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Director's Report to the National Advisory Council on Drug Abuse - September, 2009

Research Findings - Brain and Behavioral Development Research

fMRI and the Effects of Prenatal Methamphetamine Exposure on Verbal Memory

Efforts to understand specific effects of prenatal methamphetamine (MA) exposure on cognitive processing are hampered by high rates of concomitant alcohol use during pregnancy. Dr. Elizabeth Sowell and her colleagues at UCLA examined whether neurocognitive systems differed among children (ages 7-15) with differing prenatal teratogenic exposures when they engaged in a verbal paired associate learning task while undergoing functional magnetic resonance imaging. Groups did not differ in age, gender, or socioeconomic status. Participants' IQ and verbal learning performance were measured using standardized instruments. The MA group activated more diffuse brain regions, including bilateral medial temporal structures known to be important for memory, than both the alcohol-exposed only and the CON groups. These group differences remained after IQ was covaried. More activation in medial temporal structures by the MA group compared with the alcohol-exposed only group cannot be explained by performance differences because both groups performed at similar levels on the verbal memory task. More diffuse activation in the MA group during verbal memory may reflect recruitment of compensatory systems to support performance of the verbal memory network. Differences in activation patterns between the MA and alcohol-exposed only groups suggest that prenatal MA exposure influences the development of the verbal memory system above and beyond effects of prenatal alcohol exposure. Lu LH, Johnson A, O'Hare ED, Bookheimer SY, Smith LM, O'Connor MJ, Sowell ER. Effects of prenatal methamphetamine exposure on verbal memory revealed with functional magnetic resonance imaging. J Dev Behav Pediatr. 2009 Jun;30(3):185-192.

Early Parental Care Important for Hippocampal Maturation

The effects of early life experience on later brain structure and function have been studied extensively in animals, yet the relationship between childhood experience and normal brain development in humans remains largely unknown. Dr. Hallam Hurt and her colleagues used data from a study on prenatal cocaine exposure to examine this question. The data set included ecologically valid in-home measures of early experience during childhood (at age 4 and 8 years) and high-resolution structural brain imaging during adolescence (mean age 14 years) and examined the effects on later brain morphology of two dimensions of early experience: parental nurturance and environmental stimulation. Parental nurturance at age 4 predicted the volume of the left hippocampus in adolescence, with better nurturance associated with smaller hippocampal volume. In contrast, environmental stimulation did not correlate with hippocampal volume. Moreover, the association between hippocampal volume and parental nurturance disappeared at age 8, supporting the existence of a sensitive developmental period for brain maturation. These findings suggest that variation in normal childhood experience is associated with differences in brain morphology, and hippocampal volume is specifically associated with early parental nurturance. The results provide neuroimaging evidence supporting the important role of warm parental care during early childhood for brain maturation. Rao H, Betancourt L, Giannetta JM, Brodsky NL, Korczykowski M, Avants BB, et al., Early parental care is important for hippocampal maturation: Evidence from brain morphology in humans. Neuroimage 2009 Jul 9. [E-pub ahead of print].

Response Inhibition among Early Adolescents Prenatally Exposed to Tobacco: An fMRI Study

Children prenatally exposed to tobacco have been found to exhibit increased rates of behavior problems related to response inhibition deficits. The present study compared the brain function of tobacco-exposed and unexposed 12-year-olds during a Go/No-Go response inhibition task using an event-related functional MRI (fMRI) design. Prenatal alcohol exposure, neonatal medical problems, environmental risk, IQ, current environmental smoke exposure, and handedness were statistically controlled. Tobacco-exposed children showed greater activation in a relatively large and diverse set of regions, including left frontal, right occipital, and bilateral temporal and parietal regions. In contrast, children unexposed to tobacco showed activation in the cerebellum, which prior research has indicated is important for attention and motor preparation. The diversity of regions showing greater activation among tobacco-exposed children suggests that their brain function is characterized by an inefficient recruitment of regions required for response inhibition. Bennett DS, Mohamed FB, Carmody DP, Bendersky M, Patel S, Khorrami M, Faro SH, Lewis M. Response inhibition among early adolescents prenatally exposed to tobacco: An fMRI study. Neurotoxicol Teratol. 2009 Apr 5. [E-pub ahead of print].

