Interviews with Cure Leaders

The Doctor Who Cured HIV

 An Interview with Gero Hütter, M.D.

This isn’t another story about the “Berlin patient” — a.k.a. Timothy Brown, the first, and to date the only, man who’s ever been considered “cured” of his HIV infection. His story has been told many times, in many ways, and in many publications — including ours, so there’s no need to retell it. By comparison, we’ve seen relatively little about the man who cured him: Gero Hütter, M.D., an oncologist in Berlin who was previously unknown in the HIV field. And with good reason: Until the Berlin patient, Hütter had never treated an HIV-infected cancer patient before, nor had he conducted any HIV-related research studies.

While in New York City for a speaking engagement, Dr. Hütter was kind enough to visit with us. Relaxed and mild-mannered, he discussed the Berlin patient’s case — how he approached it, how he weighed the risks and the benefits, and what we’ve learned from the process. He also shared his thoughts on how the case transformed his career, and on what needs to happen for the HIV/AIDS medical community to repeat the Berlin patient’s success and yield a second “cured” patient (and a third, and a fourth, and …).

 

The Makings Of A Miracle

gerohuetter620-size-598Question:  Explain to me how a clinician who is trained as a hematologist and a cancer researcher ends up being the guy who changes the way we think about the approach to an eventual cure for HIV.

Answer:  [Laughs] This is what I always want for my patients: I want the best treatment. This was a challenge, from when I saw Timothy and I realized that we have to do this transplantation. For me, it was the first patient with HIV which received allogeneic transplantation.

We know from patients with leukemia that eradication is achievable. And we cannot accept, in patients with leukemia, that any of these leukemia cells will survive, because they are the basis of any relapse of leukemia. So you have to cure these patients and get rid of the leukemia. And if this works with leukemia, why shouldn’t it work with HIV?

You make it sound like it’s such a natural, logical conclusion. But we’ve known about this mutation — that people whose CD4 cells don’t have the CCR5 receptor are largely immune to most forms of HIV — we’ve known this since the mid-to-late ’90s. Yet nobody had thought to try this before.

That’s not quite correct. There are several others who had this idea before me. And they had made approaches to realize that. For example: the StemCyte [Cord Blood Bank] built up cord blood units, with tested cord blood units for the CCR5 mutation in 2001.

The gene therapy approaches targeting CCR5, they are older than the Timothy Brown case. But this case has supported their work. The techniques were available, and the idea was available, but it needed something that enhances the whole development.

After the Timothy Brown case was published, the funding and the support for such new approaches were opened, and now the development has come much more quickly and rapidly.

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When you first thought to do this, this was a shot in the dark, right? Timothy’s prognosis was pretty grim. No one had actually attempted this type of treatment before. Did you think, “Might as well give it a shot”?

Yeah. I would have felt better if I had tested it before. [Laughs] I knew it was probably possible. It’s not easy to test the same condition in animals, but you could see some effects in animals.

In this case, it was clearly a shot in the dark. I studied the literature. I looked in PubMed, up and down, to see if there was anything published on this point: What happens if a patient who is HIV infected changes the CCR5 phenotype? And I found absolutely nothing. It’s never been tested before, not even in vitro.

This was very surprising. It could be that no one really thought about this possibility. And the other explanation could be that they have tested it, it’s gone wrong and no one got published. I was a little bit nervous about this point.

We were a little bit scared that we didn’t really know what could happen: You have high selective pressure against the virus, when we changed this immune system to CCR5 depleted cells, and no one really could say how the virus would behave.

[But then we realized that] the worst thing would be that he changes his tropism to the CXCR4 receptor, and then as long as he takes his antiretroviral medication, there’s no harm for the patient. So we got optimistic that we could dare this experiment and that the risks are not too, too big.

I think it’s easy for a lot of us to grasp on to this and say, “Here is the cure. Here is the future. Here is where it’s going to happen.” I’m guessing you’ve heard this kind of question a lot: “Is this the path forward?”

