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Director's Report to the National Advisory Council on Drug Abuse - February, 2010



Research Findings - Brain and Behavioral Development Research

Altered White Matter Microstructure in Adolescent Substance Users

Chronic marijuana use during adolescence is frequently comorbid with heavy alcohol consumption and associated with CNS alterations, yet the influence of early cannabis and alcohol use on microstructural white matter integrity is unclear. Building on evidence that cannabinoid receptors are present in myelin precursors and affect glial cell processing, and that excessive ethanol exposure is associated with persistently impaired myelination, Dr. Sunita Bava and her colleagues used diffusion tensor imaging (DTI) to characterize white matter integrity in heavy substance using and non-using adolescents. The investigators evaluated 36 marijuana and alcohol-using (MJ+ALC) adolescents (ages 16-19) and 36 demographically similar non-using controls with DTI. The diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics. MJ+ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ+ALC users. Findings suggest that fronto-parietal circuitry may be particularly impacted in adolescent users of the most prevalent intoxicants: marijuana and alcohol. Disruptions to white matter in this young group could indicate aberrant axonal and myelin maturation with resultant compromise of fiber integrity. Findings of increased anisotropic diffusion in alternate brain regions suggest possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing. Bava S, Frank LR, McQueeny T, et al. Altered white matter microstructure in adolescent substance users. Psychiatry Res. 2009 Sept 30;173(3):228-237.

Prefrontal Cortex Morphometry in Abstinent Adolescent Marijuana Users: Subtle Gender Effects

Adult human studies suggest frontal dysfunction associated with chronic marijuana (MJ) use, but due to continued neuromaturation, adult studies may not generalize to adolescents. Dr. Krista Medina and her colleagues aimed to replicate this finding in adolescents by examining prefrontal cortex (PFC) morphometry in chronic MJ-using adolescents following 1 month of monitored abstinence. Data were collected from MJ users (n = 16) and controls (n = 16) aged 16-18. Extensive exclusionary criteria included co-morbid psychiatric and neurologic disorders. Substance use and anatomical measures were collected after 28 days of monitored abstinence. PFC volumes were ascertained from manual tracing by reliable raters on high-resolution magnetic resonance images. After controlling for lifetime alcohol use, gender and intracranial volume, MJ users did not differ from controls in PFC volume. However, marginal group-by-gender interactions were observed (P < 0.09): Female MJ users demonstrated comparatively larger PFC volumes while male MJ users had smaller volumes compared with same-gender controls. Further, group status and total PFC volume interacted in predicting executive functioning (P < 0.05). Among MJ users, smaller PFC total volume was associated with better executive functioning while the opposite pattern was seen among the controls. These preliminary results indicate that gender may moderate the relationship between MJ use and PFC morphometry. Given the relationship between larger PFC total volumes and poorer executive functioning among MJ users, female MJ users may be at increased risk for neurocognitive consequences. Future research will measure PFC gray and white matter separately and follow boys and girls over adolescence to examine the influence of MJ use on neurodevelopment. Medina KL, McQueeny T, Nagel BJ, Hanson KL, Yang TT, Tapert SF. Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects. Addiction Biol. 2009 Sept;14(4):457-468.

Adolescent Engagement in Dangerous Behaviors is Associated with Increased White Matter Maturity of Frontal Cortex

Myelination of white matter in the brain continues throughout adolescence and early adulthood. This cortical immaturity has been suggested as a potential cause of dangerous and impulsive behaviors in adolescence. Dr. Gregory Berns and his colleagues examined this hypothesis in a group of healthy adolescents, age 12-18 (N = 91), who underwent diffusion tensor imaging (DTI) to delineate cortical white matter tracts. As a measure of real-world risk taking, participants completed the Adolescent Risk Questionnaire (ARQ) which measures engagement in dangerous activities. After adjusting for age-related changes in both DTI and ARQ, engagement in dangerous behaviors was found to be positively correlated with fractional anisotropy and negatively correlated with transverse diffusivity in frontal white matter tracts, indicative of increased myelination and/or density of fibers (ages 14-18, N = 60). The direction of correlation suggests that rather than having immature cortices, adolescents who engage in dangerous activities have frontal white matter tracts that are more adult in form than their more conservative peers. Berns GS, Moore S, Capra CM. Adolescent engagement in dangerous behaviors is associated with increased white matter maturity of frontal cortex. PloS One 2009 August 26;4(8):e6773.

