Marc I. Rosen

Cue-dose Training with Monetary Reinforcement: Pilot Study of an Antiretroviral Adherence Intervention

AbstractOBJECTIVE: To assess the feasibility and efficacy of two interventions for improving adherence to antiretroviral therapy regimens in HIV-infected subjects compared with a control intervention. DESIGN: Randomized, controlled, pilot study. SETTING: Department of Veterans Affairs HIV clinic and community-based HIV clinical trials site. PARTICIPANTS: Fifty-five HIV-infected subjects on stable antiretroviral therapy regimens. Subjects were predominantly male (89%) and African American (69%), and had histories of heroin or cocaine use (80%). INTERVENTIONS: Four weekly sessions of either nondirective inquiries about adherence (control group, C), cue-dose training, which consisted of the use of personalized cues for remembering particular dose times, and feedback about medication taking using Medication Event Monitoring System (MEMS) pill bottle caps, which record time of bottle opening (CD group), or cue-dose training combined with cash reinforcement for correctly timed bottle opening (CD+CR). MEASUREMENTS: Opening of the pill bottle within 2 hours before or after a predetermined time was measured by MEMS. RESULTS: Adherence to the medication as documented by MEMS was significantly enhanced during the 4-week training period in the CD+CR group, but not in the CD group, compared with the control group. Improvement was also seen in adherence to antiretroviral drugs that were not the object of training and reinforcement. Eight weeks after training and reinforcement were discontinued, adherence in the cash-reinforced group returned to near-baseline levels. CONCLUSIONS: Cue-dose training with cash reinforcement led to transient improvement in adherence to antiretroviral therapy in a population including mostly African Americans and subjects with histories of drug abuse. However, we were not able to detect any sustained improvement beyond the active training period, and questions concerning the timing and duration of such an intervention require further study. Randomized, controlled clinical studies with objective measures of adherence can be conducted in HIV-infected subjects and should be employed for further evaluation of this and other adherence interventions.

Human therapeutic cocaine vaccine: safety and immunogenicity

This randomized, double blind, placebo controlled, phase I clinical trial assessed the safety and immunogenicity of a therapeutic cocaine vaccine TA-CD in 34 former cocaine abusers: 8 at 13 microg active vaccine, 10 at 82 microg and 10 at 709 microg, with two additional subjects getting placebo in each cohort. All got intra-muscular injections at 0-2 months and were monitored for safety and antibody production for 3 months. Of the 34 subjects 27 completed the full course of three injections, of these, only 24 returned for the final scheduled visit at day 84. The vaccine was well-tolerated and had no serious drug-related adverse events, although three subjects at the highest dose experienced brief post injection twitching. Fifteen subjects on TA-CD therapeutic vaccine were followed for 1 year. Antibody levels were correlated with vaccine dose and number of injections. Anti-cocaine antibodies were detected after the second injection, peaked at 3 months and declined to baseline by 1 year. Thus, the therapeutic vaccine was well tolerated with dose related increases in antibody levels, and a high proportion of patients recruited into the study were retained.

A Closer Look at Depression and Its Relationship to HIV Antiretroviral Adherence

BackgroundDepression consistently predicts nonadherence to human immunodeficiency virus antiretroviral therapy, but which aspects of depression are most influential are unknown. Such knowledge could inform assessments of adherence readiness and the type of depression treatment to utilize.PurposeWe examined how depression severity, symptom type, and change over time relate to adherence.MethodsMicroelectronic adherence and self-reported depression data from 1,374 participants across merged studies were examined with cross-sectional and longitudinal analyses. Depression variables included a continuous measure, categorical measure of severity, cognitive and vegetative subscales, and individual symptoms.ResultsAt baseline, mean adherence was 69%, and 25% had mild/moderate and 18% had severe depression. In cross-sectional multivariate analyses, continuous depression, cognitive depressive symptoms, and severe depression were associated with lower adherence. In longitudinal analysis, reductions in both continuous and categorical depression predicted increased adherence.ConclusionsThe relationship between global continuous depression and nonadherence was statistically significant, but relatively weak compared to that of cognitive depressive symptoms and severe depression, which appear to pose strong challenges to adherence and call for the need for early detection and treatment of depression.

