MALE SPEAKER 1: Good morning, ladies and gentlemen. Welcome again to the Plenary sessions of the 14th International AIDS Conference. This morning, we have the honor and the big privilege that the plenary sessions are going to be chaired by Edwin Cameron. Edwin Cameron is a judge of the Supreme Court of Appeals in South Africa. He’s a person living with HIV and AIDS, and he’s been involved in the fight for the respect of the human rights, and also involved in issues related with AIDS. In Durban two years ago, he delivered the first Jonathan Mann Memorial Lecture, and he is a very good (MS?) from Durban to Barcelona. Judge Cameron?
[applause]
EDWIN CAMERON: Ladies and gentlemen, good morning. How are you? Well, I think that your antilliousness this morning is going to be rewarded. We have an excellent session for you, in terms of both content and the distinction and stature of our speakers. The title is “HIV Treatment and Care in the New Century.” We have some of the world’s foremost clinicians and basic scientists and researchers, people at the forefront of this field. We also have an activist voice from Africa, whom I’ll be introducing in a moment. So, an important session, and one in which I hope we will have your participation.
It’s my pleasure to introduce our first speaker, who is Professor Michael Saag, who is Director of the University of Alabama AIDS Outpatient Clinic in Birmingham, Alabama. He’s also the Associate Director of Clinical Care and Therapeutics at the University of Alabama AIDS Center. Professor Saag has published extensively in medical journals and books on the subject of basic science of HIV and clinical treatment of HIV. He’s extensively involved in AIDS treatment and policy, and his presentation is titled “Current Controversies in Antiretroviral Therapy.” It’s my pleasure to introduce him.
[applause]
MICHAEL SAAG: Thank you very much. It’s an honor to be here. I’d like to thank the organizing committee for inviting me to speak. My topic today is controversies in HIV care, specifically with regard to antiretroviral management. A lot of these controversies have been addressed in different sets of guidelines published from the HHS in the United States to WHO, but coming out in today’s Journals of the American Medical Association, there are guidelines coming out from the International AIDS Society USA – updated guidelines – and I’m going to base a lot of my comments today on what these new guidelines have to say. This is an international panel that was convened first in 1996 and has been updating the guidelines ever since. The topics that I’m going to focus on in the time that I have with you today are issues surrounding when to start therapy, what to start, when and how to change therapy, therapeutic interruptions – treatment interruptions – and, ultimately, what are the benefits of therapy. I’m going to try to make this a global commentary.
Let’s start with when to start. The answer has been, very quickly, when the patient’s ready. It almost doesn’t matter what the clinical status is of the patient; what matters is that the patient is ready to commit to therapy. But it seems to me that over the last three or four years, it also matters when the provider is ready, when the provider is confident that this is the right time. What we’ve been dealing with over the last several years is what CD4 count should we start with? It’s been a mystery; it’s been a moving target. And for a lot of people who are either new to the field or have not really been keeping up with the history, what I thought I would do for you today is review a little bit of the biology and how the biology has evolved, and our improved understanding has related to these changing recommendations about when to start therapy.
What you can see in this diagram is the life cycle of HIV. At the top, the HIV-infected cells produce viral progeny, the red virions, that come down and infect the light blue cells, which are the uninfected, activated CD4 lymphocytes. The darker pool of cells just below that are the uninfected, unactivated cells that are really not easily infected in vivo or in vitro. So it’s really the activated cells that are the strongest target, and these cells then come up and are infected and start producing new viral progeny. Off to the upper right-hand side, in the light blue, are the latently infected CD4 lymphocytes that Dr. Fauci is going to talk more about in his talk. But the concept that we had back in 1996, with the treat early, treat hard concept, was that we would give antiretroviral therapy and block the infection long enough such that those HIV-infected cells would die off and not be replaced by infection of new cells. Over time, that would eliminate that population of cells, and those cells in the upper right-hand corner, those latently infected cells, if we could block long enough, we would have elimination of those cells as well.
The concept in 1996 was that the cells that were HIV-infected and producing virus live on average of one to two days, and the latently infected cell was estimated to live about 14 to 21 days. So the concept was, if we could block 100 percent with antiretroviral therapy, the latently infected cells [break] and we could have eradication or cure. The problem is, over the last several years, those latently infected cells have been found to live not 14 days, but on the average of a minimum of six months, and, as Dr. Silicano described, perhaps as long as 44 months, on average – meaning that it would take 60 years of continuous antiretroviral therapy to eradicate. So, back in 1996 when we thought the possibility of eradication was a reality that we could achieve, the concept, of course, was to treat early and treat hard. But now the concept – especially with some of the metabolic complications of therapy that have come along – the concept is to wait a little while.
The other issue that I think is important to understand as we think about therapeutics is, how do these cells die? As they are eliminated, what happens is, you get a drop in viral loads. So, in essence, what happens is you block the infection of new cells with antiretroviral therapy, the HIV-infected cells that are producing virus die off rapidly, and you get a precipitous drop in viral replication as measured by viral load. If we look carefully at the microenvironment inside the lymph nodes and lymphatic tissue, what you see here is an infected cell producing virus in an environment of mostly unactivated cells around it. So, those yellow cells that are in the neighborhood are really not good targets for the virus. So, in essence, this cell sits there producing billions of virions in the course of its lifespan, but really, at steady state, it’s only infecting one cell to take its place at the time it dies in one to two days. And the way that could happen is that, a number of the viruses that are produced might not be infectious, and, also, it’s waiting for the moment when another activated cell happens by, and then it’s able to have this one specific virus come in, infect that cell, and at the time that cell gets infected, the original producing cell – at least at steady state – dies off, and the viral load therefore remains constant. The critical point here is that viral load is really a reflection of the number of infected cells in the body producing viruses, demonstrated on the last slide, where, if you block the infection of new cells, the infected cells die off. They’re not replaced, and the viral load drops. So the number of virions in the bloodstream that we measure with viral load is a direct reflection of the number of cells in the body that are producing virus. And that concept is critical.
What happens with antiretroviral therapy? In essence, when that uninfected, activated cell comes by, it’s protected. It has, in essence, a force field around it, if you want to think about it that way, and those virions are not able to infect. Therefore, as that middle cell dies off, it’s not replaced and the viral load drops. The take-home point here, with regard to starting therapy, is that when we start we want to make sure that the protection of that uninfected cell is strong enough, that we have enough potency – hence, the term “treat hard.” At least treat hard enough to give this cell a chance to avoid infection. The other take-home point is that resistance happens when the viruses – perhaps by chance – have mutated in the course of production and are able to penetrate that protection and then begin to infect those cells and, once infectious progeny is developed, it starts reproducing viruses that have resistance mutations, and therapy fails. So this is the concept of “treat hard.”
What about the concepts of “treating early”? Well, in the cure paradigm, treating early was based on the concept of having the possibility of eradication, combined with these data that were presented by John Mellers (MS?) and colleagues from the Max cohort. And the take-home point here is – and you’ll notice these numbers look familiar, because the CD4 count strata that were evaluated in this long-term cohort study shows that the natural progression to AIDS really was involved with CD4 counts that were lower, but also viral loads that were in the 50,000 range. The problem is, this comes from a cohort of patients who were mostly not treated. So this is a natural history of untreated patients. But when you treat, the viral load drops off dramatically, and therefore, this concept of viral load is not as germane today, as we start therapy. So, using viral load as an initiation and concept is really falling by the wayside. In the new guidelines, the concept is to focus on CD4 count, and not focus so much on viral load but, rather, use the viral load to determine how often you check the CD4 count so you’re able to identify those rapidly progressing patients.
