Analysis of Kenya study shows simultaneously confronting AIDS, malaria and waterborne illness improves health.

A volunteer in 2008 shows people from the Lurambi District in Western Kenya how to use incecticide-treated bednets to prevent the spread of malaria

The great paradox of global health efforts is that regions of the world most plagued by poverty, poor infrastructure and rampant disease are often the most difficult to support. Now, scientists have demonstrated that confronting several diseases at once can make the most of thinly-stretched donor dollars and national health care budgets, to help to save lives.

A new analysis published this week in the open-access journal PLoS ONE (Feb. 3) focused on a combined public health campaign in Western Province, Kenya led by the Swiss-based company Vestergaard Frandsen, the Kenyan Ministry of Health and the U.S. Centers for Disease Control and Prevention (CDC). The analysis looked at the cost effectiveness of simultaneously confronting the problems of HIV/AIDS, malaria and diarrhea caused by waterborne pathogens.

The researchers used the results of the campaign to build an analysis of the impact such efforts could have if carried out more broadly. The analysis found that for every 1,000 people reached through such campaigns, some $16,015 in health care costs would be avoided and more than 16 lives would be saved. As a result, local populations would gain hundreds of years of healthy life. The cost would be $32 per person, but averted health care costs would be greater, leading to the net savings.

“That’s a very attractive deal,” said James G. Kahn, M.D., M.P.H., a professor of health policy, epidemiology and global health at the University of California, San Francisco, who is the senior author on the PLoS ONE study and led the economic aspect of the research. “This kind of a campaign is an excellent use of global health dollars.”

Health care workers distributed “CarePacks” at 37 locations in Kenya over seven days in 2008. These packs contained insecticide-treated bed nets to reduce the spread of malaria, water filters for preventing diarrheal diseases, and condoms.

Some 47,000 people ultimately received the packs, which also contained educational information as incentive for local residents to participate in a voluntary HIV testing and counseling program.

By combining efforts to reduce the burdens of malaria, diarrhea and HIV/AIDS, the program efficiently stretched the impact of its funds, Kahn said, which is important in areas where per capita health expenditures may amount to little more than a few dollars a year. Combining these public health efforts into one program also saved a great deal of time, he added.

“This program was implemented in seven days, reaching 80 percent of the local population,” Kahn said. “This rapid implementation means more health benefits were quickly achieved.”

Other co-authors of the article, “Integrated HIV Testing, Malaria, and Diarrhea Prevention Campaign in Kenya: Modeled Health Impact and Cost-effectiveness” are N. Muraguri, B. Harris, E. Lugada, T. Clasen, M. Grabowsky, J. Mermin and S. Shariff.

Kahn is based in the UCSF Philip R. Lee Institute for Health Policy Studies, the Department of Epidemiology and Biostatistics, and Global Health Sciences.

In addition to UCSF, authors on this study are affiliated with the Kenyan Ministry of Public Health and Sanitation, CHF International, the London School of Hygiene & Tropical Medicine, the ESP/UN Foundation, and the CDC.

The analysis was funded by the U.S. National Institute on Drug Abuse and by the company Vestergard Frandsen, which managed the campaign and manufactured the water filters and bed nets distributed.

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.

UC Merced biochemist is working to find a new way to block HIV.

Patricia LiWang, UC Merced

Patricia LiWang put two and two together last year. The UC Merced biochemist combined bits of two proteins to create the potential ingredients of a powerful new microbicide.

If all the kinks are worked out, and the ingredients make it into a tube and onto a shelf, they can block HIV from entering and infecting human cells in a sexual setting. Their potency is up to 100 times greater than existing HIV inhibitors. While most of the glamour these days is associated with vaccine research, LiWang is hopeful microbicides still have a chance in a world that needs every tool possible to prevent HIV infection.

LiWang grew up in a small working-class town in Pennsylvania and never knew she wanted to be a scientist until she went to MIT. “I thought I wanted to be an electrical engineer, because that’s what everyone did back then. Of course, they make you take a chemistry course for engineering, and I thought, wow, I really love this. I kept putting off the engineering courses and taking the chemistry courses,” she says.

