Survey: Many patients suffer from battle fatigue’

Simpler dosing could be way to prevent problem

(Editor’s note: A new survey conducted by Savitz Research of Chicago and funded by GlaxoSmithKline of Research Triangle Park, NC, underscores the problem of HIV patients’ "battle fatigue," caused by years of taking antiretroviral drugs and coping with their side effects. AIDS Alert has asked survey consultant Charles F. Farthing, MD, chief of medicine at AIDS Healthcare Foundation Healthcare Center in Los Angeles, CA, and an assistant clinical professor of medicine at the University of California at Los Angeles, to discuss the problem of AIDS battle fatigue and summarize the survey’s findings. Farthing also is a principal investigator for AIDS Healthcare Foundation research and has been involved in clinical trials that address adherence issues.)

AIDS Alert: The survey refers to the term "AIDS battle fatigue." Could you please describe what this means?

Farthing: It’s a colloquial term which means patients are getting tired of taking their medications, and patients who were previously adherent are falling off the wagon and are becoming less adherent. I think a lot of clinicians have noticed that some patients who were taking antiretrovirals for two to three years quite diligently are now showing some reluctance with adherence sometimes.

I think it’s a fairly common problem, and I think it has a fair bit to do with side effects and with the relatively sizeable number of chronic side effects that have been recently described, such as lipodystrophy problems and the bone problems. These were not there at the outset for any of these patients, but now are of increasing concern to them. When you look at the responses on the survey, you can see that overwhelmingly the biggest obstacle patients describe in preventing their adherence is too many pills in the regimen — over 67%. But the next biggest area is 61% for side effects. Previously, side effects had less prominence in surveys about adherence obstacles. That isn’t too surprising, considering we’ve become aware of more side effects.

AIDS Alert: Please tell us a little about the study and how it was conducted.

Farthing: This was a telephone survey involving 317 HIV-positive individuals who responded to a questionnaire sent to 2,500 households. (Editor’s note: See "HIV adherence survey findings at a glance," in this issue.)

The purpose was to find out from patients what the problems with adherence are. Previously, some researchers observed that what patients say are obstacles and what doctors assume to be obstacles are not quite the same, at least in percentage of importance. So it is interesting to see a large survey asking patients directly, and we should pay attention to the answers. Good physicians listen to their patients, and this presents one way for physicians to listen to their patients — what are their biggest problems? — and then we can focus most on those.

AIDS Alert: Clinicians have a great deal of experience in dealing with adherence problems among chronically ill patients, such as diabetics and people with hypertension, so how is adherence to HIV antiretroviral regimens different?

Farthing: It’s different because the requirements for adherence are stricter. A number of studies have shown that you really require in excess of 90% to 95% adherence to have a really good result, as defined by having 80% of patients with less than 50 copies of viral load. Whereas, patients with only 80% to 85% adherence, which would be extremely good for the control of hypertension, for example, do not necessarily do very well with HIV at that level of adherence. Only about half of them will be undetectable, or less than half.

Also, if you’re not adherent with hypertension and you become adherent, your drugs will continue to work. But if you’re not adherent with HIV and then you become adherent, your drugs may no longer work, because the period of nonadherence has resulted in resistance to your drugs. So it’s hugely more critical for two reasons: One, to be successful you need to be more adherent, and, two, if you’re not adherent you may completely lose your chances because you may develop resistance and subsequent adherence won’t help.

AIDS Alert: From the patient’s perspective, how is adherence to antiretroviral regimens more difficult than adherence to other medications taken for chronic illness?

Farthing: Well, it depends on the regimen, but often it is more difficult to be adherent to an antiretroviral regimen because of the large number of pills involved and the chronic GI or other side effects that a patient may be suffering. However, we do now have 15 different medications, and by no means do all the patients have to have a heavy pill burden regimen or have to suffer chronic side effects. And I think we as physicians should strive very much to reduce the pill burden of the regimen for the patients, particularly when you look at the survey and realize that pill burden has a colossal psychological effect on patients. So we should strive to get them down to one or two pills twice a day rather than 10 or 12 pills twice a day. It could make a big difference, and the survey is telling us that. Another thing is that we should keep switching regimens, if we can, to get away from the side effects until we find regimens that patients are very comfortable with.

