Case reports still valuable even in the era of big data
By Anette Breindl
In general, there is no doubt that science is in an era of big data.
Genomics studies, especially, now routinely look at thousands of patients to understand which genes might underlie certain diseases, and which might make good targets. Systems biology approaches can take terabytes of data, and the National Institutes of Health has a “Big Data to Knowledge” initiative whose goal is to give researchers the training they need to make use of the massive amounts of data that modern biomedical science often has at its disposal.
But even within this era, there is still much to be learned about how to fight disease, under certain circumstances, by taking the opposite tack: looking carefully at a single patient. The importance of such single cases was evident at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston last week.
In some instances, case reports can breathe new life into an entire field. Such was the case with HIV cure research, which was revitalized five years ago by a single case report: that of “Berlin patient” Timothy Ray Brown.
A TOUCH OF INSPIRATION
“We all need a little bit of inspiration once in a while in our life, and Timothy Ray Brown provided that inspiration” for cure research, the University of Pittsburgh’s John Mellors told the audience during a talk on HIV cure research at CROI.
Brown was the first person to be cured of AIDS, after receiving a bone marrow transplant for leukemia with cells that are genetically resistant to HIV infection. He remains functionally cured since discontinuing antiretroviral treatment in 2007.
Brown’s case, reported in The New England Journal of Medicine (NEJM) in 2009, ended what Mellors dubbed the ‘cure impossible’ era, after several research labs had independently reported the existence of viral reservoirs during HIV, showing that eradicating the virus altogether would be much more challenging than scientists had once hoped.
Edward Lanphier is the CEO of Sangamo Biosciences, a Richmond, Calif.-based company developing genome editing technology. He told BioWorld Insight that whether such single case studies can lead to more general insights “starts with the disease.”
In indications like pain, where there is a broad range of outcomes and a large placebo effect, following up on a single patient’s spectacular remission is unlikely to yield anything of value.
In infectious disease, on the other hand, which is much less subjective and more quantitative, “a single patient can be highly informative.”
At this year’s CROI meeting, Sangamo scientists, with academic collaborators, presented promising results of a phase I trial that treated HIV patients with their own T cells, edited to mimic the CCR5-delta32 mutation that makes the T cells Tim Brown received resistant to HIV infection.
A third of patients treated with the procedure were able to control the virus when they went off of antiretroviral drugs for three months, and in one of the four, viral levels dropped below the limit of detection. (See BioWorld Today, March 6, 2014.)
Sangamo scientists have been working on inducing HIV resistance via gene editing of CCR5 since before Tim Brown’s case was reported.
But Lanphier said that the Berlin patient was “extraordinarily important” as proof-of-principle that such mutations could cure an established HIV infection as well as prevent such an infection from establishing itself in the first place, and “has led to a lot of interest in strategies that employ CCR5.”
Timothy Brown is not the only case report that has been important in HIV research.
At last year’s CROI, researchers reported another case which quickly became known as “the Mississippi baby” – who started HIV treatment less than 48 hours after being born, and then discontinued that treatment because her parents stopped giving her medications and taking her to medical appointments for about six months. (See BioWorld Insight, March 11, 2013.)
Instead of rebounding during that drug-free period, however, HIV remained undetectable when she reappeared, making her the second person to be cured of AIDS. A similar case again made headlines at this year’s CROI.
ILLUMINATING THE PATH
But if case reports can be very illuminating for which path to take, they can also seem to shine a light on what turns out to be a dead-end road. And here, too, HIV provides an example.
Years before Timothy Brown, unlikely as it sounds, there was another Berlin patient. And his case is instructive on the precautions that are necessary when looking at single cases.
The first Berlin patient’s story has important differences to that of Brown. In fact, in some ways his case bears more resemblance to the Mississippi baby.
The first Berlin patient’s treatment was not as chaotic as the Mississippi baby’s appears to have been. But neither was it dictated by theoretical ideas about how to cure HIV. Instead, the patient, who most likely became infected with HIV in 1997, repeatedly stopped and restarted treatment, mainly due to the side effects, before stopping altogether after about six months.
In this patient, too, there was no rebound when he stopped treatment. In 1999, a year and a half after he stopped treatment, doctors reported his case in the NEJM.
That case report, Hendrik Streeck told BioWorld Insight, set off “five to six years of intense research” with the goal of finding what had cured the patient.
Some clinical trials tested complex drug schedules meant to mimic the repeated interruptions that the first Berlin patient had experienced by happenstance.
Others tested hydroxyurea, an unconventional drug that had been part of his treatment regimen.
Ultimately, however, none of those trials amounted to anything. And as an understanding of the immune system response to HIV progressed, it became clear that the first Berlin patient’s saving grace was his genetic makeup: he has highly protective HLA alleles.
Researchers including Streeck reported that genetic makeup – which had been known to those involved with the case for some time, but had not been formally published – in a letter in the Feb. 13, 2014, issue of the NEJM.
Streeck stressed that his views do not represent the position of the Department of Defense or the U.S. Army, where he is section chief of cellular immunology at the U.S. military HIV research program. But he noted that when one patient overcomes a currently incurable disease, “there is a pressure to find something based on that patient.”
Such attention to case reports is not wrong, but there needs to be a sense of when, simply put, enough is enough. As the authors wrote in their paper, the first Berlin patient “represents a cautionary tale of drawing broad conclusions from a single patient.”
A promising observation in a single patient, Streeck elaborated, “can guide research. But it cannot define research, or the direction of research. That is true with any case study.”
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