LiWang went on to do research at the National Institutes of Health, and to professorships at Purdue and Texas A&M. Her husband does biochemical research on the mysteries of “clock” proteins, the timers in the human body researchers think affect when we wake and sleep, or even when a heart attack hits. “We have side-by-side labs,” says LiWang. “It’s very hard to get a job for two professors in same town, so we’re lucky to be at UC Merced.”

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See also this story about Patricia LiWang: UC Merced professor launches diaper drive to help the poor

UCSF-led research may reveal new ways to design future HIV/AIDS drugs.

Nevan Krogan, UC San Francisco

In perhaps the most comprehensive survey of the inner workings of HIV, an international team of scientists led by researchers at the University of California, San Francisco, has mapped every apparent physical interaction the virus makes with components of the human cells it infects—work that may reveal new ways to design future HIV/AIDS drugs.

Explored this week in back-to-back papers in the journal Nature, the survey reveals a pathogenic landscape in which HIV’s handful of proteins makes hundreds of physical connections with human proteins and other components inside the cell.

In one paper, the team details 497 such connections, only a handful of which had been previously recognized by scientists. Disrupting these connections may interfere with HIV’s lifecycle, and the existence of so many new connections suggests there may be several novel ways to target the virus.

“Have we identified new drug targets?” said Nevan Krogan, Ph.D., who led the research. “I believe we have.”

Krogan is an associate professor of Cellular and Molecular Pharmacology at UCSF and an affiliate of the California Institute for Quantitative Biosciences (QB3). He is also a faculty member at the UCSF-affiliated J. David Gladstone Institutes in San Francisco. Drawing upon the expertise of several laboratories that are world leaders in this area of research, Stefanie Jager, the lead author from the Krogan lab, collaborated with several other labs in the UCSF School of Medicine and the UCSF School of Pharmacy – including those of Andrej Sali, Alan Frankel, Charles Craik, Alma Burlingame, Ryan Hernandez and Tanja Kortemme – to carry out the global analysis.

In a companion paper, Krogan and collaborating labs of John Gross (UCSF) and Reuben Harris (University of Minnesota) investigated one such connection in detail. They discovered that an HIV protein called Vif makes a physical connection with a human protein called CBF-β, hijacking its function. This virus requires this action to function, said Krogan, which suggests that disrupting the connection may be a viable way to design new HIV/AIDS therapies.

“This is a good example of how biophysical studies can improve our understanding of disease and point the way to the exploration of potential therapeutic targets,” said Judith H. Greenberg, Ph.D., acting director of the National Institute of General Medical Sciences (NIGMS).

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Accomplished UC Irvine scientist and award-winning mentor.

Sheryl Tsai, UC Irvine

Most professors will say that they look at the “Rate My Professor” website with trepidation. It’s easy to get discouraged if a student complains that your grading isn’t fair, or you have dandruff or, even worse, that you’re boring.

Sheryl Tsai has no such fears. Her reviews are unanimous raves, and she has the teaching awards to prove it. “She’s hilarious,” writes one student. “She actually enjoys talking about biology with her students!” writes another.

An associate professor at UC Irvine, Tsai works in the hot new field of chemical biology, harnessing a compendium of scientific disciplines to the task of discovering new drugs.  In 2006, she was named a Pew Scholar for her research on the genetic modification of polyketides, natural products of plants, fungi and bacteria that can form the basis for new treatments for HIV, diabetes and cancer.

Her research has gained international recognition, but she’s just as proud of the teaching awards she’s earned at UC Irvine, including the prestigious Golden Apple Award for Teaching in the Biological Sciences. She mentors five or six students each year through UC Irvine’s Undergraduate Research Opportunities Program.

The UC Berkeley-educated Tsai grew up in Taiwan. (Her first name, Shiou-Chuan, informally became Sheryl after she arrived in the U.S.) By the time she was in high school, cultural and political ferment was loosening the grip of the island’s leaders and, as a result, Tsai says that when she arrived in Berkeley, the famously liberal city felt like home — almost.

