Dr. Jonathan Kaplan



MILLER: This is Dr. Bess Miller, and I'm here with Dr. Jonathan Kaplan. Today's date is October 17th, 2018, and we are in Atlanta, Georgia, at the Centers for Disease Control and Prevention. I'm interviewing Dr. Kaplan as part of the Oral History Project, the Early Years of AIDS: CDC's Response to a Historic Epidemic, the PEPFAR Years. We are here to discuss your experience during the early years of CDC's work on PEPFAR, the President's Emergency Plan for AIDS Relief. Dr. Kaplan, do I have your permission to interview you and to record this interview?

KAPLAN: Yes, you do.

MILLER: Jon, I've worked with you and for you throughout our 30 plus year careers at CDC, and it's a pleasure to be able to reflect on this with you. During your career at CDC, you have had a leadership role from many different aspects of HIV/AIDS [human immunodeficiency virus, acquired immunodeficiency 00:01:00syndrome] care and treatment first domestically and then internationally in establishing and implementing PEPFAR programs. We have a lot to talk about. Let's begin with your background. Would you tell me about where you grew up and your early family life?

KAPLAN: Sure. First, thank you Bess, for including me. We have known each other and worked together for a long time, so this is a pleasure. I was born in Massachusetts and moved to Ohio at the age of five, so I grew up in Columbus, Ohio, and lived there through high school. Went away to college in upstate New York and then New York City, both at Cornell University undergrad and medical school. Then sometimes I joke, with all due respect to people who live in New York City or in California, I was never a big city person, so I told people at Cornell I'm going to go as far away from New York City as possible without going 00:02:00to California, and went to New Mexico for six years, internal medicine residency, infectious diseases fellowship and then I spent an extra year there in Indian Health. That was an important year in two ways. I met my wife, Linda, that year, and also that was the year working at what was then called the Albuquerque Indian Hospital. I met a person from CDC who was out there working on chronic diseases in the Native American populations. She told me about CDC, about the Epidemic Intelligence Service, EIS, and one thing led to another, and within a few months, I found myself here as a first-year EIS officer in 1980.

MILLER: Stepping back a bit, what got you interested in medicine?

KAPLAN: Well, that's a great question. I was always interested in science, and I 00:03:00was a chemistry major in college, and I suppose I had some peripheral interest in medicine at the time, but I don't think any of us in our generation can discount the importance of the Vietnam War and the importance of student deferments at the time. So, I knew that I needed to go straight out of college into something, and as I was in college, I developed an interest in not only chemistry but also biology, and I found myself applying to medical school. But actually, I can do more with that one. So, I went to medical school, and I was an okay student. Being in New York City was a challenge for me. The way medicine was taught in those years was also a challenge. We're basically in a classroom looking at walls for two years before we ever saw a patient. My motivation 00:04:00actually during those years was not the greatest, but then a very important thing happened to me, thanks to one of the most important mentors and colleagues in my life at Cornell. I had the opportunity to go halfway around the world and spend a year in Papua New Guinea at a research institute, so I took an extra year in medical school and did that between the 3rd and 4th years. That was a life-transforming year. Not only was it fun, but it basically invigorated my interest in medicine, and in research and in the odd kinds of diseases you see halfway around the world that we never would've seen in New York City. And I came back from that year a totally different person, and from there on, I was just totally into what I was doing. From there then I had a number of 00:05:00interesting experiences in my 4th year of medical school, and I went into internal medicine, went out to New Mexico, and did that training at that time, but that was a very important year.

MILLER: You had an interest in international travel. How did you take up this opportunity?

KAPLAN: So, I suppose I had some interest in travel, but I had never done much internationally except for the year after I graduated from college, I went to Europe just for the summer, and I remember that being a wonderful summer. I was a young guy and hitchhiked around Europe and went to a dozen countries, so I had a bit of the travel bug but I think that was pretty much the extent of international travel until this opportunity came along, and this was a fabulous--I can tell just a little bit more because this is really fun. My 00:06:00advisor colleague was a neurologist, and he had trained in London with a New Zealand neurologist. His name was Dr. Richard [ W.] Hornabrook, and he became Director of this research institute in Papua New Guinea [Institute of Medical Research], so my advisor had maintained connections with this person and created an opportunity for some medical students to take off and spend a year over there. So, I took advantage of that. I remember when Dr. Hornabrook came to New York, and it was almost like an interview in a way. My advisor, his name was [Dr.] Fletcher [H.] McDowell, a famous neurologist, invited me to his house. Dr. Hornabrook was there, and Dr. Hornabrook basically gave me a million reasons why a kid from New York would never want to go halfway around the world. And I recognized not only is this a test, but I really want to do this. So, one thing 00:07:00led to another, and I had an around-the-world airplane ticket and spent eight months in Papua New Guinea, and to this day, it was just a fabulous experience in lots of ways, and as I mentioned, I just came back a very different person.

MILLER: So, then you get to CDC. What was your assignment for your EIS two years?

KAPLAN: I matched in what was then the Division of Viral Diseases, and I had a wonderful supervisor who's still here at CDC, that's [Dr. Lawrence B.] Larry Schonberger, who I credit as one of the great mentors I think of my career. He taught me epidemiology. Wonderful guy. And so, I worked on a variety of different diseases. It was really a great opportunity there. So, for example, viral gastroenteritis, dengue disease, Rocky Mountain Spotted Fever. We also 00:08:00worked on the epidemiology of Guillain-Barré syndrome which is not a viral disease but it was very important in 1980 because the swine flu just 2-3 years before, I recall, about 2,000 people around the country got Guillain-Barré syndrome from the vaccine, so there was still a lot of interest in how that happened and what the epidemiology of that disease was. So, I worked on a lot of different things and also had some great outbreak investigation experience. Nothing about HIV or retroviruses yet, that came a little bit later, but the training was great, and Larry Schonberger was just a fabulous mentor and colleague.

MILLER: So, this was 1980 to '82. By the end of 1981, 159 cases of AIDS was 00:09:00reported. It wasn't termed AIDS yet. About half were Kaposi's sarcoma and half Pneumocystis pneumonia. But additional illnesses seen as possible manifestations of this unexplained disease were being reported in the same populations in New York City and California, and one of these was the so-called generalized or Unexplained Lymphadenopathy Syndrome, and I remember you did your first work on HIV exploring the natural history of the Lymphadenopathy Syndrome. Can you tell us about this work, what is Lymphadenopathy Syndrome and how you got involved in studying it?

KAPLAN: Sure. Thanks, Bess, and as you're well aware, we actually worked on this a little bit together during that time period. What happened was, so turn the clock back to 1982. So, I'd now been at CDC for two years finishing EIS, I 00:10:00stayed in the same division, but the opportunity to work on some new things. What we now know as AIDS had first been described in June of '81 so I'd only been at CDC one year when that very famous MMWR [Morbidity and Mortality Weekly Report] June 1981, the first cases of pneumocystis and Kaposi's were described in gay men in New York and Los Angeles. So here we are in 1982, and we had a number of men in Atlanta who were actually referred to us from a physician who's still around in Atlanta-- gay men with enlarged lymph nodes in their neck and other places around the body and developed this name Lymphadenopathy Syndrome. At this point, somehow, and I don't remember how the connection happened, I met Dr. Thomas [J.] Spira, who I think has been interviewed as part of this project. 00:11:00Tom is a remarkable guy. Still works at CDC, still a friend. Tom is an immunologist and a clinician by training and I think he ran the immunology lab at CDC and he developed a connection with this practitioner in Atlanta and now we had access to all these young gay men who had enlarged lymph nodes, but we also knew that they had--some of them had a history of these other diseases that were becoming known as AIDS so we knew there was a connection here. We didn't know exactly what it was yet, the virus wasn't discovered until a couple of years later, but we developed with Tom--he invited me to join him--we developed a group of 78 men, all of whom were men who had sex with men, from Atlanta who had enlarged lymph nodes. We were epidemiologists. We developed a case definition for this syndrome. A couple of years later when HIV was discovered 00:12:00and a test developed, 75 of the 78 men were found to be HIV positive and we followed these men for years and--

MILLER: Can I ask, now as CDC epidemiologists, medical officers, we don't usually see patients clinically. Where did you see these patients? In offices? How did that work?

