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On Dec. 1, the U.S. Department of Health and Human Services updated its Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. We are pleased to have with us David Wohl, M.D., to provide a summary of the changes. Dr. Wohl is not only one of the top HIV clinicians and researchers in the United States, he's also a guidelines panel member.
Dr. Wohl, thank you so much for joining us! Can you walk us through what you think are the most critical updates to the revised HIV/AIDS treatment guidelines?
Let me first say that, while I'm on the guidelines committee, I'm going to be speaking to you today from my own personal experience and not as a representative of the guidelines themselves.
We're discussing the Department of Health and Human Services HIV/AIDS treatment guidelines. To put together these guidelines, the U.S. Office of AIDS Research Advisory Council gathers together a panel of experts in HIV care and research from all walks of life. Some are doctors who treat patients. Some are doctors who do research. Some are nurses. Some are community members -- there are four or five people living with HIV on the panel. There are also pharmacists and representatives from different governmental agencies.
The panel meets and talks and considers the available data. What we try to do is make heads and tails of lots of different HIV/AIDS data coming from research throughout the world. Our goal is to find the best evidence for what we should do in clinic for our patients.
The guidelines that came out on Dec. 1, World AIDS Day, basically reflect what's gone on during the last year or so in the HIV treatment world. I'll be summarizing several important changes to the guidelines.
When to Start HIV/AIDS Treatment: Earlier Treatment Recommended for Everyone
Click here for a full PDF of the revised Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
One of the changes to the guidelines is the level of the CD4 cell count (T-cell count) at which it is recommended that people start HIV/AIDS treatment. This level has been a moving target and has changed over the years, which reflects how good our HIV drugs are and the data we have that indicate that treating at a certain time point is better than not treating at a certain time point.
It helps to look at this historically. We used to treat really early in HIV disease, when CD4 cell counts were at 500, but that was a long time ago when we had very few HIV medicines that worked. Back then, we basically had AZT [Retrovir, zidovudine].
We didn't see studies that showed that there was much benefit to that, because AZT alone doesn't work very well. Then we had studies that showed that starting at a CD4 count of 200 and below is probably where you get the most bang for your buck, so we started treating people who had a CD4 count of 200 and below.
Then newer therapies came out that were more potent, and research showed very clearly and very quickly that waiting for 200 was not a good idea when we have really good therapies, because you can get benefits even earlier. So the guidelines shifted once again, this time to starting treatment when someone's CD4 count has reached 350, because that's the number between 200 and 500.
More recently there have been more data that have come out -- much of it from studies looking at large groups of people followed over time -- that indicate that there might be a benefit to starting HIV therapy even earlier than 350. That is the discussion that you're going to hear when people talk about these new guidelines: The shift has been to try to treat earlier, and we're seeing this in clinics throughout the U.S.
Sometimes, guidelines are issued and they'll make recommendations and then people follow them. Sometimes, guidelines reflect what's already starting to happen in clinic, because everyone reads the data -- everyone reads the evidence.
What we're seeing in these new guidelines is a recommendation that at a CD4 count under 350, it's a no-brainer: People should start therapy. At CD4 counts between 350 and 500, treatment is recommended. In fact, these guidelines note that we should be giving people therapy at that CD4 cell count based upon the available data that we have.1 There are some really good data.
For CD4 counts over 500: There is discussion of how half the guidelines panel thought that was a really good idea, and half the panel thought that there really wasn't enough data to support that recommendation. The panel was evenly divided regarding starting therapy at CD4 counts above 500 versus waiting until under 500.
I think that we'll get more data over time that can help make this decision clearer, but we're seeing a real shift to starting HIV therapy at a higher CD4 cell count, above 350. Treating at CD4 counts between 350 and 500 is recommended here in these guidelines. That's a big change.
Dr. Wohl, what are the benefits of starting HIV/AIDS treatment at CD4 counts above 500 versus waiting to start treatment? There was a whole section of the guidelines devoted to considerations like inflammation that have made starting treatment earlier a convincing argument.
At the large HIV/AIDS research meeting known as the Conference on Retroviruses and Opportunistic Infections, Mari M. Kitahata, M.D., M.P.H., presented her study showing that HIV-positive people who waited until their CD4 count was less than 500 to start HIV treatment did not do as well as those who started treatment before their CD4 count was less than 500. To hear a summary of this study (as well as a study with different results), click here.
