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This Month in HIV: A Podcast of Critical News in HIV
  

The First Man to Be Cured of AIDS: An Update on the Amazing Story -- This Month in HIV

An Interview With Jeffrey Laurence, M.D.

September 2009

This podcast is a part of the series This Month in HIV. To subscribe to this series, click here.

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amfAR Holds a Think Tank Meeting at MIT

That's amazing. Who were the 10 experts you invited? I think everyone would be curious to see that list.

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The first person was Sandra Bridges. She's worked on HIV from the very beginning and helps coordinate research for the Division of AIDS, at the NIH. John Coffin from Tufts University co-discovered the ultrasensitive assay, which can detect less than a third of virus per mL of blood. Mort Cowan, at the University of California at San Francisco, has been working on the gene therapy of HIV for about a decade, and is head of a transplant program there, at UCSF. Steven Deeks, also from the University of California at San Francisco, did a baboon stem cell transplant, probably about 10 years ago, in an attempt to see whether baboon cells, which are resistant to HIV infection, could be used to help the immune system of a young man who had HIV. Dr. Gero Hütter is the physician for the patient. Judy Lieberman, from Harvard University, has spent a long period of time trying to create animal models for a way that HIV and also herpes viruses might be cured by making cells resistant to infection by herpes viruses and by HIV using gene therapy. David Margolis is head of the Department of Infectious Diseases at the University of North Carolina and a long-term AIDS researcher. John Zaia is from the City of Hope, outside of Pasadena, Calif. He heads a bone marrow transplant program there. John has also been working for almost a decade on the potential of stem cell transplants to treat HIV. Dong Sung An is from Irvin Chen's group at UCLA [University of California, Los Angeles]. He's involved in monkey studies related to the use of stem cell therapies in animals as models for curing HIV.

When we do these think tanks from amfAR, there's also staff invited. So Kevin Frost, who's our chief executive officer at amfAR, was in attendance. We always invite one journalist to cover it. The journalist was Pulitzer Prize winner Mark Schoofs. His Pulitzer Prize winning work was related to circumcision and condom use in Africa. [Click here to read Mark Schoofs' articles.]

amfAR Think Tank Attendees

• Dong Sung An, Ph.D.
University of California, Los Angeles
• Sandra Bridges, M.D.
Division of AIDS, NIAID
• John Coffin, Ph.D.
Tufts University
• Mort Cowan, M.D.
University of California, San Francisco
• Steven Deeks, M.D.
University of California, San Francisco
• Kevin Frost
CEO, amfAR
• Gero Hütter, M.D.
Charité-Universitätsmedizin Berlin
Berlin patient's physician
• Jeffrey Laurence, M.D.
Senior Scientist for Programs, amfAR
Weill Cornell Medical College
• Judith Lieberman, M.D., Ph.D.
Harvard University
• David Margolis, M.D.
Center for Infectious Diseases
University of North Carolina
• Mark Schoofs
Wall Street Journal
• John Zaia
City of Hope

Was that a one-time meeting, or is this an ongoing think tank?

That was a one-time meeting, but due to this meeting, my editorial in The AIDS Reader6 and my commentary for amfAR, I started getting calls from transplant programs throughout the United States saying they think they have an eligible patient for this.

So, with amfAR's blessing, a core group of transplanters was created that would make certain that we had the best protocol to treat the next eligible person that had a match. Some people from the group that I just mentioned are on this panel, but I also have additional people from Johns Hopkins University and Harvard.

What's Stopping U.S. HIV Researchers From Working on Experiments Like This?

What's the status of that?

Thus far, we've had two individuals who are virtually identical twins of the Berlin patient; that is, they are 40-year-old individuals who were treated with HAART [highly active antiretroviral therapy] for HIV for many years that unfortunately developed acute myelogenous leukemia and needed, and got, treated with chemotherapy, but will need bone marrow transplants.