KAPLAN: The men came to us. They came to CDC. They came into the building, and they met us up in one of the rooms in the immunology branch where Tom worked. So, we'd meet them there, and there were a number of things that we did with them. We obtained their histories. What was happening with their illnesses, we took careful measurements of all their lymph nodes in the neck and other places. Tom's main interest being immunology, took a lot of blood samples from these 00:13:00men. Over the years, we learned a remarkable number of things about what became known as HIV later, and I can't remember exactly how many years we continued to do this, but unfortunately, these men came around in the wrong time of history because this is the early '80s. So, we discovered the virus, it was discovered in '84, we now knew what they had, but we didn't have the HIV drugs yet. So, these men one by one coming down with these pretty awful opportunistic infections. Which I know we'll be talking a little bit more about here in due course. But we had no HIV-specific drugs. The first one came around was AZT, which was 1987, and then a couple more came around, but we didn't have what we now know is the combination of powerful antiretroviral drug combinations until 00:14:001996, so most of these men died. When I think back, and I'm glad to have the opportunity to say this now because I don't know that I've ever said this publicly. I think these men were heroes. You think of what they did. They came to us. They drove their cars, parked here, came into our offices, endured our questions about their histories, we felt their lymph nodes, took a lot of blood samples. The only thing that they ever got or were ever promised was the knowledge that they were contributing to something that would hopefully help people in the future. And I think they were real public health heroes for helping us and as I mentioned before, because of the time of history they came around, essentially all of them have passed away. Not all of them. Actually, that's another story I can get into if you permit me here. But we learned a 00:15:00tremendous amount from these men. In fact, the 75 HIV-infected men--Tom Spira would probably answer this better than I, but I would bet that we ended up with one scientific, maybe a scientific manuscript for every two of those. At least 30 to 40 papers came out of this.

MILLER: So, this is unusual for CDC. Did you need special permission to see patients, to draw blood? I'm not familiar with something like this before or since. How did it work?

KAPLAN: So, Tom Spira would be the one to really best answer that question. He was the primary investigator. So, there was a protocol, and it went through whatever approvals it had to go through in those days, so it was all accepted. People knew what we were doing, and it was under research. I'm sure in some form. So, we had a protocol, and the various questions we're trying to answer 00:16:00were articulated in the protocol. But in terms of clinical care, again, the men came here, we drew blood, but we were not providing for their care. That was understood. We were not their doctors. Their primary doctor was, as I mentioned, the one person who was in Atlanta. His name was Dr. [James S.] Jim Braude, who took care of all these men, so their care was not here. So yes, it was an unusual situation because, in a way it was clinical research which we don't generally do at CDC.

MILLER: You mentioned that there were many papers written. Can you share with us what some of the key findings were?

KAPLAN: Sure.

MILLER: This was before could --early on--.it was before you could do HIV testing, but there were a lot of immunology questions.

KAPLAN: So, as I mentioned, Tom's main interest is immunology. He was and is an immunologist, and he was the primary investigator on this project. That was his main interest in trying to learn as much as possible about the immunologic abnormalities and the evolution of the immunologic abnormalities in these patients. So now we think generally of a CD4 [T-cells] lymphocyte count. That's our measure of immunologic function in HIV patients. So that was one of many, many tests that Tom was performing in his laboratory. He was looking at all kinds of markers of CD4 cells, their function, and their enumeration, CD8 cells. There are probably a lot of other things he looked at, too. So that was his main interest, and he would be the one to ask about the most important immunologic findings he made. I think we were gradually learning, and this project certainly 00:18:00reinforced that the depletion of CD4 cells is the single most important marker for immunologic function and for susceptibility to all the horrible infections that these patients were getting.

MILLER: So now we think of the lymphadenopathy syndrome as sort of an early manifestation, but I'm sure some people progressed at different rates. Do you remember some of the opportunistic infections you saw at this stage?

KAPLAN: Sure. Just like you said, the most important marker for progression, I think, turned out to be the CD4 lymphocyte count, and that finding has certainly held up to this day. I'll mention a couple of things. We learned about some other markers that were important, too. In fact, when we look back, I think that we may have been one of the first to describe a low hemoglobin as an important marker for immune progression. We described that-- subsequently, lots of other investigators described that. A very simple marker for how ill and how quickly 00:19:00the person will become ill. So, I remember that was one thing that we learned. So, we recorded their histories of the various infections they were getting, and they were the ones that other AIDS patients were getting at that time--Pneumocystis pneumonia, Kaposi's sarcoma, mycobacterium avian complex [MAC]. All the things that became wrapped up in the AIDS definition these patients developed, so we knew from the beginning this is all connected in some way, we just weren't sure how yet until HIV itself was discovered and then things started to piece together a little bit more. We also, I remember, learned some interesting behavioral things, and we got into all kinds of things with these men, and I remember one small thing that we wrote. We asked these young gay men what they were doing about their sexual behaviors. And I remember 00:20:00learning that the most profound factor for changing behavior was having someone very close to them like a partner die of AIDS, which I thought that was a really important thing to know at that time because we were very interested in behavioral change. You know, what does it take for people to change these high-risk behaviors, does it take really a loved one dying. This is one of many things we learned from these men. As I mentioned, there were upwards of 30 or maybe 40 papers that we ended up getting from this whole experience.

MILLER: Let's move to 1993 when you became the Assistant Director for Opportunistic Infection or OIs with the Division of HIV/AIDS, and then the Associate Director for OIs in the Division of AIDS, STD [Sexually Transmitted Diseases] & TB [tuberculosis] Lab Research. Here you were in charge of a large research program with the objective of reducing OIs. This was a time when the 00:21:00number of AIDS cases had risen exponentially, so by 1993, there were an estimated 174,000 cases of AIDS in the U.S., with about fifty-percent of these patients dying. So what diseases were killing all of these AIDS patients?

KAPLAN: Okay, so a very broad question. Before we get there, if you permit me, there was one other anecdote I just wanted to throw in about the earlier discussion topic. I still take care of one of these men who had lymphadenopathy syndrome. As I mentioned, they all came around at the wrong time of history, and most of them died. I thought they had all died. About two years ago--I still do some clinical work at the VA [Veterans Administration] Hospital here in Atlanta, I take care of HIV patients, and I saw a man who came in, and I had never seen him before, and I introduced myself. I said I'm Dr. Kaplan, and I don't think 00:22:00we've met. And he said, oh, yes, we have. Okay, can you enlighten me here? And all of a sudden, the memories started lighting up. He obviously looked a little bit different, this is 30 years later, but he was one of our men who clearly survived. He was lucky enough to survive that whole time. A few people did, I guess, and he had been in and out of care in different places, including at the VA, but I just had never seen him, and now he's my patient. So, I can say he's my longest-standing patient I've known him for over 30 years. I actually ran into another one in Atlanta, too. So anyway, just getting back to that experience, it was a remarkable experience.

