Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy.

BACKGROUND AND OBJECTIVES: Neurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses. METHODS: Participants underwent comprehensive neuropsychological testing and completed standardized questionnaires measuring depressive symptoms, perceptions of own functioning, and activities of daily living as part of an observational study. Brain MRI and lumbar puncture were optional. Coarsened Exact Matching was used to reduce between-group differences in age and sex, and weighted linear/logistic regression models were used to assess the effect of HIV on outcomes. RESULTS: Data were analyzed from 155 PWH on ART for at least 15 years and 100 HIV-negative controls. Compared with controls, PWH scored lower in the domains of attention/working memory (PWH least square mean [LSM] = 50.4 vs controls LSM = 53.1, p = 0.008) and motor function (44.6 vs 47.7, p = 0.009) and a test of information processing speed (symbol search 30.3 vs 32.2, p = 0.003). They were more likely to self-report a higher number of cognitive difficulties in everyday life (p = 0.011). PWH also reported more depressive symptoms, general anxiety, and use of psychiatric medications (all with p < 0.05). PWH had reduced proportions of subcortical gray matter on MRI (ß = -0.001, p < 0.001), and CSF showed elevated levels of neurofilament light chain (664 vs 529 pg/mL, p = 0.01) and tumor necrosis factor α (0.229 vs 0.156 ng/mL, p = 0.0008). DISCUSSION: PWH, despite effective ART for over a decade, displayed neurocognitive deficits and mood abnormalities. MRI and CSF analyses revealed reduced brain volume and signs of ongoing neuronal injury and neuroinflammation. As the already large proportion of virologically controlled PWH continues to grow, longitudinal studies should be conducted to elucidate the implications of cognitive, psychiatric, MRI, and CSF abnormalities in this group.

Coordination of inflammatory responses in children with perinatally acquired HIV infection.

OBJECTIVE: We investigated dynamics of inflammatory biomarkers in children with perinatally acquired HIV (PHIV) who started antiretrovirals at age less than 3 years and achieved sustained virologic control (HIV plasma RNA <400 copies/ml). DESIGN: This was a retrospective analysis of inflammatory biomarkers in children enrolled in a randomized trial of early (<3 years of age) PI-based versus NNRTI-based regimens (P1060), who achieved sustained virologic control and participated in a neurodevelopmental follow-up study (P1104s) between ages 5 and 11 years. METHODS: We measured 20 inflammatory biomarkers using ELISA or chemiluminescence at onset of sustained virologic control (Tc) and at P1104s entry (Te). RESULTS: The 213 participants had median ages of 1.2, 1.9, and 7 years at antiretroviral initiation, Tc, and Te, respectively, with 138 on protease inhibitor-based and 74 on NNRTI-based regimens at Tc. Eighteen markers decreased and two increased from Tc to Te (Te-Tc). Biomarker subsets, particularly cytokines, the chemokine IP-10, and adhesion molecules sICAM-1 and sVCAM-1, correlated at Tc, Te, and Te-Tc. At Tc, higher biomarker levels were associated with younger age, female sex, HIV plasma RNA at least 750 000 copies/ml, lower nadir CD4 + %, lower nadir weight z scores, and NNRTI-based treatment. Greater Te-Tc biomarker declines were associated with younger age, male sex, higher Tc biomarker levels, lower nadir CD4 + %, and NNRTI-based treatment. Duration of controlled viremia and nadir height z scores showed mixed associations. CONCLUSION: Biomarker expression showed substantial coordination. Most markers decreased after virologic control. Demographic and clinical variables associated with biomarker patterns were identified. Mechanistic studies of these biomarker patterns are needed to inform interventions to control inflammation.

A Value-Added Health Systems Science Intervention Based on My Life, My Story for Patients Living with HIV and Medical Students: Translating Narrative Medicine from Classroom to Clinic.

