Frailty increases the risk of death in people with HIV


Frailty is associated with increased mortality risk for middle-aged people living with HIV, investigators from the Netherlands report in the Journal of Infectious Diseases. Frailty was also associated with an increased risk of developing serious illnesses normally associated with ageing. The researchers, led by Dr Eveline Verheij of the University of Amsterdam, also found that frail HIV-negative individuals also had an increased risk of death and serious illnesses.

“We found that in comparable populations of middle-aged HIV-positive and -negative participants, the frailty phenotype was strongly and consistently associated with increased risk of both all-cause mortality and incident comorbidity. Both effects were independent of other risk factors such as age and smoking behaviour,” comment Dr Verheij and her colleagues. “These data further contribute to the growing evidence base of the utility of the frailty phenotype for predicting adverse clinical outcomes in ageing but generally younger HIV-positive populations, even among those whom have maintained excellent control of HIV disease for prolonged periods of time.”

The diseases of ageing are an increasingly important cause of serious illness and death in people with HIV. In the general population, frailty among the over 65s is predictive of adverse health outcomes and death. Dr Verheij and her colleagues noted that frailty can occur at younger ages among people with HIV than their HIV-negative peers. They therefore designed a prospective study to see if the presence of frailty was predictive of increased mortality risk and the development of co-morbidities among HIV-positive and HIV-negative individuals over the age of 45.



Describes a general decline in physical health and a loss of reserves, most often seen in older people. Frailty leads to a person being less robust and less able to bounce back after an adverse event. A person with frailty may move more slowly, have lost some of their physical strength, have less energy and be less mentally agile. 


The presence of one or more additional health conditions at the same time as a primary condition (such as HIV).


The phenotype of an organism is all of its observable characteristics, defined by the genotype and the environment.  



person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

The study population consisted of 598 HIV-positive and 550 HIV-negative participants enrolled in the AGEhIV cohort. The participants were regularly assessed using the Fried Frailty Phenotype – an established tool for the diagnosis of frailty which takes into account weight loss, low physical activity, walking speed, exhaustion and decreased grip strength were all evaluated. People were diagnosed as frail if at least three of these conditions were present and as pre-frail if they had one of two of the conditions. Individuals were classified as robust if they had none of these health complaints.

Co-morbidities included in the study assessments were chronic obstructive pulmonary disease (COPD), hypertension, diabetes, cardiovascular disease, kidney dysfunction, osteoporosis and non-AIDS-defining cancers.

Most participants were male with a median age in the early fifties. Most of the HIV-positive participants (96%) were taking antiretrovirals and had an undetectable viral load (91%). During follow-up, 8% of HIV-positive and 5% of HIV-negative participants became frail. In addition, pre-frailty was diagnosed in 57% of people living with HIV and 49% of HIV-negative people.

People diagnosed with frailty were older, more likely to be HIV positive, to smoke, to drink alcohol and to have a greater number of pre-existing co-morbidities.

During a median of four years of follow-up, 3.3% of participants died, including 31 (5.2%) people living with HIV and seven (1.3%) HIV-negative individuals.

Of the people who died, 29% were frail at enrolment and 53% were pre-frail.

The mortality rate was 26 per 1000 person-years among those who were frail, compared to 7 per 1000 person-years among pre-frail individuals and 2 per 1000 person years among robust individuals.

Frailty was independently associated with increased mortality risk after taking into account other risk factors including HIV status, smoking and alcohol use. Although the mortality risk associated with frailty did not differ according to HIV status, the researchers urge that this finding should be treated with some caution. They note that the small number of deaths among the HIV-negative participants limited their ability to detect differences in risk between the HIV-positive and HIV-negative groups.

Among people with HIV, frailty remained an independent predictor of mortality risk even after taking into account lowest ever CD4 cell count and body shape (waist and hip measurements, proxies for lipodystrophy).

"Routine use of a frailty assessment could help predict and prevent adverse outcomes in ageing people living with HIV."

There were 497 HIV-positive and 479 HIV-negative participants in the co-morbidity analysis. When combined, 8% and 43% were classified as frail and pre-frail. Incident co-morbidities were documented in 31% of frail and 20% of pre-frail individuals. A co-morbidity was diagnosed in only 14% of robust participants. Hypertension, decreased kidney function and osteoporosis accounted for three-quarters of all the diagnosed co-morbidities.

Both frailty and pre-frailty were strongly associated with the diagnosis of a new co-morbidity, an association that remained robust after taking into account age and HIV status. Closer analysis of the HIV-positive participants showed that frailty remained a predictor of co-morbidities after demographic factors were taken into account (OR = 1.92; p = 0.027). This association was not substantially affected when also taking into account the use of older antiretrovirals and amount of time spent with a detectable viral load.

“Although hypothesized to drive comorbidity risk in people with HIV, markers of chronic inflammation, immune activation and microbial translocation did not influence the association between frailty and incident comorbidity,” note the authors. “These findings suggest a distinct independent pathophysiological pathway, not captured by factors measured in our study.”

The investigators suggest that routine use of a frailty assessment could help predict and prevent adverse outcomes in ageing people living with HIV.

“Evidence suggests that once identified as being frail, sustained physical activity may improve the frailty score among elderly persons,” conclude Dr Verheij and her colleagues. “Future studies should investigate if such interventions may similarly modify the frailty-phenotype in ageing people with HIV to reduce their risk of morbidity and mortality.”