Maternal Smoking During Pregnancy and Newborn Neurobehavior: Effects at 10 to 27 Days

Dr. Laura Stroud and her colleagues examined effects of maternal smoking during pregnancy on newborn neurobehavior at 10 to 27 days. Participants were 56 healthy infants (28 smoking-exposed, 28 unexposed) matched on maternal social class, age, and alcohol use. Maternal smoking during pregnancy was determined by maternal interview and maternal saliva cotinine. Postnatal smoke exposure was quantified by infant saliva cotinine. Infant neurobehavior was assessed through the NICU Network Neurobehavioral Scale. Smoking-exposed infants showed greater need for handling and worse self-regulation and trended toward greater excitability and arousal relative to matched, unexposed infants (all moderate effect sizes). In contrast to prior studies of days 0 to 5, no effects of smoking-exposure on signs of stress/abstinence or muscle tone emerged. In stratified, adjusted analyses, only effects on need for handling remained significant. Effects of maternal smoking during pregnancy at 10 to 27 days are subtle and consistent with increased need for external intervention and poorer self-regulation. Along with parenting deficits, these effects may represent early precursors for long-term adverse outcomes from maternal smoking during pregnancy. That signs of abstinence shown in prior studies of 0- to 5-day-old newborns did not emerge in older newborns provides further evidence for the possibility of a withdrawal process in exposed infants. Stroud LR, Paster RL, Papandonatos GD, Niaura R, Salisbury AL, Battle C, Lagasse LL, Lester B. Maternal smoking during pregnancy and newborn neurobehavior: Effects at 10 to 27 days. J Pediatr. 2009 Jan;154(1):10-16.

A Methodological Study of Maternal Recall of Smoking in Pregnancy

Retrospective recall of smoking during pregnancy is assumed to be substantially biased, but this has rarely been tested empirically. Dr. Lauren Wakschlag and her colleagues examined the validity of an interview-based retrospective recall more than a decade after pregnancy, in a cohort with repeated, multimethod characterization of pregnancy smoking (N = 245). Retrospective smoking patterns were examined in relation to prospective reported and biological estimates of overall and trimester-specific smoking status and intensity. Characteristics of women whose smoking status was misclassified by either prospective or retrospective measures were compared with women whose status was congruent for nonsmoking across timepoints. In general, sensitivity and specificity of recalled smoking were excellent relative to both prospective self-reported and cotinine-validated smoking status and trimester-specific intensity. However, measures were less congruent for amount smoked for women who recalled being heavy smokers. Further, retrospective measures captured some smokers not identified prospectively due to smoking that occurred prior to assessments. Women who would have been misclassified as nonsmokers based on either prospective or retrospective assessment differed significantly from congruently classified nonsmokers in a number of maternal, family, and neighborhood, but not child behavior, characteristics. When epidemiological studies of the impact of smoking in pregnancy use retrospective methods, misclassification may not be a significant problem if prenatal smoking is assessed in terms of the pattern across pregnancy. This type of interview-based recall of pregnancy smoking may be relatively accurate, although optimal measurement should combine retrospective and prospective self-report and biological assays, as each provide unique information and sources of error. Pickett KE, Kasza K, Biesecker G, Wright RJ, Wakschlag LS. Women who remember, women who do not: A methodological study of maternal recall of smoking in pregnancy. Nicotine Tob Res. 2009 Jul 28. [E-pub ahead of print].

