Article Title:World AIDS Day - 2002
Category:HIV
Author or Credit:GayNZ.com
Published on:30th September 2002 - 12:00 pm
Published by:GayNZ.com
Story ID:50
Text:WHEN TO START TAKING HIV DRUGS Summary: Toxic side effects associated with protease inhibitors, one of the main drug categories used to control HIV] are leading international medics to start treatment later, rather than soon after infection. This is a position that NZ clinicians have already adopted for some time. One of the big shifts from [the 1998 international conference in] Geneva to this conference was about when to start Highly Aggressive Anti-Retroviral Therapy (HAART) and the reasons for that. Researchers have realised over the last four years the high levels of toxic side effects associated with protease inhibitors, so they are now starting treatment later. Also, in '98 they did very much have a view that it may have been possible to eliminate HIV if you hit early and hit hard... there were people then who were advancing the prospect of complete elimination of HIV. What has happened recently is a move from starting treatment at 500 T-cells per ml down to 350 T-cells per ml. In the band between 350 and 250 T-cells per ml, clinical decisions are made as to whether you should be on HAART or not. Some people start at 350, some people start at 250 and that's a matter for the clinician and the patient to determine. Once you're at 200 T-cells per ml the recommendation is that everybody should be on HAART. And also as soon as you become symptomatic everyone should be on HAART. Less than 200 and you should always be on HAART. So basically the position has changed and interestingly it's gone very much around full circle to the position that the NZ clinicians have adopted for a long time, which about four or five years ago was regarded by some as a conservative position - leaving it perhaps a bit too late. So we've returned to a recommendation, an international consensus recommendation, that is very similar to the one that has been used up at Auckland Hospital's Ward 9C for some time. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) PROGRESS CONTINUES ON DEVELOPING NEW HIV DRUGS Summary: Around 21 new HIV treatments are in development, including a whole new class of drugs called entry inhibitors. There are a large number of new drug treatments "in development." By that I mean they are more than just an idea in some scientist's mind or marks on a whiteboard, but actually in development. There were around 21 mentioned, including a whole new class called entry inhibitors which are a very exciting prospect because, rather than worrying about tinkering with HIV inside the cell, entry inhibitors stop HIV from getting inside in the first place. There are three subtypes of entry inhibitors that are now being looked at which block virus entry at various steps. So if you think about the whole business of treating HIV infection, what you're looking at doing is finding ways of interrupting the reproduction of the virus right from the first step when it starts to get inside the cell to the last step where it buds off from the cell and floats away as another free living virus. There are many separate steps throughout that process and you can only interrupt those steps in places where you aren't going to completely disrupt the normal way that cells work. The HIV virus gives you a whole lot of discrete options where you can go in with a drug of some kind and interfere with the virus without interfering with the cell. If you hit HIV in a way that upsets the normal cellular processes you're going to damage the cell, and you're going to create side effects. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) DRUG RESISTANCE PROBLEM GROWING Summary: Up to one quarter of new infections may be resistant to current drug treatments. Researchers are now spending more and more time investigating an important topic that flows directly from Highly Aggressive Anti-Retroviral Therapy - the sexual transmission of multi-drug resistant strains of HIV, a steadily increasing problem. Since the conference, one major study from the United Kingdom has reported that up to one in four new HIV transmissions might be resistant to current drug treatments. Once established, resistance appears to remain in most cases, which strongly reinforces the need to prevent transmission of drug resistant virus in the first place. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) LATENT RESERVOIR RULES OUT ELIMINATION OF HIV Summary: With present drug treatments the elimination of HIV is not a possibility. Resistance of HIV to drugs does not develop if the virus is suppressed to a very low level in the body. One of the ideas behind the old position of "treat hard and treat early" was the belief that it may be possible if we work the right way with the current range of drugs to completely eliminate HIV. This was a major theme four years ago and in Geneva in '98 [the previous international conference venue] there was great optimism, headline news- making optimism, about the possibility of eliminating HIV. This year at Barcelona researchers were very clear that with present drug treatments the elimination of HIV is not a possibility. That's because the virus