There is considerable heterogeneity, however, in profiles of neurocognitive functioning across individuals with HIV and AUD . Patterns of alcohol consumption rarely remain static throughout the course of an AUD, but rather are often characterized by discrete periods of heavy use. This episodic pattern of heavy consumption may similarly impact the stability of HIV disease , which may in part explain why some PWH with AUD exhibit substantial neurocognitive deficits while others remain neurocognitively intact. Self-report estimates of alcohol use, however, often fail to predict neurocognitive performance . Methods for quantifying heavy drinking are also inconsistent across studies. For example, some studies classify individuals based on DSM criteria for AUD whereas others define heavy drinking based on “high-risk” patterns of weekly consumption . These methods characterize the chronicity of drinking and psychosocial aspects of alcohol misuse, but they are sub-optimal for quantifying discrete periods of heavy exposure and high level intoxication that may confer higher risk for neurocognitive dysfunction. Binge drinking, defined by the National Institute on Alcohol Abuse and Alcoholism as 4 or more drinks for women and 5 or more drinks for men within approximately 2 hours, may more precisely capture discrete episodes of heavy exposure. The relationship between binge drinking and neurocognitive functioning remains poorly understood across the lifespan and particularly in the context of HIV. Thus, the current study examined two primary aims to better understand the impacts of HIV, binge drinking,plants racks and age on neurocognitive functioning. The first study aim examined the independent and interactive effects of HIV and binge drinking on global and domain-specific neurocognitive functioning.

We hypothesized that: 1) neurocognitive performance would be poorer with each additional risk factor such that the HIV-/Binge- group would exhibit the best neurocognition, followed by the single-risk groups , and finally the dual-risk group; and 2) these group differences would be explained by a detrimental synergistic effect of HIV and binge drinking on neurocognition. The second study aim examined whether the strength of the association between age and neurocognition differed by HIV/Binge group. We hypothesized that: 1) older age would relate to poorer neurocognition; and 2) that this negative relationship would be strongest in the HIV+/Binge+ group.Participants included 85 PWH and 61 HIV- adults who reported drinking alcohol in the 30 day period prior to their study visit. Participants were further stratified based on their recent binge drinking status, resulting in the following four groups: HIV+/Binge+ , HIV-/Binge+ , HIV+/Binge- , HIV-/Binge- . All participants were enrolled in NIH-funded research studies at the University of California, San Diego’s HIV Neurobehavioral Research Program, and gave written informed consent as approved by the UCSD Institutional Review Board. The current cross-sectional study is a secondary analysis of data from each participant’s baseline visit at the HIV Neurobehavioral Research Program from 2003-2019. Exclusion criteria for the current analysis were: 1) current diagnosis of non-alcohol substance use disorders ; 2) diagnosis of psychotic or mood disorder with psychotic features; 3) presence of a neurological or medical condition that may negatively affect cognitive functioning, such as traumatic brain injury, stroke, or epilepsy; 4) positive urine toxicology for illicit drugs or positive Breathalyzer test for alcohol on the day of study visit; 5) report of no “recent” alcohol consumption . A modified timeline follow-back interview was used to assess drinking behavior in the last 30 days . Binge drinking was assessed per NIAAA criteria for binge drinking . Binge drinking behavior was dichotomized such that participants who had any binge drinking episode in the last 30 days were classified as binge drinkers .

Lifetime history of alcohol exposure, including quantity and frequency, was assessed via a semi-structured timeline follow-back interview that evaluates drinking patterns across different periods in an individual’s life. Current depressive symptoms were assessed using the Beck Depression Inventory-II, a self-report measure . The Composite International Diagnostic Interview was administered to evaluate current and lifetime mood and SUDs . Notably, the parent grants from which baseline data were drawn were funded prior to the publication of the DSM 5. Therefore, diagnoses were made in accordance with DSM-IV criteria where alcohol/substance abuse is met when participants report recurring problems as a result of continued alcohol/substance use; and alcohol/substance dependence is met when participants experience symptoms of tolerance, withdrawal, and/or compromised control over their alcohol/substance use . In order to remain consistent with the current DSM 5 criteria and nomenclature, alcohol/substance abuse and dependence criteria were combined to capture AUD and SUD. Participants were tested for HIV by enzyme-linked immunosorbent assay with Western Blot confirmation. All participants completed a comprehensive medical evaluation including self-report measures, structured neurological and medical evaluations, and blood samples to assess the presence of medical comorbidities and HIV disease characteristics. HIV viral load in plasma was measured using reverse transcriptase-polymerase chain reaction , where viral load was deemed undetectable below 50 copies/mL. Participants were administered a comprehensive battery of neurocognitive assessments measuring global and domain-specific neurocognitive performance: global function, verbal fluency, executive function, processing speed, learning, delayed recall, working memory, and motor skills . Raw scores from each neuropsychological test were converted into demographically-corrected T-scores .