Developmental Consequences of Prenatal Tobacco Exposure

This paper exhaustively reviews results from published, in press, and conference proceedings from 2007 and 2008 that link in-utero tobacco exposure to neurodevelopmental outcomes in exposed offspring. Prenatal tobacco exposure (PTE) affected speech processing, levels of irritability and hypertonicity, attention levels, ability to self-regulate, need to be handled, and response to novelty preference in infants. In early childhood, PTE effects were mostly behavioral outcomes including activity and inattention and externalizing behaviors, including conduct disorder and antisocial behavior. In adolescents, PTE predicted increased attention deficit hyperactivity disorder, modulation of the cerebral cortex and white matter structure, and nicotine addiction. Several studies found moderating effects with PTE and genetic susceptibilities including dopamine transporter, serotonergic synaptic function, and monoamine oxidase pathways. Other studies suggested that environmental and genetic factors might be more important than the direct teratological effects of PTE. The majority of studies reviewed were prospective and tobacco exposure was quantified biologically. Most demonstrated a direct association between PTE and neurodevelopmental outcomes. More work is needed to examine multifactorial influences. Effects of PTE on offspring appear to be moderated by genetic variability, neurobehavioral disinhibition, and sex. Cornelius MD, Day NL. Developmental consequences of prenatal tobacco exposure. Curr Opin Neurol. 2009 April;22(2):121-125.

Allelic Variation of Calsyntenin 2 (CLSTN2) Modulates the Impact of Developmental Tobacco Smoke Exposure on Mnemonic Processing in Adolescents

Deficits in attention and mnemonic processing and to abnormal function of medial temporal lobe structures that support mnemonic processing have been linked to exposure to tobacco smoke during development. The purpose of this study was to test whether genetic variation may mediate individual differences in vulnerability to the effects of developmental exposure to tobacco smoke. The impact of allelic variation within CLSTN2 was examined in 101 adolescents who were systematically characterized for prenatal and adolescent exposure to tobacco smoke. While subjects performed an encoding and retrieval task, verbal and visuospatial memory was assessed and functional magnetic resonance imaging data were acquired. The results replicated prior findings of a beneficial effect of the CLSTN2 C allele on verbal memory. This beneficial effect was eliminated by adolescent exposure to tobacco smoke and was associated with increased activation of entorhinal/perirhinal cortex during early and delayed retrieval in CLSTN2 C allele carriers. These findings extend previous work demonstrating that calsyntenins play an essential role in learning and indicate that this role is modulated both by CLSTN2 genotype and, during adolescent development, by exposure to tobacco smoke. Jacobsen LK, Picciotto MR, Health CJ, Mencl WE, Gelernter J. Allelic variation of calsyntenin 2 (CLSTN2) modulates the impact of developmental tobacco smoke exposure on mnemonic processing in adolescents. Biol Psychiatry. 2009 Apr 15; 65(8):671-679.

Effects of Alcoholism Severity and Smoking on Executive Neurocognitive Function

Prior research has revealed neurocognitive deficits in chronic alcoholic men. The causes of these deficits may be due to the direct effects of alcohol toxicity; however, other factors that include pre-existing cognitive deficits, comorbid psychiatric disorders or other substances of abuse cannot be ruled out. Cigarette smoking is often comorbid with alcoholism, but the combined effects of smoking and alcohol toxicity have yet to be determined. The purpose of this study was to examine the effects of combined chronic alcoholism and chronic smoking on neuropsycho-logical measures of a broad range of executive measures including reaction-time. The sample was recruited from a community and consisted of 240 alcoholic and non-alcoholic men. The results revealed that both alcoholism and smoking are correlated negatively with executive function. However, alcoholism revealed a more generalized effect in that alcoholism severity did not predict executive function when IQ was included in the regression analyses. In contrast, chronic smoking was related to processing speed deficits, irrespective of IQ, suggesting the deficits caused by chronic smoking are more specific. The current results reinforce the importance of smoking when considering cognitive function in alcoholism. Glass JM, Buu A, Adams KM, Nigg JT, Puttler LI, Jester JM, Zucker RA. Effects of alcoholism severity and smoking on executive neurocognitive function. Addiction 2009 Jan; 104(1):38-48.