Well, what about, when is too late? These data from our cohort of patients at UAV shows that, among patients who started therapy for the first time in the HAART (MS?) era, they demonstrate that waiting until 200 cells is too late. What I’m showing you here is actual survival. You can see that by two years – as shown by Hogg et al. data from Vancouver, as well as yesterday that was demonstrated by Matias Egger (MS?) – you can see that the majority of patients that have CD4 counts in the higher ranges are alive two to four years after starting at above 200, but those who are less than 200, by four years, in our cohort, up to 35 percent of them had died. So what I can say, for sure, is that waiting until a CD4 count is less than 200 is too late. We need to start earlier. How much earlier is not entirely clear but, certainly, if we’re going to say 200 is the cut point, that’s really too late. And that’s true all over the world, both in resource-rich and resource-poor countries. So every patient, ideally, who has a CD4 count less than 200, should be on retroviral therapy.
A problem, even in our city – in Birmingham, Alabama, in the U.S. – what we’ve found is that, despite having the resources that we could treat, that the majority of patients in that cohort that I just showed you are showing up in our clinic in the year 2000 with an average CD4 count of 100 cells. That means, as a global community, we need to identify patients that are infected, get them into treatment early, so that we can have some benefit. Because in our population of patients, where I treat patients, the question of when to start is almost moot, because the number of patients showing up are showing up later.
On the other side, there’s a study that was recently published from Dr. Opervill (MS?) et al., that showed that in a cohort of patients who were studied in Switzerland, that the individuals who started treatment with a higher CD4 count actually had fewer AIDS-defining events and had less deaths, in terms of natural deaths – that is not deaths due to suicide or accidents. So there are data that suggest, as the guidelines have now recommended, to initiate therapy around a CD4 count of 350 in asymptomatic patients, and, for symptomatic patients, at any time they present.
So now, what to start? That’s the more difficult question, because there are fewer data to help us. In general, what I would say to do is focus on the durability. Again, going back to the cohort just to be consistent with you – of the patients that I just described – we looked at the durability in the first regimen and found it to be 1.6 years among people who started their first regimen. What that means is that half the patients then, by definition, have not even made it to two years on their first regimen. Most of them in the early stages had dropped off of their first regimen because of toxicity, and, in later stages, because of problems with viral load rebound. Tomorrow, there’s going to be a presentation of A60-G384 – I refer you to that late breaker session – but, in essence, what they’re evaluating, for the first time, is a strategy concept of starting with different nucleocide regimens or non-nukes or protease inhibitors and moving forward to defining not only end points, but, as one therapy fails, how salvageable is it for other therapies? I think what we can say, for sure, is that what to start with – it cannot be prescribed as a single best regimen, but, rather, as the guidelines are now recommending, need to be tailored to individual patients.
What about when and how to change therapy? A lot of that depends on what the definition of failure is. In essence, in a first treatment situation, we would define this as a success, so that any viral replication at all, in the face of 16 to 24 weeks of treatment, we would define as virologic failure. Therefore, when that happens, when you have virologic failure early, you want to intervene right away and treat aggressively so that you don’t give the chance of resistance to happen. In later stage patients who have been through multiple regimens, then failure becomes not so much a prevention of resistance, which was the first goal of therapy; rather, our goals of therapy at that point become the prevention of CD4 count decline. We’ve found that if you can keep the viral load around threefold or .5 loss below baseline, that the decay in CD4 counts rarely, if ever, happens. The bottom line here is, how you manage failure is really dependent on the individual patient, and treatment failure must be managed individually and be tailored to their regimens. These, again, are placed in the guidelines.
Moving on to treatment interruptions, this is something that’s been talked about at a lot of conferences over the last several years. What I can tell you is that as many different reasons to do treatment interruptions – be it immunologic stimulation or perhaps saving resources or avoiding toxicity – but in the case of the failure situation, of patients who have virologic failure, in that situation the concept was to take a patient that was multi-drug resistant, and stop therapy and allow the virus to revert back to wild type. In that situation, as Steve Deke (MS?) showed very nicely in his studies, you have a conversion to wild type in about eight to ten weeks. This was originally shown by Veronica Miller and her group, and then these data from Steve Deke, published in the New England Journal of Medicine, demonstrate clearly that, at the time that conversion from resistance to wild type occurs, there’s a precipitous drop – that’s the center line there in each of these sections – in CD4 count, and that’s why people are concerned about treatment interruptions in this setting. Is it something we should be using in practice? My answer would be “not yet.” And, indeed, the guidelines also say that this is something that should await further data. There’s an ACTG study – 5086 – that is now up and running and that will address this issue very nicely.
Well, let me finish my talk focusing on the benefits of therapy, because this is what it really is all about. How does what we do in treatment of patients make a difference? We have a lot of data now – at least in the United States and in Europe – that shows that treatment is associated with improved outcomes dramatically, especially in terms of survival. And these data are shown from the U.S. Public Health Service. The question is: How has this benefit been derived? There’s a recent study out of the New York City Health Department that has looked at the causes of death over the course of two years, the beginning era of the AIDS epidemic and then the treatment era. What they’re able to show, in the top part of this slide, is those patients who, in the early stages – that’s the lower line of survival, the patients who did worse from 1990 to 1995, who had pneumocystis pneumonia – that their deaths were much more rapid than in the treatment era, where the majority of patients are still alive some five years after being diagnosed with PCP, and the same benefit with Kaposi’s Sarcoma. The reason that these are important is because, just by looking at these two examples, we can see that it’s not just the treatment of the (MS?) that’s made a difference. It’s clearly associated with antiretroviral therapy, and, as I’ve demonstrated to you before, starting therapy before the CD4 counts get too low is critical.
But what about the cost of therapy? What I’m going to share with you today, for the first time, is a cost analysis based on actual utilization in a clinical setting – again, going back to our patient base in Birmingham. What we were able to do is a cost-outcomes analysis over the course of several years, but I’m going to show you the year from 2000-2001. In all patients who were receiving their primary care, we were able to capture all encounters with our health care system – that means everything they did: surgeries, procedures, clinic visits, hospitalizations – and we also captured every medicine they were on, including start and stop dates. We were able to assign costs via Medicare reimbursement rates, so we assumed that everyone had Medicare, and whatever Medicare in the U.S. would reimburse, and we assigned medication costs based on average wholesale price. Out of our 700 or so patients who were followed for the course of that year, we excluded patients who died during the year, so discount what I’m telling you, because we do not include in the advanced patient group those patients who died. You should probably estimate up the cost to patients who had advanced disease. At any rate, these are the demographics, I think they speak for themselves. Notice that 86 percent are on ART, and most of the patients are doing quite well with viral loads of around 1000 or so, and CD4 counts in the 300s.
These are the data we were able to derive. The mean annual cost overall for patients was about $18,000 per patient per year. But, as you can see here, when you break it down by CD4 count category, there is about $34,000 per year for those with advanced disease, compared to around $13-14,000 per year for those with CD4 counts greater than 350 and gradations in between. This is really striking in terms of showing a direct cost:benefit of keeping patients healthy. Again, remember, the less than 50 group do not include those who died within the year.
