Dr. Nathan Shaffer



MILLER: This is Dr. Bess Miller, and I'm here with Dr. Nathan Shaffer. Today's date is October 1, 2018, and we are in Atlanta, Georgia, at the Centers for Disease Control and Prevention [CDC]. I am interviewing Dr. Shaffer 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 [acquired immune deficiency syndrome] Relief. Dr. Shaffer, do I have your permission to interview you and to record this interview?

SHAFFER: Yes, you do.

MILLER: Nathan, you've been a leader in the field of Prevention of Mother-to-Child HIV [human immunodeficiency virus] Transmission, PMTCT, since the early days. The landmark study of short-course AZT [azidothymidine] for PMTCT, which you led in collaboration with Thai researchers, was a watershed 00:01:00event and allowed for affordable and broad-based scale-up of this lifesaving intervention in developing countries. Throughout your career, you have been a leader at CDC, at WHO [World Health Organization] and other UN [United Nations] agencies in research, program implementation, evaluation, and guideline development in the fields of PMTCT and Pediatric HIV in countries throughout Africa and Asia. You were the CDC lead for the mother-to-child transmission Initiative before PEPFAR, and then as a critical leader for PEPFAR at CDC, you started and developed the CDC Global AIDS Program PMTCT Strategy and Team and embarked on early implementation in PEPFAR-supported countries. More recently, you've played a lead role in the development of the EMTCT initiative dedicated 00:02:00to the Elimination of Mother-to-Child HIV transmission. We have a lot to discuss. But first, let's begin with your background. Would you tell me about where you grew up and your early family life?

SHAFFER: Sure. Thank you. I grew up just outside of New York City and basically spent my early years in the New York area and went to college at Yale College [University] in Connecticut and studied, although I had a strong science background, I actually studied philosophy and the humanities and was not really geared towards medical school when I finished college, and I took two years off doing a variety of different jobs and then I actually had to go back to school to do my premed courses. I decided that I did want to go into medicine and potentially into public health. I was very interested in that, so I was able to go to Columbia 00:03:00College School of Medicine.

MILLER: What did interest you in going into medicine? How did that take place?

SHAFFER: As I thought about what I wanted to do as a professional career, I was really very interested in first having direct contact with other people working broadly with other professionals but really making a difference and I appreciated the importance of health on an individual level and on a social level and health as a right of people. So, I was very interested in some of the social and justice issues in terms of access to health, and I was interested in the science of it, but I think I was looking for something in terms of a service profession.

MILLER: So medical school would've been in the '80s?

SHAFFER: Yes. I finished medical school in 1982 and then--

MILLER: When you were in medical school and then internship and residency, did you see much AIDS at that time, early AIDS [acquired immune deficiency syndrome], and then more definitive AIDS?

SHAFFER: Yes. That was just at the cusp as you know very well the first uncharacterized cases were beginning to be seen in the late '70s, early '80s, and my recollection is that in retrospect, I saw a few cases as a medical student in New York City. I did a lot of work at Harlem Hospital in New York and that subsequently became kind of an epicenter so in retrospect both some of the 00:05:00prodrome TB [tuberculosis] cases, some of the unclear pneumonia cases and just the wasting diseases that I saw as a medical student clearly were AIDS. It was more clear when I was a resident. I did my residency in internal medicine at Boston City Hospital, a big city hospital, where it served a lot of immigrants, a lot of people with drug problems, and others. I remember very distinctly seeing people that seemed to be characterized, seemed to have this unknown illness that then we put together, and reading from the reports from CDC we realized was HIV or AIDS at the time. I also did a clinical clerkship, I think it must have been in 1981, out at San Francisco General Hospital on the GI [gastrointestinal] service and, again, I didn't know it at the time, but I think 00:06:00almost every single person I saw there had a complaint probably related to AIDS at the time.

MILLER: What were some of the illnesses that you saw during the residency? Were you seeing a lot of pneumocystis [pneumocystis carinii pneumonia]?

SHAFFER: We did see pneumocystis, we saw Kaposi's sarcoma, but what actually struck me, and I still reflect on this now and then, young men in primary care clinic who were presenting with lymphadenopathy and we couldn't really characterize what it was, and it was before it was well appreciated that this was a prodrome for HIV and AIDS. There actually were articles written at the time of idiopathic lymphadenopathy of unknown consequence, but we kind of 00:07:00dismissed it at the time. Just asked people to come for follow up and because this was a big city hospital, we didn't necessarily have such good follow up of some of these episodic cases of young men, aside from the very fulminant, very dramatic bad cases. I did see quite a number of people die in the hospital from end-stage AIDS, but what really stuck with me were that for young men, in particular, we didn't really--we didn't appreciate all the social and behavioral risks, we didn't necessarily get into all of that, but just understanding their (clinical) presentations. I wish we knew more at the time, and I wish we could've helped them more than we did, and we didn't really understand what we were seeing at those early times. But I think that in general, as a resident from '82 to '85 in internal medicine at a big city hospital, there was a 00:08:00significant amount of HIV disease.

MILLER: So then how did you get interested in public health?

SHAFFER: Well, I was in the primary care medicine track, and I was working when I had time available at a number of community health centers and actually my career path at the time, I thought I was going to work in primary care. There was a big movement to support community health centers and to provide more access to people that were underserved, and I worked during my residency, and then after residency, I worked for a year at two primary healthcare centers in the Boston area serving primarily immigrant and inner-city communities. But at the same time, even during my residency, I had some contact with CDC, and I was particularly influenced by two infectious disease--both infectious disease and 00:09:00sexually transmitted disease -- doctors who had connections with CDC. One of them had been at CDC, and the other was working closely with CDC, and they both talked about and encouraged me to think about it. I think it was still when I was a resident, there was a visit from CDC, and there were several people from CDC that came up to Boston, and I attended it. I remember, [Dr. Arthur L.] Art Reingold was one of the people who came up and was promoting the EIS [Epidemic Intelligence Service], and I didn't really know too much about it and was really very interested and followed up and looked into that and applied, and I really had two pathways. Either I was going to continue in primary care medicine or come down to the CDC. I decided to come to CDC thinking that I really needed 00:10:00more experience-- up to that point, my training was really all clinical, and I needed to--while I was interested in public health, I needed to learn something about public health and epidemiology and I'm very grateful that CDC accepted me into EIS. I know I had strong clinical credentials and strong interest but compared to the credentials that people have these days, I wonder whether I would have gotten into EIS now. But be that as it may, I thought I would come to CDC to EIS for two years and then continue with my primary care public health work, but I also knew that I had an interest in global health and international health and that certainly took off when I came to CDC.

MILLER: Tell us more about that. Had you done any international travel for other reasons?

SHAFFER: Only personal reasons. I had done a fair amount of travel on my own exploring things. That was a time a lot of people were traveling in the 1970s and '80s and in a more carefree way, I had traveled a bit in Mexico and South America and I had not been to Africa but I was just very interested in world events and exploring new places and very aware of public health problems particularly in Africa. So, I was interested, but I think it was more theoretical and untested.

MILLER: So, then you got to CDC, and where were you assigned for your EIS fellowship, and what did you do?