In 2018-2019, at the Keck School of Medicine of the University of Southern California (KSOM), we developed and piloted a narrative-based health systems science intervention for patients living with HIV and medical students in which medical students co-wrote patients' life narratives for inclusion in the electronic health record. The pilot study aimed to assess the acceptability of the "life narrative protocol" (LNP) from multiple stakeholder positions and characterize participants' experiences of the clinical and pedagogical implications of the LNP. Students were recruited from KSOM. Patients and staff were recruited from the Maternal, Child, and Adolescent/Adult Center for Infectious Disease and Virology (MCA) at Los Angeles County+USC Medical Center. Ten patients, seventeen students, and ten MCA staff participated in the pilot study. Qualitative methods were used to gather data from students', patients', and staff's perspectives. Three themes emerged from the thematic analysis: (1) patients' life narratives conveyed their unique life experiences and voices; (2) the protocol could result in wide-ranging effects on HIV care; (3) the LNP enabled students to contribute value to patients' healthcare. Across groups, participants considered the LNP an acceptable intervention. The LNP, its limitations, and implications for HIV care, narrative medicine, and health information technology are presented.

Plasma biomarker factors associated with neurodevelopmental outcomes in children with perinatal HIV infection and controlled viremia.

OBJECTIVE: We examined relationships between plasma biomarkers and neurodevelopment in children from sub-Saharan Africa with perinatal HIV (PHIV) with controlled viremia on antiretroviral therapy (ART). DESIGN: Longitudinal retrospective cohort study of children with controlled blood HIV replication. METHODS: Children (N = 213; 57% girls) started ART at less than 3 years of age, had neurodevelopmental assessments (cognition, attention/impulsivity, motor proficiency, global executive functions) at 5-11 years, and achieved controlled viremia (HIV-1 RNA <400 copies/ml for ≥9 months before initial assessment). Twenty-three plasma biomarkers were measured at onset of controlled viremia, week 0 (first neurodevelopmental assessment), and week 48 (second neurodevelopmental assessment). Factor analysis was conducted at each time point. Multivariable linear regressions assessed associations between factors and neurodevelopmental scores. RESULTS: Median age at week 0 was 7.0 years. Eighteen biomarkers loaded on six factors: a (L-10, IFNγ, IFNα2, IL-1ß, IL-6, IP-10, TNFα); B (sCD163, sICAM-1, sVCAM-1, CRP); C (sE-selectin, sP-selectin); D [MIP-1ß, vascular endothelial growth factor (VEGF)-A]; E (sCD14, CRP); and F (CX3CL1, MCP-1). Higher factor B scores were consistently associated with worse cognition and attention/impulsivity, and higher factor D scores with better attention/impulsivity. CONCLUSION: These results suggest a detrimental effect of increased endothelial cell activation (sICAM-1, sVCAM-1) and monocyte/macrophage scavenger function (sCD163) and a beneficial effect of increased CCR5 ligand and HIV entry blocker MIP-1ß and angiogenesis stimulant-VEGF concentrations on the neurodevelopment of children with PHIV. The model that emerges is of vascular inflammation leading to neurodevelopmental deficits. The role of persistent HIV replication in the central nervous system also needs to be further explored.

Patient Co-Participation in Narrative Medicine Curricula as a Means of Engaging Patients as Partners in Healthcare: A Pilot Study Involving Medical Students and Patients Living with HIV.

This paper describes a pilot study of a new model for narrative medicine training, "community-based participatory narrative medicine" (CBPNM), which centers on shared narrative work between healthcare trainees and patients. Nine medical students and eight patients participated in one of two, five-week-long pilot workshop series. A case study of participants' experiences of the workshop series identified three major themes: (1) the reciprocal and collaborative nature of participants' relationships; (2) the interplay between self-reflection and receiving feedback from others; and (3) the clinical and pedagogical implications of the CBPNM model. Principles and proposed outcomes of the CBPNM model are presented.

IMPAACT 2016: Operationalizing HIV Intervention Adaptations to Inform the Science and Outcomes of Implementation.

