Publications by authors named "Reena Deutsch"

58 Publications

Cerebrospinal fluid CXCL10 is associated with the presence of low level CSF HIV during suppressive antiretroviral therapy.

J Neuroimmunol 2021 Jan 21;353:577493. Epub 2021 Jan 21.

Department of Psychiatry, University of California at San Diego School of Medicine, 220 Dickinson Street, San Diego, CA 92103-8231, United States of America; Department of Medicine, University of California at San Diego School of Medicine, 220 Dickinson Street, San Diego, CA 92103-8231, United States of America.

Surrogate markers of HIV central nervous system (CNS) persistence are needed because direct HIV measurements from the CNS require specialized protocols and are not always detectable or quantifiable. We analyzed paired plasma and CSF samples from people with HIV (PWH) on suppressive therapy (ART) with a validated HIV single copy RNA assay. Two potential markers of CNS persistence were measured (CXCL10 and sCD30). We then examined associations with CSF HIV RNA positivity in univariable and multivariable analyses. Among 66 individuals, 18.2% had detectable CSF HIV. Individuals who had detectable HIV in CSF had higher CSF CXCL10 concentrations (median 514 pg/ml versus median 317 pg/ml, p = 0.019), but did not have significantly different CSF sCD30 concentrations (median 7.5 ng/ml versus median 7.6 ng/ml, p = 0.78). In the multiple logistic analysis, both higher CSF CXCL10 (p = 0.038) and plasma HIV detectability (p = 0.035) were significantly associated with detectable CSF HIV. Both sCD30 and CXCL10 correlated positively with NfL and NSE, two neuronal markers. This study demonstrates that CSF CXCL10 concentrations reflect low level HIV CNS persistence despite virologic suppression on ART. Given that it is readily detectable and quantifiable, this chemokine may be a promising biomarker to evaluate HIV eradication therapies that target the CNS.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577493DOI Listing
January 2021

Neurocognitive impairment is worse in HIV/HCV-coinfected individuals with liver dysfunction.

J Neurovirol 2019 12 7;25(6):792-799. Epub 2019 Jul 7.

Division of Infectious Diseases, Department of Medicine, University of California, San Diego, CA, 92093, USA.

Infections with HIV and hepatitis C virus (HCV) can individually and jointly contribute to neurocognitive impairment (NCI). Rates of NCI in HIV/HCV-coinfected persons range from 40 to 63% but its correlates have not been described. In this study, we examined HIV/HCV-coinfected adults on antiretroviral therapy (ART) with undetectable HIV RNA in blood (n = 412) who were assessed using a comprehensive neuropsychological test battery. Demographics, host and viral biomarkers, and markers of liver dysfunction were compared between impaired (n = 198) and unimpaired (n = 214) participants using logistic regression. The cohort was predominantly middle-aged men, half of whom (48%) had NCI. The odds of NCI increased by almost two-fold when serum albumin was < 4 g/dL, 1.7-fold when alanine aminotransferase (ALT) levels were > 50 IU/L, and 2.2-fold with every unit increase in log AST to Platelet Ratio Index (APRI). These readily available clinical biomarkers of NCI measure hepatic injury and/or dysfunction, suggesting a mechanism for the effects of HCV infection on NCI. They may identify patients at increased risk of NCI who could be prioritized for early initiation of HCV treatment to protect or improve cognition.
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http://dx.doi.org/10.1007/s13365-019-00767-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923581PMC
December 2019

Cerebrospinal fluid viral escape in aviremic HIV-infected patients receiving antiretroviral therapy: prevalence, risk factors and neurocognitive effects.

AIDS 2019 03;33(3):475-481

University of California, San Diego, San Diego, California.

Background: During antiretroviral therapy, HIV RNA can be detected in cerebrospinal fluid (CSF) when it is undetectable in plasma, a condition termed 'CSF viral escape'. The aim of the current study was to determine the prevalence and risk factors for CSF viral escape in two large cohorts in the USA.

Methods: A total of 1264 HIV-infected volunteers enrolled in two US cohorts at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was less than 50 copies/ml while receiving stable antiretroviral therapy (ART) (>6 months) and if they had HIV RNA measured in CSF at their most recent visit between 2003 and 2011. Potential risk factors were identified using univariable and multivariable regression.

Results: CSF viral escape was detected in 55 adults (4.4%; 95% CI: 3.4-5.6), who had a median CSF HIV RNA of 155 copies/ml [interquartile range (IQR: 80-283)]. Patients with or without CSF viral escape had similar rates of neurocognitive impairment (38.2 vs. 37.7%; P = 0.91). CSF viral escape was independently associated with the use of ritonavir-boosted protease inhibitors [odds ratio (OR): 2.0; 95% CI: 1.1-3.8] or unboosted atazanavir (OR: 5.1; 95% CI: 1.3-16.1), CSF pleocytosis (OR: 7.6; 95% CI: 4.2-13.7) and abnormal CSF total protein (OR: 2.1; 95% CI: 1.1-3.7).