gets into some of the long-lived cells in the body and it persists there as part of those cells. The best example of this is the memory T-cells subset. When you give someone a vaccination for measles at six months of age the body remembers the measles virus throughout the whole life of the individual, and that's because the memory of "measles" is held in the memory T-cells. HIV infects that long-lived reservoir and elimination is therefore a major biological problem because these cells are designed to persist for the life of the individual. It's not the exact same cell... the cell reproduces and takes HIV along with it inside, and that cell reproduces in turn and also takes HIV along with it and so on. The particular cells that the immune system uses to fight HIV infection are the very ones that are infected and this really means we must expect, given all our present knowledge of biology and all our present knowledge of drug treatments, that it is unlikely that it will be possible to eliminate HIV completely once someone is infected. To give an idea of the statistical problem: if you had one out of a million of these memory T-cells infected, even if no more virus was re-expressed in the individual, it would take between 66 and 73 years to eliminate the last of those viruses by a natural process of die off, so you can see that it's just not likely to happen. The other basic problem is that every time there is a viral rebound and viral load comes up, you replenish that reservoir. So with current drug therapies elimination is not a prospect. However it does appear that so long as people are able to stick with the requirements of the dosage regimes - which with the new ones that are coming through is going to be made easier - and you can keep HIV levels below detectable, you may be able to stop the evolution of the virus so you don't get drug resistant strains appearing. Resistance doesn't develop so long as you can keep suppression at that low level, so that's probably good news for long term control but bad news for elimination. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) VIRUS VARIABILITY AT THE HEART OF RESEARCH CHALLENGES Summary: Difficulties faced by vaccine researchers are caused by the incredibly high mutation rate of HIV and the many different strains which result. This is one of the most significant things about HIV, and understanding what's going on in drug treatment and understanding the difficulties around vaccine development depends on understanding virus variability. HIV has an incredibly high mutation rate. Every time an HIV virus reproduces itself there are up to ten mutations that happen somewhere in its genetic material. Most of those result in a progeny virus that is non-viable and dies. But because HIV mutates at an incredibly high rate quite a high proportion of mutations result in a different viable virus, maybe with one base mutation. As well as reproducing itself at a higher rate than most viruses HIV does a thing called recombination, which is a bit like 'viral sex.' The best way to describe recombination is when you get two viruses in one cell at once they swap genetic material one to another and a third virus is created through that process which is a mixture of both parent viruses. Because these three processes are going on inside every individual with HIV in places all around the world we've developed a phenomenal diversity of HIV strains. The best way to think about that is for every individual who has an established infection with HIV, they have more different variants of HIV inside them at any one point in time than the entire world population does of variants of influenza virus. Now you know that a problem with influenza vaccine development is that every time a new winter comes along we have to go off and get a new vaccination for influenza because the one we had last year in not right for this year's strain. So this neatly illustrates one of the biggest problems in vaccine development and it's something to do with the fundamental biology of HIV. I think everybody also knows about the fact that there are various subtypes of HIV and they are emerging in different ways around the world. Just to do it alphabetically, the majority of the epidemic of HIV in Russia at present is the result of IDU transmission, and the majority of those cases, somewhere just over 94% in Russian prisons in fact, are a result of infection with subtype A, which appears to be quite readily transmitted by blood to blood contact through infected needles and syringes. Subtype B is differently adapted to gay transmission through anal sex and subtype C for heterosexual transmission through vaginal sex. This is because certain strains of HIV preferentially target different cellular receptors that are found at these sites. And one of the things that has been going on in Africa which underscores the problem - one of the big changes in HIV internationally at the moment - is the exploding epidemic in Southern Africa, South Africa and Botswana in particular, of subtype C. Subtype C, which is quite easy to transmit heterosexually, is spreading incredibly quickly in Southern Africa and this explains why there is such a rapidly growing epidemic in that part of the world. In subtype C the mutation rate is higher, it recombines faster and it differentially infects Langerhans cells which are found in the vagina and on the penis, especially the foreskin. It is also more easily transmitted mother to child. People were saying at the conference that when you look at subtype C we may be seeing the HIV/AIDS epidemic moving into a new gear, and it is a heterosexual transmission gear in Southern Africa. