• Our News
• Announcements
• CCR connections
• Research Highlights
• Office of Communications

Our News - In Their Own Words - Yarchoan Interview

Combating HIV/AIDS-Related Cancers

NOTE:  This interview is an excerpt from NIH Radio Podcast, episode 14

Bill Schmalfeldt:
This marks the 25th year since the first reported cases of AIDS in 1981.  By 1984, thanks to the groundbreaking efforts of investigators at the National Cancer Institute, scientists at the NCI, along with a team at the Pasteur Institute in France, were able to identify the cause of AIDS, the HIV virus.  Since that time, there's been much more research, many things learned, more things yet to be learned. 

There at the forefront of that effort to find cures for some of the complications, especially cancers that are associated with HIV and AIDS, is Dr. Robert Yarchoan, Chief of NCI's HIV/AIDS and Malignancy Branch.  In 1983, he joined Dr. Samuel Broder to work in the National Cancer Institute's newly formed AIDS therapy program, along with Drs. Broder and Dr. Hiroaki Mitsuya.  Dr. Yarchoan conducted the initial clinical testing of many anti-HIV drugs.  Dr. Yarchoan, first of all, thanks for being with us today on NIH Research Radio.  Can you tell us about the early days in that research to find effective treatments for HIV?

Dr. Robert Yarchoan:
It was actually a very exciting period. From my own perspective, it was very hard to get any sort of handle on this new disease and how to approach it until the virus, HIV, was discovered.  And actually, the discovery of that virus and the demonstration that it was the cause of AIDS enabled scientists to really focus their effort on ways of treating it for the first time.  Dr. Broder had a very small group at the NCI.  It was really him, Dr. Mitsuya and myself.  And when it became clear that HIV was the cause of AIDS, we got together, and Sam said, "Look, let's just drop everything and try to develop some sort of cure for this, or at least a good therapy for it.”  At that time, we really reprogrammed our whole laboratory's effort to do that.

Bill Schmalfeldt:
Now, in the early going, there was some suspicion that there might be some recreational drug usage that led to this T-cell deficiency.  What tipped you guys off to the fact that it was in fact a virus?

Dr. Robert Yarchoan:
Well, I mean, the whole history of looking for the cause of HIV is actually quite interesting to read in retrospect.  At the time, there was a group of people that had a group of really bewildering symptoms and it was pretty reasonable to consider everything that might be going on, and one of them was the possibility that some new drug had gotten into the population.  I think the finding that people that had received blood transfusions also came down with HIV or AIDS made it clear that it was some sort of transmissible agent. 

And there was then a period of time of really focusing on transmissible agents as the cause and retroviruses were an area of some suspicion for a while.  HTLV-I had been discovered just a couple of years before by Bob Gallo and Bernie Poiesz.  Post-doc work and HTLV-I is associated with a form of immunodeficiency, so this made people very interested in looking for other retroviruses. 

Bill Schmalfeldt:
For the layman, when we talk about intramural research, what are we talking about?

Dr. Robert Yarchoan:
Intramural research in the NIH is research that's funded by the U.S. government and takes place on the campuses of the NIH.  The main campus is here in Bethesda.  There's one in Frederick, Maryland.  There's also one out in Montana. 

Bill Schmalfeldt:
So those intramural researchers at the NCI that played a key role in the development of drugs for treating HIV infections and AIDS, and I'm talking about the cocktail therapy, which has drastically reduced the number of deaths and new cases of AIDS since it became available in 1995.  Tell us a little bit about how you and your colleagues were instrumental in coming up with this therapy.

Dr. Robert Yarchoan:
Well, I mean, I think you have to remember that a cocktail is composed of individual components.  And the important thing is to get individual components that work.  The first AIDS therapies that were effective really were made available around 1987 or so.  And the first drug was AZT.  AZT was developed by our lab in collaboration with the Burroughs Wellcome Company.  When AIDS was found to be caused by HIV, one of the things that we did, and Dr. Mitsuya really spearheaded this effort, was to try to develop an assay to test for drugs that would work.  HIV kills T-cells and we developed an assay with a special line to look for drugs that would block the killing of the T-cells by HIV.  And as soon as he got the assay going, we started testing drugs, some that we got off the shelf ourselves.  Dr. Broder ran to different companies to try to identify interested companies, and some of them sent us samples of drugs to test.  And one of those was Burroughs Wellcome.