Conclusions: In this large study of aviremic patients receiving ART, CSF viral escape was uncommon and was linked to evidence of central nervous system inflammation and the use of protease inhibitors, but not with worse neurocognitive performance.
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http://dx.doi.org/10.1097/QAD.0000000000002074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361539PMC
March 2019

Accuracy of predictive ability measures for survival models.

Stat Med 2017 Sep 7;36(20):3171-3180. Epub 2017 Jun 7.

Laboratoire de Statistique Théorique et Appliquée, UPMC, Paris, France.

One aspect of an analysis of survival data based on the proportional hazards model that has been receiving increasing attention is that of the predictive ability or explained variation of the model. A number of contending measures have been suggested, including one measure, R (β), which has been proposed given its several desirable properties, including its capacity to accommodate time-dependent covariates, a major feature of the model and one that gives rise to great generality. A thorough study of the properties of available measures, including the aforementioned measure, has been carried out recently. In that work, the authors used bootstrap techniques, particularly complex in the setting of censored data, in order to obtain estimates of precision. The motivation of this work is to provide analytical expressions of precision, in particular confidence interval estimates for R (β). We use Taylor series approximations with and without local linearizing transforms. We also consider a very simple expression based on the Fisher's transformation. This latter approach has two great advantages. It is very easy and quick to calculate, and secondly, it can be obtained for any of the methods given in the recent review. A large simulation study is carried out to investigate the properties of the different methods. Finally, three well-known datasets in breast cancer, lymphoma and lung cancer research are given as illustrations. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.7342DOI Listing
September 2017

Latent Toxoplasma Infection and Higher Toxoplasma gondii Immunoglobulin G Levels Are Associated With Worse Neurocognitive Functioning in HIV-Infected Adults.

Clin Infect Dis 2016 Dec 28;63(12):1655-1660. Epub 2016 Oct 28.

Department of Medicine, University of California, San Diego.

Background:  Human immunodeficiency virus (HIV)-associated neurocognitive disorders persist despite suppressive antiretroviral therapy (ART). Because latent Toxoplasma infection (LTI) may adversely impact brain function, we investigated its impact on neurocognitive impairment (NCI) in people living with HIV disease.

Methods:  Two hundred sixty-three HIV-infected adults underwent comprehensive neurocognitive assessments and had anti-Toxoplasma gondii immunoglobulin G (anti-Toxo IgG) measured by qualitative and quantitative enzyme-linked immunosorbent assays.

Results:  Participants were mostly middle-aged white men who were taking ART (70%). LTI was detected in 30 (11.4%) participants and was associated with a significantly greater prevalence of global NCI (LTI positive [LTI] = 57% and LTI negative [LTI] = 34%) (odds ratio, 1.67; 95% confidence interval, 1.17-2.40; P = .017). Deficits were more prevalent in the LTI vs the LTI group in 6 of 7 cognitive domains with statistical significance reached for delayed recall (P < .01). The probability of NCI increased with higher CD4 T-cell counts among LTI individuals but with lower CD4 T-cell counts in LTI persons. A strong correlation (r = .93) between anti-Toxo IgG levels and global deficit score was found in a subgroup of 9 patients. Biomarkers indicative of central nervous system inflammation did not differ between LTI and LTI participants.

Conclusions:  In this cross-sectional analysis, LTI was associated with NCI, especially in those with higher CD4 T-cell counts. Longitudinal studies to investigate the role of neuroinflammation and neuronal injury in LTI patients with NCI and trials of anti-Toxoplasma therapy should be pursued.
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http://dx.doi.org/10.1093/cid/ciw655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146725PMC
December 2016

A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis.

J Pain Res 2016 31;9:587-98. Epub 2016 Aug 31.

VA Northern California Health Care System, Mather, CA; Department of Physical Medicine and Rehabilitation, University of California, Sacramento, CA.

A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat.
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http://dx.doi.org/10.2147/JPR.S113138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012851PMC
September 2016

Maintenance of Blinding in Clinical Trials and the Implications for Studying Analgesia Using Cannabinoids.

Cannabis Cannabinoid Res 2016 1;1(1):139-148. Epub 2016 Jul 1.

Department of Psychiatry, Center for Medicinal Cannabis Research, University of California, San Diego, San Diego, California.

The design of analgesic clinical trials invariably involves a comparison between placebo and active study medication. An assumption is made that treatment effects can be approximated by subtracting the response to placebo from that attained with the use of active study medication. However, the psychoactivity of cannabinoids may unmask their presence and lead to an expectation and/or conditioning of pain relief. For example, study participants biased toward the belief that cannabis is beneficial for their condition might be more inclined to report positive effects if they were to accurately identify the active treatment because of its psychoactivity. This may lead to incorrect assumptions regarding the efficacy of a cannabinoid. Methodologies designed to counteract unmasking need to be implemented in the design phase of a study. During the clinical trial, it is also important to query participants as to which treatment they believe they have received. Blinding can be considered to be preserved when the accuracy of treatment guesses is not considerably different than random guessing, which is estimated to be correct 50% of the time. After a study has been completed, the use of statistical methodologies such as regression and mediation analysis are worthy of consideration to see whether psychoactive effects biased the results.
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http://dx.doi.org/10.1089/can.2016.0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549444PMC
July 2016

An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease.