Okay, now we're transitioning to a new time. So, there was a time in between, and we're up to 1993, so I actually had the opportunity while I was in viral diseases to work on some non-AIDS-related retroviruses. We won't go into that 00:23:00because they're much less important than HIV, but in 1993 I had the opportunity to move over to the domestic AIDS division-- it was the Division of HIV/AIDS Prevention run by [Dr.] Harold [W.] Jaffe. So, Harold, a longtime friend, colleague, hired me. So, this is what we were faced with at the time. HIV was essentially a death sentence. Men, mostly men in the United States, were dying of these pretty awful diseases which we call opportunistic infections, meaning as the CD4 count declines, immunologic function deteriorates, people become susceptible to a wide variety of these infections. We mentioned a couple of them, pneumocystis, it was then Pneumocystis carinii pneumonia, now the name of 00:24:00the bug has changed to what we call Pneumocystis jirovecii but we just still call it Pneumocystis pneumonia. Kaposi's sarcoma and mycobacterium avium complex, I mentioned these. There are actually over 20 of these infections that were incorporated into the AIDS case definition and so a variety of diseases caused by viruses, bacteria, fungi, protozoa, all of these. So, men, mostly men, again, were dying of all these diseases and we had at that time in 1993 AZT [azidothymidine] which had come around in 1997 and also a couple of other drugs we had, ddI [didanosine] and ddC [zalcitabine], but these drugs were not really saving people's lives. The powerful combination antibiotics didn't come around until 1996, which was later.

So, I came to work for Harold and so I'll throw a couple of other things in here. In terms of trying to do something about these infections, we, as I mentioned, could really do nothing about the underlying cause other than these drugs like AZT, which really weren't doing that much. But for Pneumocystis pneumonia, we knew that there was a combination antibiotic, which we commonly knew as Bactrim. Clinically it's called trimethoprim-sulfamethoxazole. It's a combination of two drugs which could be given to people with advanced HIV. That is, people with CD4 counts less than 200, prevent Pneumocystis pneumonia. And in 1992, a group of people--I was not yet involved in that because I came over in 1993, but a group of people at CDC and NIH [National Institutes of Health] and probably some people in academia put out some recommendations for the prevention 00:26:00of Pneumocystis pneumonia using Bactrim. This (article) was published in 1992 in MMWR, and in 1993 there were similar recommendations for children who also developed this disease and could be prevented using this drug called Bactrim. In 1994, mycobacterium avium complex was addressed similarly, so it was around the time I came over, and there were guidelines for preventing that disease. So, Harold and I, when I came over, thought--and I can't remember exactly where the idea came from, it probably came from Harold because he's such a smart guy, why don't we address this systematically. There are over 20 of these AIDS-defining conditions. So okay we've dealt with Pneumocystis pneumonia, we've dealt with mycobacterium avium complex, can we look at all of them in a systematic way to see how we can prevent these infections in our patients with HIV. And we knew 00:27:00that there was a combination of approaches for the ones that I just mentioned. There were what we called antibiotic chemoprophylaxis, basically medicines to prevent the disease. There was also at least one that would be bacterial pneumonia where we could vaccinate people against pneumococcus, a pneumococcal bacterial disease. And then there were a number of these conditions for which various exposures, environmental exposures, for example, behaviors might be able to prevent some of these diseases. An example I'll mention here is pets, particularly cats, which is a whole interesting discussion which maybe we can talk a little bit more about. Then for some of them, we knew that there's no way at all that we can prevent this disease, so we thought, okay, how can we go about and do this in a systematic way. So, this is my job then at the time. I 00:28:00had a title called Associate Director for Opportunistic Infections. We obviously made that title up and worked in the Office of the Director in Harold's division. So, we put together a collaborative group. We got the National Institutes of Health involved and my main colleague there was [Dr.] Henry Masur, and then the Infectious Diseases Society of America [IDSA] and my main colleague there at the time was [Dr.] King [K.] Holmes who was from the University of Washington. To this day, I remain friends with these guys. This is a collaboration that just worked really well. We had to engage a lot of other people, a lot of people from academia who were subject matter experts in a lot of these diseases, and also people with HIV and I want to be able to say something more about that because I learned a lot in this process about listening to people, particularly the people who were trying to help. So, we put 00:29:00together a consortium of people, and we had a big meeting. This was probably back around 1995, and oh, it would've been '94 because we came out with comprehensive guidelines. We called them CDC NIH IDSA for the institutions I mentioned, Guidelines to Prevent Opportunistic Infections in HIV-infected Persons. In 1995 we had a big supplement (in the MMWR). The first one was (for managing) clinical infectious diseases. We had systematic guidelines for these diseases, and I'll mention a little bit more about the format for that. And also had background papers that people wrote about their particular bug. And we organized these in--we were focused on prevention at the time, so we had to have kind of a format. We organized these according to how to prevent exposure to the particular pathogen and, once exposed, how to prevent disease like through 00:30:00vaccination or chemoprophylaxis and then also how to prevent disease recurrence if the patient got this and they might get it again. So, it was a remarkable exercise, and as I mentioned, I learned a lot about listening to people. So, I guess if you allow me, I'll just say a little bit more about pets because this is a very important thing that we learned. We knew that there were some important infections you could get from pets, and the most important one is toxoplasmosis. It's a brain infection, toxoplasmic encephalitis. It's a protozoal bug that cats get and it's excreted in their feces and for people who empty kitty litter boxes there's potential for exposure to the organism which then can end up getting access to the body usually in a fecal-oral so it's by 00:31:00mouth and then could develop into a form of the organism that can go to the brain and cause encephalitis. Well, it would've been very easy at the time to say don't own pets. I mean some people just said that. You know, HIV-infected people should not own pets. Well, time out. You know, pets are very important to people, and they're companion animals, and the HIV community were very quick to let us know that you can't tell us to get rid of our cats. This has to be a little bit more nuanced than that, so please think about that a little bit more. So we did, and in the end we never told anybody to get rid of their cats but we did make recommendations about ways to clean a kitty litter box, to make sure to use gloves, wash your hands, change the kitty litter box often because what 00:32:00happens is in the feces it takes a few days for the cysts to develop and mature and become infective. The longer the kitty litter box lasts there, the more infectious it might become. So, the bottom line of that is I learned how to listen, and we had a lot of people at the table. We had, as I mentioned, government people, people from academia, research people, but the AIDS community was a very important participant in all of those exercises.

So anyway, to make a long story short at this point, these guidelines first came out in 1995. We know they had a lot of impact from the readership of these guidelines. They were considered the main source for clinicians and for patients 00:33:00around the country about how to prevent these infections. Now, over the course of several years, a few things happened. First of all, at one point in there, we expanded to include not just prevention but also treatment, and we had several revisions of these guidelines. In fact, there were at least five up to about the year 2012. I think was the last one. So, what happened in 2012? By this time, we had--and by the way, I should also mention that the pediatric group split off to develop their own guidelines, which are still out there. So, our guidelines for prevention and treatment of opportunistic infections in HIV-infected adults assumed kind of a life of its own and went through at least five revisions, all published in MMWR and other journals. The one in 2012 was so big-- it was the 00:34:00largest MMWR supplement ever published. For people who know that publication to the extent that it's still published in hard copy, usually, staples are used to put it together. We had to have a glue binding like a telephone book would have. It's a huge document. It basically went through all the resources we could to get this done. MMWR did not have all the editorial staff. We had to provide some of our own. We realized that here going forward, this is going to have to change. We're gonna have to go online and get away from these hard copy publications. So, since 2012, it's maintained a life of its own online. It's still there.

MILLER: You mentioned MMWR for this and for use cotrimoxazole for prevention of pneumocystis and so on. Can you say a little bit more about the role MMWR, the Morbidity and Mortality Weekly Report, CDC's publication, played in doing all of this?

