It’s been more than two decades, but Lisa Patton remembers the statistics 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 focused on treating the opportunistic infections associated with HIV.”
Patton has been working for the AIDS Clinical Trials Group’s (ACTG) Network Coordinating Center at Social & Scientific Systems (SSS) since 1989. She took the job right out of college. By then the Network was in its third year after being born in the home of National Institutes of Health (NIH) researcher Maureen Myers, PhD.
“I ran the 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. NIAID’s Director 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 with a January 1986 deadline. John Mills, MD, recalls using a word processor about the size of a small car to write the ACTG proposal for the University of California San Francisco site over the Christmas and New Years holiday in 1985.
“I had never used a word processor before, but I realized that the quantity of text required for the proposal made that essential,” he says. “It was my first real introduction to computers.”
This process yielded a dozen research sites around the US in June 1986 and a data management center in September 1986. That same summer, Myers hired infectious diseases specialist Judith Feinberg, MD. Like Mills, Feinberg remembers having to embrace computers. Myers taught her Word Perfect.
“I had a lot of trouble at first,” Feinberg recalls. “My first document looped back onto itself, but I got better over time. I had to because we only had one secretary.”
The first dozen research sites were called AIDS Treatment and Evaluation Units or ATEU’s. Mills 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, a group of several Boston hospitals. Hirsch also served as Chair of the ACTG’s Executive Committee from 1986-1988. The ATEU’s investigators held their first meeting in September 1986 at NIH.
“Our first Network meeting occurred just as AZT was proven effective,” Hirsch says. “So our first two initial trials were built off of this discovery.”
Volberding took the lead of the Network’s 019 trial. This investigated whether it was beneficial to put people living with HIV on the anti-HIV medication AZT before they progressed to AIDS. The lessons learned from that trial still make Volberding proud.
“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 the Network was making important advances in HIV treatment and care, Congress allotted more money for research and an additional dozen sites were added. These sites were 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.
“We were pleased and excited to be a part of the ACTG,” he remembers. “There were no other clinical trial opportunities in the city so we were able to enroll a large number of participants into the ACTG’s early AZT studies.”
In 1987, the AIDS Treatment and Evaluation Units and the Clinical Studies Groups united under one name – the AIDS Clinical Trials Group Network. The Network investigated HIV in adults and children.
The Network also established several committees to flush out its scientific agenda. Oncology, Immunology, HIV Treatment and Opportunistic Infections committees were created. Mills become Chair of the Opportunistic Infections committee. Since HIV came complete with a whole host of potential additional illnesses, he and Feinberg decided to adopt a divide and conquer approach to researching opportunistic infections.
“Realizing that this was a very broad challenge since it involved multiple pathogens, I established a number of subcommittees to come up with research agendas for the major opportunistic infections – herpes viruses (herpes simplex and cytomegalovirus), pneumocystis pneumonia, cryptococcal meningitis and others,” 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.”
Patton remembers the committees’ structure being driven by the ACTG’s scientific agenda, a practice still in place today. Technology has made coordinating the activities of these committees much easier though. Before email, Patton remembers polling investigators’ assistants for their availability.
“You would conduct a conference call query by FAX or by calling each investigator’s secretary,” Patton says. “Instead of emailing conference call agendas or study documents, you would FedEx everything. And then when we did get email, it was one central inbox. So each email was printed out and distributed.”
The long hours required for researching HIV took its toll on investigators’ personal lives. Feinberg 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.”
Corey took over leadership of the ACTG’s Executive Committee from Hirsch in 1988. Since he was based in Seattle and there was no budget for hotel stays, his meetings at NIH headquarters in Bethesda, Maryland, meant grueling days.
“The flights weren’t non-stop either,” he remembers. “I would travel from Seattle to Chicago and then onto DC. I would be in meetings all day and then catch the 6:30 p.m. flight back toward the west coast. I did this 20 times alone in 1990.”
In addition to the taxing pace, several prominent community activists publically criticized ACTG investigators. Corey and Hirsch were two members of what one activist dubbed “The Gang of Five.” The activist spoke to the Wall Street Journal claiming Corey, Hirsch and three other ACTG investigators were controlling HIV.
“I remember in 1990, I was heading to an AIDS conference in San Francisco and playwright Larry Kramer was being interviewed by National Public Radio,” Hirsch recalls. “Kramer said no investigators were listening to the community and he suggested that maybe an assassination would get our attention. I was very scared and hid my name badge under my jacket the entire meeting.”
NIAID Director Fauci took charge of the situation suggesting 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.
“One of my most vivid memories with the ACTG is 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. Dr. Fauci had been correct. Including the community was necessary to diffusing these myths about research.”
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, fellow ACTG investigator Tom Merigan, MD, and Network Statistician Steve Lagakos, PhD, were eating dinner in the city’s French Quarter 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 anti-HIV medication AZT alone, AZT plus ddI or AZT plus ddC. It took several years to get the study off the ground. But 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. Earlier clinical trials measured these endpoints by continually tracking a study participant to see whether or not they developed AIDS, lived or died. Gathering these endpoints would take years. By using laboratory assays, trials could be completed much quicker.
“175 was groundbreaking,” Hirsch says.
By 1995, the ACTG decided to focus solely on treating HIV in adults. The pediatrics arm of the ACTG became it’s own Network under NIAID.
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 stateside, 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 or PEARLS tested the safety and efficacy of three drug combinations for the initial treatment of HIV in seven countries with culturally 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 the antiretroviral drug efavirenz given 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 was not the drug combination being prescribed for the initial treatment of people living with HIV in resource-limited settings.
“It’s neat to see the ACTG continue to grow and make an impact by moving into that international phase,” says Corey, who since leaving the ACTG has become Principal Investigator of the HIV Vaccine Trials Network and President of Fred Hutchinson Cancer Research Center. “I’m proud to see the conceptual framework stand the test of time.”
NIAID refunded the ACTG in December 2013 for an additional seven years of research. The Network 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.”
Phair served as Chair of the ACTG’s Executive Committee from 1992-1994. He left the Network in the late 1990s, but remains impressed with what was accomplished.
“I think everyone was surprised that within less than 15 years we went from recognition to effective therapy,” he says.
Now retired, Myers reflects on the creation of the ACTG and admires the willingness of staff to sacrifice their personal lives to move studies forward.
“I’ll forever be in awe of the dedication the staff at NIAID and at each site had to fighting this virus,” Myers says. “It didn’t matter if you were on vacation. You would call in from your hotel room or from the beach. Nothing stood in the way. I hardly took the time to grocery shop back then.”
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, who is an investigator at the ACTG’s University of Cincinnati site. “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 patients’ 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.”