SHAFFER: I was in what was called at the time the Enteric Diseases Branch or the Diarrheal Diseases Bacterial Branch, and I was assigned to surveillance systems 00:12:00to look at diarrheal diseases like Salmonella and Shigella and botulism and cholera, and I had opportunities to travel and investigate different chronic diarrheal conditions both in the Indian Health Service in the southwest of the United States, botulism outbreaks among Native Americans in Alaska and the first time I went to Africa I investigated a cholera outbreak in Guinea Bissau in West Africa, and that was my first introduction, quite a dramatic one, to a very poor country in Africa.

MILLER: Did you choose bacterial diseases? Was it a very competitive slot? Do you remember why you chose that?

SHAFFER: It had the reputation--first of all, it was a very congenial group, to 00:13:00be sure, with good supervision but it had a reputation of having a lot of opportunities for outbreak investigations and very good clear methodologies for the kind of EIS training that one looked for at CDC.

MILLER: So then, after EIS, you didn't leave, you ended up in the Malaria Branch. How did that happen?

SHAFFER: I was looking to stay on at CDC. I was interested, among other diseases, in malaria. I think at that point I already was beginning to be more interested in HIV and AIDS as well, but I was able to take a one-year assignment in the Malaria Branch for some additional training and that got me--I probably spent half of the year in Africa with the Malaria Branch, and that was very, very formative both in terms of learning about malaria -- it's kind of one of the things about CDC, you get put into a position, everyone assumes you're an 00:14:00expert. I really didn't know anything about malaria at the time, and at the home base, I just spent a lot of time learning how to read malaria slides and doing finger pricks and doing all of that and learning some of the laboratory (methods). At that time, there was intense interest in the potential interaction between malaria and HIV. There was even some concern, which didn't pan out at all fortunately, that malaria or mosquitoes were transmitting HIV because of where HIV seemed to be exploding in Africa. But there was also a concern for the question that people that were coinfected with malaria and HIV, did they have a risk of more severe malaria or vice versa would malaria tip to the fulminant 00:15:00progression of HIV. So, a lot of our field work was actually in Kinshasa, Zaire, now the [Democratic Republic of the] Congo, and as you know, there was the first CDC international HIV field station in Kinshasa founded by [Dr.] Jonathan [M.] Mann. At that time, [Dr. Robert W.] Robin Ryder was the head of that, and we were very fortunate that they allowed us as a base to do some malaria HIV studies. So, I spent a lot of time at Projet SIDA in Kinshasa, met a lot of the key early leaders actually in international HIV in Projet SIDA, and did a number of studies at the main hospital.

MILLER: You were looking at pediatric HIV if I recall in Zaire. Can you tell us 00:16:00a little about what the scene was like? Were there dying babies, what was the scenario when you were there?

SHAFFER: Yes. This was in 1988-89. What we were mostly looking at was the risk of transmission of pregnant women who were HIV positive and the risk of transmission of HIV to the baby and the interaction with malaria because pregnant women also were at risk of having clinical malaria and having more severe malaria, and I was actually following up on some studies that one of my predecessors, [Dr. Alan [E.] Greenberg, had started and I was basically doing follow up. So, we did prevalence studies or seroprevalence because we had the 00:17:00test now for HIV screening and so we could test pregnant women to see what was the proportion of pregnant women that were positive. Projet SIDA--this was not my work, but Projet SIDA was well known at the time of doing pioneering cohort studies to look at the risk of transmission from mother to baby. So, we concentrated just cross-sectionally on the prevalence of the disease and characterizing the severity of the disease, particularly malaria, in conjunction with HIV. But one of the striking things at that time, Kinshasa, was viewed as one of the real hotspots for HIV, and our studies of pregnant women showed the prevalence was about five percent, which, of course, in our understanding seems to be quite high compared to the U.S. situation. But one of our findings was that the prevalence had really not changed, it had not increased, from the 00:18:00earlier studies (we were following up on) and we used the same methodologies. So, one of the intriguing questions always that has been around is why HIV didn't actually get worse in Kinshasa and in the Congo after that time, especially given not only the beginnings of infection (the HIV epidemic) but also the relatively poor public health and medical infrastructure and the civil disruptions that were constantly ongoing at the time. But Kinshasa and Zaire prevalence stayed about the same, and then HIV began to take off in Eastern and Southern Africa in a much more serious (worse) way. One of the people that I met in Kinshasa was [Dr.] Margaret [L.] Oxtoby who was developing a pediatric and family focus for HIV under [Dr.] Martha [F.] Rogers back at CDC and Margaret, and I worked a little bit together in Kinshasa and she invited me after my work 00:19:00to join the HIV group and start focusing on mother-to-child transmission and pediatric HIV, so I made a rapid transition there.

MILLER: So just looking at what was known at that time about the vertical transmission of AIDS, there were data from the U.S., Zaire, and elsewhere. What was the understanding at that time? So, we're looking at '88.

SHAFFER: Yes, '88-'89. My senior supervisor during those early years was Martha Rogers, and she was really one of the leaders in this field and I think if I remember right, we understood by then that the transmission risk without any 00:20:00interventions was about 30 or 35 percent, about 1 out of 3 pregnant women with HIV would transmit disease. We had a sense--I don't think it was clearly characterized, that women that were more clinically symptomatic and, therefore, more advanced in their disease would be more likely to transmit (to their baby). I don't think that we were doing--we didn't appreciate the correlations with CD4 [t-cell] counts and certainly not with viral load, that came much later. We didn't have it (easily available) at that time, but around that time, tests for diagnosis of infection in infants were being developed with PCR [polymerase chain reaction]. But one of the dilemmas was it was difficult to diagnose HIV in the exposed infant, (that is) infants born to infected mothers because the antibody from mothers was persistent in the baby and would interfere with the 00:21:00assay and would persist for about 18 months. Another area of interest and concern, there were strong suspicions that there might be transmission via breastfeeding of mothers, but at that time, it was not well characterized, and I think that Martha was one of the lead people that studied that and defined that route of transmission. So, we knew about the routes of transmission, but one of the things that went on for a number of years was that we didn't really have any way of blocking or interrupting, preventing the transmission. (By then) We knew in general that women that were more clinically advanced in their disease would have a higher risk of transmission to their baby. We also knew, unfortunately, that the infants that were infected, many of them would progress very rapidly in their disease, and about 50% of them would not live beyond one year of age.

MILLER: Were you traveling quite a bit during this period?

SHAFFER: That was a source of some creative tension in the family. I was traveling a lot, as I mentioned, about 50% of the time during my malaria time (work) in Africa where I really got quite an introduction both to African public health issues and to the HIV epidemic, but I had a young family and I decided in part to take a position back at CDC with Margaret where I could focus on domestic HIV and Martha had pioneered some studies and developed a cohort in the New York and New Jersey area looking at mother-to-child transmission of HIV with the New York City Health Department and [Dr. Pauline A.] Polly Thomas and others 00:23:00were looking at this, and so I said, okay, I had a great experience doing international work, but maybe I need to focus on domestic work while I was starting a family. And I did some work in Atlanta at Grady [Memorial] Hospital with colleagues here at Emory [University Hospital] and Grady. So for two years I was working in New York and Atlanta on domestic studies, I learned much more about how to manage, run and analyze data from cohort studies which involved enrolling and following up HIV-positive pregnant women, looking at the risk factors of why some women became positive while others remained negative, what could we learn about the incidence in terms of which age groups were being affected and what behavioral groups were being affected, (and risk factors for mother-to-child transmission). By this time there was a clear PCR test for HIV 00:24:00diagnosis, and we could also measure CD4 counts, and so I got very involved with the logistics of transporting overnight blood samples on ice from different study sites to CDC which was the only reference lab at that point doing CD4 testing and doing PCR testing.

