One on One With Cal Cohen, M.D.

Stalemate -- but Not Checkmate: An Expert Takes on the Challenges

Jeff Berry: What do you see as some of the most challenging issues you encounter as a clinician in treating patients with HIV?

Cal Cohen: There are a number of infectious diseases that you take a pill for a couple of days and they're gone. If you have pneumonia, if you have strep throat, if you have syphilis ... you treat it and it's gone. Unfortunately, HIV is the opposite model. As far as we know, it will probably never leave the body. And therefore, we're talking about stalemate, we're not talking about checkmate. We're talking about a regimen that maintains control of this virus because when it grows, it causes damage. So we have to stop its growth, for as long as people are alive.

To me, that's what continues to be the most fulfilling part of this field; for almost everybody -- we can get the virus under control these days. Almost everybody. Obviously, that's terrific. The days of pneumocystis and cryptococcal meningitis and resistant viruses and all that stuff -- those were miserable days and those were miserable diseases. Dealing with death and disease you can't stop is a miserable, sad story.

These days, treatment is way better than that. That's great. When HIV is controlled, it's quite remarkable how well people do. We know at the current time that when somebody starts on a regimen, that most people who take most of their meds will do fine [emphatic pause], and most people won't have virologic breakthrough.

That's the importance of adherence. That's what creates the dividing line -- between the likelihood of treatment failure, that the regimen is going to fail and then if all doesn't get better the next time, you're going to be stuck with untreatable HIV vs., hey, no, your HIV is under control and we can focus on the fact that you don't like your job and you don't like your boyfriend. Or you do and what do you plan to do to celebrate? And those kinds of things are very important, but obviously they are a luxury to focus on if your viral load is 200,000 and your CD4 is 20, and you're coughing.

We're not glib enough to think HIV is irrelevant even if the viral load is undetectable. Nevertheless, most of us are very confident that if the viral load is undetectable, most people are fine most of the time.

But on the other hand, it's taking medicine every day, every day, every day, at least so far. We've done some research, called the FOTO study, to show that daily meds are not necessarily the only way to go about this, at least for those whose virus is suppressed on three of the longer-acting antiviral medications. But for now, even with the possibility of short breaks, we are talking meds most every day. For some people that's fine, but there are some people for whom that's just hard to do, for whatever reason. And for the people for whom it's easy, it is in some ways incomprehensible that it's ever hard. But a clinician's job, obviously, is to take care of both kinds of people.

There are times in which people can go from one category to another. For example, there's someone whose life is going well and they're taking their meds, and life is good, and they have access to health care. But things can change. Depression is certainly among the most common reasons why some people may just say, "The heck with it. It isn't worth it anymore. I don't care about my HIV meds because I don't care about a long and healthy life anymore." Other people slip into drug abuse, whether it's crystal meth or other drugs, and they're no longer so dedicated to the ongoing daily medicines to control their HIV because other things sometimes take precedence. For others, it's economics, which is obviously a worry for our health care system nowadays. Can I afford these meds? A clinician needs to ensure that those issues are handled, because that makes the difference for those people who will maintain control of HIV so that it may not even be in the top 10 medical concerns in their lives. Or it may be at the bottom of the top 10, but not at the top of the top 10.

JB: We're seeing an aging population of people living with HIV. Any idea about the complications of inflammation, whether as a result of HIV or the medications used to treat it?

CC: I think it's worth noting the obvious, that this is part of the point of getting HIV under control. It's worth reminding ourselves that as we all age, things can and often do start to go wrong. Putting that into context, yes, we are, as a field, now concentrating on changes that happen to people as they mature, and since heart disease is very common, there's been a lot of interest and focus on that. In addition, we're certainly worried that when HIV is uncontrolled, it increases the risk of heart damage and heart attack.

Similarly, when we treat HIV with some medications, the risk is also higher than with other medications. There are two versions of that story. There are medicines that change the known risk factors, meaning that they change your cholesterol values in ways that we think is unfavorable. That's real and we try to avoid those meds as much as we can. These days, most of us start people on the most cholesterol and lipid-friendly regimen we have, and that's great.

