Considering that alcohol consumption increases HDL cholesterol levels, it has been proposed that the association between HDL cholesterol and lowered risk of coronary heart disease is mediated in part by alcohol-induced increases in HDL cholesterol . Other possible mechanisms underlying the observed beneficial effect of low-risk drinking on neurocognition among HIV- individuals in our sample may involve lifestyle factors and/or indicators of socioeconomic status not measured in the current study. For example, previous research exploring beneficial effects of drinking have suggested that low-risk alcohol consumption may be an indicator of higher socioeconomic status and engagement in a healthier lifestyle that includes better nutrition and physical activity . Moreover, persons of lower socioeconomic status may not have the means to afford alcohol and be more medically compromised which could lead to voluntary or medically recommended abstinence . In addition, it is also well known that individuals of higher socioeconomic status are less likely to experience negative consequences from alcohol use compared to those of lower socioeconomic status who drink the same amount . It is possible that our sample of HIV- participants were of relatively high socioeconomic status, especially compared to our sample of PWH, as HIV disproportionately affects individuals from lower income areas with fewer resources . Although we examined associations between certain HIV disease characteristics, alcohol use, and neurocognition, PWH face additional biopsychosocial disadvantages that may explain the lack of beneficial effects of low-risk drinking among this group. Even in the context of low-risk use, the immuno suppressant properties of alcohol may counteract the cardio protective effects on downstream neurocognitive health among PWH,vertical rack grow as immunosuppression leads to greater viral infectivity, replication, and subsequently poorer neuronal integrity . Furthermore, our HIV groups had different proportions of individuals with current and lifetime depression, with significantly higher rates among PWH.
Depression is known to have adverse effects on neurocognitive performance in HIV , possibly limiting the expression of potentially beneficial effects of low-risk drinking among our PWH sample. The current study has several limitations. Although we detected effects that remained statistically significant after adjusting for relevant covariates, there could be potential unmeasured health and lifestyle confounders such as disability, social status, and reason for drinking, that may mediate the association between alcohol consumption and neurocognition. Next, our sample of low risk drinkers, especially among the HIV- group, had fewer drinkers on the high end of the low-risk drinking range, more alcohol abstainers, and more drinkers on the lower end of the low-risk drinking range. Furthermore, we did not have any method to verify self-reported alcohol abstinence. Despite our skewed sample in terms of levels of alcohol consumption, we still detected robust effects even after adjusting for relevant covariates. Objectively measured recent alcohol consumption would have reduced the possibility of misreporting alcohol abstinence, drinking quantities, and frequency; however, we believe structured interviews are still clinically relevant given that our timeline follow back was only 30 days prior. Future alcohol consumption research should employ methodologies to capture real time and ecologically valid data, rather than relying on retrospective recall. While the full range of “low-risk” drinking does not have discretely defined cut-points for minimal, light, and moderate alcohol use, our inclusion of the J-N technique allowed us to identify specific boundaries of recent alcohol consumption in which alcohol confers neurocognitive benefits or risks among HIV individuals. Although these analyses may help clinical efforts at identifying intervals of safe drinking for certain populations, interpretations must caution against the differences in low-risk drinking criteria for men and women. According to the NIAAA criteria for low-risk drinking, we included women who self-report 0-30 drinks in the last 30 days, and men who self-report 0-60 drinks. Therefore, the results of the J-N technique for lower regions of significance are applicable to both men and women, whereas the results in the upper regions of significance are applicable only to men. Future work with equal sample sizes by sex should investigate the associations between recent drinking and neurocognitive function to further adjust for sex differences.
In conclusion, our results are consistent with the hypothesis of a curvilinear association between recent alcohol consumption and neurocognition within the range of low-risk drinking and only among HIV- older adults, such that intermediate levels of recent alcohol use were associated with better neurocognition compared to alcohol abstinence as well as lower and higher ranges of low-risk consumption. Among PWH, there were no detected beneficial or deleterious effects of low-risk alcohol consumption on neurocognition, suggesting that other factors that may supersede the neurocognitive effects of low-risk alcohol consumption in the context of HIV. Uptake of HIV pre-exposure prophylaxis using daily oral emtricitabine-tenofovir disoproxil fumarate has increased considerably since 2012.However, reports from clinical implementation suggest high rates of PrEP discontinuation.The use of stimulant drugs such as cocaine has received little attention in the PrEP literature despite elevated prevalence in high priority populations.In fact, the use of stimulants is higher among men who have sex with men and transgender women compared to the general population.Surveillance reports from major metropolitan areas in the United States suggest that stimulant use is increasing and will continue to do so in the near term.Methamphetamine use doubled between 2011 and 2014 in New York City, and in some regions, rates are at their highest since 2005.San Francisco also observed a resurgence of cocaine use among MSM in recent years with as much as 23% of respondents in 2014 reporting cocaine use in the last six months.An estimated 13–22 million people globally use cocaine, and the highest prevalence of cocaine use disorders is in North America.Stimulant use is a potential barrier to achieving the optimal public health benefits of PrEP. Important clinical questions around adherence, retention in care, and renal toxicity among persons who use stimulants remain unresolved. Studies from our team and others have found some evidence that stimulant-using MSM can achieve prevention-effective adherence and rates of retention comparable to non-users.However, these studies have largely relied on self-reported drug use, which is prone to misclassification.Biological measures of stimulant use are more reliable than self-reported measures due to social desirability bias. In a prior study, we found that stimulant use, confirmed using urine immunoassays, was associated with sub-optimal PrEP adherence in the first month.