J Pain 2016 09 7;17(9):982-1000. Epub 2016 Jun 7.

VA Northern California Health Care System, Sacramento VA Medical Center, Mather, California; Department of Physical Medicine and Rehabilitation, University of California, Davis Medical Center, Lawrence J. Ellison Ambulatory Care Center, Sacramento, California.

Unlabelled: Using 8-hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, most of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta 9-THC on 3 separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was used to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model showed a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (eg, good drug effect, feeling high, etc) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all P < .0004). Psychoactive and subjective effects were dose-dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. Because the 2 active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord.

Perspective: A crossover, randomized, placebo-controlled human laboratory experiment involving administration of vaporized cannabis was performed in patients with neuropathic pain related to spinal cord injury and disease. This study supports consideration of future research that would include longer duration studies over weeks to months to evaluate the efficacy of medicinal cannabis in patients with central neuropathic pain.
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http://dx.doi.org/10.1016/j.jpain.2016.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007175PMC
September 2016

The effects of antiretroviral treatment initiation on cognition in HIV-infected individuals with advanced disease in Pune, India.

J Neurovirol 2015 Aug 7;21(4):391-8. Epub 2015 Mar 7.

National AIDS Research Institute, Post Box 1895, G-73, MIDC, Bhosari, Pune, Maharashtra, 411026, India,

There has been a reduction in the most severe cases of HIV-associated neurocognitive disorders (HAND) with advances in antiretroviral treatment (ART). But the prevalence of milder forms of HAND still remains high. Data from systematically conducted studies on the effects of ART on cognition are scanty in India, where HIV-1 clade C is prevalent. The purpose of the present study was to assess the effect of antiretroviral therapy in HIV-seropositive (HIV+) individuals (n = 92) with CD4 cell counts <200 cells/mm(3). The overall and domain-specific levels of cognitive functioning were determined using a locally recruited normative sample, and a change in neurocognitive functioning at the 1-year follow-up visit was analyzed. Results revealed cognitive impairment in 44.6 % of the HIV+ group at baseline. At the 1-year follow-up, the group showed significant improvement in the Learning domain (p < 0.05). HIV+ individuals showing improvement in the global cognitive scores had a significantly lower baseline CD4 cell count compared to others. Overall, the degree of improvement associated with the magnitude of rise in CD4 suggests the possibility that early, mild subclinical deficits may also benefit from treatment.
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http://dx.doi.org/10.1007/s13365-015-0329-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512904PMC
August 2015

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients.

AIDS 2015 Mar;29(5):559-69

aDepartment of Pharmacology, University of Oxford, Oxford, UK bDepartment of Neurology cPsychiatry, Johns Hopkins University, Baltimore, Maryland dHIV Neurobehavioral Research Program and Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California eDivision of Epidemiology, Department of Health Sciences Research and Department of Neurology College of Medicine, Mayo Clinic, Rochester, Minnesota, USA fDepartment of Chemistry, University of Oxford, UK.

Objectives: To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients.

Design: Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV-infected patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening.

Methods: The metabolic composition of CSF was analysed using H nuclear magnetic resonance (H NMR) spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features.

Results: Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92%, sensitivity of 88% and 96% specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, β-glucose and creatinine to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%.

Conclusion: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.
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http://dx.doi.org/10.1097/QAD.0000000000000580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340743PMC
March 2015

Individualized texting for adherence building (iTAB): improving antiretroviral dose timing among HIV-infected persons with co-occurring bipolar disorder.

AIDS Behav 2015 Mar;19(3):459-71

Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA,

HIV+ persons with co-occurring bipolar disorder (HIV+/BD+) have elevated rates of medication nonadherence. We conducted a 30-day randomized controlled trial of a two-way, text messaging system, iTAB (n = 25), compared to an active comparison (CTRL) (n = 25) to improve antiretroviral (ARV) and psychotropic (PSY) adherence and dose timing. Both groups received medication adherence psychoeducation and daily texts assessing mood. The iTAB group additionally received personalized medication reminder texts. Participants responded to over 90 % of the mood and adherence text messages. Mean adherence, as assessed via electronic monitoring caps, was high and comparable between groups for both ARV (iTAB 86.2 % vs. CTRL 84.8 %; p = 0.95, Cliff's d = 0.01) and PSY (iTAB 78.9 % vs. CTRL 77.3 %; p = 0.43, Cliff's d = -0.13) medications. However, iTAB participants took ARVs significantly closer to their intended dosing time than CTRL participants (iTAB: 27.8 vs. CTRL: 77.0 min from target time; p = 0.02, Cliff's d = 0.37). There was no group difference on PSY dose timing. Text messaging interventions may represent a low-burden approach to improving timeliness of medication-taking behaviors among difficult-to-treat populations. The benefits of improved dose timing for long-term medication adherence require additional investigation.
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http://dx.doi.org/10.1007/s10461-014-0971-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359057PMC
March 2015

Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study.

