MACS : Multicenter AIDS Cohort Study

In the fall of 1983, a group of investigators met at the National Institutes of Health (NIH ) to design a prospective epidemiological study of the newly recognized immunodeficiency syndrome in men who had sex with men (MSM) in Los Angeles, San Francisco, and New York. Upon completion of designing the protocol, recruitment of MSM began in April of 1984 into the investigation which was named The Multicenter AIDS Cohort Study or MACS. The first wave of participant recruitment was completed by March 31, 1985. Since then three more periods of enrollment have been opened; the first in 1987 to increase the participation of African-American (AA) MSM in the study and the second in 2001 to again increase participation by AA and Hispanic MSM. In 2011, the last enrollment period was initiated focusing on men with recent HIV infections to replace recent losses caused by death and dropouts. As of March 2017, 7355 men have volunteered and participated in the MACS with 2235 of them still active; 38% are non-white and half of all participants are older than 58 years of age. In Chicago, 1683 men have enrolled into the study.

The initial recruitment in 1984-85 was carried out before we had a laboratory test to determine who was a risk of developing AIDS. HIV had been suggested as the cause of the immunodeficiency in 1983 by investigators at the Pasteur Institute in Paris but this was not confirmed until the spring of 1984 by investigators in San Francisco and the NIH. However, a blood test to determine who was infected did not become available until the spring of 1985. When the original group of MSM who had joined the MACS underwent testing, it was discovered that approximately 40 percent of the cohort was infected.

This allowed the MACS to address two important issues. First, we could determine the behaviors, clinical findings and laboratory results which were associated with progression from HIV infection to AIDS. Secondly, among the uninfected men, the behaviors that led to HIV infection and the early signs and symptoms of this viral infection could be elucidated. To date, 767 uninfected men at entry into the MACS acquired HIV infection during the study, 342 of these men developed AIDS, and 84.2% of these men have died.

Early in the course of the study it became apparent that dementia was a major problem for men who developed advanced HIV infection and AIDS. MACS investigators organized a working group of neurologists to investigate this problem. The most important early finding was that severe central nervous system (brain and spinal cord) problems were seen only in persons with AIDS and that there was no reason for HIV infected men without AIDS to be restricted in their work. This finding became the basis of World Health Organization recommendation which was widely accepted advising that persons with HIV infection need not be restricted in their activities.

During the period of the 1980s, the death rate among the infected MACS participants was very high. As of the fall of 2016, close to 56 percent of men who entered the MACS with HIV infection have died. The MACS investigators were among the first to demonstrated that the T-Helper cell count below 200/mm³ were associated with a high rate of pneumocystis pneumonia (PCP) and helper cell counts below 100/mm³ put individuals at risk for cytomegalovirus retinitis, atypical mycobacterial infections, and infection of the brain with the parasite Toxoplasma gondii. Giving antibiotics to prevent some of these opportunistic infections helped but the early agents available to treat the HIV infection did not prevent progression to AIDS or death.

An early observation of MACS investigators was that the progression of newly acquired HIV infections to AIDS differed from individual to individual. Determinants of this heterogeneity included age at the time of infection and host genetics. The genetic makeup of an individual determines their immune response to HIV which in turn controls the rate of viral replication. Lower levels of replication result in slower progression of untreated HIV infection. Host genetics also determines susceptibility to HIV infection. The MACS contributed to the discovery of an uncommon mutation which protects people with this mutation from the usual form of HIV which is transmitted sexually.

With the availability of effective antiretroviral therapy in late 1995, progression to AIDS and death decreased dramatically. Close to 80% of participants in the MACS taking drugs have suppressed HIV replication and the median T-helper cell count is near 600/mm³. Stopping drug treatment results in progression of HIV infection and disease. With the greatly improved survival of infected participants, the MACS has focused on the health status of men who were living longer. To accomplish this investigators have been recruited into working groups with interest in diseases of the heart, lungs, kidneys, liver and metabolic diseases such as diabetes. The behavioral working group has continued to study behaviors to determine why men fail to adhere to treatment. Recreational drugs and alcohol use have been shown to be associated with poor adherence. Drug use also is associated with a marked increase in the risk of acquiring HIV infection. The neurology working group continues to investigate brain function among aging HIV infected men and the aging working group is attempting to determine whether or not HIV infected men age more rapidly than infected men.

The long follow up and presence of both HIV infected and uninfected men provide the MACS with a unique insight into men’s health.

As MACS participants grow older, it has become important to understand the effects of HIV on the aging process. The purpose of the MACS Bone Strength Study is to understand whether older HIV-positive men have a higher risk of fracture compared to HIV-negative men of a similar age. For this, approximately 400 men from the MACS study have undergone a series of tests including DXA and CAT scans, a blood draw, and some simple clinical tests. In fact, many people in the MACS study have participated in these simple clinical tests, as the balancing assessments were recently added to the standard set of tests given to all MACS participants, and anyone between the ages of 60 and 69 has been asked to participate by doing reaching assessments and chair stands. Based on the self-reported data from those participating in the MACS and those participating in the BOSS, preliminary results show that poor balance confidence doubled the odds of falling, where balance and physical function tests did not predict falls. And while there was no significant difference in the proportion of men with HIV who fell versus those without, the HIV group had significantly higher rate of falls with fracture.

The MACS has done multiple Cardiovascular sub-studies and has just recently begun it’s third. The cardiovascular studies have been conducted to explore the relationship between HIV infection and the narrowing, blockage or hardening of the heart, also known as atherosclerosis. The second cardiovascular study run in 2009/2010, included 764 participants of the MACS, aged 40-70 years. Findings showed that a greater prevalence and extent of non-calcified plaque – more prone to rupture, therefore precipitating thrombosis and acute coronary syndromes than calcified plaque – among HIV positive men than HIV negative men. These findings suggest that men with HIV infection are at an increased risk for the development of coronary artery disease. Now, the third MACS cardiovascular sub-study has commenced with the objective of determining whether atherosclerosis increases faster in HIV positive men than in HIV negative men. 172 men of the MACS study who have participated in the two prior subclinical cardiovascular protocols are getting a series of CAT scans, some after having an injection of contrast dye, to take pictures of the blood vessels and body fat, as well as a blood test.

Many men of the MACS study have participated in the POPS sub-study, and although many participants have anticipated the mouthwash rinse with lackluster enthusiasm, the study has been doing very important work in regards to oral HPV. Due to the assistance of the MACS participants who helped with this study, the POPS was able to observe an increased risk for oral HPV for those with a reduced current CD4 cell count, and no history of a tonsillectomy. The study also observes an increased risk of oral HPV with greater numbers of recent partners for oral sex and rimming for HIV uninfected, and increased risk with greater number of lifetime partners for HIV infected. Factors such as gender, smoking habits, and age significantly decreased the clearance of infection.