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HIV's Silent Dangers Make Early HIV Treatment Critical, Expert Says
A Discussion About Inflammation, Early Treatment and Universal Treatment Access -- Wafaa El-Sadr, M.D., M.P.H., United States

July 21, 2009

There's nothing like hearing the results of studies directly from those who actually conducted the research. In this summary, you'll hear Wafaa El-Sadr, M.D., M.P.H., discuss her plenary paper. It is followed by questions from reporters and comments by Julio Montaner, M.D., president of the International AIDS Society. To see her presentation, click here. To review her slides, click here.

Wafaa El-Sadr, M.D., M.P.H.
Wafaa El-Sadr, M.D., M.P.H.

Wafaa El-Sadr: I spoke this morning on HIV inflammation, and the subtitle of my talk was, "A Paradigm Shift."1 Largely I was talking about a couple of things. What should be our goal in managing people with HIV? And ultimately, our goal is that people with HIV would have similar survival to people without HIV. They would live just as long, and they would live just as well as people without HIV.

How can we achieve this? I think we've made tremendous progress by using antiretroviral therapy in dramatically decreasing morbidity and mortality. However, we may have also missed the boat in some areas. We have assumed that after somebody's infected that they have many, many years of what's called clinical latency -- many, many years when they're infected but they're actually doing well, or they appear to be doing well. It's only when they become sick, or they've advanced a bit with HIV, or advanced HIV, that then we start thinking of what other treatments we should provide them.

There are data now that seem to suggest that during that long period when the person appears to be quite well, there are ongoing processes in their bodies, due to HIV itself, due to the virus, that may be causing some damage, some unseen damage that may ultimately have a very large impact on a person's survival, and a person's wellness.

I think the goal is to try to think about how can we use the interventions we have. Can we use antiretroviral therapy, for example, to try to dampen some of this damage that's ongoing? We don't know if that's going to be effective or not. We need to study it. We need to invest in more studies that can answer that question definitively. Because getting it right is very important: really figuring out when to use antiretroviral therapy. How early should we use it in HIV disease has major implications. We need to know the benefits. We need to know the risks. Because we can't take a chance on that answer, because it has implications for millions and millions of people who will start therapy based on our guidance.

The second issue is that -- so there's one gap, largely in developed countries, which is the gap between people with HIV in survival, and those without HIV. Then there's another gap, obviously, between people with HIV in rich countries and in poor countries. Clearly, there's the gap of providing access to treatment and other interventions for people with HIV -- not just antiretroviral therapy.

In poor countries, we still have a long ways to go. Only about a third are getting access. We have a ways to go. And even people who get access to treatment are not doing as well as we want them to do. They're starting treatment very late. Also, even when they start antiretroviral therapy, they seem to be at very high risk of what we call early mortality. So we have a lot of questions we need to answer. We don't have all the answers yet.

I think the message is that some people are under a mistaken impression that we've solved AIDS, that we've solved HIV, that now we know how to treat it, we can get it out there, and all the answers are there. I believe there are lots of answers at the genetic level, at the research level, as well as the implementation level. And we have to continue to push the science and push the implementation and push the practice, based on evidence.

Reporter #1: I'm Natasha Bolognesi, and I'm reporting for the Canadian Network - Education. My question is: How does your concept of starting ARV treatment earlier during the clinical latency period compare with studies which suggest that some ARV drugs actually may contribute to comorbities, such as cardiovascular disease, for example?

Wafaa El-Sadr: I think we don't know the answer to the question. I am advocating -- based on what we know from the studies available to us --that it appears that there may be definite benefits to earlier initiation of ART. But there also are likely, as well, definite risks. Clearly, there will need to be studies to be done that further our understanding of how do we balance the metaphysic risks. And especially in the health care group of individuals; in such a population you want to really make sure that the benefits way outweigh the risks. Because if you're going to treat huge populations early, you want to know that most people will gain the benefits, rather than the risks.

In a more advanced population with HIV, you clearly are then willing to bear more of the risks to get the benefits. So I think it's weighing the risks and benefits that's a very complex balance.

I do believe that there are very intriguing, interesting data that suggest that earlier treatment could be advantageous. By earlier, I'm talking about above 350. I'm not talking about that people who should be getting treatment today are not getting it. In those populations I believe that the question should be studied, needs to be studied, and studied quickly. And investment should be made to make sure that these studies are done and done appropriately, and all the measurements are done within those studies.

I have to, though, caution that the vast majority people in the world are not getting access to treatment, even at the current thresholds. And that should be our focus -- to get people on treatment at the current threshold.

So I think that pathogenesis, these mechanisms, guide us to pushing harder to try to answer the questions and also to think about how are we going to answer the questions? What are we going to look for, exactly, in those studies?

