July 10, 2002
Robert Murphy presented the FRAMS II data. The number of study acronyms is making it very difficult to keep up with all the different trials. You should not confuse this trial with the FRAM study presented yesterday by Carl Grundfeld. That was a large cross-sectional study of lipodystrophy and metabolic complications across multiple sites in the U.S. This is a metabolic sub-study of the Atlantic study.
The Atlantic Study is an ongoing prospective, randomized, international trial of d4T + ddI combined with 3TC, nevirapine (NVP), or indinavir (IDV) in treatment-naive patients. It enrolled 298 patients and its virologic results have been presented many times, the last iteration during this conference.
While the original study was in progress, interest in the metabolic complications associated with the treatment of HIV infection increased and the investigators decided to conduct a sub-study of the original study to examine this issue. Of the original 298 patients, data on 82 patients (approximately equally distributed by study arm) with evaluations at 144 weeks was presented. Enrollment in this study occurred approximately 120 weeks after starting the original regimen. After entry, patients were followed every 24 weeks and had multiple tests performed, including body questionnaires, DEXA, abdominal CTs and multiple metabolic parameters.
Lipoatrophy was found in approximately 50 percent of patients, and it was considered severe in half of those. The frequency of lipo accumulation was lower, approximately 25 percent experienced severe fat accumulation.
There were no clear differences in the incidence of these problems among the three different arms -- although, when followed over time, the amount of visceral adipose tissue in patients in the nevirapine and 3TC arms increased. It is important to remember that these problems occurred, in most cases, after patients had been on therapy for more than 100 weeks. There were no significant differences in the amount of lipoatrophy between the different arms of the study when measured by DEXA or CT. There were no differences in other DEXA parameters (i.e., body composition measured by BIA and serum metabolic parameters) between the three different arms of the study.
At the end of his talk Dr. Murphy pointed out the study's serious limitations.
FRAMS was small in size and because patients enrolled in the study after taking antiretrovirals for 120 weeks, they did not have a baseline evaluation of the metabolic parameters of interest in this study. Neither did they consider the changes in antiretroviral therapy that took place during the study, and the fact that those changes were much more frequent in the indinavir arm of the trial. There is also the risk of a serious selection bias, because only the patients who were able to tolerate the drugs for over 18 months entered the study.
I think these very serious limitations limit the utility of this information and the implications for clinical practice. The data generated by this trial might be used in the future design of a large trial asking that question, although it is likely that the question will be answered sooner than that when the results of longitudinal trials like ACTG 5005 become available.
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