number of men in Malawi feel powerless when they find out their partners have contracted HIV and find it easier to simply walk away.”

Virginia Tancioco, UC Riverside

Tancioco, 30, a student also of the five-year dual degree UCLA PRIME Medical School Program, said Malawi appealed to her because of her interest in public health.

“Malawi offers me an opportunity to work with an underserved population — another of my interests,” said Tancioco, who is considering a career in emergency medicine. “Many pregnant women in Malawi are not taking the medication that prevents transmission of HIV to their unborn children. Is this cultural? Is it a mistrust of doctors? A fear of them? Are the clinics too far and inaccessible? Are the drugs unaffordable? We would like to find out.”

She expects the trip also will help her appreciate things she takes for granted in the United States.

“Here, you switch on a light, and there it is,” she said. “In Malawi, some villages lack electricity. I expect this trip will be an invaluable learning experience for me in that sense as well.”

Hoffman, who co-directs the Global Health Education Program at UCLA, said Wickman and Tancioco were chosen for their passion for serving underprivileged populations, as well as their maturity, cultural competency and enthusiasm for global health.

“Over the summer in Malawi, Danielle and Virginia will be collecting important information to help improve access and adherence to care for women of reproductive age living with HIV,” she said. “They will have the opportunity to learn about HIV care in Malawi, a country ranked among the poorest in the world, and will be making important contributions to our knowledge of specific issues related to treatment of HIV-positive women in rural Malawian communities. I hope this experience will further strengthen their desire to work in global health and that they will return to Southern California better able to serve the diverse UCLA-UCR community because of their unique opportunity.”

Judy Gbadebo, UC Riverside

Gbadebo, 26, is no stranger to global health. She spent six months in South Africa in 2009, working directly with TB and HIV patients while examining patient care in underserved populations.

In Ghana she will focus on malaria prevention efforts for children and families in the village of Sorano. In collaboration with the Ghana Health and Education Initiative, she will examine the usage rates of insecticide treated nets and facilitate community education to reduce the transmission of infection.

“Although I enjoyed working with patients one-on-one in South Africa, I returned from the experience wanting to help patients on a larger scale and create sustainable change,” Gbadebo said. “Malaria is a devastating problem in Ghana, but through widespread education and standardized preventative solutions, it is quite solvable. I hope my research there will make an impact on the community that will generate long-lasting results. I expect my work abroad will improve my understanding of how to implement patient education and awareness as an avenue of preventative medicine.”

Dr. Emma Simmons, the associate dean for student affairs at the UCR School of Medicine, believes Gbadebo is perfect for the internship in Ghana.

“Judy is passionate about global medicine and helping the underserved,” she said. “She is also not naïve to the challenges that she will face during this internship. She has already had some insights into the politics and gravity of health care delivery in developing countries and she is determined to continue to do her part, at every level of her training in medicine, to make a sustainable impact. Her focus and commitment to study the behavioral and societal factors that influence the spread of infectious diseases, specifically malaria, in Ghana is a testament to that.”

Finding their passion

Wickman, who attended Murrieta Valley High School, is grateful that UCR gave her opportunities to find her passion.

“It was in a class I took at UCR on global health and agriculture development in developing countries that I found myself reading up on women’s health issues,” she said. “It got me interested in empowering women to create change in their communities and be invested in health and well being.”

UCR gave Tancioco the opportunity to get to know professors in a smaller and more intimate program.

“To my surprise, I was able to directly approach my professors for letters of recommendation,” said Tancioco, who attended James Logan High School in Union City. “I had expected hurdles to jump over and very limited access.”

The UCR School of Medicine’s mission of serving an underserved population appeals strongly to Gbadebo, who attended Foothill High School in Pleasanton.

“A health care disparities course through the Medical Scholars Program at UCR exposed me to a variety of issues in health disparities,” said Gbadebo, who will be joined in Ghana by a student at the UCLA David Geffen School of Medicine.  “It is here that my passion for global health and forming parallels in my own local community flourished.”

Groundbreaking 10-year UCSF research examines causes of death among HIV patients.

What is the connection, if any, between sudden cardiac death and people with HIV/AIDS? And can that knowledge help prolong their lives?

In a comprehensive, retrospective 10-year UC San Francisco study, researchers found patients with HIV/AIDS suffered sudden cardiac death at a rate four times higher than the general population.

“As part of my ongoing research in 2010, we were looking at every instance of sudden death in San Francisco,” said first author Zian H. Tseng, M.D., an electrophysiologist and an associate professor of medicine in the UCSF Division of Cardiology. “I noticed that many of these cases involved individuals with HIV infection, who were dying suddenly. I wondered if there was some sort of connection there.”

He posed this question to Priscilla Hsue, M.D., a UCSF associate professor of medicine and the director of the HIV Cardiology Clinic at San Francisco General Hospital and Trauma Center (SFGH), who is one of a few cardiologists in the country who specializes in HIV. To her knowledge, no one had ever explored the link between HIV and sudden death, and that is when they began collaborating on this research.

In a paper scheduled to be published May 15 in the Journal of the American College of Cardiology, Tseng, Hsue and other researchers conducted a retrospective study of 2,860 HIV patients from April 2000 to August 2009 at SFGH’s Ward 86, the first HIV/AIDS-specialized clinic, to comprehensively characterize all deaths. They studied medical records, death certificates, paramedic reports, and interviews with family members, doctors, and other clinicians.

Sudden cardiac death and HIV/AIDS

During that period, eight percent died during an average of 3.7 years of follow up. Cardiac-related deaths accounted for 15 percent of overall mortality. Of that group, 86 percent died of sudden cardiac death.

“To put that in context, we’re able to compare the rate of sudden death in this population with the overall San Francisco population,” Tseng said. “So adjusted for age, race, demographics, and other variables, the rate of sudden death in the HIV population is more than four times higher than the general population.”

“The fact that the vast majority of cardiac deaths were sudden is surprising and implies that we as clinicians need to be aware of this potential health issue among patients with HIV,” Hsue added. “Our findings also highlight many things that we still don’t know about HIV and sudden death. Did these individuals die of unrecognized coronary artery disease? What can we be doing as clinicians to identify patients at risk and to intervene beforehand?”

Categorizing sudden cardiac death

By 2003, sudden cardiac death made up the largest number of non-AIDS deaths among HIV-positive patients in San Francisco.  These deaths were largely among individuals with evidence of well-controlled HIV disease.

Researchers used well-published criteria for retrospectively identifying death as either HIV-related or sudden death-related. If there was any doubt, they classified sudden death as an HIV death.

“In other words, for someone with a CD4 (T-cell) count less than 50 who died suddenly, we classified that as an HIV death, rather than a sudden death because of the profound immunodeficiency,” Tseng said.

More than 17,000 people with AIDS in the United Stated died in 2009, and more than 619,000 people have died since the epidemic began. Still, the number of people living with HIV continues to rise. More than 1.2 million people in the United States are HIV-positive, according to the U.S. Centers for Disease Control and Prevention.

“Now that HIV-infected individuals are living longer with the benefit of antiretroviral therapy, non-AIDS conditions are becoming increasingly important and at the top of this list is cardiovascular disease,” Hsue said.

