The results of this study indicate that the presence of a FRP in HIV-positive men prior to HAART initiation was an independent predictor of development of AIDS or of death despite HAART in most, but not all, of the analyses conducted. This was true among both men who did not have AIDS and among those who did. Among the subset of men who achieved virologic suppression within 1 year after HAART initiation, it was true in all analyses. Furthermore, the association of the FRP with outcomes was independent of pre-HAART levels and nadir of hemoglobin and CD4+ T-cell count, peak HIV viral load, and other potential confounders, including liver and kidney function in the men who had these data available (78% and 49%, respectively, among the AIDS-free men at HAART initiation). In addition, HCV status had no effect on these findings in AIDS-free men and only a minor effect in the men with AIDS. Thus, the association between the FRP and time to AIDS or death did not seem to be confounded by many of the HIV-related and -unrelated biomarkers that are associated with mortality after initiation of antiretroviral therapy (39
). The FRP as defined in this study uses extant data from the MACS cohort and has been demonstrated to relate to a previously validated medical syndrome of frailty (21
In the population of men who were AIDS free at HAART initiation, the adjusted association between the FRP and time to AIDS or death was significant when using proportion of visits with FRP (>25% vs ≤25%) or when using two or more visits with the FRP as the cutoff but not when using FRP ever versus never. A stronger association between the FRP and time to AIDS or death was also observed among the subpopulation of men AIDS free at HAART who achieved virologic suppression within 1 year after HAART when the FRP was used as >25% versus ≤25% of the visits than when using FRP ever versus never. This finding suggests the hypothesis that a certain “burden” or threshold of frailty is required to affect later outcomes as has been hypothesized (42
). The clinical implication of this would be that a recurrent or sustained presentation of the FRP may indicate an increased risk for AIDS or death after HAART. Although monitoring the proportion of visits with the FRP may be difficult in clinical settings, our data also suggest that the number of visits with the FRP predicted outcomes approximately as well as the proportion of visits. This may provide a more clinically feasible method of monitoring expression of the FRP and of testing its clinical import. However, this suggestion should be considered with caution because it is based on relatively few observations.
If confirmed in additional studies, the finding that the FRP independently predicts poorer outcomes after initiation of HAART has a number of important implications. First, biologically, it supports prior findings that frailty, a syndrome associated with aging and with catabolic diseases including congestive heart failure, may be a final common pathway that is initiated by these diseases but then independently modifies the outcomes associated with the precipitating pathology. Second, and clinically, it helps to explain differences in clinical outcomes among those who receive HAART, and it may—in the short-term—identify ways to distinguish those at low or high risk of poor outcomes after HAART. This may also suggest a need for additional therapeutic approaches for HIV-positive people with the FRP as recently proposed for older adults at risk of poor surgical outcomes after elective surgery in whom a preoperative screen for frailty was the best tool for identifying the high-risk group (45
). A related point is that because the FRP is associated with low CD4 T-cell counts, FRP assessment in settings where CD4 T-cell testing is limited could help identify people who should be receiving HAART, although the reversibility of the FRP by HAART remains to be studied.
These biological and clinical implications may be related. Although the effect sizes were relatively imprecise, our finding that the FRP as a whole was more predictive of AIDS or death than any of its four components taken individually is consistent with prior reports validating the frailty phenotype as a distinct clinical syndrome (4
). Furthermore, as with diabetes mellitus, where the duration of the illness predicts mortality (46
), our finding that HIV-positive men who had the FRP at more than 25% of visits were at significantly elevated risk of poor outcomes suggests that it is the persistence of the phenotype over time that provides greatest specificity of the relationship with adverse outcomes. This would be consistent with other reports indicating that severity of frailty is associated with adverse outcomes, such as loss of independence (20
) and mortality (5
). Other prior work indicates that the severity of frailty is related to the number of physiologic systems that are dysregulated (10
), with the characteristics of a complex system (15
). Ultimately, we may be seeing evidence of physiological dysregulation that can be initiated by HIV infection, other catabolic diseases, or physiologic processes of aging itself, which results in an independent process of fraying of the complex system of a resilient organism and in an emergent property of greater vulnerability (8
). The extent to which specific underlying conditions contribute to this fraying was not evaluable in this study, but the specific conditions examined (ie, anemia and liver and renal disease) did not materially affect the relationship between the FRP and the risk of AIDS or death after starting HAART. However, the analysis of contributions of underlying conditions was necessarily incomplete and was also limited by missing data for liver and particularly renal status.
Other limitations of the study should be mentioned. The data were obtained from an observational study, so it cannot be concluded that frailty was a causal factor of AIDS or death. As mentioned, even after the adjustments made, residual confounding may still have been present due to unmeasured confounders. Because we measured a frailty-related phenotype rather than the clinically validated frailty phenotype (5
), we may have misclassified some men as being frail (or nonfrail); although such nondifferential misclassification would be expected to bias estimates conservatively, the present results should still be confirmed with the validated frailty phenotype. In this study, the majority of men initiated HAART before 1998, and most had been exposed to mono- and dual-therapy prior to HAART; therefore, the present study is not representative of people who start HAART now. Furthermore, HAART regimens have become less toxic since 1998, which theoretically could affect relative survival, although adjustment for the time of HAART initiation did not change the results in this study. Our study population was exclusively male and predominantly White, so our results cannot be generalized to men of other ethnicities or to women. Although significant associations were observed, the number of men who had the FRP was small (less than 10% of men who were AIDS free at HAART initiation). Because of the small number of men who had both AIDS and FRP before HAART initiation, we cannot exclude an effect of particular AIDS-defining conditions on the outcome of mortality. Despite these limitations, however, the present findings support the need for further studies of prevalence and mechanisms of frailty in people with HIV infection.
The findings of this study suggest that HIV-infected individuals may respond better to antiretroviral treatment if started as early as possible in the course of frailty. This possibility may be less important when HAART is initiated at higher CD4+ cell counts at which frailty is less common (22
). However, it could be more important in places where CD4+ T-cell counts and viral loads, and HAART itself, are not readily available. The five criteria for frailty can be assessed relatively easily and inexpensively through questionnaires and performance tests, and the four components of the FRP can be assessed simply through questionnaires. Interventions to identify HIV-infected persons at high risk of frailty and to prevent or reverse onset of frailty regardless of HIV status are needed everywhere.