AIDS Quest to Kill `Sleeping' Virus Enlists Merck Cancer Drug
The 30-year-long search for a cure for AIDS, the world’s deadliest viral infection, may get a renewed boost from an unlikely source: a little-used Merck & Co. cancer drug.
Researchers at the University of North Carolina in Chapel Hill plan to test Merck’s drug, Zolinza, next year in about 20 people infected with HIV, the AIDS virus. The goal is to determine if Zolinza, or a medicine like it, can force HIV out of cells where it can reside, concealed from attack by potent antiviral treatments, said David Margolis, a professor of medicine who’s leading the research.
While AIDS drug cocktails can eliminate more than 99 percent of virus from an infected person, the treatment isn’t a cure because a remnant of the virus remains hidden in certain cells. For years, scientists have sought a simple way to drive the remaining virus into the bloodstream where the drugs can clear them from the body. Zolinza, approved in 2006 for use against a rare type of blood cancer, may work by blocking an enzyme that helps the virus avoid detection.
“It’s really all about trying to move the field ahead,” Margolis said in a telephone interview. “We don’t expect to cure anybody, but we expect to really show whether it can work the way we think it does in people -- or not.”
Zolinza earned Whitehouse Station, New Jersey-based Merck $15 million in 2008, the last year it disclosed sales of the drug, for treating a malignancy of white blood cells that affects the skin. In a laboratory test published last year, Margolis used the medicine to coax HIV out of hiding in cells taken from infected patients. Now he wants to replicate the result inside the body. Success would show he’s on the right track to finding a cure.
“There is a good chance that it will cause some activation of latently infected cells,” said Robert Siliciano, a professor of medicine at Johns Hopkins University in Baltimore who first identified the cells in which HIV hides out, and isn’t involved in the Zolinza trial. “Nobody knows if it will work, but it’s important to try.”
AIDS was first observed as a mysterious illness among gay men in the U.S. in 1981, the same year Margolis started medical school at Harvard University in Boston. Since then it’s killed more than 25 million people, mostly in Africa.
Medicines developed over the past 20 years by companies including GlaxoSmithKline Plc and Bristol-Myers Squibb Co. control HIV without purging it from the body. Combination regimens can drive virus levels down so low that patients can live healthy lives. But since a small amount of the virus can remain hidden, the infection can re-emerge and endanger patients if treatments are ended.
“We’re never going to cure anybody unless we go for this latent pool,” Siliciano said. In May he received $360,000 from the New York-based Foundation for AIDS Research to identify drugs approved for other diseases that may work against latent HIV, just as Margolis is doing.
The costs of treating HIV rise every year as more people become infected, and because people need to stay on medication to keep HIV at bay. President Barack Obama in February requested $14.1 billion for the treatment and care of AIDS patients in the U.S. next year, 6.8 percent more than the $13.2 billion in the 2010 federal budget, according to a report by the Kaiser Family Foundation, a Menlo Park, California-based nonprofit health research group.
Governments, companies and foundations are increasing their investments in cure research, spurred by treatment costs, advances in science and the failure of researchers to develop a vaccine. The U.S. National Institutes of Health last month offered $8.5 million a year for five years for research projects aimed at finding a cure. The Foundation for AIDS Research in May gave $1 million to four research groups in Sweden and the U.S. for the same purpose.
“It’s gone from being a hopeless problem to one that people think we should devote a big effort to,” Siliciano said. “I used to be very pessimistic about the likelihood of finding a cure. I guess I’m less so.”
Gilead Sciences Inc., the world’s biggest maker of AIDS medicines, started work on finding a cure in 2009 and wants to test an experimental drug in monkeys next year. Johnson & Johnson’s Tibotec unit, which also started looking for a cure last year, is screening thousands of compounds and plans to design experiments in rodents and monkeys that would allow it to test the most promising candidates.
“We should not and cannot continue to accept that HIV is a long-term chronic illness that commits patients to lifelong treatment with associated toxicities,” said Sharon Lewin, head of infectious diseases at the Alfred Hospital in Melbourne. “In the absence of an effective vaccine, we must seriously pursue the possibility of cure,” Lewin said in a speech at the International AIDS Conference in Vienna last month.
Scientists are exploring two main ways of clearing viral reservoirs. The first involves reducing them to such low levels they can be corralled by the immune system, allowing patients to go off medications without the virus rebounding. The second strategy involves making patients resistant to HIV infection by giving them a genetic mutation that makes it impossible for the virus to enter cells.
The Zolinza trial is part of the first effort. Margolis said his work was inspired by the failure of a Dutch study a decade ago. The scientists tried to flush out HIV using antibodies, proteins made naturally by the body to fight infection, to activate all the cells that typically host latent virus. The treatment over-stimulated the subjects’ immune systems, causing lasting damage to some patients.
