In his blog post, Sean Strub raises serious concerns about three central issues. The first is the on-going debate about when to start ARV treatment. The second involves proposed new studies seeking to improve HIV testing utilization and linkage to care. The third regards the benefits that ARV treatment can have on preventing new HIV infections. There is a good deal that needs to be refuted and/or clarified in order to have an open discussion on these issues.
First, on the issue of when to start ARV therapy, I should begin with some background history. In 1989, a recommendation was made to start AZT monotherapy at <500 CD4 cells and well before the development of AIDS. That recommendation was made with little supporting data. After a year or so, it was clear that the recommendation was wrong. People who started AZT early actually did worse than those who started later. That mistake cost many people their lives. Unfortunately, the same mistake was made repeatedly - with dual therapy (AZT/ddI or ddC) in the early 90s, with AZT and 3TC a bit later. Each time, the recommendation to start early was proven wrong.
When HAART came out in 1996, the US Public Health Service ARV guidelines panel reviewed the scant information on when to start HAART. Once again, many of the scientists on the panel pushed hard for a recommendation of "hitting hard, hitting early" - starting at <500 CD4. But this time, the AIDS treatment activists on the panel - myself, Mark Harrington and the late Martin Delaney of Project Inform - all argued strongly that the recommendation should be to start later, at <200 CD4 cells or at signs of HIV symptoms. Our view was that we had no data whatsoever about early use of HAART - not one single study had been done. And we had made the mistake too many times before. These drugs were approved faster than any drugs in the history of drug development, thanks, in part to our activism. But that meant we had much less data by which to determine how to use them effectively. At that time, we had no information about the development of drug resistance, the need for high levels of adherence, or about most of the side effects from the drugs including lipodistrophy and body changes. And, we argued that if the US PHS put out a guideline recommending starting at 500 t-cells, there would be no way to ethically study the when to start question.
We lost the initial battle. The first HAART guideline recommended early treatment. And over the course of the next three years, we learned about the adherence challenges and the many serious side effects. Many, many people started treatment earlier than necessary and with inferior drugs. And, the definitive clinical trial was never done. Three years later, we were effective in getting the guidelines revised to a recommendation of starting at <200 t-cells or HIV symptoms.
But much has happened since then. There is now a significant amount of very compelling data from cohort and other studies around the world showing that earlier treatment has a positive impact on survival and in delaying not only AIDS-related illnesses but other illnesses that are the result of living with overly active immune system that is constantly battling viral replication, including heart disease, cancers, premature aging, as well as exacerbation of hepatitis C and TB progression. Although this data does not take the form of the more preferable "when to start" randomized clinical trial, it is increasingly compelling. Enough so that doctors and people living with HIV can make a very reasonable decision to use ARVs much earlier than we would have a few years ago. And because the drug regimens are now easier to take and with fewer side effects, the downside of starting earlier has decreased. Starting early isn't the only path, but it is a reasonable path. A change in the PHS guidelines in 2005 reflects this, recommending treatment at <350 CD4 cells. Now, the PHS is changing its guidelines once again to recommend starting at <500 CD4 cells. Again this is based on the data described above. Many doctors and researchers even believe that people should start therapy no matter what their t-cell count is. And they believe this because they think their patients will live longer and better lives for it.
The START study that Sean mentions would answer the question of when to start. Personally, I would prefer that the government (both the U.S. and the San Francisco Dept. of Health) wait until data from the START study is available before changing their recommendations. I think that public health officials have a responsibility to be more conservative in their recommendations, which should be based on the results of randomized clinical trials whenever possible. The emergence of other long-term side effects is one important reason to ensure that the START study is completed. The guideline recommendations will seriously hinder START enrollment in the US.
However, doctors and patients should have the ability to make more aggressive decisions about starting treatment if they feel, after analyzing the available data, that this is the best course of action. Similarly, I think Project Inform has every right to make its own policy decisions based on review of what is currently known. It is not fair nor just to accuse any of those involved in these decisions - guideline panelists, physicians, advocacy groups or people living with HIV - with some sort of underhanded conspiracy to coerce people onto early treatment for the sake of prevention or any other purpose. The data is there and starting early is justified. Again, it is not the sole approach, but it is a very viable one.