The one thing we don't have that could be extremely helpful here is a randomized study. By randomized, I mean you randomly take half the people and say, "You, with the CD4 cell count over 500, you start therapy; and you, with the CD4 cell count over 500, you don't start therapy; and let's see how you guys do."
Even with that study design -- and there is a study like that under way in the very early stages [the study is called START and is currently recruiting] -- it's still not completely certain that the people selected will be representative. However, it's the best way we have to determine whether or not one strategy is better than another. We don't have the results from this study yet.
What we have are other data that point the way to whether or not one strategy is better than another. There are studies that look at large groups of people who started HIV therapy at a high CD4 cell count versus a bunch of people who didn't start therapy at a high CD4 cell count. These studies show that there may be some differences between the two groups -- especially in that 350-to-500 range, and even in one study that looked at people who started therapy when their CD4 counts were above 500: People who delayed starting therapy didn't do as well, whether we're talking about AIDS progression -- meaning getting sicker -- or even death.1
There are also a lot of data that show that HIV-positive people whose HIV is not under control have more inflammation. Inflammation is a big, long word that just basically means swelling. Swelling is not only what happens when you hit your thumb with a hammer. There can also be chemical inflammation where there are chemicals that your body makes that say, "Whoa, there's an infection here and we have to fight it. T cell, you do this. B cell, you do that. Immune system, get revved up and fight this."
In HIV-negative people, we know that being in a state of chronic inflammation is not good for your body. It's not good for your organs: It's not good for your heart; it's not good for your kidneys. Inflammation over time wears down the body. If you have inflammation from HIV, the hypothesis is that this is bad for you.
One of the reasons why HIV therapy does a good job of helping people, even those with higher CD4 cell counts, may be that it reduces inflammation by getting rid of virus as much as possible, and virus promotes inflammation. There's this vicious cycle that's broken if you can get rid of as much of the virus as possible. But that's not conclusive.
We don't have the studies yet that are going to make that a slam dunk, where we know we're going to have to start therapy the minute someone's diagnosed, regardless of his or her CD4 cell count. What you see here in the guidelines is a discussion of the various pros and cons.
One "pro" is that we could prevent opportunistic infections, we could prevent all the things we always knew about, but we may also be preventing inflammatory-related diseases. There are not a lot of data that say that that is exactly what happens, but there are enough data there to say that it's possible and that things are pointing in that direction.
Then there are the "cons" that everyone knows about: You'll have to take therapy longer; there could be long-term toxicity that we don't know about; there's the cost of taking medicines.
We used to think these medicines were highly toxic until we did a study called the SMART [Strategies for the Management of Anti-Retroviral Therapy] study,2 in which we randomized people who had high CD4 cell counts to take medicines and continue on their medicines, or stop their medicines. The people who stopped their medicines got sick, even at high CD4 cell counts.
HIV therapies have their toxicity. But HIV itself has its toxicity. HIV is a toxic virus with lots of side effects. HIV medicines can have some side effects, but I think that the virus probably trumps what's going on with the medicines. However, there may be a point where there's more of a balance, where if you start too early, the longer-term toxicities outweigh the benefits of therapy. We just don't know where that point is, or if it even exists. That's what we have to see.
So people in this situation really need to have long discussions with their HIV/AIDS specialists and carefully think through the decision regarding when to start treatment. There's no clear guidance here on when to start treatment for people who have over 500 T cells.
Exactly. I think "over 500" is a real gray area. With the last guidelines, the gray area was over 350. I think the nice thing that we're seeing with some clarity here in these guidelines is that, at CD4 counts between 350 and 500, therapy is recommended.
For people with a CD4 count over 500, this is becoming a target of investigation. This is an area where we're now more and more concerned. I think what we're saying in these guidelines is, basically: Should HIV be an infection that we treat from the very beginning, like we treat other infections?
There are not too many infections where you are diagnosed and the doctor says to you, "We can treat it. We have medicines. But you know what? Let's wait until you get sicker. Let's wait until it gets worse and then once there's some damage done, we'll repair that damage and treat you."
