A Global Health Paradigm for Defense, Development, and Diplomacy

Office of the Science and Technology Adviser
Dr. Maureen Goodenow
Washington, DC
February 28, 2013

 BILL COLGLAZIER: Well, good morning, everyone. Let me welcome you to another one of the Jefferson Science lectures. My name is Bill Colglazier, the Science and Technology Adviser to the Secretary. And one of the real fun parts of my job is being in my office of the steward for the Jefferson Science Fellowships which is almost a decade old. This year we have 12 Jefferson Science Fellows that at work at a number of areas of the Department. The Fellows are tenured academics at U.S. universities from a range of different disciplines. They come and work all over the Department and some also in USAID.

And earlier this week we just went through the interviews for next year’s class of fellows. They sort of come from August to August and we’re going to have 13 fellows next year and I think that’ll be a terrific group. But it’s a pleasure to introduce Maureen Goodenow, who’s going to speak to us today in an area of her expertise. The title of her talk is “HIV/AIDS Pandemic: A Global Health Paradigm for Defense, Development, and Diplomacy”. She is a -- this year, right now she’s a senior advisor in the EAP, the East-Asia Pacific Affairs office and she works on APEC, the Asia-Pacific Economic Cooperation activities and meetings.

In her regular job, at the University of Florida, she’s a professor of pathology, immunology, and laboratory medicine. She holds the Stephanie W. Holloway University Endowed Chair for AIDS research at the University and she’s also Director of the Florida Center for AIDS research. She has a long track record in research, more than 25 years of extramural research funding from NIH and foundations, currently focusing very much on the inflammation of technology such as high-throughput next generation genomics, bioinformatics, systems of biology, and applications to human immunity and pathogen interactions.

She got her PhD in molecular genetics from the Albert Einstein College of Medicine and she was a postdoctoral fellow at the Sloan Kettering Institute and she also spent time as a visiting scientist at the Pasteur Institute in Paris. So these are all premier places in medicine and especially working on the issues related to HIV and AIDS. So it’s, as I said, a great pleasure to have Maureen here. We look forward to your talk.

MAUREEN GOODENOW:  Thank you very much, Bill. That was a lovely introduction. I want to make a disclaimer. I have a slide of disclaimers that I was asked to present but I have to put another disclaimer on here because while I have done a lot of research in HIV/AIDS, it’s very much been from the molecular virology aspect and so I worry about being called an expert in this particular area and this is the reason why I’m here this year, so you can kind of see how I’ve progressed and where I have to go before I finish this first year of my fellowship.

The overview of the presentation is -- I’m going to give you a review of the HIV/AIDS pandemic and national security in the 21st century, which is the Defense piece. The impact of the development funds and biomedical advances on the trajectory of the pandemic and then the economic aspects of HIV/AIDS as a framework for expanded health care and the Asian Pacific during the 2013 Indonesia host year, and that’s sort of the diplomacy piece of the talk.

So, to put this into a framework, I think it’s important for us to look back at the beginning of the 21st century and say, what was the lay of the land and what was going on? And what happened in 2000, was that the UN Security Council, for the first time, addressed a health issue, which was HIV/AIDS as an issue of international security. That in 2001, the UN General Assembly convened a special session on HIV/AIDS, and the underlying premise here was that there was huge concern about HIV/AIDS affecting national security, not only international but within the United States. And this could be done or was worried to be done by destabilizing political and economic systems and weakening the military.

So, what was the lay of the land, in terms of HIV/AIDS, that led to these landmark discussions and institution of new policies in global health? Well, the first thing was, is that the estimated prevalence of HIV in Africa was a serious concern and what you can see here, prevalence is based on the percent of the people or percent of the adult population who were known to be HIV infected. HIV, just to clarify the terms a little bit, HIV is the virus, AIDS is the disease that the virus causes. Usually in the setting like this it’s called HIV/AIDS and we’re talking about infection and disease. But what you can see, for examples in Botswana, over one in three adults were infected by HIV and adults were considered -- the definition or the age range is about the age of 15 to about 40 or 45. And the numbers of countries that had one in five and one in ten but in local regions the infection, and in specific groups of people, the infection could be as high as five and ten, 50 percent of the adult population could be affected.

