August 17, 2006
Probably the most common endocrine abnormality seen in men with HIV is hypogonadism (or low testosterone levels). Symptoms may include fatigue, weight loss, muscle mass loss, depression and low libido. This problem sometimes goes undiagnosed by providers. It is still not clear whether these low testosterone levels arise from a disruption of the primary pituitary function that is caused by HIV activity in the brain or are related to testicular failure from HIV-induced inflammation in testicular cells. In one study,1 symptomatic HIV-infected patients with AIDS-related illnesses were found to be more likely to have lower testosterone levels than asymptomatic HIV-infected patients and HIV-uninfected trial participants. These patients were also found to have significant weight loss.
The study being reviewed here is a substudy2 of the previously reported 384 study3 by the AIDS Clinical Trials Group (ACTG). ACTG 384 was the very first trial to try and answer some questions about the impact of the initiation of various antiretroviral therapies on the levels of testosterone and muscle mass in HIV-infected men.
In this substudy, Michael Dubé and his colleagues measured testosterone levels using a more reliable "free" testosterone testing method. Laboratories generally measure "total" testosterone levels, however, sex hormone binding protein levels may be elevated in HIV-infected patients causing the total testosterone levels to be falsely normal. Free testosterone testing is more technically demanding and accurate, but also more expensive.
The investigators followed 217 treatment-naive, HIV-infected men who were part of the ACTG 384 trial. These patients had free testosterone levels evaluated at baseline and were not permitted to receive any testosterone supplements.
The men's muscle mass was determined by measuring fat-free mass (FFM) using bioelectrical impedance analysis (BIA). Both free testosterone and FFM were remeasured over a period of 64 weeks. Trial participants were randomized to start antiretroviral therapy with either a nucleoside backbone of zidovudine (AZT, Retrovir) + lamivudine (3TC, Epivir) or stavudine (d4T, Zerit) + didanosine (ddI, Videx) plus either efavirenz (EFV, Sustiva, Stocrin) or nelfinavir (NFV, Viracept) or both drugs.
The median age of the trial participants was 37 years old. Fifty-three percent were white, 32% black and 14% Hispanic. Median body mass index (BMI) was 23.7 kg/m2 and FFM was 60.5 kg. Median CD4+ cell count was 262. HIV RNA was 5.2 log.
Free Testosterone Level Results
At baseline, the median free testosterone level was 94 picograms per milliliter (normal free testosterone levels are more than 50 pg/mL). Only 6% of the men had low testosterone levels. For the whole group, free testosterone levels significantly rose at 16, 32 and 64 weeks (+16, +14 and +15 pg/mL, respectively) after the initiation of antiretroviral medications. Surprisingly, at week 64, those men who were on zidovudine + lamivudine had a greater testosterone increase than the stavudine + didanosine group (+30 and +1 pg/mL, respectively). When comparing efavirenz to nelfinavir, men on efavirenz had greater increased testosterone levels than patients on nelfinavir (+30 and -5 pg/mL, respectively).
Fat-Free Mass Results
After 64 weeks of therapy, FFM significantly increased by 1.1 kg for the whole group. A significant FFM increase was seen with both backbones. However, men on zidovudine + lamivudine had more of an increase than those on the stavudine + didanosine backbone (+2.9% and +0.9%, respectively). Patients on efavirenz as a third drug had more of an increase in FFM than those in the nelfinavir group (+3.3% and +0.7%, respectively).
In the beginning, changes in free testosterone were not significantly correlated with changes in FFM, but the correlation was seen at week 64. Patients with a lower CD4+ cell count and a higher viral load at baseline seem to have a significant increase in FFM.
In this study of antiretroviral-naive, HIV-infected men, only 6% showed low testosterone levels using the free testosterone assay. This number may seem low when compared with previous data because any patients who may have been diagnosed with hypogonadism prior to entry and were receiving testosterone replacement therapy would have been excluded from the study.
After the initiation of antiretrovirals, free testosterone levels generally increased and patients gained FFM. There may be many factors contributing to these gains, such as viral load decrease, CD4+ increase, recovery from illness and overall improvement in general health.
It is very interesting and surprising to see the differences in free testosterone and FFM increases that result from using different antiretroviral regimens. Patients on zidovudine + lamivudine had greater increases than stavudine + didanosine users did. Patients on efavirenz had greater increases than those on nelfinavir.
In another poster looking at the same patient cohort,4 also presented by Dubé, patients on stavudine + didanosine and nelfinavir were found to have lower limb fat after therapy initiation.5 It is very perplexing to explain all these correlations between the metabolic changes seen and the effects of each class of medications. We definitely need more metabolic substudies in future clinical trials of both currently approved drugs and those in development.
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