I'm being somewhat facetious here, but we don't do that with other infections. We do that with HIV, and we've done it for a long time, sometimes with good reason.
The question is: Is there still a good reason to do that? We're getting closer to understanding the answer to that question, but we don't have it yet. At least now we're putting it within our sights, saying that this is a span of CD4 cells, 500 and above, where we have to find out: Is therapy justified or not? Here are the data points that say it is. Here are the concerns that say we should be careful. You see that balance between these two strong arguments played out in these guidelines.
Let's say a person's CD4 count is 600. Is there a reason to start treatment just to preserve the CD4 count of 600, because when it goes down to 500, she or he might not be able to get it up to 600 again?
Generally we don't see that. Most people who have a CD4 cell count that's still above 200 or so can get a robust response after starting treatment. Some people who are older -- patients who are in their 60s or 70s -- may not see as robust a response. But generally, if you have a CD4 cell count of 500, you can usually get it higher.
I think the converse of that is if you have a CD4 cell count of 600 and you don't get treated, how long is it going to be before you start therapy anyhow? Are we talking about delaying therapy for 18 months, or 24 months? Then the question becomes: Why not just start treatment now?
I think that there are a lot of concerns here, a lot of discussions. We're in this gray zone of above 500 where we don't have the randomized data. We have these large cohorts, these large groups of patients, but there could be bias that's introduced in those cohorts that we can't tease apart. They're not as instructive as a nice randomized study. We're not going to have that for a while. In the meantime, we have to make decisions for ourselves.
Of course, it requires a conversation. When I see patients in the clinic who have a higher CD4 cell count, we talk about this and it depends on a number of factors: "Do you have the wherewithal to start treatment? Are you having any symptoms that could be related to HIV that treatment might help? What's your viral load?" If someone has a really, really high viral load, I might be more excited about starting him or her on treatment than if he or she had a low viral load.
These are all the features that go into this discussion. It's a very personalized decision.
Dr. Wohl, what would you do if you were HIV positive?
If I had HIV infection, I would want to start therapy early. I'd want to start therapy soon after I was diagnosed.
For all the reasons you mentioned?
Yes. I can't tell you that the data are conclusive, as I've said many times already, but I think there are dots that you can connect. Personally -- it's a fair question -- I would want to start therapy earlier rather than later.
In terms of adherence, I think I could take therapy every day. I don't think it would be easy for me. But I think I could do it and I think I could have myself monitored to make sure that I wasn't suffering side effects, and if I were, to make modifications as needed. But I think I could handle it. It takes a commitment, but I think I would do it. I don't think I'd want the virus doing stuff to me for all that time before I started at a CD4 count of, let's say, 350.
HIV/AIDS Treatment at Any CD4 Count Urged for Some
Are there people who should always start HIV treatment regardless of CD4 count?
Yes, there are some people who, almost regardless of their CD4 cell count, should start HIV therapy. We know that people who have hepatitis B could benefit from medicines that treat hepatitis B. Some of those medicines are also HIV medicines and it can get complicated. Many of the patients who have hepatitis B should really be on HIV therapy at the same time.
When I talk about hepatitis B, I don't mean you've been exposed in the past. I mean the virus is actively in your blood, doing bad stuff to you. Hepatitis B is another thing that we can treat with the same medicines that we use to treat HIV. That can be done really nicely and can get both viruses undetectable.
People who have kidney disease should start HIV therapy immediately. Most kidney disease in people with HIV is related to HIV itself. We know that when you start HIV therapy and have kidney disease, your kidney function gets better. I would say, as both the U.S. Department of Health and Human Services guidelines and guidelines that are issued by another committee, the International AIDS Society-USA [IAS-USA], indicate, you should be treated if you have kidney disease and you're HIV positive.
Finally, regardless of CD4 cell count, it makes sense for pregnant women to start therapy to prevent transmission of the virus to the baby.
Another group that the IAS-USA guidelines recommend that we think about treating is people who have cardiovascular disease, because inflammation is bad for the heart. That's another softer indication, but people have talked about that as well.
For anyone who has symptoms: It's important to note that you may have a high CD4 cell count, but you may have symptoms related to HIV -- recurrent infections, an opportunistic infection, thrush, diarrhea. I would treat those people. The guidelines are very clear about that.
