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Anticholinergic medication use in elderly people living with HIV and self-reported neurocognitive impairment: a prospective cohort study
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Abstract
Background
Anticholinergic (ACH) medications have been associated with neurocognitive impairment, particularly in the elderly. This study determined prospectively the prevalence of prescribed ACH medications and their association with self-reported neurocognitive impairment (SRNI) in elderly people living with HIV (PLWH) of the Swiss HIV Cohort Study (SHCS).
Methods
A literature review was performed to identify ACH medications, which were scored 0 to 3 (higher score indicating more ACH burden). Prescriptions were reviewed in July 2019 for all SHCS participants ≥65 years old to assess the prevalence of ACH medications. Association between ACH burden and neurocognitive impairment was evaluated using the SHCS SRNI questions addressing memory loss, attention difficulties and slowing in reasoning.
Results
One thousand and nineteen PLWH (82% male) with a median age of 70 (IQR = 67-74) years were included. Most participants were on ART (99%). The average number of non-HIV drugs was 5.1 ± 3.6, representing a polypharmacy prevalence of 50%. Two hundred participants (20%) were on ≥1 ACH medication, with an average ACH score of 1.7 ± 1.3. SRNI, adjusted for age, sex, CD4, nadir CD4, viral load, efavirenz use and polypharmacy, was associated with depression (OR = 4.60; 95% CI = 2.62-8.09) and a trend was observed with being on ≥1 ACH medication (OR = 1.69; 95% CI = 0.97-2.95). In a subgroup analysis of participants without depression (n = 911), SRNI was associated with the use of ≥1 ACH medication (OR = 2.51; 95% CI = 1.31-4.80).
Conclusions
ACH medication use is common in elderly PLWH and contributes to SRNI. The effect of ACH medications on neurocognitive impairment warrants further evaluation using neurocognitive tests.
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Jakeman et al. aimed to determine the proportion of patients ≥65 years within the Swiss HIV Cohort Study (SHCS) who receive drugs with anticholinergic (ACH) activity, and evaluated the impact of ACH medication use on self-reported neurocognitive impairment.
Authors performed a literature review to identify commonly used ACH drugs, and scored the ACH burden of each identified medication on a scale between 1 (low activity) and 3 (high activity). In addition, a cross-sectional review of all people living with HIV 65 years or older under active follow-up in the SHCS was performed to estimate the proportion of individuals who receive ACH drugs, and multivariable logistic regression was used to evaluate its impact on patients’ neurocognitive function, which was assessed using three screening questions.
The study included 1918 patients, 85% were male, the median age was 70 years (IQR 67-74) and 91% had HIV RNA <20 copies/mL. Of those individuals aged ≥65 years, 50% received 5 or more non-HIV drugs (polypharmacy). ACH medication use was identified in 200 individuals (20%), and the majority of those drugs had a low ACH activity. Antidepressants were the most commonly prescribed ACH drugs (49%), followed by antipsychotics (7%), benzodiazepines (6%), antihistamines (6%), urinary antispasmodics (5%), opioids (5%) and corticosteroids (5%). Overall, depression showed the strongest association with neurocognitive impairment (aOR 4.60, 95% CI 2.62-80.9). However, in an analysis of individuals without depressive symptoms (n = 911), only the use of drugs with ACH activity (aOR 2.51, 1.31-4.80) and detectable HIV viral load were associated with neurocognitive impairment.
In summary, the present study shows that one out of five elderly people living with HIV in Switzerland receive ACH drugs. Although most of these drugs have a low ACH activity, its use was associated with neurocognitive impairment. These findings indicate that physicians need to be aware that many drugs have ACH activity and their use should be limited in people living with HIV aged 65 years or older. Further studies are needed to assess whether stopping drugs with ACH activity improve neurocognitive function.
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Considering that PLWH may be more sensitive to ACH [anticholinergic ] drugs and that higher ACH medication use and burden has been documented in PLWH compared with HIV-uninfected individuals,23,32 efforts should be made to avoid ACH drugs in elderly PLWH.
In conclusion, ACH drug use is common in elderly PLWH and contributes to SRNI - self reported neurocognitive impairment, including drugs with a low ACH burden. The effect of ACH medications on neurocognitive impairment warrants further evaluation using neurocognitive tests. Furthermore, studies will need to address whether reducing ACH burden can improve neurocognitive function.
