Cost-Effectiveness of Genotypic Antiretroviral Resistance Testing in HIV-Infected Patients with Treatment Failure

BACKGROUND: Genotypic antiretroviral resistance testing (GRT) in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure. METHODS: We developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4%) and societal (discount rate 2%) perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY) gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials. RESULTS: Patients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and$US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were$US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving. CONCLUSIONS: GRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension

BACKGROUND: Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. METHODS AND RESULTS: Four hundred seventy‐seven patients with mild‐to‐moderate Alzheimer disease were randomized to the calcium‐channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH‐related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow‐up visits. Mean age of the study population was 72.2±8.2 years and mean Mini‐Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by −7.8/−3.9 mm Hg for nilvadipine and by −0.4/−0.8 mm Hg for placebo (P<0.001). Across the 78‐week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8–1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH‐related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. CONCLUSIONS: This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild‐to‐moderate Alzheimer disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340

Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: Data from NILVAD

Background: Previous evidence suggests that slower gait speed is longitudinally associated with cognitive impairment, dementia and falls in older adults. Despite this, the longitudinal relationship between gait speed, cognition and falls in those with a diagnosis of dementia remains poorly explored. We sought to assess this longitudinal relationship in a cohort of older adults with mild to-moderate Alzheimer Disease (AD). Methods: Analysis of data from NILVAD, an 18-month randomised-controlled trial of Nilvadipine in mild to moderate AD. We examined: (i) the cross-sectional (baseline) association between slow gait speed and cognitive function, (ii) the relationship between baseline slow gait speed and cognitive function at 18 months (Alzheimer Disease Assessment Scale, Cognitive Subsection: ADAS-Cog), (iii) the relationship between baseline cognitive function and incident slow gait speed at 18 months and finally (iv) the relationship of baseline slow gait speed and incident falls over the study period. Results: Overall, one-tenth (10.03%, N = 37/369) of participants with mild-to-moderate AD met criteria for slow gait speed at baseline and a further 14.09% (N = 52/369) developed incident slow gait speed at 18 months. At baseline, there was a significant association between poorer cognition and slow gait speed (OR 1.05, 95% CI 1.01-1.09, p = 0.025). Whilst there was no association between baseline slow gait speed and change in ADAS-Cog score at 18 months, a greater cognitive severity at baseline predicted incident slow gait speed over 18 months (OR 1.04, 1.01-1.08, p = 0.011). Further, slow gait speed at baseline was associated with a significant risk of incident falls over the study period, which persisted after covariate adjustment (IRR 3.48, 2.05-5.92, p < 0.001). Conclusions: Poorer baseline cognition was associated with both baseline and incident slow gait speed. Slow gait speed was associated with a significantly increased risk of falls over the study period. Our study adds further evidence to the complex relationship between gait and cognition in this vulnerable group and highlights increased falls risk in older adults with AD and slow gait speed. Trial registration: Secondary analysis of the NILVAD trial (Clincaltrials.gov NCT02017340; EudraCT number 2012-002764-27). First registered: 20/12/2013

Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD

OBJECTIVE: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. DESIGN: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. SETTING AND PARTICIPANTS: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. RESULTS: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (\u3b2 = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. CONCLUSIONS AND IMPLICATIONS: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD

Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: Data from NILVAD

Background: Previous evidence suggests that slower gait speed is longitudinally associated with cognitive impairment, dementia and falls in older adults. Despite this, the longitudinal relationship between gait speed, cognition and falls in those with a diagnosis of dementia remains poorly explored. We sought to assess this longitudinal relationship in a cohort of older adults with mild to-moderate Alzheimer Disease (AD). Methods: Analysis of data from NILVAD, an 18-month randomised-controlled trial of Nilvadipine in mild to moderate AD. We examined: (i) the cross-sectional (baseline) association between slow gait speed and cognitive function, (ii) the relationship between baseline slow gait speed and cognitive function at 18 months (Alzheimer Disease Assessment Scale, Cognitive Subsection: ADAS-Cog), (iii) the relationship between baseline cognitive function and incident slow gait speed at 18 months and finally (iv) the relationship of baseline slow gait speed and incident falls over the study period. Results: Overall, one-tenth (10.03%, N = 37/369) of participants with mild-to-moderate AD met criteria for slow gait speed at baseline and a further 14.09% (N = 52/369) developed incident slow gait speed at 18 months. At baseline, there was a significant association between poorer cognition and slow gait speed (OR 1.05, 95% CI 1.01-1.09, p = 0.025). Whilst there was no association between baseline slow gait speed and change in ADAS-Cog score at 18 months, a greater cognitive severity at baseline predicted incident slow gait speed over 18 months (OR 1.04, 1.01-1.08, p = 0.011). Further, slow gait speed at baseline was associated with a significant risk of incident falls over the study period, which persisted after covariate adjustment (IRR 3.48, 2.05-5.92, p &lt; 0.001). Conclusions: Poorer baseline cognition was associated with both baseline and incident slow gait speed. Slow gait speed was associated with a significantly increased risk of falls over the study period. Our study adds further evidence to the complex relationship between gait and cognition in this vulnerable group and highlights increased falls risk in older adults with AD and slow gait speed. Trial registration: Secondary analysis of the NILVAD trial (Clincaltrials.gov NCT02017340; EudraCT number 2012-002764-27). First registered: 20/12/2013