What about symptoms like neuropathy?
There are fewer data on those kinds of symptoms. For people who have neurological problems related to HIV, whether it be neuropathy or cognitive dysfunction, there's theoretically a basis for why therapy may help those individuals, but we don't have a lot of data that say that if you get on therapy, things will improve. I think that we don't know as much about those problems as we do these other conditions where we have data.
Which HIV/AIDS Medications to Start With: Changes to the Preferred List
We just discussed when to start treatment. What do the new guidelines say about what to start treatment with?
What to start with is really about trying to decide -- from among the different options you have available -- how to craft a menu of HIV therapies that looks good. The key thing to remember here is that this is all based upon data of groups of people. There could be 800 people in a study and we're looking at which drug combination does better at getting the viral load down and which drug combination does better as far as being tolerable. These are comparative studies in large groups of people. For you, it may be different. It may be that you come in and you have a specific circumstance where the therapy that looks great in a study would be a really, really bad idea for you. So regimens have to be individualized.
There's a list of HIV drugs that the guidelines panel puts together. Some of them are considered "preferred" medications. Based upon the science, these drugs look like they should work the best and be better tolerated than others.
Then there are these other drugs on the "alternative" list that may have come in second, but for some people, they could be the better option.
These lists really help guide clinicians and individuals living with HIV about what the studies show, which regimens look good, which regimens look worse. Remember, nowadays, "worse" means only 70 percent of people, instead of 78 percent, became undetectable in two years. Generally drugs on the preferred and alternative lists really work well. Factors such as individual preference, copayments, formulation, pill count or side effects have a lot to do with whether people get on therapy or not.
Trust your doctor, your nurse, your PA [physician assistant]. These are people who are advising you. Do your own research and see what makes sense. The guidelines are not generally written for individual people, but there's plenty of stuff on TheBody.com that's written for everyone to understand, all about the different therapies and their pluses and minuses.
I noticed Isentress [raltegravir] was added to the preferred list and Kaletra [lopinavir/ritonavir] was removed from the preferred list and moved to alternative.
Kaletra is still a good therapy for many people and it's a popular drug. It's now considered an "alternative" because there are a couple of studies that showed that compared to other boosted PIs [protease inhibitors], drugs of the same class, it came in second overall. It still did a good job, but it came in second.3
That's a consideration for many people. For people who are on Kaletra, that doesn't mean that you have to rush out and change it. Quite the contrary. I think most clinicians will keep people on Kaletra who are doing well on Kaletra.
It's a matter of what we think about when we're starting someone with HIV therapy now. We have to talk about it. There are advantages and disadvantages to every single combination and this is one of the things specialists have to talk about with individuals. Yes, a drug may no longer be listed as "preferred," but it's an "alternative." For many people, an alternative could be preferred, like I said before.
Isentress is a drug in a new class. There was a nice comparative study against Sustiva [efavirenz, Stocrin].4 It looked just as good. I think this is another option for people. It's something that's starting to be embraced. It's a twice-a-day medicine, compared to Atripla [efavirenz/tenofovir/FTC], which is a once-a-day medicine.
How much inroad is it going to make? For some people it's a good idea, especially people who can't take Sustiva because of the vivid dreams and other central nervous system side effects, and who can't take Norvir [ritonavir], which is what we use to boost PIs. It's another option and you can't say it can't be preferred because in a head-to-head trial it did just as well as one of the "preferred" regimens. Many of us think that this is a really good option for people starting on therapy.
Is there any sense that a new drug added to a list is better than the older drugs? Some people just think, "It's new. It must be better." There also have been rumors that Isentress may be stronger than other HIV meds. If someone is on another regimen, should they switch to the newest one?
I think what you're getting at is: Do you want to be the first to get the new thing, or do you stick with the tried and true and wait, such that you end up being a late adopter rather than an early adopter?
Some want to be the first one on the block to use a new drug. Others want the drug to be out there for a while. It's very individual. I think people should use these guidelines. They're really well thought out. They're evidence-based. I think you have to have a really good reason not to follow these guidelines.
