HIV/AIDS: Yale covers the waterfront

Since it was first clinically observed in 1981, HIV/AIDS has become perhaps the greatest epidemiological challenge of the last half-century. The last two decades have seen significant advances in scientists’ understanding of and ability to treat the disease, but in epidemiological terms, with more than 34 million cases worldwide and 2.7 million new HIV infections per year, HIV/AIDS remains a dangerous pandemic.

The diverse group of Yale scientists working in the field mirrors the complexity of the disease itself: at Yale, not only are biologists, epidemiologists, and clinicians working in tandem to understand, treat, and prevent the spread of HIV/AIDS, but so are economists and mathematical modelers.

With colleagues in social work and nursing, Warren A. Andiman, M.D., professor of pediatrics and epidemiology, established the Yale AIDS Care Program in 1986. The program expanded as the patient population grew, and in 1991 Gerald Friedland, M.D., a renowned clinician and researcher, joined the faculty. Andiman became director of the Pediatric AIDS Care Program, and Friedland, professor of medicine and epidemiology, became director of its adult counterpart, the Yale AIDS Program. Since then, Yale faculty have been at the front lines of care for those with HIV.

The Yale AIDS Program’s Nathan Smith Clinic (NSC), established in 1990, was the first in Connecticut dedicated exclusively to the care of adults with HIV. Today the NSC is the largest HIV clinic in Connecticut, serving more than 850 patients, including those on Medicaid and Medicare and the uninsured. All patients are assigned a primary care provider and also have access to specialty services, including psychiatry and women’s health, and linkages with substance abuse programs—particularly important given the prevalence of mental illness and substance abuse among the HIV-infected population.

Embracing not only patient care but also clinical research and the training of medical students, residents, and fellows, the Yale AIDS Program—a part of the Section of Infectious Diseases in the Department of Internal Medicine—reflects the School of Medicine’s three missions of research, education, and patient care. But it also has a fourth mission of community service, says Merceditas S. Villanueva, M.D., associate professor of medicine and the program’s director since 2009. “Community” can refer to both the local and international communities, but in some regards, Villanueva says, the two are closely linked.

A number of successful programs that have been piloted in New Haven have seen subsequent implementation around the world. In the early 1990s, Edward H. Kaplan, Ph.D., and Robert Heimer, Ph.D., and Kaveh Khoshnood, Ph.D., M.P.H., demonstrated the success of New Haven’s needle/syringe exchange program (NSEP), one of the first in the nation. Established with special permission from the Connecticut state legislature, the program’s goal was to slow the spread of HIV infection among injection drug users (IDUs) by providing them with free, sterile syringes. By 1992, Kaplan, now the William N. and Marie A. Beach Professor of Management Sciences at the School of Management, professor of public health at the School of Medicine, and professor of engineering and the School of Engineering and Applied Sciences; Heimer, professor of epidemiology and public health and associate professor of pharmacology; and Khoshnood, associate professor of epidemiology; had accumulated enough data to show, via mathematical models, that the program was reducing new HIV infections by a third.

Kaplan, Heimer, and Khoshnood’s work was the first to offer hard evidence of the efficacy of NSEPs as an HIV prevention strategy. Since then, Yale faculty have worked to implement NSEPs in broader domestic and international settings. For instance, Heimer has evaluated NSEPs in Russia and Estonia, and Frederick L. Altice, M.D., M.A., professor of medicine and public health, has implemented a needle exchange in Malaysia, where he’s worked since 2005 (see related story).

Another local initiative that has seen global implementation is the HIV in Prisons program, launched in Connecticut in 1991. Altice and colleagues in the Yale AIDS Program, including Sandra A. Springer, M.D., assistant professor of medicine, and R. Douglas Bruce, M.D., M.A., M.Sc., assistant professor of medicine and epidemiology, have worked to treat HIV-infected inmates in prisons around the U.S. and abroad—not only for HIV, but also for the other ailments that often affect them, such as tuberculosis, mental illness, and substance abuse.

Although the success of New Haven’s NSEP has dramatically reduced the rate of HIV infection via shared needles, there is still a wide overlap between those with HIV and those with substance abuse disorders, particularly among prisoners. “HIV is a proxy for risk-taking behavior,” explains Bruce. And because drug addiction can interfere so drastically with successful treatment of HIV, “often we have to address that before we can address HIV care.”

Bruce came to Yale in 2000 and worked alongside Altice and Springer for several years, treating HIV-infected inmates in New Haven’s prison system. “As things evolved, I realized that some of the treatments we were offering in mobile settings and in the jail weren’t sufficient,” he says. Specifically, he was dissatisfied with the amount of time it took to get drug users on methadone—a synthetic opioid used to treat addiction to opioids like painkillers and heroin. Due to its low cost, methadone is a practical means of addiction treatment, but, due to regulations in clinics, it used to take up to eight weeks to get a person into methadone treatment in New Haven. Within that lengthy period, substance-dependent people who were struggling in the community or who had been released from prison and were unable to stop using drugs on their own usually ended up in the hospital, jail, “or worse, dead,” Bruce says. The cycle simply wasn’t ending. “Eight weeks was too long.”