Antidepressants, including tricyclic antidepressants, were the most commonly prescribed medications with ACH activity (n = 127, 49%), followed by antipsychotics (n = 18, 7%), benzodiazepines (n = 16, 6%), antihistamines (n = 15, 6%), urinary antispasmodic anticholinergics (n = 12, 5%), opioids (n = 12, 5%) and corticosteroids (n = 12, 5%). Table 3 lists the most commonly prescribed ACH medications during the evaluation period. see table 3 below
The use of medications with anticholinergic (ACH) activity has been associated with neurocognitive impairment, including dementia.1,2Elderly patients are at increased risk for both peripheral and CNS side effects of ACH medications due to a decrease in cholinergic neurons or receptors in the brain, decreased ACH drug metabolism and elimination, and increased permeability of the blood-brain barrier.3
Many commonly used medications have ACH activity (e.g. antidepressants, antipsychotics and antihistamines). Concomitant use of ACH medications may result in increased cumulative ACH burden and medication side effects.
In people living with HIV (PLWH) rates of neurocognitive impairment remain high despite advances in HIV therapy.17-19 Risk factors for neurocognitive impairment identified in PLWH include duration of HIV infection, CD4 cell count, chronic inflammation, toxicity associated with ART, increased cardiovascular risk and depression, older age, unemployment and history of CNS infections.17,19-22 In addition, it was recently reported that use of ACH medication is higher in PLWH compared with HIV-uninfected individuals.23
Detectable HIV viral load was associated with SRNI. [self reported neurocognitive impairment]
Consistent with previous studies,17,21,38 depression was a main driver of SRNI in our study.
This association is not surprising, considering that, in depressed individuals, executive function, speed of information processing, attention and working memory and verbal episodic memory have been reported to be impaired.39 Higher depression burden has been associated with steeper neurocognitive decline compared with low depression.40 It has been suggested that the relationship between cumulative depression burden and neurocognitive decline may possibly relate to sustained depressive symptoms and stress, which can lead to chronic neuro-inflammation and subsequent neuronal damage.41
In our study, the most frequently reported complaint was memory loss, followed by concentration difficulties and complaints of mental slowing. It should be highlighted that the sensitivity of the three cognitive screening questions has been reported to be low in individuals with symptomatic forms of HAND,36,37 as well as in individuals with asymptomatic forms of HAND.19 For instance, the positive and negative predictive values of the three questions to predict cognitive impairment, using the Frascati criteria, were shown to be poor (0.35 and 0.7, respectively) in middle-aged PLWH mostly virologically suppressed.17
In this population of well-controlled PLWH (91% with HIV viral loads <20 copies/mL), SRNI was documented in 8.6% of patients. This is less than the previously reported SRNI prevalence of 25.1% by Metral et al.17 in PLWH with a mean age of 54.5 years enrolled between 2013 and 2016 (79.7% were male with a similar rate of HIV control, when considering the threshold of <50 copies/mL). In our present study, SRNI was also defined as a ‘yes, definitely’ response to at least one of the EACS screening questions. A possible explanation for the lower prevalence of SRNI in our study may be related to the fact that older individuals may minimize issues of memory loss, attention deficits and slow reasoning, attributing changes to the normal course of ageing.
This study shows that ACH medication use (even drugs with a low ACH burden) is associated with SRNI in PLWH ≥65 years of age. This finding is not unexpected, considering that medications with ACH properties have been shown to increase the risk of cognitive decline in HIV-uninfected elderly individuals1,2 and to reduce brain volumes, as well as alter white matter integrity.27 There is robust literature supporting worsening cognitive performance, particularly in memory and executive functioning, associated with ACH medication use in the general elderly population.2
…..In addition, cumulative ACH burden has been associated with greater cognitive impairment in HIV-uninfected elderly individuals.29
Although the risk of neurocognitive impairment has generally been attributed to drugs with a high ACH burden (i.e. score of ≥3), our study shows, interestingly, that even low-burden ACH medication use is associated with SRNI. This observation may be a result of higher sensitivity to ACH drugs in PLWH compared with HIV-uninfected individuals. Rubin et al.32 showed that female PLWH have increased cognitive vulnerabilities to ACH medications compared with HIV-uninfected females.
The authors hypothesized that neurotoxicity resulting from HIV viral proteins may have additive or interactive effects with ACH medications. In addition, the types of ACH medications used by the different groups may have also contributed to the differences seen. Differences have been observed among drug classes with respect to their ACH effect on cognitive performance. For instance, antipsychotic drugs were shown to have a large effect on executive function, whereas small and moderate effects were observed for drugs targeting the gastrointestinal tract or metabolism, opioids and anxiolytics.29
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