Despite Sean's assertions, the NIH-sponsored study that will seek to improve uptake of HIV testing and linkage to care - unfortunately labeled the "test and treat" study - is NOT placing people who test positive on treatment regardless of CD4 cell count. The study seeks to improve testing rates, link people to care, and offer treatment to those who meet current treatment guidelines. This is not a study testing the impact of earlier use of ARVs for prevention purposes. It is a study looking for ways to improve testing uptake and use of care. Up to 33% of people in the U.S. find out they have HIV by developing AIDS. This is a figure that has not improved in over 15 years. This is criminal. And this is not only a US problem. All over the world, testing uptake is horrible. This study is looking at ways to fix this. Treatment will be offered and recommended. Let's hope those who need it are able to access and accept treatment and use it properly. For some, it will save their lives.
The final issue involves the impact that ARV treatment can have in preventing new HIV infections. The data from Vancouver, from San Francisco and most importantly, from a large study of sero-discordant couples in Africa is showing that people taking ARVs are much less likely to transmit HIV. We still have much to learn, but it is very possible that ARV treatment may be the most effective HIV prevention tool we have and will have for many years to come. This is ground breaking news. Nowhere in Sean's piece does he acknowledge the potential good here. I don't want to transmit my HIV to anyone. Prevention is a challenge for all of us - positive or negative. If there is a way to help me make sure that I can't infect someone else, I want it. And I think most people living with HIV feel the same way.
Of course, treatment-centered prevention doesn't replace the need for condom distribution and other prevention interventions. But those interventions on their own have shown very limited effectiveness both in the US and around the world. Condoms won't end the AIDS epidemic. And there is no vaccine on the horizon for years and years to come. If we have a new tool that can effectively prevent HIV transmission, then we need to learn how to use it. And we all have a responsibility to figure out how to use this information in ways that can both protect from harm those of us having to take ARVs as well as protect others so that they never have to take them.
Of course, the threat of stigma and discrimination remains one of the greatest challenges we face in successful implementation HIV treatment and prevention efforts. We have always faced the danger of discrimination in our attempts to live with HIV openly and with dignity. The courage of people living with HIV to overcome these dangers as they seek out information, care and treatment has been and continues to be one of the most inspiring stories in the history of public health. We all need to be able to access treatment and live freely without fear. "Treatment as prevention" approaches do not alter this, but, rather make the need to overcome discrimination all the more important. Can we scale up HIV testing within a context of protecting human rights? We must do this whether we are using ARVs for prevention or not. Should patient confidentiality and choice be protected? We have advocated this course since 1981 as the only way we can expect people living with HIV to successfully engage in care. So, treatment as prevention doesn't really raise new issues in this regard.
There is a lot to learn. There are a whole slew of unanswered questions and challenges. Does earlier treatment put me at risk for more side effects or drug resistance? We don't know. A better first line combination regimen would go far to alleviate these risks, especially in resource-poor countries. That is within our grasp right now with some good advocacy and political commitment.
Personally, I have been on ARVs for 15 years now. If I had started three years earlier (given the drugs we have today), would it have made a difference? I don't know. But I plan and hope to be on ARVs for many years to come, so that three years doesn't seem like such a big deal to me right now.
Should EVERYONE start early, of course not. But maybe many of us can and will. And in doing so, maybe we can see a real decline in new HIV infections in New York and San Francisco and Johannesburg and Moscow and Bangkok. That would make me very happy.
Discussion about treatment-centered prevention approaches are taking place not because of some vast conspiracy to mistreat people living with HIV, but because the science is beginning to show us that treatment can prevent HIV. New scientific understanding of HIV and treatment is what has driven and transformed the response to HIV ever since the virus was first discovered. That is what is driving this discussion. In 1996, all of a sudden we had new tools to save our lives. But we didn't know how to use them. But we learned. That is what is happening now. And it's very exciting.
First, on the issue of when to start ARV therapy, I should begin with some background history. In 1989, a recommendation was made to start AZT monotherapy at <500 CD4 cells and well before the development of AIDS. That recommendation was made with little supporting data. After a year or so, it was clear that the recommendation was wrong. People who started AZT early actually did worse than those who started later. That mistake cost many people their lives. Unfortunately, the same mistake was made repeatedly - with dual therapy (AZT/ddI or ddC) in the early 90s, with AZT and 3TC a bit later. Each time, the recommendation to start early was proven wrong.