The social landscape was really scary and I think part -- a major contributor to looking at the implications of the epidemic and what I’m showing you here in blue are the estimated actual number, estimated numbers of infected people as opposed to prevalence in blue and what you can see, for example in South Africa, there were well over -- there were multiple millions, two million or more people infected. The problem and the outcome of the infection among the adults is that there were huge populations of orphans who were being generated as a result of parents dying and in many of the countries you can see that the number of orphans was equal to the number of infected individuals. And so the fear was whole generations of children growing up basically without any socialization or any kind of family cultural infrastructure.

And then finally, another big issue was the change in the life expectancy. This was really dramatic in countries, for example, like Botswana and South Africa, where the life expectancy in 1993 was well over 60 years, and in five years of the HIV/AIDS epidemic in these countries, the life expectancy dropped by 10 to 15 years.

Concomitant with all of these health issues and the global implications of them was looking at what was being spent at the time towards the end of the 20th century, what was being spent to deal with the problem and what is here, from the UNAIDS, is that as you can see in blue and purple is the amount of dollars in each of the countries that was being spent either by the national government or by international donors, which in most cases other than Uganda was a very small proportion of the amount of dollars that were being spent. In contrast, and for comparison, what you can see is what these countries were spending at the time on their military spending. So this was a serious problem.

So in the year 2000, when all of these -- attention at the UN and within the U.S. Government, the situation was, is that millions of people in Africa had infections or disease from HIV/AIDS. The prevalence was as high as 20 to 30 percent, and probably higher in some small pockets of populations. There was a significant decrease in lifespan, unprecedented number of orphans, and limited deployment of resources for HIV/AIDS. And so what I’d like to do now is put this into a perspective of how did this happen? How did we get to the beginning of the 21st century with this horrific pandemic and what could be done about it?

So HIV, in contrast to some of the British tabloids, was not a government agent that had been developed or was not some residual mid-1900 remnant of former political leaders. In fact, HIV originated by zoonosis. It means that the virus that now causes HIV/AIDS entered the human population from animals, from an animal transmission, and what you can see in this particular slide is a genealogy relationship among a whole bunch or a large number of different animal species that carry viruses that are similar to and linked to HIV in the human population. But what you can see in the upper part of the phylogenetic tree is that HIV is most-closely related to SIV.

So how did this happen? Well, actually it was not a matter of just a simple transmission from a single animal into the human population. In fact, the origins of HIV started with these non-human primates at the top of the slide, mangabeys and the mono monkey, these viruses were transmitted into chimpanzees and it was the chimpanzee virus that was transmitted into humans and basically established HIV-1M, which is the major group and the virus that is the most prevalent throughout the world. There were other transmissions into the human population. On the left you can see the chimpanzee virus went into another human and it’s called a small sub-group of HIV-N, and then there was another transmission from the chimpanzees into the gorilla; the gorilla transmission -- there was a transmission then of the gorilla virus into the human population. So this is a really complicated series of events and it’s very different from, for example, influenza where you get a transmission from the animal right into the human population.

Similar though to influenza, this virus had to adapt to its new host and it had to be able to set up transmission from human to human and because of the type of virus this is, it’s a lentivirus, it makes a lot of mistakes, it has a lot of mutations introduced into its genome and so there’s a lot of ways that the virus can adapt to a new host and then there can be positive selection for transmission among humans. So where did this happen? So it turns out that this particular group of chimpanzees -- there’s about four sub species of them -- or sub groups of them -- of these animals, but it was really the ones in red that were localized in this region in the western part of Africa, around Cameroon, Equatorial Guinea, and Gabon, where it’s been shown that the virus most likely entered the human population in that region. So while there are four different sub types of these kinds of chimpanzees, and two of them are known to carry these types of viruses, it was really just one of the particular -- one of the animals in the Trivolities group, that actually transmitted to humans.