Introduction: Uptake of evidence-based interventions for adolescents and young adults living with HIV (AYA-LWH) in sub-Saharan Africa (SSA) is complex, and cultural differences necessitate local adaptations to enhance effective implementation. Few models exist to guide intervention tailoring, yet operationalizing strategies is critical to inform science and implementation outcomes, namely acceptability, appropriateness, feasibility, fidelity, and sustainability. This paper describes operationalizing the ADAPT-ITT framework applied to a manualized trauma-informed cognitive behavioral therapy (TI-CBT) intervention addressing mental and sexual health for AYA-LWH in SSA in preparation for a randomized controlled trial (RCT). Methods: Phase 1 of the RCT focused on operationalizing ADAPT-ITT steps 3-7 to tailor the intervention for use in eight sites across Botswana, Malawi, South Africa, and Zimbabwe. Well-defined processes were developed to supplement the general guidelines for each step to provide clear, consistent direction on how to prepare and conduct each step, including documenting, assessing, and determining adaptations, while maintaining intervention fidelity. The processes provided efficient standardized step-by-step progression designed for future replication. All sites participated in Phase 1 using the created tools and strategies to translate and present the TI-CBT to community stakeholders for feedback informing local adaptations. Results: The research team developed and operationalized materials guiding adaptation. A translation review process verified local adaptability, maintained core concepts, and revealed differing interpretations of words, idioms, and culturally acceptable activities. Strategically designed tools comprised of feedback and translation verification forms resulted in meticulous management of adaptations. Robust collaborations between investigators, research managers, site personnel, and topical experts maximized multidisciplinary expertise, resulting in ~10-15 personnel per site facilitating, collecting, assessing, and integrating local feedback. Processes and tools operationalized in steps 3-7 effectively addressed implementation outcomes during community engagements (n = 108), focus groups (n = 5-8 AYA-LWH and caregivers per group), and strategic training of youth leaders. Discussion: This paper offers a novel generalizable approach using well-defined processes to guide intervention adaptation building on the ADAPT-ITT framework. The processes strengthen the science of implementation and provide much-needed specificity in adaptation steps to optimize and sustain real-world impact and help researchers and community stakeholders maximize existing infrastructure, culture, and resources to inform implementation strategies.

Effect of HIV and Interpersonal Trauma on Cortical Thickness, Cognition, and Daily Functioning.

BACKGROUND: Interpersonal trauma (IPT) is highly prevalent among HIV-positive (HIV+) individuals, but its relationship with brain morphology and function is poorly understood. SETTING: This cross-sectional analysis evaluated the associations of IPT with cognitive task performance, daily functioning, magnetic resonance imaging (MRI) brain cortical thickness, and bilateral volumes of 4 selected basal ganglia regions in a US-based cohort of aviremic HIV+ individuals, with (HIV+ IPT+) and without IPT exposure (HIV+ IPT-), and sociodemographically matched HIV-negative controls with (HIV- IPT+) and without IPT exposure (HIV- IPT-). METHODS: Enrollees completed brain MRI scans, a semistructured psychiatric interview, a neurocognitive battery, and 3 measures of daily functioning. Demographic and clinical characteristics of the 4 groups were described, and pairwise between-group comparisons performed using χ tests, analysis of variance, or t-tests. Linear or Poisson regressions evaluated relationships between group status and the outcomes of interest, in 6 pairwise comparisons, using Bonferroni correction for statistical significance. RESULTS: Among 187 participants (mean age 50.0 years, 63% male, 64% non-white), 102 were HIV+ IPT+, 35 were HIV+ IPT-, 26 were HIV- IPT-, and 24 were HIV- IPT+. Compared with the remaining 3 groups, the HIV+ IPT+ group had more activities of daily living declines, higher number of impaired Patient's Assessment of Own Functioning Inventory scores, and lower cortical thickness in multiple cerebral regions. Attention/working memory test performances were significantly better in HIV- IPT- compared with the HIV+ IPT+ and HIV+ IPT- groups. Basal ganglia MRI volumes were not significantly different in any between-group comparisons. CONCLUSION: IPT exposure and HIV infection have a synergistic effect on daily functioning and cortical thickness in aviremic HIV+ individuals.