Unfortunately, there are two obstacles. The first obstacle is getting a match. The person I was so enthused about here at our own hospital had no matches among the 13 million adult donors that we searched. There were some acceptable matches from our cord blood program, which uses blood from the placenta where you can get stem cells. The trouble is that because you don't get a whole lot of blood from a placenta, and therefore you don't get a whole lot of stem cells, you often need to use two or three of them. The statistical improbability of finding two or three exact matches that will also be delta32 CCR5 negative is just astronomical.

Basically, we cannot find matches for the individuals that we're presented with. The hope is though that somewhere we will find a match.

Why can't you use the people in Germany?

It's a worldwide match, so the German registry's on our registry. However, the tissue-type match has to be exact. Remember, I mentioned that Dr. Hütter initially went about finding a match the way we all do, by searching among the 13 million people in the worldwide registry, and he found 232 acceptable matches.1

"This could never, ever have been done in the United States first. It could be done in Europe because they have a socialized medicine system. No one asked the question who's paying for this."

Had he not been concerned about curing the person of leukemia and curing the person of HIV, he could have used patient number one out of 232. Instead, he set out to test all 232 for the delta32 mutation and then use the person with that mutation. I mentioned before that the odds -- at least among Caucasians, and the vast majority of people who contribute to these banks are Caucasian -- are 1.5 percent.

So out of 232 individuals, statistically, Hütter was bound to find one match with the delta32 mutation, and he did. Number 61 out of 232 was not only an exact tissue-type match, but also had the delta32 mutation.

Our second problem has to do with money. This could never, ever have been done in the United States first. It could be done in Europe because they have a socialized medicine system. No one asked the question who's paying for this. Forget about HIV right now -- if you have leukemia in the United States, and you need a bone marrow transplant, most insurance companies will pay for 10 screens. Some of the more unusual ones might pay for 20 at a time. So you can search through the 13 million in the adult bone marrow registry. If you need to, you can also go through the cord bloods. You come up with a bunch of matches and insurance will pay for calling in the first 10.

The likelihood that you'll find a person who is available is very good.

Usually, we don't even need to go through all 10. But that's not going to help someone with HIV. As I mentioned, Dr. Hütter's patient had 232 matches. They could have taken the first one. He wouldn't have gotten to number 61. He wouldn't have gotten to number 10, certainly not number 20, or 30, or 40. It took him 61 tries. They would have never been able to call in patient number 61 after having had 60 other perfectly good matches.

Couldn't this be done through an NIH or academic study?

"What we really need is a new program for the bone marrow registry in the United States, if not worldwide, where we get permission initially to test for CCR5 in everyone, the way we test for tissue types and several other things that are mandated. If we had information about CCR5 status, we wouldn't have to bother calling potential matches in to test them for CCR5. We would just do this search for free on the computer."

Someone would have to pay for it. Calling the people in takes administrative money. Doing the confirmatory typing test is about 2,000 dollars a pop.

Again, all this is free in Germany. Then there's the CCR5 testing, which we could probably do in an experimental lab for maybe five or six dollars.

What we really need is a new program for the bone marrow registry in the United States, if not worldwide, where we get permission initially to test for CCR5 in everyone, the way we test for tissue types and several other things that are mandated. If we had information about CCR5 status, we wouldn't have to bother calling potential matches in to test them for CCR5. We would just do this search for free on the computer.

What we at amfAR are trying to do is raise funds to do CCR5 typing on tissues that are already in banks that are accessible to us. For example, at City of Hope, they have a registry of about 40,000 available cord bloods. They could all be tested for CCR5 if funds were available. There are many other institutions that have these registries, not all of which are actually in the worldwide registry, in terms of cord blood because it's a relatively new thing that could be tested.

I think to add CCR5 information to the list of things that a potential donor is tested for will take some political will within the transplant community itself. It would be great if we could do it. It's one of the things that we're advocating for at amfAR.

How much money do you need to do this?