So, really in fact the HIV pandemic is a result of a perfect storm. There’s a rare zoonote of transmission from primates to humans and this is estimated to have occurred in the early 20th century. HIV is a type of virus that mutates constantly so you’re able to sustain virus transmission between humans. The disease that it causes, the autoimmune deficiency disease that it causes, occurs years after infection. So it’s not like you get sick and you know right away that someone’s got the virus. You have this long period that can extend from five to 10 years in untreated individuals where you don’t really know that someone is sick. And that there are localized clusters of infection, the early localized clusters of infection, most likely spread by connectivity, urbanization, and conflict. And the first case that was actually described, the first human case of HIV, was described in the United States in 1983.

This map shows, sort of, an example of how the epidemic increased over time in Africa, starting in the upper left, in 1982 and what you really just need to look at is the development of color darker and darker over time to 2005. And what you can see is that, particularly on the East coast of Africa, there’s a whole section of prevalence that seemed to occur roughly at the same time and what I’ve put in the middle here, so that you can understand the connectivity issue, is a map of the major roads in the Trans-African highway system. And what you can see in red on that highway is a major connection along the East coast and what you can also see up on the West coast a major East-West connection on the West coast.

Because the virus changes so much, it’s possible to follow it and it has its own molecular fingerprint if you will and we can follow this. And it shows us that there’s multiple sub types of HIV that have initially emerged in different parts of the world or different parts of Africa, and by looking at these sub types you can see too that at the genetic level, a course along the East coast, you can see that the blue circles, which represent sub type C, are present almost along that East coast, which corresponds to the spur of the Trans-African highway in that region. Likewise, on the East-West corridor on the West coast you can see there’s a different collection of HIV sub types in that region.

The issue of sub types is really important because initially as I mentioned they were very localized. Most of the sub types represented by different colors appeared in Africa. The major sub types in Western Europe and in the Western hemisphere was sub type B in the 1980’s and 1990’s but if you look carefully, for example in the United States, you can see in that major population of sub type B, little slivers of other colors and that’s indicating in the United States, as elsewhere, other sub types are appearing mostly by people who travel or migrate into the country.

The other important point about this that I want to make is that in addition, if you can read carefully on the slide, you can see some of the -- on the legend side, initials called “CRF”. This stands for Circulating Recombinant Forms of HIV. So what’s happening is not only is the virus evolving naturally within people but if there’s co-infection there’s a possibility of two different sub types to recombine and basically generate a new sub type of virus and you can see by the colors, particularly in Africa, that a lot of these sub types, for example the yellow on the West coast there, is CRF-02, which is a major part of that epidemic there as a new recombinant form. So in many ways HIV is still an emerging pathogen. So the lay of the land globally was in the early 2000’s was, that there are about 33 million people infected and the major issue was, is that there was net infections of two to three million per year. So it was really a major problem in terms of not only the number of people infected but how the epidemic was increasing every year.

So what could be done? By 2000, there were really some good tools in the repertoire. One was, is that you could diagnose infection by the virus before the disease developed. The second thing is that there was an expanding repertoire of treatments that were available and it was already shown in a number of studies, both in the United States and Africa, that prevention and education could have an impact on the spread of the infection. And in fact one of the hallmark papers of a research project that was published in 1994 showed that AZT, or zidovudine, which was the first drug found to be effective against HIV, could reduce mother-to-child transmission by 67 percent and that was an amazing finding and really started the wheels rolling for a lot of clinical trials and implementation of treatment to prevent mother-to-child transmission.