KAPLAN: Yeah, thank you, Bess. It's an important question. Obviously, MMWR was our primary mode of getting this information out, and this is CDC's publication. Over the years, MMWR has always had the weekly but have had different series of other types of publications, including these supplements. So, CDC was front and center in terms of getting this information out. Right from the beginning in--yeah go back to '95. We published an MMWR, all the subsequent revisions came out in MMWR, but we also used other medical journals as well but CDC was always front and center in terms of MMWR being the main place we'd publish these guidelines which meant not only a tremendous commitment from MMWR and their 00:36:00staff but also from all the subject matter experts. So, we are a public health institution here with a lot of subject matter expertise, so for all of these bugs, over 20 of these opportunistic infections that we included, we had subject matter experts here at CDC. So, they all participated and gave of their time to help us develop recommendations, to the research of the literature, write background papers. So, there was a tremendous investment on the part of CDC and the part of MMWR and all these subject matter experts to make all this happen. At this point, many years later, the website that maintains these is actually an NIH website. However, I did all this until a couple of years ago when I retired 00:37:00although they're still nice enough to include my name, but the subject matter experts are still mostly, or in great part, from CDC. And now, the document is maintained online with revisions made as necessary. So, it's still a collaboration as it was in the beginning between CDC and NIH and actually now the HIV Medicine Association of the Infectious Diseases Society of America, but the subject matter expertise, a lot of it still comes from here, so a lot of energy goes into it, but it's now a document that's maintained online. MMWR is no longer a part of it since 2012.

MILLER: You've been seeing patients at the VA. I'm not sure when that started. Did you experience patients with these severe opportunistic infections in your 00:38:00own VA clinic experience, although many of them might've been hospitalized, but even as an outpatient before ART. was available? Did you see some patients with these opportunistic infections?

KAPLAN: Well, the answer--so first of all, I've been, fortunately, during all my CDC years, really, after EIS, I was allowed to do some clinical work. It was actually part of our job in a way as commission officers in the public health service. So, I started seeing HIV patients actually initially at our DeKalb County health facility early on, and then I switched to the VA at some point, I can't remember when I did that, seeing patients in the outpatient department. What that means is the sickest patients who were admitted to the hospital I would not see because I was not doing hospital work. If they can walk in to an 00:39:00outpatient department, obviously patients are relatively healthy at the time. So, yes, in the sense that a lot of our patients had developed these diseases and had been in the hospital, I would usually see them afterward when they're walking into the clinic. So I may not have been involved in the inpatient part of their care but I was certainly involved in the outpatient part which involved not only the antiretroviral drugs which obviously came along later but in terms of preventing additional prevention for these opportunistic infections and for those who had had them for what we called secondary prophylaxis or chronic maintenance therapy to give them medicine to make sure they didn't get it again.

MILLER: So, were you using fluconazole for cryptococcal meningitis, or was the mainstay Bactrim? Do you remember what some of the infections you were trying to prevent in Atlanta, Georgia?

KAPLAN: Sure. Well, not only Atlanta but also around the country because the guidelines we developed were useful around the whole country--actually around the world as well. And I mentioned there are a number of modes of prevention, but in terms of antibiotic chemoprophylaxis, the main ones in use were Bactrim to prevent Pneumocystis pneumonia and also, we used azithromycin to prevent mycobacterium avium complex. Interestingly, after all these years, Bactrim we still use for people who have a low CD4 count even if they're on antiretroviral therapy because they're still susceptible. We now know that for mycobacterium avium complex, that it's becoming such a rare disease and people who are on antiretroviral therapy do so well that just recently, literally in the past six months, the recommendations have pretty much dropped for using azithromycin to 00:41:00prevent MAC disease. So, I'll get to fluconazole in a minute since you mentioned that. So, the main ones have always been Bactrim and up to the present time azithromycin to prevent MAC. Also, vaccinations, particularly against pneumococcal disease, there are two vaccines we use to prevent that. Now, fluconazole is an interesting one. I'll just mention this quickly because there are fungal diseases here that we're talking about, candida, cryptococcal disease, also some other ones that are a little bit less common. Fluconazole has never been used as primary prophylaxis in the United States. We've never recommended it. I'll mention here that science has to back up all the recommendations we make, and fluconazole was never shown to have a mortality 00:42:00benefit to prevent cryptococcal disease mainly because less of it here than in other places. For people who have had a disease like cryptococcal meningitis, then as chronic maintenance therapy, fluconazole may be used to keep them from recurring with it afterward. So, it has a use, but it was never used as primary prophylaxis here, it's never been recommended in the U.S.

MILLER: So, in January of 2004, you moved to the Division of Global HIV/AIDS to work on PEPFAR and soon became Chief of the HIV Care and Treatment branch. So just to start off, what made you decide to work on PEPFAR programs?

KAPLAN: So, at the time, I had an interesting job at the time. From our earlier 00:43:00discussion, I was in the Division of HIV/AIDS Prevention, our domestic program, for a number of years. I was given an opportunity, or let's just say I was asked, to become Division Director of the Laboratory Division. At the time, Harold Jaffe left that job to become a Center Director, so I became Director of a Laboratory Division, which no longer exists. It was called the Division of AIDS, STD and TB Laboratory Research, DASTLR. So, I did not have a laboratory background. I did that for a few years, and I knew the whole time that this was probably not the best match. I'm glad to do this to the best of my ability but probably not the best match for my experience and expertise. So around 2004, I guess that was the beginning of it, I was approached by [Dr. Robert James] R. J. 00:44:00Simonds who worked in the International HIV program which had had kind of a life before then. Actually, it was called the LIFE [Leadership and Investment in Fighting an Epidemic] Initiative early on. It became the Global AIDS program. Around this time, this is when the President's Emergency Plan for AIDS Relief was getting started and actually started with a State of the Union Address by President George W. Bush, I think it was January of 2003 if I recall. So, R. J. approached me and said, why don't you come over? So, I looked at this, and I thought, hmm, this is HIV, it's international, a lot of resources are going to be coming down to work on this, and in terms of care and treatment this is right up my alley because I've been working on opportunistic infections. So, I think 00:45:00it took me about one minute to say yes. So, I made that transition. Initially, I worked for R. J., and then there were some changes in the HIV Care and Treatment branch, and I became chief of it about a couple of years later, and that's what I did for the last 12, 13 years of my career.

MILLER: So, looking back on those early PEPFAR days and years, you began to travel a lot to PEPFAR supported countries. Can you, from a broad perspective, tell us what you saw with regards to AIDS care and treatment in those countries and the management of opportunistic infections?

KAPLAN: So, at the beginning, this was an eye-opening experience. So, yes, I was involved in a number of ways early on in the effort, and one of these was to 00:46:00help specific countries develop their plans. And there were three countries that I was specifically involved in as part of the initial what we called core teams, meaning you'd have a person from CDC, a person from USAID [United States Agency for International Development], a person from the Department of Defense. So, I was involved specifically and spent a lot of time in three countries from the onset. Those were Mozambique, Uganda, and Ethiopia. I'll mention Uganda here in that I'd actually had some experience in Uganda, which is another really memorable part of my career. I had been to Uganda a couple of times early on, and the devastation from this epidemic was remarkable. So as an example, when 00:47:00you go to Uganda, the International Airport is Entebbe but the capital city, the big city, is--well actually Entebbe is the capital. The large city is Kampala, which is about maybe 20 miles away. Driving from Entebbe to Kampala, it was amazing how many coffin makers there were besides the road. It wasn't just one or two or three. Everyone was making coffins, and people were dying like flies in Uganda at the time. It was really devastating. Now, in terms of what people were getting, some of the most important infections there were common with the United States, but actually, the biggest difference was tuberculosis so. Obviously, Bess, this has been an important part of your career also, but 00:48:00internationally TB, we came to know as the most important infection in terms of morbidity and mortality affecting AIDS patients. There was a lot of TB. In the U.S., we had less TB in the U.S., so it had been not as big a factor, but internationally, TB was the big one. There was a lot of oral candida infections which we call thrush, and I could probably name a bunch of others. Kaposi's sarcoma, there was a fair amount of that. So, in general, overlapped with things we'd seen in the United States but tuberculosis was the big, big, big one and we actually to this day we know that's the case in Africa and other parts of the world. So, a lot of TB and various other infections, so the spectrum was a little bit different. The important thing is people are just dying, and of course here now we are with PEPFAR, we have an opportunity to try to do 00:49:00something about it.