When we look at the annual cost by component, another very striking thing becomes apparent. Over 85 percent of the cost, no matter where the patient was in their stage of disease, is owed to antiretroviral medicine and non-antiretroviral medicine. So the driving force of cost, in the United States, of care is medication cost. You’ll notice that hospitalization is really just a fraction of the overall cost. But notice, on the far right hand side – and I’m trying not to whine here – the clinic costs are only $300 to $400 per year, and that’s assuming that Medicare reimburses for every patient. In our population, we have 35 percent indigent care, so we’re probably getting on average about $200 per patient per year to do what we do. The obvious take-home point is: we cannot stay in business at that sort of rate. When we break it down by cost category, what’s interesting is you say, what’s the benefit of spending the money on medicines? The take-home point it, those patients who got better in the course of the year – we divided it up at six months, and at six months we said are they better, are they not better (in terms of a CD4 count strata) – those who got better had significantly lower costs. Those who got worse had significantly more costs, and if we break it down in terms of individual components, what we’re able to see is that it’s really, in the advanced patients, the non-antiretroviral therapy costs that go up, that contribute to most of that cost differential, as you would imagine. That is, as people get sick (MS?), the hospital costs go up some, but the antiretroviral therapy costs stay the same. So, in conclusion, the cost of care in the United States is directly related to stage of disease. And I would argue around the world that’s going to be the case as well. Medication is the prime cost driver; non-ART costs and hospitalization costs increase with advanced disease; disease improvement is associated with significant decreasing costs; clinic reimbursements are insufficient to sustain operations at any clinic; and you’re seeing private practice physicians in the United States not able to continue to practice any more because of that. In essence, government support in the United States – and I would argue, around the world – is essential, because we are having our cost of care subsidized by Ryan White programs and other government programs, and we would not be able to keep our doors open were it not for that. So as we think about putting care into the resource-poor countries, we should keep in mind that the infrastructure investment has to be there. We should not ignore that fact or be deterred by the data that’s shown here about cost of medicines. It’s not that simple, and we need to move forward.
I’d like to acknowledge my colleagues at UAV who have worked on this, in particular: Ray Chin, Stephanie Call, Andy Westphall, Gretchen Cloud, and others. I’d also like to acknowledge GlaxoSmithKline, particularly Sissy Palm (MS?) who, in 1996, encouraged us to go in this direction, to collect these cost data. I’d like to thank the National Institutes of Health for sponsoring us through our CIFAR grant, the Mary Fisher Care Fund at UAV that’s helped us get this work done, and the colleagues who worked on the guidelines with us at the International AIDS Society USA. Thank you very much.
[applause]
EDWIN CAMERON: Many thanks, Dr. Saag, for a most informative talk. And Dr. Saag’s talk provides, I think, a somber and very appropriate setting for the next plenary speech at this conference. The first conference that I intended of the International AIDS Conferences was in Amsterdam in 1992. I then attended the conference in Berlin in 1993. And one of the features of those conferences – and those who’ve been at more conferences than I’ve been will know this – they were characterized by the presence of angry people. People who were angry with the scientists, angry with the governments, angry with their organizations, angry with the conference itself, angry with themselves, that not enough was being done. Not enough was being done by anyone. And many of those voices of anger were people who were themselves dying of AIDS. And that, I think, is one of the things that we are missing from this conference. We are missing the voices of the tens of millions of people who are dying of AIDS.
[applause]
Those of us who are here, who have AIDS, like myself, are living because of the sort of clinician that Dr. Saag is. We’re living because we’ve received antiretroviral treatment. There has been anger at this conference. At the opening, the Spanish Health Minister received the brunt of that anger. And yesterday, I believe that at a senior lecture, United States Secretary of Health, Tommy Thompson, received anger as well.
[applause]
I don’t want to involve myself in the domestic politics of either Spain or the United States – I think South Africans, who want to speak to their health ministers, know where to go. But are we sufficiently angry? The poor people of the world, who are not on treatment, are not at this conference. But there is someone who’s going to speak to us, and he’s a person who’s ill. And that is why he isn’t here this morning. His name is Zackie Achmat. He’s an activist whose commitment to justice goes back to the apartheid struggle, which he joined as a young teenager in Capetown. He was imprisoned, arrested and detained by the apartheid police, and kept in jail. But the struggle for justice that Zackie committed himself to in apartheid South Africa has not ceased. His commitment as a gay man to equality for gays and lesbians, and, now, his commitment to treatment access for everyone with AIDS everywhere in the world. He was due to have been here this morning, and he couldn’t travel because he has a lung infection, a bacterial viral infection which is, fortunately, not yet AIDS-defining. But he has prepared a video for us. On the video you will see something of the visionary leadership that Zackie has produced. You will also see his courage. And you will now see the video. Thank you.
[applause]
ZACKIE ACHMAT: Good morning. I’m really sorry not to be able to be with you today. However, when we last met, in Durban, we had hope, and we had ideals about HIV treatment. Today we have thanks. In (MS?), outside Capetown, Medicins sans Frontieres – Doctors without Borders – have illustrated that people with HIV and AIDS, a majority with long existent or severely damaged immune systems, could recover life, health, and dignity with antiretroviral therapy. The majority of its patients, who started antiretroviral therapy at primary health care level, had fewer than 48 CD4 counts, and viral loads greater than 170,000 (MS?). Over a six-month period, the majority of them – over 90 percent – achieved undetectable viral loads and, more importantly, were able to reconstitute their immune systems. This followed up on the success of (MS?) and the people of Haiti. So today when we speak to you of antiretroviral therapy access in poor countries, we speak not only with arguments, not only with hopes, not only with desperation, but, actually, with facts and the lives of people themselves.
The global community decided to campaign for affordable medicines and antiretroviral access in poor countries and communities in the wake of the Durban 2000 conference. That campaign has given many of us the hope and the will to survive. There are many successes and challenges that our movement globally has achieved over the last few years. I want to highlight some of these successes and challenges.
In the constitutional court judgment on the issue of mother to child HIV prevention, the court quotes the South African government assessment of HIV and AIDS as an “incomprehensible calamity.” Although the facts and arguments I will use are rooted in South African realities, in many instances the arguments elsewhere are similar or they can be used to illustrate the differences. In its annual budgetary reports to the Finance Ministry, the Department of Health stated, last September, “South African models of likely mortality from HIV/AIDS predict that cumulative deaths will almost likely reach between 3.4 and 4.5 million by 2010, in the absence of significant breakthroughs in preventative or curative technologies in the near future.” The Department went on to then look at the impact of HIV disease already upon our overstretched and overburdened health care system, and said the largest single impact of HIV/AIDS on the public health sector lies in the hospital sector. Research commissioned by the Department of Health indicates that in the year 2000 an estimated 628,000 admissions to public hospitals were for AIDS-related illnesses, which amounts to 24 percent of all public hospital admissions. Modeling indicates very clearly that as more people who are already HIV positive become sick every year, this demand for hospitalization will increase steadily every year in the absence of significant alternative interventions. We would like to ask: What are these interventions?
The Department shows that, in financial terms, the cost of hospitalizing AIDS patients in public facilities is already likely to be at least 3.6 billion rand in the current financial year, or 12.5 percent of our total public health care budget. This cost to the public health care system is about treating people without an effective program of treating opportunistic infections without an effective program of using protocols and without any antiretroviral therapy interventions. To us this is not only a matter of the cost to the state and so on, but the lives of mothers, the lives of women, the lives of children, the lives of men, all of us in productive years, many of us not yet having reached the prime of our lives.
Central to all our work on HIV prevention and treatment are the issues of life, dignity, and access to health care. HIV prevention and treatment cannot be separated. The impact of HIV and AIDS will reap on already infected people, on the public health care system, the health care system itself will buckle under the burden of disease, and therefore not to treat HIV effectively will destroy the already weakened health care systems in poor countries. And therefore, just from a purely public health care perspective, it is shortsighted to say that we should focus on prevention and exclude treatment. On the other hand, it is unconscionable because what we are speaking of are current statistics, and not our lives. Our lives matter. The 5 million people in South Africa with HIV matter. And the millions of people throughout the world who are already infected with HIV, their lives matter.
