The Body Covers: The 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention
An Interview With Mark Holodniy, M.D.
July 25, 2007
Dr. Holodniy, I know you went to the session yesterday on when to start treatment.1 Have you changed your practice about when to start people on therapy, and if so, why?
Well I haven't changed my practice at this point. I think the guidelines2 are there, and people are using those guidelines. What was argued yesterday is that we need to do a very large study to answer that question if the pendulum is going to go back the other way now. I think in the United States [HIV-infected people are started on treatment] at a CD4 count of around 350 and in Europe and other places it's around 200 -- but given some of the evidence now that people with HIV infection off treatment, even with higher CD4 counts, have more adverse events and poorer outcome this may change.
The question is: Does HIV treatment mitigate the bad outcomes that those people are having? The problem, though, is that those studies have to be very big and very long. The endpoints have to be different; you're not looking for virologic outcome and you're not looking for the number of people that are going to be dying. You have to look for other adverse events. What was being argued for [yesterday] is looking at non-AIDS serious adverse events as an endpoint that could be measured, because people continue to have those all the way along the spectrum of disease.
Which non-AIDS-related adverse events are you referring to?
Things like cardiovascular disease -- so, heart attacks -- kidney problems, diabetes ... a variety of medical illnesses that tend to affect HIV-infected patients more than, perhaps, the population that's uninfected.
What's curious about that is that a lot of people with HIV are genetically predisposed -- or they lead a life that predisposes them -- to diabetes and heart disease. How do you figure out which is the HIV and which is the eating too much fat and not exercising?
That's a big problem. Part of that I'll have to leave to the statisticians to determine what variables go into the mix to define whether those patients are at greater risk in the beginning, versus at lesser risk after they've started treatment, or not. I think as other types of assays mature, we'll be able to predict better who is at risk, and maybe even target therapy a lot better.
There were some posters that were presented here [at IAS] looking at pharmacogenomics. That's actually potentially predicting who may have a better or worse response to a particular HIV drug or combination of drugs. That may be part of the mix: that you just don't start everybody on the same thing; it's going to be tailored to a particular regimen based on the underlying genetics that a patient has.
Which assays are you referring to?
There are pharmacogenomic assays that look at variants of various enzymes that we all have in our bodies. Some of the cytochrome enzymes that we know can be inhibited by drugs like ritonavir (RTV, Norvir), for instance, people have genetic mutations that change how the enzyme works. Some people, for instance, will metabolize those drugs faster; some people will metabolize those drugs slower. If those tests were available -- and they're not yet, in the clinic -- they might change how a doctor thinks about what regimen they put them on.
There are other posters at this conference looking at the question of abacavir hypersensitivity.3,4 There are clearly genetic variants which predispose people to having a hypersensitivity reaction, and those that don't. If you had a genetic test you could use in the clinic, and you found that those people who had that particular genetic variant that put them at greater risk for having a hypersensitivity reaction, you wouldn't give them the drug. I think that's the next focus of where things will go in the clinic. Although, we have no studies at this point in time to validate using any of those in the clinic.
It sounds like it's going to make it amazingly difficult for a practitioner to deal with all these customized treatments.
That's correct, but I think it explains in part why some people have more side effects to efavirenz (EFV, Sustiva, Stocrin), for instance, or why some people might fail a protease inhibitor regimen more often than others, because of what that person is made up of.
We have, for many years, basically been giving the same regimen to a 95 lb. woman and a 280 lb. man. She may be white and he may be African American. And we then expect that they're going to have the same treatment response. Yet, that woman may have different side effects and she may have a very different virologic response than that man.
Once we've now begun to figure out these kinds of variants and how they may affect how people metabolize the drug, and how they may affect how the virus is impacted by those drugs. We're going to have to get to that point. It's like breast cancer: There are certain markers now that are predictive of utilizing certain drugs versus others for breast cancer therapy, and those are now in clinical practice. We're going to get there with HIV.
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