Sertraline Pharmacokinetics in HIV-Infected and Uninfected Children, Adolescents, and Young Adults.

Objective: Due to potential disease and drug interactions, the appropriate sertraline starting dose and titration range may require adjustment in pediatric patients living with HIV. This is the first report of sertraline pharmacokinetics in HIV-infected youth. Methods: IMPAACT P1080 was a multicenter pilot study describing psychiatric medication pharmacokinetics in HIV-infected and uninfected youth. Participants were stable on sertraline, >6 to <25 years old, and (1) HIV-uninfected (HIV(-)), (2) HIV-infected taking efavirenz (EFV), or (3) HIV-infected taking boosting ritonavir/protease inhibitor (PI/r). Sampling occurred at pre-dose, 2, 4, 6, 12, and 24-h post-dose. Analyses were performed for sertraline and N-desmethylsertraline, and CYP2D6 phenotyping was completed with dextromethorphan. Results: Thirty-one participants (16 HIV(-), 12 PI/r, and 3 EFV) had median (range) weight, age, and dose of 69.5 (31.5-118.2) kg, 21.8 (9.1-24.7) years, and 75.0 (12.5-150.0) mg once daily. Sertraline exposure was highest for HIV(-) and lowest for EFV cohorts; median dose-normalized AUC 0-24 was 1176 (HIV(-)), 791 (PI/r) and 473 (EFV) ng*hr/mL, and C24 was 32.7 (HIV(-)), 20.1 (PI/r), and 12.8 (EFV) ng/mL. The urinary dextromethorphan/dextrorphan (DXM/DXO) ratio was higher in HIV(-) vs. PI/r cohorts (p = 0.01). Four HIV(-) participants were CYP2D6 poor metabolizers (ln(DXM/DXO) of >-0.5). Conclusions: HIV(-) cohort had the highest sertraline exposure. Sertraline exposure was ~40% lower in the PI/r cohort than in HIV(-); the need to alter sertraline dose ranges for PI/r participants is not clear. The impact of efavirenz on sertraline needs further investigation due to limited numbers of EFV participants.

Mental Health Diagnoses, Symptoms, and Service Utilization in US Youth with Perinatal HIV Infection or HIV Exposure.

Youth perinatally HIV infected (PHIV) or HIV exposed, but uninfected (PHEU), are aging into adolescence and adulthood with multiple complex risk factors for mental health (MH) problems and poor MH treatment utilization. Our aims were to estimate prevalence of MH diagnoses, clinically significant symptoms, and MH treatment utilization among youth with PHIV and among PHEU youth, 10-22 years old. We also aimed to identify correlates of diagnoses and treatment utilization. Analyses of data from standardized interviews, behavioral assessments, and chart review of 551 youth revealed that 36% had a previous or current MH diagnosis, with no significant HIV status group differences. Prevalence of clinically significant symptoms was 15% for both groups, of whom a third had no diagnosis, and half were not receiving treatment. Among youth with a current MH diagnosis, those with PHIV had greater utilization of services than PHEU youth (67% vs. 51%; p = 0.04). Factors associated with MH diagnoses and/or treatment utilization included caregiver characteristics, age and sex of child, HIV status, and stressful life events. Prevalence of MH diagnoses was higher than in the general population, but lower than in similar perinatally HIV-exposed cohorts, with some unmet service needs, particularly in PHEU youth. Family characteristics warrant careful consideration in early diagnosis and treatment of MH problems among youth affected by HIV.

Overlapping Risky Decision-Making and Olfactory Processing Ability in HIV-Infected Individuals.