Bill Schmalfeldt:
Now, in preparing to chat with you today, I saw where you were impressed by a female patient you had suffering from AIDS, and she had a fungal infection of a fingernail that AZT seemed to help.  Can you tell us about that?

Dr. Robert Yarchoan:
Yes, let me just take a couple of steps back.  Around the beginning of 1985 or so, several drugs were found to be active against HIV.  One of them was a drug sent under Code Compound S, that turned out to be AZT.  Also DDC and DDI, which were compounds that we bought from biotech companies or chemical companies, were found to be active.  And the first one we tested was AZT, because there were some preliminary work and we could get it into people quickly, and our interest at that time is to try to move as quickly as possible.  So we conducted a Phase I study in which we got people with HIV infection who had some sort of documented evidence of virus in their body.  And at first, we saw some patients having increases in their CD4 count.  We really didn't have any mechanism of monitoring the virus at that time.

Bill Schmalfeldt:
Now what is a CD4 count?

Dr. Robert Yarchoan:
I'm sorry.  Let me take a step back.  The CD4 count is a type of T-cell that's very important in the body's immune response and the hallmark of AIDS and HIV infection is that these cells, the number of them goes down and you lose the function of their cells, and people start getting these exotic infections.  So we saw some patients in which the CD4 count increased.  This was of interest to us, but the increases were often fairly subtle, and it wasn't really clear that it was making any difference. 

We had one patient, a female, who had gotten HIV from a blood transfusion, and she had a fungal infection of her fingernails, which is something that normal people really wouldn't get to this degree.  And what we noticed is we treated her for HIV, is that suddenly she started growing out normal fingernails, and you could see a line where the horrible infection and the normal --

Bill Schmalfeldt:
You mean when you treated her with AZT?

Dr. Robert Yarchoan:
With AZT.  And this was really clear evidence that not only were we seeing a change in a lab value, but we were making a clinical difference in patients.  And actually as we continued on, we saw this in some other patients as well. 

Bill Schmalfeldt:
As a researcher, how exciting was that to you?

Dr. Robert Yarchoan:
You know, there is this combination of excitement and not wanting to jump ahead of yourself.

Bill Schmalfeldt:
You don't want to jinx it?

Dr. Robert Yarchoan:
Right, jinx it by being too excited and then being disappointed.  So one always has to wear two hats in doing this sort of work.  One is the hat of being enthusiastic about what you're doing, and the other is the hat of really being steely eyed and being very critical of your results.  And you need to do both simultaneously.

Bill Schmalfeldt:
Now, you were talking about symptoms of AIDS, symptoms of HIV, and you mentioned cancers that come up.  And I'm talking about Kaposi's Sarcoma.  And before the AIDS epidemic, that was something nobody ever heard of, and now, ten percent of the cancers associated in developing countries like Congo and Uganda are Kaposi's Sarcomas? 

Dr. Robert Yarchoan:
Right.

Bill Schmalfeldt:
What's the NCI doing to try to combat that?

Dr. Robert Yarchoan:
Kaposi's is actually very interesting.  It's a tumor that was originally discovered in the late 1800s in a population in Eastern Europe.  And for a number of years, the reports of this tumor appearing in Eastern Europe and some of the Mediterranean countries, Italy for example, it was even there, reasonably rare.  And in this country, occasionally it would show up and one would get all the medical students to come and see the patient and they'd be told "Look at this case.  You'll never see another one in your life."  Well, that changed in 1981 when a number of gay men in New York and some cities in California suddenly started developing this tumor.  And it was clear that there was something new going on.  And that, plus pneumocystic pneumonia, which is another opportunistic manifestation of AIDS, was one of the first signs that there was a new disease.

In the early days of the epidemic, Kaposi's Sarcoma was very common in people with HIV infection.  Since the development of HART, and when we say HART, it stands for highly active anti-retroviral therapy.  And HART really is a combination of some of the earlier drugs that we developed, AZT, DDC, and DDI, plus another class of drugs, often protease inhibitors.  And if you mix three of them together, you can often suppress HIV to the point where you really start seeing dramatic improvements in patients.  And it's been found since the development of HART that actually the incidence of Kaposi’s sarcoma was going down.  And in addition, that some patients with Kaposi's sarcoma are treated just by taking anti-retroviral therapy. 