Heritability and a Genome-Wide Linkage Analysis of a Type II/B Cluster Construct for Cannabis Dependence in an American Indian Community

Prior research has indicated a moderate genetic influence on cannabis dependence. The investigators of the current study investigated whether it is possible to use hierarchical average linkage and K means-cluster analysis to subtype individuals with cannabis dependence into a dichotomous construct. Using a community sample of 606 American Indians, a genetic linkage analyses was utilized to also examine the heritability of this construct and its behavior. Ninety-one per cent of cannabis-dependent partici-pants fell into one of the two subtypes: Type A/I cluster (n = 114, 56%) and Type B/II cluster (n = 70, 35%). Heritability was significant for the Type B/II cluster (versus no diagnosis) and evidence for linkage was found on chromosome 16 and on chromosome 19. Regions of interest for this phenotype were also located on chromosomes 14, 21, 22. Other studies have identified these same areas of the genome for drug dependence phenotypes. The findings of this study provide a useful approach to characterize heritable versus non-heritable subtypes of cannabis dependence. The results may have important implications in characterizing clinical course and in matching treatment strategies. Ehlers C, Gilder D, Gizer I, Wilhelmsen K. Heritability and a genome-wide linkage analysis of a type II/B cluster construct for cannabis dependence in an American Indian community. Addict Biol. 2009;3:338-348.

Cognitive Development and Lead Exposure in Poly-Drug Exposed Children

The impact of early postnatal lead exposure measured at age 4 on children's IQ and academic achievement at 11 years of age was examined. The sample consisted of 278 inner-city, primarily African American children who were polydrug exposed prenatally. Regression analyses indicated a linear effect of lead exposure on outcomes and no moderating effects of polydrug exposure. An IQ loss of about 4.1-5.4 Full Scale IQ points was estimated for each 10 microg/dL increase in blood lead level at ages 4, 9, and 11 years as a function of blood lead level at age 4. Decrements in scores on tests of non-verbal reasoning were consistently associated with higher lead levels at age 4, while verbal decrements became apparent only at age 11. Lower reading summary scores at 9 and 11 years were consistently associated with higher lead exposure, while decrements in mathematics were not apparent until 11 years. Subgroup analyses on children with blood lead levels <10 microg/dL showed detrimental lead effects even at the 5 microg/dL level, providing additional evidence of adverse effects occurring at blood lead levels below the current 10 microg/dL public health blood lead action level. Min MO, Singer LT, Kirchner HL, Minnes S, Short E, Hussain Z, Nelson S. Cognitive development and low-level lead exposure in poly-drug exposed children. Neurotoxicol Teratol. 2009 Jul-Aug;31(4):225-231.

Intrauterine Cocaine Exposure and Executive Functioning in Middle Childhood

This longitudinal study by Dr. Deborah Frank and her colleagues evaluated whether the level of intrauterine cocaine exposure (IUCE) or the interaction between IUCE and contextual variables was related during middle childhood to executive functioning, as assessed with the Stroop Color-Word and Rey Osterrieth Complex Figure tests. The Stroop Interference score measures verbal inhibitory control while the Rey Osterrieth Organizational score evaluates skills such as planning, organization and perception. Examiners assessed children at 9.5 and 11 years of age. Level of IUCE (Unexposed; Lighter, and Heavier) was documented by positive postpartum maternal reports and infant meconium assays. In covariate-controlled regressions, level of IUCE was not significantly associated with Stroop Interference or Rey Osterrieth Organization scores. However, in covariate controlled post-hoc tests comparing the "Heavier" exposed group to the combined "Lighter/ Unexposed" group, children in the Heavier group had significantly poorer Stroop Interference scores, but there was no significant group difference for Rey Osterrieth Organizational scores. Children's average Organization scores in "Unexposed", "Lighter," and "Heavier" exposed groups were well below the test norm means. Results of this study indicate that heavier IUCE may be associated with mild compromise on school-aged children's ability to inhibit prepotent verbal responses. Rose-Jacobs R, Waber D, Beeghly M, Cabral H, Appugleise D, Heeren T, Marani J, Frank DA. Intrauterine cocaine exposure and executive functioning in middle childhood. Neurotoxicol Teratol. 2009 May-Jun;31(3):159-168.