When HAART came out in 1996, the US Public Health Service ARV guidelines panel reviewed the scant information on when to start HAART. Once again, many of the scientists on the panel pushed hard for a recommendation of "hitting hard, hitting early" - starting at <500 CD4. But this time, the AIDS treatment activists on the panel - myself, Mark Harrington and the late Martin Delaney of Project Inform - all argued strongly that the recommendation should be to start later, at <200 CD4 cells or at signs of HIV symptoms. Our view was that we had no data whatsoever about early use of HAART - not one single study had been done. And we had made the mistake too many times before. These drugs were approved faster than any drugs in the history of drug development, thanks, in part to our activism. But that meant we had much less data by which to determine how to use them effectively. At that time, we had no information about the development of drug resistance, the need for high levels of adherence, or about most of the side effects from the drugs including lipodistrophy and body changes. And, we argued that if the US PHS put out a guideline recommending starting at 500 t-cells, there would be no way to ethically study the when to start question.
We lost the initial battle. The first HAART guideline recommended early treatment. And over the course of the next three years, we learned about the adherence challenges and the many serious side effects. Many, many people started treatment earlier than necessary and with inferior drugs. And, the definitive clinical trial was never done. Three years later, we were effective in getting the guidelines revised to a recommendation of starting at <200 t-cells or HIV symptoms.
But much has happened since then. There is now a significant amount of very compelling data from cohort and other studies around the world showing that earlier treatment has a positive impact on survival and in delaying not only AIDS-related illnesses but other illnesses that are the result of living with overly active immune system that is constantly battling viral replication, including heart disease, cancers, premature aging, as well as exacerbation of hepatitis C and TB progression. Although this data does not take the form of the more preferable "when to start" randomized clinical trial, it is increasingly compelling. Enough so that doctors and people living with HIV can make a very reasonable decision to use ARVs much earlier than we would have a few years ago. And because the drug regimens are now easier to take and with fewer side effects, the downside of starting earlier has decreased. Starting early isn't the only path, but it is a reasonable path. A change in the PHS guidelines in 2005 reflects this, recommending treatment at <350 CD4 cells. Now, the PHS is changing its guidelines once again to recommend starting at <500 CD4 cells. Again this is based on the data described above. Many doctors and researchers even believe that people should start therapy no matter what their t-cell count is. And they believe this because they think their patients will live longer and better lives for it.
The START study that Sean mentions would answer the question of when to start. Personally, I would prefer that the government (both the U.S. and the San Francisco Dept. of Health) wait until data from the START study is available before changing their recommendations. I think that public health officials have a responsibility to be more conservative in their recommendations, which should be based on the results of randomized clinical trials whenever possible. The emergence of other long-term side effects is one important reason to ensure that the START study is completed. The guideline recommendations will seriously hinder START enrollment in the US.
However, doctors and patients should have the ability to make more aggressive decisions about starting treatment if they feel, after analyzing the available data, that this is the best course of action. Similarly, I think Project Inform has every right to make its own policy decisions based on review of what is currently known. It is not fair nor just to accuse any of those involved in these decisions - guideline panelists, physicians, advocacy groups or people living with HIV - with some sort of underhanded conspiracy to coerce people onto early treatment for the sake of prevention or any other purpose. The data is there and starting early is justified. Again, it is not the sole approach, but it is a very viable one.
Despite Sean's assertions, the NIH-sponsored study that will seek to improve uptake of HIV testing and linkage to care - unfortunately labeled the "test and treat" study - is NOT placing people who test positive on treatment regardless of CD4 cell count. The study seeks to improve testing rates, link people to care, and offer treatment to those who meet current treatment guidelines. This is not a study testing the impact of earlier use of ARVs for prevention purposes. It is a study looking for ways to improve testing uptake and use of care. Up to 33% of people in the U.S. find out they have HIV by developing AIDS. This is a figure that has not improved in over 15 years. This is criminal. And this is not only a US problem. All over the world, testing uptake is horrible. This study is looking at ways to fix this. Treatment will be offered and recommended. Let's hope those who need it are able to access and accept treatment and use it properly. For some, it will save their lives.