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) LONG-TERM NON-PROGRESSORS MECHANISM STILL NOT UNDERSTOOD Summary: A very small number of people infected with HIV are alive and well after 24 years of living with the disease, even without drug treatment. These people appear top have a mechanism for controlling HIV but scientists have yet to understand or identify this mechanism. About 3% of people with HIV appear to stay well with HIV, live without drug treatment, maintain control of the virus and stay well. Some of them have been infected with HIV for over 24 years and counting. They've been called long-term non-progressors and it's kind of the flip side of the individuals who become infected with HIV and become sick very quickly. A combination of factors is responsible for those situations, and we know that the factors include things in the virus and things in the individual. Some people seem to have a component in their immune system which enables them to control HIV better, and these long term non-progressors appear to have a quite robust control mechanism. Work has been going on about this now for the last twelve years when researchers managed to spin down a solution from people who were long term non-progressors. They realised there was something in that solution which remains unidentified even after twelve years of trying to find it. It appears that something is secreted not by CD4 helper T-cells but by CD8 killer T-cells, and that it is some kind of soluble component. It is a new part of the immune system that hasn't yet been described. People are still trying to work out what it is, it's a incredibly difficult process to try and do that because it is present in such extremely small quantities. It does seem that those individuals who are long term non-progressors do have a mechanism for controlling HIV and obviously a lot of people are trying to work out what that mechanism is because it's got big implications for treatments and so forth. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) INFECTION WITH MULTIPLE STRAINS DOES HAPPEN Summary: Despite previous theories it appears that once a person is infected with one strain of HIV they can pick up new strains as well. Unsafe sex between positive people is therefore not a benign practice. Countries like Australia and the UK have been putting out recommendations - which the NZAF has believed were wrong for some time - that there was no risk if positive men had unprotected sex or if positive couples had unprotected sex. Once you had HIV you couldn't swap it backwards and forwards, or that was their theory. The process where you have an HIV infection and another strain gets established later on is called superinfection. It is generally accepted in biology that once you've been infected with something it's harder to get infected again, that's the whole basis of vaccination. But that depends upon people having an immune system which is functioning properly, so stopping getting infected a second time is a result of certain things to do with immune system function. With HIV there's never been any guarantee that parts of the immune system aren't being disturbed by the original infection, but still people have just assumed that you can't get it again. The difficulty of proving that superinfection does happen is compounded because of the variants of the virus that are in all HIV positive individuals. So it's been quite a hard task to prove with empirical data that you can be infected by HIV for a second time. At this year's international HIV conference one of the world's top HIV clinicians presented a case of an individual who had HIV subtype B, the one that's commonly transmitted by anal sex in gay men. This individual had his infection completely under control and had been on Highly Aggressive Anti-Retroviral Treatment (HAART). He then went on a treatment break and during that time had unprotected anal sex. He turned up three weeks later with a high fever and a large viral rebound. Because this guy was under very careful clinical monitoring they were able to establish that this was a new infection. He had been infected with a new strain, and it was only 12% different in terms of genetic structure to the one that he already had. So it was very like the original one... and that's an important point. But even though this guy had the first strain completely under control, after he went back on HAART he was not able to control the second virus as well, so his T-cell numbers started to fall and they have continued to fall and he has continued to get sicker. What we learn from this is that we're talking here about superinfection. We're not talking about a situation where an individual is simultaneously infected with two stains of HIV, which is called co-infection, and they then mount an