Infant Neurobehavioral Dysregulation: Behavior Problems in Children with Prenatal Substance Exposure

In this study Dr. Barry Lester and his colleagues from the Maternal Lifestyles Study tested a developmental model of neurobehavioral dysregulation relating prenatal substance exposure to behavior problems at age 7. The sample included 360 cocaine-exposed and 480 unexposed children from lower to lower middle class families of which 78% were black. Structural equation modeling was used to test models whereby prenatal exposure to cocaine and other substances would result in neurobehavioral dysregulation in infancy, which would predict externalizing and internalizing behavior problems in early childhood. Structural equation models were developed for individual and combined parent and teacher report for externalizing, internalizing, and total problem scores on the Child Behavior Checklist. The paths in the models indicate that there are direct effects of prenatal substance exposure on 7-year behavior problems as well as indirect effects, including neurobehavioral dysregulation. Prenatal substance exposure affects behavior problems at age 7 through two mechanisms. The direct pathway is consistent with a teratogenic effect. Indirect pathways suggest cascading effects whereby prenatal substance exposure results in neurobehavioral dysregulation manifesting as deviations in later behavioral expression. Developmental models provide an understanding of pathways that describe how prenatal substance exposure affects child outcome and have significant implications for early identification and prevention. Lester BM, Bagner DM, Liu J, et al. Infant neurobehavioral dysregulation: Behavior problems in children with prenatal substance exposure. Pediatrics. 2009 Nov;124(5):1355-1362.

Neonatal Neurobehavior Predicts Medical and Behavioral Outcomes

This study examined the NICU Network Neurobehavioral Scale (NNNS) as a predictor of negative medical and behavioral findings at 1 month to 4.5 years of age. The sample included 1248 mother-infant dyads (42% born at <37 weeks' gestational age [GA]) who were participating in the Maternal Lifestyles Study (MLS), a longitudinal study of the effects of prenatal substance exposure on child development. Mothers were recruited at four urban university-based centers and were mostly black and on public assistance. At 1 month of age, infants were tested with the NNNS. Latent profile analysis was conducted on NNNS summary scales to identify discrete behavioral profiles. The validity of the NNNS was examined by using logistic regression to predict prenatal drug exposure and medical and developmental outcomes through 4.5 years of age including adjustment for GA and socioeconomic status. Five discrete behavioral profiles were reliably identified; the most extreme negative profile was found in 5.8% of the infants. The profiles showed statistically significant associations with prenatal drug exposure; GA and birth weight; head ultrasound; neurologic and brain disease findings; and abnormal scores on measures of behavior problems, school readiness, and IQ through 4.5 years of age. The NNNS may be useful to identify infant behavioral needs to be targeted in well-infant pediatric care, as well as for referrals to community-based early intervention services. Liu J, Bann C, Lester B, et al. Neonatal neurobehavior predicts medical and behavioral outcome. Pediatrics. 2009 Dec 7. [Epub ahead of print].

Neurobehavioral Assessment Predicts Motor Outcome in Preterm Infants

This study examined whether the Neonatal Intensive Care Unit Network Neurobehavior Scales (NNNS) at 44 weeks predict motor outcome at 2 years in preterm infants from the Maternal Lifestyles Study (MLS). Data were collected on all preterm infants (<36 weeks) in the MLS who underwent an NNNS at 44 weeks (n = 395) and neurologic examination at 12 to 36 months or Bayley Psychomotor Development Index (PDI) at 24 months (n = 270). Logistic regression analyzed NNNS summary scores associated with cerebral palsy (CP) or PDI <70, while controlling for birth weight

Prenatal Cocaine Exposure and Physiological Regulation at 13 Months of Age

This study examined the association between prenatal cocaine exposure (PCE) and autonomic regulation at 13 months of age. Measures of respiratory sinus arrhythmia (RSA) were obtained from 156 (79 exposed, and 77 nonexposed) infants during baseline and during tasks designed to elicit positive (PA) and negative affect (NA). There was a significant suppression of RSA during the negative affect task for nonexposed infants but not for exposed infants. Maternal symptoms of depression or anxiety (MDA) did not mediate this association. However, gender and MDA did moderate this association such that exposed boys and exposed infants whose mothers had higher levels of MDA had an increase in RSA during a task designed to elicit NA rather than the typical pattern of RSA suppression. These results suggest that there are several possible pathways from PCE to physiological dysregulation during late infancy. Schuetze P, Eiden RD, Danielewicz S. The association between prenatal cocaine exposure and physiological regulation at 13 months of age. J Child Psychol Psychiatry. 2009 Nov;50(11):1401-1409.