And, so, it is not simply a question of the cold statistics that we’re putting to you, but a question of valuing every person’s life equally. Just because we are poor, just because we are black, just because we live environments and in continents that are far from you, does not mean that our lives should be valued any less. It is critical that every treatment activist also becomes a prevention activist. Active prevention of mother to child transmission, assisting rape survivors, all these issues, and, above all, the use of condoms – condoms, condoms, by everyone who’s positive, make it clear that everyone with HIV should use condoms – such a prevention message is critical to all our treatment efforts. And, therefore, the dichotomy between prevention and treatment is one that this conference should lay to rest immediately, and we need to stop the counterproductive debate.
[applause]
Let us return to the practical concerns. What are the obstacles to getting a vision of the World Health Organization, that 3 million people should be on treatment by the year 2005? What are the practical obstacles to this? The partial, passive actions, and insufficient donations by drug companies will not assist in the long term to deal with the epidemic on a sustainable and effective manner. What is required is generic competition, and therefore we appeal to all the guideline drug companies to issue nonrestrictive, voluntary licenses at between 3 and 4 percent royalty, to ensure that poor countries and communities have access to antiretroviral therapy, and to eliminate the unnecessary conflict between the activist community, governments, and the drug companies. To be able to deliver drugs to people, to be able to save the lives of millions of people with HIV and AIDS, we need effective public health care systems.
And we can only start by endorsing both (MS?) and also the World Health Organization’s Commission on Macroeconomics report that regards health care as an essential public good and absolute essential, not only for dignity and life, but a component of a sustainable development strategy for most developing countries. Therefore, we would endorse the request for additional funding for health care systems across the globe, by the World Health Organization, to ensure that public health care systems are effective and that they deal with HIV and AIDS, with TB and malaria, and with all the diseases of poor people. A necessary element to enable public health care systems to deliver antiretroviral therapy to poor countries, is the funding of the Global Fund on AIDS, TB and Malaria. It is unfortunate that that fund has not received these necessary amounts of between 7 and 10 billion or 11 billion dollars called for by the UN Secretary General, Kofi Annan. We believe that the United States, Europe, Japan, countries like South Africa and Brazil, all have an important contribution to make to that fund, to ensure that all poor people get access to treatment with antiretrovirals. We appeal to you to step up the activism in your countries to ensure that the Global Fund has the money that it needs.
There is an additional element essential for all of us to get access to lifesaving treatment, and that is political will. Many of you will note that the South African government’s position on HIV and AIDS was not only scandalous, did not only reduce many of us to despair, did not only take away the hope of many, many thousands of people in our country, but it also threw health care workers and our system into disarray. That position has fortunately now changed. However, we still believe that all of us should be vigilant, that we should encourage the South African government and all its officials, its representatives, to maintain a position that HIV does cause AIDS in fact, and, more importantly, that HIV can be treated as well as prevented. Unfortunately, our government has not yet committed formally to a national treatment plan, in a country where nearly 300,000 people will die this year of AIDS-related illnesses. However, it is not only our government that is lagging behind. Regrettably, the richest corporation in our country, the Anglo-American Corporation, cancelled its pilot programs to treat gold miners and miners who have suffered and lived in single sex hostels on their mines, far from their families, who have HIV – they’ve cancelled their antiretroviral programs. We appeal to them to reinstate those programs and to treat the workers who have used their bodies and sacrificed their bodies and their families to ensure that that company makes the enormous amounts of profits that it does on the world market for gold and other minerals. We appeal to the entire private sector to make it possible for people to be treated, including companies such as Coca Cola, Ford Motors, Daimler Benz has done a superb job, we appeal to all of them to work together to ensure that people across the globe have access to treatment, their workers in particular.
We have seen many successes. A tremendous example to all of us has been the Brazilian program, and we commend the Brazilian government for an effective program. As all of you will know, tax-supported (MS?) in importing generic antiretrovirals into South Africa form the programming (MS?). We will continue to support that act. And we want to set an example that can work. However, we appeal to the Brazilian government to lead a political campaign to be able to export its drugs to other countries in Latin and Central America, because there are many poor people in Ecuador, in Nicaragua, and many of the other countries of that region who need these medicines urgently. It will not only sustain the Brazilian program in the long run, because of economies and scale and cost-effectiveness, but, most importantly, it will give hope to the region itself.
On our doorstep, in Botswana, that government has committed itself to a comprehensive treatment program for its people. However, its President, Festus Mogae, mentioned that he’s not sure how sustainable that program will be. We appeal to the Gates Foundation, to the Merck Corporation, to the United States government, to ensure that Botswana is able to use generic antiretrovirals to lower the prices and to be able to make its program sustainable so that the more than one-third of its population that are already affected will be able to have treatment on a sustainable and effective manner.
A critical element to be able to deliver treatment to people will be treatment literacy programs. Every day, in our communities, we are able to educate people in workshops about nevirapine, about AZT, about side effects – we are able to sing songs about these drugs, we are able to educate people about fluconizol (MS?), about proctomoxizol (MS?) – these are things that none of us knew. These are medical terms, pharmacological names that none of us knew when we were first diagnosed or even much later. But, fighting for our lives has made it essential and necessary for us to learn these things. Everyone can learn them. In our communities, we do workshops with people who’ve never opened a pharmacological textbook, but most of our people can speak eloquently and articulately about the medicines they need to take, their side effects, and how to look after themselves. We believe that, by working together, nurses, doctors, scientists, patients, government – all of us – we can achieve the necessary required treatment literacy that will make high adherence possible.
Over the last two years, it has been the power of ordinary people that has held drug companies accountable, that have made our governments accountable, that have made the global community accountable. Most importantly, from Treatment Action Campaign, we want to thank the Health Gap Coalition, MSF, (MS?)’s Health Crisis, all our African comrades. We want to thank our Brazilian comrades, Pelovita (MS?), and people across Asia and Europe. We want to say to you that you have made our work much easier, and we hope that our work at home will be of some assistance to you. In the words of the labor movement, an injury to one is an injury to all.
[applause]
EDWIN COLEMAN: Ladies and gentlemen, we will take your applause and your commitment back to Zackie. We will take, also, your determination to join him in the fight to secure treatment access for all poor people. Zackie has, himself, said that he will not take antiretroviral treatment until, at very least, there are nationally directed pilot projects to supply such treatment to people in South Africa. Let us make that the goal of all of ourselves in this conference, and let us imagine, in fighting for it, that those 20 and 30 millions of people are at this conference as angry and as clamant as the treatment activists of the former era were here. Thank you.
[applause]
Our next speaker is Dr. Anthony Fauci. He will be introduced by Professor Lars Kallings, who is Secretary General of the International AIDS Society. Professor Kallings was the founding president of the IAS; he was also the chairman of the 4th International AIDS Conference in Stockholm. Barcelona is his last conference, because he will be retiring at the end of this year. It’s a particular pleasure to ask him to step forward to introduce Dr. Fauci.
[applause]
LARS KALLINGS: Thank you very much. Anthony Fauci is Director of the National Institute of Allergy and Infectious Disease at the U.S. National Institutes of Health, and Chief of the NAID Laboratory of Immuno-regulation. In a more than 30 years research career at NIH, Dr. Fauci has made contributions to basic and clinical research on the pathogenesis and treatment of immune-mediated diseases. From the earliest days of HIV/AIDS pandemic, Dr. Fauci’s work has illuminated the immune effects caused by HIV, as well as the mechanisms of induction of HIV expression by endogenous cytokines. He has been instrumental in developing strategies for the therapy and immune reconstitution of patients with HIV/AIDS, and also, importantly, for a vaccine to prevent HIV infection.
