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,cannabis drainage system 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, 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+ group had 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 nonalcohol 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 .

Multiple linear regression revealed significant interactions between age and HIV/Binge group on neurocognitive outcomes of learning , delayed recall , and motor skills . Specifically, the association between age and each of those three neurocognitive outcomes was significantly more negative in the HIV+/Binge+ group compared to that of the HIV-/Binge- group . This interaction was not significant for any other neurocognitive outcome . Additional analyses comparing age-slopes between all groups revealed that the difference in age-slopes between the HIV+/Binge- and HIV-/Binge groups approached significance for delayed recall and motor skills , such that the HIV+/Binge- group had a stronger relationship between age and those neurocognitive domains. Total drinks in the last 30 days, sex, and lifetime non-alcohol SUD were not significant predictors of any neurocognitive outcomes.Given the rapidly growing population of older adults with and without HIV along with the increased rates of binge drinking among them,indoor cannabis grow system 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. Notably, findings from this report appear to be driven specifically by our binge drinking variable, as total 30-day alcohol consumption did not significantly predict any neurocognitive outcome above and beyond binge drinking. Although there are a dearth of studies examining the specific impact of binge drinking on neuropsychological outcomes compared to that of chronic drinking over a longer span of time, some evidence suggests that the repeated periods of high level of intoxication and withdrawal from binge drinking exacerbates the detrimental neurobiological effects of alcohol . Future research is needed to examine chronicity of binge drinking and whether there may be a specific threshold associated with the greatest level of CNS risk. Still, given evidence that binge drinking may be at least as detrimental to the central nervous system as alcohol dependence, public safety measures that aim to reduce binge drinking behavior may have widespread benefits, especially among older PWH. While this study has strengths in novelty, use of a comprehensive neuropsychological battery, and clinical relevance, it also has several limitations. First, the HIV/Binge group-specific sample sizes were relatively small, particularly in Binge+ groups. Although this limited our ability to examine a full factorial three-way interaction between age, HIV status, and binge drinking status, we were still able to examine the novel age by HIV/Binge group interaction with adequate statistical power. Next, our assessment of binge drinking is based solely on self-report and may be subject to error by recall bias, memory difficulties, and/or social desirability bias; however, the majority of alcohol and substance use research relies on self-report of use. In addition, while binge drinking data specifically pertained to use within the last 30 days, we do not know exact amounts of time between participants’ last binge episode and their participation in the study, limiting our ability to comment on how recency relates to cognitive performance. Future research may benefit from the use of more objective measures of alcohol use in daily life to more accurately characterize alcohol use patterns . Finally, our exclusion of participants with current non-alcohol substance use disorders limits generalizability to others with binge drinking behavior and/or alcohol use disorder among whom polysubstance use is common. In summary, the current study demonstrated detrimental additive effects of HIV and binge drinking on neurocognitive functioning, and that older adults appear to be most vulnerable to these adverse effects particularly in the neurocognitive domains of learning, delayed recall, and motor skills.