With the widespread availability of effective antiretroviral therapy (ART) beginning in the late 1990’s, HIV infection has been transformed into a chronic disease. Survival among people living with HIV (PLWH) is now approaching that of the general population. However, there appears to be an acceleration of aging processes in PLWH. Aging-related comorbidities, such as cardiovascular disease, pulmonary disease, diabetes, heart failure, and kidney disease are more frequent and tend to occur at an earlier age in those living with HIV (Schouten et al., 2014; Guaraldi et al., 2011; Gonciulea et al., 2017; Drozd et al., 2017). Markers of biologic aging, such as epigenetic alterations in cellular DNA – a “clock” for cellular aging – are similar to persons without HIV who are over five years older (Fülöp et al., 2017; Horvath et al., 2015).
Among PLWH, the clinical and public health significance of frailty has become more widely recognized (Piggott et al., 2016). Multiple studies have shown a high prevalence of physical frailty is this population. In the AGEhIV Cohort Study in Amsterdam, the prevalence of frailty, using the physical frailty phenotype, was 10.6% in PLWH compared to 2.7% in age, sex, and race-matched controls. The prevalence of pre-frailty was also significantly higher in PLHW (50.7% v 36.3%). Even after adjustment for demographic factors, smoking, hepatitis C infection, comorbidities and depression, HIV-infection was associated with a doubling of the odds of frailty and pre-frailty (Kooij et al., 2016). In the Multicenter AIDS Cohort Study, a study of men who have sex with men, the prevalence of frailty was also higher in PLWH compared to demographically similar HIV-uninfected men (12% vs 9%), particularly in those who had a past history of AIDS (Althoff et al., 2014).
The Impact of HIV Infection on Frailty
The etiology of the higher prevalence of frailty in PLWH is multifactorial, with both infection and treatment contributing to the problem. Chronic inflammation, which is present in PLWH even when HIV viral load is undetectable, leads to accelerated cellular senescence, mitochondrial dysfunction, and metabolic dysregulation (Erlandson et al., 2014). These changes in physiology are known to develop during aging and are thought to play a role in the development of frailty in the general population. Infection with HIV therefore causes a premature onset of these processes.
Antiretroviral therapy (ART) for HIV infection is likely to have both direct and indirect effects on physical function. Nucleoside analogue reverse transcriptase inhibitors (NRTI) that are thymidine analogues, including AZT and d4T, were used extensively in PLWH when combination antiretroviral therapy became available and have direct effects on mitochondrial function. These changes result in persistent body composition alterations (subcutaneous lipoatrophy and relative central lipohypertrophy), insulin resistance, and dyslipidemia, which in turn may predispose these individuals to more accelerated aging-related declines in physical function (Kooij et al., 2016). Although in the current HIV treatment era these medications are seldom used, their adverse effects may persist in those who were previously exposed. Efavirenz, a previously widely used non-NRTI, has been linked to frailty in a study the AIDS Clinical Trial Group, although it is unclear if this association is causal (Erlandson et al., 2017). More recently, the integrase strand transfer inhibitors (InSTI or commonly “integrase inhibitors”), which are currently a key component of most ART regimens, have been linked to significant weight gain (Eckard & McComsey, 2020). Whether these changes in adiposity will predispose PLWH to faster declines in physical function as they age is an important area of inquiry.
Impact of Frailty on those living with HIV
An increased prevalence of frailty among PLWH at a relatively young age stands to have a major impact on both health and quality of life as the HIV population ages. By 2035, an estimated 70% of the HIV population in the US will be over 50 years old, with 25% over 65 years of age (Smit et al., 2017).
Frailty among PLWH, as in the general population, is associated with multiple adverse outcomes, including falls, fractures, and mortality (Kelly et al., 2019; Erlandson et al., 2019; Sharma et al., 2019). Frailty is also related to decreased muscle mass (sarcopenia), which is associated with mortality in PLWH, especially when coupled with accumulation of visceral fat, in a phenotype reminiscent of sarcopenic obesity (Scherzer et al., 2011; Hawkins et al, 2018). In the FRAM study, PLWH in the lowest tertile of skeletal muscle mass had twice the mortality of those in the highest tertile, an effect that was especially prominent in those with the most (i.e., highest tertile) of visceral fat (Scherzer et al., 2011).
Applying Knowledge of Frailty in HIV
Understanding the pathogenesis of frailty in PLWH is the first step towards robust interventions. One important research question is whether the mechanisms underlying frailty and impaired physical function are similar or different from frailty in the general population. Are there molecular pathways that are more or less activated? Are the physical manifestations of frailty pathways, such as immunosenescence, mitochondrial dysfunction, and hormonal dysregulation, the same as the general population in PLWH? If differences exist between PLWH and the general population, this would suggest that the strategies to alter the physical function trajectory may also differ.
Over the past 30 years, the health of PLWH has been radically transformed with advances in our understanding of HIV, improved antiretroviral treatments, and their more widespread availability. Advances in frailty science will help improve the health and well-being for PLWH in the next 30 years.