Maternal Report of Sleep Problems in Children with Prenatal Polydrug Exposure

Sleep data were collected by maternal report in a prospective longitudinal follow up of cocaine-exposed and unexposed children. There were 139 participants: 23 with no prenatal drug exposure, 55 exposed to cocaine alone or in combination with other drugs, and 61 exposed to drugs other than cocaine. Characteristics differed between exposure groups including birth size, caretaker changes, maternal socioeconomic status, and postnatal drug use. Compared to those with no drug exposure, children with prenatal drug exposure other than cocaine experienced greater sleep problems according to mother's report. Prenatal nicotine exposure was a unique predictor of sleep problems. Early sleep problems predicted later sleep problems. Together, these preliminary findings suggest possible neurotoxic sleep effects that persist over time. Larger studies, however, need to be conducted that better control for potential postnatal confounding factors. Stone KC, High PC, Miller-Loncar CL, Lagasse LL, Lester BM. Longitudinal study of maternal report of sleep problems in children with prenatal exposure to cocaine and other drugs. Behav Sleep Med. 2009;7(4):196-207.

Reward-Related Brain Function and Sleep in Pre/Early Pubertal and Mid/Late Pubertal Adolescents

The onset of adolescence is a time of dramatic changes, including changes in sleep, and a time of new health concerns related to increases in risk-taking, sensation seeking, depression, substance use, and accidents. As part of a larger study examining puberty-specific changes in adolescents' reward-related brain function, Dr. Stephanie Holm and her colleagues at the University of Pittsburgh examined the relationship between functional neuroimaging measures of reward and measures of sleep. A total of 58 healthy participants 11-13 years of age completed a functional magnetic resonance imaging scan using a guessing task with monetary rewards and 4 days of at-home actigraphy and self-reported sleep ratings. Sleep variables included actigraph measures of mean weekend minutes asleep, sleep onset time, and sleep offset time, as well as self-reported sleep quality. During reward anticipation, less activation in the caudate nuclues was associated with fewer minutes asleep, later sleep onset time, and lower sleep quality. During reward outcome, less caudate activation was associated with later sleep onset time, earlier sleep offset time, and lower sleep quality. It has been hypothesized that adolescents' low reactivity in reward-related brain areas could lead to compensatory increases in reward-driven behavior. This study's findings suggest that sleep could contribute to such behavior. Because decreased sleep has been associated with risky behavior and negative mood, these findings raise concerns about a negative spiral whereby the effects of puberty and sleep deprivation may have synergistic effects on reward processing, contributing to adolescent behavioral and emotional health problems. Holm SM, Forbes EE, Ryan ND, Phillips ML, Tarr JA, Dahl RE. Reward-related brain function and sleep in pre/early pubertal and mid/late pubertal adolescents. J Adolesc Health 2009 Oct;45(4):319-320.

Smoking in Pregnancy and Disruptive Behaviour in 3-year-old Boys and Girls

Maternal smoking during pregnancy has been consistently associated with disruptive behaviour in male offspring; however, results for girls are inconsistent and little is known about emergent patterns in young children. Additionally, it is unclear whether maternal smoking is independently associated in offspring with hyperactivity-inattention or only when it co-occurs with conduct problems. Further, few studies have controlled for a broad range of maternal psychosocial problems. Associations between self-reported smoking in pregnancy and maternal reports of externalizing behaviour were analyzed in more than 13,000 3-year-old boys and girls in the UK Millennium Cohort Study. Conduct and hyperactivity-inattention problems were assessed using the Strength and Difficulties Questionnaire. Boys whose mothers persistently smoked throughout pregnancy were at significant risk of conduct and hyperactivity-inattention problems compared with sons of non-smokers: the effect was stronger for heavy smokers. After excluding children with co-occurring problems, conduct-only problems remained a significant risk for sons of heavy smokers; and hyperactivity-inattention only for sons of light or heavy smokers. Daughters of light or heavy smokers were at significant risk of conduct-only problems. Relative to non-smokers, daughters of pregnancy quitters had significantly reduced odds of having conduct or co-occurring problems, although only 79 and 20 girls met these criteria, respectively. Associations between maternal smoking during pregnancy and disruptive behaviour in 3-year-old children vary by sex, smoking status and whether or not conduct or hyperactivity problems occur together or separately. Hutchinson J, Pickett E, Green J, Wakschlag LS. Smoking in pregnancy and disruptive behaviour in 3-year-old boys and girls: An analysis of the UK Millennium Cohort Study. J Epidemiol Community Health 2010 Jan;64(1):82-88.