MILLER: So, PCR testing for the infants.

SHAFFER: PCR testing for the infants that had been developed by [Dr.] Chin-Yih Ou. One of the nice things at that time, as an epidemiologist, I was (very) involved with the laboratory, so I really had an opportunity to work very closely with laboratory colleagues at the time.

MILLER: Can you comment further on CDC's role in all of this? What niche would 00:25:00you say CDC played and up to the point of PEPFAR in terms of its leadership for HIV/AIDS.

SHAFFER: Certainly, from the early '90s, CDC was a leader in the mother-to-child area, with different studies set up by some of my supervisors and (especially) because of the cohort studies that had been established in New York and Atlanta. CDC has a real leadership role. CDC continued its cohort studies looking at risk factors and what we called natural history of mother-to-child transmission and risk. Those were ongoing in Kinshasa, and then [Dr.] Kevin [M.] De Cock started Projet RETRO-CI [Retrovirus Côte d'Ivoire] in Ivory Coast and was looking at the risk of mother-to-child transmission in HIV-1 and HIV-2. NIH [National Institutes of Health] at the same time by the early '90s had really begun to 00:26:00focus also on mother-to-child transmission. They also began to establish cohort studies and put more funding into that, and they then sponsored a study, which we can talk about in a moment, that was really the landmark study in getting everything started to look at how to interrupt transmission. But I think that CDC played a key role but (at the time) was looking at natural history studies (looking at risk factors for infection and transmission). I think there were guidelines that began to come out from the U.S. Public Health Service on testing pregnant women for HIV and women that tested positive were advised not to breastfeed at the time because of the (risk of transmission via breastfeeding)--

MILLER: How did CDC and NIH work together during these relatively early years?

SHAFFER: I wasn't directly part of that, and I was not on any committees or task forces. I think that there was a friendly competition between the two groups, but there was a lot of interaction, particularly on the guidelines. I think that NIH began to focus much more on how to develop interventions and clinical issues, and CDC continued to look more at the epidemiology. Now, that changed a little bit. I was in a unique position. Even though, if you recall, I said that I wanted to work domestically, I had an opportunity in 1991, yet another (international HIV) field station was being developed in Bangkok, Thailand under 00:28:00[Dr.] Bruce [G.] Weniger, again, to look at what seemed to be an explosive epidemic of HIV in Southeast Asia. In Thailand (HIV) prevalence was really rising very quickly. Bruce and Margaret encouraged me to think about developing cohort studies in Thailand and so actually for two years I went back and forth to Thailand and developed an early natural history cohort study, again, looking at the risk of infection -- why mothers acquired infection and what was the risk of infection from mother to baby. These were some of the same questions, but this was a different subtype of HIV, subtype E, and at that time, it was an important question as to whether different subtypes had the same (or different) characteristics, in addition to different HIV strains like HIV-1 and HIV-2. So, 00:29:00there was a different strain. Also, were the tests that we were using, were they as sensitive to pick up these other subtypes. But in the middle of my natural history studies NIH in 1994 issued the results of the very famous ACTG-076 [AIDS Clinical Trials Group] study which was really a very intensive study in the U.S. looking at how to interrupt mother-to-child transmission and they were very successful at decreasing transmission to about 1/3 of the risk by giving AZT to the mother during pregnancy, intravenous AZT to the mother during labor and delivery and then giving postpartum AZT for six weeks to the baby. This was (rightly) viewed as really a breakthrough triumph. It was not only a proof of 00:30:00concept that HIV transmission could be interrupted by drugs, but it had practical public health implications in the U.S. At the same time, we were very concerned that it was obvious that most of the burden of disease was in developing countries and this very elegant, very expensive, and very difficult-to-administer (multi-prong) ACTG-076 regimen would be difficult if not impossible to provide in developing countries.

MILLER: So, in the middle of all this you make a 180 and decide to go to Thailand with your family. How did that come about? How did you convince everyone that was a good idea?

SHAFFER: Well, there was exciting work to do there, and I was being welcomed to have an opportunity there. Fortunately, my wife who is also an epidemiologist at 00:31:00CDC had worked in Thailand in the refugee camps when she was a medical student and really had a strong affinity for Asia and for Thailand and she was very encouraging of my getting involved and game for picking up the family and having a life experience of moving there, so we literally moved there with a one- and a four-year-old for truly a family adventure and then my own public health adventure in Thailand.

MILLER: What was that like getting there and setting up a life in Thailand?

SHAFFER: It was exciting and challenging and very, very fast-paced. We didn't have much time to prepare basically. We physically moved, and then I had to 00:32:00start work immediately, and there was real pressure to keep the cohort studies going and soon to move into a clinical trial, which I want to mention. But on a personal level in terms of the family, we had support. There was a very nice apartment, but life in Bangkok was complicated in terms of the tremendous or infamous traffic congestion and the time it took to get around--the smog and pollution. I remember very well it was before they had moved to unleaded gasoline. The pollution in the air was bad. They were also tearing up the city because they were building a subway system which was not finished until 1999, so during the 1990s traffic was much worse because the city was being torn up to 00:33:00build the subway system and the sky train. But what really stands out is the congeniality and the support, the close relationships among my Thai colleagues, which was just very exciting. We just had a wonderful working relationship and a personal and friendly relationship, so I think it was really a very, very nice experience. I made a lot of lifelong friends there.

MILLER: So, what were the terms of reference for this assignment, and who was your boss?

SHAFFER: Initially, before I went over to start some of the cohort studies, I was working with Bruce Weniger, who was the first director of the Thailand project, and then [Dr. Timothy D.] Tim Mastro took over as the director. I had 00:34:00been working with him a bit, and we were working long distance, and after he had been there about six months, he was able to secure a position for the head of the epidemiology research unit under him, and he was beginning to staff up the office and hire a number of expatriates. So, my terms of reference was more broad. It was not just in MTCT [maternal to child HIV transmission], it was to do epi studies on HIV but with the understanding that I would probably concentrate on mother-to-child transmission because that was my area and I already had a lot of ongoing work in that. So, Tim was my supervisor the whole time I was in Thailand. When the ACTG study came out in 1994, we quickly changed gears, looked at that, and with a lot of input and brainstorming among key 00:35:00people both in Atlanta and of course in Thailand (we focused on whether) we could do another study that actually would look at a simplified intervention that would follow on with the ACTG-076 but would be a feasible intervention for developing country settings both in terms of the lower cost, and more limited contact and intervention with the patients, something that could be applied in a variety of different settings. So, we actually developed a common protocol between Thailand and Côte d'Ivoire, the two CDC field sites, to look at what we called "short-course AZT' to take the 076 study and to significantly shorten it and simplify it, so we worked in concert.

MILLER: Can you tell us a little bit about doing this study, not the type of things that are in the methods sections of manuscripts but what did it take to do this study in Thailand where you were and then in Côte d'Ivoire. Were the Thai colleagues very interested in this? Were the cohorts, the base that you started with, how did you do this?