Researchers believe HIV changes the electrophysiology of the heart in a way so pronounced that it causes conduction abnormalities. And many HIV medications can throw off the heart’s electrical cycle, which increases the risk of sudden death. These and other variables could be contributing factors.

“Acknowledging the limitations of a retrospective analysis, what’s interesting about this study is that it opens up many related questions we can ask in future studies, such as which high-risk patients might benefit from defibrillator implantation?” Tseng said.

Tseng is in the middle of a prospective citywide study on sudden cardiac death, including studying HIV patients and monitoring their progress.

Tseng is the first author of the paper; Hsue is the senior author; co-authors include Eric Secemsky, M.D., of the UCSF Department of Medicine; David Dowdy, M.D., Ph.D., Sc.M., of the Johns Hopkins Bloomberg School of Public Health’s Department of Epidemiology; Eric Vittinghoff, Ph.D., M.P.H., of the UCSF Department of Epidemiology and Biostatistics; Brian Moyers, M.D., of the UCSF Division of Cardiology; Joseph Wong, M.D., of the UCSF Department of Medicine and San Francisco VA Medical Center; and Diane Havlir, M.D., of the San Francisco General Hospital HIV/AIDS Division.

This study was supported by funds from the U.S. National Institutes of Health (NIH). Tseng has received minor honorarium from Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, please visit www.ucsf.edu.

UC Davis a step closer to launching human clinical trials involving stem cells.

Joseph Anderson, UC Davis

UC Davis Health System researchers are a step closer to launching human clinical trials involving the use of an innovative stem cell therapy to fight the virus that causes AIDS.

In a paper published in the May issue of the Journal of Virology, the UC Davis HIV team demonstrated both the safety and efficacy of transplanting anti-HIV stem cells into mice that represent models of infected patients. The technique, which involves replacing the immune system with stem cells engineered with a triple combination of HIV-resistant genes, proved capable of replicating a normally functioning human immune system by protecting and expanding HIV-resistant immune cells. The cells thrived and self-renewed even when challenged with an HIV viral load.

“We envision this as a potential functional cure for patients infected with HIV, giving them the ability to maintain a normal immune system through genetic resistance,” said lead author Joseph Anderson, an assistant adjunct professor of internal medicine and a stem cell researcher at the UC Davis Institute for Regenerative Cures. “Ideally, it would be a one-time treatment through which stem cells express HIV-resistant genes, which in turn generate an entire HIV-resistant immune system.”

To establish immunity in mice whose immune systems paralleled those of patients with HIV, Anderson and his team genetically modified human blood stem cells, which are responsible for producing the various types of immune cells in the body.

Building on work that members of the team have pursued over the last decade, they developed several anti-HIV genes that were inserted into blood stem cells using standard gene-therapy techniques and viral vectors (viruses that efficiently insert the genes they carry into host cells). The resulting combination vector contained:

• a human/rhesus macaque TRIM5 isoform, which disrupts HIV from uncoating in the cytoplasm
• a CCR5 short hairpin RNA (shRNA), which prevents certain strains of HIV from attaching to target cells
• a TAR decoy, which stops HIV genes from being expressed inside of the cell by soaking up a critical protein needed for HIV gene expression

These engineered blood stem cells, which could be differentiated into normal and functional human immune cells, were introduced into the mice. The goal was to validate whether this experimental treatment would result in an immune system that remained functional, even in the face of an HIV infection, and would halt or slow the progression toward AIDS.

The results were successful on all counts.

“After we challenged transplanted mice with live HIV, we demonstrated that the cells with HIV-resistant genes were protected from infection and survived in the face of a viral challenge, maintaining normal human CD4 levels,” said Anderson.
CD4+ T-cells are a type of specialized immune cell that HIV attacks and uses to make more copies of HIV.

“We actually saw an expansion of resistant cells after the viral challenge, because other cells which were not resistant were being killed off, and only the resistant cells remained, which took over the immune system and maintained normal CD4 levels,” added Anderson.

The data provided from the study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validated its potential application in future human clinical trials. The team has submitted a grant application for human clinical trials and is currently seeking regulatory approval, which is necessary to move on to clinical trials.

“This research represents an important step in our fight against HIV/AIDS,” said Richard Pollard, chief of infectious diseases at UC Davis and one of the study’s co-authors. “Clinical trials could give us the critical information we need to determine whether our approach truly represents a functional cure for a terrible disease that has affected millions and millions of people.”

The study was supported by UC Davis Health System start-up funds from the Dean’s office for the Stem Cell Program and by the James B. Pendleton Charitable Trust. This work was also supported in part by the Gin and Imy Mar stem cell research fund.

Other authors were Rachel X. Chen, Jon E. Walker, Jeannine McGee, Catherine Nacey, Richard B. Pollard, Mehrdad Abedi, Gerhard Bauer and Jan A. Nolta, all affiliated with the UC Davis Institute of Regenerative Cures.

UCSF professor Warner Greene recognized for HIV/AIDS research.

Warner Greene

Warner C. Greene, M.D., Ph.D., a professor of medicine at UC San Francisco who directs virology and immunology research at the Gladstone Institutes, has been inducted as president of the Association of American Physicians (AAP).

The AAP is one of the oldest and most prestigious professional organizations of physicians. Greene, a senior investigator at UCSF-affiliated Gladstone, was elected a member of the AAP in 1990. He became an AAP councilor in 2005 and then president-elect for 2012.

“As a long-time member of the AAP, I am honored to represent my colleagues and help guide the association,” said Greene. “I look forward to promoting the AAP’s mission of advancing science in medicine.”

Under Greene’s direction, virology and immunology research at Gladstone takes a multidisciplinary approach to fighting HIV/AIDS — which remains a global scourge, with more than 30 million people worldwide living with HIV. He studies the molecular mechanisms that underlie HIV infection, and recently his lab provided new insight into how the virus kills CD4 T cells and simultaneously triggers inflammation that promotes further disease progression. His laboratory and their collaborators have also identified human amyloid fibrils in semen that enhance the ability of HIV to infect new cells — a discovery that one day could help stem the global spread of this deadly pathogen.

“I am delighted that Greene is being acknowledged for his remarkable and continuing contributions to the scientific basis of medicine,” stated Lloyd “Holly” Smith Jr., M.D., consultant to the president of the Gladstone Institutes and emeritus professor of medicine and associate dean at UCSF. “His selection as president of the Association of American Physicians is a testament to his standing as an international leader in the application of biological science for the advancement of health care.”

A widely recognized expert in virology and immunology, Greene is a member of the Institute of Medicine of the National Academies and a fellow of the American Academy for the Advancement of Science. He is also the president of the Accordia Global Health Foundation, whose mission is to overcome the burden of infectious diseases in Africa by building centers of excellence, strengthening medical institutions and building health care capacity.

Greene also serves as co-director of the UCSF-GIVI Center for AIDS Research and is a member of the executive committees of the AIDS Research Institute and the Biomedical Sciences graduate program at UCSF. He is the author of more than 330 scientific papers and has been recognized as one of the 100 Most Cited Scientists in the world.

Before joining Gladstone in 1991 as the founding director of the Gladstone Institute of Virology and Immunology, Greene served as a senior investigator at the National Cancer Institute and a professor of medicine and Howard Hughes investigator at Duke University Medical Center.

