Brave Enough to Say "Cure"
Brave Enough to Say "Cure"
Newly announced results from an experimental HIV trial offer hope that an AIDS cure isn’t as impossible as once thought
Richard Moreau has taken part in many HIV/AIDS-related clinical trials over the years, but this experience was entirely new to him. “You take part in a trial and that is generally the end of it. There is little, if any, follow-up,” he said. “If you happen to remember, and you want to see how it turns out, you try to find what research journal publishes the results. That’s about it.”
What happened that day at Wistar was different.
On December 12, 2011, some months after taking part in the study, Moreau, along with researchers, physicians, advocates, and fellow participants, gathered to discuss the results of their relatively small clinical trial. It was a collaborative effort, led by Montaner,
with contributors at the University of Pennsylvania, Drexel University, and other institutions. In the study, Moreau and other patients who had been on daily regimens of antiretroviral therapy (ART), a mix of three or more HIV-fighting drugs, suspended their treatment in favor of weekly doses of “Pegasys,” a form of interferon-alpha. The human immune system manufactures interferon-alpha to “interfere” with the ability of viruses to replicate within cells.
And despite the small size of this particular trial, the news was huge.
“Our data shows that our human immune response can be made to control HIV in people who have otherwise lost that ability and, if sustained by natural interferon production, it establishes proof-of-concept that a functional cure is theoretically possible,” said Luis J. Montaner, D.V.M, D. Phil., professor in Wistar’s Tumor Microenvironment and Metastasis Program and director of the Institute’s HIV-1 Immunopathogenesis Laboratory. “And while we still have much to pursue with this early clinical finding, I firmly believe this gives us hope that one day we can control — and eventually eradicate — HIV in absence of antiretroviral therapy.”
According to Montaner, the trial showed that interferon-alpha sustained control of HIV in nine of 20 patients while also decreasing measures of HIV reservoirs — populations of cells that harbor HIV-1 out of reach of the medications available today — in patients otherwise dependent on ART. No other clinical strategy to date has shown an impact on decreasing integrated HIV DNA levels in HIV-infected humans.
Moreau was quick to grasp the consequences of Montaner’s words. His doctor had told him that his CD4 (white blood cell) count is as high as it has ever been, and that his viral load — how much HIV-1 RNA is floating in his blood stream, a sign of viral activity — is undetectable. His doctor, however, also noted signs of depression (a common side effect of interferon therapy), which caused Moreau to drop out of the trial despite his clinical gains.
“I consider myself well-informed, but I can’t claim to understand all of the things Dr. Montaner said and I certainly appreciate that they all made it a point to talk with us about it,” Moreau said. “I did not even finish the trial, and I still feel that I’m a part of this.”
“I think it makes a difference in building trust within the community,” he added.
That is a sentiment with which the trial’s organizers would agree, as institutions have often had difficulty in recruiting patients for HIV research studies locally.
The difference with this trial, according to Montaner, is that they have a lasting partnership with Philadelphia FIGHT, a community HIV/AIDS organization, part primary care facility and part advocacy organization. With FIGHT’s involvement, the researchers have been able to conduct a number of small yet powerful HIV-related medical studies.
On March 7, 2012, Montaner’s team described their discoveries to colleagues at the Conference on Retroviruses and Opportunistic Infections in Seattle, Washington, and officially announced the trial’s results to the world.
Putting Interferon to the Test
The Pegasys trial is not the first time interferon-alpha was tried in relation to HIV-1. It is just the first time that researchers have been able to find a strategy to sustain HIV-1 suppression using interferon in people on antiretroviral therapy. Interferon can be a very toxic drug, with many side effects when used at doses large enough to achieve clinical effect.
However, Pegasys is a different form of interferon than used in earlier trials. Since human interferon does not persist long enough in the body to serve as a useful antiviral drug, pharmaceutical researchers modified it by adding polyethelyne glycol (PEG) to the interferon molecule, making it last longer in the bloodstream with less toxicity. This “pegylated” form of interferon was approved in 2008 to treat hepatitis B and C infections.
“To be honest, we braced ourselves for the idea that this may not have any effect,” Montaner explained, “but there was enough evidence to believe that this formulation of interferon was worth trying and that a recovered immune system would respond differently if primed with interferon before stopping antiretroviral therapy.”