OBJECTIVE: Given neuroimaging evidences of overlap in the circuitries for decision-making and olfactory processing, we examined the hypothesis that impairment in psychophysical tasks of olfaction would independently predict poor performances on Iowa Gambling Task (IGT), a laboratory task that closely mimics real-life decision-making, in a US cohort of HIV-infected (HIV+) individuals. METHOD: IGT and psychophysical tasks of olfaction were administered to a Washington DC-based cohort of largely African American HIV+ subjects (N=100), and to a small number of demographically-matched non-HIV healthy controls (N=43) from a different study. Constructs of olfactory ability and decision-making were examined through confirmatory factor analysis (CFA). Structural equation models (SEMs) were used to evaluate the validity of the path relationship between these two constructs. RESULT: The 100 HIV+ participants (56% female; 96% African Americans; median age = 48 years) had median CD4 count of 576 cells/µl and median HIV RNA viral load <48 copies per milliliter. Majority of HIV+ participants performed randomly throughout the course of IGT tasks, and failed to demonstrate a learning curve. Confirmatory factor analysis provided support for a unidimensional factor underlying poor performances on IGT. Nomological validity for correlations between olfactory ability and IGT performance was confirmed through SEM. Finally, factor scores of olfactory ability and IGT performance strongly predicted 6 months history of drug use, while olfaction additionally predicted hallucinogen use. CONCLUSION: This study suggests that combination of simple, office-based tasks of olfaction and decision-making may identify those HIV+ individuals who are more prone to risky decision-making. This finding may have significant clinical, public health value if joint impairments in olfaction and IGT task correlates with more decreased activity in brain regions relevant to decision-making.

A Pilot Study of Reduced Olfactory Bulb Volume as a Marker of PTSD in Childhood Trauma-Exposed Adult HIV-Infected Patients.

Evidence suggests that olfactory bulb (OB), a key structure in odor processing, may also be involved in mechanisms of traumatic stress. In animals, chronic stress reduces OB plasticity, and olfactory bulbectomy results in stress-enhanced startle reflex and autonomic dysregulation. However, OB morphometry has not been adequately studied in the development of stress disorders following childhood trauma in humans. The researchers conducted a pilot study evaluating the relationships between OB volume, childhood trauma, and lifetime posttraumatic stress disorder (PTSD) in a sample of 16 HIV-positive individuals, 13 of whom were exposed to childhood trauma of 9 developed PTSD. Participants were recruited from a larger cohort of inner city-dwelling HIV-positive populations in Washington, DC. Mean OB volumes were significantly reduced when PTSD and non-PTSD groups were compared, p = .019, as well as when trauma-exposed PTSD-positive and trauma-exposed PTSD-negative groups were compared, p = .008. No significant difference was observed when trauma-exposed and nonexposed participants were compared. The association between PTSD and right OB volume remained strong p = 0.002 after adjusting for group differences in sex, age, depression, hippocampal volume, and total intracranial volume. Because this study is limited by small sample size, further elucidation of relationships between OB, trauma, and PTSD should be investigated in larger cross-sectional and prospective studies and in diverse cohorts.

Concordance Between Self-Report and Performance-Based Measures of Everyday Functioning in HIV-Associated Neurocognitive Disorders.

Self-report is typically used to differentiate between asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) in the assessment of HIV-associated neurocognitive disorders (HAND). Yet, it is unclear whether the lack of self-reported functional impairments in individuals with ANI is indicative of a genuine absence of functional impairment, or of inaccurate self-reports. In the present study, we examined the relationship between previously validated self-report (patient's assessment of own functioning inventory; instrumental activities of daily living inventory) and performance-based (the Texas Functional Living Scale) measures of functional abilities in 112 virologically-controlled HIV-infected, and 40 well-matched, HIV-uninfected participants. Participants with symptomatic cognitive impairment (CI) had significantly lower overall scores and higher rates of impairment on a performance-based measure of everyday functioning as compared to participants with either asymptomatic CI or normal cognitive performance (WNL [within normal limits]; all p < 0.05), while asymptomatic CI and WNL participants had comparable rates of impairment and performance within the average range on the performance-based measure. The concordance between self-report and performance-based measures of everyday functioning in asymptomatic and symptomatic CI provide support for ANI and MND as clinically distinct diagnostic entities, and support the use of self-reports as appropriate measures of everyday functioning in the diagnosis of HAND.

