Although a significant minority of patients remained ARVnaı¨ve throughout the study follow-up, we wanted to estimate adherence to combination highly active antiretroviral therapy stratified by psychiatric diagnosis and SU diagnosis status for study participants who did receive HAART. Adherence was measured using electronic pharmacy dispensing refill records; the “days supply of HAART medication was divided by the “total time elapsed between first day of HAART initiation and last day of HAART medication supply’’ over the first 12 and 24 months of study follow-up. All data analyses were conducted using SAS software, version 9.1 .The distributions of demographic and HIV-related clinical and behavioral characteristics by psychiatric diagnosis status are presented in Table 1. The results of w2 tests indicate significant differences in most characteristics between those patients with and without a psychiatric diagnosis. However it can be seen that the categories of these characteristics were still very similar in distribution in both groups. Finding significant results for very small differences in distributions is likely the consequence of having a very large sample size in this study. The majority of patients were white, male, 30–49 years of age at baseline, and belonged to the men who have sex with men HIV transmission risk group. CD4 Tlymphocyte cell counts measured at or near time of study entry were comparable in both patients with and without a psychiatric diagnosis. Similar results were observed for HIV RNA levels. Of the 2472 patients with a psychiatric diagnosis, 83.9% had one or more psychiatry department visits. The proportion of patients with any ARV therapy experience at baseline was similar across psychiatric disorder status,plant grow trays with on average 35% of all patients having no ARV experience. Throughout study follow-up, approximately 25% of all patients remained ARV naı¨ve.
Among those who were receiving HAART during study follow-up, mean adherence was estimated as 82.4% among patients with a psychiatric diagnosis at 12 months after initiation of HAART and 83.7% among patients with no psychiatric diagnoses; similar mean adherence was observed at 24 months. Patients diagnosed with SU problems showed mean adherence of 81.1% at 12 months after initiating HAART in comparison to 83.5% among patient without a SU problem diagnosis. Because adherence rates were similar across diagnostic status, we did not conduct a sub-analysis of ARV-experienced patients only, where adherence would have been included as a covariate in the regression model. The distribution of cause of death cross-tabulated by psychiatric diagnosis is presented in Table 2. The majority of deaths among patients with or without a psychiatric diagnosis were attributed to HIV/AIDS. The remaining causes of death had proportionately the same distribution across categories of psychiatric diagnosis status, with the possible exception of suicide which was twice as common among patients with a psychiatric diagnosis in comparison to patients with no diagnosis. Examining all-cause mortality for the entire study follow-up, we found an age-adjusted mortality rate of 28.6 deaths per 1000 person–years for patients with a psychiatric diagnosis versus 17.5 deaths for those without a psychiatric diagnosis. To examine the joint effects of psychiatric diagnosis, psychiatric treatment visits, SU diagnosis, and SU treatment on mortality, relative hazards were estimated using Cox proportional hazards regression. As mentioned in Statistical methods, the effects of psychiatric diagnosis/treatment and SU diagnosis/treatment were not additive, with statistically significant interactions between these covariates. RHs and 95% Confidence Intervals estimated from unadjusted and adjusted models are presented in Table 3. Categories of diagnosis and treatment are ordered from lowest to highest RH in the unadjusted model 1.
In comparison to patients with neither a psychiatric diagnosis nor a SU diagnosis , the highest risk of dying was found among patients with dual diagnoses but who had no psychiatric treatment visits and no SU treatment . This effect was somewhat attenuated after adjustment for potential confounders but remained statistically significant . Similar results were observed for patients who had a psychiatric diagnosis but no psychiatric services and no SU diagnosis that were very similar to those parameter estimates in model 2.During 12 years of follow-up , we observed a higher mortality risk for HIV-infected patients diagnosed with both psychiatric and SU disorders in comparison to patients with neither diagnosis. However, we observed that psychiatric and SU treatment, in general, reduced mortality risk in single and dual diagnosed patients, and remained statistically significant even after adjustment for age, race, immune status, HIV viral load, anti-retroviral therapy use, and other potential confounders. Accessing psychiatric treatment reduced mortality risk among dual diagnosed patients who were treated or not treated for SU disorder. Previous studies of individuals with HIV infection have found that those with psychiatric disorders are at elevated risk for poor medication adherence and clinical outcomes.There is substantial evidence that depression, stressful life events and trauma affect HIV disease progression and mortality.This effect has been found even controlling for medication adherence, in a study that showed that HAART adherent patients with depressive symptoms were 5.90 times more likely to die than adherent patients with no depressive symptoms.Depressive symptoms independently predicted mortality among women with HIV,and also in a separate study of men.Similarly, in multivariate analyses controlling for clinical characteristics and treatment, women with chronic depressive symptoms were 2 times more likely to die than women with limited or no depressive symptoms .Among women with CD4 cell counts of less than 200 10/ L, HIV-related mortality rates were 54% for those with chronic depressive symptoms and 48% for those with intermittent depressive symptoms compared with 21% for those with limited or no depressive symptoms.