The final issue involves the impact that ARV treatment can have in preventing new HIV infections. The data from Vancouver, from San Francisco and most importantly, from a large study of sero-discordant couples in Africa is showing that people taking ARVs are much less likely to transmit HIV. We still have much to learn, but it is very possible that ARV treatment may be the most effective HIV prevention tool we have and will have for many years to come. This is ground breaking news. Nowhere in Sean's piece does he acknowledge the potential good here. I don't want to transmit my HIV to anyone. Prevention is a challenge for all of us - positive or negative. If there is a way to help me make sure that I can't infect someone else, I want it. And I think most people living with HIV feel the same way.
Of course, treatment-centered prevention doesn't replace the need for condom distribution and other prevention interventions. But those interventions on their own have shown very limited effectiveness both in the US and around the world. Condoms won't end the AIDS epidemic. And there is no vaccine on the horizon for years and years to come. If we have a new tool that can effectively prevent HIV transmission, then we need to learn how to use it. And we all have a responsibility to figure out how to use this information in ways that can both protect from harm those of us having to take ARVs as well as protect others so that they never have to take them.
Of course, the threat of stigma and discrimination remains one of the greatest challenges we face in successful implementation HIV treatment and prevention efforts. We have always faced the danger of discrimination in our attempts to live with HIV openly and with dignity. The courage of people living with HIV to overcome these dangers as they seek out information, care and treatment has been and continues to be one of the most inspiring stories in the history of public health. We all need to be able to access treatment and live freely without fear. "Treatment as prevention" approaches do not alter this, but, rather make the need to overcome discrimination all the more important. Can we scale up HIV testing within a context of protecting human rights? We must do this whether we are using ARVs for prevention or not. Should patient confidentiality and choice be protected? We have advocated this course since 1981 as the only way we can expect people living with HIV to successfully engage in care. So, treatment as prevention doesn't really raise new issues in this regard.
There is a lot to learn. There are a whole slew of unanswered questions and challenges. Does earlier treatment put me at risk for more side effects or drug resistance? We don't know. A better first line combination regimen would go far to alleviate these risks, especially in resource-poor countries. That is within our grasp right now with some good advocacy and political commitment.
Personally, I have been on ARVs for 15 years now. If I had started three years earlier (given the drugs we have today), would it have made a difference? I don't know. But I plan and hope to be on ARVs for many years to come, so that three years doesn't seem like such a big deal to me right now.
Should EVERYONE start early, of course not. But maybe many of us can and will. And in doing so, maybe we can see a real decline in new HIV infections in New York and San Francisco and Johannesburg and Moscow and Bangkok. That would make me very happy.
Discussion about treatment-centered prevention approaches are taking place not because of some vast conspiracy to mistreat people living with HIV, but because the science is beginning to show us that treatment can prevent HIV. New scientific understanding of HIV and treatment is what has driven and transformed the response to HIV ever since the virus was first discovered. That is what is driving this discussion. In 1996, all of a sudden we had new tools to save our lives. But we didn't know how to use them. But we learned. That is what is happening now. And it's very exciting.
Hi David, first of all would like to give you a warm welcome to the Poz blogs, I am glad in meeting new bloggers over here :). Ah, nice pic too, LOL.
I read your post carefully... and well... i guess i would like to comment about it, i read Sean's post as well and i personally agree with many things he said. Off course, coming from third world my concern about early starting is different... not only because of the impact it may have on my defensive system... but being sincere... about the real availability of meds to do it.
We are still living in a world where meds are not available for everyone. That in part is one of the reasons why not everybody is taking meds just right now... we don't have enough medicines for those who really need them and governments don't have enough money to buy them and supply them for every single poz patient. I don't thik so. To suggest early starting should ensure.. and i repeat ENSURE there are enough meds for everybody and that is not happening. Yeah, perhaps right now some people might have some expectations on how many patients would have to start taking meds if these new guidelines are stablished... but from one year to another... the amount of patients needing to take meds under this guidelines can increase exponentially. Are Governments ready to cover this? I think they are failing right now offering proper health care to those who need it... i am in doubt they can offer correct supply of meds for those who need it under new guidelines. Plus.... do they really have the money to do it? take also into account we are still taking very expensive meds... at least here. A single bottle of meds costs sometimes more than may whole salary... and it is supposed i would need 2 different meds (2 bottles) per month. I personally won't start a treatment i am not sure i can maintain specially if my life is on risk.
