In this study of MRI-measured total body SM mass, we found that age-associated SM changes occurred at a similar rate over 5 years in HIV-infected adults as it did in similar-aged HIV-negative controls. Even after multivariable adjustment, estimates for SM change were similar between younger (35–40 years) as well as older (40–45 years) HIV-infected participants and controls. These data suggest that over 5 years, the typical rate of age-associated SM loss is not greater or accelerated in 33- to 45-year-old HIV-infected adults in the era of modern ARV therapy.
There were differences between men and women in the association of HIV infection with SM levels at both exams. After controlling for age, race, lifestyle factors, and adiposity, HIV-infected men had less total SM than control men at baseline, and their SM remained lower than in controls after 5 years. It is likely that some of the HIV effect on SM may be mediated by lifestyle factors and especially the decreased adiposity of lipoatrophy. However, despite the significant attenuation of the HIV effect in men when controlling for lifestyle and especially AT, there is an additional effect of HIV in men, beyond what these factors reflect. By contrast, HIV-infected women, who start with greater AT, appeared to have greater total SM at Year 5 compared with control women after multivariable adjustment, with little attenuation when adjusting for AT. These findings are consistent with the previously published hypothesis that the greater AT mass at baseline in women protects against subsequent loss of SM (35
Regardless, comparisons by sex indicated that over 5 years, the average change in SM in HIV-infected men and women was similar to control men and women over the examined control age range. In HIV-infected participants, we found that an increase in CD4 count over the 5 years of study was a strong predictor of more gain/less loss in SM (and conversely CD4 decrease was associated with more loss/less gain in SM). This might have been expected because low CD4+ T-cell count and high plasma HIV viremia are associated with a lower muscle protein synthesis rate, and ARV therapy–induced improvements in immune and virologic status increase muscle protein synthesis and reduce some aspects of muscle proteolysis (38
), although the precise molecular level regulator is not clear.
We found that higher CD4 count and indinavir exposure were associated with greater Year 5 SM, even after controlling for total AT. The indinavir finding appears to contradict in vitro and rodent findings, where indinavir exposure acutely reduced SM protein synthesis and impaired protein translation initiation and efficiency in cultured C2C12 myocytes and in rats (40
). Although the positive association of CD4 count with SM is not novel (4
), we find no other reports in the literature of a positive relationship of indinavir with muscle mass. We cannot rule out confounding factors in those who were able to continue longer use of indinavir. Of note, unlike stavudine and efavirenz, indinavir did not show an independent association with SM change.
After adjustment, exposure to stavudine was associated with more loss in SM, whereas efavirenz was associated with smaller losses in SM. The association of stavudine use with lower SM even after multivariable adjustment for AT raises the question of other toxic effects of stavudine, perhaps on nerve or muscle. Laboratory animals (42
) and HIV-seronegative adults (44
) exposed to a short course of stavudine experience sustained adverse effects on SM mitochondrial DNA copy number, biogenesis, and function, but their relationship to muscle protein mass has not been reported. We are unaware of any data on the effect of efavirenz on SM. In contrast, the Nutrition For Healthy Living Study found little association of stavudine with lean body mass changes (14
) and did not report on efavirenz use.
There are some limitations to our study. At baseline, the HIV-infected participants spanned a wider age range (19–76 years) than the controls (33–45 years). This limits our ability to compare the estimated rates of SM change in HIV+ versus control in older participants. This was an observational study, so we cannot infer a causal link between stavudine, efavirenz, or indinavir use with SM amounts or changes. The findings suggest against SM declining substantially faster in HIV-infected adults than in similar-aged controls. The broad confidence intervals in leave open some possibility that clinically relevant SM loss may be accelerated in HIV-infected adults. However, the distribution of SM change was much broader in HIV-infected men and women compared with controls, even in age-restricted analyses. These data suggest that greater weight loss does occur in a subset of HIV-infected participants, and the multivariable analysis supports the concept that weight change is related to CD4 count. An additional limitation is that the SM measure at baseline included intermuscular AT, whereas at Year 5 SM and intermuscular AT were measured separately. We dealt with this by adding intermuscular AT to SM to make the Year 5 measurement comparable to baseline. Although we controlled for physical activity, we were unable to control for muscle strength or quality. Previous studies have found that muscle function may be more important than mass in predicting morbidity and mortality (11
). We also did not assess for the frailty-related phenotype, which is increased in HIV infection (47
); the frailty-related phenotype is strongly associated with low CD4 count, consistent with our finding of a positive association of change in CD4 count with change in SM. Finally, there may have been incomplete or inadequate control for factors that may confound or explain the association between HIV infection and SM. For example, we did not measure gonadal steroid levels, which decline with age and are lower in HIV infection.
Multivariable Linear Regression Analysis of Year 5 Muscle Mass by HIV Status
A major strength of our study is the comparison of SM change over 5 years directly measured using MRI in HIV-infected and control adults. This allowed us to account for normal SM changes with aging. The controls were enrolled in the VIM substudy (24
) of the CARDIA cohort, where the average BMI is similar to that of the nationally representative sample of NHANES. A further strength of our study is the ability to adjust for AT amount and changes, which influence SM.
In conclusion, 5 years after the first exam in the FRAM study, average change in SM was similar in HIV-infected and control participants. HIV-infected men had lower SM compared with control men, even after controlling for demographics, lifestyle factors, and AT. HIV-infected women had similar or slightly higher SM than control women. We found suggestive evidence against substantially accelerated SM loss in HIV infection. HIV-infected participants were more prone to gain as well as lose SM compared with controls. Increased CD4 count was associated with more SM gain/less loss and decreased CD4 count with more loss/less gain. Given that an increase in CD4 count is an indication of the effectiveness of ARV therapy and a decrease in CD4 an indication of failure of ARV therapy, our data support the concept that effective ARV therapy has an important impact on changes in SM. As HIV muscle loss and wasting 5% or more have been associated with morbidity and mortality (8
), the long-term consequences of the wide spectrum of SM loss or gain found here need additional study.