If you're going to come up with some other combination of drugs that are not on the preferred or alternative lists of the guidelines, there has to be a fantastically compelling reason to do that. There are those reasons, but these are really good guidelines. I think the combinations listed here are what people should start treatment with.
Preventing HIV Transmission
Another new addition to the guidelines was a section about prevention for HIV-positive people. Could you talk about that?
I think that the guidelines are reflecting an increasingly important awareness that HIV therapy is also part and parcel of HIV prevention. We know that when people take HIV medicine, they become somewhat less infectious -- probably not absolutely 100 percent non-infectious. We know that there is virus in the genital secretions that may be there even though we can't detect virus in the blood, and that these two compartments can be different.
We also know that if someone gets an STD [sexually transmitted disease], like chlamydia or gonorrhea, the viral load in the semen or vaginal secretions can spike, even if their blood viral load is undetectable.
There's a lot that is talked about here about trying to marry HIV therapy to behavioral interventions. The idea is that we can talk to people about how to be safe and not transmit the virus to others, and there are good, creative ways to do that. Some of them -- most of them -- involve using a condom. But there are other ways too. Maybe also thinking about HIV therapy and using that to augment the behavioral strategies that exist. But too many clinics don't use behavioral interventions.
More and more clinics have to think about how to integrate behavioral interventions that get people to be safe, rather than just telling people they should use condoms. Telling people they should use condoms just doesn't work. We've spent a lot of time and money finding out about that. But there are ways to motivate people to be safe, to do things that would decrease tremendously the risk of transmitting their virus to somebody else.
Part of that is getting tested. People who are transmitting the virus to others often don't know that they're HIV positive. Getting people tested is a big deal. Everyone reading this, especially if you've not been tested before, should get tested and should be deputized and try to find someone else who hasn't been tested and get them tested. Everyone should be tested.
Treatment as Prevention
Can you explain the philosophy of HIV treatment as HIV prevention? What does that mean?
The idea here is that if we can find people who are HIV positive who, let's say, don't know that they're HIV positive, have them find out that they are positive and then offer them treatment, we've done a couple of things. One is we've made a person aware that they have this infectious disease. That alone may impact their sexual behavior.
Two, there's an opportunity now for us to introduce behavioral interventions such as counseling, motivational techniques, all sorts of things that may be appropriate for a particular type of person. It may motivate them not to do things that might spread the virus to others.
Third, we can get them on HIV therapy. We know that HIV therapy seems to reduce people's infectiousness. We don't know if it does it absolutely, but it does seem to decrease the risk of infection to others to some degree. That degree is not completely spelled out, but these are opportunities.
About 25 to 28 percent of people with HIV in the U.S. don't know that they're infected. There are estimates that those people may be responsible for half of all HIV transmissions.
We've got to get people to find out if they're HIV positive, so HIV testing has to be expanded. We need to treat those who are HIV positive so that we improve their health and also reduce their risk of transmitting HIV to others. We need to apply behavioral interventions that are appropriate. Then, we need to continue to follow those people. Keep those people on therapy. Keep those people in clinic. Keep them working on their behavioral interventions. We need to promote behavioral techniques that can help people understand best ways, best strategies, best reminders, whatever it will take to keep people from transmitting the virus to others. There are effective ways of doing that and all of us know that.
That's the whole concept in a nutshell: Find, test, treat, retain in care, and maybe we can help reduce HIV transmission in this country, which seems to be on an upswing.
I'm afraid we've come to the end of our time. Thank you, Dr. Wohl.
This transcript has been lightly edited for clarity.
Click here to view a summary of the changes in the guidelines.
Got comments on the new guidelines? The guidelines committee notes that the public has a two-week window to submit comments (until December 14). But the guidelines committee will accept comments at any time via e-mail at email@example.com.
- Kitahata MM, Gange SJ, Abraham AG, et al, for the NA-ACCORD Investigators. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. April 30, 2009;360(18):1815-1826.
- 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.
- Molina J-M, Andrade-Villanueva J, Echevarria J, et al. CASTLE: atazanavir-ritonavir vs lopinavir-ritonavir in antiretroviral-naive HIV-1-infected patients: 96-week efficacy & safety. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-1250d.
- Lennox JL, DeJesus E, Lazzarin A, et al, and STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. September 5, 2009;374(9692):796-806.
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