Clin Infect Dis 2015 Feb 31;60(3):473-80. Epub 2014 Oct 31.

University of California, San Diego.

Background: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery.

Methods: We investigated the incidence and predictors of NC change over 16-72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change.

Results: Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001).

Conclusions: NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.
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http://dx.doi.org/10.1093/cid/ciu862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303775PMC
February 2015

Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline.

Neurology 2014 Jun 9;82(23):2055-62. Epub 2014 May 9.

From the University of California (I.G., D.R.F., R.D., S.P.W., F.V., R.J.E., S.L.L., T.D.M., J.H.A., J.A.M., I.A., A.G., C.F.-N., D.M.S., R.K.H.), San Diego; the University of Washington (A.C.C., C.M.M.), Seattle; Washington University (D.B.C.), St. Louis, MO; University of Texas Medical Branch (B.B.G.), Galveston; Johns Hopkins University (J.C.M.), Baltimore, MD; and The Icahn School of Medicine at Mount Sinai (S.M., D.M.S.), New York, NY.

Objective: While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline).

Methods: A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7-63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood.

Results: The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1-3.6; p = 0.02) for SR, 5.8 (CI 3.2-10.7; p < 0.0001) for PB, and 3.2 (CI 2.0-5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not.

Conclusions: This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.
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http://dx.doi.org/10.1212/WNL.0000000000000492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118496PMC
June 2014

"Frontal systems" behaviors in comorbid human immunodeficiency virus infection and methamphetamine dependency.

Psychiatry Res 2014 Jan 13;215(1):208-16. Epub 2013 Nov 13.

Department of Psychiatry, University of California, San Diego, CA, United States. Electronic address:

Human immunodeficiency virus (HIV) infection and methamphetamine (MA) dependence are associated with neural injury preferentially involving frontostriatal circuits. Little is known, however, about how these commonly comorbid conditions impact behavioral presentations typically associated with frontal systems dysfunction. Our sample comprised 47 HIV-uninfected/MA-nondependent; 25 HIV-uninfected/MA-dependent; 36 HIV-infected/MA-nondependent; and 28 HIV-infected/MA-dependent subjects. Participants completed self-report measures of "frontal systems" behaviors, including impulsivity/disinhibition, sensation-seeking, and apathy. They also underwent comprehensive neurocognitive and neuropsychiatric assessments that allowed for detailed characterization of neurocognitive deficits and comorbid/premorbid conditions, including lifetime Mood and Substance Use Disorders, Attention-Deficit/Hyperactivity Disorder, and Antisocial Personality Disorder. Multivariable regression models adjusting for potential confounds (i.e., demographics and comorbid/premorbid conditions) showed that MA dependence was independently associated with increased impulsivity/disinhibition, sensation-seeking and apathy, and HIV infection with greater apathy. However, we did not see synergistic/additive effects of HIV and MA on frontal systems behaviors. Global neurocognitive impairment was relatively independent of the frontal systems behaviors, which is consistent with the view that these constructs may have relatively separable biopsychosocial underpinnings. Future research should explore whether both neurocognitive impairment and frontal systems behaviors may independently contribute to everyday functioning outcomes relevant to HIV and MA.
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http://dx.doi.org/10.1016/j.psychres.2013.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967865PMC
January 2014

A concise panel of biomarkers identifies neurocognitive functioning changes in HIV-infected individuals.

J Neuroimmune Pharmacol 2013 Dec 8;8(5):1123-35. Epub 2013 Oct 8.

Department of Psychiatry, UC San Diego, San Diego, CA, 92093, USA.