Cocaine-Exposed Infant and Caregiver Behavior: Gender Differences

Prenatal cocaine exposure and the role of gender were evaluated by Dr. Michael Lewis and his colleagues using risk factor analyses to determine whether 6-month-old cocaine-exposed male infants demonstrated greater disruptions in infant-caregiver socioemotional interactions during a Still-Face test. Overall, non-cocaine-exposed infants spent more time looking at toys, compared with cocaine-exposed infants; nonexposed female infants spent more time scanning the environment, compared with nonexposed male infants. When female caregiver behavior during the Still-Face was evaluated, differences emerged in amount of time the caregiver spent vocalizing to the infant. She vocalized more to a cocaine-exposed infant compared with a nonexposed one; she reduced vocalizing more during the test if the cocaine-exposed infant was female. An exposure by gender interaction emerged in the amount of change in caregiver vocalizations; however, the overarching hypothesis that male cocaine-exposed infants are at higher risk than nonexposed male, nonexposed female, and cocaine-exposed female infants was not supported. Because this interaction was evident in this cohort at 24 months, future research is needed to determine at what age an interaction begins to emerge in this cohort. Lewis MW, Phillips G, Bowser M, DeLuca S, Johnson HL, Rosen TS. Cocaine-exposed infant behavior during still-face: Risk factor analyses. Am J Orthopsychiatry. 2009 Jan;79(1):60-70.

Prenatal Cocaine Exposure and Infant Cortisol Reactivity and Regulation

In these two studies by Dr. Rina Eiden, the role of prenatal cocaine exposure on infant hypothalamic-pituitary-adrenal axis activity, infant reactivity and regulation were examined at 7 months of infant age. Participants were 168 caregiver-infant dyads (87 cocaine exposed, 81 not cocaine exposed; 47% boys). In the first study, maternal behavior, caregiving instability, and infant growth and behavior were assessed and children's saliva was sampled before, during, and after standardized procedures designed to elicit emotional arousal. Results revealed cocaine-exposed infants had greater cortisol reactivity compared to non-cocaine-exposed infants. Infant gender and caregiving instability moderated this association. The findings support a dual hazard vulnerability model and have implications for evolutionary-developmental theories of individual differences in biological sensitivity to context. In the second study, it was hypothesized that cocaine exposed infants would display higher arousal or reactivity and lower regulation during a procedure designed to arouse anger/frustration. Results indicated that cocaine exposed infants were more reactive to increases in the level of stress from trial 1 to trial 2 but, unlike the control group infants, exhibited no change in the number of regulatory strategies as stress increased, Infant birth weight moderated the association between cocaine exposure and infant regulation; among cocaine exposed infants, those with lower birth weight displayed higher reactivity compared to those with higher birth weight. Contrary to expectations, there were no indirect effects between cocaine exposure and infant reactivity/ regulation via environmental risk, parenting, or birth weight. Results are supportive of a terato-logical model of prenatal cocaine exposure for infant reactivity/regulation in infancy. Eiden RD, Veira Y, Granger DA. Prenatal cocaine exposure and infant cortisol reactivity. Child Dev. 2009 Mar-Apr;80(2):528-543 and Eiden RD, McAuliffe S, Kachadourian L, Coles C, Colder C, Schuetze P. Effects of prenatal cocaine exposure on infant reactivity and regulation. Neurotoxicol Teratol. 2009 Jan-Feb;31(1):60-68.

ERP Study of Risk-Taking and the Feedback Negativity Response to Loss among Adolescents with Prenatal Drug Exposure

Dr. Linda Mayes and Dr. Carl Lejuez examined event-related brain potentials in a high-risk sample of 32 adolescents (50% Female) who were exposed to cocaine and other drugs prenatally. Adolescents were selected for extreme high- or low-risk behavior on the Balloon Analog Risk Task, a measure of real-world risk-taking propensity. The feedback error-related negativity (fERN), an event-related potential (ERP) that occurs when an expected reward does not occur, was examined in a game in which choices lead to monetary gains and losses with feedback delayed 1 or 2 s. Feedback type, feedback delay, risk status, and sex were all associated with fERN variability. Monetary feedback also elicited a P300-like component, moderated by delay and sex. Delaying reward feedback may provide a means for studying complementary functioning of dopamine and norepinephrine systems. Crowley MJ, Wu J, Crutcher C, Bailey CA, Lejuez CW, Mayes LC. Risk-taking and the feedback negativity response to loss among at-risk adolescents. Dev Neurosci. 2009;31(1-2):137-148.