Culturally Sensitive Approaches to Identification and Treatment of Depression among HIV Infected African American Adults: A Qualitative Study of Primary Care Providers' Perspectives.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent among HIV-infected (HIV+) individuals, and is associated with non-adherence to antiretroviral therapy (ART), and accelerated disease progression. MDD is underdiagnosed and undertreated among low-income African Americans, who are disproportionately impacted by the HIV epidemic. To improve detection and treatment of depression among African Americans living with HIV/AIDS, it is important to understand culturally and contextually relevant aspects of MDD and attitudes about mental health treatment. METHODS: A focus group session was conducted with seven providers and staff at a primary care center that serves a largely African-American community heavily impacted by the HIV epidemic in Washington, DC. Data were analyzed using an inductive approach to distill prominent themes, perspectives, and experiences among participating providers. RESULTS: Five themes emerged to characterize the lived experiences of HIV+ African-American patients: (a) Changes in perceptions of HIV over time; (b) HIV is comorbid with mental illness, particularly depression and substance abuse; (c) Stigma is associated with both HIV and depression; (d) Existing mental health services vary and are insufficient and (e) Suggestions for optimal treatment for comorbid HIV and depression. LIMITATION: This study reflects the views of providers from one clinic in this community. CONCLUSION: Substantial economic disadvantage, pervasive childhood adversity, limited education and limited resources jointly put members of this community at risk for acquisition of HIV and for development of depression and addictions. These contextual factors provide an important reminder that any patient-level depression identification or intervention in this community will have to be mindful of such circumstances.

The Association Between Post-traumatic Stress Disorder and Markers of Inflammation and Immune Activation in HIV-Infected Individuals With Controlled Viremia.

BACKGROUND: Post-traumatic stress disorder (PTSD) may be associated with chronic immune dysregulation and a proinflammatory state. Among HIV-infected individuals, PTSD is associated with greater morbidity and mortality, but the association with immune dysfunction has not been evaluated. This study explores the association between PTSD and selected markers of inflammation and immune activation in a cohort of HIV-infected, virally-suppressed individuals. METHODS: HIV-infected adults who were virologically controlled on antiretroviral medications were recruited through a screening protocol for studies of HIV-related neurocognitive disorders. Each participant underwent blood draws, urine toxicology screen, and completed the Client Diagnostic Questionnaire, a semistructured psychiatric interview. RESULTS: Of 114 eligible volunteers, 72 (63%) were male, 77 (68%) African American, and 34 (30%) participants met criteria for PTSD. Participants with PTSD were more likely to be current smokers (79%) than those without (60%) (p = 0.05). The PTSD cohort had significantly higher total white blood cell counts (5318 and 6404 cells/uL, p = 0.03), absolute neutrophil count (2767 and 3577 cells/uL, p = 0.02), CD8% (43 and 48, p = 0.05), and memory CD8% (70 and 78%, p = 0.04); lower naïve CD8% (30 and 22%, p = 0.04) and higher rate of high-sensitivity C-reactive protein >3mg/L (29 and 20, p = 0.03). DISCUSSION: A high prevalence of PTSD was identified in this cohort of HIV-infected adults who were virally suppressed. These results suggest that PTSD may be associated with immune dysregulation even among antiretroviral therapy-adherent HIV-infected individuals.

Poor CD4 count is a predictor of untreated depression in human immunodeficiency virus-positive African-Americans.