Neurocognitive (NC) impairment (NCI) occurs commonly in people living with HIV. Despite substantial effort, no biomarkers have been sufficiently validated for diagnosis and prognosis of NCI in the clinic. The goal of this project was to identify diagnostic or prognostic biomarkers for NCI in a comprehensively characterized HIV cohort. Multidisciplinary case review selected 98 HIV-infected individuals and categorized them into four NC groups using normative data: stably normal (SN), stably impaired (SI), worsening (Wo), or improving (Im). All subjects underwent comprehensive NC testing, phlebotomy, and lumbar puncture at two timepoints separated by a median of 6.2 months. Eight biomarkers were measured in CSF and blood by immunoassay. Results were analyzed using mixed model linear regression and staged recursive partitioning. At the first visit, subjects were mostly middle-aged (median 45) white (58 %) men (84 %) who had AIDS (70 %). Of the 73 % who took antiretroviral therapy (ART), 54 % had HIV RNA levels below 50 c/mL in plasma. Mixed model linear regression identified that only MCP-1 in CSF was associated with neurocognitive change group. Recursive partitioning models aimed at diagnosis (i.e., correctly classifying neurocognitive status at the first visit) were complex and required most biomarkers to achieve misclassification limits. In contrast, prognostic models were more efficient. A combination of three biomarkers (sCD14, MCP-1, SDF-1α) correctly classified 82 % of Wo and SN subjects, including 88 % of SN subjects. A combination of two biomarkers (MCP-1, TNF-α) correctly classified 81 % of Im and SI subjects, including 100 % of SI subjects. This analysis of well-characterized individuals identified concise panels of biomarkers associated with NC change. Across all analyses, the two most frequently identified biomarkers were sCD14 and MCP-1, indicators of monocyte/macrophage activation. While the panels differed depending on the outcome and on the degree of misclassification, nearly all stable patients were correctly classified.
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http://dx.doi.org/10.1007/s11481-013-9504-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874146PMC
December 2013

Response to Stacey and Moller's letter to the editor.

J Pain 2013 Oct;14(10):1252-3

VA Northern California Health Care System, Department of Physical Medicine and Rehabilitation, University of California Davis Medical Center, Sacramento, California. Electronic address:

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http://dx.doi.org/10.1016/j.jpain.2013.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161205PMC
October 2013

Dual-mixed HIV-1 coreceptor tropism and HIV-associated neurocognitive deficits.

J Neurovirol 2013 Oct;19(5):488-94

HIV coreceptor usage of CXCR4 (X4) is associated with decreased CD4+ T-cell counts and accelerated disease progression, but the role of X4 tropism in HIV-associated neurocognitive disorders (HAND) has not previously been described. This longitudinal study evaluated data on 197 visits from 72 recently HIV-infected persons who had undergone up to four sequential neurocognitive assessments over a median of 160 days (IQR, 138–192). Phenotypic tropism testing (Trofile ES, Monogram, Biosciences) was performed on stored blood samples. Multivariable mixed model repeated measures regression was used to determine the association between HAND and dual-mixed (DM) viral tropism, estimated duration of infection (EDI), HIV RNA, CD4 count, and problematic methamphetamine use. Six subjects (8.3 %) had DM at their first neurocognitive assessment and four converted to DM in subsequent sampling (for total of 10 DM) at a median EDI of 10.1 months (IQR, 7.2–12.2). There were 44 (61.1 %) subjects who demonstrated HAND on at least one study visit. HAND was associated with DM tropism (odds ratio, 4.4; 95 % CI, 0.9–20.5) and shorter EDI (odds ratio 1.1 per month earlier; 95 % CI, 1.0–1.2). This study found that recency of HIV-1 infection and the development of DM tropism may be associated with HAND in the relatively early stage of infection. Together, these data suggest that viral interaction with cellular receptors may play an important role in the early manifestation of HAND.
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http://dx.doi.org/10.1007/s13365-013-0203-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921071PMC
October 2013

Low-dose vaporized cannabis significantly improves neuropathic pain.

J Pain 2013 Feb 11;14(2):136-48. Epub 2012 Dec 11.

VA Northern California Health Care System, and Department of Physical Medicine and Rehabilitation, University of California, Davis Medical Center, Sacramento, California 95817, USA.

Unlabelled: We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain.

Perspective: The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning.
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http://dx.doi.org/10.1016/j.jpain.2012.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566631PMC
February 2013

Relationships among neurocognitive status, medication adherence measured by pharmacy refill records, and virologic suppression in HIV-infected persons.

J Acquir Immune Defic Syndr 2013 Mar;62(3):282-92

Department of Medicine, Division of Infectious Diseases, Johns Hopkins University, Baltimore, MD, USA.

Background: Optimal antiretroviral therapy (ART) effectiveness depends on medication adherence, which is a complex behavior with many contributing factors, including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence.

Methods: A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington. Pharmacy refill records were the primary method to measure ART adherence, indexed to a "sentinel" drug with the highest central nervous system penetration-effectiveness score. Standardized neuromedical, neuropsychological, psychiatric, and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and relationships between adherence and changes in plasma and cerebrospinal fluid HIV RNA concentrations between visits.

Results: Among 80 (33 at JHU and 47 at University of Washington) participants, the mean adherence score was 86.4%, with no difference between sites. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV infected for a longer period of time. Worse performance in working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits.

Conclusions: Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support.
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http://dx.doi.org/10.1097/QAI.0b013e31827ed678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906725PMC
March 2013

Sustained attention deficits among HIV-positive individuals with comorbid bipolar disorder.

J Neuropsychiatry Clin Neurosci 2012 ;24(1):61-70

San Diego State University/University of California, San Diego Joint Doctoral Program in Clinical Psychology, San Diego, CA, USA.