Q: Your undergraduate and master’s degrees are from the University of Taiwan. Is university education different there?

A: Most of the professors have Ph.D.s from the United States, so it was very Americanized. Taiwan is a very open country with a big influence from the United States.  I grew up watching “The A-Team” every night.

Q: Berkeley isn’t exactly like the rest of America. Was it a shock?

A: Not really. I think the reason I felt comfortable at Berkeley was the emphasis on social justice. That year, the city of Berkeley increased parking fees, and to show their opposition, people knocked the heads of the parking meters off and planted flowers in them. Everywhere in the city, you saw flowers planted in the beheaded parking meters.

Amyloid fibrils in semen, shown here in red, enhance HIV infection by helping HIV — shown in green -- find and attach to its target, CD4 T white blood cells.

Breakthrough by Gladstone Institutes offers new hope in fight against global pandemic.

Scientists at the Gladstone Institutes have discovered new protein fragments in semen that enhance the ability of HIV, the virus that causes AIDS, to infect new cells—a discovery that one day could help curb the global spread of this deadly pathogen.

HIV/AIDS has killed more than 25 million people around the world since first being identified some 30 years ago. In the United States alone, more than one million people live with HIV/AIDS at an annual cost of $34 billion.

Previously, scientists in Germany discovered that HIV transmission is linked to the presence of an amyloid fibril in semen. This fibril—a small, positively charged structure derived from a larger protein—promotes HIV infection by helping the virus find and attach to its target: CD4 T white blood cells. In tomorrow’s issue of Cell Host & Microbe, researchers in the laboratory of Warner C. Greene, M.D., Ph.D., who directs virology and immunology research at Gladstone, describe a second type of fibril that also has this ability. Gladstone is affiliated with UC San Francisco.

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New programs that use HIV drugs to prevent infection can help reduce drug resistance when implemented properly, UCLA researchers say.

A new weapon has emerged to prevent HIV infection. Called pre-exposure prophylaxis, or PrEP, it is a strategy of providing medications to at-risk people before they are exposed to the virus. Having shown great promise in recent phase 3 clinical trials, PrEP may soon be rolled out for public use.

Because PrEP is based on the same drugs used to treat HIV-infected individuals, the big public health fear is that the dual use of these drugs will lead to skyrocketing levels of drug resistance. But in a new study, UCLA researchers say the exact opposite is likely to happen.

Sally Blower, director of the UCLA Center for Biomedical Modeling and a professor at the Semel Institute for Neuroscience and Human Behavior at UCLA, and colleagues used sophisticated computer modeling to determine that a PrEP prevention program used alone, or current HIV treatment programs used alone, could indeed, separately, increase drug resistance. But if used together, the researchers say, resistance is likely to decrease.

Their findings appear in the current online edition of the peer-reviewed journal Scientific Reports, published by Nature Publishing Group.

“This was a very big surprise,” said Blower, the study’s senior author. “We found that this counterintuitive effect will only occur if adherence to the PrEP prevention program, where individuals have to take a daily pill, is very high. This counterintuitive effect occurs when the beneficial effect of PrEP in preventing infections is so great that it overcomes both its own detrimental effect on increasing resistance and the detrimental effect of current HIV treatments on increasing resistance.”

Africa is ground zero for HIV and AIDS, a continent where the death rate is simply “awful,” Blower said. Since the country of Botswana was one of the sites for the PrEP drug trial, Blower and her colleagues chose it for their modeling. Botswana has the best health care system in Africa, they said, yet 30 percent of women and 20 percent of men are infected with HIV.

“Botswana is likely to lead the way in rolling out PrEP,” said Virginie Supervie, first author of the current study and a former postdoctoral fellow in Blower’s laboratory. “So officials there are worried about increasing levels of resistance.”

Most health officials feel that if you have a good treatment program in place, it makes sense to establish a good prevention program in the same place. Health officials plan to implement PrEP prevention programs only where treatment programs are highly successful and levels of resistance are low, the researchers said.

