Suad Kapetanovic

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. 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. 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. 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.

With growing numbers of HIV-seropositive (HIV+) women of child-bearing age and increased access to effective clinical protocols for preventing mother-to-child transmission (MTCT) of HIV, mental health-related factors have become increasingly relevant due to their potential to affect the women’s quality of life, obstetric outcomes and risk of MTCT. This review synthesizes evidence from 53 peer-reviewed publications examining mental health-related variables in pregnant and postpartum HIV+ women. The presentation of results is organized by the level of socioeconomic resources in the countries where studies were conducted (i.e., high-, middle-, and low-income countries). It is concluded that psychiatric symptoms, particularly depression, and mental health vulnerabilities (e.g., inadequate coping skills) are widespread among pregnant HIV+ women globally and have a potential to affect psychological well-being, quality of life and salient clinical outcomes. The current body of evidence provides rationale for developing and evaluating clinical and structural interventions aimed at improving mental health outcomes and their clinical correlates in pregnant HIV+ women.

Objective: To examine the relationship between markers of vascular dysfunction and neurodevelopmental outcomes in perinatally HIV-infected (PHIV+) and perinatally HIV-exposed but uninfected (PHEU) youth. Design: Cross-sectional design within a prospective, 15-site US-based cohort study. Methods: Neurodevelopmental outcomes were evaluated in relation to nine selected vascular biomarkers in 342 youth (212 PHIV+, 130 PHEU). Serum levels were assessed for adiponectin, C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), monocyte chemoattractant protein (sMCP-1), intercellular adhesion molecule-1 (sICAM-1), and P-selectin (sP-selectin). The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) was administered at entry, yielding a Full-Scale IQ score, and four index scores. Factor analysis was conducted to reduce the biomarkers to fewer factors with related biological roles. Structural equation models (SEMs) were used to measure associations between resulting factors and WISC-IV scores. Results: Mean participant age was 11.4 years, 54% were female, 70% black. The nine biomarkers were clustered into three factor groups: F1 (fibrinogen, CRP, and IL-6); F2 (sICAM-1 and sVCAM-1); and F3 (MCP-1, sP-selectin, and sE-selectin). Adiponectin showed little correlation with any factor. SEMs revealed significant negative association of F1 with WISC-IV processing speed score in the total cohort. This effect remained significant after adjusting for HIV status and other potential confounders. A similar association was observed when restricted to PHIV+ participants in both unadjusted and adjusted SEMs. Conclusion: Aggregate measures of fibrinogen, CRP, and IL-6 may serve as a latent biomarker associated with relatively decreased processing speed in both PHIV+ and PHEU youth.

With widespread access to antiretroviral therapy in the United States, many perinatally HIV-infected (PHIV+) children are surviving into adolescence and adulthood, becoming sexually active and making decisions about their reproductive health. The literature focusing on the reproductive decisions of individuals behaviorally infected with HIV can serve as a springboard for understanding the decision-making process of PHIV+ youth. Yet, there are many differences that critically distinguish reproductive health and related decision-making of PHIV+ youth. Given the potential public health implications of their reproductive decisions, better understanding of factors influencing the decision-making process is needed to help inform the development of salient treatment and prevention interventions. To begin addressing this understudied area, a “think tank” session, comprised of clinicians, medical providers, and researchers with expertise in the area of adolescent HIV, was held in Bethesda, MD, on September 21, 2011. The focus was to explore what is known about factors that influence the reproductive decision-making of PHIV+ adolescents and young adults, determine what important data are needed in order to develop appropriate intervention for PHIV+ youth having children, and to recommend future directions for the field in terms of designing and carrying out collaborative studies. In this report, we summarize the findings from this meeting. The paper is organized around the key themes that emerged, including utilizing a developmental perspective to create an operational definition of reproductive decision-making, integration of psychosocial services with medical management, and how to design future research studies. Case examples are presented and model program components proposed.

Objective: To evaluate baseline T-cell activation and neurodevelopmental outcomes over time in a cohort of perinatally HIV-infected (PHIV-infected) children with severe disease. Design: Pediatric AIDS Clinical Trials Group protocol 366 (PACTG 366) was a partially randomized, open-label, multicenter 96-week antiretroviral treatment-algorithm study. Neurodevelopmental status, measured by age-dependent evaluations (Bayley scales of infant development-II; Wechsler preschool and primary scale of intelligence-revised; Wechsler intelligence scale for children-III), was a secondary outcome. Methods: Linear mixed models were used to assess the baseline and follow-up neurodevelopmental outcomes in relation to immune activation, measured by CD38 and human leukocyte antigen (HLA) DR expression on peripheral CD4⁺ and CD8⁺ T cells at study baseline. Models were adjusted for age, sex, race/ethnicity, baseline viral load, baseline CD4%, cytomegalovirus (CMV) infection status at entry, study treatment arms, central nervous system penetrance score of antiretroviral regimen at entry, and viral load response 16 weeks postentry. Results: Among 126 PACTG 366 enrollees who were at least 1 year old and had both immune activation and age-appropriate neurodevelopmental assessments at baseline, 80 (63%) were black non-Hispanic, 71 (56%) males, 122 (97%) were on antiretrovirals, and 45 (36%) were in Centers for Disease Control and Prevention (CDC) disease category C at entry. CD4⁺CD38⁺HLADR⁺%, CD4⁺CD38⁻HLADR⁺%, and CD8⁺CD38⁺HLADR⁺% were positively associated with full-scale Intelligence Quotient scores (FSIQ) (slope = 0.18, 0.70, and 0.15, respectively; P = 0.02, 0.03, and 0.04, respectively). CD4⁺CD38⁺HLADR⁻% was negatively associated with FSIQ (slope = −0.16, P = 0.01). Conclusion: Contrary to HIV-infected adults, in PHIV-infected children higher CD4⁺CD38⁺HLADR⁺% may be associated with a neuroprotective effect and higher percentage of CD4⁺CD38⁺ but HLADR⁻ T cells may be deleterious.

The Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY) study is a prospective, multisite, longitudinal cohort of U.S. HIV-infected youth. This analysis was limited to perinatally HIV-infected youth (n=197), 13 years and older, with selected variables completely abstracted from HIV diagnosis through 2006. We evaluated relationships between ever having one or more nonsubstance related medically documented psychiatric diagnoses and three risky health behaviors (substance abuse, preadult sexual activity, and treatment adherence problems) recorded between 2001 and 2006. Logistic regression was used for all binary outcomes and participant age was included as a covariate when possible. All 197 participants included in the analysis were prescribed antiretroviral therapy during the study period; 110 (56%) were female, 100 (51%) were black non-Hispanic, and 86 (44%) were Hispanic; mean age at the last visit was 16.8 years, ranging from 13 to 24 years. One hundred forty-six (74%) participants had a history of at least one risky health behavior. There were 108 (55%) participants with at least one medically documented psychiatric diagnosis, 17 (9%) with at least one record of substance abuse, 12 (6%) with documented preadult sexual activity, and 142 (72%) participants with reported adherence problems. In the final model, a history of at least one psychiatric diagnosis was associated with having at least one of the three risky behaviors (odds ratio [OR]=2.33, p=0.015). There is a need for a continued close partnership between HIV specialty care providers and mental health services treating perinatally HIV-infected youth with an added focus on improving treatment adherence.