Frailty is an ageing-related state of increased vulnerability to stressors due to decrease in physio-logical and functional reserves. It is a high-risk state, predictive of adverse health outcomes 1. The inflammatory effects of HIV-infection, HIV-related illnesses and the side-effects of antiretroviral-therapy (ART) have all been suggested as possible reasons for the association between frailty and HIV/AIDS 2. Though the AIDS epidemic has plateaued in India, there are an estimated 2.401 million people living with HIV/AIDS (PLHA) 3. Indian PLHA constitute a third of the world’s HIV-population and with them living longer due to universal availability of effective anti-retroviral therapy (ART), long-term co-morbidities like cardiovascular disease and metabolic syndrome are being increasingly recognised. Frailty in Indian PLHA has, however, not been study in detail.

A widely accepted screening tool for assessing frailty is the Fried criteria. Fried et al. developed a standardised frailty phenotype (FP) by employing data from the Cardiovascular Health Study, in HIV uninfected men and women aged 65 years or older 4. The Multi-centre AIDS Cohort Study (MACS) made a seminal contribution by validating FP for evaluating frailty in PLHA by comparing its results with those obtained using a frailty-related phenotype (FRP) 56.

The prevalence of frailty in PLHA ranges from 5 - 28.6% depending on the type of population studied ^7,8. Not only is frailty present in younger PLHA but it has also been observed that PLHA develop frailty earlier than those without HIV infection 9101112. In a recent systematic review and meta -analysis, Yamada and colleagues found the overall pooled prevalence of frailty and pre frailty to be 10.9% (95% Confidence interval (CI), 8.1 -14.2%) and 47.2% (95% CI, 40.1% - 54.4%) respectively in PLHA aged 50 or older. These figures were comparable to the pooled prevalence of frailty and pre-frailty in HIV negative community-dwelling elders >65 years of age 13. A recent study on HIV-positive and HIV-negative middle-aged individuals showed that when compared to robust individuals, those with frailty had increased risk of both all-cause mortality (mortality rates/1000PYFU 25.7 (95%CI,14.2 - 46.4 vs 2.3 (95% CI, 1.1-4.9) and incident comorbidity (OR2.59, p<-001) irrespective of HIV status 14. Apart from health complications, frailty leads to lower economic productivity and greater requirement for assistance. Clearly, there is a strong case for identifying frailty in younger PLHA and managing it. Younger patients possess better functional reserves compared to elderly patients and interventions maybe effective if frailty is detected early 15.

Pain is a common symptom in PLHA 16. Recent studies suggest that the assessment of pain can be used to predict frailty and that pain may be a phenotype of frailty 171819. Similar data reporting high prevalence of pain in PLHA is available from the Indian population as well 1520. However, some studies have also questioned the role of pain in predicting frailty 1821.

Studies of older PLHA consistently support associations between markers of inflammation and frailty. Such markers include C-reactive protein (CRP), Interleukin-6 (IL-6) and D-dimer. Higher levels of CRP and IL-6 directly affect muscle atrophy, thereby contributing to frailty. D-dimer is a product of fibrin formation as well as degradation, and is a marker of activation of the coagulation-fibrinolytic systems. A report that frail older adults stand an increased risk of developing venous thromboembolism potentially links increased blood coagulation and fibrinolytic activity in frail patients 11222324252627282930.

Several studies report higher levels of inflammatory markers such IL6, CRP and markers of thrombosis like D-dimer in PLHA exhibiting FP compared to their non-frail counterparts, despite good ART regimens11313233. Frailty has an inverse association with duration of ART. Rees et al. reported a high prevalence of frailty in HIV patients who were on ART <5 years. The prevalence of frailty halved in in those on ART for 5-10 years. And beyond 10 years of ART, most PLHA were non-frail 15. Önen et al.,in the SUN-Study observed that half of their study participants exhibiting frail and pre-frail phenotypes were under 50 years of age 11. Data evaluating frailty in PLHA are available from other Asian countries and Africa 3435. However, to the best of our knowledge, there is no such data from India.

The primary objective of this study was to assess the prevalence of frailty in young PLHA. Secondary objectives were to study the association of pain assessment in predicting frailty PLHA and to assess if levels of CRP, IL-6 and D-dimer were associated with frailty in PLHA.

