A study published in the July 1st edition of the Journal of Infectious Diseases (now online) has found that few men beginning potent anti-HIV therapy had low free-testosterone levels. Antiretroviral treatment led to increases in testosterone levels and lean body mass. Among the antiretroviral agents used in this study, efavirenz (Sustiva), AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir) led to greater free testosterone increases than d4T (stavudine, Zerit), ddI (didanosine, Videx) or nelfinavir (Viracept).
Low testosterone levels have been frequently reported in HIV-positive men, especially in more advanced disease. Lower testosterone levels are associated with lower lean body mass (i.e., muscle mass) and other clinical problems including depression and fatigue. Several studies have reported improvements in serum testosterone levels in people taking potent antiretroviral therapy. However, studies often report total serum testosterone levels rather than free testosterone levels, which are a more meaningful measure.
Investigators conducted a sub-study of a larger trial. The parent trial, ACTG 384, enrolled 980 treatment-naïve participants at 23 US sites between 1998 and 1999. ACTG 384 compared four treatment arms. Participants were randomized to a dual-nucleoside backbone of either AZT and 3TC or d4T and ddI. A second randomisation paired this backbone with either nelfinavir or efavirenz, for a total of four possible three-drug combinations.
The substudy, A5005s, monitored free testosterone levels and other metabolic parameters for 213 participants drawn from the larger trial. All were male and treatment-naive. The median age was 37, ethnicity was 52% white, 32% black, and 14% Hispanic. The median CD4 cell count was 263 cells/mm3 and the median viral load was 5.2 log10 copies/ml.
A free serum testosterone level of 50 pg/ml or higher is considered normal. At the study baseline, the median free testosterone level was 92 pg/ml, and only 13 participants (6%) had subnormal levels. Older or heavier men, and those with lower CD4 cell counts, were more likely to have subnormal testosterone at baseline.
Free testosterone levels increased by week 16, and the increases were generally sustained over the 64-week course of the study. At weeks 16, 32 and 64, levels were 17, 14 and 15 pg/ml above baseline, respectively (p < 0.01). At week 64, the median increase in AZT/3TC recipients was 31 pg/ml, compared to only 3 pg/ml with d4T/ddI (p = 0.001). With efavirenz, the median increase was 30 pg/ml compared to a 3 pg/ml loss with nelfinavir (p = 0.05).
At the beginning of the study, the median fat-free mass (roughly equal to total muscle mass) was 60.5 kg. By the end of the study at week 64, the participants had gained an average of 1.2 kg (2%, p < 0.001). More fat-free mass was gained by those on AZT/3TC than d4T/ddI (1.8 vs. 0.5 kg, p = 0.04) and efavirenz than nelfinavir (2.1 vs. 0.4 kg, p = 0.003). White men and those with lower baseline CD4 counts were likely to have greater gains in fat-free mass.
The study was limited by its inclusion of only men, and by the significant time lapse since data collection. The researchers suggest that since many similar studies have specifically investigated people with weight loss and more advanced HIV disease, their own findings may indicate that low serum levels of free testosterone are not as common as previously reported. They conclude that “increases in free testosterone level and [lean body mass] occur after initiation of potent antiretroviral therapy, but the magnitude of these increases may vary with different antiretroviral drug regimens,” and note that since “the metabolic effects of different NNRTIs and protease inhibitors can vary widely within these classes of drugs, our results must be considered specific to the particular agents studied and not necessarily a class effect.”
Dubé M et al. Effects of potent antiretroviral therapy on free testosterone levels and fat-free mass in men in a prospective, randomized trial: A5005s, a substudy of AIDS clinical trials group study 384. Clin Infect Dis 45 (online edition), 2007.