A couple of weeks ago, at a press conference that was full of promise and caveats, doctors announced that they had removed all detectable traces of HIV from two patients, both treated at Brigham and Women’s Hospital in Boston. Even after going weeks without antiretroviral drugs, there was no sign of the virus in their bodies. The doctors were careful not to say their patients were “cured” since there could be reservoirs of the virus in their cells that could form the foundation of a future relapse. But for now, they are cautiously optimistic not only about their patients’ prospects, but also for what the results could mean for future HIV therapies.
The keys to the Boston patients’ “cure” were the bone marrow transplants they underwent two-and-a-half and four-and-a-half years ago. Normally, doctors wouldn’t recommend such a drastic procedure for HIV alone—the treatment carries a 20% risk of death—but both patients had life-threatening lymphomas, complications of their HIV. The patients were on chemotherapy for their cancer, and that treatment, too, helped knock HIV back on its heels by depleting the immune system and killing diseased cells. The bone marrow transplants not only successfully treated their cancer, they also replaced the original, HIV-infected cells.
For years after their transplants, the Boston patients remained on antiretroviral drugs. But for two and four months now, they have been off their medications, and the virus remains at bay. Despite the apparent success, says Dr. Timothy Heinrich, a physician at Brigham and Women’s Hospital in Boston and one of the patients’ doctors, “It may be hard to say ever that it’s gone for good.” Instead, he says, it’s better to think of it like cancer, that the virus is in remission. While a cure would be a more heartening diagnosis, remission is far better than the life-sentence an HIV diagnosis was just two decades ago.
More than offering just hope, the success of the procedures has been a boon to HIV research. “We’ve learned a lot about the fact that antiretroviral therapy is very good at protecting these uninfected [donor] cells,” Heinrich says. “It seems like these uninfected cells replaced and cleared out a majority of those cells that were already infected from the patient.”
“It’s a proof of concept,” says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. “It says that even though you, in fact, have a very unusual situation, you can at least prove that it’s possible to rid the body of HIV.”
“This is not a practical approach for the thousands and millions who are HIV infected who would like very much to be off antiviral therapy,” he adds. “Obviously we are going to have to figure out a way to [get rid of the virus] that isn’t such a high-risk endeavor for the patient.”
Previously, a handful of HIV patients received bone marrow transplants, but many of the procedures took place before effective antiretroviral treatments existed. Most patients ended up dying from complications, their cancers, or uncontrolled HIV that hampered their recovery. Even now, the procedure comes with a high risk of death. There were originally three Boston patients; after six months, one of the patients died following the return of his lymphoma.
Aside from their remission, the Boston patients are also noteworthy for how they differ from the first “cured” patient, Timothy Ray Brown, known as the Berlin patient. A few years ago, Brown underwent a similar procedure for his leukemia and HIV, but his treatment came with a twist—the donor cells he received had an unusual mutation that prevented HIV from infecting them. Because of the mutation, he was able to stop taking his medications immediately and is considered “functionally cured.” Brown was incredibly fortunate—bone marrow with this mutation is extremely rare.
None of the Boston patients received marrow with this mutation. That is, in part, what gives doctors hope. If the approach used to treat the Boston patients—transplanted bone marrow without the beneficial mutation, followed by a period of antiretroviral medications—proves to be successful in the long term, doctors may consider it for other patients. However, with such a high risk of complications and death, this treatment is not an option for the vast majority of people with HIV. Currently, doctors recommend that only those HIV-positive patients suffering from a handful of life-threatening cancers should undergo such a procedure.
Henrich says results from the Boston patients’ follow-up tests will be a gold mine of data for clinicians and researchers. For example, one of the big unanswered questions in HIV research is how low the “residual reservoir” of virus must be before a patient can be considered functionally cured. Currently, antiretroviral therapy prevents the virus from replicating further, but it does not eliminate the virus particles which are already in the cells. Doctors will be watching the Boston patients to see, now that their drug therapy is stopped, whether the remaining virus will begin replicating again, triggering the return of the disease.
To monitor the level of virus in the Boston patients, doctors counted the number of virus particles in cells taken from both the blood and the gut—both common places for HIV to hide. Currently, there is no detectable viral DNA in the two Boston patients; that means virus levels are 1,000 to 10,000 times lower than before the transplant, Henrich estimates. If this level turns out to be low enough to prevent HIV from returning without antiretroviral drugs, it may be considered as a benchmark for future therapies. But if the virus comes back in either of the Boston patients, the level will likely have to be lowered.