Acute cocaine effects on absolute cerebral blood flow

Abstract Cocaine use has been associated with vasoconstriction and stroke, and several studies have demonstrated that it decreases relative cerebral blood flow (rCBF) in humans. However, rCBF has not been quantitated. We compared 40 mg IV cocaine hydro-chloride to placebo effects on absolute rCBF in four cocaine users using 99mTc-HMPAO SPECT with a modified microsphere model for CBF quantitation. Cocaine produced significant decreases in rCBF in all regions studied with a mean decrease of 30% in absolute whole brain blood flow (P = 0.002) which was 3-fold greater than relative blood flow changes.

Racial/Ethnic Disparities in ART Adherence in the United States: Findings From the MACH14 Study

Background:Minority race/ethnicity is generally associated with antiretroviral therapy nonadherence in US-based studies. Limitations of the existing literature include small samples, subjective adherence measures, and inadequate control for potential confounders such as mental health and substance use, which have been consistently associated with poorer adherence. Methods:Individual-level data were pooled from 13 US-based studies employing electronic drug monitoring to assess adherence. Adherence was operationalized as percent of prescribed doses taken from the first 12 (monthly) waves of data in each study. Depression symptoms were aggregated from several widely used assessments, and substance use was operationalized as any use of cocaine/stimulants, heroin/opiates, ecstasy, hallucinogens, or sedatives in the 30–365 days preceding baseline. Results:The final analytic sample of 1809 participants ranged in age from 18 to 72 years and was 67% male. Participants were 53% African American, 14% Latino, and 34% White. In a logistic regression adjusting for age, gender, income, education, and site, race/ethnicity was significantly associated with adherence (P < 0.001) and persisted in a model that also controlled for depression and substance use (P < 0.001), with African Americans having significantly lower adherence than Latinos [odds ratio (OR) = 0.72, P = 0.04] and whites (OR = 0.60, P < 0.001). Adherence did not differ between whites and Latinos (OR = 0.84, P = 0.27). Conclusions:Racial/ethnic differences in demographics, depression, and substance abuse do not explain the lower level of antiretroviral therapy adherence in African Americans observed in our sample. Further research is needed to explain the persistent disparity and might examine factors such as mistrust of providers, health literacy, and inequities in the health care system.

A Money Management-Based Substance Use Treatment Increases Valuation of Future Rewards

OBJECTIVE A positive association between delay discounting and substance use has been documented; substance users tend to discount future rewards more than non-users. However, studies detailing the responsiveness of delay discounting to interventions are lacking, and few have examined how any behavioral intervention affects delay discounting and whether these effects moderate changes in substance abuse. This study assesses the effectiveness of a money management intervention, Advisor-Teller Money Manager (ATM), in reducing delay discounting over time and the relationship of these effects to changes in cocaine use. METHOD Ninety psychiatric patients with histories of cocaine and/or alcohol use were randomly assigned to 36-weeks of ATM treatment or to a minimal-attention control condition. Delay discounting and cocaine use were measured throughout the intervention with a 52-week follow up measure of cocaine use. Analyses were conducted of (a) the effect of ATM on slopes of delay discounting and cocaine abstinence and (b) the relationship between change in delay discounting and change in cocaine abstinence. RESULTS The ATM intervention was associated with significantly less delay discounting and less cocaine use over time relative to controls. Increases in delay discounting were associated with decreased abstinence from cocaine. CONCLUSIONS ATM treatment decreased delay discounting rates and these effects extended to cocaine use. Concrete conceptualizations of future events, as occur in financial planning, with higher perceived probability may account for higher valuation of future rewards in counseled patients.

Patterns of antiretroviral therapy adherence and impact on HIV RNA among patients in North America

Objective:Adherence to antiretroviral therapies (ART) is the strongest predictor of viral suppression among individuals infected with HIV, however, limited data exists to understand the patterns of adherence that confer the greatest benefit across different ART regimens. Design:Longitudinal data pooled from 16 studies conducted between 1997 and 2009 across the United States. Methods:Adherence was measured using Medication Event Monitoring System. Percentage of time with sufficient drug concentrations (covered time) and the length of the longest treatment interruption during the 28 days prior to plasma HIV-RNA measurements were calculated. Logistic regression with generalized estimating equations was used to estimate medication-specific adherence estimates on detectable HIV-RNA (>400 copies/ml). Results:One thousand and eighty-eight participants with 3795 HIV-RNA measures were studied. Both lower covered time and greater longest interruption showed dose–response relationships with the odds of detectable HIV-RNA; however, estimates did not vary by medication regimen. Compared with 93–100% coverage, periods of 0–25% covered time had a three-fold increased risk of detectable HIV-RNA [odds ratio (OR) = 3.22, 95% confidence interval (CI): 2.48–4.19]. Similarly, compared to longest interruptions of 0–48 h, longest interruptions of 21–28 days had a nearly four-fold increased risk of detectable HIV-RNA (OR = 3.65, 95% CI: 2.77, 4.81). Conclusion:We found that adherence was consistently strongly associated with treatment response across ART regimens. Of the patterns of adherence, longer interruptions may have greater impact than covered time. Future research should investigate additional methods for examining adherence patterns, understanding the determinants of consecutive missed doses and the evaluation of interventions designed to address interruptions in treatment.