With funding from the National Institutes of Health, the Commonwealth of Pennsylvania’s CURE fund (see The Need for CURE), The Philadelphia Foundation Robert I. Jacobs Fund, the Stengel-Miller Family, and a supply of pegylated interferon donated by the drug’s manufacturer, Genentech/Roche, the trial got underway. The clinical team began recruiting patient volunteers from clinics at Penn, Drexel, and Philadelphia FIGHT’s Jonathan Lax Center.
Unlike previous studies, this trial would be conducted after patients had already been on ART. “When someone is first infected with HIV-1, the immune system is overwhelmed, and the natural release of interferon into the bloodstream is ineffective as cells that produce it are quickly impaired,” Montaner said. “But in our study, conducted at a later stage of chronic infection after long-term treatment in an individual, we saw that adding interferon to a recovered immune system can have a dramatic effect in directing responses against HIV-1 to both control and reduce its detection within places we know it can hide.”
The trial followed the progress of 20 men and women of various backgrounds and ethnicities as they started on one of two different doses of interferon while still on ART. The patients then discontinued ART, and maintained interferon treatment for up to 24 weeks. For patients, the trial lasted 24 weeks or until either their HIV-1 levels rose or CD4 T cell counts dropped to a pre-determined level, at which point they would resume ART. Nine patients saw their HIV-1 levels suppressed for three months, while eight patients maintained low HIV-1 levels for the entire 24 weeks.
Remarkably, 45 percent of trial participants were able to sustain viral control under 400 copies of the virus per milliliter by the halfway point of the trial. About as many patients showed more than 50 percent reduction in circulating HIV reservoirs, as measured by the laboratory of Una O’Doherty, M.D., at the University of Pennsylvania.
“In our previous studies, we have seen that when people suspend ART, their viral loads begin to creep upward while their white blood cell count gradually drops,” Montaner said. “We expected to see the same thing during this trial, but we were, frankly, surprised to see patients maintain the gains made through ART using only interferon that modulates our body’s response rather than acting directly against HIV as all current HIV drugs do.”
How Pegasys Took Flight
Moreau first found out he was infected with HIV in 1987. Despite almost 25 years as HIV-positive, he still regards himself very fortunate. He responded well to early antiretroviral drugs and is still healthy to this day. He is one of legions of men and women whose HIV status could be considered “chronic.” This status comes with a price: a daily cocktail of drugs for the rest of his life.
In industrialized nations it is a price paid willingly, as seen through declining AIDS-related deaths in the United States despite a steady rate of new cases. In undeveloped nations, especially in Africa, the cost remains far too high for most to reach, and the resulting deaths are far too common.
For years, Moreau has taken part in clinical trials for new HIV/AIDS therapies. When he was younger, he was directly involved with advocacy, which in the late 1980s and early 1990s was militantly focused on getting attention and funding for the AIDS crisis. As the urgency of the crisis abated, however, Moreau continued to look for opportunities to take part in the HIV community. “I’m incredibly fortunate to be as healthy as I am today, and I feel an obligation to take part in trials,” Moreau said.
As the Pegasys trial began recruiting patients, it was Moreau’s physician who recommended he take part. Without patient volunteers medical trials could never happen. And, in turn, useful new therapies would never make it into practice. Many trials never get off the ground due to a lack of willing volunteers.
While Montaner and his team have also struggled to accrue patients, he finds it easier than most. Montaner’s relationship with the Philadelphia HIV/AIDS community dates back nearly 17 years, when he first joined Wistar as an assistant professor. It was around the time he first met Jane Shull, executive director of Philadelphia FIGHT, while she was running an informational booth at a college volunteer fair. They discussed his difficulty in getting the data he needed to drive the science of HIV-1 infection forward.
“It became clear to Luis and me that we needed to collaborate, even though we only had a small clinical site in those days,” Shull said. “Luis needed blood samples, which we could provide, and I could see that he was up to do science, which would help everyone.”