MILLER: So, who was in these countries, Ethiopia, Mozambique, and Uganda? How was the care provided to patients? Would they just go to an outpatient clinic, were they dying at home, was there palliative care management? How was health service delivered to all these sick people?

KAPLAN: Well, the health services were obviously inadequate. So, continuing with Uganda as an example, the hospitals there--there were hospitals in Kampala, they were overloaded with AIDS patients. There were an inadequate supply of people, of supplies, of diagnostics, of drugs. All these things were in short supply, and the conditions in the hospitals weren't great. They were so crowded that 00:50:00people would come in there, there would be patients lying on the floor, they would be in the hallways, and their families would be camping out all over the place, by the bed, out in the yard by the hospital. So, the hospitals were very overcrowded with all those inadequacies, death rates very high. The clinics were very meager at the time. So, at the time we started PEPFAR there actually was a little bit of antiretroviral therapy, there were the powerful HIV drugs that were being administered mainly by--there was actually a leader in Uganda, a guy named [Dr.] Peter [N.] Mugyenyi, who is sometimes known as the father of antiretroviral therapy in Africa, a Ugandan. He was working at a research institute, which I guess included a medical facility, the Joint Clinical 00:51:00Research Center in Kampala. There were a few people getting these drugs, but for the most part, the clinics really weren't there. There were hardly any drugs there except for a unique place like that. Laboratory facilities (were) essentially nonexistent. So basically, people were dying, and the healthcare provision was poor.

MILLER: Now, looking at these countries, for example, as time went on, most of the PEPFAR-supported countries had CDC country offices with technical leads in the countries. Can you describe how you interact with that in terms of beginning to offer antiretroviral therapy and scale-up services?

KAPLAN: Okay, so the important thing about the beginning of PEPFAR is obviously 00:52:00CDC played a huge role, but it wasn't just us. It was a U.S. government effort which was made clear from the beginning from our leaders up in Washington. It was an effort of the Centers for Disease Control, the U.S. Agency for International Development, USAID, the Department of Defense, the Peace Corps had a role, and there were some other agencies that played a role, the Health Resources and the Services Administration, HRSA, had a role. So, we were told from the beginning we've got to all work on this together. So, a lot of interesting stories about some of these initial visits to these countries where basically we're getting together with people, many of them on the ground had never met each other, but were asked to come together and play in the sandbox 00:53:00well and come together with a U.S. government program, leave your uniforms at the door. Now, in all the big countries we worked in, CDC did have a presence already, and, of course, our CDC colleagues had ideas about how they wanted to go about things. Colleagues from the other agencies had different ideas. So, from the very beginning, it was a real exercise in collaboration and getting people to talk to each other, which presented tremendous challenges. Our CDC offices, we have fabulous people at our institution, and I think the one thing that's special about the CDC offices and our people at the time was a commitment to science-based interventions. We have always been a science-based agency, and 00:54:00we wanted to make sure that what we were doing had a firm science base. Obviously, we wanted to accomplish the missions of what we're trying to do in PEPFAR and care and treatment is just part of it, and that's the part that I did, but obviously there were many other elements to what we were doing, specifically prevention, data management, just a lot of other counseling and testing, so a lot of other aspects to what we were doing, and we had a lot of technical expertise in our CDC offices. So, I think right from the beginning our strengths were the remarkable people we had, and I'm talking about Atlanta-based people that obviously the in-country staff who were in the process of being hired to be part of our programs, the commitment to science and the technical expertise. Those were the things we really brought to the table, and sometimes 00:55:00people from the other agencies thought a little bit differently about things, and that led to just some--I learned a lot about collaboration and getting along with people during those years.

MILLER: How about working with the Ministry of Health in terms of strategy development and implementation? Can you give some examples of how that did or did not work?

KAPLAN: Okay, sure. Thanks for that question because it's critical. I mentioned at CDC we have a commitment to science, and we have a lot of technical expertise. We are a public health institution, and a priority right from the beginning was to work with the host country government to try to make this work in a way that would be compatible with their public health programs. So, it was always from the beginning a high priority for us in Atlanta, and for our CDC 00:56:00offices to work with the ministries of health with the idea that whatever we do is your program and eventually with any luck, depending on in-country resources, the country will take it over, we won't be needed here anymore. So, this is a priority for us from the beginning, and I have to say other agencies didn't quite look at it that way all the time. They didn't have the history of working with host country governments the way we did at CDC, but it was always a priority for us to work with the ministries.

MILLER: So, how would that happen? How would that take place?

KAPLAN: So that could happen in a number of ways. Sometimes we had people actually detailed to the Ministry of Health to live there and to work there even though they're still a CDC person. It would always involve lots of meetings with the ministry with people at different levels there to try to decide on the 00:57:00program and what we were trying to do. But sometimes we had people embedded there, and I think we still do that. You asked about whether it worked. Well, sometimes, and sometimes not. It depends a lot on the kind of expertise in the ministry, their commitment, and their expertise in some of these programs. It depends a lot on people. So if you had really dedicated people at the ministry who had the same goals that we did in terms of trying to help their people and save lives, then the collaborations might work better than at other times when they were poorly staffed, and they didn't have people, or they weren't very committed, or they were taking money on the side. I mean right from the beginning working in these countries there's always an issue there, too, about whether monies are getting diverted in the wrong direction.

MILLER: Speaking of money, these were huge amounts of money. This was a $15 billion over a five-year commitment, and so many of these countries would be getting $100 million $200 million a year. Money that they had never seen the likes of. How was this spent? What were the expenses in getting an ART program going in a country?

KAPLAN: Okay, so, first of all, you touched on the "B" word, the Billion word, and that is worth emphasizing. When this whole thing started with President Bush's State of the Union Address, it was mentioned--I think it was mentioned in his address $15 billion over five years. This is the largest commitment to a single disease ever made in the history of the world. No one in public health 00:59:00had ever heard the "B" word before. Sometimes the "M" word for Millions but the "B" word was just unheard of. So, this is a huge amount of money. So, administering this was obviously a huge challenge. So, in terms of the HIV Care and Treatment Programs, we had to embark on a number of things starting with (the) purchase of the drugs. Fortunately, the drugs purchased internationally were not the same as when we get them domestically here. There are various agreements, and I'm not really an expert on how this is done in generic drugs but also just agreements with drug companies to get drugs for less money overseas. So, purchase of the drugs. Then you have to have the people and the clinics. And as I mentioned at the very beginning here, the infrastructure 01:00:00wasn't really there. There weren't that many clinics, and they were poorly staffed, and they looked terrible-- they needed renovation. So, we had to identify the sites, and then there were a lot of partners involved. It's not just the Ministry of Health, there are a lot of partners that we gave money to, some of whom were already involved in a country, let's say university programs, for example.