The prevalence of frailty and pre-frailty was 6.58% and 23.02%, respectively. This is similar to previously published literature7. Our study findings are strictly restricted to PLHA <50 years. Most Western studies include older subjects and their age itself would lead to their being pre-frail or frail. A case in point is the high rates of frailty reported by Jacqueline McMillan among middle-aged and older people living with HIV. The mean age of her subject population (n = 700) was 59.2 with 84% people in the age group of 50 – 64 yrs (range 50 - 92). Most had been on ART for at least 15 years and 93% had undetectable viral loads. The mean CD4 count was 594 cells/µL. Frailty (FI>0.21) was seen in 74.6% of the subjects 38. Our decision to select subjects in the age group of 20 - 50 was influenced by Onen’s observation that half of the pre-frail and frail participants in their study were <50 years of age and due to our interest in studying frailty in your PLHA 6. We also only enrolled subjects who had been on ART for 2 - 5 years. The reason being that most opportunistic infections and immune-reconstitution inflammatory syndromes (IRIS) mostly occur in the first two years of ART and that two years is adequate for immune restitution and viral suppression. Significant association between low CD4 count and frailty and a positive relationship between length of ART and not being frail is well established 78. In Rees’s study the prevalence of frailty halved after 4 years of ART and became negligible by 10 years of ART 15. And more compellingly, our centre was established only 2009 and hence there were not many patients with more than 5 years follow up at our centre.

Unlike studies in Caucasian populations, which have reported low physical activity to be the main marker of frailty, our study identified weak grip strength and self-reported exhaustion to be the commonest frailty markers 19. We offer the following explanation for this: firstly, most of the study participants, being daily wage workers, had no choice but to be physically activity to ensure daily sustenance. They responded that they managed to go about their daily activities as demanded by their work, despite exhaustion. Secondly, younger PLHA were less likely to report low physical activity compared to elderly PLHA. Weak grip strength could either be due to poor nutrition, ethnicity or due to effects of chronic inflammation, more specifically IL-6 induced sarcopenia. Calf and mid-upper arm circumferences had no significant association with frailty.

The prevalence of pain in our study participants at 21.7% is similar to estimates by Nair et al who reported a pain prevalence of 24.5% in out-patients 1520. Apart from recurrent headaches, the major sites of pain were the calves and the back. Those who complained of pain were more likely to exhibit frailty/pre-frailty (Odds ratio: 4.08, Chi square: 12.58, p < 0.05). Frail/pre-frail PLHA also scored ‘pain severity and interference in daily activities higher’ compared to their non–frail counterparts. Petit et. al were the first to describe a link between pain and frailty in PLHA albeit in an older population 19. Our observations corroborate this finding but in a younger population subset. We suggest that pain may be a surrogate marker of frailty/ pre-frailty in young PLHA.

No correlation was seen between baseline CD4 count and occurrence of frailty. However, CD4 count at the time of assessment was inversely proportional to frailty as was noted by Rees and Desquilbet 78. Similarly, Δ CD4 (CD4 at assessment/CD4 at baseline - 1) was also inversely proportional to frailty. The average CD-4 count increase following ART in frail/pre-frail patients was significantly lesser in comparison to their non-frail counterparts. Our findings reflect previously published literature in this regard 510.

Levels of hs-CRP were significantly higher among frail/ pre-frail PLHA as compared to non-frail PLHA (HsCRP p = 0.017). These findings are similar to those reported in earlier studies 141821. However, unlike most published literature, our study did not detect a significant association between D-dimer and serum IL-6 levels and frailty/pre- frailty phenotypes (p = 0.4) 14222324252627.

All the subjects enrolled in our study were on ART for a duration 2 to 5 years for reasons mentioned previously. Our study results favoured our assumption since the prevalence of frailty/pre-frailty decreased as the duration of ART increased. This observation is similar to those made in previous studies 15.

To the best of our knowledge, this is the first study in India on frailty in PLHA and its association with pain and inflammatory markers. Our study is not without limitations: our sample size is relatively small, and we did not have an HIV-uninfected group for comparison. We interpreted weak grip strength and walking time using cut-offs designed primarily for Caucasian populations Ethnicity and genetics are likely to have a role in grip strength, which is part of Fried’s criteria. Once a reference cut-off is established for the Indian population, and Fried’s criteria modified, future studies may reveal different estimates of frailty in Indian population. Lastly, the study’s cross-sectional design prohibits drawing conclusions of causality and directionality of associations found.

Future studies are required to establish age and sex adjusted cut-offs for grip-strength and walking-time in the Indian population for better application of Fried’s criteria in this population. We also believe that the nutritional status of PLHA in India needs to be studied in detail as it may have an association with frailty/pre-frailty. The association of serious co-morbidities and increased mortality with frailty is a matter of concern with PLHA living longer.

In this first-of-its-kind study on frailty in young PLHA (mean age 37 yrs) from the Indian sub-continent, the prevalence of frailty and pre-frailty was 6.58% and 23.02%, respectively. Multivariate analysis showed a strong association of frailty with pain severity, CD4 count at time of assessment, hs-CRP levels and duration of ART. Detecting and addressing frailty in young PLHA might reduce incident co-morbidities and all-cause mortality and reduce healthcare costs.

The study was funded by an Indian Council of Medical Research short-term scholarship grant (ID 2018-04971).