Neuropsychological Correlates of Suboptimal Adherence to Metformin

The goal of this study was to determine if neuropsychological function is associated with adherence to prescribed medication. Altogether, 79 patients with type II diabetes at a VA primary care clinic had adherence to the antihyperglycemic drug metformin measured with MEMS® caps over a 4-week period. They completed several tests of neuropsychological function: Mini-Mental Status Exam (MMSE), Trails A and B, Stroop, Digit Span, Digit Symbol, and Grooved Pegboard. In separate multivariate analyses, Stroop word score and time to complete Trails B were independently associated with adherence, as was age. Secondary analyses of the relationship between neuropsychological variables and other adherence-related measures were conducted. Low scores on the MMSE and non-Caucasian ethnicity were associated with missed appointments. None of the neuropsychological variables were associated with glycosylated hemoglobin. These results suggest that cognitive abilities should be considered when counseling patients concerning their adherence.

Opiate dependence and withdrawal: preliminary assessment using single photon emission computerized tomography (SPECT).

Naloxone (0.8 mg, s.c.) effects on opiate withdrawal signs and symptoms and regional brain function were assessed in 10 methadone-maintained patients and 10 healthy subjects in a double-blind, placebo-controlled study. Regional brain function was assessed using single photon emission computerized tomography (SPECT) by evaluating the uptake of [99mTc]d,l-hexamethylpropyleneamine oxime (HMPAO) in the brain, a process related to regional cerebral perfusion. Comparisons of patients and healthy subjects after saline infusion suggested that chronic opiate dependence was associated with lower corrected activity ratios (regional count density/whole brain count density) in frontal and parietal cortices and greater activity ratios in the thalamus. Opiate-dependent patients, but not healthy subjects, developed opiate withdrawal signs and symptoms after naloxone administration. Following naloxone administration, patients undergoing opiate withdrawal exhibited lower whole brain count density than healthy subjects. They also had lower activity ratios in frontal and parietal cortices and increased thalamic activity ratios relative to healthy subjects receiving naloxone. Naloxone administration in healthy subjects, but not opiate withdrawal in patients, was associated with decreased right parietal cortex and increased right temporal cortex and left basal ganglia activity ratios. Relative to naloxone effects in healthy subjects, opiate withdrawal was associated with decreased whole brain count density and a reduced right temporal cortex activity ratio. This preliminary study reports an initial evaluation of HMPAO-SPECT imaging for assessing regional alterations in brain function during opiate dependence and withdrawal. While group differences were reported, the small magnitude of regional alterations in patients undergoing opiate withdrawal raised concern that HMPAO-SPECT methods employed were inadequate for assessing human regional brain function during phases of opiate addiction. Other emerging functional brain imaging technologies should be evaluated relative to improved HMPAO-SPECT methods for this purpose.

A pilot study of dextromethorphan in naloxone-precipitated opiate withdrawal

Dextromethorphan and its metabolite dextrophan antagonize N-methyl-D-aspartate (NMDA)-mediated activity in pre-clinical studies. We examined dextromethorphans effects on naloxone-precipitated opiate withdrawal in opiate-dependent subjects stabilized on 25 mg of methadone. Subjects received challenges on three different days with 0.4 mg of intramuscular naloxone. Pretreatment 1 h before naloxone was with dextromethorphan in a double-blind, balanced, randomized design with either placebo, dextromethorphan 60 mg, or dextromethorphan 120 mg for six subjects; and placebo, dextromethorphan 120 mg, or dextromethorphan 240 mg for five subjects. There was considerable inter-individual variability in the response to dextromethorphan, but no net attenuation by dextromethorphan on any withdrawal measure assessed. Two of three subjects detoxified from methadone with dextromethorphan 60 mg orally every 4 h demonstrated considerable withdrawal.