Yeah. If you look at the HIV research, we have no better answers for cure questions than what we have now with the CCR5 receptor, gene therapy. We have approaches in targeting, unmasking and killing, specifically, reservoir cells. But they are all connected with the cure question.

And the cure question, 10 or 5 years ago, was no real question. If someone said to you, “I want to cure HIV,” all you’d have to say is, “You’re mad. This is not possible. This is a retrovirus which degrades, and you can’t get rid of the genomic material.” This was the dogma of this case.

The way of thinking about cure has changed a little bit. This makes the process open for alternatives to the current antiretroviral therapy — it does not have to be only the stem cell approach. There are other approaches derived from this case, which are also promising.

We’ve known for a while that the CCR5 receptor is the primary way through which HIV enters a CD4 cell. But there’s still so much that we don’t really know about the CCR5 receptor. How much have we learned over the past few years?

Very little. We know that the CCR5 deletion is much older than HIV, and the mutation appeared thousands of years ago. The distribution, what we see now — in Europeans, this deletion is high; in Africans and Asians it is absent — this is a distribution which happened in the last 10,000 years. There must be some kind of advantage for these carriers, and we don’t know all the reasons why.

We don’t know exactly the function of CCR5. We know that it probably plays a role in another infection, the West Nile virus infection. But all of the details are very unclear. There are some studies focusing on carriers of the CCR5 deletion, and whether they have high risk of any other disease. But these associations are very weak; there’s no clear association of any disease with the deletion.

Why hasn’t there been a Patient No. 2 yet?

We have had requests from other institutions — taken together, I think we have now 15 other patients with HIV in need of urgent transplantation, because of leukemia, lymphoma, and so on. And some of them had just one [potential donor match]. Who gets that donor that was tested and was CCR5 negative?

Some had many potential donors — 60, 120, such as Timothy had — but sometimes mathematics fail. And the probabilities [of success] are 1 percent.

So this is a problem. I think it’s a question of time. If you wait long enough, you will find a patient who will have the same conditions like Timothy.

The other point is that we don’t have access to every patient who has the possibility to do this. There are many more patients with HIV who get transplants by allogeneic transplantation than we get information about. Because some institutions didn’t really know about [the Timothy Brown] case. Some knew about this case and said, “Oh, this is so uncommon, this mutation; it doesn’t make sense to test for it.” They didn’t start with it. If you don’t start with the investigation, you will never find a second patient.

This is the biggest problem, I think: We have information about less than 5 percent of all these patients who get transplantation. If we have access to all of these and test them, the probability is much more higher to find a second patient.

Is this a uniquely European thing that you did? Could what you did with Timothy Brown not have been done anywhere else?

No: They tried it, too, in the U.S. But the circumstances are not like in Europe, or especially not Germany. We have in Germany a unique situation: We have 80 million Germans, and 3.5 million of them are registered in donor registries. It’s very high. It’s the highest proportion in the whole world.

Do you know how that compares to the U.S.?

You have 7 to 8 million in the U.S. But the difference, the second difference, is: These 8 million in the U.S. are derived from hundreds of stem cell registries. Every county, every state, every hospital, every institution has its own registry. And in Germany we have a central registry for all of these. So it’s much easier to assess these registered donors.

That’s also the reason why it works so well. You can do this in any country, but it works so well [in Germany] because we have this central registry, with a large number of registered donors. This was part of the success.

 

The Evolution of a Cancer Doctor

 

Gero 87919034385How many HIV-positive cancer patients had you treated before you met Timothy?

None.

Was he the first HIV-positive patient that you had interacted with?

No. I’ve seen many HIV patients, through my students and sometimes my medical training. But most HIV/cancer patients, they are old patients or they are in other departments with specialized HIV treatment. It’s uncommon that an HIV patient would come to our department. It’s only the case if they have diseases like leukemia or aggressive lymphoma, which cannot be treated by other institutions.

The bulk of your practice and the bulk of your research: Where had that been focused on, up until 2006?

My research focus was on leukemias, on resistance against chemotherapy and stem cell treatment.

Had that always been your passion? Or is that something that developed out of your education?

