Acquired Immunodeficiency Syndrome (AIDS) is a disease of the immune system due to infection with the Human Immunodeficiency Virus (HIV), leaving the patient vulnerable to life-threatening infections.1 The advent of combination antiretroviral therapy (cART) substantially prolonged the life expectancy of patients, by suppressing viral load and improving immune function with consequent reduction of opportunistic AIDS-related diseases.1

On the other hand, the combination of long-term HIV infection and cART treatment may harm several physiological systems, thereby increasing the risk of non-AIDS related diseases.1,2 In people living with HIV (PLHIV) those morbidities often coexist at an earlier age.3 Given the high prevalence of patients suffering from multimorbidity,3 this has become a major focus of research in HIV settings.2 Indeed, some authors claim that health-care providers should be aware of a potential “accelerated aging syndrome” in PLHIV.4,5 In short, they evoke the possibility that combined effects of HIV infection and treatment-related factors may exceed “normal” aging in the development of health problems. A better understanding of biological decline in PLHIV treated with cART would be crucial to support multidisciplinary interventions to attenuate or reverse those losses.

A recent review using cluster analysis summarized the most common patterns of comorbidities among PLHIV.2 Cardiovascular diseases and musculoskeletal disorders consistently appeared among the most described morbidities. In fact, there is extensive evidence of progressive losses of skeletal muscle mass and strength in PLHIV treated with cART.6-8 In addition, reduced bone mineral density (BMD) and high prevalence of osteoporosis vs. controls have been reported, particularly in women.9,10 Other major changes include body fat redistribution (peripheral lipoatrophy and central accumulation), greater insulin resistance, hyperlipidemia, and vascular dysfunction,1 which are highly prevalent in older patients,11 especially in those with osteoporosis, fracture, and sarcopenia.12

Like aging, HIV infection is associated with pathologies affecting cardiovascular, muscle, and bone health,13,14 which share common molecular and physiological mechanisms, risk factors, and clinical implications.12,15However, we could not find prior studies that concomitantly compared markers of muscle, bone, and vascular health in PLHIV vs. age-matched and older non-infected controls. This would be helpful to test the hypothesis of accelerated reduction in tissue function due to prolonged HIV-infection and cART. In a few words, it would be possible to verify whether those markers are similar in PLHIV and healthy individuals, or if they approach the profile exhibited by older individuals. Therefore, this study compared muscle mass and strength, BMD, and vascular function in middle-aged PLHIV treated with cART vs. age-matched and older non-infected controls. We hypothesized that the combination of prolonged HIV-infection and cART would increase the rates of muscle and bone loss, as well as metabolic changes predisposing the development of vascular dysfunction. Hence, markers of muscle, bone, and vascular health in PLHIV would be closer to values exhibited by older individuals and than to those observed in age-matched non-infected counterparts.

Table 1 presents the clinical characteristics of the participants. As expected, OLDER was older than PLHIV and CONT (P < 0.001). On the other hand, the three groups were similar regarding all characteristics, except for resting mean blood pressure which was lower in CONT vs. PLHIV and OLDER (P < 0.001). In PLHIV, time ranges of HIV infection and cART intervention were of 5 to 30 years and 3 to 30 years, respectively. As for the cART regimen, 58.3% of patients were using protease inhibitors, 100% nucleoside reverse transcriptase inhibitors, 33.3% non-nucleoside reverse transcriptase inhibitors, and 8.3% integrase inhibitors.

Table 2 depicts data for body composition. Body mass (P = 0.54) and BMI (P = 0.12) were similar across groups. OLDER exhibited higher body fat (P = 0.02) and lower lean mass than CONT (P = 0.02), while these measures were similar between PLHIV and CONT (P = 0.9 and 0.8; respectively). The BMD showed to be more preserved in CONT vs. PLHIV and OLDER (P < 0.01). Fig. 2 exhibits isokinetic strength data. Peak torque and total work were lower in OLDER vs. PLHIV and CONT (P = 0.001).

Fig. 2.