Greene earned a bachelor’s degree at Stanford University and an M.D./ Ph.D. degree at the Washington University School of Medicine. He completed his internship and residency training in Medicine at the Massachusetts General Hospital at Harvard.

Other Gladstone colleagues who are also members of the AAP include R. Sanders Williams, M.D., Gladstone president; Robert W. Mahley, M.D., Ph.D., senior investigator and president emeritus; Lennart Mucke, M.D., senior investigator, who directs neurological research at Gladstone; and Eric Verdin, senior investigator involved in virology and immunology research.

The AAP, a nonprofit, professional organization founded in 1885 is composed of more than 1,900 active and honorary members dedicated to the pursuit of medical knowledge and the advancement through experimentation and discovery of basic and clinical science and their application to clinical medicine.

Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Women in resource-poor countries can successfully follow process, UC Davis study finds.

UC Davis research shows that women in Tanzania could flash heat their breast milk to reduce the chances of HIV transmission.

An international team led by UC Davis researchers has found that mothers in sub-Saharan Africa could successfully follow a protocol for flash-heating breastmilk to reduce transmission of human immunodeficiency virus (HIV) – the virus that causes AIDS – to their infants.

Flash-heating breastmilk is recommended by the World Health Organization (WHO) for HIV-infected mothers during times of increased transmission risk. The technique involves expressing breastmilk into a glass jar that is placed in a small pot of water and heated until the water boils.

Previous research from UC Davis and UC Berkeley showed that this process inactivates HIV in breastmilk, while retaining the milk’s nutritional and infection-fighting properties. But whether or not women in poor countries would be willing and able to successfully use the technique had not been established.

Published in the May issue of the Journal of Acquired Immune Deficiency Syndromes, the current study showed that women in Dar es Salaam, Tanzania – a resource-poor urban area – could follow the protocol consistently over an average of about 10 weeks, with some mothers utilizing the method up to a full year.

“More women with HIV than we anticipated were willing and able to flash heat their breastmilk and make it safe despite very limited resources,” said Caroline Chantry, professor of pediatrics at UC Davis Children’s Hospital and lead author of the study. “These findings show that the World Health Organization’s recommendations are feasible in a real-world setting.”

Even in the absence of HIV medications, HIV-positive mothers in resource-poor regions are advised to exclusively breastfeed their children for six months. When compared to partial breastfeeding, exclusive breastfeeding can reduce the chances of mother-to-child HIV transmission during the first months of life. Physicians believe this is because mixed feeds increase the likelihood of allergens or contaminants that compromise the epithelial lining of a baby’s digestive tract, making it easier for HIV to pass through. But while longer-term breastfeeding substantially increases the likelihood of HIV transmission, early cessation of breastfeeding is associated with high morbidity and mortality in developing areas.

“It’s a very high-risk period for diseases and deaths from gastrointestinal infections,” Chantry said. “Flash heating can help women provide nutrient and antibody-rich breastmilk to their infants beyond 6 months of age and reduce the possibility of HIV transmission at the same time.”

To find out if women would use the protocol, Chantry and her team enrolled 101 HIV-infected mothers and their infants in the study: 86 infants were still alive and participating in the study at 5 months of age when the infants were tested for HIV. Of these infants, 72 were HIV negative, and more than half of their mothers chose to flash heat their breastmilk.

Peer counselors provided the necessary equipment and then visited the mothers weekly to offer instructions on flash heating and observe how well they followed the protocol, which included washing their hands, cleaning utensils, bringing the milk to the correct temperature (typically 72.9° C) and then allowing it to cool before feeding it to children with a spoon or cup.

“These mothers succeeded in flash heating with only modest support from trained peer counselors rather than professional health-care providers,” Chantry said. “This method is inexpensive in terms of costs and workforce and could be sustainable in resource-limited settings.”

Untreated and flash-heated breastmilk samples were collected every two weeks for bacterial analysis. The flash-heated milk was found to be bacteriologically safe.

Chantry said that the study sets the stage for a clinical trial to determine whether flash heating improves infant-health outcomes and to evaluate the cost-effectiveness of health improvements in addition to averted HIV infections.

“Our focus is on improving both HIV-free ‘thrival’ as well as HIV-free survival,” Chantry said. “WHO has also called for research on the feasibility of supporting and sustaining this practice on a large scale.”

In addition to Chantry, study authors were Sera Young, Janet Peerson and Kathryn Dewey of UC Davis; Waverly Rennie, Monica Ngonyani, Clara Mashio and Margaret Nyambo of University Research Company, Dar es Salaam, Tanzania; Kiersten Israel-Ballard and Peggy Koniz-Booher of PATH, Seattle; Mecky Matee of Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; and Deborah Ash of Academy for Educational Development, Dar es Salaam, Tanzania.

“Feasibility of Using Flash-Heated Breastmilk as an Infant Feeding Option for HIV-Exposed, Uninfected Infants after 6 Months of Age in Urban Tanzania” was funded by the National Institutes of Health (grant number R01HD057602). Reporters can request a copy of the study by emailing karen.finney@ucdmc.ucdavis.edu.

UC Davis Children’s Hospital is the Sacramento region’s only nationally ranked, comprehensive hospital for children, serving infants, children, adolescents and young adults with primary, subspecialty and critical care. It includes the Central Valley’s only pediatric emergency department and level I pediatric trauma center, which offers the highest level of care for critically ill children. The 129-bed children’s hospital includes the state-of-the-art 49-bed neonatal and 24-bed pediatric intensive care and pediatric cardiac intensive care units. With more than 120 physicians in 33 subspecialties, UC Davis Children’s Hospital has more than 74,000 clinic and hospital visits and 13,000 emergency department visits each year. For more information, visit children.ucdavis.edu.

UCSF study sheds light on tricky task of diagnosing thickening of arteries.

Priscilla Hsue, UC San Francisco

By Kate Rauch

With the remarkable success of antiretroviral drugs, people with HIV are living longer. However, recent attention is turning to the link between HIV and chronic conditions, including cardiovascular illness.

As it turns out, people with HIV are at greater risk for heart disease than others. But the reasons for this vulnerability aren’t well understood.

A recent study by UC San Francisco cardiologist Priscilla Hsue, M.D., who in 2004 started the world’s first cardiology clinic for HIV patients at San Francisco General Hospital, sheds light on one conundrum facing doctors in the field — the tricky task of diagnosing atherosclerosis, or thickening of the arteries, a precursor of heart attacks.

Often referred to as a silent killer, atherosclerosis progresses without obvious symptoms. Hsue, an associate professor at UCSF’s School of Medicine, looked at two methods used to diagnose the condition — carotid ultrasound, which measures the inside thickness of the carotid artery, and a CT scan, which tests for calcium in the coronary artery. Calcium deposits in the coronary artery or thickening in the carotid artery can indicate advancing atherosclerosis.

Hsue confirmed that HIV indeed is a risk for atherosclerosis. She also discovered that looking at the carotid artery rather than calcium was more effective at gauging the condition in people with the virus.

For reasons that remain unclear, a significant number of HIV parents in the study showed thicker carotid arteries, without any unusual calcium, compared to the control group without the virus.

Hsue is already applying the results in new research. In a current five-year investigation of atherosclerosis in HIV patients, she is tracking 400 participants, regularly measuring their carotid artery thickness, along with HIV disease characteristics and traditional cardiovascular risk factors such as smoking.