But in a second counterintuitive finding, the UCLA researchers say this conventional approach is actually the worst strategy. Instead, they suggest, PrEP programs should be rolled out around treatment programs that are having little success and where rates of resistance are high. Their model shows that this unconventional approach would prevent the maximum number of infections and result in the greatest decrease in drug resistance.

“By cutting down infections, the PrEP programs will decrease the number entering treatment programs, and therefore, fewer individuals will acquire drug resistance,” Blower said. “So introducing PrEP around the worst treatment programs will have the most impact on reducing resistance.”

A PrEP clinical trial that involved men who had sex with men and transgender women who had sex with men found that PrEP reduced the risk of acquiring HIV infection by 44 percent. Two other PrEP trials, which involved heterosexual men and women, showed significant reductions in risk, ranging as high as 73 percent.

“These results are very promising,” Supervie said. “Our model shows that if the roll-out of PrEP is carefully planned, it could decrease resistance and increase the sustainability of treatment programs. But if it is not, resistance could increase, and the sustainability of treatment programs in resource-constrained countries could be compromised.”

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From research to global outreach, UCSF commemorates three decades of AIDS.

UC San Francisco has been working for the past 30 years as a leader in AIDS basic and clinical research, patient care, policy development and community and global outreach – efforts that continue today. With World AIDS Day this week, UCSF commemorates three decades of AIDS.

Thirty years after the first cases of HIV/AIDS were reported in San Francisco, Los Angeles and New York, experts believe the epidemic has reached an important crossroads, where new infections can be warded off in a wide variety of ways. Read more.

As physicians working on the frontlines of HIV/AIDS since its start 30 years ago near retirement, UCSF is looking to attract and train the next generation of doctors to specialize in HIV/AIDS medicine. Read more.

A cheaper laboratory test that helps guide anti-retroviral drug treatment for people with HIV/AIDS may be just as effective as a more sophisticated test, a group of international researchers has found – a discovery that could be particularly important in rural Africa. Read more.

The New Generation Health Center, which seeks to reduce the number of unintended pregnancies and sexually transmitted infections among high-risk youth in San Francisco, is hosting a fundraiser on Dec.1 to support its community outreach activities. Read more.

Ellen Schell, R.N., Ph.D., director of International Programs for the Global AIDS Interfaith Alliance and an associate adjunct professor in the UCSF School of Nursing, reflects on the uphill battle to combat AIDS in Malawi, a tiny, impoverished country of 15 million. Read more.

For more information: View UCSF’s special package of AIDS stories, media coverage, timeline and historical facts

Related coverage:

• UC San Diego’s Douglas Richman discusses AIDS/HIV advances
• UCTV programs on AIDS/HIV

The gel could significantly reduce HIV transmission.

Peter Anton, UCLA

A topically applied microbicide gel containing a potent anti-HIV drug has been found to significantly reduce infection when applied to rectal tissue that was subsequently exposed to HIV in the laboratory, according to a new study by the UCLA AIDS Institute. The gel was also found to be safe and acceptable to users.

The first-ever phase 1 clinical trial of the rectal HIV-prevention drug known as UC781, a non-nucleoside reverse transcriptase inhibitor, is described in the current edition of the online journal PLoS ONE.

HIV in bloodstream at undetectable levels not associated with increased markers of inflammation or risk of death.

Phyllis Tien

Low level HIV viremia — the presence of HIV in the bloodstream at levels undetectable by standard tests — was not associated with increased blood markers of inflammation or coagulation, or with increased risk of death, in adults taking highly active anti-retroviral therapy (HAART) for HIV infection, in a study led by researchers at the San Francisco VA Medical Center and the University of California, San Francisco.

“This answers an important question in the HIV research and patient community, namely whether low level viremia is associated with persistent immune activation in patients being treated for HIV,” said senior investigator Phyllis C. Tien, M.D., an SFVAMC physician and an associate professor of medicine at UCSF.