At the same time, though, we are aware of some studies that show that some of these medications contribute to an increased risk of heart attack despite, or in addition to, whatever they do to cholesterol and other changes. That's been the focus of the past couple of years of work, mainly around the drug abacavir [Ziagen], and also to some extent around the use of [lopinavir/ritonavir] Kaletra, the protease inhibitor. And a few of the other protease inhibitors, for example, fos-amprenavir [Lexiva], all are in this category of medications that at least have an association with a higher than predicted risk of heart attack in people who are on them vs. people who are on other treatments.

These data are certainly controversial. There are studies that see this, there are studies that don't. There are people who feel that this is some important signal to respect and there are other people who feel that the whole thing is probably just a mis-reading of the data we have. So there's controversy. And each clinician has to decide how much they want to use that information to make judgments.

Nevertheless, even with the controversy it's important to recognize that we do have some medications that consistently are not shown to be associated with a higher risk of these problems. I think many of the revisions in the most recent guidelines from the DHHS in 2009, which just came out on December 1st, summarize which medicines at the current time seem to have the lowest risk of changing both the known factors -- like changes in cholesterol -- and changes in the unknown risk factors. And do well to control HIV with fewer risks.

JB: In your opinion, if you had a patient who was on, say, Kaletra and they were experiencing these changes over a long period of time, would you switch them? Or is that irreversible once that damage is done?

CC: Let me make sure I understand. Let's define irreversible -- like for somebody who had a heart attack?

JB: No, just elevated triglycerides over a period of time.

"We also know there are rules for how to switch without creating virologic breakthrough."

CC: There's no doubt that if somebody is on, say, Kaletra and has elevated triglycerides, that we have a lot of studies, all of which have shown we have medications to use instead of Kaletra that would reliably lower the triglyceride fraction.

There's actually some ambiguity about this topic -- in terms of which of the lipid fractions are important. There's controversy in, for example, how important triglycerides are in predicting the risk of heart disease. Nevertheless, let's just say we have someone with what we call globally abnormal lipids. We do have a number of studies that show we have medicines that can usually improve the lipid profile. We also know there are rules for how to switch without creating virologic breakthrough.

So, in recent years, we've had a lot of information about how to switch and how to switch correctly. We also have recent studies to show us that sometimes we get it wrong and that there are rules to the game and that switching should be done by somebody who knows the rules of the game. It shouldn't be done by somebody who doesn't understand HIV medications.

JB: Do you think there's still a need for expanded access to newer agents for those currently failing therapy or will there be over the next year or two? If so, should the drug companies always provide an EAP [expanded access program] or only in certain circumstances? And if so, what should those be?

CC: At the current time, probably the only expanded access likely to be relevant are for drugs that offer advantages to people whose virus can't be controlled without that drug. The only drug that I'm aware of for which that may be potentially true is the maturation inhibitor called bevirimat. It's being developed as it often, though not always, is active against resistant viruses -- resistance specifically to other drugs in other classes. So that's the drug that, in the next year or so, may be critical to have in an EAP. Others may also be identified, such as newer integrase inhibitors. We shall see.

JB: Can you talk a little bit about treatment as prevention?

CC: First, let's review the basics. We know enough intellectually so that we don't need to use treatment as prevention, right? We know how the virus is transmitted and therefore, people who are negative can stay negative, even if they have sex with positive people. I'm saying the obvious, but it is true. I think it's reasonable to reassure the negative partner of an HIV-positive person that we know the rules of the game of sex and we know, for example, kissing is not going to transmit this virus and that there are things that they can do sexually that just don't transmit HIV.

So, if we then accept that despite knowing that, we still have an epidemic of 55,000 new infections in the U.S. every year, many suggest we need to try something else. In other words, our strategy historically that says only that people should be protecting themselves -- it just hasn't fully worked, so what else can we do?

If somebody says, "I'm positive in a relationship where my partner is negative, and I would like to go on treatment so I can protect him or her," that approach seems very much supported by the data we have so far. There's very little doubt that when somebody is positive and on treatment they're much less infectious to partners than if they're off treatment. I think that's pretty clear, even if not guaranteed.