There is an understandable reluctance to switch a medicine when a patient is doing well virologically, but I think we should definitely consider that if the patient has a high pill burden or if there are other side effects, because even if they are doing well virologically now, if they’ve got chronic side effects and they’ve got a high pill burden then they might wander into AIDS battle fatigue, as it were, and cease to be adherent.

It’s frequently said that "if it ain’t broke, don’t fix it," meaning if the patient has virological control, then don’t change the regimen. But if "broke" could be interpreted more liberally than just looking at viral load, such as if a patient is suffering from chronic side effects, then to some extent it is broke and it’s not the perfect regimen for them. And at some point they may go on to be fatigued and give up. So we shouldn’t only look at "broke" as viral load. We should try to reorganize the regimen. If a patient has a naive virus, then all the regimens work equally, so we shouldn’t be too scared to change the regimen. If we know that the virus is resistant to a number of drugs already, then switching is a little more complex and hazardous. But if you’re switching for reasons of intolerance, then of course you can go back to the drugs; it’s only if you’re switching for resistance that you can’t go back. And that’s a concern patients have, so one should reassure them that they can go back to the drugs if they’re switching for intolerance.

AIDS Alert: How should a clinician determine this?

Farthing: The pill burden is obvious, and you question the patient about side effects. Of course, every patient is different, and you have to listen very closely to them and individualize therapy. There are some patients where the pill burden truly doesn’t bother them. They’ll take their pills and are quite content to do so. But we need to listen closely to patients, and if they say the number of pills is overwhelming and they don’t like it, then we should strive very hard to reduce the pill burden for that patient. If the patient’s virus isn’t already resistant to a number of drugs, then it’s relatively easy to simplify their regimen with the large number of pills we have to choose from. Of course, it’s not only the number of pills. The survey also shows that patients are concerned about food restrictions, and the frequency of having to take pills.

We can pretty much manipulate any antiretroviral regimen to avoid food restrictions and to reduce frequency to two doses a day. Even though some of the protease inhibitors have FDA-recommended dosage regimens of three times a day, with the addition of ritonavir, most of the protease inhibitors can be given twice a day. And with the use of ritonavir, the meal restriction is removed.

Also, the advances from the pharmaceutical industry in the last two years — the development of new drugs like efavirenz and abacavir, of multi-drugs like Trizivir with AZT, 3TC, and abacavir in one pill, or of Kaletra with lopinavir and ritonavir — have helped in reducing pill burden.

AIDS Alert: Should clinicians take a more active role in asking their patients about pill burden, since patients may not bring it up during a check-up?

Farthing: I think that in the battle to achieve 100% adherence with our patients, there are many things we can do, and some physicians pay a tremendous amount of attention to it, and others don’t. I think it really should be a top priority issue for us, because if we keep our patients adherent and well, then we don’t have anything else to do. If we do that, we won’t have to be treating them in the hospital; we won’t have to be treating secondary infections; we won’t have to be worrying about prophylaxis. So this is a direction most of our energies should be going. Yes, we should be asking our patients all the time, do they find it easy? Are they having problems? And what can we do to make it easier for them?

One idea we picked up at AIDS Healthcare Foundation from Dr. Chris Matthews, a private practitioner in San Diego, is a questionnaire given to patients every time they come in for primary care visits. Each time they come to the clinic before seeing the doctor, they fill out this questionnaire asking them about their adherence, so the doctor doesn’t have to spend the time asking these extra questions.