Chronic depressive symptoms were also associated with significantly greater decline in CD4 cell counts after controlling for other variables.These mechanisms could help to explain the greater risk of mortality observed in our sample. Our findings strongly highlight the importance of access to psychiatric and SU disorder treatment for this population. It was estimated that during a 6-month period, 61.4% of 231,400 adults in the United States receiving treatment for HIV/AIDS used psychiatric or SU disorder treatment services.A significant number of HIV-infected patients report accessing psychiatric services.Such visits are associated with decreased risk of discontinuing HAART.Burnam et al.found that those with less severe HIV-related illness were less likely to access psychiatric or SU disorder treatment. One study found that engagement in SU disorder treatment was not associated with a decrease in hospital use by HIV-infected individuals with a history of alcohol problems.Improvement in depression was associated with increase in HAART adherence among injection drug users.26The translation of preclinical theories of alcoholism etiology to clinical samples is fundamental to understanding alcohol use disorders and developing efficacious treatments. Human subjects research is fundamentally limited in neurobiological precision and experimental control, whereas preclinical models permit fine grained measurement of biological function. However, the concordance between preclinical models and human psychopathology is often evidenced by face validity alone. The aim of this study, therefore, is to test the degree to which one prominent preclinical model of alcoholism etiology, the Allostatic Model, predicts the behavior and affective responses of human subjects in an experimental pharmacology design. The Allostatic Model was selected for translational investigation due to its focus on reward and reinforcement mechanisms in early vs. late stages of addiction. In this study, we advance a novel translational human laboratory approach to assessing the relationship between alcohol-induced reward and motivated alcohol consumption. A key prediction of the Allostatic Model is that chronic alcohol consumptions results in a cascade of neuroadaptations,custom grow room which ultimately blunt drinking-relate hedonic reward and positive reinforcement, while simultaneously leading to the emergence of persistent elevations in negative affect, termed allostasis. Consequently, the model predicts that drinking in late-stage dependence should be motivated by the relief of withdrawal related negative affect, and hence, by negative reinforcement mechanisms. In other words, the Allostatic Model suggests a transition from reward to relief craving in drug dependence.
The Allostatic Model is supported by studies utilizing ethanol vapor paradigms in rodents that can lead to severe withdrawal symptoms, escalated ethanol self-administration, high motivation to consume the drug as revealed by progressive ratio breakpoints, enhanced reinstatement, and reduced sensitivity to punishment. Diminished positive reinforcement in this model is inferred through examination of reward thresholds in an intracranial self-stimulation protocol. Critically, these allostatic neuroadaptations are hypothesized to persist beyond acute withdrawal, producing state changes in negative emotionality in protracted abstinence. Supporting this hypothesis, exposure to chronic ethanol vapor produces substantial increases in ethanol consumption during both acute and protracted abstinence periods. . Despite strong preclinical support, the Allostatic Model has not been validated in human populations with AUD.Decades of human alcohol challenge research has demonstrated that individuals differences in subjective responses to alcohol predict alcoholism risk. The Low Level of Response Model suggests that globally decreased sensitivity to alcohol predicts AUD. Critically however, research has demonstrated that SR is multi-dimensional. The Differentiator Model as refined by King et al suggests that stimulatory and sedative dimensions of SR differentially predict alcoholism risk and binge drinking behavior. Specifically, an enhanced stimulatory and rewarding SR, particularly at peak BrAC is associated with heavier drinking and more severe AUD prospectively. The Differentiator Model also suggests blunted sedative SR is an AUD risk factor, however, effect sizes for sedation are generally smaller. Both the LR and Differentiator models have garnered considerable empirical support in alcohol challenge research ; however, both models share some limitations. Human subjects research has not adequately tested whether SR represent a dynamic construct across the development of alcohol dependence and whether the motivational structure of alcohol consumption is altered in dependence vs. early non-dependent drinking. Recently, King et al. reported that the elevated stimulating and rewarding SR in heavy drinkers remained elevated over a 5-year period. Furthermore, this outcome was particularly strong among the ~10% of heavy drinking participants who showed high levels of AUD progression. In two previous alcohol challenge studies, we showed that stimulation/hedonia and craving are highly correlated among non-dependent heavy drinkers, whereas no stimulation-craving association was evidenced among alcohol dependent participants. These results were interpreted as being consistent with the Allostatic Model, insofar as the function of stimulation/ hedonia in promoting craving appeared diminished in alcohol dependence. Of note, however, neither study observed the hypothesized relationship between negative affect and craving among dependent participants. A primary limitation of these previous studies was the utilization of craving as a proxy end point for alcohol motivation and reinforcement. A recent study of young heavy drinkers found that both stimulation and sedation predicted free-access self-administration via craving. However, since this study did not include moderate–severe AUD participants, it is unclear whether the association between stimulation and self-administration is blunted in later-stage dependence. This study was designed to test whether SR predicts motivated alcohol self-administration and whether this relationship is moderated by alcohol use severity, thus providing much needed insight about the function of SR in alcohol reinforcement and advancing an experimental framework for translational science. Heavy drinkers ranging in their severity of alcohol use and problems completed a novel intravenous alcohol administration session consisting of a standardized alcohol challenge followed by progressive-ratio alcohol reinforcement. On the basis of the Allostatic Model, we predicted a strong relationship between stimulation and self-administration at low alcohol use severity, whereas no such association would be observed at greater alcohol use severity. Conversely, it was hypothesized that negative affect would be a stronger predictor of alcohol self administration among more severe participants. These two hypotheses would thus capture dependence-related blunting of positive reinforcement and enhancement of negative reinforcement.This study was approved by the Institutional Review Board at UCLA. Non-treatment seeking drinkers were recruited between April 2015 and August 2016 from the Los Angeles community through fliers and online advertisements . Initial eligibility screening was conducted via online and telephone surveys followed by an in-person screening session. After providing written informed consent, participants were breathalyzed, provided urine for toxicology screening, and completed a battery of self-report questionnaires and interviews. All participants were required to have a BrAC of 0 mg% and to test negative on a urine drug screen . Female participants were required to test negative on a urine pregnancy test. Inclusion criteria were as follows: age between 21 and 45, caucasian ethnicity , fluency in English, current heavy alcohol use of 14+ drinks per week for men or 7+ for women, if female, not pregnant or lactating, and using a reliable method of birth control , and body weight of less than 265lbs to reduce the likelihood of exhausting the alcohol supply during the infusion.