But also what happened in 2003, as a result of the interest of the U.S. Government and the world in this problem, the U.S. Global Assistance for HIV/AIDS was established in 2003. So it was a very rapid time -- it was a period from 2000 to 2003 of a lot of activity and a lot of mobilization across around the world. And so PEPFAR was proposed, the President’s Emergency Plan for AIDS Research, and what was requested was $15 billion over five years. And in fact what happened Congress, in a bipartisan support in 2003, passed the U.S. Leadership Against HIV/AIDS Tuberculosis and Malaria Act and authorized $18 billion over five years.

So, what is PEPFAR? PEPFAR has done amazing amounts of activities worldwide and I think they really are a transforming factor in the whole epidemic and really in global health in general. PEPFAR has shifted the accountability from measuring the amounts of investment to actually measuring the results from the investment, how many new infections can you prevent, how many deaths do you prevent. And it also set up a unique interagency model which went across the U.S. Government and it also -- while I’m not going to talk about this, the interactions between the U.S. Government and PEPFAR and international agencies like the World Health Organization, UNAIDS, some of the private partners that came in like the Gates Foundation, there’s an amazing network and my reading of the -- sort of the history of this is that PEPFAR was really a catalyst in getting of this other activity going.

In fact, because of the success, and I’ll just show you some of the data on the next few slides, PEPFAR in 2008 was reauthorized for five additional years. The title’s changed a little bit. It’s now called the U.S. Global Leadership against these three diseases and Congress authorized $48 billion to study the three diseases over the period of 2008 to 2013 -- 2009 to 2013. So the goals for PEPFAR are to rapidly expand the international HIV services, to build clinical capacity, implement strategic information systems, build a coalition of partners, and develop sustainability. And so what exactly have they done? So what I’m going to show you now are a series of slides that look at the total global HIV infections and the scale on the left side is number of persons in millions. So you can see that between 1990 and 2000, the epidemic increased worldwide to about 35 million which I already showed you. New infections were somewhat leveling off at about three-and-a-half to four million five million a year by 2000 and the number of deaths was still increasing sharply. And as you can see it’s up to almost one-and-a-half to two million people. In the 10 years or this first 10 years of the 21st century what you can see is that HIV infections, for the first time, are leveling off. There is a decrease in new infections and there’s also a decrease in deaths. The issue is though that the number of new infections still exceeds the number of deaths. So this still means that the trajectory of the epidemic is expanding.

What PEPFAR has done is to implement, directly and with a large number of partners, aid programs across the globe and I’m just showing you this as sort of almost a shock and awe to show the extent of the engagement globally in health in this particular area and also just as a specific example what you can see in the graph below is that there’s a huge increase up 2011 in the number of adults and children who have been receiving antiretroviral therapy because of PEPFAR.

So while overall when you look at the global picture you can get one view of the epidemic. If you actually look at different regions you can see that there are subtle differences that are actually quite important. So for example on the left in sub-Saharan Africa, there’s definitely a decline in new infections but while there are far fewer people infected in the Asian Pacific region, what you can see is that there is what looks like it could be a disturbing increase in the trend of new infections. So what’s going on not only regionally but within certain components of the population within countries is really an important issue in terms of targeting what you want to do about the epidemic.

The Asian-Pacific region, as I said, there was a disturbing what could be a trend in increased infections and when you look at the color distribution of the changes of infection and this is prevalence, what you can see is, by 2011 there’s a lot more darker colors than there were in 1990. Some of this is due to reporting. For example, you can see China shows up in 2011 with a very low prevalence of infection whereas in 1990 they’re one of the gray countries, which meant there was no data. India we still have no data -- no good data on. So I think this is probably the picture in East Asia-Pacific region is underestimating the extent of infection and the epidemic. But in view of what’s going on in the East Asia Pacific, Bill mentioned that one of the major activities of the office that I’m in is facilitating the Asia Pacific Economic Cooperation or APEC. And this is a group of 21 economies that rim the Pacific and it actually includes North America, South America, and New Zealand, Australia, and countries along the Western rim of the Pacific and it does include Russia and China. Each year one of the economies is the host and this year in 2013 Indonesia is the host country and they have put on their agenda as a major portion of the health agenda for APEC is HIV/AIDS and this is the first time that it’s appeared in this particular venue. It’s not the first time for many of these countries or economies to be dealing with it because many of them are PEPFAR countries and they’re dealing with it through the World Health Organization or UNAIDS. That’s more from the humanitarian point of view. What the health ministers are trying to now show is that in collaboration and conjunction with the finance ministers that there’s an economic and fiscal benefit of healthy populations.