immune response to both of them at the same time. We're talking about a situation where there is already an infection back in time, and there has been a full immune response mounted. The person has the first virus under control and then they get infected again by a new one. And what happens is that it escapes immune control in a way that HAART does not always seem to be as able to manage. A second reported case of superinfection was a little more complicated. This individual had a strain A/E infection that was also under control where T-cell levels were good and the amount of virus was low. He went on a treatment break and traveled to Brazil, had unprotected sex with several men in Brazil, came back three weeks later and developed a mild seroconversion-type illness. Virologists were able to look into that and establish that even though this guy had never been to Brazil before, he now had a unique strain of HIV which is only found in Brazil. So it's almost inevitable that this was once again superinfection. There were also three other cases of superinfection discussed and in a recent Journal of Virology (August) two of those cases are reported amongst IDU users in Thailand. The key worry is that it's potentially clinically damaging, although we do not know how often this happens yet... we don't know if it's regular or rare. The reason why the NZAF has always argued that people should be cautious about this in absence of empirical data (and the above is the empirical data we've got coming in now because people are actively looking for it and able to prove it) is that there are so many recombinant strains of HIV. It is clearly very hard to get an infection with two different strains of HIV in one single cell, but it obviously happens reasonably often. We know that HIV is relatively difficult to transmit. In any one case it's not easy, so what you have to do is double that difficulty by a factor of two to get them two strains into the same cell. It's a big ask both statistically and biologically. The follow-on problem is that we see so many recombinant strains that an even much larger pool again almost certainly exists of people who have different strains of HIV inside them but in different cells. The likelihood is that such a large pool would not be possible if superinfection did not happen. That's a simplified summary of the theoretical argument. Now we finally have empirical corroboration in the form of cases that were studied in detail as they happened. Bruce Kilmister (Body Positive): What doesn't quite fit with that is that, given the fact that this is a relatively new message which been around for maybe two or three years, there was a situation earlier where a lot of positive people thought "well if I'm positive and you're positive lets have unsafe sex." There was a real culture of that and the large amount of unsafe sex between seroconcordant partners doesn't seem to have manifested into superinfection. Tony Hughes (NZAF): But how can you be sure it hasn't? Bruce Kilmister: Well, there aren't documented cases. Tony: That's true, but you don't know that if some of the time people have a treatment failure - their viral load goes from undetectable to a rebound peak - that a subsequent infection might not be the reason why that has happened. Bruce Kilmister: It could, and there could be a mix also of very different strains... which I tend to give more credibility to because of people going from, say, the United States to Brazil where there could be cross infection of different types. But I still need to be convinced because of the amount of unsafe sex that's been going on and not manifesting itself as superinfection. Peter Saxton (NZAF): Just because we're not seeing the evidence in the scientific literature, that doesn't mean it's not actually happening. One of the points I got from the Barcelona conference is that this is something people have just started to look at. Some of the cases where it has been documented have been in the context of a clinical trial where individuals have been tracked very, very closely. So when what look like treatment failures have occurred they have been able to be analysed in a lot more detail for the very first time and this has only been happening very recently. But just because the evidence is coming through now doesn't mean it hasn't been happening for quite a while. Tony Hughes: There's a great adage in science which people often forget and it says "absence of evidence is not the same thing as evidence of absence." We've had absence of evidence (a lack of empirical data) and people have thought it was evidence of absence (that there is nothing going on). We now have clear proof that superinfection is happening. It's very important to know about this because it has very important clinical implications for people with HIV. I think it's a disaster if we are saying to people with HIV, say to a couple of gay guys or a couple who are both HIV positive "there is no harm to your health in throwing away condoms," if in fact there is the potential for significant harm to health. I mean, what does the Hippocratic oath in medicine say? The first duty is to do no harm. So I think we are in a position where the empirical science is now catching up with what some very experienced virologists have suspected has been happening for a long time. Jack Dragicevich (Body Positive): Do you think that in the coming years we will have a greater indication how often this occurs? Tony Hughes: I think we will, in the sense of having the kind of laboratory studies that you need to prove all these things. It's all relatively new stuff. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) HIV TRANSMISSION RISK INCREASED BY SEVERAL FACTORS Summary: Positive people are much more infectious in the weeks following their own exposure to the virus than at later stages. If a person has herpes they are more likely to both transmit and to acquire HIV infection. Four years ago at the Geneva conference there were a number of quite contested discussions about whether people were more likely to transmit HIV at certain stages immediately after infection. Think of HIV as having an incubation period of fourteen days and a peak viral level at day 30, then the level of virus drops down to reach a thing which is called the viral set point, which is where the amount of HIV more or less stabilises. That happens at around day 100. New evidence was presented at this year's conference that, predictably, people are more infectious in the early period than they are later on. The risk from day 30 for the next five weeks or so could be up to 20 times greater for a susceptible sexual partner by one estimate that was presented at the conference. Worryingly, that might be just the time where the person doesn't know that they have HIV because they haven't been tested, and so forth. More information about transmission risk came out about the effects of herpes lesions. We've known since around 1988 that herpes is an added risk for HIV. Herpes lesions are a significant co-factor for both increased transmission and increased acquisition of HIV. But the message is now coming out clearer than ever that the risk is independent of viral load. If someone has herpes they are more likely both to transmit and to acquire HIV infection. Also, when your viral load goes very high your rate of HIV transmission increases. But even if you have virus below detectable levels evidence was also presented at the conference that you can still transmit. Less likely to transmit, yes, but still transmit nonetheless. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) SUCCESSFUL VACCINE DEVELOPMENT IS FAR AWAY Summary: A whole new field of vaccine development is emerging, driven by genetic engineering and molecular biology. Good vaccines remain the goal for defeating HIV but the likelihood that a fully protective one will be developed in even the medium term is remote. At the first international AIDS conference in Atlanta in 1985 people said "we will have a vaccine for HIV within two years." Well, here we are in 2002 and 1987 was a long time ago. People now understand that the scientific problems that must be overcome to create a vaccine for HIV are just enormous... genuinely enormous. What has happened is that a whole new field of vaccine development is emerging, and it is being driven by genetic engineering and molecular biology. Researchers are now looking at three different kinds of vaccines for HIV. The classic vaccine is a protective vaccine... you jab someone and they are not able to acquire HIV infection. That's proving exceptionally hard to accomplish for HIV. People are still continuing to work on finding a protective vaccine for HIV, but don't hold your breath. They're now also looking at the possibility of developing a prophylactic vaccine whereby you vaccinate someone and it doesn't stop them from getting HIV but it stimulates their immune system so that they are more likely to control it and hopefully not get sick. And the last type of vaccine is one you give to someone who already has HIV. It's called a therapeutic vaccine and the idea is that it will stimulate the immune system and decrease the chance that that person's HIV infection will result in illness. So researchers are now looking at those three different approaches. Most HIV is sexually transmitted, and most of the vaccines that they now give to people are injected vaccines, so they're looking at new kinds which stimulate mucosal immunity because if you want to stop sexual transmission you've got to stop the virus from entering through the vaginal or anal mucosa. They're now looking at various ways of doing that including vaccines that are sniffed and intravaginal administration is another possibility. The need to develop an effective HIV vaccine is very urgent so good vaccines remain the eventual goal but the likelihood that we will find a fully protective one in even the medium term is remote, but people continue to work hard at it. All we can do right now is hope that something effective is found in the end. (Edited from the transcript of a September presentation given by Tony Hughes, Research Director of the NZAF, in Hamilton in September. With additional material from a subsequent presentation in Whangarei. The presentation reported on trends emerging from this year's International HIV conference in Barcelona.) GayNZ.com - 30th September 2002    
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