Global and domain-specific continuous T-scores were derived from averaging the demographically-corrected T-scores across all tests and within each neurocognitive domain, respectively . These global and domain-specific T-scores were used as primary outcomes for comparisons of neurocognition between HIV/Binge groups. Demographic, psychiatric, medical, alcohol and substance use, and HIV disease characteristics were compared between the four HIV/Binge groups using analysis of variance or chi-square tests, as appropriate. Pair-wise comparisons were conducted to follow up on significant omnibus results using Tukey’s Honest Significant Difference tests for continuous outcomes or Bonferroni adjustments for categorical outcomes.To examine the first study aim, one-way ANOVA and Tukey’s HSD tests were used to compare mean global and domain neurocognitive T-scores between the four HIV/binge drinking groups. For any significant one-way ANOVA result, a 2 x 2 factorial ANCOVA was used to model independent and interactive effects of HIV and binge drinking status,plant growing trays covarying for total drinks consumed in the last 30 days and any demographic or non-alcohol-related clinical characteristics that differed between groups at p<0.05 . These demographic covariates were included to increase confidence that any observed difference in neurocognition between HIV/Binge groups would not be attributable to confounding effects of age and sex that may that may exist above and beyond the T-scores’ demographic corrections. To further support any findings indicating additive main effects, Jonckheere-Terpstra tests for ordered alternatives examined whether there was a statistically significant negative relationship between the number of risk factors and neurocognitive performance . Finally, to examine the second study aim, multiple linear regressions modeled the interaction between age and HIV/Binge status group on global and domain-specific T-scores, also covarying for total drinks consumed in the last 30 days, sex, and lifetime history of non-alcohol. Our examination of age as a predictor of demographically-corrected T-scores will allow understanding of how the effect of age in certain vulnerable groups may go above and beyond that of normal controls on whom demographic corrections were based. Parametric statistics were used because the outcome variables were continuous and had normal distributions in each HIV/Binge group. All analyses were performed using R, version 3.5.0.Demographic and clinical factors by HIV/Binge group are displayed in Table 1. The HIV-/Binge- group was younger than both HIV+ groups , and the HIV+/Binge+ grouphad a higher proportion of men compared to the two HIV- groups .

Regarding alcohol and substance use characteristics, the two Binge+ groups had significantly higher quantity and frequency of alcohol use in the last 30 days, higher proportions of current and lifetime AUD, higher lifetime quantity and frequency of alcohol use, and a higher proportion of lifetime non alcohol SUDs compared to those of both Binge- groups . Alcohol use characteristics, including frequency of alcohol binges in the last 30 days, did not differ between the HIV-/Binge+ and HIV+/Binge+ groups . For each of those neurocognitive outcomes with a significant omnibus result, follow-up pairwise comparisons showed significant differences between only the HIV-/Binge- and the HIV+/Binge+ groups, with HIV+/Binge+ participants exhibiting poorer performance . Results of the 2 x 2 factorial ANCOVAs are shown in Table 2. Additive main effects of HIV status and binge drinking status were detected on global function and processing speed, however none of the interactions between HIV and binge drinking status on neurocognitive outcomes reached statistical significance. Additive main effects of HIV and binge drinking were further supported by results from Jonckheere-Terpstra tests indicating significantly lower global and processing speed performance by each increase in risk factor count . Binge drinking was also a significant predictor of delayed recall and working memory. Of note, the effects of binge drinking on neurocognition were not attenuated by accounting for total drinks in the last 30 days, which did not significantly relate to any neurocognitive outcome .Given the rapidly growing population of older adults with and without HIV along with the increased rates of binge drinking among them, studying the combined effects of HIV and binge drinking across the lifespan is timely and important. Partially consistent with our first hypothesis, the HIV+/Binge+ group demonstrated the worst global neurocognitive functioning ; however, the combined effects of HIV and binge drinking on global neurocognitive functioning exhibited an additive, rather than synergistic, pattern . Consistent with our second hypothesis, we found a novel interaction with age and HIV/Binge drinking group such that the HIV+/Binge+ group displayed a stronger negative relationship between age and three domain-specific neurocognitive outcomes compared to the HIV-/Binge- group. Importantly, the alcohol-related detriments to neurocognition appeared to be specific to binge drinking, as total 30-day alcohol consumption was not a significant independent predictor of any neurocognitive outcome in our statistical models. These findings suggest that recent, discrete episodes of heavy alcohol exposure relate to poorer brain function and highlight the need for interventions to reduce binge drinking behavior among PWH, especially older PWH, in order to promote cognitive health. The findings showing additive main effects of HIV and binge drinking are consistent with several other studies demonstrating additive, but not synergistic, effects of HIV and heavy alcohol use on neurocognitive functioning . In fact, there is only one study to our knowledge that has shown an interactive effect of HIV and heavy alcohol on neurocognition, specifically in the domains of motor and visuomotor speed . Our finding of HIV/Binge group differences in neurocognitive domains of processing speed, delayed recall, and working memory is also consistent with the frontostriatal and frontolimbic neural damage that has been observed in studies of adults with HIV and heavy alcohol use . As briefly discussed, there are a number of possible mechanisms underlying the relationship between heavy alcohol use and adverse neurocognitive outcomes in HIV, including those related to antiretroviral therapy ; possible pharmacokinetic interactions with alcohol . Recent research, however, has revealed neuroinflammatory and neuro-immunological effects as major pathways underlying the relationship between heavy alcohol use and neurobiological damage , with several of these neuroimmune pathways overlapping with effects from HIV . Although these immunobiological underpinnings are still poorly understood in the context of comorbid HIV and heavy drinking, this represents an important line of research needed to develop potential targeted interventions for reducing the incidence and/or severity of neurocognitive impairment in this population. The current study also uniquely found that the negative relationship between age and neurocognitive functioning was steepest among the PWH who reported binge drinking in the last 30 days, particularly in the domains of learning, delayed recall, and motor skills. Our findings are consistent with what is known about the greater vulnerability to brain atrophy and neurocognitive deficits in older PWH and older adults who drink heavily . Furthermore, this result showing an age by HIV/Binge group interaction is also similar to findings from a previous study in which age was found to be a significant predictor of demographically-corrected episodic memory scores only among individuals with comorbid HIV and AUD . Speculation about accelerated aging or neurocognitive decline cannot be made from our data, as they are cross-sectional; however, this result does suggest that older adults are the most susceptible to adverse neuropsychological outcomes in the context of HIV and binge drinking. Notably, this result also held when restricting the maximum age range to 60 years old for all groups, indicating that HIV/ Binge group differences in delayed recall and motor skills emerge even in the earlier stages of older adulthood.