As I, myself, have been involved in organizing almost all of the 14 conferences, I can reveal some insight into the discussion in the scientific program and conference committees. There is always an attempt to get new faces as plenary speakers. The only exception is Tony Fauci, as he is definitely the best in all categories. Therefore, Tony is always a winner in the selection process, and I’m extremely happy to have been asked to introduce him at this conference to update us about immunopathogenic mechanisms of HIV disease. Tony.
[applause]
ANTHONY FAUCI: Thank you, very much, Lars, and I would like to thank the organizers for giving me the opportunity to address you today. As you can see from this slide, the topic of my discussion is the immunopathogenic mechanisms of HIV disease, with a particular emphasis on the multifaceted impact of viremia on the host. Just for a very quick and brief review, the effect of HIV viremia on the host includes immune cell depletion and dysfunction, adver and activation of the immune system, select organ dysfunction, such as CNS, kidney, and others, and, importantly, as we have heard in this meeting, the establishment and replenishment of a latent and persistent viral reservoir.
Let’s briefly review, from the historical standpoint, the question of immune cell dysfunction. Years ago, in the very early 80s, we among other early laboratories, even before the actual description of HIV itself, noted that, in individuals with AIDS, there were profound defects and abnormalities of D cells, of T cells, of sototoxic (MS?) T cells, as well as NK cells. Most recently, now that we have the ability to compare viremic with aviremic patients, we’ve had the opportunity to re-look at some of these phenomenon. And I’ll start first, very briefly, with the concept of perturbation of B-cell function and antibody production.
Most recently, we reported from our laboratory that viremic patients have a phenomenon where there is the induction of the phenotypic and functional perturbations of B-cells. And this is manifested, simply, if you look at a particular function, such as the proliferation of B-cells in response to a typical B-cell receptor stimulus – in this case, anti-IGMs. Note the striking difference between HIV-infected viremic and, in this case, normal controls; but also, if you compare them to infected individuals whose viremia has been repressed by appropriate antiretroviral therapy. Of note, there is also a marked skewing of the expression of the complement receptor, CD21, as shown very clearly on the cyto-4 (MS?) metric analysis, again comparing affected with normal controls. But the same is true between viremic and aviremic patients. Of note is that if you take the CD21 expressing cells in a high or low capacity and look at them, as shown in the slide is a striking dichotomy. In the red is the low CD21, which predominates in viremic patients, and, as you can see, in response to a variety of stimuli, the ability to proliferate is markedly depressed, if not virtually absent. In contrast, on the right hand side of the slide, in the red bar with the low CD21, in responses to differentiating and antibody secretion are, in fact, hyper-responsive. In fact, if you take that to the level of the cell itself, you see normal B-cells in electron microscopy, with the characteristic morphologic features, and the CD21 high cells from individuals who are HIV infected, are indistinguishable from normal B-cells. But when you look at the CD21 low cells from HIV-infected viremic patients, you see a plasmacytoid-type appearance suggesting and artificial pushing towards aberrant activation and antibody secretion.
Let’s move on to the affect of viremia on CD8 positive T and natural kilocell mediated antiviral responses. As shown on this slide, we look at viremic compared to aviremic patients – and, note, on the bottom of the slide, all of the aviremic patients are on HAART except for a few, who are untreated and still aviremic. But also note that the CD4 and the CD8 counts are approximately the same. The only difference between these individuals is the presence or absence of viremia. Here, again, note the striking difference. Would you look at CD8 positive T-cell contact, or soluble factor mediated suppression of virus replication upon the autologous CD4 positive T-cells? Note the expression and secretion of virus as measured by P24, with CD4 alone, and the modest, but nonetheless significant suppression – both directly by CD8 and by CD8 soup in the viremic individuals – with a modest, but not complete abrogation with an antibody to CC chemokines. In contrast, on the right, in the aviremic patients, virtual complete suppression and cell functional integrity, not only of the CD8s, but of the CD8 soup and, note again, that this is almost completely abrogated – excuse me, it’s abrogated but not completely at all – by the antibody that CC chemokine indicating another non-CC chemokine factor that has been described, very nicely, years ago by Jay Levi, and it still eludes us in its precise identification.
If you look at NK cell contact, you again see the same sort of thing. Modest suppression in the viremic patients, with almost complete abrogation with antibody to CC chemokine. In the aviremic patients, virtual complete suppression, reflecting functional integrity and, again, pointing by the antibody studies, that virtually all of this is CC chemokines.
Let’s move on quickly to a very important topic that we have been working on and other laboratories have been working on. You heard from Bob Silicano (MS?) on Monday, and that is the establishment and the replenishment of a latent and persistent viral reservoir, with its important implications for what we mean and what the possibilities are for eradication. I won’t review this – Bob did an excellent job of this on Monday, and Mike Saag just reviewed part of it now, just a few moments ago – that the bottom line is, that individuals that get infected, the vast proportion of CD4 positive T-cells ultimately die, either directly or through immune-mediated clearance, and, for a small proportion, reverts to a resting, latently infected pool. Historically, we and others – and these are papers from a few years ago from our lab, from Doug Richmond and from Bob Silicano – were able to clearly demonstrate that, despite years of suppression of viremia, if you look carefully you will find remnants of a replication-complement pool of HIV in the resting CD4 positive T-cells. In fact, you could definitively prove this when you empirically interrupt therapy and find that, consistently, in whatever laboratory you look and whatever country you look, you find that the pool allows for a rebound of viremia upon discontinuation of therapy, clearly showing there was not eradication.
We pursued this years ago, and some of you may remember that we gave individuals HAART plus IL2, and, in fact, searched for, in the limitations of technique, a persistence of the reservoir in the blood and lynph node and could not find it. As you can see in that slide, the blue bar is below the level of detection. In those same patients we interrupted therapy. The viremia returned, but also what returned was the replenishment of the detectable reservoir, telling us two things: One, the reservoir was still there; two, viremia markedly replenished it. And so we then started to focus very carefully on what kind of perturbations occur in this resting CD4 positive T-cell compartment. And I’m going to go through a couple of studies with you and give you the bottom line with them. First, we look at the resting CD4 positive T-cell reservoir in viremic versus aviremic patients. What we did is, we purified resting CD4 positive T-cells, and we incubated them to look for the spontaneous production of virus under a variety of conditions and measured by the standard assays. First, look morphologically. When you purify these cells and you compare aviremic with viremic patients, they look exactly the same. If you do a more sophisticated phenotypic analysis by cytophormetric (MS?) analysis, particularly looking at cell surface markers of activation, on this slide measuring CD25, CD69, and HLADR, note the viremic and aviremic patients are phenotypically identical with regard to their resting CD4 positive T-cell reservoir. However, when you culture these cells – and look on the left to the viremic individuals – in media alone you get good virus production, cyclosporine-A, which blocks cellular activation, does not block it. HAART, which blocks cell-to-cell spread, does not block it, whereas actinomycin-D, which blocks all RNA, including viral RNA, essentially shuts it off. I might note that pronase treatment does not abrogate this, which means that we’re not looking at the release of adherent virions to the cell. Look then, at the right hand side of the slide. In the aviremic patients, you see no virus production, regardless of the conditions. Therefore, this suggested an important physiological difference in the resting pool between viremic and aviremic patients.
So we pursued this with a DNA microanalysis, looking at the expression of several genes. The methodology is now well proven. We took the RNA from CD4 positive T-cells and we used what is commonly used now, a synthesis of the hybridization of the CRNA, onto an aphymetrics (MS?) gene chip with an algonucleotide (MS?) array that contained 12,600 genes and, in a very complicated way that we cannot explain right now given the time restraints, you can analyze the data by what’s called a significant analysis of microarrays algorithm. Said briefly, it means you look at the genes that are expressed. But also you do a literature-mining approach in which you try to determine, are there clusters of genes that fall into a certain category?