“Pretty much since that time I’ve been looking at selectively purging the virus without activating the cell,” Margolis said.
He published a paper in the journal Lancet in 2005 showing that Depakote, an approved treatment for bipolar disorder made by Abbott Laboratories, reduced the number of infected resting cells by as much as 84 percent when combined with Roche Holding AG’s AIDS drug Fuzeon, in a study involving four patients. Subsequent research by Margolis and others contradicted those findings.
“David deserves a lot of credit for moving the field with those initial studies,” Daria Hazuda, Merck’s worldwide antiviral franchise head, said in a telephone interview.
Now Margolis is trying again with Zolinza. Like Depakote, Zolinza targets an enzyme called histone deacetylase, or HDAC, that helps HIV go to sleep in cells by interfering with its ability to replicate. By blocking HDAC, Zolinza would reactivate the virus, kickstarting reproduction.
From there, nature would take its course: HIV would exit and kill its host cell, and enter the bloodstream in search of new cells to infect. Anti-AIDS drugs would prevent it from doing so, and with nowhere left to go, the virus would die after several hours.
Margolis and his colleagues plan to give about 20 patients a few doses of Zolinza, then measure whether it’s had any effect on the amount of virus the immune cells are producing. That will tell them whether they’ve succeeded in disturbing the reservoir.
Zolinza, also known as SAHA, may not be suitable as a cure for AIDS because of its potential to cause genetic mutations that lead to cancer, Margolis said. The U.S. Food and Drug Administration accepts that risk when the drug is being used in patients who already have cancer. It probably won’t tolerate the risk for use in other diseases, Margolis said.
‘Getting a Tan’
The FDA has approved the trial “because we will so severely limit the exposure to SAHA that the risk of inducing cancer is felt to be negligible, like getting on a plane and taking a flight to New York, or lying on the beach and getting a tan,” he said.
Margolis plans to apply to the NIH for funding “in the next few weeks.” If the trial succeeds or fails early, it may cost less than $500,000. A longer trial may cost as much as $1.5 million over three years, he said.
Merck supports the study, and is continuing its own research on other drugs that it might be able to combine with HDAC inhibitors, Hazuda said.
“Everybody has now come to the conclusion that it’s going to take a combination of different approaches,” Hazuda said. “Because there are HDAC inhibitors that are already licensed to treat other diseases, they may provide at least an anchor upon which to build a first-generation regimen.
Gilead is also experimenting with about a dozen families of its own HDAC inhibitors, said Romas Geleziunas, the company’s director of biology. The aim is to select one to test in monkeys as early as next year. The challenge is identifying a drug that’s powerful enough to activate HIV and not so powerful it causes collateral damage, he said in a telephone interview.
Geleziunas said he has “no idea” what the research project might mean for Gilead commercially.
“We’re all just trying to get our heads around the science, and trying to prove that in animal models these things have even a slight hope of working,” he said. “I really have no idea where this is going to go.”
Tibotec isn’t limiting itself to HDAC inhibitors, said Bruce Malcolm, the Beerse, Belgium-based company’s senior director of HIV research and early development.
“We’re casting a wide net,” Malcolm said in a telephone interview. “We’ll go about looking for anything and everything that proves useful, especially since we feel in the end it will probably be some combination of compounds that will be put together that will lead to the best efficacy and minimal toxicity.”
The second strategy has scientists looking for clues from the only person known to have been cured of HIV. The man, who researchers call “the Berlin patient,” was a leukemia sufferer who received a bone marrow transplant from a donor resistant to HIV in 2006. The donor’s cells lacked a protein on the surface called CCR5 that the virus needs to latch on. Without it, the virus can’t get a grip on the cell and infection is averted.
Sangamo Biosciences Inc., a biotechnology company based in Richmond, California, started two trials last year aimed at achieving the same result in a simpler way. Its approach uses a cold-causing virus as a Trojan horse to smuggle a CCR5-deleting gene into the body. The company said in November that one trial subject who had stopped taking AIDS drugs had undetectable levels of HIV one month later, though the virus was detectable after six weeks.
‘Before I Die’
Some scientists are skeptical a cure will be ever achieved, given HIV’s ability to integrate itself into the DNA of cells.
“We’ve never eradicated an integrated virus,” said David Cooper, director of Australia’s National Centre in HIV Epidemiology and Clinical Research. “That doesn’t mean we can’t do it, but it would be the first. At the end of the day, a vaccine is the best approach.”
Margolis is more optimistic.
“I’m 51,” says Margolis. “I’m not doing this because I think that I can’t succeed before I die.”