MILLER: Who were some of the other partners already in-country or soon to become in-country working on setting up ART programs

KAPLAN: So, a big one, and early on there were--I'd be hard-pressed to remember this. When you talk with [Dr.] Tedd [V.] Ellerbrock sometime, he'll tell you about the so-called Track One program that started from the beginning. We had four main collaborators. One of them, for example, was ICAP, that's the International AIDS Program at Columbia University. So, they were involved over there. Johns Hopkins had a program over there. I'll have to remember the others 01:01:00now, but there were some programs, and they initially became part of the so-called Track One program because they already had some experience, they already had some presence in Africa, they already had offices there, so they were logical people to go through. So, we had partners like this plus the Ministry of Health, so we had to make sure we had the facilities working with them, the drugs, the training of people, hiring more people, the laboratory backup for the laboratory tests, the renovation of the facilities. When we looked at a lot of these places, the roof would be leaking and water coming in, so we had to do a lot of renovations, data management, keep track of what we were doing. So, HIV Care and Treatment involved all of those things, and actually, that's just the antiretroviral drugs part. We haven't yet talked about 01:02:00the non-HIV drug part of HIV care, which is a great story in and of itself.

MILLER: I want to get to that. Can you tell me a little bit about the strategy initially of getting drugs to people? Were these services at a district level, were they at a higher tertiary care level? How did the ill get to these clinical services initially? I think as time went on, there was a desire to have you do more peripheral, but initially, do you remember what the approach was?

KAPLAN: Initially, we had to get things going quickly because the idea was, we have all this money, we want to get started right away. So, at the onset, you want to work with what's there, so at the beginning, the places that either were or could become clinics were generally in the big cities affiliated with 01:03:00hospitals. So that was the logical place to start right there. As time went on and we wanted to expand these programs, obviously we had to do more than that. We had to get out to more peripheral areas of the country, to districts and even communities, and find ways to develop clinics and to get people out there and the drugs and all the other aspects of care out there. So, I think it's fair to say that initially it was very capital city-based near the hospitals but over time it expanded, and now at this time, we're talking about hundreds and hundreds of facilities in some of these countries that go way beyond the big cities.

MILLER: You mentioned beyond setting up the ART clinics, looking at all the 01:04:00other care and support activities. Can you describe some of those?

KAPLAN: Sure. So, this is the whole story, and it's a wonderful story because it was another exercise and challenge of how we go about administering our programs. So, besides the HIV drugs, and we'll just say at the beginning that was the focus because these are the lifesaving drugs. In fact, it was really the combination antiretroviral therapy regimens, three drugs, that didn't come onboard until about 1996 that really made all this possible. It wasn't until that happened till people started to think, wow, maybe we can actually do something internationally. And here PEPFAR comes along about seven years later. That's not an accident. Those drugs had to come along because, unlike the single drug like AZT we had back in 1987, 1996 was a key year. That was the year that 01:05:00the first so-called third most powerful drug in the cocktail. Protease inhibitors came along in 1996, and since then, others have come along. But these were the three-drug combinations that these really saved lives, so that's what made this whole thing possible. So that was always the cornerstone, and actually, I'll go back--I'm getting to your question here but when the initial program was laid out by President Bush--I can't remember whether this was probably articulated soon thereafter by our office in Washington what became the Office of the Global AIDS Coordinator. We had the so-called two-seven-ten goals. So, what were those? What that meant was over the five years and the "B" word, the 15 billion dollars over five years, the goal was to give antiretroviral therapy, these HIV drugs, to two million people, to give HIV care in a broader 01:06:00sense, I'll mention in a minute what that means, to ten million people, and to prevent seven million infections. The two-seven-ten goals. Those were our mantra at the beginning of this. All right, so what do we mean by broader HIV care? In addition to the antiretroviral drugs, we're talking about the prevention and treatment of opportunistic infections with more specific modalities, not just the HIV drugs. We're talking about food and nutrition because a lot of people were starving out there. In fact, on at least one occasion I remember going into a country and sitting down with all these high-level people and thinking about all the things we could do and somebody just stopping the conversation with "let's start with a good meal, that's what these people need the most, there's a lot of malnutrition." So, food and nutrition. End-stage care. A lot of people dying so so-called palliative care, pain management, which a lot of patients in 01:07:00the final stages of HIV have. Social services like, for example, people are starving, how about just a little bit of a micro loan so they can make a garden and grow food to feed themselves and maybe sell a little bit to their neighbor. Mental health services. Treatment of sexually transmitted infections. These were all on the table to get to the ten million. Nobody had really defined how we're gonna do that. We called it Care. Actually, another good story about that. Initially, that whole area was called palliative care. Now, that was an issue from the beginning. Most of us walking around in the street usually think of palliative care meaning care of a terminally ill patient for whom we can do nothing else, making sure they're pain-free. But there was a whole kind of a feel and very passionate people who wanted to interpret palliative care more broadly to basically be everything, what we were doing for all of our patients. 01:08:00So initially, this whole area was called palliative care. Subsequently, many years later we changed the name, so we had issues with nomenclature right from the beginning, how to define what we were doing, what the priorities would be, how-to guide the countries, what do we do with this whole area, what are we trying to do to ten million people. I was very fortunate to be involved in the leadership of this at CDC and also in Washington during this time, so I lived through all these years, and there were people who were very passionate about different parts of this. He had their whole community groups focused on palliative care, and they would tell us what we should do and what the money would be used for.

MILLER: Which community groups? Communities--

KAPLAN: Well, they're whole associations. I forget the names now. There's the American Palliative Care Association, APCA.

MILLER: U.S. based.

KAPLAN: U.S. based, right. These are nongovernment people. And then food and nutrition. There were people at one of our sister agencies like USAID, who were totally focused on that. That was their area of expertise-- they wanted to feed people. Well, we can't use all the PEPFAR money to buy food. So, these were the kinds of challenges we had to deal with early on, and how do we name what we're doing, how do we define it, how do we keep from spreading ourselves so thin that we're wasting the money. In fact, I remember the first global AIDS coordinator getting up at one of our big meetings and saying we can't be a mile wide and an inch deep, can't do that. So, trying to direct all this was a real challenge. It evolved tremendously over the years that I was involved. I'll just say from the CDC standpoint, we're science-based, we wanted to make sure to do the things 01:10:00with the most impact, so the biggest thing for us right at the beginning was Bactrim. That was what we were focused on. A lot of people out there didn't know what Bactrim was. But just like it had been in the United States, it could be a lifesaving drug overseas actually for more reasons than the United States. In the United States, it's a drug that primarily prevents Pneumocystis pneumonia, but in Africa, it prevents Pneumocystis pneumonia, it prevents toxoplasma encephalitis, that infection we mentioned, it prevents various protozoal diseases in the gut like isosporiasis, it prevents malaria, a huge issue in Africa. So just getting Bactrim on the map, making sure everyone understood its importance, and using that, that was our first priority. But then we went on in a number of directions. Also, I haven't mentioned here, WHO [the World Health Organization]. WHO figured into this a lot because, over the years, I was 01:11:00involved in at least three different renditions of WHO guidelines in the use of Bactrim, which actually goes by the name cotrimoxazole overseas. So that was a priority from the beginning but managing all these very passionate interests and trying to keep our eyes on the prize-- what's the best way to spend this money-- was a great challenge. I mean, I loved the challenge--it was tough at times to get through this.

MILLER: So, Bactrim itself was relatively inexpensive. What was the thinking in terms of how to get it out in a widespread way beyond the hospitals where patients were coming in for ART care? What was the thinking about approaching all these patients, some in rural areas, some in--

KAPLAN: Well, the first thing there was making sure it was understood who should 01:12:00get the drug. Now I'd have to really think back over the various renditions of the guidelines. I think I mentioned in the United States we recognized early on only the people with the most advanced disease who needed Bactrim, people with CD4 counts less than 200. Overseas, we can be a little bit more expansive than that. First of all, we didn't have CD4 counts on everybody so operationally it was a lot easier just to give it to everybody, and then if people had CD4 count capabilities or other ways of looking at advanced disease, it could be restricted to some fashion, but then again, remember the drug also worked against malaria, and everybody get malaria. So early on some countries just gave cotrimoxazole to all the patients.

MILLER: All the HIV patients?

