How COVID Research Is Impacting HIV Cure Research
The Pressure Is Mounting for the BEAT HIV Team to Beat the Clock Before Time & Funding Run Out
by Chip Alfred
It was a day none of us in Pennsylvania will forget. On March 16, Governor Tom Wolf ordered a statewide shutdown to slow the spread of COVID-19, urging all residents to “stay calm, stay safe, stay home.” As you can imagine, most of us were not feeling particularly calm in that moment, especially everyone working on two clinical trials in Philadelphia. To really grasp the impact of the lockdown on this research study and why it could not have come at a worse time, we need to go back about four years to when the BEAT-HIV Collaboratory began.
In 2016, The Wistar Institute in Philadelphia was awarded a $23 million grant by the National Institutes of Health (NIH) to establish a five-year partnership of thirty leading HIV researchers to work together to advance a cure for HIV. The BEAT-HIV Collaboratory, which includes the University of Pennsylvania and Philadelphia FIGHT Community Health Centers, is one of six sites nationwide known as the Martin Delaney Collaboratories, a flagship NIH program on HIV cure research with sites in San Francisco, Boston, Seattle, Washington, D.C., and Chapel Hill, North Carolina.
“The BEAT-HIV Collaboratory is looking for strategies to achieve remission without therapy, meaning the virus can stay stable and without coming back, or to actually get rid of the virus altogether and not need any type of therapy to manage what otherwise would have required therapy for life,” says Dr. Luis Montaner, a Director of the BEAT-HIV program and Leader of the HIV Research Program, Vaccine & Immunotherapy Center at The Wistar Institute.
The BEAT-HIV project proposed two clinical trials. One is a gene therapy trial, which involves testing the effectiveness of genetically modifying CD4+ T cells to eliminate the need for antiretroviral medication. The other trial proposes an innovative strategy to reduce HIV DNA by combining the use of interferon-alpha with two broadly neutralizing antibodies. There was so much interest in the work of the Collaboratory, which began with nineteen investigators, that it now includes eighty researchers from across the globe.
With such a complex clinical trial, the preliminary stages, including establishing protocols and securing all the legal and regulatory approvals (NIH, FDA, and local institutional review boards), took about a year longer than similar studies would typically take. It wasn’t until early 2020 that the recruitment teams at Philadelphia FIGHT and the Hospitals of the University of Pennsylvania were ready to begin screening prospective clinical trial participants.
But when the state shut down in March, everything came to a screeching halt. “The University of Pennsylvania made the unprecedented decision to cease all non-critical research operations. I’ve never seen anything like it before,” recalls Ken Lynn, Managing Director of HIV Curative Research Operations at the University of Pennsylvania School of Medicine. Linden Lalley-Chareczko, Research Program Director at Philadelphia FIGHT, was in the same boat. “We were training our clinicians to be designated clinicians on the study when COVID hit, she tells A&U. “We had to basically stop everything and turn our entire focus to COVID.”
That was definitely not the news Dr. Montaner wanted to hear. “We were on track to complete the most definitive step forward in the clinical understanding of how close to a cure we can get, and as soon as we started opening the trial, COVID arrives,” he says. “It was coming at a point where we were about to realize what we had been planning for over four years, and here comes a shutdown of the U.S., the state, the hospital, everything.”
Dr. Pablo Tebas, Director and Principal Investigator of the AIDS clinical trial unit of the University of Pennsylvania, is the Project Leader for both BEAT-HIV trials. “COVID has had a profound impact on all of the studies that we are doing,” he says. The gene therapy trial initially enrolled a few patients in January and February, right before the lockdown, which forced the study to be halted. The big problem with halting the study was that individuals already on the trial had to be stopped from proceeding to the planned analytic treatment interruption (ATI), taking a patient off HIV medications to analyze the effects of the experimental HIV treatment methods. This was done for the participants’ health and safety, as Tebas explains. “With ATI you have to measure their viral load every week, so we had to delay the ATI and resume the study when lockdown ended.”
The big question for everyone became what to do next. Not knowing how long the lockdown would last, the research teams at Penn and Philadelphia FIGHT worked hard to prepare for whatever might happen and how they might make up for lost time. “It wasn’t planning as usual; it was planning for every contingency, every emergency, every possible resurgence of COVID,” says Lalley-Chareczko. When things opened back up in June, time was of the essence. The current BEAT-HIV grant has an end date in 2021. Drugs manufactured specifically for this project had an expiration date. The first priority was the interferon/antibodies combination study. Twenty-one participants needed to be recruited, screened, and enrolled in a short period of time. The original plan was to enroll two individuals per month for ten months, but that timeline needed to be collapsed. Since June, “we condensed ten months of screening and enrollment to three-and-a-half months,” says Lynn.