Researchers say that you don’t want to ask, "Are you taking all of your pills?" because patients feel pressure to say "Yes," and so they lie. They’re also probably more likely to lie in person than they are to a questionnaire because of the psychological pressure. The first question is, "Are your drugs easy to take?" because if they say "No" to that then it’s easier for them to admit to non-adherence. So the next questions are "What are your pills?" "What are the doses?" "How many times a day do you take them?" and "Have you got any meal restrictions?" We very frequently find out that patients have gotten confused and they’re taking the wrong numbers of pills, so we check that every visit with the questionnaire. And then only after asking those questions, does the questionnaire say, "Do you miss any doses, and what percentage of your pills do you take?" (Editor’s note: To see HIV patient adherence questionnaire, click here.)

Very frequently, the patient admits to taking 80% to 85% of their pills, and of course that’s pretty good. But then we have these graphs in the office and we can say, "Look, 80% to 85% of taking your pills only means a 50% chance of success, so you may think you’re doing well, but you’re not doing well enough."

Then we ask questions like "Would you like a device to help you remember to take the pills?" and we offer them beepers that we program to go off twice a day, watches that beep, and key chains that beep. We also offer multi-chambered pill boxes and a course in antiretroviral therapy to learn more about it and more about how to take it. In fact, we try to get all patients to attend that course before they commence taking antiretroviral therapy, and that’s an idea we adopted from Dr. Robert Scott in Oakland, CA, a private practitioner.

AIDS Alert: David Morris, who was diagnosed with HIV in 1983, says that he has been adherent to his antiretroviral regimen for the nearly 16 years any drugs were available. As a result, his HIV levels are still undetectable. What makes someone like David different from the average person who is infected with HIV and who is far less willing to adhere to the medication schedule? (Editor’s note: See story on Morris, "18-year survivor discusses HIV battle fatigue," in this issue.)

Farthing: In my experience, about a third of patients take their pills very reliably, and you don’t have to work hard for their adherence; a third with a lot of good help are going to be decently adherent, but need a lot of good help. But about a third are a big problem, and then there is a small percentage, less than 10%, who are highly non-adherent and no matter what you do you can’t convince them to take their medications, and one almost has to do directly observed therapy to keep them alive.

I think the degree of nonadherence is way in excess of what any of us would have predicted and of what we thought during the first years of the epidemic, and it’s way more than what many physicians working with AIDS patients currently believe it to be. This is because they believe their patients, who are way overestimating the degree of adherence.

AIDS Alert: Will we only see adherence problems increase as people begin to live with HIV infection for two decades and longer? Or do you expect that many people with the infection will begin to treat their drug regimens as simply another activity of daily living?

Farthing: I think the simpler you can make the regimen, the more they can incorporate it into their daily routine. One of the battles is to make them do that and to make it an automatic behavior. Sometimes we admit patients into an immediate care facility and give them their therapy for a few weeks so that it gets into their routine. Some great philosopher said that if you’ve done something 60 times, it becomes a habit. So if you can monitor them very closely and get a relative or friend or health care worker to directly observe it for a period of time, then it might switch into an automatic behavior. Obviously, it’s much more likely to do that if it’s one pill twice a day rather than 12 pills twice a day.

One of my patients, when I simplified his regimen from 12 pills twice a day to two pills twice a day, said, "Oh, Dr. Farthing, that’s much better. Now I just have hypertension where before I had AIDS." I said, "Excuse me?" He said, "When you’re taking 12 pills twice a day, Dr. Farthing, you’re being constantly reminded that you have a very serious illness; you’re being constantly reminded that you have AIDS, and you want to deny that and therefore want to pretend to forget it and therefore you don’t want to take your pills because they remind you of the seriousness of your disease. Whereas, if you’re taking just a couple of pills a day, then you can just have hypertension or some common illness that other people take pills for, and it’s not a big deal and it’s not as big of a psychological impact."

It’s a very psychological business. One of the reasons patients don’t comply is because constantly complying reminds them of their disease, but that’s less of a factor if they have fewer pills to take.