The goal is better prevention and treatment, Hsue said, adding that an urgent need exists to be able to better diagnose and treat individuals with HIV who are at increased risk for cardiovascular disease.

Hsue is also conducting a unique investigation of pulmonary hypertension in HIV patients, a rare and deadly form of elevated pressures on the right side of the heart..

About one in 2,000 people with HIV develop pulmonary hypertension, compared to one in one million in the general population. “It’s a quick-moving, devastating disease,” Hsue said. “We don’t know what puts people at risk. Are there things we can do with respect to HIV infection or on the cardiovascular side to prevent this or delay disease progression?”

Some study participants have advanced pulmonary hypertension, some early signs, and some are symptom-free. Over five-years, Hsue is regularly monitoring their pulmonary artery pressures, HIV disease characteristics, symptoms and exercise tolerance.

Much of this work, including the regular blood tests, heart ultrasound, right heart catheterization, lung tissue sampling and caring for patients after procedures, is being provided through Clinical Research Services (CRS) offered by UCSF’s Clinical and Translational Science Institute (CTSI).

“The infrastructure and resources provided by CTSI are crucial,” Hsue said. “They help streamline clinical research, allowing researchers like me to see more patients, and perform more complicated procedures for research purposes.”

CTSI is a member of the National Institutes of Health-funded Clinical and Translational Science Awards network. Under the banner of Accelerating Research to Improve Health, it provides a wide range of services for researchers, and promotes online collaboration and networking through tools such as UCSF Profiles.

CTSI also recently launched the UCSF Participant Recruitment Service, which offers a suite of services to support investigators in efforts to recruit study participants, potentially making it easier for researchers such as Hsue to engage in research.

PrEP treatment will target populations at risk for HIV infection in urban centers.

In these scanning electron micrographs from Thomas Deerinck at UC San Diego, multitudinous HIV-1 particles exit from a cultured HeLa cell. The image is false-colored.

The California HIV/AIDS Research Program (CHRP) of the University of California announced today (April 17) that it has awarded grants totaling $11.8 million to three teams of investigators to test a potential HIV prevention pill among high-risk HIV-uninfected people in California.

The studies also will examine new strategies to engage and retain HIV-infected people in care and treatment. These combined strategies are expected to help curb the HIV epidemic in California.

Two of the research teams will offer the HIV prevention pill — part of an intervention known as PrEP (pre-exposure prophylaxis with antiretroviral drugs) — to an estimated 700 high-risk uninfected men who have sex with men (MSM) and to transgender women (male-to-female transgendered people) in Los Angeles, San Diego and Long Beach over the next four years. PrEP also includes the provision of risk-reduction counseling and other services.

These researchers also will assess the implementation of testing and linkage to care plus treatment — known as “TLC+” — a strategy to locate, engage and retain HIV-infected people in care and start them on life-saving treatment for HIV infection. The TLC+ intervention will include some 3,000 people in Southern California.

A third research group will not fully implement PrEP or TLC+ at this time, but will instead plan and pilot PrEP/TLC+ implementation strategies for young MSM of color in Oakland, Richmond, Berkeley and other East Bay locations.

This will be the largest PrEP/TLC+ demonstration project initiative in the U.S. and the first to test PrEP in these Southern California communities.

“HIV has been with us for more than 30 years, and it’s time to provide some new interventions for high-risk people so they have options to protect themselves and prevent further transmission,” said George Lemp, Dr.P.H., director of the UC-based CHRP. “We hope this new approach can finally help to curtail the epidemic in this state.”

“These studies will provide critical information on the implementation of PrEP and TLC+ strategies in California and will help guide state and national efforts to address the epidemic,” Lemp added.

“UC is pleased to support this important initiative in California, which we believe is unique in the nation,” said Steven Beckwith, UC vice president for research and graduate studies.”We are pleased that UC resources and talent can play an important role in addressing these health care challenges as the research arm of the state.”

In these California demonstration projects, PrEP will be delivered as part of a comprehensive prevention package including risk-reduction counseling, sexually transmitted infection screening, and other components. Daily tenofovir/FTC (Truvada, a tenofovir/emtricitabine two-drug combination pill manufactured and distributed by Gilead Sciences Inc. of Foster City) will be offered to eligible uninfected high-risk men who have sex with men, as well as to transgender women. Gilead Sciences will provide the drug to support these studies. The studies will adhere to safety and implementation guidelines issued by the Centers for Disease Control and Prevention.

Previous international research has shown PrEP to be very effective in preventing new HIV infections among MSM and selected other risk populations, but only when taken as prescribed in addition to ongoing risk-reduction counseling, said Lemp. Recent studies have suggested that mixed results found for some populations may be due to a lack of consistent adherence to the medication, leading to suboptimal or ineffective levels of drug in the body, he noted.

In addition, Lemp said, other studies have suggested that identifying people infected with HIV and rapid institution of antiretroviral therapy not only improves survival of those treated, but also lowers the level of HIV virus in the community and might ultimately reduce HIV transmission rates.

The three grantee consortiums for this initiative include:

The Division of HIV and STD Programs at the Los Angeles County Department of Public Health in collaboration with UCLA, the Los Angeles Gay and Lesbian Center, AIDS Project Los Angeles, and the OASIS Clinic at Charles Drew University (total four-year budget: $5,767,146).  The L.A. County PrEP and TLC+ for HIV Prevention (PATH) consortium will conduct extensive screening for HIV among populations in high disease burden locations in Los Angeles County. The L.A. County PATH PrEP demonstration project plans to enroll 375 high-risk MSM and trangender women, who will receive a customized prevention package that may include PrEP. Of these, about 300 people will receive daily tenofovir/FTC-based PrEP, and will be assessed for safety, feasibility, adherence (using a real-time and full drug-level monitoring plan), risk behavior and HIV seroconversions over a 48-week period.

The L.A. County PATH TLC+ strategy plans a social network testing intervention among high-risk MSM (about 750 participants), with linkage to care for newly diagnosed HIV positive people. The group also will test strategies to re-engage out-of-care HIV-infected people using social networks, a peer navigation program and an intensive case management strategy (about 1,200 participants in this component).

“This demonstration project provides a unique opportunity to rigorously evaluate the feasibility, acceptability and effectiveness of biomedical HIV prevention strategies that have shown efficacy for reducing HIV transmission but have not been tested more broadly in high-risk communities outside of the clinical trial setting,” said Jennifer Sayles, M.D., M.P.H., medical director at the Los Angeles County Department of Public Health, Division of HIV and STD Programs, and assistant professor of medicine at UCLA. “Operational and implementation research conducted through this grant will allow us to answer some of the critical public health questions most relevant to curbing our local epidemic.”

The University of California, San Diego (lead project investigator Richard Haubrich, M.D.), in collaboration with the UCSD Antiviral Research Center and Owen Clinic; the L.A. County-University of Southern California Rand Schrader Clinic; the Harbor-UCLA Medical Center; the San Diego County HIV, STD and Hepatitis Branch; and the Long Beach Health and Human Services Agency (total four-year budget: $5,688,621). The California Collaborative Treatment Group (CCTG) consortium will conduct extensive HIV screening in San Diego, Los Angeles and Long Beach, including a social network-based testing strategy. The CCTG plans to enroll 400 eligible high-risk MSM, who will receive daily tenofovir/FTC-based PrEP, into a randomized study that evaluates whether a text messaging-based adherence intervention can improve their adherence to the PrEP medication. The study will follow participants for safety, feasibility, adherence, risk behavior and HIV seroconversion over a period averaging about two years.