To do the simplest thing, that is to just test the available cord blood stem cells that are available through these private banks like City of Hope, we're probably talking about, with administrative costs, at most 10 dollars a pop. If each of these banks has 30,000 or 40,000 samples, then we're talking about 300,000 to 400,000 dollars to screen all of them.

Can our listeners donate to amfAR to get this thing moving?

They can donate to amfAR and designate it for the cure. That would be one of the things that we're looking at. But I don't want anyone to think if they give one dollar that's going to pay for one person's testing; I can't guarantee that. It basically goes towards these kinds of studies, like typing patients for CCR5 and research into trying to move this out of just this one peculiar scenario to "How do we develop this into a cure for everyone?" That's the kind of research that amfAR's talking about and that we'd like people to donate to.

What does it say about the HIV research community in general that this experiment was done by someone who's completely outside the HIV research community? The patient's physician, Gero Hütter, isn't an HIV specialist.

He's a young hematologist. It says a lot about our health care system. It doesn't say anything about our research. Everybody and their brother who has ever heard of HIV knew that this was possible and wanted to do it.

I've had protocols available to do HIV stem cell therapies for almost four, five years. It's just that what you need is the appropriate patient. So it's not for the lack of knowledge. Everyone was waiting for someone who was HIV positive and young, who then developed a disease like leukemia, severe lymphoma or myeloma, and required a bone marrow transplant. That person just happened to walk in the door in Berlin.

That was the first obstacle. You had to actually find the person. Statistically, the likelihood of finding a person like that is one person every two years in Germany.

I've calculated that we should find about 10 people just like that every year in the United States. I've already had three such patients, in just a few months, referred to me.

So we know those people are out there to replicate. The second obstacle has to do with what I mentioned about insurance and the way we screen people.

In Germany, Dr. Hütter was able to go through all of that because he didn't have to worry about doing the extra tissue typing and whether the patient was going to be able to afford it and so forth and the patient wasn't even a German citizen.

Amazing.

In the United States, the way we pay for health care is very different. If you're doing a transplant to cure leukemia, it is perfectly reasonable for the insurance company to then say, "We've had a long history. We know that just paying for the first 10 matches is all you need to do." And they're right.

"Physicians in the bone marrow transplant community are trying to work around some of these rules, trying to see whether we can get CCR5 testing added to the list of other things that people are tested for. When you volunteer to be a donor, rather than just testing your blood type and your tissue type, and testing for certain infections, what if they also tested for CCR5?"

But if we're trying to cure HIV, we need to bring in everybody that's a potential donor to test them for the CCR5 mutation. I haven't tested that with an insurance company, but I'd bet they'd look at it with an askance eye because it's an experimental procedure. As you know, insurance companies don't pay for experimental procedures.

What a tragedy that one of the impediments to a possible cure is structural.

Right, but again, I should mention that this is a cure for the one-in-a-million person.

But it is structural. That is absolutely, positively correct. Physicians in the bone marrow transplant community are trying to work around some of these rules, trying to see whether we can get CCR5 testing added to the list of other things that people are tested for. When you volunteer to be a donor, rather than just testing your blood type and your tissue type, and testing for certain infections, what if they also tested for CCR5? It would add an incredibly small amount to the cost of the work. It's not going to do anything for the 13 million who are already in the registry, but wouldn't it be nice to have that information for the next 13 million that volunteer over the years? That's something we're working on.

Can activists accelerate this process?

Activists can accelerate a lot of things. The last meeting that I had with this group of transplanters was in April. I need to see where we are and how far they've gotten, and then I may ask for your help.

What Is the Most Important HIV Research Being Done Now to Address Finding a Cure for HIV/AIDS?

In your opinion, what is the most important research being done regarding curing HIV?

It's figuring out how we take this proof of concept from one patient and do it on demand.