Because urine tests have a narrow window of detection and qualitative assays limited our ability to quantify stimulant drug levels, further research is needed to understand how varying degrees of stimulant drug exposure influence PrEP adherence and engagement in care. Another important gap in the literature is that little is known about the renal safety of PrEP in persons who use stimulants such as cocaine. Although PrEP has been associated with only a modest decrease in creatinine clearance,growing cannabis vertically it is uncertain whether concomitant use of stimulants can exacerbate renal dysfunction. Cocaine use is associated with glomerular, tubular, vascular, and interstitial damage, and can precipitate acute kidney injury.To address these gaps in the literature, we assessed the associations of biologically confirmed cocaine use with PrEP adherence , PrEP care engagement, and renal function in the iPrEx open label extension . iPrEx OLE is described in detail elsewhere.Briefly, participants were male sex at birth, reported having anal sex with men, age 18 or older, and must have participated in a previous PrEP clinical trial. Follow-up was scheduled every month for the first three months and quarterly thereafter for up to 72 weeks. All participants provided informed consent. This study was approved by the Institutional Review Board at the University of California, San Francisco. Cocaine use was measured by determining concentrations in scalp hair samples collected at the first quarterly visit. We focused on cocaine as this was the most commonly used stimulant in our sample, consistent with the high prevalence of cocaine use in MSM and transgender women. Hair samples were collected quarterly after PrEP initiation from a subset of participants who joined a hair sub-study.Approximately 100 strands of hair were cut from the occipital region and samples were stored and shipped in aluminum foil at room temperature. Hair analysis provides up to a 3-month surveillance window and is routinely used in forensics to determine amount of exposure to various illicit substances.Hair samples from 410 participants were sent to a commercial laboratory for analysis and tested using a standard 5-panel drug test . Hair samples from 10 participants were rejected due to insufficient quantity and were, thus, excluded from this analysis. Samples were screened for cocaine analytes using enzyme-linked immunos orbent assay and positive results confirmed using gas chromatography-mass spectrometry . For this analysis, we utilized a confirmatory cutoff of ≥ 500 pg/mg of cocaine analyte as proposed by the Substance Abuse and Mental Health Services Administration.Cocaine exposure was stratified based on levels used in prior studies.Cocaine levels between 500–3,000 pg/mg corresponded to “light use” and levels >3,000 pg/mg indicated “moderate to heavy use.” Tenofovir concentrations in blood plasma were assessed in all participants in one of the study visits during the first three months after receiving PrEP using validated assays.Plasma concentrations reflect dosing within the previous week. Our adherence outcome was plasma tenofovir concentrations below the level of quantitation, as levels within the detectable range have been associated with >90% protection against HIV.35 Disengagement from PrEP care was defined as a gap in follow-up visit greater than four months. We used study follow-up as an indicator of clinical care engagement as the study’s follow-up schedule closely mirrored that of current PrEP clinical guidelines.To monitor renal function, serum creatinine was measured at baseline and at each quarterly visit. Creatinine clearance was estimated by the Cockcroft-Gault equation. Renal adverse events were graded based on the Division of AIDS Adverse Events Grading Table.
Multivariable logistic models adjusting for age, ethnicity, and transgender identity estimated the association between level of cocaine use and plasma tenofovir concentration. Cox proportional hazard regression models estimated the association between cocaine use and time to disengagement from care. Regression models used robust variance estimators to account for clustering within study sites. Mean differences in creatinine clearance by followup week and cocaine exposure was estimated using linear mixed effects models with a time by cocaine interaction fit by restricted maximum likelihood. All p-values are two-sided, and analyses were conducted using Stata 14 .The 400 participants included in this analysis were mostly MSM , Hispanic/ Latino , and completed at least secondary education . Ten percent were transgender women. At baseline, median age was 29 years. One-in-five participants tested positive for recent cocaine use with a median cocaine concentration of 2,513 pg/mg . Of those who tested positive for cocaine analytes, 52% were classified as light users and 48% were moderate to heavy users. Participant characteristics and hair drug analysis results are summarized in Table 1a. There was no statistically significant difference in creatinine clearance over time among persons who tested positive for cocaine compared to those who did not . The mean difference in creatinine clearance between groups ranged from 0.93 mL/min to 2.85 mL/min over the 72 study weeks . When we limited our analysis to only those with evidence of PrEP adherence during the first three months, we also found no meaningful difference in creatinine clearance between groups, ranging from differences of 0.06 mL/min to 1.48 mL/min over 72 weeks . There were 26 instances of serum creatinine elevations during follow-up that were at least 1.1 times the upper limit of normal or 1.5 times above the baseline level. Of these elevations, four were in participants who tested positive for cocaine and 22 were in nonusers . Serum creatinine levels were elevated at more than one visit in five participants, none of whom tested positive for cocaine use. Overall, 15/26 creatinine elevations were above the normal range. Of these, three were in participants who tested positive for cocaine use and 12 were in non-users . We found that cocaine use at any level was associated with lower odds of achieving prevention-effective adherence in the first three months after starting PrEP. The first few months following PrEP initiation is a particularly critical period as adherence during this time is predictive of future adherence patterns.These findings underscore the importance of providing comprehensive care at the time of PrEP initiation that includes an assessment of cocaine use and other potential barriers to optimal adherence.