The group also will assess the impact of active linkage and engagement (ALERT) specialists, who will work to ensure that people recently testing HIV positive (or who have fallen out of care) are engaged into HIV care and that eligible high-risk HIV-uninfected people are offered PrEP. The goal of the ALERT specialist is to reduce the time from HIV diagnosis to initiation of treatment. The CCTG investigations will involve some 1,500 participants.

“There is no question that biomedical HIV prevention strategies, such as PrEP for HIV-uninfected and initiation of early antiretroviral therapy for HIV-infected people, can prevent future HIV infection,” said Richard Haubrich, M.D., CCTG director and UC San Diego professor of medicine. “The key is to empower people to initiate and maintain strict adherence to therapy. Ultimately, we hope these efforts will result in a reduction of new HIV infections in high-risk populations and improved clinical outcome for those who are currently HIV infected.”

The East Bay AIDS Center at Alta Bates Summit Medical Center in Oakland and Berkeley (lead project investigator Jeffrey Burack, M.D., M.P.P., B.Phil.), in collaboration with the Center for AIDS Prevention Studies at UC San Francisco (total one-year budget: $336,730). This consortium will develop and refine innovative strategies for outreach, HIV testing, sexual health services and linkage to care for young MSM of color in Oakland, Richmond, Berkeley and other East Bay locations. The group will conduct a pilot study of clinic-based social network testing and self-testing for HIV, in the context of an innovative sexual health services program. The East Bay consortium also will plan and pilot strategies to offer PrEP to high-risk HIV-uninfected young MSM of color. The researchers will study model programs for engaging young HIV-positive MSM of color in primary care and will conduct focus groups and in-depth interviews to assess needs and priorities of this population, with the goal of eventually fielding a larger scale prevention program that incorporates culturally appropriate PrEP and TLC+.

“Young MSM of color in urban California are especially vulnerable to HIV, with annual rates of new infection comparable to those in sub-Saharan Africa,” said lead project investigator Jeffrey Burack, M.D., M.P.P., B.Phil., co-medical director of the East Bay AIDS Center and associate clinical professor at UC Berkeley and UCSF. “But these very people most at risk have been woefully under-researched when it comes to prevention interventions that will actually reach them. With CHRP’s support, we hope to implement and evaluate promising new interventions to stem the relentless surge of HIV through our community, potentially reducing its terrible toll on young lives and its costs to our health care system.”

The California HIV/AIDS Research Program (CHRP) provides state funding for cutting-edge, merit-reviewed, HIV-related research conducted at nonprofit research institutions and community-based organizations throughout California. The program has awarded more than 2,000 research grants to more than 50 California institutions since 1983. A 2006 survey of California investigators found that more than $5 in federal and other grant support was generated for every dollar invested by CHRP in California-based research.

For more information about the California HIV/AIDS Research Program, visit www.californiaaidsresearch.org.

UCLA-engineered stem cells seek out and kill HIV in living organisms.

Scott Kitchen, UCLA

Expanding on previous research providing proof-of-principle that human stem cells can be genetically engineered into HIV-fighting cells, a team of UCLA researchers has now demonstrated that these cells can actually attack HIV-infected cells in a living organism.

The study, published April 12 in the journal PLoS Pathogens, demonstrates for the first time that engineering stem cells to form immune cells that target HIV is effective in suppressing the virus in living tissues in an animal model, said lead investigator Scott G. Kitchen, an assistant professor of medicine in the division of hematology and oncology at the David Geffen School of Medicine at UCLA and a member of the UCLA AIDS Institute.

“We believe that this study lays the groundwork for the potential use of this type of an approach in combating HIV infection in infected individuals, in hopes of eradicating the virus from the body,” he said.

In the previous research, the scientists took CD8 cytotoxic T lymphocytes — the “killer” T cells that help fight infection — from an HIV-infected individual and identified the molecule known as the T cell receptor, which guides the T cell in recognizing and killing HIV-infected cells. However, these T cells, while able to destroy HIV-infected cells, do not exist in great enough quantities to clear the virus from the body. So the researchers cloned the receptor and used this to genetically engineer human blood stem cells. They then placed the engineered stem cells into human thymus tissue that had been implanted in mice, allowing them to study the reaction in a living organism.

The engineered stem cells developed into a large population of mature, multi-functional HIV-specific CD8 cells that could specifically target cells containing HIV proteins. The researchers also discovered that HIV-specific T cell receptors have to be matched to an individual in much the same way an organ is matched to a transplant patient.

In this current study, the researchers similarly engineered human blood stem cells and found that they can form mature T cells that can attack HIV in tissues where the virus resides and replicates. They did so by using a surrogate model, the humanized mouse, in which HIV infection closely resembles the disease and its progression in humans.

In a series of tests on the mice’s peripheral blood, plasma and organs conducted two weeks and six weeks after introducing the engineered cells, the researchers found that the number of CD4 “helper” T cells — which become depleted as a result of HIV infection — increased, while levels of HIV in the blood decreased. CD4 cells are white blood cells that are an important component of the immune system, helping to fight off infections. These results indicated that the engineered cells were capable of developing and migrating to the organs to fight infection there.

The researchers did note a potential weakness with the study: Human immune cells reconstituted at a lower level in the humanized mice than they would in humans, and as a result, the mice’s immune systems were mostly, though not completely, reconstructed. Because of this, HIV may be slower to mutate in the mice than in human hosts. So the use of multiple, engineered T cell receptors may be one way to adjust for the higher potential for HIV mutation in humans.

“We believe that this is the first step in developing a more aggressive approach in correcting the defects in the human T cell responses that allow HIV to persist in infected people,” Kitchen said.

The researchers will now begin making T cell receptors that target different parts of HIV and that could be used in more genetically matched individuals, he said.

Other study authors are Bernard R. Levin, Gregory Bristol, Valerie Rezek, Sohn Kim, Christian Aguilera-Sandoval, Arumugam Balamurugan, Otto O. Yang and Jerome A. Zack, all of UCLA.

The National Institutes of Health, the California HIV/AIDS Research Program, the California Institute for Regenerative Medicine, the UC Multicampus Research Program and Initiatives from the California Center for Antiviral Drug Discovery, and the UCLA Center for AIDS Research (CFAR) funded this study.

The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.

UCSF and SF General are both major training grounds for doctors who specialize in HIV/AIDS, and numerous research collaborations exist across the Bay Bridge.

At two of the largest hospitals near downtown Oakland, doctors have heard the same story so many times from young African-American men undergoing treatment for HIV/AIDS that they practically know it by heart.

They felt ostracized during their teen years. They first explored their sexual identities in secret. Their earliest encounters were covert trysts. But after a while, they found what they thought to be true love and acceptance in the arms of a much older man—whom they later discovered exposed them to HIV.

