Our findings highlight that NNRTI-based ARV have a significant impact on the development of frailty in PLWH. Additionally, the longer median duration of HIV infection observed in the frail group suggests that prolonged HIV infection, extended ARV exposure, and aging-related physiological changes may collectively contribute to frailty development. However, ARV duration alone should not be considered a direct surrogate for aging.
These findings underscore the importance of individualized ARV selection, particularly in aging PLWH with multimorbidity. While NNRTI-based regimens have demonstrated long-term virologic efficacy, their association with frailty risk warrants further investigation. Clinicians should carefully assess comorbidities, polypharmacy, and potential drug-drug interactions when optimizing ARV in older adults. Moreover, while dual therapies may reduce the pharmacological burden, they might not be sufficient to address aging-related complications in PLWH with immunosenescence.
The evolving profile of PLWH due to aging is associated with the development of both frailty and geriatric syndromes, which may be linked to negative health outcomes22. Previous studies have consistently reported a higher prevalence of frailty in PLWH compared to the general population, with an earlier onset. Our findings align with this evidence, highlighting the importance for studies to better delineate the temporal relationship between ARV exposure, immune recovery, chronic inflammation, and frailty development. The prevalence of frailty in PLWH is estimated to range from 4 to 10%, potentially reaching up to 50% in patients over 50 years old, according to studies conducted primarily in North America and Europe23. Regarding geriatric syndromes, their prevalence in patients aged 60 years is estimated to be around 20%. These findings underscore the challenge of managing and providing comprehensive care for HIV population24.
Improvements in antiretroviral therapy have enabled optimal immunovirological control in PLWH, leading to increased life expectancy and, consequently, a longer duration of living with HIV infection. However, an increase in the prevalence of frailty has been observed as the duration of HIV infection extends, as shown by Desquilbet et al. and Felker et al., who reported higher frailty rates in individuals with prolonged HIV exposure26,27. This may be explained by the physiological ageing processes associated with HIV infection25. Additionally, prolonged exposure to antiretroviral treatments based on NNRTIs and PI/b has been linked to the development of pre-frailty and frailty26. Our results align with this trend, showing that NNRTI-based regimens and individuals who have been on active ARV for over 10 years are more prevalent in frailty PLWH.
The presence of comorbidities is significantly associated with the development of geriatric syndromes in both the seronegative population and HIV patients27. Our multivariate logistic regression analysis identified comorbidities as a key factor in this interplay, potentially mediating or confounding the relationship between ARV duration and frailty. Moreover, the longer median duration of HIV infection observed in participants with geriatric syndromes highlights the role of prolonged HIV exposure and extended ARV use in the development of these syndromes. This finding reinforces the importance of optimizing long-term ARV management in aging PLWH. PLWH are at a higher risk of developing cardiovascular disease, which has a multifactorial etiology, including chronic inflammatory processes to which these patients are subjected, as well as the effects of ARV. Some studies suggest that ARV may contribute to a chronic low-grade inflammatory process, even while maintaining optimal immunovirological control, which is associated with the development of these comorbidities28. Therefore, the risk differs between individuals aging with HIV infection who develop cardiovascular disease and HIV-negative individuals who acquire HIV at an older age and subsequently develop cardiovascular pathologies.
It is also important to highlight that participants in our study who did not present with geriatric syndrome were younger, which may partially explain the lower prevalence of comorbidities observed. Younger individuals generally exhibit fewer age-related conditions, and this demographic factor likely influenced the observed differences.
Dual antiretroviral therapy is beneficial due to its ability to reduce the pharmacological burden and the risk of drug interactions, which can pose a challenge in polypharmacy among PLWH. Additionally, these antiretroviral regimens have demonstrated efficacy and safety comparable to triple therapy in PLWH with controlled infection. However, in geriatric PLWH, where immune function may be compromised by both age and related comorbidities, dual therapy may not effectively address complications associated with HIV-related aging, such as chronic inflammation and immunosenescence, potentially promoting the development of geriatric syndromes29. Therefore, consistent with our data, dual therapy in geriatric patients may pose a risk and necessitates a thorough analysis and careful selection of patients for dual antiretroviral therapy. This approach helps avoid inappropriate selection of antiretroviral regimens in complex clinical contexts that may result in suboptimal outcomes and clinical deterioration.
Despite these results, it is essential to acknowledge some methodological limitations. One notable limitation is the smaller proportion of participants on regimens composed of 2 NRTIs with a PI/b or INSTI, which may have reduced the statistical power for detecting associations specific to these regimens. Consequently, the findings related to these regimens should be interpreted with caution. The observational nature of the study limits our ability to establish definitive causal relationships, highlighting the need for prospective research or randomized controlled trials to confirm these associations. Additionally, the study was conducted at a single center, which may limit the generalizability of the findings to other populations. However, the extended duration of the study, spanning more than a decade, and the use of multivariable logistic regression models to control for confounding variables, contribute to the robustness of the findings.
The study’s strengths should also be highlighted, such as the use of validated tools like the Fried frailty phenotype scale and MRCI, which ensure accurate and standardized assessment of frailty and treatment complexity. Notably, our findings indicate that patients with an MRCI score ≥ 11.25, identifying complex treatment regimens, exhibited a significantly greater prevalence of frailty and geriatric syndromes. This underscores the importance of considering regimen complexity beyond the quantitative measure of polypharmacy. The MRCI allows for a more nuanced evaluation by incorporating qualitative factors, such as dosing frequency and administration complexity, which are critical for optimizing therapeutic strategies in aging PLWH. Additionally, the inclusion of a large cohort of patients and the evaluation of multiple geriatric syndromes allows for a comprehensive understanding of how ARV and other HIV-related factors influence these outcomes. These aspects strengthen the study’s internal validity and provide a solid foundation for future research in this field.
This study highlights the importance of integrating frailty and pharmacotherapeutic complexity assessments into routine clinical practice for older PLWH. Early interventions based on these assessments, such as optimizing therapeutic regimens and reducing unnecessary polypharmacy, can help mitigate the progression toward frailty and improve functional outcomes. Furthermore, these findings could inform the development of specific health policies that allocate resources to specialized services for the comprehensive management of aging in PLWH.
In summary, our findings suggest that ARV-related factors, including regimen composition and treatment duration, may be associated with frailty PLWH. However, given the observational nature of this study, prospective research is needed to establish causal relationships and investigate whether specific ARV modifications could mitigate these risks. The findings presented provide a critical foundation for the implementation of clinical strategies aimed at improving the quality of life in aging PLWH. This knowledge underscores the need for personalized approaches and multidisciplinary strategies to optimize treatments, prevent associated complications, and ensure healthy aging in this population.