In a clinic at New Haven’s Hill Health Center, as well as one in the Fair Haven section of New Haven, Bruce set out to make quick treatment more accessible for people with substance abuse disorders. “We’ve made it so you can get into treatment in 24 hours, and have captured a larger piece of a very ill pie,” he says.

Springer’s work focuses on the adherence of HIV-positive prisoners to antiretroviral (ARV) medications, particularly during and following release from prison, when patients are most likely to relapse into patterns of alcohol and opioid use. Her novel research involves evaluating the use of extended-release naltrexone—which can be given just before release from prison but has longer-lasting benefits than comparable treatments—to manage addiction and to improve HIV treatment outcomes.

In recent years, Bruce has worked to implement methadone treatment programs internationally. In 2009, he was invited to Tanzania to help launch what was the first use of methadone as a public health intervention in sub-Saharan Africa. Despite the success of such programs, there is much work yet to be done. To decrease the number of new HIV infections each year, “we have to take a significant number of people with HIV out of the injection pool,” Bruce says. “To do that, we have to get tens of thousands of people into treatment.”

The advent of ARV therapies in the mid-1990s was a major breakthrough, effectively changing HIV/AIDS from a fatal disease to what is now considered a chronic, manageable disease. “People are not dying in the numbers they used to,” Villanueva says. One of the earliest ARV medications, stavudine, was developed at Yale by the late Professor of Pharmacology William Prusoff, Ph.D., and the late Tai-Shun Lin, Ph.D., senior research scientist. In 1994, stavudine—which works by thwarting replication of the retrovirus—was approved by the Food and Drug Administration as a treatment for HIV. Known more commonly under the trade name Zerit, it has been used in combination with other drugs to extend the lives of many thousands with HIV.

Today, clinical trials of new antiretroviral therapies are an active component of the School of Medicine’s efforts to better understand and treat HIV/AIDS. Michael J. Kozal, M.D., professor of medicine, uses new sequencing technologies such as DNA micro-arrays and ultra-deep genomic sequencing methods, to understand the genetic factors that make patients resistant to ARV medications. As director of HIV Clinical Trials at Yale and chief of the Section of Infectious Diseases at the VA Connecticut Healthcare System in West Haven, Conn., Kozal spearheads trials of new HIV medications, and has been able to offer patients alternatives when older treatment modalities fail.

In the clinical realm, one of the most encouraging recent successes has been the eradication of transmission of HIV from mother to child during pregnancy and childbirth. At Yale-New Haven Hospital, the virus has not been transmitted from an infected mother to a child in more than 15 years. Yale’s Pediatric AIDS Clinic, in fact, has only several dozen patients still on treatment, the youngest of whom is 16. When these last patients reach adulthood, they will transition to adult clinics, and then the clinic will likely close its doors, says Andiman, the clinic’s director.

Andiman credits this achievement—part of a trend taking place across the U.S.—to the implementation of HIV screening of pregnant women. If a woman is known to be HIV-positive, certain precautions, such as tailored ARV regimens for mothers and the use of breast-milk substitutes for infants, can be taken to drastically reduce the chances of transmission.

Such advances have resulted in remarkable improvements in the U.S., but in many places where the disease is most prevalent, a lack of resources has impeded progress. In Pretoria, South Africa, for instance, where one quarter of all pregnant women have HIV, without treatment about 40 percent of children born to infected mothers become infected. Brian W. Forsyth, M.B.Ch.B., professor of pediatrics and in the Child Study Center, has conducted a number of studies aimed at improving the prevention of mother-to-child transmission in sub-Saharan Africa and other resource-poor areas, where, Andiman says, “the problem is one of access [to care], money, and political will.” Resource allocation is of critical importance, says A. David Paltiel, Ph.D., professor of public health. Paltiel uses mathematical models to predict the ways certain treatments or preventative measures—making HIV screening routine, for instance—would affect both the epidemic’s trajectory and the economics of treatment and prevention. “Our work helps decision-makers know what every dollar spent will buy,” says Paltiel, who is also a professor at the Yale School of Management.

“What’s good in the first world is good in the third world,” says Forsyth, who is working to put in place in South Africa those measures that have bred success in the U.S.

According to Villanueva, American physicians, privileged with resources, funding, and supportive government policies, have a duty to help the less well-off, and it’s a responsibility that Yale scientists and physicians have not taken lightly.

“Yale brings to the table so many talents, and has been a conduit to improving the care for HIV/AIDS within the local and international communities,” Villanueva says. “The people that I work with are very out-of-the-box thinkers, and the research spawned in our program is motivated by their huge hearts.”