And this becomes important when you look at this representation of how international assistance is being distributed or is distributed across the world, and this again is from the UNAIDS report from 2012. The light gray are high end economies so they are not really included in this analysis and the dark gray, like China, India, and some of the other ones in the Middle East and Africa, there are no data available. But for those where there are data, what you can see is that there’s a range in the share of HIV care and treatment expenditures that international assistance is providing. So in the countries that are in the dark orange, mostly in central Africa and western Africa, they are receiving about 75 to 100 percent of their expenditures on HIV and care and treatment from international sources. But what you can see if you look down in the East Asia and the South Pacific region is that green here is Thailand and they’re only receiving about 25 percent of their expenditures from international sources. So you can see where even though the infection is limited or less dramatic in these regions, many of these economies are funding a lot of the activities themselves and so the economic impact in these regions can be really, really significant.

Looking ahead, the UNAIDS are looking back somewhat, UNAIDS reports show what the resources have been for low-middle income countries and what you can see here is that over the course of the last four to five years there’s been an increase from 42 percent to 51 percent in the red segment of the domestic either government and/or partnerships expenditures and the international component in the low-middle incomes has been diminishing. So there’s more attention being paid by these economies to this particular issue, but what you can see here is that in order to maintain and to make these kinds of changes in how the expenditures are made, the increase has been from 11.5 billion in 2007, an almost 50 percent increase by 2011.

Likewise, how the money is being spent has been changing, and this is a really important point. So the current expenditure is about 5.7 billion in a select group of 100 low-middle income countries and again this is UNAIDS 2012 data. What you can see on the left-hand panel is that the current expenses are about 5.7 billion and the right-hand panel the predicted needs to achieve the goals are almost double that, 10.7 billion. And how the money is being spent is -- there are shifts in the targeting of the populations and targeting how the money is being spent and this is really important because for example by shifting from four percent in the current year, the blue sector which is actually the popular or the greenish sector which is actually populations at higher risk, shifting from or increasing targeting that group from four percent to 16 percent has a dual consequence or a dual benefit and that is, you’re really targeting people who need it and you’re spending your money very, very wisely. So for example some of the considerations are that if you have a population say in Africa where male circumcision is very low and we know that that is a major factor that can reduce transmission, then you want to target and put resources into that type of prevention activity. In contrast, in some of the Muslim countries where circumcision is more common you might not want to put that much effort into that particular type of transmission but worry more if the population is in sex workers and in drug users, for example.

So knowing how the virus is being spread within sub-populations in a country and a region is really important information that guides then how you deploy your resources in a very targeted way. So one of the major breakthroughs in why treatment is so, is even more important than it has been, is this landmark study that was published just last year, it was called “Breakthrough of the Year” by Science Magazine, for the AAAS fellows here, and it basically showed that early HIV treatment prevents HIV transmission. And what they showed in this particular study was the reduced heterosexual transmission by 96 percent if you started treating infected people early, and following partners that were not HIV infected. This was a stunning result that in connection with the -- or in combination with the mother-to-child transmission has really put powerful tools and given us really strong scientific basis for policies that we should be treating, and treating early.

