Paths to a cure: Dr. Dan Kuritzkes discusses experiences of two patients

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When Dr. Dan Kuritzkes of Harvard Medical School and Brigham and Women’s Hospital presented his team’s findings on two HIV-positive men who remained on antiretroviral therapy while undergoing stem cell transplants, and in whom the levels of HIV DNA had since dropped to undetectable levels, he was careful to emphasize that he was not claiming that the patients had been cured.

“One of our concerns in presenting these data was to be very cautious and responsible, emphasizing the limitations of the data, while at the same time being excited about the significance and novelty of the findings,” he said.

Following the emergence two years ago of the story of  “Berlin Patient” Timothy Brown, who doctors now call “functionally cured” — meaning that he no longer needs medicine to control the virus, nor can he transmit it to anyone else — the excitement over more evidence that HIV DNA can be reduced to the point where it has not yet been found in two more people who have been HIV positive, was contagious, though.

“While most of the reporters who wrote about this understood we were not claiming to have cured these two patients, most of the editors construed it to mean these two patients had been cured,” Kuritzkes said, laughing as he recounted one story headlined “Two patients cured!” over a story emphasizing that while both patients showed promising signs, neither had stopped antiretroviral therapy.

What did happen was this: After both patients’ stem cell transplants, HIV initially remained detectable in their bodies. Then, as donor cells, which had been exposed to the antiretroviral medicine the patients were taking, replaced the patients’ cells, their levels of HIV dropped, until 8 months later, it was undetectable. Their levels of HIV antibodies were reduced to levels low enough to be “comparable to what was seen in the Berlin patient,” Kuritzkes said. But what makes their story novel, in the quest to map new routes to a cure, is that what led to that point was different from what led to the Berlin patient’s cure. The Berlin patient was not on antiretroviral treatment at the time of his transplant — the rigors of chemotherapy had made that impossible. He was, however, the recipient of donor cells chosen deliberately from one of the roughly one-in-a-hundred people, who, lacking a receptor  — the CCR-5 receptor — that HIV needs to latch onto, are genetically immune to HIV.

That was not the case with the two patients whose cases Kuritzkes presented. There was nothing particularly rare, nothing unique  about them, their HIV, or about their donors, that doctors know of. What’s exciting about that, and you can hear it in his voice when he says it, is that their experience, if they discontinue antiretroviral treatment and remain as they are now, would show the possibilities for preventing HIV acquisition through preexposure prophylaxtic antiretroviral treatment: “PrEP on a cellular level!” Kuritzkes said.

He spoke with Science Speaks about the research that led to this point, and what is next.

How did you encounter these two patients?

My colleague Tim Henrich developed a protocol asking how does chemotherapy and stem cell transplant affect the viral reservoir. (After he put out a query to cancer treatment centers in the area, Dana-Farber Cancer Institute directed him to two patients who had remained on antiretroviral therapy and were doing well. Both patients had had stem cell transplants and were being monitored, their treatment managed by oncologists.)

What can you tell me about the first patient?

The first patient had been infected from birth. We’re trying not to provide too much information. He’s a young man, and had been on antiretroviral therapy for several years. We’re not sure how long. He developed Hodgkin’s lymphoma, possibly related to his HIV, it is a little hard to say for certain.

What can you tell me about the second patient?

The other patient was an older gentleman who had been infected also for a very long time, since the mid-1980s. He had actually done quite well for two decades, without needing antiretroviral therapy — he was not an elite controller (or long-term nonprogressor, a person living with HIV who controls the virus without medication).

You have mentioned that both were able to stay on their antiretroviral treatment through the chemotherapy and the transplant, because they received a milder form of chemotherapy, than for example Tim Brown, the Berlin patient, who had to discontinue treatment for his HIV because of the effects of his chemotherapy. Why were these patients on a milder chemotherapy?

For a couple of reasons. Success rates in some centers is sometimes better with reduced intensity conditioning (pre-transplant chemotherapy). Each center has its own approach. There is a lot of variation from center to center. In any particular case, the oncologists are trying to do what is best in terms of treating the patient’s underlying malignancy and giving them the best chance of surviving their cancer.

There were two reasons they were able to stay on their antiretroviral therapy. They didn’t get as sick, and didn’t have drug-drug interactions.

You have said that the donors were not HIV-immune, or lacking the CCR-5 receptor as the Berlin patient’s was. Was there anything special that you know of about the donors?

It is unlikely. We don’t have access to the donors, but we have access to the cells. We would like to show that we can infect the cells in the laboratory.

When are you going to do that?

It’s hard to say. We will eventually. We have a limited number of cells and we want to use as many cells as we can to try to detect HIV. To siphon off some cells for the sake of infecting them is a lower priority.

You’ve mentioned that the only way to determine that these patients don’t have replicable HIV lingering in their bodies will be to discontinue their antiretroviral treatment and watch them very carefully. Has either patient since discontinued treatment, or do you anticipate that either patient will discontinue treatment in the near future?

Both patients remain on therapy. We’ve urged them to continue treatment. We could only discontinue their treatment through a research protocol. Both patients have been on suppressive regimens for some time. If they stop treatment under careful observation, we could monitor them.

What would be the worst case scenario if they did need to be on the treatment to contain the virus?

We have every reason to believe that resuming treatment in that setting would rapidly suppress the virus again, and as treatment would be started promptly, there would be little risk of harmful consequences. That’s why we are particularly keen that if these patients were to stop therapy, that it would be in this kind of controlled setting. We think this can be done with high safety and little risks to the patients but should be done as part of a carefully designed research protocol. (That protocol would need to be approved, including by a board evaluating research involving  human subjects).

What are the ramifications of your research, in terms of suggesting future steps in research for a cure?

The experience of our patients indicates we could rely on antiretroviral treatment to protect uninfected cells from being infected.

We have identified two other patients who are undergoing stem cell transplants who will be staying on their medication, and who we will be following from the beginning.

Do you believe a cure that is generalizable to the extent of being available to patients on a widespread scale in resource-poor settings is possible?

Right now it’s hard to say whether we are or not going to be able to develop a cure that can be used worldwide. First we have to find out if we can cure patients even if it takes arduous and expensive approaches. Then we can work to see how they can be generalized. We certainly won’t ever get there if we don’t try.

Have the results of the Berlin patient and your findings had any effect on funding for cure research?

There’s no question that the Berlin patient experience recast the entire question of whether a cure or functional cure is possible, and provided a rationale for investment or renewed investment towards research for a cure. In the case of our two patients, we’ve only just presented the data, so it’s too soon for this to have any impact.

What was your experience at the International AIDS Conference last month?

It was really gratifying to see the conference back in the United States after 22 years, and see that not only was the conference here, but it was a conference where a number of significant results were presented, it went off smoothly, and focused attention not only on the progress that’s being made, but the gaps that remain.

Did you find the talk of the “beginning of the end of AIDS” and of an “AIDS-free generation” realistic, premature, or overly hyped?

I think it’s perhaps a little premature to talk about the beginning of the end of AIDS, though I think the potential is certainly there. I would view the comments and Secretary Clinton’s statement as promising — we have the tools in hand to have an AIDS-free generation and the limitations in achieving that goal are really ones of political and economic will to devote the resources and develop infrastructure to attain that goal.

 

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