The mission of the AIDS clinical trials group (ACTG) network is to cure HIV and reduce the burden of disease due to HIV infection and its complications, including tuberculosis and viral hepatitis.
Established in 1987, the AIDS Clinical Trials Group (ACTG) is the world’s largest and longest running HIV clinical trials network.
The ACTG conducts groundbreaking research to improve the treatment of HIV and its co-infections, including tuberculosis and viral hepatitis, as well as its co-morbidities. The ACTG also seeks to advance approaches to ultimately cure HIV. ACTG clinical trial units in 12 countries serve as major resources for HIV/AIDS research and training/education in their communities.
ACTG studies have had a profound impact on the well-being of people living with HIV worldwide, helping to establish current paradigms for treating HIV and contributing to dramatic decreases in HIV-related mortality worldwide.
It’s been three decades, but Lisa Patton remembers it as if it were yesterday.
“You were given about six months to live if you were presenting with HIV and pneumocystis pneumonia and you were given a little more than a year if you had HIV and Kaposi sarcoma,” she says. “That is why our research in part initially focused on treating the opportunistic infections associated with HIV.”
Patton has been working for ACTG’s Network Coordinating Center at Social & Scientific Systems (SSS) since 1989. By then the Network was three years old after being born in the home of National Institutes of Health (NIH) researcher Maureen Myers, PhD.
“I ran NIH’s National Institute of Allergy and Infectious Diseases’ (NIAID) antiviral program,” says Myers. “Once HIV was discovered, there was tremendous pressure on the government to do something. Dr. Tony Fauci asked Dr. John LaMontagne and I to set up a research network focused on the HIV epidemic. Hundreds of people were dying daily so we took this mission personally.”
The rough outline of the Network created on Myers’ dining room table grew to requests for proposals, yielding a dozen research sites around the U.S. in June 1986 and a data management center in September 1986.
The first dozen research sites were called AIDS Treatment and Evaluation Units or ATEU’s. John Mills, MD and Paul Volberding, MD, ran the University of California San Francisco site. Larry Corey, MD, was the Principal Investigator of the University of Washington site in Seattle. And Martin Hirsch, MD, led the Harvard site The ATEU’s investigators held their first meeting in September 1986 at the NIH.
“Our first Network meeting occurred just as AZT was proven effective,” Hirsch recalls. “So our first two initial trials were built off of this discovery.” Volberding took the lead of ACTG’s 019 trial, investigating whether it was beneficial to put people living with HIV on AZT before they progressed to AIDS. The lessons learned from that trial still have implications today as Volberding explains: “The evidence that AZT reduced progression and mortality in those with up to 500 CD4 cells was the start of the long battle to get people to recognize the harm of HIV infection at all disease stages,” he says. “It was a game changer.”
Recognizing that the ACTG was making important advances in HIV treatment and care, Congress allotted more money for research and added a dozen more sites called the Clinical Studies Groups. The Chicago AIDS Clinical Studies Group included sites at Rush and Northwestern universities. John Phair, MD, served as the Chicago sites’ Principal Investigator.
In 1987, the AIDS Treatment and Evaluation Units and the Clinical Studies Groups united under one name – the AIDS Clinical Trials Group Network — investigating HIV in adults and children.
The ACTG established several committees to flesh out its scientific agenda, including Oncology, Immunology, HIV Treatment, and Opportunistic Infections.
“Realizing that this was a very broad challenge since it involved multiple pathogens, we established a number of subcommittees to come up with research agendas for the major opportunistic infections,” Mills says. “With this team in place, we were able to develop, initiate and complete clinical trials to define the optimal treatment and preventative strategies for more of these infections.”
The long hours took their toll on investigators’ personal lives. Judith Feinberg, MD remembers keeping a toy box under her desk at NIH for her two and a half year old son to play with while she worked. “You worked seven days a week for about 100 hours,” she recalls. “My son would play under my desk until he fell asleep. There was just so much to do.”
In addition to the taxing pace, several prominent community activists publicly criticized ACTG investigators, leading Dr. Fauci to suggest that community members be allowed to attend the ACTG’s meetings. By the end of 1990, each site sought the local community’s involvement when developing studies.
“I remember when one of the activists came up to me during the first ACTG meeting in Washington, D.C. that included community members,” Phair says. “He said he was discouraged because he was convinced we had some treatment we were withholding. After attending our scientific sessions, he realized there was no such magic treatment and that this was just going to take a lot of hard work and time. Dr. Fauci had been correct: including the community was necessary to diffusing these myths about research and to inform it.”
Currently, Community Advisory Boards or CABs exist at each ACTG site and members sit on the Network’s study teams and scientific committees.
In 1989, Hirsch was in Montreal for the International AIDS Conference. He was eating dinner in the city’s French Quarter with fellow ACTG investigator Tom Merigan, MD, and Network Statistician Steve Lagakos, PhD, when the idea for an innovative study was born.
“A number of pilot clinical studies suggested a benefit for certain antiretroviral combinations and we knew it was time for a large-scale, randomized and controlled trial to evaluate whether combination regimens were to become the wave of the future,” Hirsch says.
ACTG trial 175 compared AZT alone, AZT plus ddI, and AZT plus ddC. By 1995, the team had proof that combinations of anti-HIV medications controlled HIV better than single drug regimens. The team also proved that measuring HIV RNA in the blood was a marker to predict clinical trial endpoints such as the progression to AIDS or death.
By 1995, the pediatrics arm of the ACTG became its own network under NIAID (called the PACTG) and the ACTG focused only on adults.
Recognizing that the burden of HIV lay outside of the United States, the ACTG approved applications from its first international clinical research sites in 2002. Sites in Haiti, Peru, and South Africa were paired with mentor sites in the U.S., says Patton.
Study A5175 was the first major international study to come out of the Network. The Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS) tested the safety and efficacy of three drug combinations for the initial treatment of HIV in seven countries with diverse populations. The inclusion of women was made a priority and 47 percent of the trial’s 1,571 participants were women.
The results showed that efavirenz in combination with emtricitabine-tenofovir disoproxil fumarate was a safe and effective once-daily regimen, especially for women. This information changed the standard of treatment as it had not been prescribed for the initial treatment of people living with HIV in resource-limited settings.
NIAID re-funded the ACTG in December 2013 for an additional seven years of research and ACTG added sites in South Africa, Thailand, Kenya, Brazil, and Washington, D.C. Investigators continue to test novel therapeutic interventions focused on HIV-associated inflammation and resulting end-organ disease, tuberculosis, viral hepatitis, and HIV cure.
Although no longer affiliated with the ACTG, Hirsch continues to be surprised by how far HIV research has come in such a short period of time.
“In the early 1980s, hospital staff were afraid to enter the room of a person living with HIV because we didn’t know how it spread,” he says. “Now it is a manageable, chronic disease. I could never have predicted the progress we have made.”
Feinberg and Patton still work for the ACTG. Despite the chaos of those early years, Feinberg looks back fondly on that time.
“The results were so immediate back then,” says Feinberg. “I remember when we were testing drugs to treat the opportunistic infection cytomegalovirus and people continued to go blind until we found the right treatment. You really knew you were helping people and that initial impact was the most rewarding.”
Patton is now the Leadership Group Manager at the ACTG’s Network Coordinating Center. She says the commitment to prolonging participants’ lives is what has kept her happily employed with the ACTG for 25 years.
“The scientific mission, research accomplishments and the difference made in the lives of people living with HIV have kept me with the Network,” Patton says. “There is a sense of family here beyond the professional work.”