And it’s actually this type -- these types of breakthroughs that have led to the goal of having an AIDS-free generation and this is part of the PEPFAR Blueprint from 2012, the thinking is that the HIV pandemic is at a tipping point and that we should be able to look forward to an AIDS-free generation. So going forward, the clinical advantages of treatment are, not only do they reduce morbidity and disease progression, they reduce death and mortality, and now we know that it can reduce transmission, and that is it can reduce infections. And I was showing you different components of the pandemic, the fact that new infections were still going up was a major, major problem. So now we have some tools, some better tools, to treat, to prevent transmission, also there’s another whole component of treating to prevent infection. So in the case of HIV-negative people being exposed, there’s now evidence that if you treat, you can prevent them from getting infected if you treat them early enough.

There are clearly economic advantages to HIV treatment, in addition to what it does to the physical well-being of the people that receive the treatment, it’s now shown that it can actually prevent tuberculosis, it can decrease some types of cancers, for instance those that are caused by Kaposi Sarcoma virus, it definitely increases the lifespan. In the United States now the estimates are that HIV infection, if it’s treated, if it’s well treated, the lifespan of HIV infected people is virtually what it would be if they were not infected. It certainly prevents AIDS-related orphans, with all the social disruption that would accompany that, and it definitely has a positive effect on the economy, not only because people feel healthier, but it also drives a lot of industry and a lot of activity -- economic activity within the countries.

So what do we need to do long term? We still need a vaccine and we need a cure. So we need ways to protect people not infected, and we need to try to find ways that we can cure people who are, because there are still 30 to 40 million people worldwide. And without a cure, they are going to require lifelong treatments. There is progress towards a vaccine, in 2009, there was another landmark study in the New England Journal of Medicine about the ability of vaccination to prevent HIV infection. This was a really amazing trial that was put together by a huge consortium and coalition of partners. It took place in Thailand, in part because the Thai government and particularly the Thai military have been extremely active in this area, and there have been linkages with our own military, the NIH, and this a huge type of study. More than 16,000 people were enrolled in this study, and the result was that new infections were reduced by about 31 percent. Now this nowhere near as dramatic as what we saw with some of the drug therapies, but it’s the first positive result, and proof of principle that a vaccine should be possible.

But in addition to the vaccine and cure efforts that are now being targeted as major goals for research and clinical care, there’s other aspects of using the health infrastructure and capacity that was developed for HIV/AIDS as a framework for treating other diseases. And if you recall, both of the PEPFAR authorizations included not only HIV, but also tuberculosis and malaria. So these are definitely in and of themselves diseases that bring extensive morbidity and mortality, co-infections with TB and HIV are even more serious for both of the diseases than one of those infections alone, and certainly this type of framework that has been established virtually worldwide can be used for women and children’s health, for screening and treatment of cancer, also the non-communicable diseases like diabetes, cardiovascular and pulmonary diseases, as well as tropical diseases.

So instead of having a framework where only a single disease is targeted, to really start to integrate targeting all the health aspects of an individual, a family, a region, a country, the world. One of the things I think that we’re going to have to get over is “my disease is worse than your disease” and having different groups of researchers and physicians and politicians and diplomats trying to fight it out as opposed to which disease is worse and who should get the resources, we should start to look at this as being if we can -- if we have the set up to treat women and children’s health, and we’re looking at women and testing them for HIV, we may as well test them for HPV, human papillomavirus, at the same time because there’s a test, and there’s a vaccine, and there’s treatment. So it doesn’t, there’s really a lot of spill over and advantages in the investment that’s already been made in HIV/AIDS and the clinical infrastructure for it and now expanding that for other diseases.