Persistent immune activation can lead to inflammation and coagulation, which in turn can increase the risk of cardiovascular disease, clotting and stroke, said Tien. “We did not find that patients with low level viremia have increased inflammation and coagulation, which means that we need to focus on other possible mechanisms by which HIV increases inflammation and coagulation,” she said.

The study was published Wednesday (Nov. 2) in PLoS One.

Patients on HAART generally are monitored every three months, said Tien, with the goal of maintaining their virus levels below the limit detectable by standard tests — 50 to 75 copies of virus per milliliter of blood, depending on the test. However, she said, studies have shown that even among patients on HAART with low levels of virus, elevations in markers of inflammation and coagulation are associated with an increased risk of cardiovascular disease and death. Thus, she said, “researchers have been wondering whether circulating virus below the lower limit of detection might be associated with immune activation and inflammation.”

Tien and her team analyzed blood samples from 1,116 HIV-infected participants in the Study of Fat Redistribution and Metabolic Changes in HIV Infection, an ongoing nationally representative longitudinal study of HIV-infected adults in the United States — making it “the largest study to date to look at this question,” said Tien.

The testing was performed by Roche Molecular Diagnostics, which used a newly approved assay to measure the presence of virus below the clinically approved limit of 20 copies of virus per milliliter of blood.

“Contrary to presumptions in the field,” said Tien, the assay did not find that low level viremia was associated with elevated levels of IL-6, a marker of inflammation, or fibrinogen, a marker of coagulation. Furthermore, there was no association between any level of virus and the presence of C-reactive protein — another marker of inflammation — or increased risk of death.

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The miracle of organ transplantation on UCTV.

Transplantation is accepted as optimal therapy for patients with end-stage organ disease. Successful replacement of the heart, lung, liver, kidney, pancreas and small bowel can now be achieved. As a consequence, more and more patients are availing themselves to this therapy. Currently in the United States, there are more than 110,000 patients listed with the national registry awaiting transplantation; last year there were just over 28,500 transplants performed, underscoring the major disparity between need and supply.

The University of California provides half of all transplants in the state, and UC San Francisco has one of the world’s largest and most successful transplant programs. In this UCTV series from the UCSF Osher Mini Medical School for the Public, UCSF specialists share the whys, hows and what happens of organ failure and transplantation, live donor transplantation, alternative therapies, organ distribution, and organ engineering. In sum, the series will give you an understanding of how spare parts are used to produce miracles.

Programs include:

What Organ Shortage? Just Make Your Own! Stem Cells and Organ Engineering
First air date: Nov. 7

HIV Transplant: The Good, The Bad, The Unexpected
First air date: Nov. 14

Kidney Transplants: Who Needs One? How Do We Do It?
Nov. 21

Immunosuppressive Medications for Transplantation: The Good, The Bad and The Ugly
First air date: Nov. 28

Related links:

More Mini Medical School videos on UCTV

More about the UCSF Osher Mini Medical School lecture series

UCSF: Improving outcomes in organ donor transplantation

UCLA: Index devised for predicting survival after liver re-transplantation

UC San Diego: Domino liver transplant treats two rare diseases

UCLA: Donor heart arrives ‘warm and beating’ (video)

UC Davis: The gift of life: Thanking organ donor families

UCLA launches program to provide face, hand and abdominal wall transplants

UCLA’s first hand transplant patient adapting well (video)

UCSF liver transplant team shares expertise in Latin America

UC San Diego: Two hearts beat as one (video)

UC San Diego: West Coast’s first total artificial heart implanted

UC Davis: Extraordinary larynx transplant restores voice to California woman

UC Irvine recognized for its commitment to organ donation

More testing and development needed on promising discovery.

Patricia LiWang, UC Merced

In a significant step toward reducing the threat of HIV, UC Merced professor Patricia LiWang has designed what may be the most effective chemical inhibitor against infection of the virus.

“We need a fairly wide arsenal of HIV drugs because the virus is always mutating,” LiWang said. “Drugs become less effective as time goes on.”