It has a little bit development, but I started with my scientific area with my doctoral thesis. It was based on resistant phenomena against chemotherapy.

How much of your clinical and research focus has continued to be on chemotherapy resistance since news of Timothy Brown broke?

Now I’m not working clinically anymore. I changed my position to an institution which specially is for collecting and producing stem cell products or other blood-derived products. This is not clinical work. A great part of my work is now research.

Is it research on how stem cells can be used to treat all diseases, or does it focus specifically on HIV?

It’s for other diseases. But part of this research project is how to use it in the case of HIV, yes.

What kind of research have you been able to do?

We have focused on the molecular things which are associated with the CCR5 deletion. Because not everything is quite clear about this deletion — why some effects are also measurable in the transplantation setting. We know that people who have this deletion, the CCR5 deletion, they have better survival if they receive kidney grafts, after kidney transplantation. Normally, transplantation of the kidney has a survival rate of 5 to 10 years. People who have this mutation, their kidney will not be rejected.

So CCR5 deletion is part of this effect in nature. We have other immune system phenomena which have not really described what’s behind this phenomenon.

Where is your research focused right now?

Our stem cell unit is focused on treating this population of hematopoietic stem cells for hematological patients. But we have also done research on mesenchymal stem cells, which can be used for regenerative medicine. This whole stem cell area is covered from our institution.

Is regenerative medicine the idea that, if you lose a finger, it can grow back the finger? Or is that a little far-fetched?

I think this is not going to be in the next few decades. It probably is not possible. But you can replace part of tissues if you have injuries, or loss of some special tissues. Or you can rebuild a heart muscle, with mesenchymal stem cells. These cover small areas of possibility; it’s very hard to rebuild whole organs, or limbs. This is science fiction, I think.

But if you’re an HIV/HCV-coinfected person, and you’re cirrhotic, is there a potential that down the road this kind of research can lead to some liver regeneration?

Probably. I don’t know — I wouldn’t exclude this possibility.

 

Looking Toward the Future

 

Tim and Gero 145082782Before you came here this morning, you gave a talk at St. Luke’s-Roosevelt Hospital Center. What was it about?

I covered the Berlin patient story: what things we already know from the results; what is unclear and what is not detected; what are the consequences of the case; and how we can go on with this approach.

How many of these talks have you given over the past few years?

[Laughs] Oh, many. I like the idea of promoting the CCR5 story. Many people have heard of it, or read. But I think there are some details which are still [not known] for many people who didn’t read it very carefully and have [ideas] of this case which are not quite true. So it’s probably good to remember, then, what are the facts, and what can we learn from this case.

In addition to not knowing the details of the Berlin patient case, you mentioned earlier that some medical instiutions don’t think to test allogenic transplant donors to see if they have the CCR5 deletion. Is that one of the reasons that you’ve been speaking — to try to increase that level of education and communication?

Yeah. I want to promote the fact that we can do this testing for free [at our institution]. Someone will say, “Oh, no. Don’t do this testing; it will cost us too much.”

I say, “No. It doesn’t cost anything. I will cover all the costs.” But they are always unsatisfied. Some say, “Yeah, we have such a patient. But we want to do this testing alone. We don’t need your help.”

They have made, here in the U.S., a trial for patients where they specifically look for CCR5-deleted cells, and for a few patients with leukemia and so on. It’s an NIH [U.S. National Institutes of Health] trial. And all of [the people involved in] this study hadn’t made contact with me. I found out about it from their presentation at CROI that they started it.

So you just hope that you make the connections and that ultimately it will start to come together.

I’m hoping for everything. I support every work which is in this direction. So, go on, if you have patients.

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This interview appeared in the TheBody.com, written by Myles Helfand on July 19, 2012. The original interview can be found here.


 

George Stephanopoulos Interviews “The Berlin Patient” 

During 2011 amfAR Symposium in New York City

November 2011

 

 


 

Toward an H.I.V. Cure

 

Sunday marks 30 years since the first AIDS cases were reported. Since then, H.I.V. science has been translated into prevention and treatment breakthroughs, one of the greatest being the antiretroviral treatment that has ensured that millions of H.I.V.-positive people can lead healthy lives.

