April 15th, 2013 -- If you’ve been following the news lately, you may be starting to wonder why anybody ever thought curing HIV was so challenging. On March 3 we heard the news that a child appeared to have been cured. Hard on the heels of that report came the news that 14 individuals in France had been functionally cured. So what do these cases mean? How are they similar, and how do they differ? And importantly for HIV research, where do we go from here?
Much depends on how a cure is defined. Researchers are used to thinking of a cure in two different ways. One type, a sterilizing cure, requires that HIV be eradicated from the body of the infected person. The second, a functional cure, is less stringent in that it requires that the patient is able to stop taking antiretroviral therapy without suffering any adverse consequences of the HIV that remains in their body.
The Berlin Patient
A decade ago, almost nobody spoke of curing HIV infection as a realistic goal, yet we find ourselves in early 2013 with not one, nor even two, but three different types of HIV cure. The first cure—the “Berlin patient,” who we now know as Timothy Brown—has been widely reported. Mr. Brown was living in Germany when he was diagnosed with HIV infection in the mid-1990s. His infection was well-controlled by antiretroviral therapy until he was diagnosed with acute myeloid leukemia about 10 years later.
To treat the cancer, he received a stem-cell transplant, but his doctors took an extra step, finding a donor with a genetic mutation known as CCR5 delta-32. Naturally present in around 1–2 percent of Caucasians, this mutation renders people highly resistant to HIV infection. By transplanting cells from a donor with the mutation, doctors knew there was a good chance of curing Mr. Brown’s leukemia and hoped they might also eradicate—or at the very least bring under control—his HIV infection.
Since his transplant five years ago, standard clinical tests have failed to detect any HIV in Mr. Brown’s body, he hasn’t taken any antiretroviral therapy, and he has certainly not manifested any signs or symptoms suggesting he is progressing to AIDS. Why do we think this means he is cured of HIV? In almost all cases, a person who stops taking antiretroviral therapy will experience a rebound in virus, a resurgence to levels that are both easily detected and that predict a progression to disease and ultimately death.
When this case was first reported at a conference in 2008, scientists were skeptical. To quell doubts, numerous more detailed tests have been performed, using the most powerful laboratory tools available today. The viral outgrowth assay, single copy assay, PCR for DNA and RNA, antibody and other immune tests, immunohistochemistry, and digital droplet PCR results collectively suggest that if there are any pieces of the virus left in his body, they are not capable of replicating. In other words, although many scientists are still not willing to go so far as to say HIV has been eradicated from Mr. Brown, it seems increasingly likely that any virus that may be left in his body will not rebound and cause health issues associated with HIV disease. This is as good a cure as exists for any disease.
The Mississippi Child
When Drs. Deborah Persaud and Katherine Luzuriaga identified a child late last year who appeared to have been cured of HIV, they knew the case would require intensive documentation. The child had been born in Mississippi to a mother who tested HIV-positive during labor. Because this was the first point of contact between the mother and medical care, the doctors knew she had not taken antiretroviral therapy during pregnancy, an intervention that vastly reduces the chances of mother-to-child transmission of the virus.
With this in mind, the pediatrician in charge of the case, Dr. Hannah Gay, decided to administer a treatment dose, rather than the usual prevention dose, of antiretroviral therapy to the infant just 31 hours after birth, to increase the chances that HIV infection could be prevented. She figured that if the infection occurred despite this therapy, at least the infant would be starting on therapy soon after birth. Infants are normally started on a treatment dose of antiretroviral therapy at six weeks or more, so there would be few other infants who had started antiretroviral treatment so soon after birth.
Roughly the same time that treatment was initiated, two tests were conducted to determine whether the infant was infected. Both tests involved PCR on blood samples. PCR detects nucleic acids, the components of both DNA and RNA. Both tests—DNA PCR and RNA PCR—came back positive, indicating that the infant had HIV-infected cells, as well as virus in the blood. Because these tests were positive within the first 48 hours after birth, current guidelines suggest the infant was infected some time prior to birth. Over the ensuing weeks, close monitoring confirmed that the viral load dropped with successive tests, as expected when a patient is responding well to therapy.
Fast-forward over a year, and the mother and child stopped going to the doctor when the child was 18 months of age, returning to medical care at 23 months. At that time, the mother confirmed that her child had not been given antiretroviral therapy for at least five months. The doctors conducted a viral load test to determine an appropriate treatment regimen, and were very surprised when the test came back “undetectable,” meaning there were less than 48 copies of the virus in each milliliter of blood. In a child who has stopped antiretroviral therapy, the result would be expected to be as high as several million.
Not trusting the result, Dr. Gay ordered another test, which also came back undetectable. At this point, Dr. Gay contacted her colleague Dr. Luzuriaga at the University of Massachusetts Medical Center for advice. Dr. Luzuriaga, having just established a pediatric HIV cure collaboratory with her colleague Dr. Persaud of Johns Hopkins Children’s Center with funding from amfAR, knew she had the right team of scientists poised to delve more deeply into this case.
Knowing that scientists are skeptical regarding any claims of a cure, Drs. Persaud and Luzuriaga had set up their collaboratory to include scientists specializing in all the tests that had been done to confirm the cure in Timothy Brown. These highly sensitive tests collectively suggested that if there was any virus left in this child’s body, it was unlikely to be capable of multiplying and causing disease.