In this slide, with aviremic patients on the left of the bars and viremic on the right, red means expression of genes, black means no expression, and green means down modulation. Note the striking difference between the viremic and aviremic patients’ expression of genes, despite the phenotypic identity of those cells. They’re expressing transcription regulators, RNA processing genes, as well as protein trafficking and other genes, including vesicle transport.
Now, why is that occurring? A number of reasons. Possibly, cytokine-induced expression of HIV gene expression. Or, possibly viral envelope mediating triggering. Last year or two, we have looked at the role of cytokines in the induction of HIV expression, and we show that standard pro-inflammatory cytokines indeed induce HIV expression from resting CD4 positive T-cells. But now we wanted to take a look at, what about the induction of cellular gene expression that might actually favor the self-propagation of HIV and CD4 positive T-cells? So we returned to the gene chip analysis. But in this case we looked in vitro, taking envelope [?] and exposing it to non-infected immune-competent cells. The methodology is identical to what I just described to you in looking at gene expression. And, to make a long story short, the summary of that was that exposure to envelope did not induce cellular proliferation or the expression of classical cell activation markers. Around 300 genes were induced out of the 12,600 – 17 were induced that actually had previously been described as being associated with HIV replication and/or envelope signaling. Importantly, when you look at the cluster of genes, and look at the terminology and the literature-mining algorithm, cytokine was the most over-represented and achieved the highest degree of significance, as did virus replication. And, again, with time zero being the baseline, and looking progressively at one, six, and ten hours, you see the relative expression of a group of genes – in this case, genes that are shown to have promoted viral expressions, such as TNF Alpha, IO-1 dative (MS?), GRO-1, and IL-8. Note that (MS?) and (MS?) are also expressed, which in high concentration, as you know, can block findings, but can also induce the transcription of HIV.
So we can conclude from this that the envelope protein actually induces a broad and complex transcriptional program in peripheral blood cells that is conducive to the productive infection with HIV in the absence of cellular proliferation and classical markers of activation. These data suggest that envelope-mediated signaling contributes to the productive HIV infection of sub-optimally activated T-cells. So we thought we’d take it to a bit more physiologic and do an ex vivo experiment, looking at the resting CD4 positive T-cells of individuals who are HIV infected. Stimulating them with the same envelope. The methodology is simple. We looked at the purified cells of these individuals. We used either and X-4 or an R-5. We measured virus replication by standard assays, and we simultaneously looked at cell surface markers. Note the difference here. If you take GP-140 and stimulate the resting CD4 positive T-cells of HIV infected individuals, you get production of virus. But, it occurs under very interesting circumstances. This is an accumulation of data looking at untreated – by “untreated” we mean not treated with envelope – and then treated with a GP-140. Note the consistent induction of expression of virus, again occurring under very interesting conditions. And those conditions are the fact that you do not induce classical markers of cellular activation. In this case, looking at CD25 and HLADR. And on the right hand side of the slide, there’s not indication of the progression out of the G-zero, G-1 phase of the cycle. So you can summarize these data by saying HIV envelope induces the production of virus in the resting CD4 positive T-cell reservoir pool. It occurs in the absence of activation and proliferation. And, so, one can surmise that the interaction of viral envelope on virions, or on the surface of infected cells, with HIV-infected resting CD4 positive T-cells, may actually contribute to the propagation and the persistence of a low-level HIV replication in vivo.
So, in conclusion, viremia has a multifaceted affect on the HIV-infected host, including cell depletion, disruption of CD4 positive T, CD8 positive T, B, and NK-cell function. The induction of permissiveness – and this is important – to the infection of resting CD4 positive T-cells, which actually contributes to the replenishment of the latent reservoir. The envelope induces subtle effects on a complex array of gene expression in these resting cells – notably, without obvious effects on the phenotype of cells. So there’s a fundamental difference in the resting CD4 positive T-cell reservoir in viremic versus aviremic patients. In the former, true latency likely does not exist, as cells are continually poised to express virus; whereas, in the latter, much greater stability exists, and this may represent a frame, actually, of a truly latent reservoir of virus. Also, the CD4 positive T-cell reservoir for HIV is complex, heterogeneous, and is a source of viremia in aviremic individuals who rebound after discontinuation of HAART, and we and others have shown that. But also, it’s profoundly affected by the presence of active viremia.
So, what about the future? Obviously, we must continue to pursue a multi-targeted antiretroviral approach to the suppression of viremia. And we’ve heard some good news about this thus far at this conference. Also, we might attempt to identify the cellular and molecular characteristics [break] ...mainly the latent reservoir, in order to perhaps specifically target them. But as Bob Silicano appropriately pointed out on Monday, this would be a really difficult task. But also what we’re seeing is a lot of activity in the pursuit of immune-based therapy as a modality to contain viremia, either together with antiviral therapy or after discontinuing therapy.
So, finally, as some of you may know, I am a basic and clinical scientist, and I am also a public health official. But today I presented a very basic scientific talk. Why, you may ask, have I chosen to do this, and what does this have to do with the pressing global health issues that we have been considering at this meeting? The answer is that it has everything to do with these issues, since it’s a cogent example of how basic and clinical scientists in my lab, and in many labs throughout the world, have actually arrived by a very different route, at exactly the same conclusions expressed so eloquently on Sunday night by Peter Piot and the disease modelers throughout the conference. And it is really very simple. First, HIV and HIV viremia are bad. They are bad in the north, and they are bad in the south. Next, treatment works, by saving and improving lives, and, therefore, treatment should be made available as soon as possible when clinically indicated to those who need it, in the north and in the south. However, we know that today’s treatment regimens do not eradicate the virus. We must be circumspect in our interpretation of this fact. On the one hand, we must not use it as a spurious excuse for not treating people who need treatment. On the other hand, it tells us clearly that treatment alone is not the answer to the control of the HIV pandemic. Which brings us right back to the conclusion to which all of us have come, namely, you cannot separate treatment from prevention either in the north or in the south. And we have some magnificent tools at our disposal, and, although they are indeed imperfect, they nonetheless are what we have. And we must use them, in the north and in the south, or else we will be the executors of our own self-fulfilling prophecy of failure, and I do not believe that is acceptable to any of us.
Let me conclude by recognizing the individuals in my laboratory who did this work. Pictured here are Tae-Yuk Chun (MS?), who did the work on the reservoirs; Audrey Kinter (MS?), who did the work on the envelope induction in vitros; Susan Moyer, who did the B-cell work; Sham Cotolio (MS?), who did the CD8 and NK work; Jim Arthis (MS?) and Claudia Ciacollo (MS?) – Claudia is not pictured here – who did the gene expression analysis; and Mark Dibel (MS?), who did all of the clinical work in our lab. Also, I would like to fondly recognize a number of collaborators listed here, in my own laboratory and other laboratories; particularly mention Larry Corey and his group at the University of Washington at Seattle. Thank you.
[applause]
EDWIN COLEMAN: Many thanks, Dr. Fauci. And I think those of us who are not scientists and are not clinicians are very grateful to you for making the evidence and emphatic connections with the underlying themes of this conference. The whole body therapists told me that I must love my virus, but after Dr. Fauci’s disclosures this morning I think it’s going to be more difficult to do so. Ladies and gentlemen, our last speaker is Professor Jose Miro, who is an associate professor at the local university, Barcelona, Spain. He’s a consultant in infectious diseases at the Clinical Institutes of Infectious Immunology at the hospital clinic locally. He has published extensively in the area of infections, opportunistic infections, amongst people with AIDS. He has published more than 250 articles and edited several books on AIDS, and he has been deeply involved in AIDS policy formation in Spain as Secretary and President of the Spanish Working Group on AIDS. He’s also edited of the Spanish Journal of Infectious Diseases and Clinical Microbiology. His talk is “Opportunistic Infections in HIV-1 Infected Patients in this Century.” Dr. Miro.
