By Michael Smith, North American Correspondent, MedPage Today
Published: January 05, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
MICHAEL SMITH: I'm Michael Smith of MedPage Today. I'm here today with Dr. Myron Cohen of the University of North Carolina at Chapel Hill. Dr. Cohen, welcome to MedPage.
We've spoken many times about clinical matters. I want to get your insights on the clinical implications of the new guidelines of the International Antiviral Society-USA panel that were released in JAMA this summer. These guidelines have a major change. Up until now, the decision of when to initiate treatment has been guided by the CD4 cell count. What's the change?
MYRON COHEN, MD: For these guidelines, and also the DHSS [Department of Health and Human Services] guidelines which came out a little bit earlier, the recommendation is, in the absence of contravening forces, when you detect HIV infection, therapy should be started immediately, independent of CD4 count. That's a pretty big change, and it respects the accrued benefits, which are very, very strong.
SMITH: Now, you're talking here about the clinical benefits to the patient.
COHEN: Oh, I think there are two sets of benefits driving this, and they come up in the discussion in the JAMA article. One that has now, I think, pretty much been written in stone is that earlier treatment is better. It's like hypertension; people with hypertension don't feel sick, but they might be experiencing some kidney damage or eye damage. And so a physician who sees a patient with hypertension says, "Look, I know you feel well, but I really need you to take this pill," and then you monitor blood pressure.
Untreated HIV infection, it's pretty clear, has subtle but important effects, and those effects ultimately achieve clinical significance in AIDS. We would never want to see another AIDS patient. Hillary Clinton, in her speech at the IAS meeting, made that point.
HIV and AIDS are two different diseases. HIV infection can be controlled and a person can live a normal life. So what are the key steps? Number one, detection; people have to get tested. And the testing is being made easier and easier and quicker and quicker, and it works, and that requires a lot of steps, but it can be done.
And the second point is we've made -- not purposely, but we as a society and we as healthcare providers -- have made treatment complicated, okay?
Instead of just saying "High blood pressure needs to be treated," we have said, "Well, we're going to wait and not treat HIV infection." But the data that's accrued, both from observational and from clinical studies, including one I have done, demonstrate that starting people with earlier CD4 count has a fairly big impact on health and survival.
And so as you know, we started out at 250, a CD4 count of 200; then we moved it up to 350. And now I believe some countries will move to 500, and the U.S. has moved to start people immediately.
Now, let's talk about the downsides here. Pills have side effects, as do antihypertensives. So you're of course going to experience some side effects, and that's an issue. That's an issue.
SMITH: And that's something, of course, the clinician and the patient need to manage?
COHEN: Absolutely. They'll talk about the side effects.
The second downside is some small number of people, a very small percentage, were going to go on to be elite controllers and not have high viremia. That elite control will be washed away because we will be treating everybody.
But we don't know that elite controllers, even though they're controlling viremia, don't suffer some ill health consequences. Even though they're controlling the viremia, they may be experiencing subtle organ damage from the infection. And infectious disease specialists always like to treat infections, you know? We never like them untreated.
So the cost is the physical cost of the drug and dealing with the side effects, and the benefit is extending healthy life.
And another benefit that you're well aware of is that it becomes pretty clear that, at least for heterosexual transmission, you render people no longer contagious.
Now, I say that with some respect, because it's not perfect; not everybody's not contagious. Somebody must still transmit HIV. But in our own experience, it was nearly 100% prevention when people were adherent.
SMITH: I should interrupt you to say that this was the HPTN 052 trial you're talking about.
SMITH: You were the principal investigator on that and so you know it very --
COHEN: I know it backwards and forwards. And in that study, where we demonstrated virtually complete prevention of transmission, that was a powerful catalyst to thinking about earlier and earlier treatment, not just for the benefit of the individual but for public health purposes.
But as it turns out, many people want to know their status, because they want to be rendered not contagious, because of confidence in living their lives normally. So I've heard dozens of stories of people who came in and said, "I want to be tested, because if I'm infected I don't want to be transmissible." Inspiring.
SMITH: Let me ask you, from your personal clinical experience -- and presumably your clinical experience mirrors that of many doctors in this country -- what's the practical effect of this change? Are you seeing a lot of people coming in at high CD4 counts that you're saying, "Well, you're not ready to meet the guidelines yet," or are you seeing a lot of people coming in at low CD4 counts, where you would treat them in any case?
COHEN: That's a really good question, and there are a couple of points I'd like to make. First of all, once the community of caregivers thinks that it's in the patients' best interests, they're quite confident in explaining to the patient why they want them to start therapy, for all the reasons we've already talked about. So in our clinics, most people start immediately.
And then beyond that, that's bled into many other developing countries, so in many developing countries, especially in some subgroups, immediate treatment has also become de rigueur. Like, for example, for couples, the WHO very quickly said for people who know they're in a discordant relationship, the index case should be treated. The infected person should be treated immediately. Why would you risk another transmission event in that setting? And many countries have absorbed that very quickly, beyond the U.S. guidelines.