The ideas are out there on how to do it. Basically, what you need to do is mutate this gene in every single cell that you're going to transplant into a person. What if we just took the person's own cells, or that of the next available donor that walks in the door who happens not to have the CCR5 mutation -- as statistically they won't -- and genetically give them the mutation?

Can we knock out the gene for CCR5? That's called genetic engineering. We're really good at doing genetic engineering in one cell. But the average person getting transplanted is getting a few billion cells, and we have to guarantee that 100.0 percent of those few billion cells all have their genes modified. We could take a few hundred or a few thousand cells, make certain that every single one of them has that gene modified, and then grow them into billions of cells that we can inject back into the patient, but we don't know how to do that.

Some of the physician scientists that I mentioned that I invited to our think tank in September are working on that. They're working on it in mice, and they're working on it in monkeys. With current technology, in a monkey or in a mouse or in a test tube, you can knock out the CCR5 gene in maybe as much as 90 percent of the cells. But we need 100.0 percent of cells to be CCR5 negative, because if even one little cell has the capacity to be infected with HIV and it starts multiplying in your body, that's the end of your cure.

So I think it's partly a technology problem, and that's where research comes in. We know what we need to knock out: CCR5. We have people looking, as I mentioned earlier, for other things that might account for other people being resistant to getting infected with HIV. If we find those changes, we'll have other targets to knock out.

All we need to do now is come up with better technologies than the small interfering RNAs, the zinc finger nucleases, the oligonucleotide reductases, the ribozymes and so forth. All these words for ways that we knock stuff out to get us closer to 100 percent. That's where research is so important.

"This is an important area of research that needs multiple people looking at it from multiple different angles because none of those technologies are 100 percent accurate in knocking a single gene out in 100 percent of the cells."

I have a lot of faith in this kind of research. It's going to enable us to just take cells from the first acceptable donor, as if the patient didn't have HIV, knock out that gene and give it to the patient, and replicate what happened in Berlin.

Who do you think is doing the best research on a cure today in the United States, or in Canada?

It's happening throughout all the universities that I mentioned. I obviously sought to get the best scientists from the best universities, or at least representatives from those groups.

As I mentioned, University of California at San Francisco has projects looking at this. University of California at Los Angeles has projects looking at this. Tufts University has projects looking at this. Harvard has projects looking at this, and so does Duke, and so does Hopkins, and so do we at Cornell Medical.

This is an important area of research that needs multiple people looking at it from multiple different angles because none of those technologies are 100 percent accurate in knocking a single gene out in 100 percent of the cells. We need to come up with either refinements of those available technologies or new technologies. We need as many people working at this as possible, and that's what's happening.

I've been in AIDS research forever. I was actually first author on the paper by the two Nobel Laureates Drs. Luc Montagnier and Françoise Barré-Sinoussi, in which they document their virus as the cause of AIDS.7 It appeared in the same June 1984 issue of The New England Journal of Medicine as Bob Gallo's paper documenting in a large number of people that his virus was the cause of AIDS.8

I'd gone to the Institut Pasteur with about 70 blood samples from young men with unusual diseases whom I had been following since the late '70s -- that was the group Drs. Luc Montagnier and Françoise Barré-Sinoussi tested their virus on.

I've been the first scientific advisor to amfAR since it was formed by Dr. Mathilde Krim and Elizabeth Taylor, back in 1985. So I've seen all of this and many potential hopes.

"A replication of the Berlin patient with a cheap, easily accessible method of doing gene knockouts in stem cells, I think, will be the most widely available cure. But until it can be done in a person's own cells, it's just not going to be widely applicable."

I saw the miracle that HAART therapies are, but we're not going to treat our way out of this epidemic. There's not enough money in the world -- or maybe even will in the world -- to treat every single person that needs it, although people are trying. What we really need is a cure, and with more and more people working on it, I think we're going to get there.

If you were a betting man, what would you bet would most likely lead us to a cure?