AIM: To determine if efforts to improve antiretroviral therapy (ART) adherence minimizes the negative impact of depression on human immunodeficiency virus (HIV) outcomes. METHODS: A cross-sectional study of a clinic-based cohort of 158 HIV seropositive (HIV+) African Americans screened for major depressive disorder (MDD) in 2012. CD4 T lymphocyte (CD4+) counts were obtained from these individuals. Self-report on adherence to ART was determined from questionnaire administered during clinic visits. The primary outcome measure was conditional odds of having a poorer CD4+ count (< 350 cells/mm(3)). Association between CD4+ count and antidepressant-treated or untreated MDD subjects was examined controlling for self-reported adherence and other potential confounders. RESULTS: Out of 147 individuals with available CD4+ T lymphocyte data, 31% hadCD4+ count < 350 cells/mm(3) and 28% reported poor ART adherence. As expected the group with > 350 cells/mm(3) CD4+ T lymphocyte endorsed significantly greater ART adherence compared to the group with < 350 cells/mm(3) CD4+ T lymphocyte count (P < 0.004). Prevalence of MDD was 39.5% and 66% of individuals with MDD took antidepressants. Poor CD4+ T lymphocyte count was associated with poor ART adherence and MDD. Adjusting for ART adherence, age, sex and education, which were potential confounders, the association between MDD and poor CD4+ T lymphocyte remained significant only in the untreated MDD group. CONCLUSION: Therefore, CD4+ count could be a clinical marker of untreated depression in HIV+. Also, mental health care may be relevant to primary care of HIV+ patients.

Atazanavir exposure in utero and neurodevelopment in infants: a comparative safety study.

OBJECTIVE: To evaluate the safety of in-utero exposure to atazanavir and neurodevelopment in perinatally HIV-exposed but uninfected (PHEU) infants. DESIGN: Prospective cohort study of mother-PHEU infant pairs in the Surveillance Monitoring for ART Toxicities protocol of the Pediatric HIV/AIDS Cohort Study. METHODS: Pregnant women living with HIV who initiated an antiretroviral regimen during pregnancy were followed from the date of antiretroviral initiation. Women were classified according to whether the antiretroviral regimen contained atazanavir and the trimester of antiretroviral initiation. Neurodevelopment at 9-15 months was evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). We estimated mean differences for the five Bayley-III domains for atazanavir-containing regimens versus all other regimens. Models included baseline covariates and adjustment for failure to complete the Bayley-III using inverse probability weighting. RESULTS: PHEU infants were exposed in utero to atazanavir-containing (n = 167) and nonatazanavir-containing (n = 750) antiretroviral regimens. The adjusted mean differences (95% confidence interval) in Bayley-III domain scores for initiating an atazanavir-containing regimen in the first trimester were: cognitive, -1.5 (-6.2, 3.2); language, -3.3 (-7.6, 1.0); motor, -2.9 (-7.7, 1.9); social-emotional, 0.1 (-6.2, 6.4); and adaptive behavior, -0.1 (-4.3, 4.0). The mean differences for the second or third trimester were: cognitive, 0.4 (-3.2, 4.0); language, -3.4 (-6.2, -0.5); motor, 0.3 (-2.9, 3.4); social-emotional, -5.9 (-9.4, -2.3); and adaptive behavior, -2.5 (-5.9, 0.8). CONCLUSION: In-utero exposure to atazanavir-containing regimens compared with non-atazanavir-containing regimens may adversely affect language and social-emotional development in PHEU infants during the first year of life, but the absolute difference is small.

Stimulant Medications and Cognition, Behavior and Quality of Life in Children and Youth with HIV.

BACKGROUND: Limited empirical investigation exists into longitudinal changes in cognition, behavior or quality of life (QOL) in children with perinatal HIV who are prescribed stimulants. METHODS: This study was an analysis of longitudinal data from children age 3-19 years, with perinatal HIV infection, with and without prescriptions for stimulant medications [prescription (PG) and comparison (CG) groups, respectively], matched on age, availability of CD4% and outcome measures of cognition, behavior and QOL. Generalized estimating equation models were used to evaluate effects of stimulant exposure on change in measured outcomes over 3 years of follow-up, adjusting for baseline levels of outcomes and relevant covariates. RESULTS: Children in both the PG (n = 132) and the CG (n = 392) obtained mean verbal and performance (nonverbal) intelligence quotients (VIQ and PIQ, respectively) in the low-average range for age. At baseline, those in PG demonstrated more frequent signs of hyperactivity, impulsivity and conduct and learning problems than those in CG (P ≤ 0.003 in unadjusted analyses). At follow-up, after adjustment for baseline functioning and other relevant covariates, there were no significant changes from baseline in VIQ or PIQ. Stimulant prescription use, however, was associated with worsening symptoms of hyperactivity (P = 0.01), impulsivity (P = 0.04), learning problems (P < 0.001) and worsening of perceived health status (P < 0.001). CONCLUSIONS: The results suggest expectations for behavioral improvement may not align well with long-term effects of stimulant prescription use on behavior and QOL in children with HIV. Further research is necessary to determine if there are subsets of children who may benefit from stimulant therapy.