And there’s another aspect of it that I’m going to close with this particular slide about health diplomacy. Peter Hotez is a colleague of mine, he’s the Dean at the new National School of Tropical Medicine at Baylor and Peter is an amazing person and he just had this article that I thought was really appropriate for ending the talk and that is, engaging a rising China through neglecting tropical diseases. And the thrust of this particular article is that the similarities between the United States, particular the southern United States, and regions of China not only economically, but also in the types of tropical diseases are present. Most people probably don’t think about it, but the United States has a big burden of tropical diseases, particular in the southern part, and it’s like I’m at a Florida university, so we’re probably more cognizant of that than researchers in the Midwest for example. So I think that the potential that’s that the future has a huge potential for building on what’s been done in just 10 years. And while I do research in “the bench” in the molecular neurology, I really had lost track of how much had been done worldwide. In a totally novel way, amazing innovation in terms of strategies and policies and it’s been really fun to do this, so thank you very much.

QUESTION:  If you have a question, do you have to go to the --

MAUREEN GOODENOW:  Yeah, you have to use the microphone.

QUESTION:  Yes, my question was simply whether since you talked about PEPFAR funding through ’13, what are the prospects beyond ’13 for PEPFAR and some of the things you’ve laid out?

MAUREEN GOODENOW:  Yeah, that is a very good question and I don’t have the answer and that’s one of my follow up areas of research. I don’t know if anyone is here from PEPFAR or from the Global AIDS Coordinator office, but it would be interesting to hear what they have to say.

QUESTION:  There are a lot of us here and thank you so much for your presentation. It was really nice to actually hear someone speak about the HIV epidemic from the background you have and to see our program -- which is the State Department’s program -- expressed in the manner that you did. For the individual that asked what happens after post-2013, PEPFAR’s expected to continue and we’ll wait to see what the Congress wants to do with regard to re-authorization. But the program is expected to continue.

The only comment I wanted to make was that there has been over these last three to four years enormous effort made to use these advancements in science that PEPFAR isn’t supporting in countries globally and the utility of health diplomacy in this space that the State Department has done quite a bit of, including opening the new office in health diplomacy, so I just wanted to just take a moment to say thank you and to let people know that there is so much more to learn about what the United States has done in this space and we’ve actually got some materials outside if people want to know a bit more about PEPFAR, so thank you.

MAUREEN GOODENOW:  Great, yeah, I was amazed as I got into the literature and was doing the background work for this just how vast the network is and the influence of the U.S. Government, State and USAID in this space, it’s amazing.

QUESTION:  Hi. I think everyone aggress that the evidence for the decreased transmission with early drug intervention is really impressive. I was just wondering if any work has been done to model or project the potential for increased drug resistance, and how that would affect that 96 percent number, if increased drug coverage would lead to drug resistance if it’s not used all the -- completely.

MAUREEN GOODENOW:  There’s always a danger because of the ability of this virus to mutate of developing drug resistance if therapy is not sufficient to keep the replication at very low levels. There’s certainly a lot of data out there that drug-resistant viruses develop and that they can be transmitted, but I think there are subtle differences in the viruses in the type of drug resistance and which classes of drugs the virus is resistant to. So for example protease inhibitor resistance doesn’t seem to be transmitted as easily as resistance to AZT, that class of reverse transcriptase inhibitors. So there may be a fitness disadvantage that prevents or diminishes transmission, but it’s definitely -- but if you start treatment early, and it’s effective, then you can keep the virus levels low, and I think it’s important to understand: undetectable virus by a clinical assay does not you are virus-free, it just means you don’t have enough to register in the assay.

So, but if you can keep the levels down below the level of the assay, you generally are suppressing rapid drug-resistance anyway. So it, it’s a problem, but I think in a benefit/risk analysis, the benefits far outweigh the limited amount of resistance that could be transmitted. The repertoire of drugs is pretty extensive now too and I think that resistance even to drugs in a certain class doesn’t necessarily carry resistance to all the drugs in that class and we have multiple classes of drugs now that not only attack the virus directly, but also protect cells from getting infected. So there’s really -- the repertoire of drugs and the combinations that can be used I think really give us a pretty big armament that can be effective.