I do think that the momentum is there, and the rationale is there, and we have to keep pushing to get them, to get these studies done.

Reporter #2: Hi. I'm Adam Graham-Silverman, also from the U.S.A. Dr. El-Sadr, you talked about this chronic inflammation idea as a paradigm shift. But given what you and others have just said about how far things need to go just to get treatment to those who need it at the current paradigm, I'm wondering what else, what other kind of shift might this model entail, particularly for the health systems more broadly, other options for treatment. You know, if this does become the model, what other avenues will get opened up for new ways to look at treatment prevention, care and so forth?

Wafaa El-Sadr: If I understand your question correctly, I think that there is recognition of the importance of these kinds of coagulation and inflammatory markers. And the question is: what can we do about it? Is it antiretroviral therapy that's the answer? The only answer? Or is it antiretroviral therapy and something else? Can we use agents, drugs, that have effect against inflammation, for example? That may have a benefit. We don't know that, in people with HIV.

I mentioned the very large study that was done in people without HIV, that did show that using the statins -- those are drugs that are anti-cholesterol drugs that appear to have remarkable impact in the general population. We don't know what impact that might have in HIV-infected individuals.

I think it opens new avenues for trying to think about not only antiretroviral therapy, but also other potential possibilities, and other interventions, as well. I think people should really be creative and look at what's on the shelf, and what's been used before and discarded and maybe really try to go outside the box of thinking of other drugs that we haven't thought of as anti-HIV drugs. I'm not sure that they work by themselves, but they might work as adjunctive -- if they demonstrate a benefit - and can adjunctively be used with antiretroviral therapy, potentially.

Reporter #3: Are there drugs and their broader public health interventions that may also be worth looking to?

Wafaa El-Sadr: Again, same issue. The whole issue of inflammation has also possibly potentially, aiding HIV transmission, HIV acquisition. We know that, for example, having herpes infection or genital ulcers appears to make you more vulnerable to getting HIV. And treating another infection and suppressing inflammation potentially could help in that way. Although more studies have not demonstrated a benefit from such treatment, in large clinical trials.

I guess, going back to the issue of early treatment: there are two ways of thinking about early treatment. You have to think about the benefits to the individual with HIV who is getting treated. And then you have to think about the prevention benefits and that's the balance.

If, for example, we discovered that it's not really of benefit to treat people very early on for their own health, but it does help in prevention; would that be the way to go? It's an interesting question.

Or, if there's a little bit of harm in the person who is treated early, when they get side effects, or something happens to them individually, but, on the other hand, it works for prevention from them to someone else; how do we weigh those two things?

It's a really huge ethical dilemma of weighing the benefits and risks, individual risks, getting the therapy, versus the benefits and risks to others. I don't have the answer. But those are really tough questions. Maybe Julio has the answers.

Julio Montaner: I consider that my invitation to the microphone. I'm Julio Montaner, and I've been working on these things for a little bit. [Dr. Montaner is president of the International AIDS Society and Clinical Director, British Columbia Centre for Excellence in HIV/AIDS.] This panel has been wonderful in outlining some of the major issues. I want to give credit to Wafaa. Wafaa is extremely humble. She's been very, very careful in how she's describing the results of her studies. The SMART study2 was a wonderful piece of work that really taught us tremendous new information that has dramatically changed the way we approach -- I approach -- HIV treatment in the clinic.

This is the problem. The problem is that it has moved the goalpost so far out there for antiretroviral therapy that when we come here to Cape Town, and Paula is reminding us that all of this is irrelevant to her and 90% of the people in the world because there is no money, she's totally right.

So we're here to highlight the fact that the goals that were stated for the universal access in 2001 are baby goals. Because the goals today are massively greater, based on the information that is here. And the information that is here actually contains with it the solution to Paula's problem, and to the problem of the world. Because, thanks to Wafaa's interpretation of the inflammatory nature of HIV infection which, her own data shows, gets shut down and cooled off with antiretroviral therapy, the International AIDS Society-USA needed no more data to incorporate a whole host of other conditions in people with normal CD4s as individuals who are candidates for treatment.

Now, that's by no means a total consensus out there. But I think the IAS-USA guidelines3 are fairly well respected, and are trying to push the envelope, and telling us that if you have a CD4 count over 300, with no upper limit, but you've had chronic active hepatitis of any kind, if you have cardiovascular risk, if you have so on and so forth, nephropathy from HIV, and the like, you are a candidate for antiretroviral therapy.

