September 25, 2002
For people unaccustomed to the lingo that medical professionals use in clinical trials, I always say that a cross-sectional study is like taking a photograph from each patient in the study. When we do this, we cannot say much about what happened to the patient's body because we do not know how the patient looked before or after the picture was taken. Maybe he or she lost weight to look the way he or she looks now. Maybe it was the other way around. We do not know if what we see is related to what the patient is taking now, or what he or she took years ago.
A longitudinal study, on the other hand, is like a movie. You take multiple pictures of the same patient over time -- before he or she started therapy and then after so that you objectively get an idea of what happened. Thus, it is very clear that longitudinal studies are more valuable than cross-sectional studies.
I will try to avoid my biases (I am an author of this presentation), but by all means A5005s is an important study. It is the first prospective, randomized trial that has looked at the effect of starting antiretroviral therapy on fat redistribution. Most of the studies presented so far have been cross-sectional, including the large FRAMS II study presented at the Barcelona meeting.
A5005s is a substudy of ACTG 384, which was presented in Barcelona. The main questions ACTG 384 asked were:
To answer these questions, 980 naive patients were enrolled in the U.S. and Italy using a factorial design. The factorial design had six arms, stavudine plus didanosine with efavirenz or nelfinavir or both and zidovudine plus lamivudine with efavirenz or nelfinavir or both. Data from all the stavudine plus didanosine arms were combined and compared against the combined results of all the zidovudine plus lamivudine arms. The same was done with the efavirenz and nelfinavir arms.
The main goal of A5005s was to compare the effects of nelfinavir regimens to efavirenz regimens on glucose and lipid metabolism (cholesterol, HDL, LDL, and triglycerides). Secondary objectives were to do the same comparisons between zidovudine plus lamivudine and stavudine plus didanosine and to look at other metabolic parameters such as lactate levels. A group of patients also had longitudinal dual-energy x-ray absorptiometry (DEXA) scans performed to compare changes in total and regional fat, lean mass and bone mineral content among the different arms. This last part is what Michael Dubé presented today. A total of 330 patients enrolled in A5005s -- 156 patients had entry DEXAs, 127 patients (81 percent) had baseline and week 48 DEXAs, 107 (69 percent) had baseline and week 64 DEXAs. All DEXAs were analyzed centrally at Tufts University. Approximately 25 patients from each of the six arms of ACTG 384 were part of this trial. These patients were a representative sample of the ACTG study as a whole. The main outcome A5005s looked at was the percentage change in limb (arm plus leg) fat or trunk fat compared to baseline. Limb fat increased early with both NRTI regimens and PI or NNRTI regimens. At weeks 48, 64 and 80, randomization to stavudine plus didanosine resulted in a greater percentage decrease in limb fat. At week 80, randomization to nelfinavir resulted in a greater percentage loss of limb fat as well. All groups tended to gain fat in the trunk. Trunk and limb fat changes were comparable between whites and non-whites (so whites are not at higher risk for lipoatrophy).
So, this study confirms the prevailing wisdom that stavudine plus didanosine-based regimens result in a greater loss of limb fat than do zidovudine plus lamivudine-based regimens, and that patients tend to gain fat in the abdomen after the initiation of antiretroviral therapy, and in some cases (approximately 30 percent of the subjects) they do that at the same time they lose fat in their extremities. Studying this group of individuals might provide important clues about the mechanism of lipodystrophy associated with HIV or its treatment.
The main limitations of the study -- as Dr. Dubé pointed out -- are that some patients switched regimens during the almost two-year follow up. However, when the analysis was repeated, censoring the patients after the treatment switch occurred, the conclusions were the same. The study has a relatively short follow up, though 80 weeks is pretty good in comparison to other study data we have seen. And, most importantly, the stavudine plus didanosine results may not be generalizable to other didanosine- or stavudine-based regimens when these drugs are not used in combination.
This study, combined with the results of ACTG 384, definitely kills the idea of using stavudine plus didanosine as a first-line combination therapy. This combination was promoted only a few years ago by some as the best initial nucleoside combo regimen, and is still listed as a reasonable initial combination in the current U.S. government guidelines for antiretroviral therapy -- not for long, hopefully. The times, they are changing.
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