Envisage

An Unbalanced Burden

by Adam Istas

August 2008

Q: You’ve done quite a bit of research into gender disparities with regard to the diagnosis and management of HIV. Can you summarize some of your findings?

KS: Despite the fact that we’ve recognized that women are at high risk for HIV, there’s still—unfortunately—a relative lack of understanding of this risk on the part of the lay community. And this includes the general public, as well as clinicians who don’t work directly in the HIV arena. I am constantly amazed that I still have physicians calling me up because their patient had a positive HIV test, and they’re trying to figure out why it’s a false positive.

For instance, we know that there’s an increased risk of HIV with cervical dysplasia and abnormal pap smears, yet women who are diagnosed with abnormal pap smears are not routinely offered HIV testing. So there’s still this disconnect, which is unfortunate, because women are put at risk for being diagnosed with HIV later in their infection. We need to do a better job of getting the message out there that women are at risk. The U.S. Centers for Disease Control and Prevention now suggests that clinicians should offer everybody between 13 and 64 an HIV test, but I’ve got to tell you the clinical community has not incorporated that thought process.

In terms of treatment, most HIV-infected women are of childbearing potential. And many, many HIV-infected women are choosing to have children despite the fact that they have the infection. They know if they take therapy at the time they are pregnant, their risk of transmitting the virus is 1 percent to 2 percent, but a disappointment to me is that many clinicians don’t discuss this with women when they’re starting therapy. If a woman says, “I understand you’re telling me that I need to start HIV treatment because of my CD4 cell count, or because of my viral load or because of the stage of disease, but I’m thinking about having children.” That simple conversation would really change what drugs the physician might think about getting the patient started on. And that still hasn’t been incorporated in many clinical settings as part of the kind of standard HIV management strategies for women. So I think that’s something that, as a clinician, I need to think about when putting together a treatment regimen for women. We need to understand a lot more about that, and quite frankly, we need to really study that in depth.

Q: In addition to gender, are there racial and ethnic disparities as well?

KS: Certainly in terms of diagnosis we recognize that HIV disproportionately affects people of different racial or ethnic backgrounds. If you look at the U.S adult population, African-Americans make up about 13 percent to 14 percent of the adult population. But if you look at numbers of HIV and AIDS cases in this country, African-Americans consist of about 65 percent of them. So there’s a marked difference there. I’m not saying by any means that they are genetically predisposed, there’s no evidence of that whatsoever. But because of a number of factors—socioeconomic status, the way we interact with each other as human beings, etc.—they’re more impacted. Clearly, we need to know that in terms of getting the message out and targeting our health care resources for women. If you look across all HIV and AIDS cases among women, about 70 percent of all cases occur among African-American women. So again, we need to know that in terms of messages of prevention and for targeting our health care resources.

There is some evidence from clinical trials that certain medications have different pharmacokinetic parameters in different populations. Efavirenz, for instance, is a drug that comes to mind and people have looked at this. That doesn’t mean that we shouldn’t use the drug in African-Americans by any means, but we need to know these kinds of factors. There is also some evidence coming out in clinical trials that drug failure rates are higher in African-American patients than in Caucasian patients. We don’t understand why that is, but we need to know those kinds of factors so we can incorporate them into study designs. So there are a number of issues we need to think about for both gender and racial populations.

Q: Let’s talk about the global burden of HIV, specifically, mother-to-child transmission. Where are we with antiretroviral management of pregnant women globally?

KS: In most developed areas of the world, patients have access to what used to be called HAART (highly active antiretroviral therapy). If those drug combinations are used during pregnancy, the risk of transmitting now is really only about 1 percent to 2 percent. That really has been one of the staggering success stories of antiretroviral therapy. But, unfortunately, for most women in this world—outside of North America, outside of industrialized Europe—the majority of women who are pregnant don’t have access to these kinds of regimens. Where there’s access to any kind of regimens to prevent mother-to-child transmissions, the most common regimens that are used are single-dose of nevirapine or very short course regimens of dual nucleoside therapy or a combination of nevirapine and short-course AZT, for instance.

We have certainly seen that the use of those regimens has decreased transmission rates by about 50 percent. But, if you look at absolute transmission rates, we’re still talking about 8 percent to 10 percent, as opposed to 1 percent to 2 percent where we have combination regimens. So we still have a ways to go.

Q: Are most of the large-scale HIV trials statistically powered to account for differences in gender?

KS: Absolutely not. There’s only really been one study—the GRACE study that’s going on right now—that has been powered to actually look for differences in efficacy and safety. With some of the larger studies, especially the so-called “registration trials” that are done in support of regulatory approval, the regulators typically ask for gender analyses. They’re never reported in the clinical trials or in the publications, except a brief mention that there were no differences by gender. Very few say by race.

But post-hoc, there are a number of analyses that can be done to look at things like time to discontinuation, time to virologic failure, or whatever. The problem with all those post-hoc analyses is that the ability to say anything statistical is based on how many people are in each little block. Typically, there are not enough women in the study to begin with, and the studies were just never powered upfront to look for those differences.

Q: So would you advocate that drug developers incorporate that sort of statistical power in their studies?

KS: It’s difficult to do that because that would really increase the size of trials and so forth. I would advocate that when companies design and implement clinical trials, they make sure they have a good representation of the population affected, so when the clinical trial is finished, they can say something about how those drugs work in the real patient population. Powering, unfortunately, would really require a quantum leap in the number of patients in the trials.

Q: Looking forward, is this an exciting time or a frustrating time to be active in AIDS research?

KS: It’s exciting in the sense that within the past year we’ve had regulatory approval of two novel classes of agents especially for treatment-experienced patients. The fact that we have these novel classes means that we can put together really potent and active regimens for these patients, and that’s terrific news.

For treatment-naïve patients, we have advanced to a point now that we can put patients on a once-a-day drug regimen that consists of just one pill—three or four pills at most—which is a huge advance for the treatment of HIV. So we have regimens that don’t have to radically change someone’s lifestyle to comply with their HIV regimens. And that’s very exciting.

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