SHAFFER: First, we had a big advantage because we had done a natural history cohort study, and we were working out of two really big hospitals in Bangkok, one a university hospital (Siriraj Hospital, Mahidol University) and one, the largest ministry hospital (for pregnant women, Rajvithi Hospital and, for children, Bangkok Children's Hospital), and these were both very impressive, very large, very well run institutions with good clinical and academic leaders and they both had a very large number of births a year, much bigger than the average hospital in the U.S.-- I think in the range of ten to 15 thousand or 00:37:00even more births per year. The Thai colleagues, the Thai co-investigators, were very, very engaged, and very motivated. They saw HIV as directly affecting their country and being an important threat, and they wanted to participate in both studying it and to come up with some practical solutions. They had already made--building on their interventions for sexually transmitted diseases, they already had pioneered screening and testing of pregnant women for HIV and doing counseling and particularly doing group counseling for women. So, there was great interest. Personally, what was very exciting was that I wasn't just sitting in my office and certainly not just sitting behind a computer most of 00:38:00the time. I was back and forth to the hospitals a couple of times a week interacting with people, going on the wards, going into the labor room, looking over the logbooks, designing different forms and reviewing the progress of the study on a weekly basis and I put a lot of effort into building a team and a team approach with the colleagues at the hospital and with my research assistants, and that was great.

MILLER: Can you tell us a little bit about maternal and child health services at that time in Bangkok? Did most women get antenatal care, were most births in the hospital or more rural settings or at home? How did you access patients?

SHAFFER: In the urban center, virtually all deliveries took place in hospitals. There already was a large private sector in Bangkok, which has continued, but the two hospitals we worked at were very prestigious, and many women sought those out. So prenatal care was well organized. Women came relatively early to prenatal care and stayed in follow up and then came for a postpartum visit. As in many developing countries, there is a phenomenon of after the delivery particularly many of the younger women would go--it was called "to go upcountry" to go back to their home (or village) of origin, usually with their parents to live for a couple of months, so in some cases it might be hard to follow up mothers or families.

MILLER: You chose to stay in the urban areas. Did you give consideration to looking at the more complex rural settings for this study?

SHAFFER: We didn't at the time. We basically wanted to--the logistics were somewhat challenging already, and we wanted to focus on well-controlled data in well-defined settings, and we felt that we could do that rapidly in the urban settings. We thought that since we were looking at a biological issue of transmission that the results really would be generalizable to rural areas. The question you raise, which is a good one, is that the behavior patterns, the accessibility, and the level of healthcare might be very different in rural areas, and that would be something that was followed up on afterward. But in general, Thailand, while it was still considered a developing country, really had very, very good systems in place and had good maternal-child health systems. 00:41:00One of the nice things was that the obstetricians, the pediatricians, and the infectious disease doctors were really all interested in working on HIV together at the time.

MILLER: If I remember correctly, this was a placebo-controlled trial even after ACTG had shown sort of proof of principle. Can you talk a little bit about that? I know that there were concerns from an ethical standpoint of using a placebo at this stage in history.

SHAFFER: Yes. That certainly became a flashpoint. When we developed the protocol, there were really very little concerns raised about using a placebo, and the rationale was that we were really doing a very different intervention even though the ACTG study had shown (good) results. That intervention (the ACTG 00:42:00076 regimen) was not being used anywhere in Thailand and certainly anywhere in developing countries, and there was no proposal to use that. It just simply was not feasible, and the rationale behind using a placebo in the clinical trial was that we could look at the effect, the potential benefit of the short-course AZT in a very rapid, relatively small study and look to see whether it would have any benefit. And at that time, again going through the IRB [institutional review board], we really didn't know at all whether the short-course AZT that we were using, which was four weeks of AZT to the mother and during labor, would have a benefit. So, from the point of view of IRBs, there was felt to be equipoise 00:43:00about that. It was legitimately an open question. As the study continued, there were outside criticisms that were very heavy (difficult) leveled against us as investigators and leveled against CDC for doing a placebo-controlled trial. But I must say we did have a lot of discussions internally at CDC about it, and I certainly received a lot of support from CDC for this. Our studies (in Thailand and in Cote d'Ivoire) were designed to be finished relatively rapidly, and one of the benefits was that not only was this looking at a short course of AZT but it was a short study design, and again, because of the powerful diagnostic tools we could get (clear) end results very quickly in the baby. So, we were literally able to do the study from start to finish in about two years, and fortunately, 00:44:00we had very, very strong results showing that the short-course AZT was also effective in reducing the risk by about 50%. Once those results came out, the concerns and the criticism about placebo died out, lessened, and the focus of attention very rightly shifted from what was the proper study design to how could we implement that (this new, simplified regimen). One of the strong points about the study, again, which we did in conjunction with the Ministry of Health in Thailand, was that they said as part of the protocol that if the study were successful, that they would then implement the results and use this as the public health approach. So, it was not just an academic study on behalf of CDC, but it was really a very meaningful study for the Thai investigators and for the Thai Ministry and true to word, as soon as the results were published, then the 00:45:00Thai Ministry of Health focused on implementing that as a public health program.

MILLER: How was CDC received in Thailand during those years? What were the feelings, good or bad about CDC's presence in Thailand?

SHAFFER: I think CDC was very well received. We were literally on the Ministry of Health campus. We had a lot of interaction with the ministry people. There were one or two people from the ministry that were seconded to our office, and we collaborated on a lot of things. I think, as, in many countries, the Thai Ministry wanted to do things on their own. They didn't want to be overly reliant 00:46:00at all, but there had already been a training program, the FETP [Field Epidemiology Training Program], in Thailand, and there was a lot of comforts-- not only comfort but familiarity and interest in what CDC could bring. There was also an appreciation, particularly our CDC office had a very, very strong laboratory, and the laboratory did a lot of training in HIV for laboratorians in Thailand, so there was a real appreciation of the technological training and knowledge that that brought. So, I think CDC was very well respected within the ministry, and its role was appreciated, and I'm just reflecting that we worked primarily with the Ministry. We didn't necessarily work with other NGOs 00:47:00[non-governmental organizations] and UN organizations. I think that our primary focus and the appreciation was really set up as a collaboration with the Ministry of Health and that actually kind of anticipates an approach that the CDC took in terms of its later work with PEPFAR as well.

MILLER: So, CDC and the U.S. government overall had made fairly minimal efforts in addressing global AIDS prior to 1999 (apart from its international field station work). Then things began to change in late 1999. President Clinton launched the so-called LIFE Initiative--Leadership and Investment in Fighting an Epidemic, a U.S. government HIV/AIDS initiative where approximately $100 million was set aside for HIV, and then in 2002 President [George W.] Bush pledged a $500 million interagency initiative to prevent mother-to-child HIV transmission in Africa and the Caribbean. By this time, you were the team leader of the 00:48:00Prevention of mother-to-child HIV transmission team in the Global AIDS Program at CDC. Can you tell us a little bit about this initiative? This was the beginning of something very large that was coming to you and your colleagues.