All these stories point to one thing, said Kathleen Clanon, M.D., ACMC, an attending physician and the former chief of HIV services at Highland Hospital, part of the county medical center and one of the main facilities treating people with HIV/AIDS in Oakland. If the medical community is to effectively confront the HIV/AIDS epidemic in Oakland, she said, it needs to connect with communities like the one these young men belong to: a loose-knit, insular, hidden and particularly vulnerable group made up of individuals who may not know they are at high risk and may not be receiving the information they need to protect themselves.

“If we could really reach out to them effectively, we wouldn’t see new cases in Alameda County,” Clanon said.

The epidemic across the bay

In the Bay Area and the United States as a whole, the HIV/AIDS epidemic continues to spread, particularly in urban areas and within certain populations such as young African-American men.

With changes and cutbacks in health care funding looming, Oakland doctors are concerned they may not be able to adequately address their community’s needs.

For decades, the University of California, San Francisco, and the San Francisco General Hospital and Trauma Center (SFGH) have led the medical establishment worldwide in patient care, professional training and research related to HIV/AIDS. Along with the San Francisco Department of Public Health and the greater medical community in the city, UCSF has helped set the standard for care for this disease since the earliest days of the epidemic. UCSF and SFGH are both places where people with HIV/AIDS get some of the best care in the world.

[Related: In focus: HIV/AIDS in 2012, Trauma drives HIV epidemic in women, Video depicts women with HIV]

Just 10 miles away, across the Bay Bridge in Oakland, patients also receive excellent care – assuming they are diagnosed and linked to care. Many of them are not.

Doctors in Oakland describe a smoldering epidemic, growing larger every year, that is in some ways more hidden than the epidemic in San Francisco. Providing world-class care to patients there is only one part of the challenge. Finding people at high risk, getting them tested, helping them avoid the virus or linking them to care if they are already infected are also huge issues that contribute to the overall nature of AIDS in Oakland.

The city of Oakland is part of Alameda County, where an estimated 6,000 to 7,000 or more people live with HIV/AIDS, said Damon Francis, M.D., of the East Bay AIDS Center, one of the county’s major providers for people with HIV/AIDS. Francis was a chief resident at SFGH before doing a one-year fellowship at the East Bay AIDS Center and has been compiling statistics on the HIV/AIDS epidemic in the East Bay.

His statistics show that the epidemic in Oakland closely follows national trends, with more infections appearing among women, people of color, and young people. Other urban centers in California face very different epidemics. San Francisco has a much larger gay population affected by the disease and Los Angeles has many more Latinos.

That only includes those diagnosed and counted. Francis adds that the lack of a centralized approach, added to the covert nature of homosexuality among some urban African-American men, makes it particularly difficult to know how many undiagnosed infections exist in Alameda County, which includes Oakland. “We know we’re undercounting, and we know the epidemic is getting worse,” he said.

Clanon estimates the actual number is closer to 9,000 people, with about 5,000 -6,000 in care at Highland Hospital, the East Bay AIDS Clinic Kaiser Permanente sites,  and at smaller clinics and private practices scattered across the county. The city and county of San Francisco, by comparison, has more than 15,000 people living with HIV/AIDS in a population about half the size of Alameda County.

Identifying the people who are not yet diagnosed is one of the keys to turning the tables on the epidemic. Yet, when these people are hard to identify, it is also one of the core challenges, especially when it comes to young men having sex with other men.

Traditional HIV prevention messages revolve around safe sex and are usually spread via health care providers. But healthy young men may not see themselves in need of health care unless they break a leg or have some other acute injury. As such, they may not access the system and are not likely to encounter traditional prevention messages in their daily lives.

Doctors in Oakland worry that their inability to reach such at-risk populations before they are exposed to the virus keeps the epidemic moving upward.

“We worry that not only do we not have the right preventive messages but we’re not giving them in the right places either,” said Jeff Burack, co-medical director of the East Bay AIDS Center.

According to Howard Edelstein, M.D., a doctor at the Alameda County Medical Center in Oakland who also specializes in HIV/AIDS care, somewhere between a third to half of the patients they see already have advanced AIDS when they come in for the first time. This makes their treatment more complicated because people with advanced AIDS are generally sicker and may have more co-infections and other complications.

Finding money for new prevention efforts is complicated by limited funds already split among organizations that represent the various affected populations.

HIV/AIDS funding: The question of Ryan White and Medi-Cal

The impending crisis over funding for HIV/AIDS in general creates a sense of urgency. Like many parts of the country, Oakland may be facing thinning resources just as its patient pool expands. For now, though, a major amount of financial support pours into the city from federal and state programs that help to pay for antiretroviral drugs and other services for people with HIV/AIDS.

The federal Ryan White Care Act alone provides about $7 million a year for the care of low-income people with the disease in Oakland, Clanon said. That money pays for doctors, social workers, nurses, support staff and numerous clinic programs. But most of all, it pays for drugs. The law enables people to begin taking drugs right away, often the same day they are diagnosed and even before they can document their income and residency requirements.

“It has been the cornerstone of care for poor people with HIV,” Clanon said. She estimates that two-thirds of the 1,200 patients undergoing treatment for HIV/AIDS at the county hospital are supported by this federal funding mechanism.

At the East Bay AIDS Center, which currently sees about 1,400 patients, Ryan White funding is the sole source of support for nearly 200 patients, including most of the 110 HIV-positive youth in care (ages 15-24).

Nationally, the Ryan White Act provides about $2 billion a year to hospitals and clinics across the United States. It is unclear what will happen to this funding after 2013, when the current authorization is due to expire. When this expiration loomed in the past, the Congress reauthorized the funding.  But in the current political and economic climate, no one is counting on that.

“The smart money, at the moment, is that it will either be greatly changed or will go away in 2013,” Clanon said.

Meanwhile, the patient population in Oakland continues to grow. In addition to the large caseload of existing patients, doctors at the East Bay AIDS Center added three or four additional patients per week last year. The county hospital is also adding hundreds of new cases annually.

Many of the patients in Oakland rely on state Medi-Cal funds, a health insurance program for low-income Californians that also faces an uncertain future. State cutbacks to Medi-Cal already have made it difficult for some patients to find specialized treatment because fewer and fewer doctors are accepting the public insurance.

“Try to find a urologist in the East Bay who takes Medi-Cal — there aren’t any,” Edelstein said. “Try to find an orthopedist who takes Medi-Cal – again, zero.”

A shared separation

Many of the people with HIV/AIDS in San Francisco are in the same situation as people in Oakland with respect to federal Ryan White funding and state Medi-Cal issues. Many also face the same complicating societal issues — homelessness, unemployment, poverty, food insecurity, drug addiction and so on.

“It is very heavily an epidemic of the disenfranchised,” Francis said.

In part because of such similarities, medical collaborations and other exchanges long have occurred on both sides of the Bay. UCSF and SFGH are both major training grounds for doctors who specialize in HIV/AIDS, and numerous research collaborations exist across the Bay Bridge as well.

Edelstein has participated in collaborations with UCSF researchers on a number of studies, including an ongoing trial called Intervention for those Recently Informed of Seropositive Status (IRISS), which looks at the effect of early psychiatric interventions for people with HIV and depression, a common reason why people with HIV/AIDS fail to adhere to their drug regimens.