Prenatal Alcohol Exposure and Interhemispheric Transfer of Tactile Information

Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults. In Study 1, the FLT was administered to 40 heavily exposed and 23 nonexposed children from the Cape Coloured community of Cape Town, South Africa, who were evaluated for fetal alcohol syndrome (FAS) dysmorphology and growth. Anatomical images of the CC were obtained using structural MRI on a subset of these children. In Study 2, the FLT was administered to a cohort of 85 moderate-to-heavily exposed young adults participating in a 19-year follow-up assessment of the Detroit Prenatal Alcohol Exposure cohort, whose alcohol exposure had been ascertained prospectively during gestation. In Study 1, children with FAS showed more transfer-related errors than controls after adjustment for confounding, and increased transfer-related errors were associated with volume reductions in the isthmus and splenium of the CC. In Study 2, transfer-related errors were associated with quantity of alcohol consumed per occasion during pregnancy. More errors were made if the mother reported binge drinking (> or =5 standard drinks) during pregnancy than if she drank regularly (M > or = 1 drink/day) without binge drinking. These findings confirm a previous report of impaired interhemispheric transfer of tactile information in children heavily exposed to alcohol in utero and extend these findings to show that these deficits are also seen in more moderately exposed individuals, particularly those exposed to binge-like pregnancy drinking. Dodge NC, Jacobson JL, Molteno CD, et al. Prenatal alcohol exposure and interhemispheric transfer of tactile information: Detroit and Cape Town findings. Alcohol Clin Exp Res. 2009 Sep;33(9):1628-1637.

Identification of Prenatal Amphetamines Exposure by Maternal Interview and Meconium Toxicology

The Infant Development Environment and Lifestyle study is investigating the effects of prenatal methamphetamine (MAMP) exposure on infant and child development. Potential concurrent exposure to cannabis and tobacco also are evaluated. Maternal self-reported drug use and/or meconium toxicology results defined drug exposure status. It is unclear how the frequency, duration, and magnitude of maternal MAMP exposure affect qualitative and quantitative meconium results. Interviews regarding maternal drug use were collected shortly after birth; meconium specimens were screened for amphetamines, cannabis, and cotinine by immunoassay and confirmed by gas chromatography mass spectrometry. The majority of MAMP- and cannabis-exposed infants were identified by maternal interview alone. Meconium tests were more likely to be positive if the mother reported MAMP and cannabis use, particularly in the third trimester. Less than half of immunoassay-positive amphetamines (31.0%) and cannabis (17.9%) meconium results were confirmed by gas chromatography mass spectrometry. Tobacco exposure was equally detected by immunoassay cotinine screening and maternal report. Meconium concentrations did not correlate with maternal self-report status or trimester of use or frequency or route of MAMP use. Maternal self-report was more sensitive than meconium testing for identifying MAMP and cannabis-exposed neonates; however, the timing of drug exposure may influence meconium toxicology results. Most women stopped MAMP and cannabis use before the third trimester. In the first trimester, meconium has not yet formed, and based on our recent results for opiates and cocaine, drug use in the second trimester appears to be poorly reflected in meconium. Low confirmation rates in meconium reinforce the need for confirmatory testing following positive screening results and additional research to identify alternative biomarkers. Gray TR, LaGasse LL, Smith LM, et al. Identification of prenatal amphetamines exposure by maternal interview and meconium toxicology in the Infant Development, Environment and Lifestyle (IDEAL) study. Ther Drug Monit. 2009 Dec;31(6):769-775.

Amphetamine and Methamphetamine in Umbilical Cord

The use of meconium as a drug-screening matrix for newborns has been the gold standard of care for the past two decades. A recent study using matched pairs of meconium and umbilical cord demonstrated a high degree of agreement. The use of liquid chromatography-tandem mass spectrometry as a means to confirm amphetamines presumptive positive umbilical cord specimens for amphetamine and methamphetamine is described here for the first time. The limit of detection for both compounds was 0.2 ng/g. The limit of quantitation for both compounds was 0.6 ng/g. The assay was linear for both compounds up to 100 ng/g. Jones J, Rios R, Jones M, Lewis D, Plate C. Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Nov 1;877(29):3701-3706.