SHAFFER: Yes. Thank you for the reminder of the sequence of those times because a lot was happening quickly. The LIFE Initiative which really gave support to the CDC Global AIDS effort included support for mother-to-child transmission and that clearly was part of the opportunity because of the Thai short-course AZT study, similar results which were obtained in Ivory Coast and elsewhere and the 00:49:00single-dose Nevirapine trials that were done soon after in Uganda. There was tremendous effort and interest in implementing practical, inexpensive interventions to interrupt mother-to-child transmission so clearly that was one of the opportunities for prophylaxis or treatment and intervention that could be done. Out of the LIFE Initiative, as you mentioned, the MTCT Initiative came, and if I remember right, that was a $500 million mandate specifically or opportunity to fund treatment interventions to interrupt transmission. And this came out of Washington. It came out of the White House. I don't know all of the politics involved, but I had the privilege of being basically one of the point people at CDC for that, and while I was doing my technical work, I was actually 00:50:00going up to Washington about every two weeks to meet with the people developing the MTCT Initiative. One of the key leaders in that, one of my liaisons in Washington, was [Dr.] Mark [R.] Dybul, who eventually became the head of PEPFAR and now is head of the Global Fund and I worked very closely with him on that. The concept was, and this was really a collaboration with the White House, NIH, other agencies in Washington and CDC to put together--I think there were several different levels. One was to develop an organizational level-- I should also mention USAID [United States Agency for International Development] was a very key part of this, the organizational level of what this MTCT Initiative was, and then how to implement it. And during this time very quickly, the idea was (developed) mandated that there would be "focus" countries. I think about 13 or 00:51:0015 focus countries in Africa, a few in the Caribbean that would be defined as the priority countries for the intervention, and we had to come up with how we would develop implementation plans and funding plans and partnerships to implement the program. It was an extremely exciting but extremely pressured time to focus on this, and we developed--I'm not sure if I should take--if it's good to take credit for this, but my colleagues and myself developed the infamous COP, the Country Operational Plan, for countries which has had many iterations since in the development of PEPFAR. But we basically developed the idea that there should be background statement for the country, in this case very specifically on mother-to-child transmission, what was the situation, what were 00:52:00the opportunities for interventions, what were the key interventions. Then what would be the roles of the different agencies and the funding plans on a year-by-year basis and we developed a rapid accountability to develop implementation plans with funding and then to evaluate on a yearly basis how we were doing and to do this in partnership with the ministry (ministries of health). This was done primarily very closely between CDC and USAID with a very small central office in Washington, and we got the program off the ground. There was a lot of support for it. It was very exciting, and then, after about a year and a half of doing this, the full PEPFAR was announced that was really 00:53:00comprehensive. It was no longer just MTCT, and MTCT would be a part of the much larger PEPFAR initiative, and so my role and our role in the PMTCT group was to lead that section of now a much larger PEPFAR effort.

MILLER: Can you shed some light on what the situation was on the ground in say many of these African countries in terms of mother-to-child service delivery and how are you going to get an AZT intervention at the end of pregnancy to patients? What were some of the challenges in trying to make that happen?

SHAFFER: There were a lot of challenges, but fortunately, there was a lot of 00:54:00interest in all of the priority (countries for) MTCT in PEPFAR countries. The challenges really go to the heart of how do you deliver an intervention in the MCH [Maternal Child Health] setting and add it on, so it really depends on the strength of the MCH setting. We talked before about how strong the MCH infrastructure was in Thailand, so it was relatively easy not only to do a study but relatively easy to roll out a very solid intervention on those structures. In the priority countries in Africa and in the Caribbean, but primarily in Africa, first of all, the prevalence was much, much higher. We're talking about pregnant women being infected at rates of anywhere from 4 or 5 percent to as 00:55:00high as 25 or 30 percent, so the numbers were just staggering in terms of the need. Many women came late to antenatal care. The structures in terms of organizing antenatal care were more limited, and one had to think through the whole sequence of how you implement an intervention. Starting from testing of mothers and having quality testing, having appropriate counseling, having the drugs on-site to give to the pregnant women, monitoring the women, and then following up the babies. So, each country presented different challenges and were at different stages, but all the countries were interested. We did a lot of our early work in Botswana which still is one of the most heavily affected 00:56:00countries and my first EIS officer in the PEPFAR program, [Dr.] Tracy [L.] Creek, really spent half of her time in Botswana and we worked to support her there, and she did a fantastic job of helping to put in place programs to scale up the PMTCT program. Botswana, while heavily infected (i.e., very high HIV burden, including among pregnant women), was very committed as a government to implementing programs and so we had a lot of support from them to do that.

MILLER: What is involved in scaling up services like that in terms of urban and rural infrastructure strengthening?

SHAFFER: I think it starts first from, and still very much does, from the central level in terms of commitment. There has to be political commitment and clear policies, and in all of these countries, the actual written policies, you 00:57:00can't just come in as an outside government agency or an NGO and say hey this is the "best practice." Countries rely on what are the policies of the Ministry of Health and the circulars and directives, so a lot of the background work was really working with the ministries of health to develop policies. And, again, starting from the building blocks of the program to implement routine testing of pregnant women, just as syphilis testing was recommended, just as hemoglobin testing was recommended, to implement HIV testing with appropriate counseling, with appropriate hopefully human rights safeguards and taking steps for non-stigmatization. Also, we, even back then, began to encourage partner testing for HIV. So, putting in place and putting the policies in place for testing, 00:58:00counseling, providing the drug, and follow up that was needed. I think, again, from an outside group coming in, part of our role both at CDC and some of our partner organizations were really to work to understand each country. I said that the countries were different, appreciate the strengths and weaknesses of different countries and how best to do the implementation in those countries. So, we spent a lot of time in hospitals and our partners that we were funding spent time working providing side by side technical assistance to understand how could the systems work, given the overall infrastructures, how could we 00:59:00integrate the HIV PMTCT interventions within existing infrastructures. Early on, we sponsored, CDC sponsored and developed a training curriculum that we rolled out too many, many countries, and held many training sessions and adapted those training curriculums to local countries and into local languages. That was a big effort once we had the policies in place. Again, our lab colleagues worked on the quality control on the lab side.

MILLER: So, at this time, the countries had developed their own in-country CDC offices, so Botswana had a CDC office. How was CDC perceived when PEPFAR started moving into countries in Africa setting up offices, taking a very on-the-ground 01:00:00role in implementing? How was CDC viewed as you were doing the beginning of this initiative?

SHAFFER: I had the opportunity and the privilege of really working with many, many program managers, and many ministry of health officials in different countries. I think in general our work was really very well appreciated and when I went to a country --the groundwork (was usually already very well) laid (out) by the CDC country office and the people living in the country. So that was a key part of things to have people on the ground. I think that there was always some issue which you always have in public health when people are flying in internationally for one- or two-weeks making recommendations and leaving that 01:01:00can be a bit problematic. But I think the fact that we had people in the CDC office that were there, followed up, knew the situation, that was a great strength. Our partners, particularly the Columbia MTCT Plus Program, the EGPAF [Elizabeth Glaser Pediatric AIDS Foundation] Program, and other implementing partners that we funded, also developed very quickly in-country offices so that they had credibility on the ground (as well as their technical credibility). I think the unique role that I've often reflected on, and I think it was part of the mandate that CDC had in terms of the partnerships of different agencies, was CDC always funded with a cooperative agreement directly to the ministries of health. So, part of that was capacity building and technical support to the ministry -- part of CDC's role was to support the ministry. There are some dangers in public health projects where you have NGOs that have a lot of money 01:02:00that develop beautiful demonstration projects that are not linked to the public health system, so I think in that regard CDC was well appreciated. There were concerns because --HIV had a lot of different overlays. I think that some countries like South Africa and Zimbabwe early on were uncomfortable with some aspects of the CDC role and, more importantly, with the world focus on those countries and expectations. There were early concerns that the HIV approaches that were being developed by so-called Western countries were not appropriate to South Africa, Zimbabwe, and that we were actually--and there were crazy theories 01:03:00that we were involved with spreading HIV, but I think that was pretty quickly overcome. So, I think in general, the PEPFAR program was very well accepted, CDC was recognized particularly (for) strengthening ministries of health and lab and CDC also was respected for its focus on data.