Factors Influencing the Delivery of HIV-Related Services to Severely Mentally Ill Individuals: The Provider's Perspective.

BACKGROUND: Individuals with severe mental illnesses (SMI) are disproportionately vulnerable to HIV infection but are not consistently engaged in HIV-related services. OBJECTIVE: To understand factors influencing implementation of HIV-related services to individuals with SMI, we conducted a series of focus groups with multidisciplinary clinicians and staff serving individuals with SMI in outpatient, emergency, acute inpatient, and chronic inpatient levels of care. METHOD: Six focus groups with 30 participants were conducted, audiotaped, and transcribed. Our qualitative analysis drew on Grounded Theory. Using NVivo Version 9, coding was conducted by the first and senior authors; interrater reliability was verified by running Coding Comparison queries. RESULTS: The providers' narratives highlighted (1) patient-related factors, (2) stigma, and (3) administrative factors as themes particularly relevant to the delivery of HIV-related services to individuals with SMI. The reported relevance of these factors ranged across levels of care, from creating multiple barriers in the outpatient care to relatively seamless and effective delivery of full continuum of HIV-related services in the chronic inpatient environment, where adequate structural support is provided. CONCLUSION: Providers' narratives suggest that effective delivery of HIV-related services for individuals with SMI requires sustained structural support that is coordinated across levels of psychiatric care and tailored to individual patient's needs. The narratives also suggest that such support is currently not available.

Effect of cytomegalovirus co-infection on normalization of selected T-cell subsets in children with perinatally acquired HIV infection treated with combination antiretroviral therapy.

BACKGROUND: We examined the effect of cytomegalovirus (CMV) co-infection and viremia on reconstitution of selected CD4+ and CD8+ T-cell subsets in perinatally HIV-infected (PHIV+) children ≥ 1-year old who participated in a partially randomized, open-label, 96-week combination antiretroviral therapy (cART)-algorithm study. METHODS: Participants were categorized as CMV-naïve, CMV-positive (CMV+) viremic, and CMV+ aviremic, based on blood, urine, or throat culture, CMV IgG and DNA polymerase chain reaction measured at baseline. At weeks 0, 12, 20 and 40, T-cell subsets including naïve (CD62L+CD45RA+; CD95-CD28+), activated (CD38+HLA-DR+) and terminally differentiated (CD62L-CD45RA+; CD95+CD28-) CD4+ and CD8+ T-cells were measured by flow cytometry. RESULTS: Of the 107 participants included in the analysis, 14% were CMV+ viremic; 49% CMV+ aviremic; 37% CMV-naïve. In longitudinal adjusted models, compared with CMV+ status, baseline CMV-naïve status was significantly associated with faster recovery of CD8+CD62L+CD45RA+% and CD8+CD95-CD28+% and faster decrease of CD8+CD95+CD28-%, independent of HIV VL response to treatment, cART regimen and baseline CD4%. Surprisingly, CMV status did not have a significant impact on longitudinal trends in CD8+CD38+HLA-DR+%. CMV status did not have a significant impact on any CD4+ T-cell subsets. CONCLUSIONS: In this cohort of PHIV+ children, the normalization of naïve and terminally differentiated CD8+ T-cell subsets in response to cART was detrimentally affected by the presence of CMV co-infection. These findings may have implications for adjunctive treatment strategies targeting CMV co-infection in PHIV+ children, especially those that are now adults or reaching young adulthood and may have accelerated immunologic aging, increased opportunistic infections and aging diseases of the immune system.