So, if you put the story together, and look at it from the very wholistic, comprehensive way, what I'm telling you is that the most aggressive guidelines today open the door for almost universal treatment with antiretroviral therapy. Almost. People come to the clinic today. You don't say, "Do you qualify for antiretroviral therapy?" No. What you say is, "Is there any reason why I shouldn't be giving you antiretroviral therapy?"

Because you brought up the issue of toxicity of treatment. The toxicity of no treatment is so much greater. And if not, ask Wafaa. Wafaa showed in the SMART study. The SMART study, a priori, had the preconceived hypothesis that less treatment was going to be better, because you were going to save the toxicities. And guess what? Actually it was the other way around. It was worse. Because it gave you the toxicity of the HIV for interrupting therapy. So all of those things that we blamed the drugs for; actually, a lot of that was the virus.

And so if you put the story together, we should be moving forward to embrace the new state of the art and recommendations. We will get the collateral benefit in prevention, controlled epidemic, decreased inflammation, but we need to be sure that we scale up from the bottom up. We cannot start giving people treatment because they have an inflammatory this and that, when we haven't really covered 100% of those with 250 CD4s. And only then, we'll move to the 300, and to the 350. This has to be hierarchically progressed. Otherwise, it's unethical. It would be wrong. And we would not accept the authority.

Craig McClure: [Craig McClure is the executive director of the International AIDS Society.] I think it's important to add that the messaging from this conference needs to be clear that, of course, people who are sick and dying with low CD4s need to be prioritized for treatment. The problem is, those people, when they get on treatment, are dying, anyway.

They're dying of tuberculosis. They're dying of other AIDS-related conditions and non-AIDS related conditions. And the other problem is that the donor community and governments themselves in low- and middle-income countries are afraid that the money for treatment will be a bottomless pit that goes on and on and on.

So, unless we treat people that are healthier, with higher CD4 counts, we will never see an end to the expenditures that will increasingly go up, up, and up. But if we make an all-out effort to treat people earlier, treat people in a sustainable way, the epidemic will come to an end.

Reporter #4: I've heard Julio make this argument about three times. It's very compelling and it's very rational. And so what I'm ... And I've heard all these moral statements. Stephen Lewis last night, and so forth. And it just seems like it's falling on deaf ears, up there in the international community. I don't know if Julio yelling at the G-8, if it's really going to make much difference. And so I guess I'm wondering -- maybe it's an impossible question -- but what's going to make this real outside of this meeting, this argument that we really need to increase funding, not just flatten it? Not just keep it the same?

Craig McClure: You have the first answer.

Julio Montaner: You will.

Craig McClure: Exactly.

Julio Montaner: You will. That's the reason why I'm here, and that's the reason why you're here. We want you to put it on the front page today, tomorrow, the day after; and call them by their names.

The reason why we're here is because -- and you hear this every press conference -- if we were here to just talk about the science, we would be doing exactly what Paula doesn't want us to do: celebrate the science and forget about the fact that the implementation gap is growing and growing and growing. And science that is not implemented is useless. So we're here to ask you for your help to make this happen. And I can give you words. You know, it's criminal negligence. I'll give you words, if you want. But you know, we need your help to make this happen. Because the prime minister of Canada came out of the G-8 meeting saying, "Oh, by the way, you know, it's really bad that we're misleading the public, and that we make promises and we don't fulfill them. We should be changing this attitude because it lowers our credibility."

I mean, how can a leader of a country have the nerve to go to a global summit, eat and dance, and have a great time, and come out and say, "You know, it's all lies, anyways. Who cares?" And the press is not picking up on it. So we need your help to tell these people we're watching; we don't like it; and through the press, you're going to lose your votes.

Craig McClure: You'll make the difference. Communities of people living with and affected by HIV that are activists will make a difference. Researchers will make a difference. Individuals in the sclerotic international organizations that exist today, individuals who care in those organizations, will make a difference, individuals in governments will make a difference. The same people who made a difference to get us where we are today, in 2000, 2001, 2000 in Durban, that led to the resources we've had up to now, today; it's the same people that will make the difference. So please, help.

Paula Akugizibwe: [To read a summary of her presentation, click here.] I think, additionally, you've pointed out all the major role players. But we also need to start bridging the gap between the people in need and the people who make these decisions. I mean, the representation of people living with HIV at this conference, as in all conferences, is pretty low, compared to the other representation of different groups. Just like donors who give money to countries rarely engage directly with the people who are ultimately the beneficiaries of the money that they're giving. Or UNAIDS conducts national AIDS pending assessments, and it specifically states that the assessment doesn't take into consideration that these are the service users.

So it's this massive gap between the high level, where decisions are made and funding is granted, and the ground, where that money is meant to be used. And that gaps needs to start being bridged. And I think that can be done by everyone in this room.