[applause]
JOSE MIRO: Good morning. First of all I would like to thank the organizing committee for inviting me to participate in this important meeting. In the next 20 minutes I would like to review some aspects of opportunistic infections in poor resource settings, the incidence of opportunistic infections and the (MS?) of discontinuation of studies in the (MS?), and, finally, we reveal the growing problem of chronic hepatitis C and B in HIV-infected patients.
This slide has been shown several times in this conference. As you know, there are 40 million people living with HIV/AIDS in the world last year, and three million people died. Eighty-five percent of these people are living in poor-resource countries, and opportunistic infections were the most important cause of death. What do we really know about this? The clinical spectrum of opportunistic infections in developing countries, the timing of appearing and prognosis are different from developing countries. Tuberculosis and bacterial infections, mainly salmonella and pneumococcide, are the two most common causes of morbidity and mortality. Other common infections are lymphatic (MS?), PCP, toxoplasmosis, (MS?), and local regional pathogens.
In (MS?) countries, (MS?) available we learn that the prevention of opportunistic helped improve the quality of life and life expectancy of each of the infected persons. The same approach must be adopted in developing countries, where more than half of HIV-related infections and death are caused by treatable and potentially preventable infections. In this (MS?), tuberculosis, (MS?) and (MS?) has been recently been indicated by WHO and UNAIDS as part of (MS?) in poor resource settings.
In this slide I summarize the tuberculosis chemoprophylaxis studies which demonstrate that this simple intervention can reduce the incidence of tuberculosis disease and mortality. There are several (MS?) and analysis that show that (MS?) twelve months prevents tuberculosis (MS?). This imperfection has been observed with (MS?)
On the other hand, several studies show that tuberculosis chemoprophylaxis reduces mortality in each of the infected patients with a positive TSD. (MS?), no data were available from (MS?) on the role of (MS?) prophylaxis for prevention of bacterial and (MS?) infections in developing countries. (MS?) performed on HIV infected persons with orbital TB, in the eyeball, half show that (MS?) significantly reduced the number of hospital admissions and mortality. However, in one (MS?) clinical trial performed in Senegal, (MS?) neither was mortality nor the occurrence of opportunistic infections. Although in this study, (MS?) an overdose of (MS?). It is important to point out that increasing levels of (MS?) resistance (MS?) against common bacteria in the future.
The main (MS?) of this part of my talk is (MS?) will become more accessible to each of the infected persons in poor resource countries, prevention and therapy for opportunistic infection will improve quality of life and life expectancy of these patients.
What is the current situation of opportunistic infections in developing countries? As you know, HAART has dramatically reduced the incidence of opportunistic infections in each (MS?) morbidity and mortality in industrialized countries. We have observed a marked reduction of most opportunistic infections in some HIV-related (MS?) such as (MS?) and Kaposi’s sarcoma. However, in several (MS?) studies, the incidence of non-Hodgkins lymphoma has not decreased or has slightly increased during the HAART era. Despite HAART, opportunistic infections will continue appearing in the future for several reasons. In recent studies, almost one-third of cases, HIV (MS?) when patients have advanced disease, and, on the other hand, there are many patients in whom HAART fails for different reasons. We have also read that the classical opportunistic infections can have atypical representations in the HAART era due to the immune (MS?) induced by HAART. Finally, (MS?) resistance is also increasing in several bacterial and pneumocystic (MS?). These findings may have important clinical implications in the future, although right now, the clinical significance of (MS?) resistance on PCP outcome is still controversial.
As you know, HAART (MS?) in most patients. (MS?) the occurrence of opportunistic infections in HIV-related mortality. From a practical point of view, the immunological (MS?) instituted by HAART is the best preventive therapy for opportunistic infections. In fact, over the last two or three years, several type of primary and secondary opportunistic infectious prophylaxis has been safely stopped. In 1999, the U.S. Public Health Service and the (MS?) gave the first recommendation of the discontinuation of opportunistic prophylaxis using evidence based on medicine criteria, and by rating for each opportunistic infection the strength of the recommendation and its quality of evidence. The best evidence is rated as A-1, and insufficient evidence is rated as P-3. Last month, definitive guidelines were published. Among the big 5 opportunistic infections, in yellow you can see that secondary prophylaxis of toxoplasmic encephalitis, disseminated MAC disease, and (MS?) were still rated as P-3. That means that there isn’t sufficient evidence to support this recommendation.
I have some problem with my slides. In the next slide I will repeat the most recent data about prophylaxis discontinuation studies for these three opportunistic infections. Well, we have new, (MS?) toxoplasmosis. These are slides from (MS?) studies in which secondary toxoplasmosis prophylaxis was stopped in these patients who have a CD4 cell count elevated at 200 cells for more than three to six months with HAART. Almost all cases were typically the PI regimen, and plasma viral load was undetectable. There was only one true relapse among the 126 patients in whom maintenance therapy was discontinued. This is the only (MS?) trial in which toxoplasmosis that was presented on Monday at this conference. (MS?) discontinuation to have a (MS?) result to be (MS?) secondary prophylaxis, and to have a sustained response to HAART with a CD4 count rated under 100 cells, and a viral load lower than 3,000 (MS?) for more than three months. Fifty-seven patients were (MS?) in this trial. Twenty-eight stopped maintenance therapy, and 29 did not. None of the patients developed toxoplasmosis during the study period. The (MS?) confidence in (MS?) for the incidence of toxoplasmosis in the (MS?) was only five cases per 100 patient years.
The second opportunistic infection I’m going to review is disseminated MAC disease. There were also seven WHO studies in which secondary MAC prophylaxis was stopped in 225 AIDS patients who have a CD4 cell count greater than 100 cells for more than three months, with HAART. Only seven cases – three percent – relapsed.
And, finally, we’re going to review stryptococcal meningitis. Six studies have evaluated whether secondary stryptoccal meningitis prophylaxis can be stopped in AIDS patients who have a CD4 cell count rated at 100 or 150 cells for more than three months with HAART. Among the 151 patients who were weighted, only four cases – three percent – relapsed. This slide shows the first randomized clinical trial in which (MS?). It will be presented tomorrow at the conference. The study was performed in Thailand, and the criteria for discontinuation was to have a previous stryptococcal meningitis episode, to be receiving maintenance therapy with (MS?), and to have sustained response to HAART with a CD4 count greater than 100 cells per cubic millimeter, and a detectable viral load, for more than three months with a (MS?) regimen including ICP, (MS?), and (MS?). Forty-two patients were included in this trial. Twenty stopped maintenance therapy and 22 did not. Median (MS?) was 12 months, and none of the patients relapsed or died.
So, I believe that there is currently enough evidence that, for these opportunistic infections, secondary prophylaxis discontinuation is safe, and in the new guidelines the strength of recommendation for these three opportunistic infections should be changed to an A or at least a B rate.