Difficulties with sustained attention have been found among both persons with HIV infection (HIV+) and bipolar disorder (BD). The authors examined sustained attention among 39 HIV+ individuals with BD (HIV+/BD+) and 33 HIV-infected individuals without BD (HIV+/BD-), using the Conners' Continuous Performance Test-II (CPT-II). A Global Assessment of Functioning (GAF) score was also assigned to each participant as an overall indicator of daily functioning abilities. HIV+/BD+ participants had significantly worse performance on CPT-II omission errors, hit reaction time SE (Hit RT SE), variability of SE, and perseverations than HIV+/BD- participants. When examining CPT-II performance over the six study blocks, both HIV+/BD+ and HIV+/BD- participants evidenced worse performance on scores of commission errors and reaction times as the test progressed. The authors also examined the effect of current mood state (i.e., manic, depressive, euthymic) on CPT-II performance, but no significant differences were observed across the various mood states. HIV+/BD+ participants had significantly worse GAF scores than HIV+/BD- participants, which indicates poorer overall functioning in the dually-affected group; among HIV+/BD+ persons, significant negative correlations were found between GAF scores and CPT-II omission and commission errors, detectability, and perseverations, indicating a possible relationship between decrements in sustained attention and worse daily-functioning outcomes.
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http://dx.doi.org/10.1176/appi.neuropsych.11010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575087PMC
August 2012

Combined effects of aging and HIV infection on semantic verbal fluency: a view of the cortical hypothesis through the lens of clustering and switching.

J Clin Exp Neuropsychol 2012 31;34(5):476-88. Epub 2012 Jan 31.

Department of Psychiatry, University of California, San Diego, San Diego, CA 92103, USA.

The profile of HIV-associated neurocognitive disorders (HAND) has classically been characterized as "subcortical," but questions have arisen as to whether aging with HIV in the antiretroviral therapy era has subtly shifted the expression of HAND into a more "cortical" disorder (e.g., decay of semantic memory stores). We evaluated this hypothesis by examining semantic fluency and its component processes (i.e., clustering and switching) in 257 individuals across four groups stratified by age (<40 and ≥50 years) and HIV serostatus. Jonckheere-Terpstra tests revealed significant monotonic trends for the combined effects of HIV and aging on overall semantic (and letter) fluency and switching, but not cluster size, with greatest deficits evident in the older adults with HIV infection. Within the older HIV-infected cohort, poorer switching was uniquely associated with self-reported declines in instrumental activities of daily living and deficits in learning and executive functions, but not semantic memory. Results suggest that HIV infection and aging may confer adverse additive effects on the executive components of semantic fluency (i.e., switching), rather than a degradation of semantic memory stores (i.e., cluster size), which is a profile that is most consistent with combined frontostriatal neuropathological burden of these two conditions.
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http://dx.doi.org/10.1080/13803395.2011.651103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329578PMC
August 2012

Neurocognitive impact of substance use in HIV infection.

J Acquir Immune Defic Syndr 2011 Oct;58(2):154-62

Department of Pathology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.

Background: : To determine how serious a confound substance use (SU) might be in studies on HIV-associated neurocognitive disorder (HAND), we examined the relationship of SU history to neurocognitive impairment (NCI) in participants enrolled in the Central Nervous System HIV Antiretroviral Therapy Effects Research study.

Methods: : After excluding cases with behavioral evidence of acute intoxication and histories of factors that independently could account for NCI (eg, stroke), baseline demographic, medical, SU, and neurocognitive data were analyzed from 399 participants. Potential SU risk for NCI was determined by the following criteria: lifetime SU Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis, self-report of marked lifetime SU, or positive urine toxicology. Participants were divided into 3 groups as follows: no SU (n = 134), nonsyndromic SU (n = 131), syndromic SU (n = 134) and matched on literacy level, nadir CD4, and depressive symptoms.

Results: : Although approximately 50% of the participants were diagnosed with HAND, a multivariate analysis of covariance of neurocogntive summary scores, covarying for urine toxicology, revealed no significant effect of SU status. Correlational analyses indicated weak associations between lifetime heroin dosage and poor recall and working memory and between cannabis and cocaine use and better verbal fluency.

Conclusions: : These data indicate that HIV neurocognitive effects are seen at about the same frequency in those with and without historic substance abuse in cases that are equated on other factors that might contribute to NCI. Therefore, studies on neuroAIDS and its treatment need not exclude such cases. However, the effects of acute SU and current SU disorders on HAND require further study.
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http://dx.doi.org/10.1097/QAI.0b013e318229ba41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183737PMC
October 2011

Dopamine receptor D3 genetic polymorphism (rs6280TC) is associated with rates of cognitive impairment in methamphetamine-dependent men with HIV: preliminary findings.

J Neurovirol 2011 Jun 14;17(3):239-47. Epub 2011 Apr 14.

Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., MC 0603, La Jolla, CA 92093-0603, USA.

