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Comparison of dementia incidence and prevalence between individuals with and without HIV infection in primary care from 2000 to 2016
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AIDS Nov 2021 Lam, Jennifer O.a; Lee, Catherinea; Gilsanz, Paolaa; Hou, Craig E.b; Leyden, Wendy A.a; Satre, Derek D.a,c; Flamm, Jason A.d; Towner, William J.e; Horberg, Michael A.f; Silverberg, Michael J.a
CONCLUSION: Despite effective ART use and declining dementia incidence among PWH, dementia incidence and prevalence remain higher among PWH compared with PWoH. Dementia can cause significant disability and dependence, diminishing the benefits of achieving near-normal life expectancy with HIV treatment. To maintain the health and quality of life of older PWH, further research is needed to determine factors contributing to persistently elevated dementia risk among ART-treated PWH.
Dementia incidence
At baseline, 249 (1.9%) PWH and 734 (0.5%) PWoH had pre-existing dementia and were therefore excluded from analyses of dementia incidence, resulting in a total of 13,047 PWH and 154,620 PWoH. During follow-up, 326 (2.5%) PWH and 2,006 (1.3%) PWoH were diagnosed with dementia....
In this study of ART-treated PWH and demographically-similar PWoH, the incidence of dementia decreased from 2000 to 2016 for both PWH and PWoH. Reductions in incidence were greater among PWH, but dementia incidence remained 58% higher among PWH in the most recent period, 2015-2016. The overall prevalence of dementia increased from 2000 to 2016 for both PWH and PWoH. In recent years, trends in dementia prevalence are suggestive of a decrease among PWH and stabilization among PWoH. In the 2015-2016 period, dementia prevalence was 75% higher among PWH compared with PWoH. In all time periods, dementia incidence and prevalence were higher among PWH even after accounting for sociodemographics, substance use, comorbidities, and frequency of healthcare utilization. Higher incidence and prevalence of dementia among PWH were not significantly different by sex or racial/ethnic groups.
Our finding that ART-treated PWH had higher incidence and prevalence of dementia than PWoH across all time periods is consistent with growing evidence that cognitive aging may be premature and/or accelerated among PWH [35-42]. These results also align with a recent study within an independent KP Northern Californian cohort from 2013 to 2019 which found elevated dementia risk among ART-treated PWH compared with demographically-matched uninfected PWoH, even after controlling for traditional dementia risk factors [27]. Persistently elevated dementia risk among ART-treated PWH suggests that the current strategy of primarily encouraging ART initiation and adherence may be insufficient to fully protect the cognitive function of older PWH, particularly in the context of higher baseline dementia risk from the contributing effects of HIV disease on neurocognition. Indeed, unlike most HIV/AIDS-related conditions which have decreased with ART use, cognitive impairment appears less impacted [33, 38, 43, 44]. Notably, in this study, dementia incidence and prevalence remained elevated among PWH even in sensitivity analyses which restricted PWH to those with HIV RNA <200 copies/ml (a proxy for optimal ART adherence) and no prior advanced immunodeficiency (a proxy for timely ART initiation and consistent usage).
Overall, our findings underline the importance of identifying effective strategies to prevent or delay the onset of dementia in an aging HIV population, especially since cognitive impairments among PWH could have adverse impacts on ART adherence and HIV outcomes [45]. It remains unclear whether PWH may require dementia prevention measures distinct from those recommended for the general population [46]. The American Academy of Neurology currently recommends annual cognitive screening of patients aged ≥65 years[47], but some evidence indicate that PWH may develop dementia at earlier ages [27, 42]. There are currently limited data on age-associated dementias in PWH, and consensus cognitive screening guidelines for older PWH in routine clinical care have not been developed. The validation of cognitive screening tools for PWH also remains a developing area of research [2, 45, 48-50]. As the population with HIV continues to experience improved survival on suppressive ART[18], expanding our understanding of dementia risk among PWH may help identify subgroups that could benefit from enhanced cognitive surveillance or early intervention.
