The Multicenter AIDS Cohort Study, which has followed a group of 5,622 homosexual and bisexual men nationwide to determine if, when and why they contract the human immunodeficiency virus, reached its 15-year milestone on March 31. By tracking the evolution of HIV over the course of the disease, the study has formulated guidelines for determining, among other things, when those infected with HIV might expect to develop AIDS, and when they should start taking the new potent anti-retroviral therapies, or ART.
Over the years, the data from MACS have allowed investigators to map HIV's natural history and identify variables contributing to the progression to AIDS. MACS data have allowed researchers, for example, to see the relationship between viral load levels and immune system health: With a low load, the net loss of helper T cells is 36 cells per year; with a high viral load, it almost doubles to 76 cells per year. MACS data have also revealed that those individuals in whom HIV shows the greatest genetic diversity are likely to experience faster than average disease progression.
Over its 15-year history, MACS has attracted a cumulative total of more than 100 investigators who have produced more than 600 scientific papers. Two of the study's principal investigators are currently based at the School of Public Health: Joseph Margolick, associate professor, Molecular Microbiology and Immunology, who orchestrates one of the national study's laboratory research programs and directs the MACS center in Baltimore; and Alvaro Muñoz, professor, Epidemiology, whose Center for the Analysis and Management of the Data from MACS analyzes the mountains of data being generated.
MACS was launched in 1983 when B. Frank Polk, of the School of Public Health, predicted a major epidemic stemming from reports of small but growing clusters of pneumonia and Kaposi's sarcoma among homosexual men. Polk recruited study members from the gay communities in Baltimore and Washington as a way to help them fight the disease that came to be known as AIDS. Margolick says, "There were only a few people in the world who knew there was going to be a major epidemic. Frank Polk had the confidence in his own vision to go out on a limb and start this study."
The study is ongoing at four sites around the country and funding has been awarded toward the 20-year milestone in 2004. Because all study participants have their own doctors and insurance, they don't receive any treatment while in MACS; instead, they come in every six months for a full physical, as well as psychological and neuropsychological exams. They answer questions about sex partners, visits to the emergency department, the use of health maintenance organizations, medications and quality of life.
Participants also give blood samples at each visit so that viral load levels and numbers of immune cells can be determined and vials of cells can be prepared and stored for future research. Some of the vials are sent to the National Repository in Washington so that they are accessible to AIDS researchers nationwide.
The MACS has generated data on 82,382 person visits and has logged information from 68,255 CD4 (T-helper) cell measurements, all the while keeping track of some 5,084 variables (such as age, antibodies for hepatitis B, CD4 cell counts, medications, use of health services) that may affect the development of AIDS, as well as information on cigarette smoking, blood pressure and many other attributes. All these data, gathered from every patient visit at the four MACS centers, are processed at the School of Public Health by the 25-person STATEPI (Statistics in Epidemiology) group, which also houses the largest study of HIV-infected women, under the direction of Muñoz, Lisa Jacobson and Stephen Gange, all of Epidemiology.
In a paper published in the Annals of Internal Medicine in 1997, researchers used the MACS data to come up with specific guidelines for when to administer the new life-prolonging ART. Thanks to MACS, doctors now know that if a patient's degree of immune deficiency is only mild (CD4 count is above 500 cells per microliter of blood) and the amount of HIV present in the blood is low (viral load is less than 10,000 copies per milliliter of blood), he or she most likely won't develop AIDS for another three years, and so may not need to receive potent ART immediately. This three-year span before in starting potent ART is important, says Muñoz, since too-early administration could potentially create resistant strains of HIV, thus leaving the person defenseless when the full fury of AIDS finally strikes.
"These data allow incredible discrimination of risk [of getting AIDS]," explains Muñoz. "[The graph depicting who should receive potent ART], which is on almost every desk of physicians treating HIV in the United States, allowed the Public Health Service to make recommendations in a rational way."
In 1998, in an article in the Journal of the American Medical Association, researchers again looked to the MACS data to find out what happens when the sickest patients are treated with potent ART. "After randomized clinical trials had shown the efficacy of potent ART," notes Muñoz, "data from the MACS were needed to show the drugs' effect when introduced into the community at large." This study of potent ART can be boiled down to four lines on a graph--the first showing the steep descent to AIDS of those who did not take medications; two other lines showing the slightly less steep decline of those who took only azidothymidine and later combined AZT with some newer antiretrovirals; and the fourth showing the remarkably gentle slope of those taking potent ART.
Muñoz emphasizes that when the data from MACS are presented in simple computer graphics, a viewer can easily forget what lies behind the neat, multicolored charts. This is why, when first introducing new students and faculty to the MACS data, he always tells them, "We all must first bow to these data, to the amounts of work and human suffering that lie behind these simple charts."
The four MACS study centers are located at the Hopkins School of Public Health; Northwestern University Medical School-Howard Brown Clinic in Chicago; the University of California Schools of Public Health and Medicine in Los Angeles; and the University of Pittsburgh Graduate School of Public Health. MACS is funded by the National Institute of Allergy and Infectious Diseases of the National Insti-tutes of Health and supplemented by the National Cancer Institute. Data from the MACS can be accessed at www. statepi.jhsph.edu.