Precuneus Shares Intrinsic Functional Architecture in Humans and Monkeys

Evidence from macaque monkey tracing studies suggests connectivity-based subdivisions within the precuneus, offering predictions for similar subdivisions in the human. This study describes functional connectivity analyses of this region using resting-state functional MRI data collected from both humans and macaque monkeys. Three distinct patterns of functional connectivity were demonstrated within the precuneus of both species, with each subdivision suggesting a discrete functional role: (i) the anterior precuneus, functionally connected with the superior parietal cortex, paracentral lobule, and motor cortex, suggesting a sensorimotor region; (ii) the central precuneus, functionally connected to the dorsolateral prefrontal, dorsomedial prefrontal, and multimodal lateral inferior parietal cortex, suggesting a cognitive/associative region; and (iii) the posterior precuneus, displaying functional connectivity with adjacent visual cortical regions. These functional connectivity patterns were differentiated from the more ventral networks associated with the posterior cingulate, which connected with limbic structures such as the medial temporal cortex, dorsal and ventromedial prefrontal regions, posterior lateral inferior parietal regions, and the lateral temporal cortex. These findings are consistent with predictions from anatomical tracer studies in the monkey, and provide support that resting-state functional connectivity (RSFC) may in part reflect underlying anatomy. These subdivisions within the precuneus suggest that neuroimaging studies will benefit from treating this region as anatomically (and thus functionally) heterogeneous. Furthermore, the consistency between functional connectivity networks in monkeys and humans provides support for RSFC as a viable tool for addressing cross-species comparisons of functional neuroanatomy. Margulies DS, Vincent JL, Kelly C, et al. Precuneus shares intrinsic functional architecture in humans and monkeys. Proc Natl Acad Sci USA. 2009 Nov 24;106(47):20069-20074.

Exclusion and Micro-Rejection: ERP Response Predicts Mitigated Distress

Dr. Mayes and her colleagues studied time-based neural activity with event-related potentials (ERPs) in young adults during a computer-simulated ball-toss game. Experiencing fair play initially, participants were ultimately excluded by other players. Dense-array ERPs showed time-dependent associations between slow-wave activity (580-900 ms) in left prefrontal/medial frontal cortical regions for exclusion events and self-reported distress. More subtle 'micro-rejections' during fair play showed a similar distress to ERP association (420-580 ms). In both cases, greater positive amplitude neural activity was associated with less post-exclusion distress. These findings suggest that rapidly occurring neural responses to social exclusion events are linked to individual differences in ostracism-related distress. Relations emerged even during fair play, providing a window into the neural basis of more subtle social-cognitive perceptual processes. Crowley MJ, Wu J, McCarty ER, David DH, Bailey CA, Mayes LC. Exclusion and micro-rejection: Event-related potential response predicts mitigated distress. Neuroreport. 2009 Nov 25;20(17):1518-1522.

Item Response Theory Analysis of Lifetime Cannabis-Use Disorder Symptom Severity in an American Indian Community

Dr. David Gilder and his colleagues used Item Response Theory to assess Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R), lifetime cannabis-use disorder (CUD) symptom severity and its relationship to first cannabis use before age 15 years, male gender, and childhood conduct disorder in an American Indian community sample. The Semi-Structured Assessment for the Genetics of Alcoholism was used to determine demographic information, age at first use, and DSM-III-R childhood conduct disorder and lifetime CUD symptoms in a community sample of 349 American Indian participants who had used cannabis at least 21 times in a single year. Two-parameter Item Response Theory models generated marginal maximum likelihood estimates for discrimination (a) and threshold (b) parameters for nine DSM-III-R CUD symptoms along an underlying latent CUD severity continuum. Differential Item Functioning (DIF) analysis was used to assess for differences in symptom severity in groups defined by presence versus absence of age at first use before 15 years, male gender, and childhood conduct disorder. CUD symptoms of "use in larger amounts or over longer periods of time," "activities given up," and "role failure" were the most severe. All CUD symptoms fell on the moderate portion of the severity continuum. "Time spent" was more severe in individuals who first used cannabis after age 15 years, "hazardous use" was more severe in females, and "use in larger amounts or over longer periods of time" was more severe in individuals with co-morbid childhood conduct disorder. Specific risk factors for the development of lifetime CUD are associated with increased severity of several CUD symptoms in this high-risk group. Gilder DA, Lau P, Ehlers, CL. Item response theory analysis of lifetime cannabis-use disorder symptom severity in an American Indian community. J Stud Alcohol Drugs. 2009 Nov;70(6):839-849.