Wafaa El-Sadr: I think another issue that's coming up that many of you are aware of is kind of the concept that Stephen Lewis was talking about yesterday -- that HIV is sucking away resources from other key health threats. [To view Stephen Lewis's presentation, click here.]

For example, people who are saying, "Well, let's invest in health systems." Or, "Why should we be spending money on HIV? We should be spending it on child health? On child health, or other health risks."

I think, first of all, it's an erroneous assumption. We don't know. Nobody has demonstrated evidence to suggest to me that investment in HIV has negatively impacted on any other issue. I haven't seen any data to that -- or data that looks real -- that supports that claim.

But also, I think we need to think about how transformative HIV has been, in terms of the health system. I mean, having people at the table, people with HIV at the table, people in advocacy at the table, discussing health systems, is very important in shaping the health systems. There have been spillover effects influencing HIV, influencing the quality of antiviral care that we see. There has been evidence of enhanced procurement systems, enhanced laboratory systems in many countries. Keeping people alive, mothers alive, keeps children in school. Keeping people alive makes them more productive. There are data to support that from studies in Kenya, and elsewhere.

So I do think we have evidence. And we haven't used that evidence well enough that demonstrates the benefit -- the benefit of people with HIV, which is clear. But also the benefits on the societies in which they exist, in their communities and their families. And I think that's very important to help, again, demonstrate that HIV, by itself, is well deserving, this pandemic, of the investment; but also, that there are lots of benefits that are gained, as well, that have their own measurement.

Reporter #5: I'm Sylvia Mollet from Switzerland. I'm living in Mali since a few years. I have a question for a post-exposure treatment, which wasn't directly addressed here. But we speak about money and treatment. Post-exposure treatment is available in Mali since quite a while. It is given to embassies and their staff. So mainly the Europeans and Americans can be treated. All Malians can be treated, also, but they are not aware of that. It is available in hospitals, but people don't know it.

So I would like to know about financial resources. Is this the problem? Which is the large check behind this? This medication is available, but people are not informed.It's available, but there's no information about it. It's not like ARV or other medication. There is no marketing.

Wafaa El-Sadr: I think it's ... I think you're right. I mean, I think it's not been highlighted enough. I'm aware of some countries where. ... We support programs in some countries. I know that in Kenya, it's available for rape victims, for example. And people utilize it. People know that they go to a facility and they get a packet with antiretrovirals for post-exposure prophylaxis, after sexual violence. But it's not uniformly available in many countries. And I think you're right. It should be. And I think there should be more advocacy about it's availability, and the importance of having such treatment available for those instances.

Craig McClure: Amalio, would you like the final word?

Amalio Telenti: [Dr. Telenti was another plenary presenter at IAS 2009.] I just want to make a comment that is important from my side, as a laboratory person. It's that we should not forget also that science is what brought, also, treatment, and that in this very difficult fight for resources, we should make sure that we don't damage science budgets. I mean, we can do as much operation on improvement, and that's critical. But behind a new generation of treatments, or simplified treatments, or, eventually, eradication or vaccine; that needs resources. And actually it's a fraction of the resources that we're spending on treating people. So we have to be attentive with also enough money in science to avoid having to give money to people, and in the future of new effective treatments in science.

Craig McClure: Thank you for that. That's a critical comment. Two years ago in Sydney at this conference, the IAS issued the Sydney Declaration, calling for 10% of all resources for HIV to be devoted for research. Because, as good as what we've got now -- what we have is very good -- but science holds out the hope for better, better, more effective treatments, a vaccine, a cure for the future. Louise? Final comments?

Louise Kuhn: [Dr. Kuhn was another plenary presenter at IAS 2009. Click here to review a summary of her presentation.] I just wanted to say, when we talk about advocating for people to get access to treatment, that's really an important thing to be advocating for. But people don't just start at 18 years of age. And really, I think, when we talk about people who are invisible in this epidemic: children are really, fundamentally invisible -- both those that are infected with HIV, and those that are affected, because their mother is HIV infected.

The children with HIV really have special needs, and really need advocates, because their needs are different to adults. And as adults, it's our responsibility to look after them. And so I just hope that in the advocacy for adult treatment, we don't forget about the children, both those that are infected and affected; and think about programs that really incorporate child health, not as a competition, but as something that's fundamental to HIV care and treatment programs.

References

  1. El-Sadr W. Inflammation and HIV: A new paradigm. In: Programs and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract MOPL104.
    View slides: Download PowerPoint
  2. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.
  3. Scott M. Hammer; Joseph J. Eron, Jr; Peter Reiss, et al Antiretroviral Treatment of Adult HIV Infection: 2008 Recommendations of the International AIDS Society-USA Panel, JAMA. 2008;300(5):555-570.




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