A replication of the Berlin patient with a cheap, easily accessible method of doing gene knockouts in stem cells, I think, will be the most widely available cure. But until it can be done in a person's own cells, it's just not going to be widely applicable.

I've gotten phone calls from people saying, "I have HIV. I am so tired of being on these drugs. I don't have leukemia and I don't need a bone marrow transplant, but I want you to search for a CCR5 mutation for me. I'll pay for it. I want to be cured."

I have to tell them that there is a tremendously high death rate from this procedure when you're not using your own cells, but are instead using the cells of an unrelated donor. Upwards of 15 to 20 percent of people die within the first 100 days of the procedure itself. In other words, we only do that kind of procedure, as was done in Berlin, if the person's going to die from his or her leukemia if we don't do the transplant.

So someone without leukemia, or any cancer, is still at risk for death from a stem cell transplant?

Someone who needs what we call a MUD, a matched unrelated donor transplant, has within the first 100 days a 15 to 20 percent chance of dying.

It has nothing to do with their cancer?

It has nothing to do with their cancer. It's related to all that toxic therapy that is given to them -- the radiation, the immunosuppression and the cancer drugs themselves -- that make them susceptible to infections and to other unusual immune disorders that basically kill them.

That's why this is only done in an attempt to cure someone of his or her underlying disease, such as leukemia, lymphoma or myeloma, not HIV.

Clearly, what a cure is going to look like is not subjecting anyone to anything with that kind of a risk of death. A cure is going to involve knocking out these genes in the patient's own cells to remove some of that risk of dying, because the risk of dying from what's called an autologous transplant is incredibly low, on the order of 1 percent or less. So that's the way we need to get at this. Thus far, it's still at the level of research.

So it's being done in the lab, but not in humans yet?

No, there are human studies ongoing in multiple places.

If somebody wanted to join these studies, how would he or she find out about them?

Good question. At the moment, individual universities are recruiting patients. There are cancer registries for stem cell therapies, but I don't know whether the studies that I just alluded to are actually on any national registries.

How does amfAR stay current about this man in Berlin?

Through me because I organized the think tank to describe this patient, helped announce it to the world and organized the distribution of blood samples to physicians worldwide for testing. Dr. Hütter, as I mentioned, keeps in touch with me regularly, including just last night.

Because I've now become a sort of clearinghouse for other patients throughout the United States, I'm staying on top of it for amfAR and for other people interested not only in that patient's progress, but anyone else that might be treated at another university.

You said previously that the Berlin patient is doing well. Does this mean he's working? What is he doing?

After his second transplant, because he had some mental status changes, which are now thought to be related to the transplant, he had to go to a nursing facility for a while. He left the nursing facility several months ago. He's now back home. I don't know if he's back at his job, but as of yesterday, he's feeling well. He has no complaints. For confidentiality reasons, there are certain things that I'm not supposed to know, and so I'm not certain that they're going to tell me where he works, but they might tell me whether he's working or not.

So he's not interested in being interviewed or being public about this?

I've asked that question. I've not spoken to him, but the statement that I was given is that he's considering coming to the United States, and would be willing to give interviews at that point. Dr. Hütter will keep me abreast of that. It was supposed to happen in the spring, but it didn't happen. So he's not giving interviews from where he is now, but there's the potential that he may give an interview in the future.

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Copyright © 2009 Body Health Resources Corporation. All rights reserved. Podcast disclaimer.

This podcast is a part of the series This Month in HIV. To subscribe to this series, click here.


  

This article was provided by TheBody.com. It is a part of the publication This Month in HIV.
 
See Also
Timothy Brown: The Other Side of the Cure
Thoughts on the Berlin Patient and a Cure for HIV/AIDS
Tentative HIV "Cure" Presents a Guarded Sense of Hope
I'm Not Cured Yet
Is It Time to Celebrate the "Cure"?
Eliminating HIV/AIDS: How We'll Get to Zero
Can HIV Infection Be Cured?

 

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