With advances in HIV treatment, the characteristics of neurocognitive disorders among people with HIV (PWH) have changed [1-3]. Prior to the availability of antiretroviral therapy (ART), HIV-associated dementia was frequently diagnosed among people with uncontrolled HIV infection and was often associated with late-stage HIV disease, neurologic opportunistic infection, and poor prognosis [2, 4, 5]. The neurological benefits of ART are clear, as HIV-associated dementia rarely develops among those with well-controlled HIV [2]. However, cognitive impairments continue to affect 30-50% of PWH, indicating that ART use may not completely prevent or resolve neurologic complications associated with HIV infection [1, 6-10]. Most research to-date has focused on a spectrum of cognitive impairments among people with HIV, collectively called HIV-associated neurocognitive disorders (HAND) and ranging from asymptomatic impairment detectable only upon neuropsychological testing to severe impairment interfering with everyday activities [11]. Fewer studies have evaluated age-associated neurodegenerative disease including dementias such as Alzheimer’s disease and vascular dementia among PWH, but this is an important emerging concern given that most PWH in the U.S. are now greater than 50 years old [2, 12, 13].
While several studies report that the incidence and prevalence of dementia among older adults in the general U.S. population have decreased in recent years, possibly due to improvements in dementia-related risk factors such as cardiovascular disease [14, 15], these trends may not be reflected in the HIV population. In fact, given that PWH have a higher prevalence of dementia risk factors such as smoking, unhealthy alcohol use, and cardiovascular disease, the burden of neurocognitive impairment in this population is anticipated to increase as a greater proportion of PWH reach older ages [16, 17]. However, few studies have directly compared the epidemiology of dementia among PWH and age-matched uninfected individuals from the general population.
Abstract
Objective:
To compare dementia incidence and prevalence after age 50 by HIV status.
Design:
Observational cohort, 2000 to 2016.
Methods:
People with HIV (PWH) on antiretroviral therapy (ART) and demographically-similar people without HIV (PWoH), all aged 50 years and older, were identified from Kaiser Permanente healthcare systems in Northern California, Southern California, and Mid-Atlantic States (Maryland, Virginia, Washington D.C.). Dementia diagnoses were obtained from electronic health records. Incidence and prevalence of dementia, overall and by time period (i.e., 2000-2002, 2003-2004, ..., 2015-2016), were calculated using Poisson regression. Trends were examined using Joinpoint regression. Rate ratios were used to compare dementia by HIV status with adjustment for sociodemographics, substance use, and clinical factors.
Dementia ascertainment. Dementia diagnoses were identified from the electronic health record (EHR) using ICD codes, which included diagnoses of Alzheimer’s disease, vascular dementia, Parkinson’s dementia, dementia with Lewy bodies, frontotemporal dementia, and other/unspecified dementias (Supplemental Table 1, http://links.lww.com/QAD/C398). In a prior KP Northern California study, these ICD codes were confirmed via chart review to have comparable positive predictive value (PPV) for dementia in PWH (PPV=93%; 64/69) and PWoH (PPV=97%; 114/117; p=0.21), regardless of the diagnosing provider [27]. Incident dementia was defined as the first dementia diagnosis of any type occurring after ≥1 year of continuous KP membership during which time the patient received no dementia diagnosis.
Results:
The study included 13,296 PWH and 155,354 PWoH (at baseline: for both, mean age = 54 years, 89% male; for PWH, 80% with HIV RNA <200 copies/ml). From 2000 to 2016, overall incidence of dementia was higher among PWH (adjusted incidence rate ratio [aIRR] = 1.80, 95% CI = 1.60-2.04). Dementia incidence decreased among both PWH and PWoH (-8.0% and -3.1% per period, respectively), but remained higher among PWH in the most recent time period, 2015-2016 (aIRR = 1.58, 95% CI = 1.18-2.12). The overall prevalence of dementia from 2000-2016 was higher among PWH (adjusted prevalence ratio [aPR] = 1.86, 95% CI = 1.70-2.04) and was also higher among PWH in 2015-2016 (aPR = 1.75, 95% CI = 1.56-1.97).
Conclusion:
Reductions in dementia incidence are encouraging and may reflect ART improvement, but PWH are still more likely to have dementia than PWoH. Monitoring the burden of dementia among PWH is important as this population ages.
The study included 13,296 PWH and 155,354 PWoH (Table 1). Participants were similar on the matching factors of age, sex, and race/ethnicity. The average age at baseline was 54 years (standard deviation [SD]=6), 89% of participants were male, and 53% of PWH and 51% of PWoH were non-Hispanic White. PWH were more likely than PWoH to have a history of substance use, cardiovascular disease, dyslipidemia, or depression, and were less likely to have hypertension, diabetes or to be obese. All PWH were on ART prior to baseline. At baseline, 80% of PWH were virally suppressed, 51% had a CD4 cell count of ≥500 cells/μl, and 36% had prior advanced immunodeficiency (CD4 cell count <200 cells/μl). PWH in the study had been living with HIV for an average of 9 years (SD=8).
