At an international workshop on HIV persistence and reservoirs, held in St. Martin in December 2009, Robert Gallo opened the conference with a challenge on the validity of Gero Hütter’s report on his Berlin patient, Timothy Brown. It’s not unusual for a newcomer in any scientific field to be met with skepticism. However, Hütter’s shocking results and lack of background in HIV prompted an aggressive response. Gallo noted the absence of other, more established HIV researchers on Hütter’s paper. He remarked that no one but a pathologist, examining samples from the patient lying dead on an exam table, could declare HIV was cured in such a patient.
Gallo’s comments were on the minds of many in the audience. After all, this was not the first time they had been confronted with an extraordinary patient and the promise of a cure on the horizon. The original Berlin patient, Christian Hahn, had similarly garnered much excitement and been the subject of many promises. Early, aggressive therapy plus treatment interruptions had been touted as a cure in those few years before that therapy was debunked. The use of the word cure had been taboo ever since. No matter if Hütter wasn’t using the cure word himself; he was implying it in his powerful data. In their defense, these researchers wanted to protect patients, to make sure that as scientists and physicians, they weren’t raising false hope.
A dichotomy arises here. There is a protective nature in the bond that grows between patient and doctor. They know that the excitement that builds from the latest publication can evaporate when it reaches for the high bar of efficacy in real people. Researchers, on the other hand, are typically trained to minimize contact with the people behind their studies. Where physicians physically lay their hands on the skin of their patients, a researcher hides the patients behind a code of numbers and letters, obliterating all association to humanity. There is a good reason for this. Blind studies keep researchers from consciously or unconsciously influencing their observations. By keeping researchers and patients separate, the experiment has the best chance of escaping partiality and producing meaningful data. On the spectrum of physician and researcher, Hütter fit somewhere in the middle. He wasn’t a family doctor like Jessen, but he also had little experience in research. He was simply a young physician/researcher trying to find the right balance between the two.
It was not fun for Hütter as he sat in the audience, listening to his research being censured by the preeminent HIV researcher. Sitting in his hotel room that night, he quickly amended his PowerPoint presentation, adding a slide titled “Do we have to cut this patient up in slices?” He delivered his talk the next afternoon to a much smaller audience than Gallo received for his opening remarks. However, that talk, “HIV Eradication by Stem Cell Transplantation: Is It Feasible?” was an eloquent and precise representation of his work. Hütter, intelligent and soft-spoken, was convincing. His credibility was raised after his talk, especially as other, senior HIV scientists lent their support. This small conference in the West Indies, so different from when Hütter presented his poster at the Conference on Retroviruses and Opportunistic Infections, served as an incubator of sorts, bringing his research to the HIV community in a way that made sense, even if no one knew how the Berlin patient’s unique experience could ever be translated into a viable therapy for HIV patients.
• • •
When Anthony Fauci learned about Timothy Brown, just prior to Gallo’s critical remarks, his reaction was mixed. As the director of NIAID, Fauci continues to have considerable sway in how the public and research community view the HIV field. He has to be skeptical when encountering new data since his opinion is so influential. Having lived through the dark days of HIV research, when newspapers and investigators alike were declaring the end of AIDS, Fauci knew firsthand the devastating effects of raising false hope. Therefore, when The New York Times asked him what he thought about the dramatic new case, his answer was in keeping with his skeptical personality: “It’s very nice, and it’s not even surprising, but it’s just off the table of practicality.”
It’s a funny thing that sometimes when a result is spectacular, in retrospect the approach seems obvious. Now that the results of the Berlin patient’s case were published and investigators everywhere were using the once forbidden c-word, the cure of HIV no longer seemed outlandish. Hütter’s project had gone from one with data that no one believed to one that the head of NIAID called “not surprising.” Hütter had to laugh at the absurdity of it.
But were they really “just off the table of practicality?” The aggressive nature of the therapy Timothy received, a bone marrow transplant, is not trivial. As we discussed earlier, it carries considerable risk. Bone marrow transplants have a significant mortality rate. Getting the transplant means going through much of what Timothy experienced: toxic therapy to make space in the bone marrow, the possibility of graft-versus-host disease, long hospital stays, and the potential for life-threatening complications. It’s not a procedure anyone wants to sign up for. It’s certainly not how we cure HIV for most people infected with the virus.