The other point to make about this is that part of the discussion then is catalytic in another way. So on a clinical basis, the physician says, "Okay, you're 22, 23 years old, 25 years old, we're going to start you on treatment." The person says, "Well, I'm going to be on treatment the rest of my life," but that pushes us through the "Cure AIDS" discussion.
It pushes us into magical thinking, but it's not so magical. Most of us believe that the disease will not be treated the same way 10 years from now as it is today. But either we'll use infrequent injections or some very long-acting set of pills, or we'll have some modification of the disease so that daily pills will not be required for 30 or 40 years.
And my colleagues who are working on the curing of HIV infection are very confident that the disease won't look the same. Maybe for 5 years or 10 years it will look the same, but not for 30 years.
This kind of magical thinking is necessary to empower us to communicate this to our patients. And in fact, in our own clinical setting, we have a group of patients that we treated very early with acute infection who we talk to about this routinely, about we're looking towards modifying this infection the way that will get you off your treatment.
Now, this is magical thinking; it's hopeful, it's aspirational, but that's not so strange in medicine, and you really need that. But, if we go to the present day reality, I think it's pretty hard to argue against treating people immediately for their personal benefit and for the health of the public.
Now, having said that, we'll present all of our clinical trial data that will inspire the 500 to 350 range. An ongoing study is looking at a higher CD4 count, and there's great debate about that ongoing study, because it's going to be difficult to argue that the juice isn't worth the squeeze, which is why people are willing to start immediately.
There may be some adverse effects at higher CD4 count, but on the other hand, there's the clinical benefit we've spoken about in terms of protecting organs, and that's kind of in the long term, and that's where we are.
SMITH: So the clinical advice of the guidelines is if you as a physician have a patient come in at any CD4 cell count, whatever, and that person is ready to start, enter into a part of therapy, that should be a question ...
COHEN: Yeah, I would use a different language. This "ready to start" belies this supposition that all is well and don't worry about this, and that happens in some parts of clinical medicine, sometimes. For example, we used to think a blood pressure of 140 over 95 was okay, until we saw people have heart attacks and strokes, and then we said, "Whoa, the normal blood pressure is less than 120 over 80.
So "ready to start" implies a dialog with a physician ... might be misleading the patient. At this point in time, most of our evidence suggests that starting treatment and stopping replication protects from organ damage, immune damage, kidney damage, central nervous system damage, and so an immune -- an advanced aging or cellular aging, inflammation; all of that stuff is going on in a subtle way. So letting people trail their CD4 count down, I think most experts think, is a bad idea.
Now, having said that, the other point is this. In the 052 study, we looked very closely at CD4 count. When we started people at 446, that was the beginning point, right? CD4 goes up 7, 8, 900 immediately, and it's there now, today.
COHEN: When we let people go to 221 and we try and get their CD4 count back up, we have trouble getting them to cross 500. Now, maybe you don't need more than 500 cells. But most experts, most experts, would prefer you had a normal number of CD4 cells.
SMITH: So you're going to get a better result the earliest ...
COHEN: The earlier you start. And I know that other investigators are publishing some very important papers that kind of agree with this kind of position in so far as CD4 might be a surrogate.
The other point about this is as follows: The monitoring CD4 count will become increasingly irrelevant when we do this, okay? It will be a CD4 count when you start, and then viral load a couple of times a year or unless you have some other problem.
And then a CD4 count -- if you get sick -- will be kind of done using the CD4 count as a metric, a critical metric. Because once you start somebody on therapy, their CD4 is going to do whatever it chooses to do. What you care about is suppressing viremia, so it will really change clinical practice pretty quickly I think.
SMITH: Let's talk about some other small changes in the recommendations in terms of what to start with. They've added, I think, it's efavirenz and abacavir/lamivudine as a preferred regimen.
SMITH: Do those make any difference, or just expand the options?
COHEN: Well, that becomes a very intense discussion among very passionate people about what's best for an individual patient. And I think in general, the clinician really - and it's going to be hard to get treatment of HIV infection away from qualified specialists. Every study that's been done has suggested that people who know how to use these drugs and drug interactions and drug side effects do a lot better than people who aren't familiar with the drugs.
So the backbone -- most people like to talk about a backbone and then a third drug, and it's pretty clear you need at least three drugs, and then there's some evidence that the new four-drug pills might make a difference, as you know.
So I think I'd be hesitant -- I went to the British meeting, the BASHH meeting recently, and spent a day talking about this, and it was interesting. I think that this will evolve, but it's individualized, and that's what's pretty clear to me. You have to look at a patient's ability to tolerate the particular side effect, you know.
Somebody who's already got some kidney dysfunction might prefer one drug over another. Somebody who's had a history of depression and some sort of psychiatric illness might not do well with one or two of the drugs. And these are very special, individualized, so there's not one-size-fits-all.
But what's clear is some combinations lower viremia quickly, are easier to sustain suppressed viremia. And I think that we've got a great cookbook right now of drugs, and that people who know how to use them will almost certainly use them wisely.
SMITH: Dr. Cohen, thank you for this. This is very insightful, and we appreciate your time.
COHEN: Thank you. Thanks Mike.