The French Cohort
Only a week or two after the child cure story broke, French researchers reported they were following 14 people who were “functionally” cured of HIV. These adults had been treated with antiretroviral therapy during acute infection, i.e., within the first several weeks after becoming infected. All had taken antiretroviral therapy for an average of three years and then stopped.
They have now been off therapy for an average of more than seven years, and yet their CD4 cell counts are in the normal range and their viral loads are almost all below 50 copies per milliliter of blood, which is the goal for patients who are taking therapy. Although more sensitive laboratory tests have readily detected HIV in these patients, they appear to no longer need to take antiretroviral therapy to maintain their health, hence the designation “functionally cured.”
The French researchers have looked for explanations for these findings both in terms of the virus the patients were infected with, as well as genetic or other characteristics in the patients themselves. So far, there are no clear answers. In fact, the researchers note that only about 10–15 percent of patients who start therapy this early during infection can expect to similarly control their infection after they stop their medications, and so far we have no way of predicting which patients will fall into this category. Some researchers have wondered whether these 14 patients might have controlled their virus even if they had never taken antiretroviral therapy—similar to the small number of people known as “elite controllers”—although the French group has reason to believe this is unlikely.
What Does It All Mean?
What do these three different types of HIV cure tell us? First, there is as yet no cure that can be applied broadly. Timothy Brown’s cure was a grueling and even life-threatening process that cannot be recommended for patients on a wider scale. Moreover, the stem-cell donor in his case had a rare mutation—finding a tissue match for every HIV patient from among these rare gene carriers would be impossible. Mr. Brown’s case has taught researchers which kinds of tests will be needed to satisfy the rightly skeptical scientific community that a cure has taken place.
The potential to apply the findings from the child cure case is intriguing. Each year around the world more than 330,000 infants are born HIV-positive. Although a regimen of antiretroviral therapy during pregnancy, sometimes with the addition of a brief regimen in infants after birth, can prevent around 98 percent of mother-to-child transmission of HIV, efforts to scale up this intervention have so far failed to reach all HIV-positive pregnant women. Even with universal coverage, some infants would still be born with HIV. What remains to be determined—and clinical research studies are currently being planned—is whether an early course of antiretroviral treatment in infants for a circumscribed period of time can eliminate HIV infection after it has occurred.
The French cases described above are clearly examples of a functional cure—the patients all still have HIV, and yet have stopped taking their medication and have not progressed to HIV disease and AIDS. It is possible that such a cure might be effected more broadly, but the major challenge would be to identify HIV-infected people sufficiently early during the course of infection for the therapy to make this difference. Even so, it appears that only 10–15 percent of people are functionally curable this way.
It is less clear what type of cure Timothy Brown or the child have experienced. In both patients, trace amounts of the genetic material of the virus are sporadically detected. One challenge is knowing whether or not those results are “real.” In each case, the levels of virus are at the “limit of detection” of the assays being used. In other words, the virus hovers in the region in which the assays cannot definitively say whether or not the results are a false positive. Even if there really are traces of the virus left in these patients, what are the ramifications? In both cases, the patients have been off antiretroviral therapy for significant periods of time.
If either had been harboring virus that was capable of replicating, in all likelihood that virus would have rebounded by now and would be readily detectable. It therefore seems most likely that any virus they still have is either incapable of replicating (and it is estimated that 99 percent of all viruses in any infected person are replication-incompetent) either because it is defective or present only in fragments. If the only HIV present in either patient is not capable of replicating, and therefore cannot behave in the deleterious ways we care about, can we say they have a sterilizing cure?
Although most researchers might say no, one could argue that this may be as close to a sterilizing cure as we will ever come, and that such fragments may not be as concerning as they sound. Geneticists have characterized stretches of DNA found in all humans, regardless of HIV status, called human endogenous retroviruses (HERVs). These HERVs share many of the characteristics of HIV.
They are remnants of evolutionarily ancient infections with retroviruses (a class of virus to which HIV also belongs) that became incorporated into our genomes and those of our primate and mammalian ancestors. In fact, we have more DNA from these HERVs than we have DNA encoding our own proteins, leading one researcher to declare that “there is more virus in us than us in us.” Although yet to be confirmed, it is possible that trace amounts of HIV remaining in patients who are otherwise cured of the infection will be as harmless as these HERVs.
As promising as the recent reports of a cure have been, it is clear there is much work to be done to find a cure—or possibly different types of cure—that can be applied to the estimated 34 million people living with HIV today. That work will continue, with funding from amfAR, the U.S. National Institutes of Health, and other funders around the world. We owe a lot to the selflessness of the patients who have undergone the testing required to get us where we are today.
Timothy Brown is probably the single most poked, prodded, and studied patient in the history of the epidemic, and he deserves our gratitude for his bravery in coming forward and his willingness to be tested in ways that advance the HIV cure research agenda. We are also very grateful to the mother of the cured child, who has allowed researchers to conduct the intensive tests required to confirm the cure of her child, to the French patients for subjecting themselves to repeated testing, and to countless others who have participated in studies that have not yet brought us a universal cure, but are teaching us each day what it will take to cure HIV infection and bring an end to this pandemic.
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