MILLER: Was cost a factor in getting AZT to the moms, or by this time was AZT relatively inexpensive?

SHAFFER: Both AZT or single-dose Nevirapine were used at the time, depending on different settings and what the capacity was. The cost had come down very, very quickly, so the cost was less of a factor in terms of the drugs. Really the cost 01:04:00was the infrastructure involved, and actually, if you looked at it, it was the testing and the follow-up-- those costs were more. So, the cost continued to come down in those early years and were less of a factor. Now, we focused on very short course interventions in the early days 2002 to 2003, but one of the big challenges in Africa, and we knew it then, was breastfeeding transmission, and we were not offering anything to intervene in terms of breastfeeding transmission. We also knew that while our strategy focused on giving a drug to mothers very late in pregnancy, if we didn't access those mothers until extremely late, that would be difficult, and there was also a risk of 01:05:00transmission earlier in the pregnancy, so maybe we should have more expanded interventions. WHO at the time began to be convening expert guidelines committees and reviews and there was a lot of research going on in those early 2000 years looking at interventions that could still be cost-effective, (relatively) cheap to implement, but would cover more of the risk period for mother-to-child transmission. So one of the challenges technically which was incredibly exciting but also challenging to keep up with was that there was new information literally every six months on what to do, so what we adopted as a simple standard of care was superseded by new guidelines coming out of WHO and more complex regimens, and literally every two years there was a new guideline from WHO. So, while this was exciting and very promising on paper, it required a 01:06:00lot of ongoing work to do retraining, to work with countries to develop (and update) their country guidelines, and to implement broader (and more effective) programs.

MILLER: Some of the countries, I know 80% or more of the population is rural. What was the approach to rural moms who might deliver at home or ideally have a Traditional Birth Attendant [TBA]?

SHAFFER: I remember with one of my colleagues from Côte d'Ivoire who had been a co-investigator on the short course AZT study in Côte d'Ivoire, we went out for a couple of days to a rural area in Ivory Coast. We met with Traditional Birth 01:07:00Attendants and tribal leaders in the community, and it was really an incredible experience just to talk, appreciate, what giving birth was like and what kind of care was like (in rural areas). To use the example of single-dose Nevirapine which is just a one-time pill at the time of labor and then another pill to the mother immediately postpartum and one dose to the baby, the idea was that, the proposal was that the Traditional Birth Attendants could carry this as part of their TBA kit and give this to the mother in a simplified form even if they were delivering at home. This seemed relatively simple, but I'm not sure whether this 01:08:00ever really worked out for a number of reasons. First, if the mother was in a rural area, she still needed to be tested first. You still needed to know who was HIV positive and who was negative. One of the issues was disclosure in these small rural communities, and maybe the TBA might've been a relative or certainly close to the chatter of the community-- how do you protect the confidentiality of a mother who is HIV positive to give this targeted intervention? The other is that in different communities, in different countries, the status of TBAs--there was a broad range of officially credentialed to not very official. Countries were also pushing towards having more facility deliveries, and there was a schism in terms of thinking about whether we should really endorse and promote more interventions through TBAs versus supporting facility-based deliveries. We 01:09:00put a lot of effort into that, and we provided guidance on a simple TBA pack, but I'm not sure that that ever worked out. But your question really points out that we really were--the situation in rural areas is very different than a large urban hospital. One of the underlying premises for the MTCT interventions was that the simplified intervention really could be scaled up and provided in rural areas and down to the health center level. You usually have provincial hospitals, district hospitals, small health centers, and even at the small health centers, there you would have assisted deliveries within a health clinic structure. Myself and my team and our colleagues in-country spent a lot of time 01:10:00going to different facilities at the health center level checking to see what was feasible, were the SOPs, Standard Operating Procedures, were they on the wall, were all the supplies in place, was the recordkeeping in place and was this feasible to do. And we felt that it really was, and it really was integrated clearly within the MCH structure and it was prioritized, and it was partly able to be prioritized because the prevalence was so high, again, between 5% and 25% of the women had HIV in Africa and so everyone recognized that this was one of the biggest health problems that had to be addressed for pregnant women.

MILLER: I remember seeing some of those health centers and was astounded--usually there were two staff there and what they could do in terms of 01:11:00doing HIV voluntary counseling and testing, and then treating. It was just astounding. In terms of the healthcare personnel needed to implement this initiative, was this a situation where you needed to scale down and do task shifting? Were nurses doing screening and treating? How was this managed from--and we know in many countries there was a shortage of healthcare workers, so how was that approached?

SHAFFER: Training, training, training, and always a need for more staff. I think in every country that we worked in, that was the biggest complaint and concern 01:12:00that was voiced. There weren't enough healthcare workers, and they were overburdened already. But I think, as I said, there was really a recognition that HIV had to be included and we tried to make things as simple as possible --you mentioned task-shifting, which is a big buzzword at WHO now and is strongly recommended. Nurses at different levels from midwives to public health nurses, nurses really did the bulk of care at community health centers, and also nurses did most of the attended deliveries even at many hospitals and the obstetricians played less of a role partly because they only did emergency and high-risk care and there weren't that many of them. So, the backbone of the 01:13:00health system really was the nurses. The nurses already were familiar and comfortable with drawing blood, so to introduce a rapid HIV test was not that big an issue to do. And then I think that they were very glad that they actually had an intervention that they could offer -- that was really a strong motivating factor and that they could begin to see the results. But one of the issues in terms of healthcare or the healthcare staff was that there was a tremendous drain on nurses and a constant turnover, and it was a very common situation to do training and then a year later to have entirely different staff at the clinics, and that was challenging. One of the pushes of PEPFAR was to get not only for MTCT but for all of HIV to have that be part of the curriculum for postgraduate training and in-service training but also in pre-service training 01:14:00to have HIV a clear part of nursing in the medical curriculum. Nurses knew that whatever job they were going to be doing, eventually, they would also be dealing with HIV, and I think all healthcare workers knew that. There was a special cadre that was developed early on of counselors, and there was a big push for that. I remember one anecdote--not an anecdote, but it even became a best practice for a while--[Dr. Thomas] Tom Kenyon was the CDC Country Director in Botswana, and as he was supporting the scale-up of PMTCT, he basically purchased portable cabins, I think 300 of them, to physically (provide the needed space at clinics)--because space was an issue and confidential space and comfortable space for a quick laboratory. So he was able to put (portable) cabins out at 01:15:00almost every health center in Botswana, which is a relatively small country, and to add the comfortable physical space for people to work and do the HIV part of the program and also to hire counselors to do HIV counseling because in the early days before counseling was kind of deemphasized, counseling was really a big part of the program, and there were high demands on it and that could quickly become a bottleneck or a barrier to effective care.

MILLER: You mentioned that PEPFAR we know was the interagency, multiagency project and USAID played a big role in PMTCT as well. How did you and CDC people interact with USAID in-country? How did that go?