Macrophages are one of HIV-1's principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3's binding to DA, would be more likely to develop CI. Cochran-Armitage test for trends in proportions yielded significant (p < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates (p = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.
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http://dx.doi.org/10.1007/s13365-011-0028-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151555PMC
June 2011

Neurocognitive functioning in acute or early HIV infection.

J Neurovirol 2011 Feb 15;17(1):50-7. Epub 2010 Dec 15.

Department of Psychiatry, University of California, San Diego (UCSD), San Diego, CA, USA.

We examined neurocognitive functioning among persons with acute or early HIV infection (AEH) and hypothesized that the neurocognitive performance of AEH individuals would be intermediate between HIV seronegatives (HIV-) and those with chronic HIV infection. Comprehensive neurocognitive testing was accomplished with 39 AEH, 63 chronically HIV infected, and 38 HIV- participants. All AEH participants were HIV infected for less than 1 year. Average domain deficit scores were calculated in seven neurocognitive domains. HIV-, AEH, and chronically HIV infected groups were ranked from best (rank of 1) to worst (rank of 3) in each domain. All participants received detailed substance use, neuromedical, and psychiatric evaluations and HIV infected persons provided information on antiretroviral treatment and completed laboratory evaluations including plasma and CSF viral loads. A nonparametric test of ordered alternatives (Page test), and the appropriate nonparametric follow-up test, was used to evaluate level of neuropsychological (NP) functioning across and between groups. The median duration of infection for the AEH group was 16 weeks [interquartile range, IQR: 10.3-40.7] as compared to 4.9 years [2.8-11.1] in the chronic HIV group. A Page test using ranks of average scores in the seven neurocognitive domains showed a significant monotonic trend with the best neurocognitive functioning in the HIV- group (mean rank = 1.43), intermediate neurocognitive functioning in the AEH group (mean rank = 1.71), and the worst in the chronically HIV infected (mean rank = 2.86; L statistic = 94, p < 0.01); however, post-hoc testing comparing neurocognitive impairment of each group against each of the other groups showed that the chronically infected group was significantly different from both the HIV- and AEH groups on neurocognitive performance; the AEH group was statistically indistinguishable from the HIV- group. Regression models among HIV infected participants were unable to identify significant predictors of neurocognitive performance. Neurocognitive functioning was worst among persons with chronic HIV infection. Although a significant monotonic trend existed and patterns of the data suggest the AEH individuals may fall intermediate to HIV- and chronic participants, we were not able to statistically confirm this hypothesis.
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http://dx.doi.org/10.1007/s13365-010-0009-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032208PMC
February 2011

Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy.

AIDS 2011 Jan;25(2):F1-6

Department of Neurosciences, USA bDepartment of Medicine, University of California, San Diego, California 92103-8231, USA.

Objective: in HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated.

Design: prospective, comparative, single-center, cross-sectional cohort study.

Methods: clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression.

Results: of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (≥ 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ≤ 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4-5.5).

Conclusions: elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.
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http://dx.doi.org/10.1097/QAD.0b013e328341dd68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729045PMC
January 2011

Evaluating the use and timing of opioids for the treatment of migraine headaches in the emergency department.

J Emerg Med 2009 May 14;36(4):333-7. Epub 2008 Feb 14.

Department of Otolaryngology-Head and Neck Surgery, Kaiser Permanente Oakland, Oakland, California, USA.

The objective of this study was to evaluate the throughput times of patients administered opioids for the treatment of migraine headaches in the frequent emergency department (ED) visitor. A retrospective review of ED patient records was conducted. Repeat patients were significantly more likely to receive opioids as a treatment, receive multiple doses of opioids, and receive opioids as the initial pharmacological treatment compared to non-repeaters. Patients administered opioids, regardless of repeater status, had significantly longer ED stays; 142 min (95% confidence interval [CI] 124-160) vs. 111 min (95% CI 93-129), respectively, p = 0.015. Patients given multiple doses of opioids had significantly longer ED stays than patients given a single dose of an opioid; 191 min (95% CI 156-225) vs. 125 min (95% CI 101-149), respectively, p = 0.003. Delayed administration of opioids did not result in longer ED stays in those patients eventually treated with opioids. Administration of opioids for migraine headache may result in longer ED stays when compared with non-opioid migraine treatments. Judicious use of opioids as a treatment for migraine headaches is recommended.
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http://dx.doi.org/10.1016/j.jemermed.2007.07.068DOI Listing
May 2009

Two-year prospective study of major depressive disorder in HIV-infected men.

J Affect Disord 2008 Jun 28;108(3):225-34. Epub 2007 Nov 28.

Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, California 92093, USA.

Objective: The risks and factors contributing to major depressive episodes in HIV infection remain unclear. This 2-year prospective study compared cumulative rates and predictors of a major depressive episode in HIV-infected (HIV+) men (N=297) and uninfected (HIV-) risk-group controls (N=90).