Predictors of School Dropout among Adolescents in Puerto Rico

This study aims to understand the circumstances associated with school dropout in a cohort of Puerto Rican adolescents. Information related to school dropout was obtained from adolescents and their parents employing a self-administered and a face-to-face interview protocol. Prediction of school dropout was assessed through adolescent characteristics, family background, school experiences and behaviors. During the second follow-up, two years after the baseline assessment, approximately 6.2% of the adolescents reported dropping out from school. Logistic regression analysis indicates that older adolescents, whose mothers used drugs during pregnancy, who reported high rates of absenteeism, high school grade retention, and attended school where teachers were attacked or wounded by students were more likely to drop out of school. These findings emphasize the need to further understand the effects of different elements of adolescents' environment such as family and school. It has been posited that dropping out of school is a process whose characteristics can be detected long before it occurs. The fact that students who drop out are more likely to report skipping classes and grade retention can be relevant elements in prevention and early intervention for teachers and other school personnel. Calder—n JM, Robles RR, Reyes JC, Matos TD, Negr—n JL, Cruz MA. Predictors of school dropout among adolescents in Puerto Rico. P R Health Science J 2009 Dec;28(4):307-312.

Postpartum Antiretroviral Drug Resistance in HIV-1-Infected Women Receiving Pregnancy-Limited Antiretroviral Therapy

Pregnancy-limited antiretroviral therapy (PLAT) drastically reduces HIV-1 transmission to the newborn, but may select for antiretroviral drug resistance mutations in mothers. The Women and Infants Transmission Study (WITS) evaluated antiretroviral-naive, HIV-1-infected pregnant women who received PLAT between 1998 and 2005, and had 2-month or 6-month postpartum plasma samples available with HIV-1 RNA levels more than 500 copies/ml. Postpartum drug resistance mutation rates were assessed blindly using population sequencing and allele-specific PCR (ASPCR) of the M184V, K103N and D30N mutations. Factors associated with selection of drug resistance mutations were investigated. One hundred and forty-six women were included. All women received zidovudine and lamivudine during pregnancy; 76% also received nelfinavir and 8.2% nevirapine. Resistance data were available from 114 women (78%). Postpartum rates of single-class, dual-class, and triple-class resistance were, respectively, 43, 6.1 and 0% (63.2, 10.5 and 1.7% by ASPCR). In women receiving dual or triple PLAT, respectively, postpartum M184V/I rates were 65% (95% by ASPCR) and 28.7% (51.6% by ASPCR), respectively. Postpartum nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance rates among women receiving nevirapine were 25% for K103N (37.5% by ASPCR) and 12.5% for Y188C. Protease inhibitor resistance rates in women receiving nelfinavir were 1.1% for D30N (1.1% by ASPCR) and 1.1% for L90M. Dual versus triple PLAT and prolonged zidovudine exposure were associated with selection of M184V. Nevirapine use and length of zidovudine and lamivudine exposure were associated with selection of K103N. PLAT is associated with frequent selection of resistance to drugs with low-genetic barrier. Triple-drug PLAT decreases the odds for M184V selection. Routine postpartum genotypic resistance testing may be useful to guide future treatment decisions in mothers. Paredes R, Cheng I, Kuritzkes DR, Tuomala RE, Women and Infants Transmission Study (WITS) Group. Postpartum antiretroviral drug resistance in HIV-1-infected women receiving pregnancy-limited antiretroviral therapy. AIDS. 2010 Jan 2;24(1):45-53.

Antiretroviral Exposure and Lymphocyte mtDNA Content among Uninfected Infants of HIV-1-infected Women

Concern for potential adverse effects of antiretroviral (ARV) chemotherapy used to prevent mother-to-child HIV transmission has led the US Public Health Service to recommend long-term follow-up of ARV-exposed children. Nucleoside reverse transcriptase inhibitor ARV agents can inhibit DNA polymerase gamma, impairing mitochondrial DNA (mtDNA) synthesis and resulting in depletion or dysfunction. The WITS study measured the mtDNA content of stored peripheral blood mononuclear cells (PBMCs) of 411 healthy children who were born to HIV-uninfected women and 213 uninfected infants who were born to HIV-infected women with or without in utero and neonatal ARV exposure. Geometric mean PBMC mtDNA levels were lower at birth in infants who were born to HIV-infected women. Among HIV-exposed children, mtDNA levels were lowest in those who were not exposed to ARVs, higher in those with exposure to zidovudine alone, and higher still in those with combination nucleoside reverse transcriptase inhibitor exposure. A similar pattern was observed in the corresponding women. Levels of mtDNA increased during the first 5 years of life in all HIV-exposed children but achieved normal levels only in those with ARV exposure. Levels of mtDNA are lower than normal in HIV-exposed children. Contrary to expectation, PBMC mtDNA levels are significantly higher in ARV-exposed, HIV-uninfected infants and their infected mothers compared with ARV-unexposed infants and women. By 5 years, levels of PBMC mtDNA rise to normal concentrations in ARV-exposed children but remain depressed in ARV-unexposed children. Aldrovandi GM, Chu C, Shearer WT, et al. Antiretroviral exposure and lymphocyte mtDNA content among uninfected infants of HIV-1-infected women. Pediatrics. 2009 Dec;124(6):e1189-1197.