The association between Montaner and FIGHT (Field Initiating Group for HIV Trials) evolved into a series of small clinical trials testing the assumptions the medical community has made about treating HIV-infected people. One such trial studied ART interruption, temporarily halting a patient’s daily antiretroviral drugs to see if ART has made any lasting changes in how the body responds to HIV. If patients did not require ART daily, it could curb the expense of the drugs and reduce side effects.
“We need to test what we think we know in order to see if it is actually true,” Montaner said. “And, yes, if you halt ART, you begin to see an increase in viral loads within one to two weeks and a decrease in CD4 counts very soon after.”
What the ART interruption trials did, however, was provide a background “control” group for the interferon therapy trial. Data from the ART interruption trials allowed Montaner and his colleagues to compare the effects of interferon in patients to the effects of using of no drugs whatsoever.
According to Shull, FIGHT and Wistar have developed a bond over the years based on mutual respect and a willingness to explore scientific preconceptions about HIV infection.
“If [one of FIGHT’s founders] Jonathan Lax was still alive today, this would be exactly the sort of thing he’d pursue,” Shull said. “He’d be the first in line.”
Chronic to Cured?
For many people, like Richard Moreau, an HIV infection is no longer the death sentence it once was. Instead, it is a chronic infection. In the era of ART, the focus now is on efforts to create improved antiretroviral drugs and prevent infection, including a vaccine.
According to Katie Krauss, a cure for AIDS is not yet on the radar of most HIV/AIDS foundations and politicians. Krauss is executive director and founder of the AIDS Policy Project, a national HIV/AIDS advocacy organization that has, in recent years, turned its attention to the pursuit of a cure for AIDS. Her job, as she describes it, is to try to make things happen: to offer political, organizational — and oftentimes moral — support to those who want to advance progress toward a cure for AIDS. They help untangle red tape at the federal level, find innovative ways of speeding up the research process, and make sure that important cure research is not overlooked.
“I have actually had conversations with researchers where, when they began speaking of their work toward an AIDS cure, they’d start whispering, even with nobody else in the room,” said Krauss. “They would call it the ‘C’ word, or make air-quotes with their fingers; that’s how far out of the mainstream cure research seemed when we began.”
“Now, however, there is great momentum toward a cure and very promising research,” Krauss explained. “But there still isn’t enough money, and many private foundations aren’t yet aware that the research is going well or that their help is urgently needed
so that we can finish the job and cure this disease for everyone.”
In Krauss’s view, it is up to advocacy organizations to take a stand with researchers who are interested in searching for possible cures. As government research funding is not necessarily focused on a cure, it may be the advocates who can help locate new sources for research grants.
“I think we all worked so hard to get where we are, where there is now hope for a full life despite HIV, that we have downplayed the need for a cure,” Krauss said. “People are still getting AIDS; the disease still kills millions. Only a fraction of people in developing countries can access treatment, and the rest don’t survive. We still need a cure.”
This is where Shull believes that the Pegasys trial might have the biggest impact. “Interferon might not be a cure for AIDS,” Shull said, “but this trial changes the narrative, creates a new storyline where we can show people that it is possible to begin thinking about a cure.”
As Montaner says, this trial was a proof-of-concept. “While our data may not immediately change clinical practice, it identifies the first strategy that shows a clinical response where both viral replication and HIV reservoir indicators are observed to be reduced in absence of current chemotherapy,” Montaner said. “This is the type of response HIV cure research aims to achieve.”
Montaner and his colleagues have submitted their findings to a peer-reviewed journal for publication. Already, the researchers are planning the next trial, and the news of this small trial has gone global as they and others drive their knowledge further in the hope for a cure.
“It is exciting to show control against HIV-1 can be regained by way of stimulating natural mechanisms as we had no other example to date to evidence this was possible if you required therapy to begin with,” Montaner said. “Our findings also open the way to determine if we can move this clinical research strategy a step closer towards a cure-based strategy to decrease HIV reservoirs as we have already observed.”
While Moreau recognizes that he might not qualify for a second trial, he certainly wishes that he could continue to take part.
“There are still a lot of people who say HIV is manageable, and leave it at that,” Moreau said. “I don’t think we can stop there. I think we have to keep trying, that a cure is possible.”
With people like Richard Moreau, it just might be.