KAPLAN: All the HIV--just the HIV patients. Uganda is an example of that, they were a real leader in that. Other countries had a slightly more restrictive definition based on CD4 count or advanced AIDS clinically.

MILLER: Did they just sprinkle cotrimoxazole to all the OPDs [outpatient departments] and all the prenatal and TB clinics?

KAPLAN: First of all, the idea was just to make sure people were aware of its importance. Okay, drug availability. This is a drug that's commonly used and would commonly be found on the shelves in Africa and used for other things, sometimes used to treat diarrhea. So, it could be used in different ways, so people in Africa were generally aware of this drug so it was out there. Now, 01:14:00from the beginning, even as a cheap drug, we were trying to lean a little bit more on host countries to provide drugs for opportunistic infections because we were having enough trouble funding the HIV antiretroviral drugs. In some cases, some monies were used to buy Bactrim or cotrimoxazole over there but in general, and this is true for all the opportunistic infections, from the beginning we tried to lean on host countries through their own drug procurement systems to come up with the Bactrim. Sometimes it worked, sometimes it didn't work so well. The good news is they were familiar with the drug, it was cheap, and they had it. Because of other uses of the drug, I remember going to many facilities where the drug would be off the shelves because they had used it to treat diarrhea in this person or that person, and the HIV-infected population is not getting it. So, having different supply lines of what drug you can use for your general 01:15:00population and what drug hopefully you can save for the HIV patients was a challenge. Yeah, it was a challenge to get it out there. I think over the years, we succeeded in making sure everyone was aware--now everyone knows about cotrimoxazole now, and I think countries have pretty much elaborated their ways of getting the drug, but there was always that issue of finding the drug that disappeared for other purposes.

MILLER: So PEPFAR was a program implementation initiative, not a research initiative. I think that was brought out quite a bit in the beginning. But for things like cotrimoxazole, were there some implementation science studies done 01:16:00to see the effect of some of the strategies, for example, giving cotrimoxazole or fluconazole, for example? Can you share some of the attempts of trying to measure the impact?

KAPLAN: Sure. Thank you, Bess, because this brings up the whole issue of "research" in PEPFAR. As you mentioned, from the very beginning, this was an implementation exercise. Congress did not want this to be a research program. In fact, we used to joke early on not to use the "R" word. However, when you're putting programs like this into place, you have to develop information to answer questions. The questions may be more in the lines of the operational aspects of what we're doing, how to deliver care, rather than say the development of a new 01:17:00drug which was never something we would do, or randomized control trials which was generally something we would not do in PEPFAR. So, we had to be careful about how we used funds to develop new information, and it's somewhat humorous actually to think back of some of the terms that were used to keep away from the "R" word. The current one is actually implementation science. I think operational research, even though it has the "R" word, was probably used but there were various names used to try to keep from using the "R" word mainly so people in Congress wouldn't get upset. So, yes, there were a number of projects that went on specifically with regard to cotrimoxazole. I mentioned a minute ago that this drug is effective against malaria. So that led to a number of issues. 01:18:00Should we be restricting this drug to people with the most advanced disease to prevent the AIDS-related conditions, or should we give it to more people to prevent malaria because anybody can get malaria. So, there were studies done in Uganda, for example, about what happens when we give cotrimoxazole to a broader group of people and how much malaria will we prevent and what do we do about that. So, I don't remember the exact design of these, but basically, the studies in Uganda did show that when we give it to everybody, we will prevent malaria and save lives, and that includes people with higher CD4 counts. Actually, to this day, I think in Uganda, we're using cotrimoxazole universally. There are a few countries that are doing that. But that leads to some very interesting ethical questions like if you're trying to prevent malaria in all of our HIV 01:19:00patients, what about everybody else, what about their neighbors? Well, interestingly, nobody has ever really gotten stuck on that issue. I would've thought that would've been a huge ethical issue, but it hasn't been. So now in places like Uganda we give it to everybody. We know we're preventing malaria, and we could be doing the same thing for their neighbors. We're not really worried about that. So that's an example of research on cotrimoxazole. There are also studies done in children which I'm less familiar with but we also have learned, for example, that that drug in the African context not only prevents--well, Pneumocystis pneumonia may be less common over there or less commonly appreciated than it is here, but certainly toxoplasma encephalitis, some protozoal diseases, and malaria but also bacterial diseases. It's an antibiotic, a combination antibiotic, and it does prevent a lot of bacterial 01:20:00diseases, and those kill people in Africa a lot.

MILLER: What about fluconazole?

KAPLAN: So, fluconazole--I mentioned earlier that we have never used fluconazole as so-called primary prophylaxis in the United States, but Africa is a little bit different because there's a lot of cryptococcal meningitis and by the way, that is one of the worst opportunistic infections to get. It is an awful disease. It's a fungal infection of the brain. People get headaches, which are often described as the worst headache they've ever had in their lives. They can develop confusion, and it has a very high death rate, and if they are fortunate enough to recover from it, there are frequently what we call neurologic sequalae. They have neurologic abnormalities that persist forever. It's a really awful disease. So, what do we do about the prevention of this disease, which is 01:21:00the most common serious fungal infection probably around the world, certainly in Africa? I think what we know is the most important thing is to get people on antiretroviral therapy so that they never have their immunologic status deteriorate to the point where they're susceptible to this disease. The people who are most susceptible have CD4 counts under 100. That's the advanced disease. So that's the first thing is to try to prevent people from ever getting to that state. But among people who do present with advanced disease, and unfortunately, there are still a lot of them around the world, and particularly in Africa, there is another mode now that we can think of employing to try to prevent this disease. Now, to throw into this discussion, there is a test that can be done on 01:22:00patients' blood called the cryptococcal antigen test, which tells you if the antigen really means a live bug. It's actually a cheap test. It's actually in dipstick form now. So, one of the last projects that I personally was involved in involved a strategy to try to prevent cryptococcal meningitis in HIV-infected persons in Africa. The idea was to look at people with advanced disease, CD4 less than 100 and to do this test, cryptococcal antigen test, and if positive, to give them high doses of the drug you mentioned, fluconazole, which is an antifungal drug to try to prevent cryptococcal disease over and above the antiretroviral drugs that they're getting. And I had the good fortune to be involved in this study in Uganda, and actually, I'm happy to say that as of only 01:23:00about three weeks ago, the final paper was accepted for publication. I can say my CDC career extended right up to about three weeks ago. But we learned a lot from this study. We know that on a population basis, it's difficult to demonstrate a survival benefit from the intervention because only about 10% at most of the people with advanced disease will have cryptococcal antigen in their blood. However, for those who have it, it will prevent to a great degree cryptococcal meningitis. So, it is an intervention that certainly needs to be considered. WHO actually recommends this intervention now. In fact, WHO has gone a little bit farther and actually suggested if it's too difficult to implement, you could just give fluconazole to everybody with a CD4 count less than 100. As 01:24:00I mentioned, we don't do that in the United States, but there is some data to suggest that that might be valuable in Africa. So, while that drug doesn't see a lot of use in the U.S., it's very important in Sub-Saharan, Africa to prevent this awful disease.

MILLER: You mentioned some of the challenges in working with the different agencies that were part of PEPFAR, and you actually played very much of a lead role in doing just that for the care and treatment portion. I know you were co-chair of the Care and Treatment Steering Committee initially and co-chair of the Care and Treatment Technical Working Group. Can you tell us what was involved in being chair of these various groups and how that worked?