Inhibitory Deficits in Children with Attention-Deficit/HyperactivityDisorder: Intentional versus Automatic Mechanisms of Attention

Prior research has shown that children with attention deficit hyperactivity disorder (ADHD) present with deficits of intentional inhibitory mechanisms; however, the literature is lacking on whether automatic (reflexively controlled) inhibitory mechanisms are impaired in these children. The present study compared deficits in intentionally and reflexively controlled inhibition of attention in two subtypes of children with ADHD. Fifty children with ADHD were classified into one of three subtypes: predominantly inattentive (ADHD/PI), combined (ADHD/C), and those children with ADHD/C who also met criteria for comorbid oppositional defiant disorder (ADHD/C + ODD). A countermanding task was used to examine a deficit of intentionally controlled inhibition and an inhibition of return (IOR) task was chosen to examine deficits in reflexively controlled inhibition. Compared to a group of 21 children without a diagnosis of ADHD, children with ADHD required more time to inhibit responses on the countermanding tasks and the subtypes did not differ. Children with ADHD/C and ADHD/C + ODD showed substantial impairment as evidenced by a complete absence of reflexive inhibition, whereas the children with ADHD/PI were considerably less impaired on this task. The findings indicate that distraction by external stimuli may be less related to the attention problems of children in the ADHD/PI subtype. Future research is needed that specifically examines the developmental course of automatic and intentional inhibitory control among both typical and at-risk populations in that these findings would have implications for assessing the clinical efficacy of treatments for ADHD. Fillmore M, Milich R, Lorch E. Inhibitory deficits in children with attention-deficit/ hyperactivity disorder: Intentional versus automatic mechanisms of attention. Dev and Psychopathol. 2009 Spring;21(2):539-554.

Increased Sensitivity to the Disinhibiting Effects of Alcohol in Adults with ADHD

Disinhibi-tory psychopathology is believed to play an important role in the development of drug abuse disorders. Individuals with attention deficit hyperactivity disorder (ADHD) are often characterized as having behavior that is undercontrolled. In order to better understand inhibitory control as it relates to substance abuse, Dr. Mark Fillmore and his colleagues at the University of Kentucky tested the sensitivity to alcohol in individuals who have established deficits in inhibitory control; adults with ADHD. The present study used a cued go/no-go task to measure inhibitory control in ten adults with ADHD with a mean age of 23 years compared to the performance of twelve aged matched normal controls. Information was provided during the task to alert the subjects as to the probability that a go or no-go target would be presented. Given the known impairing effects alcohol has on inhibitory control, it was predicted that alcohol would produce even greater inhibitory impairment in individuals with preexisting deficits in behavioral control. The results revealed that when valid cues were used to aid a subjects' performance on the cued no-go task, controls did not demonstrate inhibitory failures. In contrast, alcohol impaired those with ADHD, regardless of cue condition (i.e. valid versus invalid). Further research is needed to better understand how the disinhibiting effects of alcohol are related to risky behavior while intoxicated. Weafer J, Fillmore M, Milich R. Increased sensitivity to the disinhibiting effects of alcohol in adults with ADHD. Exp Clin Psychopharmacol. 2009 April: 17(2):113-121.

Youth Living with HIV and Partner-Specific Risk for Secondary Transmission of HIV