The current irony is that, to be a candidate for a potentially HIV-clearing therapy, you need to be diagnosed with a severe blood cancer. That leaves tens of millions of HIV-positive people without prospects for a cure. Fortunately, Dr. David Baltimore is working to develop a similar, but less drastic, treatment. Baltimore shared the Nobel Prize in 1975 for the discovery of reverse transcriptase, the enzyme required for the reproduction of retroviruses like HIV, and is the chairman of Calimmune, a company developing new HIV therapies. His latest experimental therapy harnesses manipulated stem cells derived from a patient’s own tissue, and it’s entering clinical trials this summer. The cells will be engineered to prevent the production of CCR5, the mutated receptor that benefitted the Berlin patient, and transplanted back into the patient’s bone marrow. Since Baltimore’s treatment doesn’t require a complete bone marrow ablation, it is an outpatient procedure, and because it uses a patient’s own cells, it is less taxing. Data from twelve patients are expected in 2015.
The treatment is in the earliest stage of clinical trials, but Baltimore is hopeful that it could become widespread and inexpensive enough to be used around the world. “Although it is expensive to do it once—after you’ve done it once, you don’t have to do it again,” he says. “It will then save all the costs of drugs down the road and also be much more effective for the patient.”
If Baltimore’s treatment pans out, it would be a triumph for the HIV-positive community. But the threat of transmission would still loom. To completely eliminate HIV, it’s likely that we’ll need a vaccine in addition to any therapeutic treatments.
Developing an HIV vaccine has proved fiendishly difficult. Typically, vaccines teach the immune system to identify and destroy virus particles. When you receive a flu shot, for example, it’s loaded with disarmed or dead particles of certain strains of the influenza virus. The immune system discovers these invaders, destroys them, and commits them to memory—conferring immunity against future infections of the live virus. HIV, however, isn’t like other viruses for which we have vaccines. It attacks the immune system itself, which is why it is so difficult to develop an effective vaccine against it. At least, it has been difficult to develop one using typical approaches.
Dr. Mike McCune hopes that he can succeed where others have failed by turning conventional wisdom on its head. McCune, a researcher and clinician at the University of California, San Francisco, is trying to concoct a vaccine that will block the immune system’s response against the virus instead of boost it. He was inspired by the fact that only about five percent of babies born to untreated mothers are infected in the womb. McCune hypothesizes that the fetal immune system may develop a tolerance to the virus. That would block inflammation and halt the immune response HIV needs to thrive. McCune’s studies are in their infancy, but if successful, the vaccine could be delivered orally, he says, making it easier to administer, especially in developing countries where healthcare networks are not widely established.
The Road Ahead
The treatment the Boston patients received is not only risky, but it’s currently far too expensive for patients without health insurance or for many in developing countries. Until an HIV vaccine is developed, much of the world depends on antiretroviral medications to contain the epidemic. But even those are not reaching enough people—medications are expensive, patients don’t follow their regimen, or the medicine simply doesn’t reach those who need it. As a result, 34 million people are living with HIV, but fewer than 10 million receive treatment.
The World Health Organization (WHO) is looking to narrow that gap. The group recently released new guidelines for who should receive antiretroviral medications and when, hoping to start regimens earlier when the disease is more easily treatable. WHO now recommends beginning treatment when the amount of a certain type of white blood cell—known as CD4—drops to the bottom of the normal range, or 500 cells per cubic millimeter of blood, instead of below the normal range. (The previous standard was 350 cells per cubic millimeter.) For at risk populations, treatment can also begin following a positive HIV test without relying on CD4 counts. WHO estimates that in low- or middle-income countries this will increase the number of people who qualify for treatment from 17 million to 26 million. The additional treatments will cost money, but WHO believes the goal can be met, citing decreasing drug prices and reduced reliance on foundations and other donors as more countries include treatments in their budgets.
Fauci, the National Institute of Allergy and Infectious Diseases director, is pleased with the recommendations. “It helps the health of the individual who’s receiving the therapy, and we know from very good research that when you bring the level of virus in a person below detectable level with therapy, it makes it very unlikely that that person will infect their uninfected sexual partner,” he says. “The idea of getting more people on therapy earlier is a very good idea.”
McCune likes WHO’s initiative, too, and agrees that starting people on therapy earlier is beneficial. But the feasibility of meeting the recommendations, especially for poor countries, is unknown, he says. The drugs have side effects and must be taken every day for the rest of a patient’s life. When people are feeling fine, it can be difficult to convince them to take their medication. “It’s for these very reasons that I’m so interested in coming up with an intervention that would allow people to come off therapy,” he says. “Because if I could see that, then all of those worries go away, even in the most resource poor nation.”
Treatments like that which Baltimore is testing may require patients maintain a drug regimen, but after the intervention, the treatments could stop, just like they did for the Boston patients. “That’s what we do for cancer,” McCune says. “That’s what we want to do for HIV.”