Still, even if there is a strong sense of shared mission among doctors in San Francisco and in Oakland, differences remain. “We really don’t have anything close to what San Francisco has in terms of money and manpower to address HIV,” Francis said.

Clanon summed up the difference with a statement attributed to the Mexican politician Porfirio Diaz. President of Mexico for 40 years beginning in the 1870s, Diaz allegedly described his country using the phrase, “So far from God, so close to the United States.”

“That’s how I feel,” Clanon said.

High rate of trauma among American women with HIV/AIDS and its public health consequences revealed in two UCSF studies.

Edward Machtinger, director of the Women's HIV Program at UCSF, and clinical social worker Beth Chiarelli work together with patient Vicki Blake to address the many physical and social issues that often affect HIV-positive women.

Physical violence, sexual abuse and other forms of childhood and adult trauma are major factors fueling the epidemic of HIV/AIDS among American women. Scientists have known for years that traumatized women are at greater risk of becoming infected.

Now, two new studies from the University of California, San Francisco, and Harvard Medical School demonstrate that a high rate of trauma among women already infected with HIV also plays a role in the epidemic.

Described in back-to-back papers in the journal AIDS and Behavior, the new work demonstrates that women with HIV are exposed to trauma and suffer from posttraumatic stress disorder (PTSD) at rates far higher than those occurring in women in general.

The work may help to reframe many types of discussions about HIV/AIDS so that more clinicians take trauma into account when working with their patients.

Traumatized women fare worse in treatment for HIV/AIDS than women who have not suffered traumatic stress. Trauma also puts women in situations where they are more likely to spread the virus.

“For a long time we have been looking for clues as to why so many women are becoming infected with HIV and why so many are doing poorly despite the availability of effective treatment,” said Edward Machtinger, M.D., who directs the Women’s HIV Program at UCSF and who was the co-principal investigator on both studies. “This work clearly shows that trauma is a major factor in the HIV epidemic among women.”

[Related: In focus: HIV/AIDS in 2012, Confronting HIV in Oakland, Video depicts women with HIV]

American women with HIV are more than five times more likely to have PTSD and twice as likely to have been the victim of intimate partner violence compared to national samples of American women. The work also demonstrates the personal and public health consequences of trauma in HIV-positive women: women with HIV who report recent trauma are over four times more likely to fail their HIV treatment and almost four times more likely to engage in risky sexual behavior.

How trauma contributes to HIV/AIDS in women

The proportion of U.S. women diagnosed with HIV/AIDS has grown steadily for the last 30 years. In 1985, only 8 percent of new U.S. cases occurred in women. By 1992, that number had risen to 14 percent of new cases. Today, women account for at least 27 percent of new U.S. cases.

The new work helps understand some of the problems helping to drive the epidemic among American women, an epidemic that particularly impacts women of color.

Previous studies have shown that trauma contributes to the HIV/AIDS epidemic among American women because it is associated with variety of risky situations and behaviors among at-risk HIV-negative women and girls. But until now, no definitive estimates existed of the rates of trauma and PTSD among women and girls already infected with HIV. 

Machtinger and his colleagues used the statistical technique of meta-analysis to combine data from 29 prior studies that included 5,930 HIV-positive women to estimate the rates of trauma and PTSD in American woman with HIV. They found highly disproportionate rates of trauma exposure and PTSD — mostly between two and six times higher rates of various types of child and adult sexual and physical abuse and PTSD in HIV-positive women. This is particularly striking because rates of trauma in the general population of women are already high. As an example, the estimated rate of recent PTSD among HIV-positive women is 30 percent while that of the general population is 5.2 percent.

In a companion paper, the scientists sought to determine why so many women with HIV fare so poorly when taking HIV/AIDS drugs and also why many end up in situations where they could transmit the virus to others. To do so, the scientists analyzed detailed clinical and behavioral data collected from 113 women and female-identified transgender women in San Francisco who have HIV/AIDS.

The analysis revealed that ongoing trauma was strongly associated with both treatment failure and with risky situations and behaviors. Specifically, the study demonstrated that HIV-positive women who report recent trauma had more than four times the odds of experiencing virologic failure, a situation where the HIV virus becomes detectable in the blood despite being on antiretroviral mediations. This situation can lead to HIV-related illnesses and to the virus developing resistance to the antiretroviral medications. The work also revealed that women who had suffered recent trauma were more almost four times more likely to have had sex with someone without the virus or whose HIV status was unknown to them, and to not always use condoms with these partners.

This has important public health consequences, said Machtinger. People failing their medications are particularly infectious because their virus is not suppressed. If they have unprotected sex with someone who does not already have HIV, there is a higher risk of further infection.

“Women who report experiencing trauma often do not have the power or self-confidence to protect themselves from acquiring HIV,” Machtinger said. “Once infected, women who experience ongoing abuse are often not in positions of power to effectively care for themselves or to insist that their partners protect themselves. Effectively addressing trauma has the potential to both improve the health of HIV-positive women and that of the community.” 

The study was not large enough to determine exactly how recent trauma leads to treatment failure; one possibility is that suffering trauma interferes with a woman’s ability to take her HIV medications as consistently as necessary. The authors also believe that, for some women, substance abuse and depression are closely related to trauma and that all may contribute to the poor outcomes seen in the study.

The work identified very simple screening questions for recent and lifetime trauma which could be readily used in clinical practice. According to Jessica Haberer, M.D., M.S., of Harvard Medical School, “Our studies have the potential for immediate clinical impact in that we ascertained practical ways for clinicians to identify patients at risk.” 

For example, asking a simple question about recent trauma may help identify patients at higher risk for poor health outcomes and risk of further transmission. This may allow for a more effective allocation of scarce clinic and community resources, such as safety assessment, trauma-related therapy, medication-taking support and transmission-prevention counseling.  The authors also believe that efforts to treat substance abuse and depression may be more effective if such counseling acknowledges that ongoing trauma may be contributing to both conditions.

“We have to learn to ask about trauma and to develop creative approaches to trauma-prevention and trauma-recovery,” Machtinger said. “This is actually an amazing opportunity to have a significant impact on the HIV/AIDS epidemic, especially among minority women.”

The article, “Psychological Trauma and PTSD in HIV- Positive Women: A Meta-Analysis” by E.L. Machtinger, T.C. Wilson, J.E. Haberer and D.S. Weiss was published online by the journal AIDS and Behavior on Jan. 17. See: http://dx.doi.org/10.1007/s10461-011-0127-4.

The article, “Recent Trauma is Associated with Antiretroviral Failure and HIV Transmission Risk Behavior among HIV-positive Women and Female-identified Transgenders” by E.L. Machtinger, J.E. Haberer, T.C. Wilson, and D.S. Weiss will be published online by the journal AIDS and Behavior this month. Once the article appears online, it will be accessible at: http://dx.doi.org/10.1007/s10461-012-0158-5.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

UCSF-led study shows how interferon works to suppress virus in patients with HIV, hepatitis.

Satish Pillai, UC San Francisco

A drug once taken by people with HIV/AIDS, but long ago shelved after newer, modern antiretroviral therapies became available, has now shed light on how the human body uses its natural immunity to fight the virus — work that could help uncover new targets for drugs.

