The National Institutes of Health has awarded Albert Einstein College of Medicine of Yeshiva University a four-year, $7.2 million grant to develop a microbicide-releasing vaginal ring to prevent HIV transmission.

“While condoms are excellent at preventing the transmission of HIV, it’s often difficult for women to negotiate their use,” says principal investigator Betsy C. Herold, M.D., professor of pediatrics, of microbiology & immunology, and of obstetrics & gynecology and women’s health at Einstein. “It’s imperative that women have alternative strategies available to protect their own health. Our belief is that an intravaginal ring that delivers a combination of drugs is the best strategy.”

Vaginal rings are soft, plastic, doughnut-shaped devices designed to provide controlled release of drugs to the vagina over extended periods. At present, there are several models available for delivering contraceptives, but none for microbicides.

Dr. Herold and her colleagues will evaluate several anti-HIV microbicides, ultimately aiming for a two-drug combination. “Over the last decade, we’ve learned that when you expose HIV to a single drug, you make it easier to select for resistance,” she says. “So, we are trying to target HIV infection at two different steps very early in its life cycle, which should prevent the establishment of any infection.”

One of the drugs to be evaluated is tenofovir, which blocks reverse transcriptase, an enzyme crucial to HIV reproduction. Tenofovir is used currently as an oral systemic therapy against HIV, but it has also shown promise as a topical microbicide. The team will also test the efficacy of two so-called fusion inhibitors, including maraviroc and PIE12-trimer, which block the virus from entering target immune cells by different mechanisms.

The team will pay particular attention to choosing microbicides that preserve natural vaginal defenses against HIV. In recent years, supposedly safe microbicides were found to make women more susceptible to HIV infection. As Dr. Herold demonstrated in an earlier study, (http://www.einstein.yu.edu/home/news.asp?id=381) these microbicides most likely failed because they disrupted the vagina’s epithelial lining, which provides a protective barrier against infection.

“We want to preserve that protective barrier while adding drugs that will be at the right place at the right time when the virus presents,” says Dr. Herold. “That is why a ring, which can provide sustained delivery of the microbicide over three to four weeks, would be ideal. People wouldn’t have to remember to use it, which is a problem with gels and pills. Also, we don’t know if oral medications will get to the right place - some drugs get into the genital tract well, but some don’t.” The ring could be replaced monthly without a doctor’s supervision.

The microbicides will be incorporated into vaginal ring under development at the University of Utah, Department of Bioengineering, which is collaborating on the study.

“We’ve deliberately chosen to focus on drugs that have already been approved for systemic use or are far along in the regulatory process. This should shorten the time it takes to begin clinical trials. We know that every day that goes by, more people are getting infected with HIV,” says Dr. Herold. The researchers hope to start Phase I clinical testing within the next four years.

The need for a microbicide-releasing vaginal ring is especially urgent in sub-Saharan Africa, where the infection rate among 15 to 49 year-olds exceeds 23 percent in some countries. AIDS is the leading cause of death in sub-Saharan Africa and women account for six out of ten of those living with HIV. “But this is not just a global health problem,” says Dr. Herold. “This is a problem here in the U.S. The rates of HIV in certain regions in this country parallel the rates in many areas of developing world.”

According to the Centers for Disease Control and Prevention, the national infection rate in the United States is 1 percent; in D.C., it is 3 percent, and in the Bronx, 1.7 percent. While men still have higher rates of infection than women in the U.S., AIDS is a common killer for women - ranking third after cancer and heart disease. As of 2007, there were 9,000 women with HIV/AIDS living in the Bronx.

Marla J. Keller, M.D., associate professor of medicine and of obstetrics & gynecology and women’s health at Einstein is a co-investigator on the study. Dr. Keller is a leader in clinical studies on microbicide safety and the impact microbicides have on female genital tract mucosal immunity in HIV-infected and uninfected women. In addition to Dr. Herold, Patrick Kiser, associate professor of bioengineering at the University of Utah, is also a principle investigator on the study. Two biotechnology firms, ImQuest BioSciences, Inc. in Frederick, Maryland, and Particle Sciences, Inc. in Bethlehem, Pennsylvania, are also involved in the study.