The other point, which i think it touches us more directly is that... i see everybody really excited about this idea of meds for everyone... glad of that but... what about adherence troubles, lack of tolerance to meds?. I mean... it is not only about taking pills... and you know it, it is about the vomit, the lypo, the diarrhoea, fever, red dots on the skin, and more and more and more. You surely know as well as me, people who haven't been able to stand meds... i know drs who have left their treatment cause they simply couldn't handle it. I dearest friend of mine is now struggling with meds when i still think he could have waited more.... how does he feel? terribly. He is having "the worst time" in his own words. So what i want people to understand is... it is not only about saying "hey starting meds early is better"... what you are really saying is "take the bet with this treatment to see if you can handle it... if you do it then you will be fine... otherwise... well... you might face troubles...". That's a clearer message and this is what has to be underlined. In this specific issue we cannot be treated as a mass.. but we have to be taken in consideration like individuals... cause if this fails you will not lose a mass of people... you will lose several individuals and their lives count.
I know... i know all of us will have to start with meds sooner or later, but despite medical guidelines... it must be our own WELL INFORMED decission... not just motivated decission, but a decission well though cause it is our lives we are risking. So please... i think activists in general... should start remembering each person's tolerance to ARV differs from the other and that we are still failing in ensuring everybody can tolerate meds... lets adapt the message so people can really think about it and choose. It is their own risk they are taking. As for myself i will avoid meds as long as i can.
Ah.. and by the way, i know many drs suggest to start meds just right now with good intentions... but they don't take those drugs, they don't know how it feels... and how it pains. It's a matter that concern us poz people but the message must be really well transmitted about this and i don't see that. My personal opinion only.
"it is very possible that ARV treatment may be the most effective HIV prevention tool we have and will have for many years to come" - I have to say i totally disagree with this David. ARV are a choice, yes.. but not the only one and not the most effective one. If so we would not be losing people yet. I still think there is lot to do in terms of really educating people about this. Aha i know we have been talking about hiv for years...effectiveness is limited, yes.. and this initiative you support will also have limited effectiveness. It is not a gift sent from above. Hiv is a difficult virus and its prevention and treatment are not and will never be simple. I don't think education is wrong... i think we have to improve our ways to approach people and make them understand. It looks to me that breast cancer advocates are doing a great job....people are getting educated about it and getting tested.... where are we failing? we have to work on this.
"Should EVERYONE start early, of course not. But maybe many of us can and will. And in doing so, maybe we can see a real decline in new HIV infections in New York and San Francisco and Johannesburg and Moscow and Bangkok". Aha and from those "many of us" that might start treatment... there will be also "many" that might/will fail to tolerate the treatment or develop resistance... this MUST be explained too and emphatized. Also remember, hiv poz people might be not the ones who are infecting others (or not the only ones)... cause those of us who knows our status use protection when having sex... those who don't know their status might be infecting others too and they won't start taking meds for an illness they don't know they have. Putting lot of people in meds (if the ressources to do it appear) will for sure have impact, but how big the decline in new infections will be is something you can only guess. I wouldn't aim too high on this, it is better be conservative. There is really much more to do touch people understanding about the need for testing and to learn about the illness itself, meds are not the solution for this. A pill won't make my hiv neg friends understand their risk... specially cause they are not taking them.
"Does earlier treatment put me at risk for more side effects or drug resistance? We don't know." Off course we know David... and the answer is YES. It is simply statistics and logic my friend... if i don't take meds i won't suffer their side effects and won't develop resistance to them (unless my virus is already inmune to them). If i take meds.. any med... i will/might face side effects, and everytime i change meds i will/might face different side effects and off course... with every med i take i have the risk of failing in adhering to the treatment and develop resistance. The more meds i take the higher my probabilities to face side effects or develop resistance. That is a clearer message and people have to understand it. Off course meds are something we CANNOT avoid... but we have to understand clearly how the "game" works if we are going to make a decission. Things like this must be WELL EXPLAINED to everyone.
"the science is beginning to show us that treatment can prevent HIV" - I'm sorry for this but treatment cannot prevent hiv (you know what i mean), it is not proven yet. Treatment can fight Hiv that's the only thing we know for sure all the rest we are still guessing cause science is "beginning to show us". And by the way... as far as i know even a poz patient taking meds should keep on using condoms when having sex cause he/she is not 100% free of infecting his/her partner, it is not like people take meds can go and fuck raw just like that. So the sexual issue/logistic of having sex being poz does not changes much. This also must be clearly explained.