Dementia incidence
At baseline, 249 (1.9%) PWH and 734 (0.5%) PWoH had pre-existing dementia and were therefore excluded from analyses of dementia incidence, resulting in a total of 13,047 PWH and 154,620 PWoH. During follow-up, 326 (2.5%) PWH and 2,006 (1.3%) PWoH were diagnosed with dementia, 3,896 (29.9%) PWH and 48,084 (31.1%) PWoH ended their KP membership, and 1,135 (8.7%) PWH and 6,332 (4.1%) PWoH died. At the end of follow-up, 7,690 (58.9%) PWH and 98,198 (63.5%) PWoH were still alive and without a diagnosis of dementia. PWH were followed for an average of 5.4 years (SD=4.6), and PWoH were followed for an average of 6.0 years (SD=4.8).
From 2000 to 2016, dementia incidence was higher among PWH than PWoH in all time periods but declined for both groups over time (Figure 1). Among PWH, dementia incidence decreased from an age- and sex-standardized IR (sIR) of 6.9 cases per 1,000 person-years [95% confidence interval=4.5 to 10.0] in 2000-2002 to 2.5 cases [1.8 to 3.4] in 2015-2016. Among PWoH, dementia incidence decreased from a sIR of 2.1 [1.7 to 2.5] in 2000-2002 to 1.2 [1.1-1.4] in 2015-2016. The average decrease in dementia incidence per period was significantly greater among PWH (-8.0% [-10.6% to -5.3%]) than PWoH (-3.1% [-5.4% to -0.8%], p-interaction <0.001).
The overall incidence of dementia (i.e. all time periods combined from 2000-2016) was higher among PWH after adjustment for sociodemographics, substance use, cardiovascular disease, and other clinical factors (adjusted incidence rate ratio [aIRR]= 1.8 [1.6 to 2.0]; Table 2). In comparisons of dementia incidence by HIV status within individual time periods, dementia incidence was 1.2 to 3.7 times higher among PWH in each period, and despite decreases in dementia incidence over time, remained higher among PWH in the most recent period, 2015-2016 (aIRR=1.6 [1.2 to 2.1]). The higher dementia incidence among PWH was similar by sex (p-interaction=0.84) and by race/ethnicity (p-interaction=0.36).
In sensitivity analyses excluding PWH with detectable HIV RNA at baseline or prior advanced immunodeficiency, overall dementia incidence was similarly elevated among PWH (aIRR=1.6 [1.4 to 1.9] and aIRR=1.7 [1.5 to 2.0], respectively; Supplemental Table 3, http://links.lww.com/QAD/C398).
Dementia prevalence
From 2000 to 2016, dementia prevalence increased from 29.0 [22.7 to 36.5] to 31.2 [27.7 to 35.0] cases per 1,000 persons among PWH and from 6.5 [5.6 to 7.4] to 11.4 [10.8 to 12.0] cases per 1,000 persons among PWoH (Figure 2). Although both PWH and PWoH experienced overall increases in dementia prevalence, temporal trends differed by HIV status (p-interaction=0.02). Among PWH, dementia prevalence increased on average 1.5% [-2.8 to 6.0] per period from 2000 to 2012 and decreased on average 6.4% [-18.7 to 7.9] per period from 2013 to 2015, although neither of these trends were significant (p=0.4 and p=0.2, respectively). Among PWoH, dementia prevalence increased on average 6.2% [1.6 to 11.0, p<0.01] per period from 2000 to 2010 and was fairly stable from 2011 to 2016 (-0.6% [-4.7 to 3.7], p=0.7).
The overall prevalence of dementia from 2000 to 2016 was higher among PWH (adjusted prevalence ratio [aPR]=1.9[1.7 to 2.0]). Within individual time periods, covariate-adjusted dementia prevalence was 1.8 to 3.5 times higher among PWH compared with PWoH (Table 3) and remained higher among PWH in the most recent period, 2015-2016 (aPR=1.8 [1.6 to 2.0]). The higher dementia prevalence among PWH was similar by sex (p-interaction=0.39) and by race/ethnicity (p-interaction=0.31).
In sensitivity analyses excluding PWH with detectable HIV RNA at baseline or prior advanced immunodeficiency, overall dementia prevalence was similarly elevated among PWH (aPR=1.8 [1.6 to 2.0] and aPR=1.6 [1.4 to 1.8], respectively; Supplemental Table 4, http://links.lww.com/QAD/C398).
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