Furthermore, there is now robust evidence that early and highly active antiretroviral therapy can have a major impact on reducing H.I.V. transmission, demonstrating the “treatment as prevention” concept.

AIDS is no longer the death sentence it was, but there now remains extreme uncertainty concerning the long-term sustainability of treatment access, especially in resource-limited settings.

More than ever we need to find an H.I.V. cure. We need to invest in research that aims to find better and more cost-effective therapeutic strategies that may lead at least to a functional cure — the long-term remission of patients with a very efficient and persistent control of H.I.V. after discontinuation of treatment.

This begs the question: After 30 years of H.I.V. research, why have we still not found a cure?

The answer to that lies in the obstacles related to the complexity of the interaction between H.I.V. and its host, the persistence of H.I.V. in people on highly active antiretroviral therapy, and our limited knowledge on the very early stage of the infection. However, there are some promising signs that the pieces of the H.I.V. pathogenesis puzzle are beginning to fall in place.

What we have known for some time now is that latent H.I.V. reservoirs, where H.I.V. hides and persists, are one of the main barriers to finding a cure. It is precisely why treatment does not eradicate H.I.V. and why, when treatment is stopped, the virus rebounds.

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What we haven’t had until very recently are the scientific advances and new approaches to tackling those viral reservoirs. For instance, our basic understanding of the mechanisms of H.I.V. persistence in latent reservoirs is far superior than it was a decade ago. We are also witnessing promising developments from recent studies and small-scale testing reactivation agents that can reverse latency and “flush” the H.I.V. reservoirs.

We have also been aware that the so called “elite controllers” — those very few people who are infected with H.I.V. for at least a decade, do not take treatment and yet do not develop AIDS — were always going to be a vital part of future cure research.

Now we are gaining a better understanding of this unique group of patients. Some of the more recent science is showing that the elite controller status is related to the host genetics permitting robust cell-mediated immunity and/or restricting an infection in their CD4 lymphocytes and macrophages.

Understanding this group of people who efficiently control the virus replication and reservoirs, we believe, will be key in our search to attaining a “functional” cure that would allow long-term remission of infected individuals.

Last week’s announcement that researchers had identified a new restriction factor that inhibits an early step of the H.I.V.-1 life cycle in immune cells is greatly encouraging as well. New findings on the innate control of H.I.V. have implications for treatments and can provide us with insight into therapeutic vaccine development.

In addition, there is now a “proof of concept,” as scientists like to call it, for a cure. The case of the Berlin patient Timothy Brown, who received a stem-cell bone-marrow transplant in 2007 leading to the remission of his leukemia and now considered to be cured of AIDS, has now provided us with one.

While it is clearly unrealistic to think that this medically heavy, extremely costly, barely reproducible therapeutic approach could be replicated and scaled-up, it has nevertheless got the scientific world talking about the possibility of a cure.

Developments in gene therapy are also encouraging. The recent work by Paul Cannon with the Sangamo group using gene editing to knock out the CCR5 receptor gene on which H.I.V. relies to enter into host cells indicates that gene therapy may well prove to be an effective intervention, more readily available than chemotherapy or stem cell transplants.

I believe that given our current knowledge and innovative tools and concepts, a functional cure is a more realistic goal for the near future.

A cure will require funding commitments, strong community engagement, rigorous and innovative scientific endeavor and, above all, further collaborative multidisciplinary science with a better connection between basic and clinical research — in short, all the same ingredients that got us where we are today with the global antiretroviral treatment.

Thirty years is a long time and yes, we still do not have a cure. But if we do not seriously start looking for one, now that the science is telling us that perhaps we should be, do we want to be here in another 30 years regretting that we did not try?

Françoise Barré-Sinoussi is director of the Regulation of Retroviral Infections Unit at the Institut Pasteur in Paris and president-elect of the International AIDS Society. With Luc Montagnier, she was awarded the 2008 Nobel Prize in Medicine for their discovery of H.I.V.

 

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