Pre-COVID, recruiting participants for the BEAT-HIV trials was already a tall ask. It’s a year-long commitment with frequent clinic visits, blood draws, treatment interruption, rectal biopsies, and apheresis. This is the process of drawing about a pint of blood, separating out the white blood cells for analysis, then reinfusing the remaining blood back into the patient. When you add COVID to all of this, it makes the recruitment process even more challenging. “The environment of healthcare has changed,” says Lynn. “Trial participants don’t want to be near sick people.” Each participant who had already signed an informed consent had to be contacted again to make sure they were aware of the new risks involved. Pre-procedure COVID-19 testing for each of three rectal biopsies also became part of the process.
During the second round of recruitment for this trial, there was even more pressure than before not only to find that magic number of twenty-one participants, but to find the right twenty-one participants who could be expected to complete all the requirements of the study. Since the motivation for someone to join this study is purely altruistic, the “pitch” conversation usually focuses on finding people with the desire to make a selfless contribution to science. “I lay the facts out, making sure they have a true understanding of the history of the disease’s progression and how we got from fifteen pills to one. It’s through research,” says Lynn. “Do you want to reach for that brass ring and contribute to no pills a day?” Lalley-Chareczko adds, “Maybe it’s important to you to be one of those folks in the future that’s looked back on and thanked when we as a scientific community do get to a cure for HIV.”
While this trial attempts to complete enrollment, the focus has turned back to restarting recruitment for the gene therapy trial, which Montaner tells us should be fully enrolled by March of 2021. “If we are successful, we may be one of the few Martin Delaney Collaboratories nationally that can actually move the trial needle forward, because others may not even have a choice. They may have to shut down.” With the prospect of a second COVID shutdown looming, if these trials or others that were proposed are not completed in this funding cycle, all of the data and protocols will be compiled and can be applied toward future cure-directed studies.
Drs. Tebas and Montaner do have concerns that COVID research may take funding away from HIV research, but they are more worried about the tug of war going on for resources. “Grant funding for HIV hasn’t gone away, but we are being asked to do many things,” says Tebas, who lost some of his HIV research team members to focus on testing Remdesivir for COVID-19 treatment. Tebas notes that there is COVID-specific research funding, but it is difficult to find and train people in the middle of a pandemic. “From a national perspective, the HIV expertise, meaning people working on HIV, are already transitioning over to COVID,” Montaner remarks. “From the funding side, a lot of the infrastructure that was built and sustained for HIV trials has been redirected for COVID therapy and vaccine trials.” The competition isn’t just over infrastructure and human resources. It’s over monkeys, too. The National Primate Research Centers is the national network where requests for monkeys and other primates for animal testing are approved by an NIH committee. Now, COVID-19 projects get first pick and requests from HIV research projects may be put on hold or delayed.
With the U.S. death toll topping 250,000, cases surging both at home and abroad, and the flu season threatening a possible double whammy, of course COVID-19 is the deadly pandemic that demands all the resources we can give it right now. Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases and a member of the White House Coronavirus Task Force, predicts we could have a vaccine available as soon as early 2021. According to the World Health Organization, multiple COVID-19 vaccine candidates are under development. As of October 13, 2020, four vaccines have begun large-scale (Phase III) clinical trials in the U.S. All of this wouldn’t have been possible without the financial resources and the international partnerships that have formed in this race to find a safe, effective vaccine.
Montaner believes that the HIV pandemic helped the scientific community prepare for COVID. “The HIV infrastructure we built in the past is what’s made our ability to respond to COVID so much faster. We had already trained and developed a workforce that is a national resource of infectious disease and research development,” he says. “Before the COVID pandemic hit, the big push was to end the HIV epidemic,” states Dr. Tebas, who adds that we need to remember how essential all we are doing for HIV research is for HIV care. “People with HIV have a lot of needs and we have to answer the questions that are important in their care.”
Dr. Montaner is proud of the progress that the BEAT-HIV program has made, and he is hopeful that the NIH will continue to fund this project and more HIV cure research in the future. “We’re creating a roadmap in Philadelphia for how best to pursue cure-related studies. I think the investment we’ve made in joining community and scientific teams on how best to pursue an HIV cure will make it possible for us to go towards that goal of an HIV cure beyond COVID.”
Chip Alfred is A&U’s Editor at Large, a public speaker, and a media and public relations consultant based in Philadelphia. He is the former Community Engagement Co-Coordinator for the BEAT-HIV Community Advisory Board. Follow Chip on Twitter @ChipAlfred.