And, finally, I would like to review the impact on mortality of hepatitis C and D virus, and (MS?) of patients, and the most recent (MS?) advance in both chronic hepatitis in co-infected patients. In this slide, we can see the evolution of the annual mortality in HIV-1 infected patients from the Barcelona Hospital Clinic, which include about 4,500 patients over the last two decades. As you can see – and this is similar to (MS?) studies – mortality in HIV-infected patients started to decline in the beginning of the 90s with the introduction of prophylaxis and drug combination therapy. In addition, with the addition of HAART in 1996, mortality sharply decreased to less than five cases per 100 patient years. However, I would like to have your attention to the black dot of the square, which includes the last five years of the follow-up. Here you have the annual incidence of death in HIV and non-HIV infected people in Catalonia, matched by age and sex between 1997 and 2001. As you can see, mortality in HIV-infected patients – the red line – is still several times higher than in the general population – the yellow line. In this slide, you can see the causes of death in these patients. It is very evident that HIV-related mortalities – in orange – has decreased from 80 percent in 1997 to 20 percent in 2001. However, non-HIV-related mortality has increased simultaneously, and the most important cause of death in the last year was end-stage liver disease – in blue – which increased from eight percent in 1997 to 30 percent in 2001. Mortality caused by end-stage liver disease in HIV-infected patients is a growing problem in developing countries, and in some studies it is the leading cause of death. In this slide you have several published studied from Europe and the U.S. that compare (MS?) mortality before and after the introduction of HAART. As you can see, mortality increased several times, and in most recent studies ranges from 30 percent to 50 percent. It is important to point out that, in most cases, end-stage liver disease was caused by hepatitis C virus co-infection.
How can we explain this change in mortality? This slide shows the natural history of the hepatitis C virus infection. In the general population – the blue arrow – after hepatitis C virus infection, 80 percent of cases will develop chronic hepatitis, and after 30 years, 20 percent of these patients will have cirrhosis and end-stage liver disease. HIV co-infection accelerates the natural history of hepatitis C virus infection – the orange arrow – and this, (MS?) with current hepatitis can develop into cirrhosis faster, in approximately 15 to 20 years. Before HAART – red arrow – HIV co-infected patients progressed to AIDS and died in 10 to 15 years, and they did not have time to develop cirrhosis. However, with the dramatic improvement of survival with HAART – the green arrow – most hepatitis C and HIV co-infected patients are at risk to develop cirrhosis and end-stage liver disease if they are not treated against hepatitis C.
Hepatitis C is a global health problem. There are almost 200 million carriers worldwide, and 10 million of these are HIV co-infected. The prevalence of hepatitis C virus and HIV co-infection in industrialized countries ranges from 30 to 50 percent, and it is mainly linked to intravenous drug abuse. There are very important bidirectional interactions between hepatitis C and HIV that will be reviewed in several sessions in this conference and will not be discussed in this session. I will only share with you the new data on the therapy of chronic hepatitis C and HIV co-infected patients, because, as opposed to HIV, hepatitis C infections can be eradicated. Interferon plus (MS?) is the combination of choice. The most important advance in recent years is the introduction of (MS?) interferon which allows – because of its very long half life – once weekly administration of the drug instead of the trice weekly administration of the conventional interferon. In this slide you have the results of (MS?) clinic trials in HIV negative patients that were published within the last 12 months. The most effective are – in orange – (MS?). The (MS?) cure ranged from 54 percent to 61, and the response rate depends on the hepatitis C virus genotype. For genotype 1, the most resistant 1, the cure rate ranged from 42 percent to 46 percent. Conversely, for genotypes 2 or 3, more than 75 percent of patients were cured.
In this slide I have summarized the efficiency of different hepatitis C treatment in HIV negative and in HIV co-infected patients. As you can see, the response rate of the combination of conventional interferon plus rivavine was lower in HIV co-infected patients, in comparison with HIV negative patients. Several clinical trials with regulated interferon plus rivavine are still underway. These are the primary results of (MS?) trials conveying conventional interferon versus regulated interferon plus rivavine, in one (MS?) trial, in hepatitis C and HIV co-infected patients. As you can see, the biological response at the end of therapy, after 48 weeks of therapy, in the regulated interferon plus rivavine – in orange – range from 44 percent to 50 percent. To have the final results, we have to wait for the six months without therapy. However, yesterday afternoon Dr. Estefan (MS?) from Hospital Vitabron (MS?) in Barcelona presented the unpublished final results of (MS?) trial conducted in his hospital. The overall cure rate in HIV co-infected patients was only 31 percent. This cure is 20 points lower than in HIV negative patients. In the last column of this table, I would like to point out that there were an important percentage of treatment discontinuations, ranging from 10 percent to 30 percent, and mainly due to toxicity.
The NIH (MS?) statement, published on the Internet last month, recommended regulated interferon plus rivavine for the treatment of chronic hepatitis C patients in the general population. However, as explained before, in HIV co-infected patients this combination seems less effective, and there are many issues to be resolved in the future with regards to patient selection criteria, timing of HAART, dose and duration of the anti hepatitis C drugs, and toxicity. It is also important to point out that liver transplantation is feasible in this type of patients with end-stage liver disease, as Michel Roland pointed out yesterday.
Hepatitis B is also an important health problem. There are more than 300 million carriers worldwide and three to five million are HIV co-infected. It is very important to remember that this is a preventable disease, and all persons must be vaccinated. Like hepatitis C virus, hepatitis B virus in HIV co-infection is associated with significant morbidity and mortality. There are several anti hepatitis V drugs to treat chronic hepatitis B – interferon alpha, lamivovine (MS?), avitrovir (MS?), and (MS?). (MS?) and lamivovine are also used in the context of HAART. It is well known that the lamivovine resistant hepatitis B appears with (MS?) therapy in up to 50 percent of cases in up to two years. In these cases, (MS?) and (MS?) are active against (MS?) strains. However, although we have several important anti hepatitis B drugs, the (MS?) treatment (MS?) for this co-infection is currently under study. Liver transplantation is also effective for those co-infected patients with end-stage liver disease.
Here, the main research of my presentation. First, opportunistic infections are the leading cause of death in poor resource countries. Tuberculosis and (MS?) preventive therapies improve the quality of life and life expectancy of HIV-infected patients in these countries. Second, HAART has reduced the incidence of opportunistic infections and can change their clinical presentation. (MS?) studies and (MS?) clinical trials show that toxoplasmic encephalitis, (MS?) maintenance therapies, can be safely stopped in AIDS patients with immune (MS?) induced by HAART. Third, currently hepatitis C and/or hepatitis B virus are an important cause of morbidity and mortality in HIV co-infected patients from developed countries. And, fourth, combination therapy with regulated interferon plus rivavine is providing new opportunities to cure chronic hepatitis C in HIV co-infected patients. There are also several anti hepatitis B virus drugs to treat chronic hepatitis B. Some of them can be used in the context of HAART. However, the best treatment strategy is not known yet. In both co-infections, many problems have yet to be solved. Liver transplantation is feasible for co-infected patients with end-stage liver disease.
Before finishing, I would like to thank many colleagues and Spanish institutions for their constant support over the last two decades. They have helped to improve my understanding of the disease, the day-to-day care I provide to HIV-infected patients in the clinic, my HIV research, and my teaching. Thanks to the (MS?) colleagues and to all HIV Unit members of the hospital clinic of Barcelona. I am especially grateful to Felipe Garcia, Estefan Martinez, Jose (MS?) and Jose (MS?). Finally, I thank our patients. Together we are still learning many things about this disease, its therapies and complications. It has been a long and sometimes difficult road, but I’m sure it will be much better in the future. Thank you very much for your attention.
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EDWIN COLEMAN: Many thanks, Professor Miro. Ladies and gentlemen, on your behalf I would thank our speakers, from three continents, who have taken us through the disease itself, in its scientific and clinical intricacies, through antiretroviral treatment for it, through the opportunistic infections that it causes, and through the demand for treatment access for it. The message from this session has already been summarized by Dr. Fauci. That viral activity, and the diseases caused by viral activity, are bad, but treatment works. Those two lessons are true for people in wealthy and in poor countries. Our commitment in this conference is to bring those two lessons together. Thank you very much.
[applause]