Source
Albert Einstein College of Medicine of Yeshiva University

In a study published in The Journal of Infectious Diseases, researchers from Albert Einstein College of Medicine of Yeshiva University have identified cells in blood that predict which HIV-positive individuals are most likely to develop deadly fungal meningitis, a major cause of HIV-related death. This form of meningitis affects more than 900,000 HIV-infected people globally most of them in sub-Saharan Africa and other areas of the world where antiretroviral therapy for HIV is not available.

A major cause of fungal meningitis is Cryptococcus neoformans, a yeast-like fungus commonly found in soil and in bird droppings. Virtually everyone has been infected with Cryptococcus neoformans, but a healthy immune system keeps the infection from ever causing disease.

The risk of developing fungal meningitis from Cryptococcus neoformans rises dramatically when people have weakened immunity, due to HIV infection or other reasons including the use of immunosuppressive drugs after organ transplantation, or for treating autoimmune diseases or cancer. Knowing which patients are most likely to develop fungal meningitis would allow costly drugs for preventing fungal disease to be targeted to those most in need. (In the U.S., the widespread use of antiretroviral therapy by HIV-infected people, and their preventive use of anti-fungal drugs, has dramatically reduced their rate of fungal meningitis from Cryptococcus neoformans to about 2%.)

In this study, Liise-anne Pirofski, M.D., describes a technique for predicting which HIV-infected patients are at greatest risk for developing fungal meningitis caused by Cryptococcus neoformans. Dr. Pirofski is chief in the division of infectious diseases at Einstein.

Dr. Pirofski and her colleagues counted the number of immune cells known as IgM memory B cells in the bloodstream of three groups of individuals: people infected with HIV who had a history of fungal meningitis caused by Cryptococcus neoformans; people infected with HIV but with no history of the disease; and those with no history of either HIV infection or the disease.

“We were astounded to find a profound difference in the level of these IgM memory B cells between the HIV-infected groups,” said Dr. Pirofski. “The HIV-infected people with fungal meningitis caused by Cryptococcus neoformans had much lower levels of these cells.”

The research team wanted to know if the lower levels of IgM memory B cells in certain HIV-infected individuals resulted from the fungal disease, or whether their reduced levels of these cells preceded their development of the disease.

To find out, Dr. Pirofski analyzed frozen blood samples taken from HIV-infected patients before they had developed fungal meningitis due to Cryptococcus neoformans. Years before these HIV-infected patients were diagnosed with meningitis, their blood had far fewer IgM memory B cells than HIV-infected patients who didn’t come down with the disease. This suggests that some people are predisposed to develop fungal meningitis because they have low levels of IgM memory B cells that may be due to their genetic makeup.

These findings could be important for many other immunocompromised patients in addition to those infected with HIV. “We think that knowing whether transplant recipients or other patients taking immunosuppressive drugs have low numbers of IgM memory B cells could be useful in deciding which patients should receive antifungal drugs to prevent meningitis caused by Cryptococcus neoformans,” says Dr. Pirofski.

Krishanthi Subramanian, Ph.D., who did her thesis work in Dr. Pirofski’s laboratory, is the first author of the study.

The paper, “IgM+ Memory B Cell Expression Predicts HIV-associated Cryptococcus neoformans Disease Status,” appears in the June 15, 2009 online issue of The Journal of Infectious Diseases.

About Albert Einstein College of Medicine of Yeshiva University

Albert Einstein College of Medicine of Yeshiva University is one of the nation’s premier centers for research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750 M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral investigators. Last year, Einstein received more than $130 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five hospital centers in the Bronx, Manhattan and Long Island which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein the College runs one of the largest post-graduate medical training program in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training.

Source: Albert Einstein College of Medicine of Yeshiva University