ART Treatment Interruption After Pregnancy: Effects on Disease Progression and Laboratory Findings

The purpose of this study was to assess clinical progression and inflammatory markers among women stopping or continuing antiretroviral therapy (ART) after pregnancy. ART-na•ve women with CD4+ lymphocyte counts >350 cells/uL initiating ART during pregnancy had clinical events and laboratory markers compared over one year postpartum between those stopping (n = 59) or continuing (n = 147) ART. Slopes in CD4 count and HIV RNA did not differ between groups overall and in subsets of ZDV or combination therapy. The hazard ratio (HR) of a new class B event was 2.09 (95% CI 0.79-5.58) among women stopping ART, 1.24 (0.31-4.95) in those stopping ZDV, and 2.93 (0.64-13.36) among those stopping combination therapy. Women stopping ART had increased immune activation. No significant differences were seen in C-reactive protein, lipids, leptin, or interleukin-6. While changes in CD4 and HIV RNA levels over one year were similar between women stopping or continuing ART postpartum, higher immune activation among women stopping therapy requires further study. Watts DH, Lu M, Thompson B, et al. Treatment interruption after pregnancy: Effects on disease progression and laboratory findings. Infect Dis Obstet Gynecol. 2009;2009:456717.

Mediators of HIV-Related Stigma and Risk Behavior in HIV Infected Young Women

Stigma in HIV positive persons has been associated with numerous negative sequelae, including decreased social support, depressive symptoms, and engagement in risk behaviors. Few studies examined the interrelationships of these factors to facilitate understanding of the mechanisms by which HIV stigma influences risk behavior. This study from the Adolescent Medicine Trials for HIV/AIDS Interventions (ATN) focuses on identifying pathways between HIV-related stigma and risk behavior in 147 young HIV positive women. Depression and social support were hypothesized to mediate between HIV-related stigma and risk behavior. Structural equation modeling was used to test these hypothesized pathways, results suggested that depression was a significant mediator between HIV-related stigma and risk behavior. Implications for interventions with young HIV positive women who report high levels of HIV-related stigma include a focus on depression as a method of reducing engagement in risk behavior and improving mental health and health behaviors in persons living with HIV. Clum G, Chung SE, Ellen JM: Adolescent Medicine Trials Network for HIV/AIDS Interventions. Mediators of HIV-related stigma and risk behavior in HIV infected young women. AIDS Care. 2009 Nov;21(11):1455-1462.

Child Abuse in HIV-Positive Young Women: Linkages to Risk

In this article researchers from the ATN explore the lives of young women living with HIV who experienced physical and/or sexual abuse in childhood. Using a modified version of the Life Story Interview, 40 women recruited from HIV clinics in three different states participated in a qualitative interview. Interviews covered abuse experiences, cognitive and emotional consequences of abuse, coping strategies, and sexual behavior and relationships. Overall, these young women had complex abuse histories, often experiencing more than one type of abuse in the context of other difficult life events. Avoidance and substance use were frequently utilized as coping strategies for abuse-related distress. Young women reported sexual and relationship concerns, including avoidance of sex, sexual dysfunction, sex as a trigger for abuse memories, and difficulty establishing intimacy and trust. Relationships between abuse-related reactions and sexual risk behavior, as well as recommendations for interventions, are discussed. Clum GA, Andrinopoulos , Muessig K, Ellen JM: Adolescent Medicine Trials Network for HIV/AIDS Interventions. Child abuse in young, HIV-positive women: Linkages to risk. Qual Health Res. 2009 Dec;19(12):1755-1768.