The other factor in considering any cure for HIV is the cost. A bone marrow transplant is one of the most expensive medical procedures, costing upwards of $300,000. A transplant such as the one Timothy received, using cells from a donor, costs approximately $805,400 in the United States. This number seems outrageously high until we compare it to the cost of a lifetime of antiviral therapy that runs $709,731 without discounts. This number, however, doesn’t take into account other medical expenses that HIV patients have. As people are living longer with HIV, their medical complications and therefore their expenses are also on the rise. In the United States, survival has increased from 10 years in 1996 to 22 years in 2005. With that increased survival rate, other problems have arisen. Those with HIV are more likely to suffer from premature aging, incurring significant medical bills. Statisticians take all these factors into account when they compare therapies by QALYs, or quality-adjusted life years. QALYs measure both the quantity and quality of life gained by a medical intervention. QALYs are then used by health insurance companies, hospitals, and even nonprofits to determine cost analysis, essentially whether a medical intervention is “worth it.” Any new HIV therapy is measured using this system to determine whether it makes financial sense. By any measure, the therapy Timothy received does not make medical or financial sense for an HIV-positive person not already in need of a bone marrow transplant.
But what does make practical sense is to take the cure we’ve gleaned from Timothy and turn it into a therapy that is both medically and fiscally responsible.
Both medical and fiscal concerns are why we need a practical cure. Atripla, a popular antiretroviral drug that combines three separate medications in one pill, costs about $20,000 a year. This causes problems in the United States, where cash-strapped states have trouble covering the cost through Medicare programs, and private insurance often caps yearly expenses. In an era when HIV-positive individuals have more choices than ever before, cost can still be a limiting factor.
In addition to cost, not all patients are able to find a therapy that works for them. Jason, who has been HIV-positive since 1988, gets angry when people he knows tell him that the fight for a cure to HIV is irrelevant. “They simply don’t know what they’re talking about,” he grumbles as he sits in his family’s house in Petaluma, California. “I’ve spent decades trying to take medications I can’t tolerate, only to see my immune system crumble.” His longtime partner, Richard, agrees, saying, “The gay community doesn’t care about HIV anymore.” Even with the best medical help, Jason can’t find a therapy that restores his T cells. He is constantly battling illness as a result. As we stand in Mission Dolores Park in the Mission District of San Francisco, you can almost see the anger, mixed with grief, rising off him. In the wide-ranging world of antiviral drugs, we sometimes forget that there are people like Jason and Richard out there, still struggling.
HIV is more manageable today, but that doesn’t mean it’s easy to live with. Not everyone can find a therapy that they can tolerate, that is effective, and that they can afford. Even if they do find a therapy, those with HIV face shortened life spans. The average life expectancy is just fifty-eight years for men, compared to seventy-three for men who aren’t infected with HIV. In other countries, life expectancy is even lower. It isn’t just a matter of age. Dementia, arthritis, and other diseases of our nervous system are all found at higher rates in HIV-positive individuals. This is because HIV is able to creep into our brains. In fact, more than 40 percent of HIV-infected patients have some kind of neurological condition.
While the virus can cross the blood–brain barrier, the seal that separates our central nervous system from the blood circulating around our body, the drugs we use to target the virus cannot. Because of this, HIV is able to outrun the therapy gunning for it, and infect and replicate in the brain. A whole new virus population forms in the brain, genetically distinct from that in the blood. This new world of viruses can cause inflammation and cell death and is linked to HIV-associated dementia.
Aging and HIV is a relatively new field in HIV research. Many researchers believe that we’re just at the tip of the iceberg in learning how the virus accelerates aging. With so much research focused on prevention, few resources have looked at how to manage the effects of HIV in people over fifty. Yet as patients survive longer on new classes of antiviral drugs, this is a growing population.
HIV exhausts the immune system. Each cell in our bodies has a built-in death clock, a limited number of divisions it can make before it peters out and dies. HIV stimulates the immune system to divide at a frantic pace as it rushes to provide enough cells to target the virus. This is why some scientists think, if therapy is started earlier, before the virus decimates the T cell population, life expectancy will dramatically rise. While still controversial, some reports have shown, on average, over a decade is gained from early therapy.
If we have enough money, if we can find a combination of antiviral drugs we can live with, and if we start early, we can live a long time with HIV. The problem is that these three criteria are not always easy to come by. Our background and our geography all present hurdles, hurdles that many of us cannot jump. This is why it’s not enough simply to keep producing new HIV drugs, to stay ahead of the ever-mutating virus. We need a functional cure.
