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Measuring the potential role of frailty in apparent declining efficacy of HIV interventions.

ABSTRACT: In recent HIV intervention trials, intervention efficacies appear to decline over time. Researchers have attributed this to "waning," or a loss of intervention efficacy. Another possible reason is heterogeneity in infection risk or "frailty." We propose an approach to assessing the impact of frailty and waning on measures of intervention efficacy and statistical power in randomized-controlled trials.Using multiplicative risk reduction, we developed a mathematical formulation for computing disease incidence and the incidence rate ratio (IRR) as a function of frailty and waning. We designed study scenarios, which held study-related factors constant, varied waning and frailty parameters and measured the change in disease incidence, IRR, and statistical power.We found that frailty alone can impact disease incidence over time. However, frailty has minimal impact on the IRR. The factor that has the greatest influence on the IRR is intervention efficacy and the degree to which it is projected to wane. We also found that even moderate waning can cause an unacceptable decrease in statistical power while the impact of frailty on statistical power is minimal.We conclude that frailty has minimal impact on trial results relative to intervention efficacy. Study resources would, therefore, be better spent on efforts to keep the intervention efficacy constant throughout the trial (e.g., enhancing the vaccine schedule or promoting treatment adherence).

SUBMITTER: Hardnett FP

PROVIDER: S-EPMC4867861 | biostudies-other | 2015 Nov

REPOSITORIES: biostudies-other

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Measuring the potential role of frailty in apparent declining efficacy of HIV interventions.

Hardnett Felicia P FP Rose Charles E CE

HIV clinical trials 20151101 6

<h4>Objective</h4>In recent HIV intervention trials, intervention efficacies appear to decline over time. Researchers have attributed this to "waning," or a loss of intervention efficacy. Another possible reason is heterogeneity in infection risk or "frailty." We propose an approach to assessing the impact of frailty and waning on measures of intervention efficacy and statistical power in randomized-controlled trials.<h4>Methods</h4>Using multiplicative risk reduction, we developed a mathematica ...[more]

PMID: 26728574

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Project description:PurposeFrailty is a syndrome of vulnerability and physical decline with aging that increases risk for disability, hospitalizations, and death. To date, interventions for frailty have primarily focused on exercise and/or nutritional interventions, many of which show improvement in frailty-related characteristics, such as gait speed and lower extremity strength and function. The goal of this article was to review prior research studies investigating interventions for frailty and review the literature with regard to the role of insulin resistance and inflammation in the development of frailty. Also included is a discussion of potential therapeutic interventions for frailty.MethodsA literature search was conducted by using PubMed and the search terms frailty, interventions, and older adults. This review focused on larger studies (N ≥ 100 participants) that examined the effect of specific interventions on frailty as a primary outcome or on measures that are closely related to frailty, such as gait speed, muscle strength, and/or sarcopenia.FindingsThe results of prior studies of exercise interventions for the frailty syndrome as the primary outcome are mixed, with some but not all showing benefit. However, many exercise interventions have demonstrated improvement in components of frailty, such as strength, gait speed, and physical activity. The evidence shows that regular physical activity is beneficial for frail older adults or those at high risk of frailty and that the adverse effects related to exercise are minimal compared with the potential gains. However, questions remain as to the optimal type and duration of exercise and whether results of clinical trials are easily and feasibly implemented in a clinical setting in individuals whose motivation for exercise may be low. There is now increasing interest in pharmacologic agents that could potentially be useful in the prevention or treatment of frailty, in part based on advances in basic biology of aging research demonstrating that pharmacological agents extend lifespan in rodents. Several studies now show that obesity, insulin resistance, inflammation, and diabetes are associated with and predict frailty. Because metformin targets insulin resistance and inflammation, it is a plausible pharmacologic agent to prevent frailty. A clinical trial is underway to examine metformin's usefulness in frailty prevention.ImplicationsAlthough the benefits of exercise are known, adherence to these regimens may be difficult for individual older adults due to lack of motivation, access, or limitations due to chronic medical conditions. Studies are currently underway to examine novel agents for the prevention of frailty in older adults.

Project description:BackgroundFrailty is the pre-eminent exigency of aging. Although frailty-related impairments are preventable, and multidomain interventions appear more effective than unimodal ones, the optimal components remain uncertain.MethodsWe devised multidomain interventions against physical and cognitive decline among prefrail/frail community-dwelling ≥65-year-olds and evaluated these in complementary cluster-randomized trials of efficacy and participant empowerment. The Efficacy Study compared ~3-monthly telephone consultations vs. 16, 2 h sessions/year comprising communally partaken physical and cognitive training plus nutrition and disease education; the Empowerment Study compared the standard Efficacy Study multidomain intervention (Sessions 1-10) vs. an enhanced version redesigned to empower and motivate individual participants. Changes from baseline in physical, functional, and cognitive performance were measured after 6 and 12 months in the Efficacy Study and after 6 months in the Empowerment Study, with post-intervention follow-up at 9 months. Primary outcomes are as follows: Cardiovascular Health Study frailty score; gait speed; handgrip strength; and Montreal Cognitive Assessment (MoCA). Secondary outcomes are as follows: instrumental activities of daily living; metabolic equivalent of task (MET); depressed mood (Geriatric Depression Scale-5 ≥2); and malnutrition (Mini-Nutritional Assessment short-form ≤11). Intervention effects were analyzed using a generalized linear mixed model.ResultsEfficacy Study participants (n = 1082, 40 clusters) were 75.1 ± 6.3 years old, 68.7% women, and 64.7% prefrail/frail; analytic clusters: 19 intervention (410/549 completed) vs. 21 control (375/533 completed). Empowerment Study participants (n = 440, 14 clusters) were 75.9 ± 7.1 years old, 83.6% women, and 56.7% prefrail/frail; analytic clusters: seven intervention (209/230 completed) vs. seven control (189/210 completed). The standard and enhanced multidomain interventions both reduced frailty and significantly improved aspects of physical, functional, and cognitive performance, especially among ≥75-year-olds. Standard multidomain intervention decreased depression [odds ratio 0.56, 95% confidence interval (CI) 0.32, 0.99] and malnutrition (odds ratio 0.45, 95% CI 0.26, 0.78) by 12 months and improved concentration at Months 6 (0.23, 95% CI 0.04, 0.42) and 12 (0.46, 95% CI 0.22, 0.70). Participant empowerment augmented activity (4.67 MET/h, 95% CI 1.64, 7.69) and gait speed (0.06 m/s, 95% CI 0.00, 0.11) at 6 months, with sustained improvements in delayed recall (0.63, 95% CI 0.20, 1.06) and MoCA performance (1.29, 95% CI 0.54, 2.03), and less prevalent malnutrition (odds ratio 0.39, 95% CI 0.18, 0.84), 3 months after the intervention ceased.ConclusionsPragmatic multidomain intervention can diminish physical frailty, malnutrition, and depression and enhance cognitive performance among community-dwelling elders, especially ≥75-year-olds; this might supplement healthy aging policies, probably more effectively if participants are empowered.

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Measuring the potential role of frailty in apparent declining efficacy of HIV interventions.

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Measuring the potential role of frailty in apparent declining efficacy of HIV interventions.

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