SHAFFER: Well, that was part of my continuing education and learning to learn more about our different U.S. agencies and I didn't have really that much of an appreciation of USAID before and what their roles were, that were either similar or different from CDC but USAID certainly was always very strong in terms of funding support for maternal child health. They saw MTCT interventions as an important part of their portfolio, as well. We developed and were encouraged in the early days of PEPFAR to develop an interagency working group and I headed that for the PMTCT group and we had monthly calls with USAID and with HRSA 01:17:00[Health Resources and Services Administration] and NIH on the calls to coordinate from different headquarters leaders our strategy and to go over country-by-country what we were doing in terms of support, and we tried to have face-to-face meetings either once or twice a year. I think that was one of the--for me, it was really very nice in terms of meeting and getting outside of CDC and understanding and working with people coming from different agency backgrounds, different perspectives, and that was very helpful in understanding the strengths of different agencies. Then there was a mirror of that at the country level, and ideally, there were interagency working groups within key 01:18:00program areas, and those worked probably to varying degrees in different countries. I know that when I went to a country, I would always try to meet with both CDC and USAID even if they were doing different things and working in different parts of the country or having different partners, but it was very important to not just go as CDC working only with CDC. We began to work as PEPFAR and tried to make it one program and one "superagency". There were a lot of holes in that, there were a lot of breakdowns in that, there were different conflicts and agency agendas, but it really was--I think everyone really tried to make that work and I think the biggest issue was control over different budgets and how much money CDC would get versus USAID would get in specific 01:19:00countries and who would have control and how to coordinate that. I think there were several iterations of strategies that were way beyond my level in terms of deciding how to do that. But to come back to the point, when we went to the country, we felt like we had more partners and a more expansive view of things by working with USAID as well as CDC.

MILLER: Before we move to your WHO phase, things changed in terms of the approach to treating mothers and PMTCT in terms of getting more antiretrovirals [ARV] for right after delivery. Can you comment a little bit about that? As you 01:20:00were doing your initiative, there was a huge steamroller of getting ARVs to HIV-infected people all over Africa and then Asia, and sort of a big effort first looking at the most critically ill and then changing the guidelines in terms of at what CD4 count people would be eligible. How did that work in the MCH situation over time, and is it still probably continuing?

SHAFFER: Yes. That really is the crux of the issue. I mentioned before that there were rapid changes in the MTCT field in terms of interventions, and our Achilles Heel at the time was not being able to provide effective interventions during breastfeeding. We just didn't know whether ARVs were safe, would be well tolerated both for the mother and the baby. But at the same time, there (were 01:21:00rapid developments with) more research, more proof of the benefit of treatment, and more capacity in terms of testing, particularly around the CD4 count. So, from around 2004 to 2010, the emphasis was on identifying the most critically ill people who were felt both to need it (ARVs) for their own health but also, they would be likely to be the highest risk of transmitting HIV either heterosexually or in some other type of transmission or from mother to child. This was, again, one of the challenges and a great barrier --the premise was you needed to have a CD4 count. You either assessed the patient for signs of clinical AIDS or the appreciation was we really needed to not just wait until 01:22:00people had fulminant AIDS but to look at their immunological status and begin to treat them earlier on, so to do a CD4 count. And the guidelines were raised progressively from a CD4 count under 200 to 350 to 500 and for adults in general, and this applied also for women (including pregnant women). Now, at that time, the paradigm was in general that there would be special HIV treatment centers either at the hospital or freestanding. As I was saying, during the time from 2004 to 2010, there was really a push in terms of evidence that people should be treated earlier, and this was both in terms of evidence and capacity. 01:23:00There were concerns about the cost and how many people would-be put-on drugs and what the capacity was, but it was really an expectation that more and more people should be put on treatment.

So mothers, pregnant women with HIV were really a subset of this so we came to appreciate more and more that rather than our approach which had been on prophylaxis primarily for the benefit of trying to prevent an infection in the baby, that really maybe this could converge and mothers could and should have ART for their own health benefit and if they got their ART for their optimum health benefit, that in a sense would be the best prophylaxis as well and it would be a double win for their own health to prevent potentially horizontal transmission to a partner, and also to prevent infection to the baby. So, 01:24:00through 2010 which is just after I left CDC and went to WHO, we still had guidelines globally that were I think recommending (treatment with) a CD4 count under 500 and we still had separate guidelines for adults and special guidelines for pregnant women with HIV because of this tension or different approach between the optimal prophylaxis versus treatment. The underlying principal was that any mother that needed treatment for their own health should get it, and that would be their treatment and prophylaxis, otherwise to do an elegant and long prophylaxis intervention for the mother.

MILLER: I remember a lot of controversy over what I think was really cost-related, what priority should be given to the pregnant mothers in terms of 01:25:00full ART coverage. Can you tell us a little bit about that? I think that went on for a couple of years.

SHAFFER: Yeah. I think it was really a concern rather than controversy. I think that everyone, by this point, wanted to provide the best possible treatments, but there were two concerns. One was it really feasible in terms of the overall cost, and then the logistical cost. Again, we talked about providing interventions to pregnant mothers (during pregnancy and) at point of delivery as opposed to a special ART center, so that was an additional logistical challenge to think about that.

MILLER: Did that materialize? Was treatment then given at point of care in many settings (that were) sort of primitive MCH settings?

SHAFFER: Yes. That was really recognized by 2008, 2010 as really the optimal approach because pregnant women--it was just recognized over and over again, and understandably so, that pregnant women would in their late stages of pregnancy would not want to go to an ART clinic and then the internal medicine doctors or nurses dealing with HIV patients would not be comfortable with a pregnant woman in her 8th month of pregnancy coming (to the ART clinic), and the people in the waiting room wouldn't be comfortable. So, the ideal approach was to provide the ART in decentralized settings. But this also fortunately dovetailed with the idea that ART, as it became more available, would also be decentralized and it 01:27:00wouldn't necessarily be in the maternity but in smaller facilities -- it was unrealistic to expect them (pregnant mothers living with HIV) to be going back and forth to different clinics, sometimes over long distances. The other concern at the time, which was really still a significant concern and then continues to be with some of the drugs that we're using now as we change to newer drugs, is what is the safety of drugs? We could be fairly confident of their safety for adults on treatment, but for a pregnant woman and her newborn what was the added safety assessment of the safety profile of those drugs for pregnancy and that was an ongoing concern both in terms of Nevirapine, in terms of Efavirenz and other drugs.

MILLER: You mentioned in passing, stigma. Was that a major challenge with regard to getting pregnant women to agree to HIV testing, getting them on treatment, having to disclose their partners, and so on? So, we're covering a span here of 2003-2010 when things changed quite a bit, but can you mention that?