QUESTION:  Hi, thank you very much for that talk. I was very interested in what you were showing about the lineage of the virus, and the transmission to humans from pantribadite, and it seemed like within the family of immunodeficiency virus, we’re talking about potentially a very ancient lineage across species. Could you talk a little bit about how long ago Group M may have made that zoonotic jump and also if you think that this truly was a, sort of a black swan sort of event, something that’s highly improbable but that unfolded or whether potentially this is something we should look out for in the future: new groups jumping from chimps to humans just based on -- you didn’t mention the hunter hypothesis but through those sorts of transmissions?

MAUREEN GOODENOW:  The epidemiological or the phylogenetic analysis data suggests that subtype M crossed into humans somewhere around the beginning of the 19th century, and there are confidence intervals, and there’s some disagreement among investigators on exactly when, but I think that’s a pretty good dating period. The other part of your question is dealing with “could this happen again?” And that’s an interesting question, and we talk about that. The complexity of this transmission, and as you alluded to how the transmission occurred, and the best working hypothesis is that it probably was a transmission during collecting bushmeat, so slaughtering of the animals, you know the virus, it’s a blood transmitted virus, and it got into humans. I don’t think what we see now, or even how it emerged, means that there were only four or five transmissions; there were only four or five cases that we know of where the virus was able to adapt and be transmitted from human to human. So there might very well have been other transmissions but because they weren’t successful from the point of view of being able to be transmitted, we don’t know how many times it occurred. So, could it occur again? Well, you never want to say never.

But given what we know about the mode of transmission, that we know a lot more about surveillance, and the idea of having isolated infections and isolated populations, I think is far less likely now than it was a 100 years ago. The level of connectivity and the level of surveillance worldwide is such that we find things much faster than we ever did before so I think the idea of anything like this recapitulating to this extent with this type of virus and this mode of transmission is unlikely. I think in some ways because we do have so much -- the surveillance globally for all types of disease and infections is so much better than it used to be that I think it really actually is a challenge how to figure out how do we find these rare events before they get to big, especially when you’re looking for something that you don’t know what it is, and by the time it comes out, you know, SARS is one example, but fortunately that was relatively contained and there was a huge and rapid response to that, so I think that’s a good indication that I don’t think that we’ll face something like this quite again. Yes, Bill.

BILL COLGLAZIER:  The Howard Hughes Medical Institute helped to fund a research institute in Durban, focused particularly on co-infections of HIV and TB, serious problem of drug-resistance to TB. I was curious if you had any comments about this problem co-infection, particularly with tuberculosis.

MAUREEN GOODENOW:  There’s definitely significant evidence that having both of these infections simultaneously is a bad outcome for both of the diseases. I think they have some common target cells, for example most people think HIV infects, you know it infects the lymphocytes, that’s a particular class of your blood cells. It also infects another class of immune cells called macrophages, and these actually are the targets for TB. So TB actually infects macrophages in the lungs, so I think that the fact that there’s a common target cell could be a part of the explanation for the exacerbation of the clinical outcomes when you have both infections.

I think that the issue of drug resistance, particularly multi-drug resistance in TB is far more serious than the drug resistance -- whatever drug resistance problems we have with HIV. And I think that there issues in terms of potential drug interactions with the drugs you treat for HIV versus the drugs that you use to treat with tuberculosis, and I know there’s been research done and I don’t actually don’t know what the final outcomes are in terms of what the recommended protocols right now, but I think even for a while there was some tendency to think that you should not treat the HIV but treat the TB first, and there’s a lot of complications in terms of that. That’s why I think that it’s good that the triple approach that PEPFAR was originally mandated or authorized to do is now being expanded and there’s a huge effort, not only at the clinical side, but also at the NIH side, in terms of funding research. There’s a lot of incentives for scientists to start to look at the problem beyond their own particular infectious agent and try to get together and look at it as a more common problem, from a more integrated point of few.

QUESTION:  Let’s thank Maureen for a good talk.