"But we didn't know how to use them. But we learned. That is what is happening now. And it's very exciting." Yes we learned and we lost so many lives in the way.... If the situation is repeating it is not very exciting to me. I prefer slow steps while we finally get sure about something and are not only motivated about some new trend.
I didn't mean to be rude in case it sounded like that, i am just really concerned about this. My decission about not taking meds until really need it was taken several years ago... when i though deep about this issue, that's why this topic interest me and i share my thoughts cause i have analysed this several times. Again, I hope we can be friends and compare ideas about this and other issues while being here in poz blogs. Take care man.
Juan
Thanks to David Barr for the historical perspective on the many changes made to the US Public Health Service treatment guidelines since they were first issued in 1998.
Mistakes made earlier were attributed to scant information then available; we had to learn about the development of resistance to the antiretroviral agents as well the toxicities of newly introduced drugs.
But the propensity to develop resistance by just about any microorganism, including viruses, to antimicrobial drugs was certainly no mystery, nor was it unexpected that toxicities would probably be revealed with longer use of new drugs.
It's hard to believe that infectious diseases experts and microbiologists knew nothing at that time of the probable emergence of drug resistant HIV or of the probable appearance of toxicities on further experience with new drugs.
In reality the biggest mistake made in 1997 was in not responding to these dangers and encouraging the completion of a prospective randomised trial, such as START, in individuals with more than 200 CD4s, that could by now have reliably provided an answer to the question of whether immediate or deferred treatment is better or worse or makes no difference that is, apart from cost. At that time we did have information from controlled studies that people with less than 200 CD4s received a huge benefit from treatment.
It's not the benefits of early treatment that are in question. Of course there are benefits, but the question we need answered is when in the course of HIV disease are the benefits of treatment greater than the risks.
By now the associations of HIV infection with chronic immune activation and inflammation are firmly established. I tried to give a clear explanation of these effects in two of my own POZ blog posts (April 11th 2010). The destructive consequences of persistent inflammation are absolutely not in question.
But long term exposure to antiretroviral drugs can also have harmful effects. It can take years to recognize some of these adverse effects. For example we learned only in the last few months that under certain circumstances neurocognitive function improved in some people who stopped antiviral drugs (ACTG 5170).
So the challenge is to find out how best to use the drugs. Put another way, we must find ways to safely minimize exposure to the drugs, which until we have drugs without significant adverse effects, is what determining the optimal time to start treatment is all about. We don't know if a person deferring treatment until a CD4 count of 350 will or will not live longer with an overall better or worse quality of life than someone starting at 800 or even 500 CD4s.
We do know that at 350 CD4s, benefits of treatment far outweigh risks. But no matter what NIH guidelines committee members or authorities in San Francisco may feel, we do not yet have the most reliable evidence that benefits of treatment will outweigh risks when starting at higher CD4 numbers.
The wording of the USPHS guidelines is such that depending on whose vote you go with, I suppose might even be interpreted to mean a recommendation for every HIV positive individual to receive treatment irrespective of CD4 count.
Of course Project Inform and the authorities in San Francisco have a right to make their own recommendations, as do 50% of the guidelines committee have the right to one opinion and 50% the right to a different opinion on the same matter.
But people with HIV also have the right to know the evidence for and against the recommendations - as the NIH panel does in fact publish.
David Barr has told us that when the earliest guidelines were being discussed, activists argued that setting a start level at 500 CD4s would make it impossible to ethically conduct a trial to answer the when to start question. A recent publication in the Lancet expresses this very same concern because the USPHS now recommends initiation of treatment at 500 CD4s.
The Lancet authors find no convincing evidence that deferral of treatment initiation to 350 CD4s is associated with harm.
People living with HIV/AIDS and those providing them with care deserve and need the most reliable evidence to inform their treatment choices. START can reliably and safely tell us when it's best for individuals with greater than 350 CD4s to start treatment.
I believe that many health care providers would welcome the opportunity to present an option to their patients with greater than 350 CD4s, to enrol in a study such as START.
At the end of the day, determining when it's best to start is not something you vote on. It's something so important that you nail it down with a trial such as START.