A Merck & Co. drug for a rare type of cancer flushed out hidden deposits of HIV in a study, according to researchers who say the results provide a hint that curing AIDS may someday be possible.
The finding on Merck’s Zolinza, reported July 25 in the journal Nature, comes as researchers at the International AIDS Conference in Washington optimism a cure is on the horizon. While current treatments hold the disease at bay, stopping the drugs can be a death sentence since it allows infected cells that remain hidden within the immune system to re-emerge, spreading the virus anew.
A single dose of Zolinza reactivated the hidden cells in eight infected patients, a first step toward finding and eliminating all virus traces from the body, according to investigators at the University of North Carolina at Chapel Hill and Whitehouse Station, New Jersey-based Merck who undertook the research.
“If we ever have a cure for AIDS, a big part of it will be this type of strategy,” said Steven Deeks, a professor of medicine at the University of California, San Francisco, who wasn’t involved in the study. “It’s all about getting the virus out of the hiding place and coming up with a way to kill it.”
Over the last few years, drugmakers including Gilead Sciences Inc., Merck, and Johnson & Johnson have been quietly building up teams of researchers focused on developing ways to wipe out hidden reservoirs of the virus, said Romas Geleziunas, director of clinical virology at Gilead, in an interview at the conference.
While the research remains years away from large-scale human testing, curing AIDS “is one of the hottest topics right now in biomedical research because there are finally ideas,” he said. “Pharma now is really behind this.”
Gilead has been working on AIDS cure research for three years, according to Geleziunas. The Foster City, California- based company, which makes the HIV treatments Atripla and Viread, has two approaches in laboratory testing.
In one, Gilead scientists are working with academic researchers to test a lymphoma drug called Istodax from Celgene Corp. in a small HIV patient trial that could begin next year, said Geleziunas. If the trial shows promise, Gilead would then try to come up with an improved version. Celgene isn’t pursuing its own testing of the drug for HIV, spokesman Brian Gill said in an e-mail.
A record 34.2 million people worldwide are living with HIV, the virus that causes AIDS, according to UNAIDS, the United Nation’s division devoted to treating and preventing the disease. It remains a killer disease globally, with about 4,000 deaths a day attributed to it last year alone, the data shows.
Today’s drug cocktails have transformed AIDS into a chronic disease by preventing the virus from replicating. Yet they can’t cure the disease because the current medicines don’t kill HIV-infected cells. If a patient stops taking the drugs, the virus will eventually come roaring back, thanks to hidden deposits inside rare dormant blood cells.
In each patient, there are about a million of these infected cells, Geleziunas said. Finding a way to wake them up so they can be spotted and eliminated is a main goal of researchers sleuthing for a cure, he said.
“It is going to be a step by step slow battle, but we can see a way forward,” said David Margolis of the University of North Carolina at Chapel Hill, who led the Nature study and has been working for 18 years on ways to eliminate the hidden HIV virus deposits.
There are now roughly 12 patient trials in early stages testing various approaches to curing the disease, said Sharon Lewin, a professor at Monash University in Melbourne, Australia, in an interview. At the AIDS meeting, she said she met with representatives from about 15 drug companies interested in cure research.
“There is quite a bit of research and I think that is new,” said Lewin, who is also conducting a patient trial of the Merck lymphoma drug in HIV patients.At J&J, the world’s biggest maker of health care products, 15 researchers in Belgium are focused full-time on developing drugs that could lead to a cure, said Marie-Pierre de Bethune, a vice president in infectious diseases with J&J.
The researchers have taken 35,000 compounds from J&J’s library of experimental drugs and tested them against the virus in the lab to see which activate the dormant virus and make it reveal itself to the immune system, de Bethune said in an interview at the AIDS meeting.
Researchers will likely have to combine several medications to kill off the hidden virus deposits — one group to wake up the hidden cells and another that would then prompt the immune system to kill them.
“One drug isn’t going to do the trick to cure the disease and many approaches will be needed,” de Bethune said.
So far, there is only one person who has ever been cured of HIV, Timothy Ray Brown — the so-called Berlin Patient. His HIV was wiped out after getting a bone marrow transplant in 2007 for cancer. The donor had a rare gene mutation that made the new white blood cells resistant to infection with the AIDS virus.
“I am cleared of the AIDS virus,” Brown said at a news briefing on July 24 in conjunction with the International AIDS Conference. “It is my hope that my life and my story will inspire others to follow a path to a cure that will help everybody.”
While a bone marrow transplant isn’t a practical solution for curing HIV for the masses, Brown “showed that scientifically it was possible” to cure a patient, said Margolis, senior author of the study on Merck’s Zolinza.
“Four years ago there was virtually nobody talking about eradication research publically,” Margolis said in an interview. Now “a lot of people are jumping in.”
When Margolis started working on hidden HIV reservoirs back in 1994, researchers weren’t even sure they existed. His first grant proposal on the subject was rejected, he said.
Margolis’s new study shows that Zolinza, a type of cancer drug called an HDAC inhibitor, can turn on the dormant immune system cells infected with the AIDS virus.
All eight patients were controlled on existing drugs, and remained on their regular therapy. They received one dose of Zolinza, and then had blood cells removed during a procedure called leukapheresis.
Laboratory tests of the cells found that the average virus expression in the dormant cells increased five-fold, indicating at least some of the virus was being driven out of its hiding places, the researchers wrote. Initial results of the Margolis study were presented at a conference in March.
What isn’t clear from the study is whether the hidden HIV- infected cells were killed, Margolis said. They also don’t know what fraction of the hidden virus was activated.
Nonetheless, “this is an important step forward,” said Daniel Kuritzkes, chief of infectious diseases at Brigham & Women’s Hospital in Boston. “This is the first compelling evidence we have that we can induce virus expression from latently infected cells.”
Kuritzkes is studying additional bone marrow transplant patients infected with HIV to see if the transplants can sometimes wipe out virus reservoirs even if they aren’t from donors with cells resistant to HIV, like the cured patient Timothy Ray Brown. Initial results from this study are slated to be presented at the AIDS conference.
Merck’s head of infectious disease research, Daria Hazuda, said she doubts Zolinza itself would be a drug that eradicates HIV. The strategy behind the trials is to use Zolinza as a prototype that could pave the way for more potent compounds that are better at flushing the HIV out.
The company has “dozens” of scientists working in the early stages of research on the problem, Hazuda said.
The goal is to come up with a combination therapy, much like current treatments for hepatitis C, that can cure a significant fraction of HIV patients over a treatment course that might last a month to a year, she said.
One factor driving the resurgence of interest in cure research is the failure to come up with an AIDS vaccine, according to Hazuda. In September 2007, a promising Merck AIDS vaccine failed in large-scale trials.
“It was a real jolt to the entire field,” when an experimental Merck AIDS vaccine failed in large patient trials in 2007, Hazuda said. “I think that woke people up with respect to thinking more serious about eradication and thinking more broadly about prevention research.”
Research toward a cure “is still in the very primitive early basic science stages,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
He said it was important to pursue the studies aggressively even though the odds of success aren’t clear. The Bethesda, Maryland-based NIH has spent $122 million on HIV eradication research in 2010 and 2011, the agency said.
Other scientists are openly optimistic.
“Right now is probably the most hopeful and optimistic that we have ever been feeling about the possibility of a cure for HIV,” said Rowena Johnston, director of research for amfAR, The Foundation for AIDS Research.
“The chances are pretty good we will have a cure that will be applied widely in the next couple of decades,” UCSF’s Deeks said.