Peak torque (A) and total work (B) obtained during isokinetic strength assessment in people living with HIV (PLHIV, n=12), without HIV age-matched (CONT, n=12) and older (OLDER, n=12) controls. *P < 0.05 vs. PLHIV and CONT. Values expressed as mean ± SD.

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As for vasoreactivity analyses, no difference between PLHIV, CONT, and OLDER was detected for FBF at baseline 1 (2.48 ± 1.26 vs. 2.00 ± 0.67 vs. 2.11 ± 1.17 ml.min−1.100 ml−1, respectively; P = 0.63), after five min of arterial occlusion (15.90 ± 9.12 vs. 14.70 ± 5.60 vs. 10.74 ± 3.50 ml.min−1.100 ml−1, respectively; P = 0.14), at baseline 2 (1.54 ± 0.67 vs. 1.68 ± 0.63 vs. 1.63 ± 0.87 ml.min−1.100 ml−1, respectively; P = 0.94), and after sublingual nitroglycerine (1.85 ± 1.01 vs. 2.07 ± 0.67 vs. 2.04 ± 0.83 ml.min−1.100 ml−1, respectively; P = 0.87). Moreover, as shown in Fig. 3, no significant differences between groups were detected for %HYPER (P = 0.32) and %NITRO (P = 0.47).

Fig. 3.

Percent increase of forearm blood flow during post-occlusive reactive hyperemia related to baseline flow 1 (%HYPER) and after nitroglycerin in relation to baseline flow 2 (%NITRO) in people living with HIV (PLHIV, n=12), without HIV age-matched (CONT, n=12) and older (OLDER, n=12) controls. Values expressed as mean ± SD.

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This cross‐sectional study compared muscle mass, strength, BMD, and vascular function in PLHIV treated with cART vs. age and sex-matched HIV-negative individuals and sex-matched older controls. The main findings were: a) PLHIV exhibited similar muscle mass, isokinetic strength, and vascular function vs. age-matched controls, and greater values vs. older controls; b) On the other hand, BMD in lumbar spine, total femur and femoral neck in PLHIV approached values of older individuals, being significantly inferior in comparison to age-matched healthy controls.

Muscle mass and strength losses are recognized to occur in PLHIV,21,22 being strong contributors to early frailty and disability.23 Long-term effects of viral infection combined with cART toxicities seem to increase the risk of sarcopenia.6,7 However, age-related decline rates in PLHIV remain unclear6,8,24and some prior research even suggested that losses in skeletal muscle mass may be equivalent among PLHIV and non-infected adults over 40 years.8

Several physiological mechanisms contribute to the loss of muscle mass, such as mitochondrial dysfunction, neuro-degenerative diseases, endocrine changes, physical inactivity, and inadequate intake or malabsorption of nutrients.25 In PLHIV, the specific adverse effects of viral infection and cART cannot be disregarded as additional factors potentiating muscle catabolism.26,27 However, in the present study differences in the percentage of lean body mass and strength were not detected in PLHIV compared to age-matched controls. The relatively young age of participants in PLHIV and CONT (43 to 44 yrs) may help to explain these findings. Although the mechanisms underlying the development of premature aging syndromes among PLHIV are multifactorial, chronic immune activation and long-term persistent inflammation seem to play a key role in muscle mass and function losses.23 In this case, differences in muscle mass and function between PLHIV and non-infected individuals would be detected only in further ages.21,22 Evidently, additional research in older PLHIV is warranted to ratify this premise.

As for bone health, greater rates of osteopenia have been reported in PLHIV treated with cART vs. general population of similar age.28 Although the causes of accelerated loss in skeletal mineralization in PLHIV are not fully understood, they seem to include factors such as the use of cART (particularly protease inhibitors), low CD4 count, and the presence of chronic inflammation,9,29 in addition to other traditional risk factors, such as endocrine changes, low skeletal muscle mass, physical inactivity, nutritional deficiencies (calcium and vitamin D), smoking, and alcohol consumption.30 Actually, a meta-analytic review10 showed that the prevalence of osteoporosis among PLHIV would be more than three-fold greater vs. non-infected individuals. Moreover, cART and protease inhibitor treated patients had increased odds for reduced BMD and osteoporosis. Guerri-Fernandez et al.,31 for instance, reported a strong association between HIV infection and hip fracture incidence, with a five-fold risk increase in PLHIV vs. non-infected controls.

