Considering that majority of PWH do not report heavier drinking compared to the general population , there is a need for a more comprehensive understanding of the impact of low-risk alcohol consumption among PWH. Examination of whether low-risk drinking exerts differential neurocognitive effects based on HIV serostatus is particularly salient given the increasingly popular recommendations for older adults to follow certain nutritional guidelines . Given that HIV disease can enhance vulnerability to physiological damage from environmental stressors , there may be no level of alcohol associated with better neurocognitive functioning among PWH. Advancing age is independently associated with a higher risk of neurocognitive and neurodegenerative diseases including Alzheimer’s Disease and its precursor mild cognitive impairment . Despite use of combination antiretroviral therapy, older PWH remain particularly vulnerable to HIV-associated neurocognitive impairment and neurodegenerative diseases associated with aging . Considering alcohol consumption is common among PWH, and with advancing age these persons are at a heightened risk for neurocognitive impairment, the present study examined associations between the non-linear effect of recent low-risk alcohol consumption and HIV status on global and domain-specific neurocognitive outcomes. Within the range of low-risk drinking, we hypothesize a curvilinear association between recent alcohol consumption and neurocognition among HIV- individuals,vertical growing racks cost such that intermediate levels of low-risk drinking will be associated with better neurocognitive function compared to non-drinkers and heavier levels; however, we do not expect this curvilinear association among PWH.

Participants included 310 PWH and 89 HIV- older adults enrolled in NIH funded research studies at the University of California, San Diego HIV Neuro behavioral Research Program from 2003-2016. Participants were recruited from the greater San Diego area by the HNRP. Regulatory approval was obtained from the University of California San Diego Institutional Review Board prior to the start of protocol implementation. We have previously published several papers using other aspects of these data including medication adherence, age of first alcohol use, and neurocognitive function . The current study represents a secondary analysis of baseline alcohol use and neurobehavioral data from the HNRP. Exclusion criteria for the current analysis included 1) self reported current or past diagnosis of a psychotic or mood disorder with psychotic features; 2) presence of a neurological condition that could impair neurocognitive function ; 3) positive urine toxicology for illicit drugs or evidence of alcohol intoxication by Breathalyzer test on the day of testing; 4) current diagnosis of AUD; 5) current diagnosis of non-alcohol substance use disorders ; 6) recent “at risk” alcohol consumption as defined per the National Institute on Alcohol Abuse and Alcoholism criteria for “at risk” drinking ; and 7) aged 49 years and younger. The UCSD Institutional Review Board approved this study, and all participants provided written informed consent to participate. Current and lifetime mood and substance use disorders were assessed via The Composite International Diagnostic Interview , a fully-structured, computer-based interview . Diagnoses were made in accordance with DSM-IV criteria, as the parent grants from which baseline data were collected were funded before the DSM 5 was published. DSM-IV criteria for alcohol abuse are met when participants report continued alcohol use despite recurring problems . DSM-IV criteria for alcohol dependence are met when participants endorse symptoms of tolerance, withdrawal, and impaired control over drinking . AUD was assigned when DSM-IV criteria for alcohol abuse or dependence was met in order to maintain consistency with DSM 5 criteria and nomenclature.This form is a modified timeline follow-back measure that assesses alcohol use metrics including the quantity and frequency of alcohol use in the last 30 days .

The variable capturing the total number of drinks consumed in the last 30 days was calculated by multiplying the daily rate of alcohol consumption by the number of consumption days in the last 30 days . Total number of drinks consumed in the last 30 days will be hereafter referred to as total drinks. Participants who reported no recent alcohol consumption were included in analyses as alcohol abstainers, with total drinks coded as 0. Participants were administered a well-validated, comprehensive battery of neuropsychological tests designed in accordance with the international consensus conference recommendations for HIV-associated Neurocognitive Disorders . The battery assesses seven neurocognitive domains: verbal fluency, executive function, processing speed, learning, delayed recall, working memory, and motor skills. Individual test raw scores were converted into demographically-adjusted Tscores , which were then averaged across the entire battery and within each domain to derive mean global and domain-specific T-scores, respectively . HIV group differences on demographic, psychiatric, neurocognitive, and alcohol use characteristics were compared using independent t-tests, Wilcoxon tests, and Chi-square statistics as appropriate. Separate multiple linear regressions examined the interaction between the quadratic effects of total drinks and HIV status on global and domain-specific T-scores. Demographic variables that significantly differed by HIV status at a p < .05 threshold ) were included as covariates. Considering the high prevalence of lifetime AUD in both persons with and without HIV, lifetime AUD was included as a covariate. Additionally, diagnosis of a lifetime non-alcohol substance use disorder was included as a covariate to account for potential confounding effects of non-alcohol substance use on neurocognitive outcomes. A follow-up analysis was conducted for any model that did not reveal a significant or trend-level interaction term between the quadratic effect of total drinks and HIV status.