So I think this is a classic example where focusing and the efforts of the NCI in focusing on HIV made a major effort in preventing and also in treating a cancer.  So this is evidence of an interrelationship between the two.

Bill Schmalfeldt:
In developed countries, people with HIV/AIDS are living longer, healthier lives in general, but there are still health challenges, the increased risk of cancer, for instance.  What's being done here at the NCI under your auspices to combat that?

Dr. Robert Yarchoan:
Our group is working on several levels.  One is looking at the cancers associated with HIV.  One of the things that has happened is people have taken HART, anti-retroviral therapy, and have had improvement in their immune system.  Their risk in any given year of developing one of these classic cancers associated with AIDS, cancers like Kaposi's sarcoma, certain types of lymphoma, particularly lymphoma of the central nervous system or the brain, other types of cervical cancer, have really dramatically decreased.  And especially those cancers that are associated with profound immunodeficiency.  On the other hand, what is happening is that these patients are living longer.  And as they live longer, their risk, their total lifetime risk, of developing these cancers actually also increases.

So you have this conundrum.  They're doing much, much better in the short term, but there's a question of what's going to happen to them 10, 20 years down the line.  We're starting to see some sort of change of cancers towards those that occur with higher CD core cells in people that aren't quite as immunosuppressed.  Now our group is looking at these cancers.  It turns out that almost all the cancers that are associated with AIDS are caused by a second virus.  Kaposi’s sarcoma, for example, is caused by a virus called KSHV, which was just discovered in 1994 by Pat Moore and Yuan Chang, two investigators at Columbia.  A lot of the lymphomas are caused by Epstein-Barr virus.  So our group is really focusing on the association between these viruses and cancer, trying to really dissect this virus, understand how they cause these cancers, and then look at targeted therapies for these viruses.

Bill Schmalfeldt:
So this is a story basically where we’ve got a lot of successes, we’ve made a lot of progress, but there’s still a long way to go.

Dr. Robert Yarchoan:
Right.

Bill Schmalfeldt:
Twenty-five years since the first reported cases in 1981 -- but there’s a ripple effect.  When you make progress in one area in medicine, or in almost any endeavor, you find ways to use what you’ve learned, and apply that to other problems. What are some of the things you look at in the future, other areas that can benefit from the research you’ve done here at the National Cancer Institute?

Dr. Robert Yarchoan:
Well, let me first of all go back to some of the things that you alluded to, and that is the developing world.  A lot of the work that we’ve done has been really effectively utilized in the United States and other advanced nations, economically.  In the developing world, though, resource limitations have really limited the access of people to therapy.  And there is a lot of work to be done, just to bring what we’ve developed here to those countries. 

Kaposi’s sarcoma, for example, the virus that causes it, is not evenly distributed in the world.  And it turns out that this virus is very prevalent in parts of Africa.  And this is a devastating, devastating tumor in Africa, even at this date.  In some countries in Africa, it’s by far the most common tumor.  A lot of the work is in terms of getting the therapies that we’ve developed and others have developed in this country and applying them in Africa; getting the drugs to treat AIDS to be used in Africa so the Kaposi’s can be prevented.  And there’s a lot more that we need to be -- to understand. 

I think that in the future, we’ve discovered that these viruses can really cause cancers, particularly in immunosuppressed patients.  And one of the important things is dissecting just how these viruses can cause these cancers.  Unlike many cancers that are caused by very subtle mutations in cells, these are cancers that are caused by an exogenous agent, an agent outside the body that really affects certain key pathways in the cell.  And they’re a very nice tool for really studying how a good cell can go bad.  And a lot of the lessons that we learned from studying these can then be applied to studying other cancers.

Bill Schmalfeldt:
Dr. Robert Yarchoan, Chief of NCI’s HIV and AIDS Malignancy Branch.  Thanks so much for your time today and for sharing this information with us on NIH Research Radio.

Dr. Robert Yarchoan:
Thanks for coming in.

[end of transcript]

This transcript was prepared by National Capitol Captioning.

National Capitol Captioning
2820 Washington Blvd. #2
Arlington, VA 22201