Sedative Load in Community-Dwelling Older Adults with Mild-Moderate Alzheimer's Disease: Longitudinal Relationships with Adverse Events, Delirium and Falls

Background Older adults are frequently prescribed medications with sedative effects, which are associated with numerous adverse consequences. However, the prevalence and longitudinal associations of sedative medication use in community-dwelling older adults with mild-moderate Alzheimer's disease (AD) has not been explored to date. Objectives Our objective was to assess the prevalence of sedative medication use in community-dwelling older adults with mild-moderate AD and examine the longitudinal association between sedative medication use and adverse events (AEs). Methods The association between baseline sedative load (SL) and AEs, unscheduled healthcare utilisation, delirium and falls was assessed in older adults with mild-moderate AD over 18 months using secondary analysis of NILVAD trial data (collected from 2014 to 2016). Baseline medication use was assessed, and the SL model was applied to each participant's medication individually. The SL model classifies medications into one of four categories: (1) primary sedatives, (2) medications with a sedating component or prominent side effect, (3) medications with sedation as a potential adverse reaction and (4) all other medications with no known sedative side effects. Medications in group 1 were assigned an SL score of 2, those in group 2 were assigned an SL score of 1, and those in categories 3 and 4 an SL score of 0. SL scores for each medication participants were taking were summed and the total SL calculated as an arithmetic sum of individual medications score. A total SL score &gt;= 3 was classed as high. Statistical analysis was conducted using Poisson regression and mixed-effects linear regression, with adjustment for important clinical covariates. We also assessed the impact of SL on dementia progression and cognitive decline. Results Over half (55.7% [284/510]) of those with mild-moderate AD (age 72.8 +/- 8.3 years, 61.9% female) were prescribed a regular medication with sedation as a primary effect or prominent side effect, with 22.2% (113/510) having a high SL (&gt;= 3). The most common medications contributing to SL were antidepressants, antipsychotics, anxiolytics and hypnotics. Over 18 months, increasing baseline SL was associated with incident AEs (incidence rate ratio [IRR] 1.15; 95% confidence interval [CI] 1.11-1.19;p&lt; 0.001), serious AEs (IRR 1.23; 95% CI 1.11-1.36;p&lt; 0.001) and unscheduled general practitioner visits (IRR 1.23; 95% CI 1.13-1.34;p&lt; 0.001). Further, increasing SL was associated with a greater likelihood of incident delirium (IRR 1.30; 95% CI 1.11-1.53;p&lt; 0.001) and falls (IRR 1.20; 95% CI 1.03-1.42;p= 0.02). Associations persisted after robust covariate adjustment. SL was not associated with accelerated cognitive decline or AD progression. Conclusions In the current study, over half of older adults with mild-moderate AD were prescribed at least one drug with a sedative effect, and a significant minority had a high SL. Increasing baseline SL was associated with a greater likelihood of incident AEs, delirium and falls, highlighting the need for optimal prescribing in this potentially vulnerable cohort

Antidepressant Use and Orthostatic Hypotension in Older Adults Living with Mild-to-Moderate Alzheimer Disease

Objectives: Antidepressant use is often reported as a risk factor for Orthostatic Hypotension (OH), however this relationship has never been explored in those with mild/moderate Alzheimer Disease (AD), who may represent a particularly vulnerable cohort. Methods: We performed a cross-sectional analysis of baseline data from the NILVAD study. Participants with mild-moderate AD were recruited from 23 centres in 9 countries. Systolic and Diastolic Blood Pressure (SBP/DBP) was recorded in the seated position and after both 1 &amp; 5 minutes of standing. OH was defined as a drop of 6520 mmHg SBP/ 65 10 mmHg DBP. We examined the relationship between antidepressant use, orthostatic BP drop and the presence of OH, controlling for important covariates. Results: Of 509 participants (72.9 \ub1 8.3 years, 61.9% female), two-fifths (39.1%; 199/509) were prescribed a regular antidepressant. Antidepressant use was associated with a significantly greater SBP and DBP drop at 5 minutes (\u3b2: 1.83, 0.16-3.50, P = 0.03 for SBP; \u3b2: 1.13, 0.02-2.25, P &lt; 0.05 for DBP). Selective Serotonin Reuptake Inhibitor (SSRI) use was associated with a significantly greater likelihood of OH (OR 2.0, 1.1-3.6, P = 0.02). Both findings persisted following robust covariate adjustment. Conclusions: In older adults with AD, antidepressants were associated with a significantly greater SBP/DBP drop at 5 minutes. SSRI use in particular may be a risk factor for OH. This emphasises the need to screen older antidepressant users, and particularly those with AD, for ongoing orthostatic symptoms in order to reduce the risk of falls in this vulnerable cohort. This article is protected by copyright. All rights reserved