SHAFFER: Sure. We've always been very cognizant of that, but I think it's one thing to be intellectually cognizant and another to really appreciate the dynamics at the local level or at the country level. There are a lot of different issues, and I really can't pretend to be so familiar or characterize them, but we really were very concerned about stigma on one simple level, the 01:29:00issue of what was the attitude of healthcare workers towards patients, in this case, pregnant women who tested positive (for HIV). We might assume that healthcare workers would be very supportive of their patients but that isn't necessarily always the case, and there isn't the same level of communication and openness that we sometimes take for granted in our interaction with our healthcare providers in the U.S. So, one is what was the attitude of healthcare workers, and they did stigmatize their HIV-positive patients. There wouldn't be that kind of stigma in an ART clinic, which was dedicated to providing support, but in a more general setting where you had this special problem, that was an 01:30:00issue. Now, particularly, we were talking about this with small communities and traditional birth attendants, what is known about how is the community going to look at mothers that are HIV positive, and this, again, comes back to the breastfeeding issue. Breastfeeding is the norm-- it's very encouraged and is good for the health of the baby. (But) with our early guidance to avoid breastfeeding or to stop breastfeeding after a short period of time for HIV positive women in Africa that was difficult to do and potentially invited stigma because it just was an open signal that women who weren't breastfeeding probably had HIV and that was a concern.

Now, at the same time, I think because HIV (programs were) not just testing for HIV, but there was more and more treatment in general, and there wasn't just a 01:31:00program for pregnant women, but it was for coinfected patients with TB, it was for the general population. Over time I think HIV was becoming destigmatized or normalized in a general way, and there was true excitement that some real interventions and ART would be available, and I think more than anything that really helped destigmatize because there was something that could be done. One of the outstanding efforts in the MTCT field was the initiative that came out of South Africa that was called the Mother To Mother Program which was started by an NGO to enlist mothers that had gone through the PMTCT Program to then hire on with some small stipend to be advocates for patients and to work alongside the 01:32:00healthcare workers to basically buddy up with new HIV positive women coming through the PMTCT Program. The Mother to Mother Program was an adjunct to both kind of empower, give recognition and support to positive mothers who had gone through the program, were dealing with their own difficult circumstances, and recognize that they could then make a contribution to help others. That was a very exciting program and is still being used in many countries and part of the model of enlisting adjuncts or additional community people as part of the whole healthcare effort to respond to HIV.

MILLER: I want to leave a few minutes to talk about your work after you left CDC 01:33:00and moved to WHO in 2009. Can you tell us a little bit about your position there, and what were some of the key advances and changes in guidelines concerning PMTCT?

SHAFFER: Sure. While I was very enthusiastic about my work and the continued prospects at PEPFAR, I had an opportunity to go to WHO to be the PMTCT team leader there in Geneva, and I moved there in the middle of 2009. I had already been working closely with WHO on guidelines. I mentioned that there were guideline updates (nearly) every two years, and I appreciated the role that the guidelines played and the power of those guidelines in-country. It was one thing 01:34:00for CDC and PEPFAR to say here's our recommendation, but ultimately country ministries of health looked to the WHO guidelines to make their decisions and wanted to keep up with that. So, I saw there was an opportunity to have an impact in terms of guidelines, and there was excitement with that, so very briefly, there were two sets of guidelines that I was very involved with, the 2010 PMTCT guidelines and 2013-15 (comprehensive ART) guidelines. The 2010 guidelines were, in retrospect, the last guidelines that had separate mother guidelines and treatment guidelines.

(In 2010) We were still in the interplay between the two, and the guidelines were an advance forward in terms of expecting a higher level of intervention but they were ultimately I think confusing and also disappointing to people that 01:35:00really began to see that the only way that we could have better protocols for treatment would be to treat all people (with HIV, regardless of CD4 count or clinical condition). Again, this came back to the cost, the feasibility, the safety. We weren't really there yet with the evidence and all the support for it, but everyone began to anticipate that this is really where we were going and if we could really get to treating all people, including pregnant women, that would simplify the whole approach and also (include) pregnant mothers as just one subset of adults and all people living with HIV. So soon after our guidelines (for pregnant mothers) came out in 2010, we really began working on 01:36:00looking towards treating all, and again, avoiding the barriers of having to require a CD4 test or a viral load test before starting treatment because that was just a real limitation, and countries like Malawi took the initiative on their own. They really rejected the WHO 2010 guidelines and said, no, we're going to do something different, this is just not feasible for us, you have a nice guideline on paper but we are a very poor, resource-limited country, we cannot implement these guidelines as our standard of care, and they (Malawi) pioneered what came to be called the "B Plus" regimen for mother-to-child transmission where all pregnant mothers living with HIV would get lifelong treatment, and they would start that as early as possible in the pregnancy and they would continue during breastfeeding and continue breastfeeding and then 01:37:00transition to lifelong treatment. So, I worked very much with Malawi. We had interim guidelines in 2013 and then with a lot of support from PEPFAR, which also was very, very interested obviously in what the WHO guidelines were, and it was kind of a two-way--PEPFAR really was enthusiastic in pushing for treating all and on the other hand WHO needed to have assurance that the Global Fund and PEPFAR and other groups would really support the funding for treating all, and was that feasible, and PEPFAR also needed to make sure that if these guidelines came out, that the world did not expect that PEPFAR would support all of the treatment funding. But the most important thing was that the guidance itself be 01:38:00based on the evidence and the logistical feasibility. In 2015 the guideline at WHO came out that all adults should be treated with lifelong treatment as early as possible, including pregnant women, and this was part of what WHO called a Consolidated Guideline to bring everything together. I think that was a big step forward. So, it was an exciting time to be part of those guidelines. I was very, very glad to be there (and to be part of that process).

At the same time, just to add one more note, we began to think about a new concept of "EMTCT" or Elimination of mother-to-child transmission and so thinking back, we went from the very early years, many investigators and myself, simply looking at risk factors for MTCT [Mother-To-Child Transmission] and then 01:39:00we put the "P" in front of it PMTCT when we had some increasing opportunities for Prevention of Mother-To-Child Transmission. In some countries, they called that parent-to-child transmission rather than focusing only on the mother. But then we realized by around 2012, 2013 that some countries, even in high burden countries, already had very successful programs and were lowering the transmission rate down from a background rate of about 30, 35 percent down to around 5 percent or less and really had extremely successful programs, and were testing more than 95 percent of their pregnant women for HIV, were providing interventions and it was very exciting and actually CDC--I was no longer 01:40:00there--but CDC as part of PEPFAR was doing some early impact studies to demonstrate the actual measurable effect of this in terms of transmission and infections, not just relying on models but actually seeing infections prevented and infants who were clearly uninfected. So, we developed the concept of a framework for EMTCT that WHO is continuing to lead in countries. Currently, this applies mostly to countries that have lower prevalence, but as part of the framework for this, there's something called a "Path to Elimination" for the High Burden African Countries. It's not just waiting until you have a super successful program to get certified for that but that you have benchmarks along the way so that very high burden countries can be recognized for achieving certain milestones along the way on the path to elimination and it's both a 01:41:00galvanizing advocacy tool but really a recognition tool. One of my very proud moments as part of EMTCT, as part of this framework, and I'm still on the advisory committee for WHO for EMTCT, is that Thailand was the first country in Asia to be certified for EMTCT, so really rather remarkable from our (early) natural history studies and placebo-controlled (simplified intervention) studies in the middle of the 1990's and by 2016 or 2017 Thailand was fully certified as having eliminated mother-to-child transmission. Now, this is not eradication, but this is eliminating it (new infant infections) down to a very low-level public health program. And now Thailand, as true to their form, while they've 01:42:00clearly achieved the (WHO) benchmarks for EMTCT, they want to go further, and they're pushing the bar, and they expect in the next two years to show even more progress with this. So, this is something I'm continuing to work on (and to follow).

MILLER: What a great way to end. Thank you so much.

SHAFFER: Thank you very much.