Secondary transmission remains a significant concern among HIV-infected youth. Little is known, however, about how partner-specific sexual risk behaviors for the secondary transmission of HIV may differ between the 2 largest subgroups of HIV-positive youth, women-who-have-sex-with-men (WSM) and men-who-have-sex-with-men (MSM), During 2003-2004, a convenience sample of HIV-infected youth, 13 to 24 years of age, were recruited from 15 Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) clinical sites. Approximately 10 to 15 youth were recruited at each site. Participants completed an ACASI survey including questions about sex partners in the past year. Cross-sectional data analyses, including bivariate and multivariable regressions, using generalized estimating equations, were conducted during 2008 to compare recent partner-specific sexual risk behaviors between WSM and MSM. There were significant differences between the 2 groups in recent partner-specific sexual risk behaviors including: lower rates of condom use at last sex among WSM; a larger proportion of the sex partners of MSM reported as concurrent; and greater use of hard drugs at last sex by MSM and/or their partner. When measuring risk as a composite measure of sexual risk behaviors known to be associated with HIV transmission, both groups had high rates of risky behaviors. These data suggest that recent partner-specific sexual risk behaviors for HIV transmission are high among young infected MSM and WSM. These findings suggest the need to offer interventions to reduce the secondary transmission of HIV to all HIV-positive youth in care. However, differences in risk behaviors between young MSM and WSM support population-specific interventions. Jennings JM, Ellen JM, Deeds BG, Harris DR, Muenz LR, Barnes W, Lee SS, Auerswald CL, Adolescent Trials Network for HIV/AIDS Interventions. Youth living with HIV and partner-specific risk for the secondary transmission of HIV. Sex Transm Dis. 2009 Jul;36(7):439-444.

Risks for Non-adherence to Antiretroviral Therapy among HIV-Infected Youth

Adherence continues to be a major barrier to successful treatment with highly active antiretroviral therapy (HAART) for HIV-infected individuals. HIV-infected adolescents and young adults face a lifetime of treatment with HAART. Often, individuals who struggle with adherence to HAART face multiple barriers that impact on the success of any single modality intervention. The Adolescent Trials Network for HIV/AIDS Interventions (ATN) conducted a cross-sectional, observational study to determine the prevalence of personal barriers to adherence and to identify associations between these barriers in HIV-infected subjects aged 12 to 24. The ATN studied the following personal barriers to adherence: mental health barriers, high/low self-efficacy and outcome expectancy, and the presence of specific structural barriers. There were 396 subjects recruited from sites from the ATN or the Pediatric AIDS Clinical Trials Group, 148 of which self-identified as non-adherent. No significant differences were found between adherent and non-adherent subjects for the presence of mental health disorders. Adherence was significantly associated with all but one structural barrier. Both self-efficacy and outcome expectancy were higher among adherent versus non-adherent subjects. Grouping subjects according to low self-efficacy and outcome expectancy for adherence, adherence differed according to the presence or absence of mental health disorders and structural barriers. The data suggest that adolescents have significant rates of non-adherence and face multiple personal barriers. Rudy BJ, Murphy DA, Harris DR, Muenz L, Ellen J. Adolescent Trials Network for HIV/AIDS Interventions. Patient-related risks for non-adherence to antiretroviral therapy among HIV-infected youth in the United States: A study of prevalence and interactions. AIDS Patient Care STDS. 2009 Mar;23(3):185-194.

Transgender Female Youth and HIV Risk

This Adolescent Trials Network for HIV/AIDS Interventions (ATN) study examined the HIV risk behaviors and life experiences of 151 transgender female youth, ages 15-24, in Los Angeles and Chicago. Descriptive analyses and logistic regression modeling were used to identify life factors associated with ever having engaged in sex work. Sixty-seven percent of participants had ever engaged in sex work and 19% self-reported being HIV positive. Many factors were significantly associated with sex work for this sample population. A final multivariate logistic regression model found that lower education status, homelessness, use of street drugs, and perceived social support remained significantly associated with sex work when controlling for other factors. Findings highlight the complex HIV risk environment and suggest a need for sex work initiation research for transgender female youth. HIV prevention efforts for this population need to include broad-based approaches that take into account individual, social, and community-level factors relevant to the lives of transgender female youth. Wilson EC, Garofalo R, Harris RD, Herrick A, Martinez M, Martinez J, Belzer M. The Transgender Advisory Committee, The Adolescent Medicine Trials Network for HIV/AIDS Interventions. Transgender female youth and sex work: HIV risk and a comparison of life factors related to engagement in sex work. AIDS Behav. 2009 Feb 6. [E-pub ahead of print].

