The Body Covers: The 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention
IAS 2007 Study Summaries: An Interview With Mark Holodniy, M.D.
July 24, 2007
This is a poster that looks at the correlation of antiretroviral resistance and clinical events in the OPTIMA trial. The OPTIMA trial is a strategy trial that's been ongoing for about six years, that is a collaboration between the U.S. V.A. [Veteran's Affairs] hospitals, Canada and the U.K. It is a strategy trial where patients are randomized to either be on a three-month treatment interruption or not. Then they're randomized again to receive a standard regimen of three HIV drugs or a mega-HAART regimen, which is defined as five or more drugs. The outcome of the study is new AIDS events or death.
Now, the purpose of the current analysis was to understand whether various markers of antiviral resistance correlated with either a virologic response or the development of a new AIDS event or death. We looked at a variety of different -- what we considered to be important -- resistance markers. One was something called the phenotypic susceptibility score, which measures the number of drugs that a person's virus is still sensitive to. We also looked at genotypic scores for each of the classes of drugs. We counted the number of mutations that each patient had in each class; that would give them a score for resistance.
We also looked at specific mutations, mutations for instance, to lamivudine (3TC, Epivir) -- the M184V mutation -- or thymidine-associated mutations. We threw all these into a pot and mixed them around in a multivariate analysis. The bottom line is that, really, none of the resistance markers are predictive at baseline of whether somebody is going to have a new AIDS event or death. We did look at the level of virus patients had, we also looked at their CD4 count. Not surprisingly, CD4 count level was a very strong predictor of whether somebody was going to have an AIDS event or death.
At this point in time, the study is still blinded to treatment arms, so we can't really comment on what these patients got in terms of the strategy. This is the overall cohort of about 370 patients. I should point out a couple of things: These are patients that are very advanced in treatment, so they have three-class drug resistance to begin with -- which is why we felt we could do the study on this particular group of folks.
When you look at the number of mutations they have, the number of drugs they've seen over the course of their lifetime, and also the number of drugs they're resistant to, pretty much the entire group has multidrug resistance to almost all the drugs that were available at the time that that they came on this study. So they had very limited treatment options. I think the interesting thing will be: Early next year the study will be unblinded and we'll find out whether treatment interruptions, followed by a mega-HAART regimen of many, many drugs is advantageous or not.
Can you explain the odd note in the study's conclusion, which is: "Subjects who were tenofovir (TDF, Viread)-naive had a higher likelihood of a clinical event." What does that mean?
It's a confusing conclusion, which at this point is still not well worked out. If you look at the phenotype results of the patients, the one drug that still has some activity left at baseline for people is tenofovir. Most all the other drugs -- except for tipranavir (TPV, Aptivus), which very few patients were on or were studied for, which is also susceptible -- it's a confusing conclusion that I don't actually have an answer for.
Can you talk a little bit about the population?
Sure. This is a somewhat older population. 48 years old was the average age. It was almost entirely made up of men. From a race/ethnicity factor: 49% were white, 39% were black or African American. This study, again, was also done in Canada and the U.K.; although, the V.A. contributed about two-thirds of the patients or so, compared to the other two countries. It was also, as I said, a group that had a very advanced stage of disease. Their average CD4 count was 127 and their viral load was almost 100,000. Most of these people had seen, on average, about 10 different HIV drugs before they got onto this trial. Being a strategy trial, the doctors were free to put people on whatever drugs they wanted, as long as they maintained the strategy of the trial.
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