Predictors of Suboptimal Virologic Response to Highly Active Antiretroviral Therapy among HIV-Infected Adolescents

This study examined the prevalence and biopsychosocial predictors of suboptimal virologic response to highly active antiretroviral therapy (HAART) among human immunodeficiency virus-infected adolescents. The study was conducted at sixteen academic medical centers across 13 cities in the United States. One hundred fifty-four human immunodeficiency virus-infected adolescents who presented for at least 2 consecutive visits after initiation of HAART were included in the study. Viral load (plasma concentration of human immunodeficiency virus RNA) and CD4(+) lymphocyte count were assessed. Of the 154 adolescents enrolled in the study, 50 (32.5%) demonstrated early and sustained virologic suppression while receiving HAART. The remaining 104 adolescents (67.5%) had a poor virologic response. Adequate adherence (>50%) - reported by 70.8% of respondents - was associated with 60% reduced odds of suboptimal virologic suppression in a multivariable logistic regression model. Exposure to suboptimal antiretroviral therapy prior to HAART, on the other hand, was associated with more than 2-fold increased odds of suboptimal virologic response. Fully two-thirds of human immunodeficiency virus-infected adolescents in the current study demonstrated a suboptimal virologic response to HAART. Nonadherence and prior single or dual antiretroviral therapy were associated with subsequent poor virologic responses to HAART. These predictors of HAART failure echo findings in pediatric and adult populations. Given the unique developmental stage of adolescence, age-specific interventions are indicated to address high rates of nonadherence and therapeutic failure. Ding H, Wilson CM, Modjarrad K, McGwin G Jr, Tang J, Vermund SH. Predictors of suboptimal virologic response to highly active antiretroviral therapy among human immunodeficiency virus-infected adolescents: Analyses of the reaching for excellence in adolescent care and health (REACH) project. Arch Pediatr Adolesc Med. 2009 Dec;163(12):1100-1105.

Obesity and Dyslipidemia in Behaviorally HIV-infected Young Women

The goal of this study from the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) was to determine the nature and prevalence of abnormalities in lipids, glucose metabolism, and body composition in behaviorally human immunodeficiency virus (HIV)-infected young women and the relationship of these abnormalities to different classes of antiretroviral therapy regimens. This was a cross-sectional, multicenter study involving 173 behaviorally HIV-infected women aged 14-24 years and 61 HIV-seronegative control subjects. HIV-infected women were categorized as follows: antiretroviral therapy naive (n=85), receiving a regimen containing a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n=33), receiving a regimen containing a protease inhibitor (PI; n=36), or receiving a regimen not containing an NNRTI or a PI (n=19). Measurements included fasting lipid levels, glucose and insulin levels before and 2 hours after an oral glucose challenge, high-sensitivity C-reactive protein (hsCRP) levels, anthropometry, fat distribution (measured by dual energy X-ray absorptiometry), and antiretroviral therapy and medical histories. Race-adjusted results were compared across groups and within HIV-infected groups. The median age of participants was 20 years. Of HIV-infected subjects, 77% were African American, 35% smoked cigarettes, and 32% reported exercising regularly. More than 40% had a body mass index > or =25. Triglycerides; total, high-density lipoprotein (HDL), and non-HDL cholesterol; and hsCRP levels differed significantly among groups, with higher levels being most common among those receiving antiretroviral therapy. Indices of glucose metabolism did not differ among groups. In general, cholesterol levels, hsCRP levels, and indices of glucose metabolism worsened as body mass index increased. Obesity, dyslipidemia, and inflammation were prominent among HIV-infected adolescent women and, coupled with other risk factors, may accelerate the lifetime risk of cardiovascular disease and other adverse events. These results underscore the need for a multifaceted approach to addressing risk reduction in this population. Mulligan K, Harris DR, Monte D, et al. Adolescent Trials Network 021 Protocol Team. Obesity and dyslipidemia in behaviorally HIV-infected young women: Adolescent Trials Network study 021. Clin Infect Dis. 2010 Jan 1;50(1):106-114.

HLA-DRB1 Alleles Predict Differential Antibody Responses to Hepatitis B Vaccination in Youth

The purpose of this study by the Adolescent Medicine Trials for HIV/AIDS Interventions (ATN) was to confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination. Study participants included 255 HIV-1 seropositive and 80 HIV-1 seronegative youth. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype. Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders, 65 (40.6%) out of 160 medium responders, and 27 (27.8%) out of 97 high responders. Meanwhile, DRB1*08 was positively associated with the responder phenotype, mostly due to DRB1*0804. These immunogenetic relationships were all independent of non-genetic factors, including HIV-1 infection status and immunodeficiency. Alternative analyses confined to HIV(+) youth or Hispanic youth led to similar findings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of differential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to effective immune response to recombinant vaccines. Li Y, Ni R, Song W, et al. Clear and independent associations of several HLA-DRB1 alleles with differential antibody responses to hepatitis B vaccination in youth. Hum Genet. 2009 Nov;126(5):685-696.


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