The follow-up analysis examined the interaction between the linear effect of total drinks and HIV status on domain-specific T-scores, covarying for demographic variables included in primary regression analyses. As a secondary followup analysis, the independent effects of total drinks and HIV status were examined for any model that did not show a significant interaction term , covarying for the same demographic variables inprimary regression analyses. Regression analyses were performed using JMP Pro version 14.0.0 . Exploratory analyses, stratified by HIV status, employed the Johnson-Neyman technique to identify specific regions along the quadratic curve of total drinks at which total drinks had a statistically significant effect on neurocognition . Compared to simple slope analyses that describe quadratic effects based on how the effect of a predictor changes at different levels of that predictor, the J-N technique computes the full range of values for which the predictor slope is statistically significant. These boundaries are referred to as regions of significance. Region of significance analyses were computed using the jtools package in R statistical software . Considering long-term heavy alcohol use may have ongoing neurocognitive effects, an additional exploratory analysis examined the association between lifetime history of AUD and alcohol abstinence using a Chi-squared statistic. Finally, we explored the associations between HIV disease characteristics and global neurocognitive function using independent t-tests. We have included any significant variables as covariates in the linear regression analysis by HIV-serostatus. These analyses were performed using JMP Pro version 14.0.0 . Demographic, psychiatric, substance use, alcohol use, HIV disease, and neurocognitive characteristics by HIV group are presented in Table 1. The PWH group was significantly younger,vertical indoor growing system had a higher proportion of males, and had higher rates of current MDD and lifetime MDD than the HIV- group. With respect to recent alcohol consumption, PWH on average reported more drinks per drinking day and more drinking days within the last 30 days than HIV- individuals, yet groups were comparable on all other alcohol use characteristics. In regards to neurocognition, univariably PWH had significantly lower global function, verbal fluency, executive function, processing speed, working memory, and motor skills T scores than the HIV- group. Results of linear regressions examining the interaction between the quadratic effect of total drinks and HIV status on neurocognitive outcomes are presented in Table 2. In these adjusted models, the interaction between the quadratic effect of total drinks and HIV status was significant for global function , executive function , learning , delayed recall , and motor skills . With respect to covariates, older age, a lifetime history of MDD, and a lifetime history of a non-alcohol substance use disorder were associated with worse neurocognitive performance across multiple domains. Follow-up analyses were conducted to examine the interaction between the linear effect of total drinks and HIV status on neurocognitive outcomes that showed no significant or trend-level interaction term. Similar adjusted linear regression models revealed no significant interaction effects between total drinks and HIV status on domainspecific neurocognition . To further examine the independent effects of total drinks and HIV status on neurocognition, linear regression models examined the effects of HIV status, total drinks, and covariates from previous models on neurocognitive outcomes . In these adjusted models, HIV status was significantly associated with verbal fluency , processing speed , and working memory , such that PWH performed significantly worse than their HIV- counterparts. There were no detected effects of total drinks on domain specific neurocognitive outcomes. Additional follow-up analyses on domains that revealed significant quadratic associations were stratified by HIV serostatus . Results exploring the associations between HIV disease characteristic and global neurocognitive function suggest a significant negative association between estimated duration of HIV disease and global neurocognitive function .

Therefore, estimated duration of disease was included as a covariate in the linear regression model for PWH. The number of total drinks was not associated with neurocognition in PWH. Estimated duration of disease approached significance for global function . In the HIV- group, results indicated significant quadratic effects of total drinks on global function , executive function , learning , delayed recall , and motor skills . We applied the J-N technique to inspect these significant changes in the slope of total drinks on neurocognition as a function of total drinks within the HIV- group . Total drinks demonstrated positive, statistically significant associations with neurocognition at the lower end of “low-risk” drinking . Conversely, total drinks demonstrated negative, statistically significant associations with neurocognition at the higher end of “low-risk” drinking . Although there was a significant quadratic association between total drinks and delayed recall, the negative slope did not reach statistical significance. Finally, to examine potential ongoing neurocognitive effects of lifetime AUD among alcohol abstainers, a Chisquare statistic was calculated. Results indicate no significant association between having a lifetime history of AUD and currently abstaining from alcohol,2 = 1.11, p = .292. Our study is among the first to examine the curvilinear association between recent “low-risk” alcohol consumption and neurocognition among persons with and without HIV. Among HIV individuals, the association between low-risk drinking and neurocognition expectedly followed an inverted-J shaped pattern, with better neurocognition occurring at intermediate levels of “low-risk” drinking compared to alcohol abstinence and heavier consumption. Specifically, region of significance analyses indicated a positive slope of alcohol consumption on global neurocognitive function when the range of total drinks was zero to 18 drinks, whereas a negative slope emerged when the range of total drinks was 52 to 60 drinks; suggesting a potentially innocuous range between 18 to 52 drinks per month for HIV- individuals. This global effect was driven by abilities supported by frontal brain regions where alcohol metabolism is thought to be particularly active . Additionally, consistent with our hypotheses, there was no quadratic association between level of low-risk alcohol consumption and neurocognition among PWH. This suggests the presence of other factors that may supersede the potentially beneficial neurocognitive effects of low-risk alcohol consumption in the context of HIV. For example, age was significantly associated with global function, executive function, learning, and delayed recall in PWH, despite using age-adjusted T-scores in analyses.Extant literature suggests that the inverted-J shaped association is not unique to neurocognition, which may point towards possible mechanisms underlying the neuroprotective effect of low-risk alcohol consumption. For example, evidence supports a cardioprotective effect of low-risk alcohol consumption including a reduced risk of coronary heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, and all-cause mortality . There is a higher risk among alcohol abstainers and when alcohol consumption is high, and lower risk when alcohol consumption is low . Although our data does not directly measure pathways underlying a potential neuroprotective effect of low-risk alcohol consumption, including its specificity to HIV- adults, several plausible biopsychosocial mechanisms can be drawn from the extant literature. From a biological perspective, low-risk alcohol use has been linked to increased high-density lipoprotein levels and may carry antithrombotic, antioxidative, and anti-inflammatory effects that benefit the neurovascular unit . Additionally, alcohol may directly enhance learning and executive function via stimulation of acetylcholine in the prefrontal cortex and hippocampus .