KAPLAN: Sure. This is a situation the evolved a lot over the years, as you can imagine. So, if I go back to the beginning of PEPFAR, the two-seven-ten goals I mentioned the ten, which was HIV care in a broader sense than the HIV antiretroviral drugs specifically. So, from the beginning, I was a co-chair of our interagency Palliative Care Technical Working Group, which at some point because of the confusion about that name, we changed to the Care and Support Technical Working Group. So the challenges were, I think I alluded to this a little bit previously about how of all the many things we could do with these funds, how to figure out the best thing to do to have the most impact in our PEPFAR programs and how to agree on these things with people from not just CDC but from USAID, Department of Defense, Peace Corps, the other players. So, what 01:26:00we tried to do from the beginning is do what CDC is best at is focus on the science, what will have the greatest impact, and that's why early on our biggest priority was with cotrimoxazole to make sure it was out there, people understood its importance and to implement it. Over and above that, we always did our best to try to go with where the science led us, and sometimes there wasn't much science to guide us. At one point, we actually put together an evidence base for all the interventions we were considering. We actually published it in a supplement of the journal JAIDS, Journal of AIDS Immune Deficiency Syndromes, to try to summarize what we knew about all these interventions. So as a matter of juggling what we knew about the science, and frequently we didn't know as much as we would like to know, going on what our programs and the countries had as 01:27:00their priorities--after all they're our partners--what they wanted to do, and also I think individual expertise and passions probably had something to do with what we were doing. For example, we had people at USAID who were really good at food and nutrition. We probably ended up doing more food and nutrition because we had people whose whole career was on that topic. But generally speaking, I think the idea was to let the science drive as much as possible what we did, but we had to juggle all those different priorities, and one of them was definitely passionate people at the table. We had a lot of those, so we did our best. I'll just go fast forward with that particular topic. Over a period of time, the HIV 01:28:00care in the broader context has assumed--except for TB, which remains the single biggest issue to deal with in terms of opportunistic infections in places like Africa--the focus has shifted more toward getting more people on antiretroviral therapy. So, in the last couple of years, we had no more Care and Support Technical Working Group. I became co-chair of the Care and Treatment Technical Working Group, which encompassed everything, but we all understood the focus is really mostly on antiretroviral therapy. So that was what I did the last couple of years, I chaired that group and, again, the focus there was mostly on the HIV drugs. To some degree, we touched on the other things, but basically now, at this point, the other things were kind of left to the host country. Most of the PEPFAR resources are going into expanding ART, and a lot of the rest is left to the host country, which means in some places, a lot of things are being done, in 01:29:00some places very little is being done. I think that actually is the appropriate allocation of resources at this point because all along the big lifesaving drugs have been the HIV drugs.

MILLER: We can't possibly leave a discussion without mentioning the country operations plans. This is the administrative aspect of PEPFAR calling for the development of detailed Country Operations Plans or COPs each year as a means of requesting funds for particular interventions by specific agencies. You had a big role in organizing and conducting a review of the care and treatment component of these COPs, and it was kind of a big deal. Do you want to describe a little bit about what that process involved?

KAPLAN: Sure. Well, actually not only just the care and treatment part of the COPs, we also played roles in reviewing the entire country operational plans which was, as you can imagine, a major issue, a major challenge to look at a whole country operational plan from a country, hundreds of pages of stuff, and not just the care and treatment but everything else. So, I had to do that, too. I think it's fair to say I always enjoyed focusing on my technical area of expertise, but I did both. So maybe a few words about each. So, in terms of care and treatment, as I mentioned, in the last couple of years, care and support kind of fell off the radar screen a bit and we were focused mostly on the treatment. So here we played a role in looking at our working group, our Care 01:31:00and Treatment Technical Working Group, had a role in looking at these aspects of all the COPs. We had a lot of countries we're talking about here. We were up to like 35 or something countries that would submit COPs all at one time of year. So we'd have to look at these as an interagency group and the main things we'd be looking at would be--the overall direction to the program specifically targets what are the numbers you're trying to get to because countries were being tasked with reaching out to and offering antiretroviral therapy to as many people as possible and there were target numbers that were developed for all these countries. So how is the country doing toward achieving that target and what are the obstacles and what are their plans, how are they spending their money to do that, how much money are they spending on the drugs, how much money 01:32:00are they spending on renovation of facilities, how much on training, how much on the laboratory support, how much on data management. We had to look at all these things with the idea of having the greatest impact possible and getting to those numbers as well as we could. So broadly, that's what we were trying to do when we looked at all these programs. We looked at, okay, this is your budget, this is what you say you're trying to do, and also what's your track record, how did you do last year? If last year you only got half your target, what happened? So, these are all the things that would command our attention, and in addition to looking at the paper that was before us, obviously there was a lot of experience around the table who had been to that country what's actually happening there, are they really saying what they're really doing, or is what they say is happening really happening. So, we always had that supplemental information to help us, but the idea was to, in the end make a recommendation. This budget is 01:33:00okay, but you need to shift that money from here to there, or this budget is inadequate for doing what you're trying to do, you better get some money from someplace else. So that was our job technically to do that. Now, I could say some things about the broader COPs, but I'll just say that was a much more difficult process. I always enjoyed the technical part more because the larger COP you're talking about whole areas, not just care and treatment but the prevention and the counseling and testing and data management, laboratory support, all the agencies kind of fighting for their part of the money. Very difficult experiences which to this day I think are challenges for all the people involved in that, but necessary because somebody's got to do it. If you're gonna give hundreds of millions of dollars to a country, somebody's got to decide whether it's the right amount because we're doing all this to achieve 01:34:00results. So that's what COP reviews were all about.

MILLER: So, in closing, you were involved in the biggest budget single disease global initiative ever. Any closing thoughts on your part or on CDC's role in all of this?

KAPLAN: Oh, sure. I could probably come up with a few. First of all, I had a 35 plus year career at CDC, and I can think of lots of different phases of my career and what I did. In terms of public health impact, nothing came close to these last ten years. In fact, the numbers now, we have about 37 million 01:35:00HIV-infected people on the planet, and we're up to about 22 million who are on antiretroviral drugs, 14 million of those with PEPFAR support. Is that a phenomenal statistic or what? At the time I retired 2-1/2 years ago, we were just getting to the 10 million, which I thought was a great landmark with PEPFAR support.

Now, according to the information I have, we're up to 14 million. Over 50% of all the people getting these drugs on the planet are getting them through PEPFAR support, and you think of the number of lives you save, it's just phenomenal. So just to have been involved in this has been great and sometimes you think about the tedious parts like the COP reviews-- you put that aside and you think about what we've done and what this has meant to all these countries, many of whom like middle-income countries are starting to take this over on their own, which is the idea ultimately, they may not need us. So being part of that process, 01:36:00putting these programs out there saving lives and watching some countries better than others taking these programs over has been a wonderful experience. CDC's role. I think about my career, and what's meant the most to me and probably way at the top of the list has to be the people I've been able to work with, or did work with during my career, both in Atlanta and internationally. The dedication, the motivation to getting this work done, that was the best part of the experience. What I miss the most about working at CDC are the people. Just a tremendous opportunity and privilege to be able to work with all these people. There were challenges involved, and as I mentioned, getting together with the other agencies and deciding on a plan. I think I learned a lot about group 01:37:00dynamics and trying to work with other groups, and those were all lessons that I thought were valuable and probably helped me in other aspects of life, too. But that was part of it, too, is learning to work with people and listen. That's the main thing is listening to people, listening to the patients, listening to our partners who are doing the work, listening to people from the Ministry of Health which is not to say that everybody has the same competence and expertise, but you've got to listen, and then in the end hopefully have a path that will be the best toward achieving your results which is saving lives. So, I think back on just what a privilege it's been to be able to be part of all that and to work with all the people who've had the same goals in mind. MILLER: Well, before we end, I want to say that I was in your branch as you were branch chief, and one 01:38:00of my best memories are your branch meetings. They were very personal and always intellectually stimulating and a great part of working with CDC. Thank you, Jon.

KAPLAN: Thank you very much, Bess.