LiWang’s inhibitor, a novel combination of two existing drugs, has a strength that ranges from several times better than existing inhibitors to several hundred times better, depending on the strain of HIV. The inhibitor works by blocking HIV from entering a person’s cell at two different steps of viral entry. This so-called “entry inhibition” is at the forefront of new strategies for stopping the virus.  Other existing inhibitors have different strategies, such as preventing HIV from carrying out activities like replicating or integrating into the human genome.

There are hundreds of different strains of HIV, LiWang said, and the virus mutates when it gets inside a person’s body.

“However, since this drug is a combination of two inhibitors, it would be nearly impossible for a virus to mutate so it wouldn’t get hit with either one of these drugs,” she explained.

The research is an example of UC Merced’s faculty addressing real-world health problems.

The inhibitor is a special protein produced from harmless bacteria, which allows for large amounts to be made. The inhibitor could be added to a vaginal cream that woman could apply to guard against the virus. While condoms protect against HIV, many men in sub-Saharan Africa and other areas won’t wear them, and women often don’t have a choice in the decision.

LiWang’s findings were published in August in The Journal of Biological Chemistry. Graduate Student Bo Zhao was the first author on the paper. Marie K. Mankowski, Beth A. Snyder and Roger G. Ptakfrom the Southern Research Institute were also part of the study.

Though the discovery is promising, much more testing and development is needed before it could be used by people in countries ravaged by the AIDS epidemic. The next step would be to see if it causes inflammation or any side effects. Clinical trials would be years off.

“We hope that a company is interested in it and we hope to get funding to keep developing it and see why it works,” LiWang said.

Clinical trial points to HPV vaccine as potential preventive factor against malignancy.

Joel Palefsky, UC San Francisco

A large, international clinical trial led by doctors at the University of California, San Francisco, indicates that a vaccine to prevent anal cancer is safe and effective, according to a study reported in today’s (Oct. 27) issue of New England Journal of Medicine.

Though anal cancer is less common than other forms of the disease in the United States, the number of cases has increased in recent years, and is particularly common among men who have sex with men and HIV-infected individuals.

Anal cancer is caused by infection with human papilloma virus (HPV), the most common sexually-transmitted pathogen in the United States. The virus also causes cervical cancer in women, and the vaccine is already approved and routinely recommended to prevent this condition. The new clinical trial suggests that the same vaccine would also protect men, and likely women, against anal cancer.

In the 1990s, UCSF established the Anal Neoplasia Clinic at the UCSF Helen Diller Family Comprehensive Cancer Center, the world’s first clinic devoted to promoting research, awareness, screening and prevention of anal cancer. UCSF professor Joel Palefsky, M.D., FRCPC, who founded and directs the clinic, led the clinical trial, and has recently founded a new professional society devoted to the study of the disease.

“Almost six thousand people every year in this country are diagnosed with anal cancer, and more than 700 people die from the disease,” said Palefsky. “What this trial showed is that those cancers and deaths could be prevented.”

The trial involved a group of 602 men who have sex with men from Australia, Brazil, Canada, Croatia, Germany, Spain and the United States all of whom had at least one, but no more than five, sexual encounters and who were between the ages of 16-26 years. All were randomized into groups that either received a placebo or a three-shot injection of the vaccine Gardasil, which protects against HPV 16 and 18, the most common HPV types involved in anal cancer, and HPV 6 and 11, the most common types in anogenital warts.  The patients were enrolled in the trial from 2006-2008, and they were followed for three years after their last shot.

As described in the paper, the vaccine proved effective at reducing anal infections with HPV and precancerous lesions known as high-grade anal intraepithelial neoplasia, which are anal cancer precursors.  The trial showed that the vaccine reduced the incidence of these cancer precursors by nearly 75 percent among those who had not been previously exposed to any of the HPV types in the vaccine.  Among those who were previously exposed to one or more of the types in the vaccine, the vaccine reduced the incidence of the precancerous lesions by 54 percent.

“Based on these data, the vaccine works well to prevent HPV infection and precancerous anal disease, and will likely prevent anal cancer in men,” said Palefsky. “The ideal time to begin vaccination would be before initiation of sexual activity, but vaccination may also be useful after initiation of sexual activity.”

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