Based on these data, one could speculate that PLHIV might have greater risk to develop osteopenia than sarcopenia. Although tempting, this assumption is not possible because we did not assess the incidence of osteopenia and sarcopenia in our sample. However, it is worthy to notice that in the Multicenter AIDS Cohort Study (MACS)32 sarcopenia was present in 41% (76/185) of men living with HIV vs. 36% (67/186) (P = 0.32) of non-infected individuals, while osteopenia/osteoporosis was detected in 16% (30/185) vs. 9% (17/186) (P = 0.003), respectively. This corresponds to a greater risk ratio for osteopenia/osteoporosis (∼1.77) than for sarcopenia (∼1.13). Larger epidemiological studies calculating the risk ratio for both osteopenia and sarcopenia among PLHIV are certainly needed to confirm this premise.

As hypothesized, our data showed that BMD among PLHIV was similar compared to older adults, and lower than values observed in age-matched healthy controls. The BMD presently found in OLDER concurs with values previously reported in the elderly.33,34 To date, most studies on bone density were restricted to young and middle-aged PLHIV vs. age-matched non-uninfected counterparts, while comparative studies with older individuals are scarce.10 Therefore, our data contribute to the current knowledge by ratifying the premise that prolonged infection and cART may accelerate BMD loss in PLHIV, by means of direct comparisons with age-matched and older controls. These findings suggest that strategies to prevent early osteopenia, as hormonal replacement, calcium supplementation, or resistance training, should be considered in middle-aged patients treated with prolonged cART intervention.9,14

Our hypothesis of early vascular aging in PLHIV was not supported by vasoreactivity responses to venous occlusion (endothelial dependent vasodilation), and sublingual nitroglycerine (endothelial independent vasodilatation). Previous evidence have demonstrated that vascular dysfunction, which is a precursor of atherosclerosis and cardiovascular events, is common among PLHIV treated with cART35-37 and older adults.38 The complex interaction of traditional cardiovascular risk factors,39 exposure to cART,40 and HIV infection41 appear to predispose HIV-population to vascular dysfunction. Albeit the lack of statistical significance, the somewhat large difference between PLHIV and age-matched counterparts and the proximity of values exhibited by OLDER for %HYPER suggest that our findings could have been underpowered, due to the relatively small number of subjects or large inter-individual variability of vascular markers. Future research with larger groups are warranted to provide more conclusive information on early vascular aging in PLHIV.

Some limitations of the study must be mentioned. The careful screening of participants to avoid possible biases due to secondary diseases or medications apart from cART hindered the recruitment of a larger sample of PLHIV. As a result, a stratified analysis by sex could not be performed to dismiss sex-related bias. However, the fact that all groups were matched for sex minimized the influence of this factor in our results. In addition, the cross-sectional design is always problematic in establishing age-related effects upon biological variables. Longitudinal studies would provide useful insights of the relationship between secondary effects of HIV-infection and cART and the development of diseases, as well as to avoid cohort effects when describing changes in muscle mass, strength, BMD and vascular function over prolonged periods. Finally, the inclusion of inflammation and oxidative stress biomarkers would allow a better understanding of the hypothetical “accelerated aging syndrome” in PLHIV.

In conclusion, middle-aged patients with prolonged exposure to HIV infection and cART (3 to 30 years) showed preserved muscle mass, strength, and vascular function vs. age-matched non-infected controls. On the other hand, their BMD was lower vs. HIV-negative counterparts and similar to values of non-infected older individuals. Additional comparative studies with larger samples of infected and non-infected individuals, and including patients with longer exposure to HIV infection and cART are warranted to confirm these findings.

Conception and design of the study: KGL, GOL, GAP and JPB. Acquisition, analysis, or interpretation of data: KGL, DAB, GOL, GAP and JPB. Drafting the work or revising it critically for important intellectual content: KGL, PF, RBO, DAB, EB and JPB. All authors read and approved the final manuscript.