In an article published online this month by the journal PNAS, a group of American and Swiss researchers led by scientists at the University of California, San Francisco, presented the first clinical assessment of how this drug fights infections in people. The drug, called interferon, is a biotechnology product based on a protein the body naturally produces to fight infections.

While purified interferon was given to people with HIV/AIDS in the early days of the epidemic because it alleviated many of the symptoms of the disease, its mode of action was always something of a black box.

“Nobody knew how it worked,” said Satish K. Pillai, Ph.D., lead investigator and an assistant professor of Medicine at UCSF and the UCSF-affiliated San Francisco VA Medical Center.

Experiments in the laboratory in recent years have shown how interferon may work to suppress HIV in vitro, but there was no clinical evidence until now showing how the drug attacks HIV in treated patients. The problem is that so few people actually take interferon for HIV any more. However, interferon is still used in combination with other drugs to treat hepatitis C, which gave the team the possibility to assess its effect on HIV.

Interferon is commonly used to treat people with hepatitis C virus, and Pillai and his colleagues were able to identify 20 people enrolled in the Swiss HIV Cohort Study, which began in 1988, who have both HIV and hepatitis C. All 20 were taking interferon to treat their hepatitis C, but none were receiving antiretroviral drugs to treat HIV. This allowed researchers to examine how interferon works to suppress the virus.

How interferon works

The new work sheds further light on somewhat mysterious components of the immune system known as restriction factors, which are chemicals the human body produces to keep viruses like HIV in check and prevent them from infecting other cells.

These are just two fronts in the overall battle between HIV and the immune system — a battle in which the immune system seeks to destroy the virus while the virus constantly counters by undermining the immune system.

Unlike other parts of the immune system, where whole cells gobble up invading pathogens or attack other cells, the action of these restriction factors is more subtle and localized within the infected cell itself — one of the reasons scientists didn’t appreciate what they do until just a few years ago.

One of them, called APOBEC3, fights viruses by stealthily jumping onto new virus particles as they form. Therein, the APOBEC3 protein fouls up HIV’s genetic material by mutating it. When the virus tries to infect another cell, it no longer has the potency to replicate.

Another factor, called tetherin, takes an even more direct approach. It attaches to virus particles as they emerge from infected cells in the body and literally tethers them in place, preventing them from moving elsewhere in the body where they could infect new cells.

HIV has its own countermeasures to thwart these defenses. It produces a protein known as Vpu that neutralizes tetherin. Another HIV protein, called Vif, subverts APOBEC.

In the new study, Pillai and his colleagues showed that interferon combats HIV by mediating the action of both of these restriction factors. They collected samples from the 20 patients and measured the levels of APOBEC3 and tetherin before, during and after they took the drug interferon. The levels increased in response to interferon when the drug was in the bloodstream, and patients with the highest restriction factor levels showed the most precipitous drop in HIV viral load during interferon treatment.

While this insight does not immediately suggest new drugs or new ways of treating people with HIV, Pillai said scientists armed with this knowledge may one day figure out how to enhance this defense mechanism and specifically enhance the expression of restriction factors like tetherin and APOBEC3 in HIV-1–infected individuals.

If these factors can be induced to higher levels, their attack on the virus may become more potent — perhaps even overriding HIV’s countermeasures and helping flush the virus from infected cells.

The article, “Role of retroviral restriction factors in the interferon-α–mediated suppression of HIV-1 in vivo,” was written by Satish K. Pillai, Mohamed Abdel-Mohsen, John Guatelli, Mark Skasko, Alexander Monto, Katsuya Fujimoto, Steven Yukl, Warner C. Greene, Helen Kovari, Andri Rauch, Jacques Fellay, Manuel Battegay, Bernard Hirschel, Andrea Witteck, Enos Bernasconi, Bruno Ledergerber, Huldrych F. Günthard, Joseph K. Wong, and the Swiss HIV Cohort Study.

In addition to UCSF, the authors of this study are affiliated with the San Francisco VA Medical Center, the Veterans Affairs San Diego Healthcare System at the University of California at San Diego, the Gladstone Institute of Virology and Immunology, and the Swiss university hospitals of Zurich, Berne, Lausanne, Basel, Geneva, St. Gallen and Lugano.

This work was funded by the National Institutes of Health and through the American Recovery and Reinvestment Act. Additional support was provided by Swiss HIV Cohort Study Project 594; the Veterans Affairs Merit Review; and several Swiss National Science Foundation Grants. The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation and the Swiss HIV Cohort Study Research Foundation.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

New treatments are coming for liver-damaging virus.

Alex Monto, UC San Francisco

Hepatitis C virus — not AIDS-causing HIV — is the leading chronic virus infection leading to death in the United States, and its victims most often are baby boomers. More than half who are infected do not know it.

Researchers from the U.S. Centers for Disease Control and Prevention (CDC) found in a study published in the Feb. 21 issue of the Annals of Internal Medicine that hepatitis C had overtaken HIV as a cause of death in the United States by 2007.

Deaths in the United States due to HIV infection have been steadily decreasing, and  dropped below 13,000 in 2007, while deaths from hepatitis C infection have been steadily increasing, first surpassing 15,000 per year in 2007.

The good news, according to UC San Francisco liver specialist Alex Monto, M.D., is that there has been progress in fighting both diseases, and the kinds of drug combination strategies that have done so much to transform HIV infection from a death sentence to a manageable disease are poised to further boost cure rates for those infected with hepatitis C.

“We know that not enough people with risk factors get tested,” Monto says. “There are a lot of people walking around with hepatitis C who don’t know it.”

Monto directs the liver clinic at the UCSF-affiliated San Francisco Veteran’s Affairs Medical Center, one of four hepatitis C centers nationally within the VA system. Like boomers, veterans are disproportionately affected by hepatitis C. The VA cares for 165,000 patients who are chronically infected with the virus.

Hepatitis C infects 3 million in the U.S.

Chronic Hepatitis C has been diagnosed in about three million people in the United States. It often causes no symptoms, and many who have been infected for years or even decades may remain unaware of it until symptoms finally appear. The ultimate cause of death attributable to chronic infection is cirrhosis or liver cancer, although the disease progresses to cirrhosis in fewer than half of cases. There is no vaccine.

“The main risk factor in the United States is past injection-drug use,” Monto says. “The others most at risk are those who received blood transfusions before 1992,” Monto says, referring to the year when high-quality screening of the blood supply was implemented.

[Related: Hear Alex Monto talk about hepatitis C]

Compared to HIV or hepatitis B, the risk of hepatitis C being transmitted by sex is low, Monto says, but among men who have sex with men there has been an increase in reports of the virus being sexually transmitted, more so among those who are infected with HIV.

“Anybody with a history of ever being exposed to injection drugs or who received a transfusion before the blood supply was screened should be tested,” Monto says. “That’s not controversial at all. What has been controversial is whether or not all baby boomers should be screened.”

Another study in this week’s edition of the journal suggests that a one-time blood test ordered by primary care providers to screen for antibodies to hepatitis C in those born between 1945 and 1965 would be cost effective — costing $2,874 for each chronically infected patient identified — and would lead to the identification of more than 800,000 previously undiagnosed cases.

Those who are chronically infected may be able to reduce the likelihood of disease progression by avoiding alcohol, by maintaining a healthy weight, and by being vaccinated against hepatitis A and hepatitis B, Monto says.

Read more