• • •
Large-scale clinical trials building on Christian’s success were a failure. These trials all captured a piece of Christian’s therapy, but none of them replicated his experience. The reasons for this are manifold. On one hand, it’s difficult to recruit people recently infected with HIV. Many people aren’t like Christian and don’t know the date of their exposure so precisely. Even if they do, they may be loath to go to the doctor so soon. The reason Christian was able to get such early therapy was his relationship with Jessen. He had a family doctor he trusted and was close to. Not many young people can say the same. Particularly not in the United States, where the large-scale clinical trials were held. Young men aged 15–24 are the least likely in the United States to regularly see a primary care physician. Even if they suspect they’re infected, they usually have no relationship with a medical health professional to help them navigate the waters. This is a major stumbling block for clinical trials looking at early therapy. It’s difficult to recruit patients diagnosed quickly after infection and who are at similar stages of the disease. Because there was so much variation among patients, the trials could conclude nothing; they couldn’t even recommend when to start therapy. It was tremendously frustrating.
A catch-22 had been established. The only way to get people recently infected with HIV to seek therapy early was to have strong scientific evidence that early therapy could help. But the only way to get that evidence was to persuade more people to come in early after becoming infected with HIV.
Christian hadn’t just received early therapy; he had also already received a potent cancer drug. Unfortunately, because none of the large-scale clinical trials replicated his experience, it’s impossible to know the influence of each individual component in contributing to Christian’s cure. Unpredictably, a similar problem exists with Timothy’s cure. While it’s likely that Timothy’s cure was mediated by the genetic advantage given to him by the HIV-resistant mutation Δ32, Timothy also received a mélange of other treatments that might have influenced his cure. These included conditioning therapy, graft-versus-host disease, and the stem cell transplant itself. It was impossible to weight the influences of these factors in his cure. In both Berlin patient cases, you had an unusual finding: Doctors had cured a patient of HIV, but scientists were still debating how that cure happened.
Both Christian’s and Timothy’s cases were made more complicated by their individual genetics. Timothy was heterozygous for the Δ32 mutation before he had the transplant. He had only one functional copy of the CCR5 gene rather than the two functional copies most people have. This meant he had a genetic head start. How had this genetic advantage influenced his cure? It was impossible to measure. Christian also had an interesting makeup in his HLA, the genes that govern the immune system. It turned out that Christian’s HLA type was B*57.
People with certain subtypes of this HLA are more likely to be the special elite controllers of HIV. However, while this HLA type is seen more commonly in people who genetically control the virus, the vast majority of people with this HLA cannot control HIV. Moreover, Christian was negative for a subtype of B*57, the B*5701 gene, most commonly associated with elite controllers. Christian’s symptoms did not match those of an elite controller or even of someone slow to progress to AIDS, called a slow progressor. That’s because Christian, unlike the genetically gifted elite controllers, had high levels of virus after becoming infected with HIV, suffered from infections due to his weakened immune system, went on antiviral therapy, and experienced an increase in virus when he went off the therapy. He also didn’t harbor the crippled virus that HIV controllers have, which indicate the ability of their immune systems to mangle the virus without the help of drugs. Nevertheless, the fact that Christian has the HLA-B*57 gene created confusion.
For the physicians intimately involved with the Berlin patients’ treatment, the controversy stirred by the individual genetics of the patients seemed silly. Both Jessen and Lisziewicz believe that Christian’s cure came from the therapy he was given, combined with the early timing of the therapy. However, other researchers have postulated his control came from his individual genetics. Without a follow-up study, we may never be able to completely rule out his HLA-B*57 gene as a factor in his cure. Similarly, Hütter believes that Timothy’s cure came from the HIV-resistant cells he was given. Just as in Christian’s cure, other researchers question this. They believe Timothy’s cure may come from the myriad other medical aspects involved in his therapy. One thing we can count on: A spectacular medical finding is scrutinized to the very last detail of doubt.
For both Berlin patients, their individual genetics seemed to be getting in the way of what should be obvious: Both men had HIV and both men were cured. Both cases were mired in controversy and scientific debate. But at its heart, both therapies represented a new way of thinking about curing HIV and embodied a new strategy to get to that cure. The question was how to use what scientists had learned from these individual cases to inform new strategies. Ultimately, while both Berlin patients were cured of HIV, it wasn’t a cure that anyone would want. Scientists would have to take their inspiration from these cases and find a way to translate the ideas into therapies for everyone. By themselves, the Berlin patient cases were anomalies. The Berlin patients were not the answer. They were invitations to fulfill a promise, the promise that HIV can be cured.