Methods: By design participants at entry were without current major depression, substance dependence or major anxiety disorder. Standardized neuromedical, neuropsychological, neuroimaging, life events, and psychiatric assessments (Structured Clinical Interview for DSM III-R) were conducted semi-annually for those with AIDS, and annually for all others.

Results: Lifetime prevalence of major depression or other psychiatric disorder did not differ at baseline between HIV+ men and controls. On a two-year follow-up those with symptomatic HIV disease were significantly more likely to experience a major depressive episode than were asymptomatic HIV+ individuals and HIV-controls (p<0.05). Episodes were as likely to be first onset as recurrent depression. After baseline disease stage and medical variables associated with HIV infection were controlled, a lifetime history of major depression, or of lifetime psychiatric comorbidity (two or more psychiatric disorders), predicted subsequent major depressive episode (p<0.05). Neither HIV disease progression during follow-up, nor the baseline presence of neurocognitive impairment, clinical brain imaging abnormality, or marked life adversity predicted a later major depressive episode.

Limitations: Research cohort of men examined before era of widespread use of advanced anti-HIV therapies.

Conclusions: Symptomatic HIV disease, but not HIV infection itself, increases intermediate-term risk of major depression. Prior psychiatric history most strongly predicted future vulnerability.
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http://dx.doi.org/10.1016/j.jad.2007.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2494949PMC
June 2008

Pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion.

Br J Clin Pharmacol 2007 Jan;63(1):36-40

Department of Paediatrics and Family, University of California at San Diego, La Jolla, California, USA.

Aims: Although cysteamine was first used in the treatment of cystinosis in 1976 and approved by the FDA as cysteamine bitartrate (Cystagon) in 1994, surprisingly little pharmacological data are available for this compound. Cysteamine and its related drugs are currently being evaluated for the treatment of Huntington's and Parkinson's disease. The aim of te study was to understand the pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion.

Method: Cysteamine bitartrate was delivered through a naso-enteric catheter into the stomach (n = 8), small intestine (n = 8) and caecum (n = 4) of normal subjects. Plasma cysteamine concentrations were determined using LC-MS/MS.

Results: The rate and extent of drug absorption were assessed by comparing AUC(0, infinity), C(max) and t(max), among the gastrointestinal infusion sites. Total cysteamine exposure, expressed as area under the curve (AUC(0, infinity)) was greatest when the drug was infused into the small intestine (4331.3 +/- 1907.6 min x microM) followed by stomach (3901.9 +/- 1591.9 min x microM) and caecum (3141.4 +/- 1627.6 min x microM). Cysteamine infusion into the small intestine resulted in the most rapid rise to maximal plasma concentrations (t(max) = 21 +/- 0.56 min); t(max) was delayed to 50 +/- 26 min and 64 +/- 26 min after gastric and caecal infusion, respectively. The maximum cysteamine plasma concentration (C(max)) was reached after infusion of the drug into the small intestine (51 +/- 21 microM), which was higher than plasma C(max) concentrations after gastric (39 +/- 16 microM) and caecal infusion (23 +/- 15 microM).

Conclusions: The pharmacokinetic data generated help extend our understanding of cysteamine.
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http://dx.doi.org/10.1111/j.1365-2125.2006.02734.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2000721PMC
January 2007

Incident major depression does not affect neuropsychological functioning in HIV-infected men.

J Int Neuropsychol Soc 2007 Jan;13(1):1-11

Department of Psychiatry, University of California at San Diego, San Diego, California, USA.

The diagnosis of lifetime major depressive disorders (MDDs) and of current major depressive episodes (MDEs) are relatively common in HIV-infected individuals, and often are assumed to influence neuropsychological (NP) performance. Although cross-sectional studies of HIV-infected individuals generally have found no systematic link between current MDE or depressive symptoms and NP performance, longitudinal studies are needed to clarify whether incident MDE may impact NP functioning in at least some cases. Two hundred twenty-seven human immunodeficiency virus (HIV)-infected adult men, who did not meet criteria for a current MDE at baseline, participated in a longitudinal NP study for an average of two years. Participants received repeated NP assessments, as well as structured psychiatric interviews to ascertain presence or absence of both lifetime MDD and current MDE. Ninety-eight participants had a lifetime history of MDD, and 23 participants met criteria for incident MDE at one of their follow-up evaluations. Groups with and without lifetime MDD and/or incident MDE had comparable demographics, HIV disease status and treatment histories at baseline, and numbers of intervening assessments between baseline and the final follow-up. Lifetime MDD was associated with greater complaints of cognitive difficulties in everyday life, and such complaints were increased at the times of incident MDE. However, detailed group comparisons revealed no NP performance differences in association with either lifetime or incident major depression. Finally, NP data from consistently nondepressed participants were used to develop "norms for change" and these findings failed to show any increased rates of NP worsening among individuals with incident MDE. Our results suggest that neurocognitive impairment and major depression should be considered as two independent processes.
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http://dx.doi.org/10.1017/S1355617707070026DOI Listing
January 2007