A Podcast Discussion With Kimberly Smith, M.D., M.P.H., and Valerie Stone, M.D., M.P.H.
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Antiretroviral Dosing in Women of Small Stature
Bonnie Goldman: Is there a role for therapeutic drug monitoring in women, particularly women who are of small stature to avert these adverse affects?
Valerie Stone: It's very uncommon for clinicians to use therapeutic drug monitoring. I think it's an excellent question, though, since we have set doses that are essentially exactly the same for the drugs that we're using today.
In the old days, we were using more ddI [didanosine, Videx] and d4T [stavudine, Zerit], which did have different dosing levels based on weight. But we have no weight-based dosing right now. It does make sense that for some smaller women, it may turn out that they experience more toxicity, and have drug levels that are too high, on our standard dosing amount.
It's not clear how best we should approach that. But my approach has been that, if a woman of small size tells me that she's having substantial side effects, I will consider the possibility that it's due to high drug levels. In some cases, I have decreased the dosing frequency, or the dosing amount, based on that.
In particular, I've felt comfortable doing that with Sustiva-based regimens, based on the FOTO [Five Consecutive Days on Treatment with Efavirenz, Tenofovir, and Emtricitabine Followed by Two Days Off Treatment Versus Continuous Treatment] study that Dr. Cal Cohen was PI [principal investigator] of.
It showed that if patients take Atripla for five days out of the week, and are off treatment for the weekend, they do just as well [as those who took standard seven days per week therapy]. I have had two small-sized women who were having lots of side effects for whom I've used that approach.
But I think it makes sense to consider that for other regimens as well, although, since most of them come only in one pill size, it's hard to do.
Kimberly Smith: This might be the one place where Dr. Stone and I disagree. Back to the initial question about therapeutic drug monitoring, I haven't used it. There aren't any good studies that have shown us that it is that helpful for populations, in general, not specifically looking at the question of whether it may be more predictive of toxicity in women.
When I have a woman -- or anyone, really -- with side effects to the medications, I am very cautious about adjusting doses. I'm much more likely to give them an alternative agent.
With all due respect to Dr. Cohen, the FOTO study is somewhat frustrating to me, the reason being that it's a very small study. In an observed analysis, the folks who took the five days on and two days off did as well as the individuals who took it every day. Again, it's an observed analysis, because it's such a small study. I think it's too small of a study to be able to draw conclusions.
Certainly, we know that a drug like efavirenz and drugs like tenofovir and emtricitabine have long half-lives, and they probably will hang around for an extra day or two after a missed dose. So, yes, you can probably get away with it. But how long can you get away with it? Can everybody get away with it? It's still to be determined.
This is why I always have been very critical of studies like that -- studies that may lead to some confusion among patients. Because when we spend so much time trying to convince patients that "you've got to take your drug every day," and then we come out with a study, and it gets splashed across the lay media as, "Well, it may be OK to take your medicines five days a week, rather than seven," I think that gives patients the wrong message and potentially could lead to poor consequences.
I just don't think that we know enough to be able to dose reduce medication for HIV. Again, my strategy tends to be to prescribe an alternative medication if they don't think they can fight through it. We had to have some controversies.
Valerie Stone: Absolutely. I think it's great for people to see that experts will differ, and that there are different approaches.
I completely agree with Dr. Smith that it was a study with a small number of patients. Which is why, whenever I make changes like that, I do monitor patients very closely. Certainly, if it looks like they are doing poorly, I would make a change then. Again, I have only done it with very small patients who don't weigh very much.
But I completely understand what Dr. Smith's point of view. Her approach is much more data driven than mine.
Bonnie Goldman: Let's turn to adherence. Do you find that adherence is different for women? Are there any adherence tools that work or that you use, specifically for women? Dr. Smith?
Kimberly Smith: Is adherence different for men and women? I would have to say that we can't answer that question very well. I think there's a limited amount of data out there that suggests that there may be more discontinuation of medications in some women than in men, maybe somewhat poor adherence.] But I think part of the challenge with some of those data is that we may be looking at not just gender differences, but differences that have to do more with what's going on in their lives.
For example, I think a lot of times when we look at cohort comparisons of men versus women, often what we're looking at is a comparison of women in WIHS [Women's Interagency HIV Study] to men in MACS [Multicenter AIDS Cohort Study].
Men in MACS are very, very different than women in the WIHS cohort. Until they opened it up and added more men of color, men in MACS were overwhelmingly Caucasian, were mostly employed and tended to be middle class or on the higher earning end of things. They had a different type of lifestyle than the average woman in WIHS.
One of the studies in WIHS looked at the average household income for women in that study. The median household income for women in that study was $4,500 a year. Around 80% of the women in the study were unemployed. You're talking about completely different lifestyle issues. So the difference that we see in adherence, when we compare some of these big cohorts like that, may not be gender difference as much as socioeconomic difference.
I'm hesitant to say that there's a good study that tells us that adherence is not as good for women, or better for women. I think it really depends on who your population is. So that's the answer to the first question regarding whether adherence differs in HIV-infected women compared to HIV-infected men.
With regard to my strategies around adherence in women, sometimes women just tend to need a lot of encouragement and a lot of support. I have some patients that may need to just be called and reminded and encouraged. But that's true for a lot of my male patients as well.
Bringing this back to my personal experience: I can count on one hand the number of patients that don't have suppressed viral load in my clinic here at Rush [University Medical Center]. Unfortunately, most of those are women. What are the issues that keep those few women from being undetectable? Depression. Different priorities in their life. They prioritize the lives of, often, their children or their partners over their own situation, and so taking care of everybody else is important. Getting around to taking their medicine becomes secondary.
I do think that it's those kinds of issues that are probably prevalent more with women, who tend to be the caretakers, than they are with men, who tend to only have themselves to care for.
Bonnie Goldman: Dr. Stone?
Valerie Stone: I want to avoid repeating everything that Kim said all over again, because I think that it was right on the mark. I would just say it a little differently.
As Kim already said, it has a lot to do with who the individual is, but a lot of the women living with HIV have many of the known challenges to adherence.
Specifically, they are more likely to be depressed, more likely to have a current or past history of substance abuse or alcohol dependence, more likely to have a chaotic lifestyle, more likely to have low health literacy and more likely to have not disclosed their HIV to key people in their life. Each of those things makes them more likely to be nonadherent, or to be intermittently adherent.
I think we have to be both cognizant of that and actually really acknowledge that. Clinical programs need to build adherence programs, interventions and at least approaches around the fact that many HIV-infected women will be challenged because of these things.
I agree that in terms of adherence interventions, we don't do, and I don't do, anything that's rocket science. Basically, I think that most women just want more encouragement, more contact and more than one provider who is the person that they relate to around their medicine.
We have primary nurses in our practice here. We make sure that our women patients meet their primary nurse at their first visit. The nurse often gives them a follow-up call after we start them on medicine to make sure that they understand how they are supposed to take the medicine.
I tend to have more frequent follow-up visits within the first two months after starting women patients on antiretrovirals to make sure they understand, and that they are encouraged and that they have their questions answered, particularly around side effects. I think that this often goes a long way in terms of optimizing their adherence over time. It's just getting off to the right start over those first couple of months.
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