I think the piece of this that is going to get a lot more interesting next year is what do we do for treatment as prevention for the negative person, what's called pre-exposure prophylaxis. I think that's now become very interesting because that changes the whole story line. Now, somebody who's positive can be on treatment to protect their partner, but somebody who's negative can potentially go on treatment to protect themselves.

Where some people get nervous with this conversation is if people then say, "Now that I'm on treatment and my viral load is undetectable, my partner and I can do anything we want because the risk is essentially zero." I think that's where the controversy brews because it is entirely possible that their risk still isn't zero, because there are men who have HIV in their seminal fluid even though in their blood it is undetectable. We know that's real and there are studies showing that three to four percent of men fall into that category -- and we don't know who they are unless we do viral load in seminal fluid and most labs don't have that capability. So the messaging still has to be "Yes, it's much less risky to you -- on the other hand, this doesn't mean that you can feel as confident as we wish you could feel." So this is better and may make the odds go from one percent risk to one in a thousand risk, but it doesn't make it zero.

"For me, the biggest exasperation is the intrusion of for-profit insurance companies on decision-making."

JB: We're seeing more and more individuals being diagnosed and coming into care with substance abuse and mental health issues. What are you seeing in your patients and how are you addressing those issues?

CC: Well, in my personal practice I'm not seeing more and more. I'm seeing a steady amount. I think the drug many of us are challenged by the most is crystal methamphetamine. Certainly, its use in urban gay men is well-documented and of concern to many of us, partly because of what it does to people. It seems to have a power to make people prioritize sexual experiences at the expense of other things in life, like holding a job, like having an income, and even taking HIV meds. And that's always regrettable, and when people are in that struggle, sometimes it's hard to convince them that they're in it.

Sometimes it takes lots of discussions and lots of time. Sometimes it takes multiple discussions with multiple people. A very wise psychiatrist named Glen Treisman in Baltimore, whose life's work is dealing with psychiatric issues and substance abuse, said the key to dealing with substance abuse is you confront it. You're honest and you confront it. You say, "This is what's going on with your life. You don't think so, but it is. And if you are able to change this direction, your life won't be going in this downhill direction. That doesn't mean that your life will be perfect. There are always challenges." Some people say, "I don't really care." "You don't understand." "This is way better than you'll ever find out" and that's it. But, as Glen said, part of medicine is this persistent optimism that you are an agent of people's health for whatever it is that they're ready to change. You say this is where this is going and if you want help to go somewhere else, that's why I'm here.

JB: What do you find most exasperating about your work?

CC: Exasperating? Probably for me the biggest exasperation is the intrusion of for-profit insurance companies on decision-making that we want to do, because they are prioritizing expense rather than health. Being told that when I prescribe a new regimen for somebody, oh, let's say [Isentress, Intelence, and Prezista], and being told the pharmacy can't dispense one of those three because the insurance company doesn't approve that. To me that's just profoundly irritating that some likely extraordinarily ignorant human being -- ignorant meaning they don't know what I'm about to talk to them about -- is going to answer the phone and through a series of buttons, allow me to take care of somebody who I have spent 20 years figuring out how to prescribe for, and I think that they have no business in intruding on it. I appreciate the economics, but it makes me craaazy that the system doesn't seem to figure out that some of us should be allowed to do what we do without the intrusion of that stuff.

JB: Wow. I never thought about that aspect of it.

CC: It's even worse, in some ways, because when the pharmacy or pharmacist is under-informed and they give that person two of the three meds but not all three, because the third one is not approved, and the person then takes the two of the three but not all three, then that is potentially disastrous. I've had that thankfully rarely, but those are the kinds of scenarios that I truly want to just put on the front page of the New York Times and say this insurance company just jeopardized this person's life and if this person's life is shorter as a result of what just happened here I hope that they pay millions of dollars in fines for the kind of stuff that they do to us. And it makes me enraged, as you maybe can tell. It's a rare event, but boy, I don't think it's going away.

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