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The effects of antiretroviral therapy on testosterone levels and fat-free mass.

To the Editor—Dubé et al. [1] analyzed free testosterone levels and fat-free mass over time following antiretroviral therapy. The authors concluded that increases in both parameters were higher among patients receiving zidovudine plus lamivudine than among those receiving stavudine plus didanosine; increases in both parameters were also higher among patients receiving efavirenz than among those receiving nelfinavir. The effect of antiretroviral therapy on testosterone levels is debatable. Similar to Dubé et al. [1], some authors found increases in testosterone levels following antiretroviral therapy [2], whereas others did not find such increases [3]. There seem to be some unclear aspects in the study by Dubé et al. [1] that may have had an influence on their results. The authors found that certain baseline characteristics, such as CD4 cell count, weight, and age, were independently associated with baseline testosterone levels. Therefore, it would be interesting to know the distribution of each of these parameters among the different treatment arms. Similarly, it would be interesting to know the baseline testosterone levels in the patients receiving each therapeutic regimen, because the amount of increase in testosterone level following therapy might be influenced by the baseline value and by the other baseline characteristics, regardless of the drugs administered. Dubé et al. [1] also stated that their results must be considered to be specific to the particular agents studied. A common problem in attributing specific effects to a particular antiretroviral drug is that patients are also receiving several other drugs, which may directly or indirectly modify such effects. In this respect, it would have been useful if the authors had described separately the distribution of patients, as well as the testosterone levels and fat-free mass, according to the 4 therapeutic groups. Although a multivariate analysis was reported in the fat-free mass evaluation, such an analysis was not reported in the evaluation of testosterone levels. It is possible, for example, that the higher increases in testosterone levels observed in the efavirenz group, compared with those observed in the nelfinavir group, might reflect that more patients in the efavirenz arm were also receiving zidovudine plus lamivudine. In fact, contrary to the authors’ findings, we found that patients receiving nelfinavir had significantly higher total testosterone levels than did those receiving efavirenz, although the comparison between these studies may be difficult because of different designs [4]. In addition, it is unclear how the group that received both efavirenz and nelfinavir was managed. In fact, Dubé et al. [1] reported that patients receiving efavirenz had greater increases in fat-free mass than did patients receiving nelfinavir with or without efavirenz. Consequently, the same drug, efavirenz, was present in both comparison groups. Moreover, the intent-totreat analysis indicated that some patients in this already relatively small sample study did not receive the drugs initially prescribed during the 64-week follow-up period. Therefore, the results at week 64 cannot be attributed to the initial drugs as reported, especially considering that metabolic drug interactions at the time of sampling may influence the steroid hormone concentrations [2, 5, 6]. Finally, there was no reference to adherence to therapy or to clinical or viro-immunological outcomes, which are important points, considering that the increases in testosterone levels and free-fat mass may also be the consequence of improvements in the health status of the patients.