Recruitment Venues for At-Risk Young Males and Females from Urban Neighborhoods: Findings from the Adolescent Trials Network for HIV/AIDS Interventions

Finding and accessing members of youth subpopulations, such as young men who have sex with men (YMSM) of color or young females of color, for behavioral or disease surveillance or study recruitment, pose particular challenges. Venue-based sampling strategies--which hinge on where individuals congregate or "hang out" rather than where they live--appear to be effective alternatives. Methods used to identify venues focus on engaging members of social networks to learn where targeted populations congregate. However, it is not always clear if and how these methods differ according to gender, whether the youth accessed at a venue are actually from neighborhoods in which the venues are found, and whether the location of venues relative to neighborhoods of residence is different for young men and young women. This study by the Adolescent Trials Network for HIV/AIDS interventions (ATN) illustrates the gender differences in venue type and venue location where eligible youth study participants from high-risk neighborhoods could be accessed for HIV research across 15 research sites. The findings indicate that the study's method led to identifying venues where one quarter or more of the youth were eligible study participants and from the high-risk neighborhoods. Sites targeting young women of color had a higher proportion of eligible study participants who were also from the high-risk neighborhoods than sites targeting YMSM. Clubs were most commonly identified by sites targeting YMSM as recruitment venues, whereas neighborhood-based service or commercial centers were more common venues for young women of color. This study reveals how venue-based recruitment strategies can be tailored and resources maximized by understanding the key differences in the types of venues preferred by males and females. Chutuape KS, Ziff M, Auerswald C, Castillo M, McFadden A, Ellen J, Adolescent Trials Network for HIV/AIDS Interventions. Examining differences in types and location of recruitment venues for young males and females from urban neighborhoods: Findings from a multi-site HIV prevention study. J Urban Health. 2009 Jan;86(1):31-42.

An HIV Prevention Protocol Reviewed at 15 National Sites: How do Ethics Committees Protect Communities?

This study examined whether ethics committees reviewing community-based participatory research concentrate on the protection of communities, in addition to individual participants, using data from 15 Adolescent Trials for HIV/AIDS Intervention (ATN) sites. Eighty-two ethics committee concerns related to consent (35%), protocol procedures (49%), data collection (17%), and HIPAA (6%) were identified. Concerns generally involved individual level subject issues; only 17% were related to community issues. To improve community-level protections in research, the ATN authors recommend that both ethics committee members and research staff receive education concerning protection and respect for communities, that a community member group be established to advise researchers throughout the planning and implementation of community-level studies and that local ethics committee boards include members with community-level experience. Deeds BG, Castillo M, Beason Z, Cunningham SD, Ellen JM, Peralta L and the Adolescent Trials Network for HIV/AIDS Interventions. An HIV Prevention Protocol Reviewed at 15 National Sites: How do ethics committees protect communities? J Empir Res Hum Res Ethics. 2009 Jun;3(2):77-86.

Clear and Independent Associations of Several HLA-DRB1 Alleles with Differential Antibody Responses to Hepatitis B Vaccination in Youth

To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, the Adolescent Trials Network for HIV/AIDS Interventions (ATN) analyzed 255 HIV-1 seropositive (HIV+) youth and 80 HIV-1 seronegatives (HIV-) enrolled into prospective studies. 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 out of 78 non-responders, 65 out of 160 medium responders, and 27 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, Shao W, Shrestha S, Ahmad S, Cunningham CK, Flynn PM, Kapogiannis BG, Wilson CM, Tang J. Clear and independent associations of several HLA-DRB1 alleles with differential antibody responses to Hepatitis B vaccination in youth. Hum Genet. 2009 Jul 14. [E-pub ahead of print].

Short-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load Suppression

This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on/3 days off) in HIV+ adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV/AIDS Interventions (ATN) and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal/early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies/ml plus a preentry value below 200 copies/ml and an entry CD4+ T cell count above 350 cells/mm3. Of the 32 subjects enrolled, 37.5% had confirmed viral load rebound >400 copies, with 56% coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4+ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV. Rudy BJ, Sleasman J, Kapogiannis B, Wilson CM, Bethel J, Serchuck L, Ahmad S, Cunningham CK, Adolescent Trials Network for HIV/AIDS Interventions. Short-cycle therapy in adolescents after continuous therapy with established viral suppression: The impact on viral load suppression. AIDS Res Hum Retroviruses. 2009 Jun;25(6):555-561.


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