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Adherence to antiretroviral therapy (ART) is a major challenge for many youth living with HIV (YLWH). In this prospective proof-of-concept study, we assessed the feasibility and acceptability of conducting a study of video directly observed therapy (VDOT) as a method of improving medication adherence in YLWH who had a history of poor adherence to ART. The study had four phases; phase I – VDOT daily (4 months) using Facetime®; phase II – daily texting (2 months); phase III – weekly texting (3 months); phase IV – no intervention (3 months). Participants were seen in clinic on a monthly basis for assessment and laboratory evaluation. Five of eight eligible participants were enrolled. All achieved virologic suppression one month after enrollment. Three of five completed the study protocol and maintained virologic suppression through the 12-month period of study. Participant responses to the end-of-study questionnaire indicated satisfaction with the intervention and thought VDOT was helpful to them. Healthcare providers thought that the intervention was effective for some youth but was at times burdensome. This proof-of-concept study demonstrated that VDOT may be effective at improving medication adherence in previously poorly adherent YLWH and that larger studies of VDOT for such patients are both feasible and warranted. [ABSTRACT FROM AUTHOR]

Perinatally infected children living with HIV (CLWH) face lifelong infection and associated inflammatory injury. Chitinase-like 3 protein-1 (CHI3L1) is expressed by activated neutrophils and may be a clinically informative marker of systemic inflammation in CLWH. We conducted a multi-centre, cross-sectional study of CLWH, enrolled in the Early Pediatric Initiation Canadian Child Cure Cohort Study (EPIC4). Plasma levels of CHI3L1, pro-inflammatory cytokines, and markers of microbial translocation were measured by enzyme-linked immunosorbent assays. Longitudinal clinical characteristics (viral load, neutrophil count, CD4+ and CD8+ T-lymphocyte counts, and antiretroviral (ARV) regimen) were abstracted from patient medical records. One-hundred-and-five (105) CLWH (median age 13 years, 62% female) were included in the study. Seventy-seven (81%) had viral suppression on combination antiviral therapy (cART). The median CHI3L1 level was 25 μg/L (IQR 19–39). CHI3L1 was directly correlated with neutrophil count (ρ = 0.22, p = 0.023) and inversely correlated with CD4/CD8 lymphocyte ratio (ρ = −0.35, p = 0.00040). Children with detectable viral load had higher levels of CHI3L1 (40 μg/L (interquartile range, IQR 33–44) versus 24 μg/L (IQR 19–35), p = 0.0047). CHI3L1 levels were also correlated with markers of microbial translocation soluble CD14 (ρ = 0.26, p = 0.010) and lipopolysaccharide-binding protein (ρ = 0.23, p = 0.023). We did not detect differences in CHI3L1 between different cART regimens. High levels of neutrophil activation marker CHI3L1 are associated with poor virologic control, immune dysregulation, and microbial translocation in CLWH on cART. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The utility of routine therapeutic drug monitoring (TDM) in children living with HIV has not been extensively studied. The purpose of this study was to assess this strategy. METHODS: This was a single-center, prospective observational study of routine TDM for protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and integrase strand transfer inhibitors (INSTIs) in children living with HIV who were receiving antiretroviral therapy (ART) between February and December 2014. Outcome measures included the proportion of serum antiretroviral (ARV) medication concentrations in the therapeutic range (target values extrapolated from adult data) and the effect of serum concentrations on virologic control, medication adherence, and toxicity. RESULTS: Forty-eight children with a median age of 13 years (interquartile range, 3-18) were included. Median viral load (VL) and CD4% were <40 copies/mL (range, <40-124) and 37.4% (range, 8.4-47.9), respectively. Adherence was considered excellent in 95.8% of patients. Of the 50 serum trough concentrations (PI n = 19 [38%]; NNRTI n = 27 [54%]; INSTI n = 4 [8%]), 66% (n = 33) were in the therapeutic range, 12% (n = 6) were subtherapeutic, and 22% (n = 11) were supratherapeutic. There was no statistically significant correlation between serum ARV concentrations and patient demographics, VL, CD4%, or adherence. No clinically significant adverse events were noted. One dose adjustment was made for a subtherapeutic serum raltegravir concentration, likely attributable to interaction with ritonavir. CONCLUSIONS: This study does not support routine TDM in healthy children living with HIV who are well controlled on antiretroviral medication regimens. A more targeted strategy, such as when adherence is questioned or when there are suspected drug interactions, may be more appropriate. [ABSTRACT FROM AUTHOR]

To explore how the International Classification of Functioning, Disability and Health, a rehabilitation framework, can provide a holistic understanding of stigma experiences of three women living with human immunodeficiency virus in Lusaka, Zambia. A secondary analysis of three cases by drawing on interview transcripts collected as part of a larger longitudinal study with eighteen women living with the virus. The interview tool used the rehabilitation framework to ask questions about the impact of the virus on the body, daily activities, social participation and the future. Vignettes were produced for each of the eighteen women including information on stigma and the rehabilitation framework. Three case studies were developed from women who provided comprehensive accounts of stigma and the International Classification of Functioning, Disability and Health. Stigma experiences aligned well with three dimensions of the International Classification of Functioning, Disability and Health: participation restrictions, environmental and personal factors. These domains were used to understand stigma in three forms (i.e. enacted, self and structural stigma) as experienced by these women. More research is needed to ascertain how stigma and rehabilitation are related in other environments and populations and to explore how to mitigate stigma within the rehabilitation context. Rehabilitation professionals deal with aspects of stigma and discrimination in their clinical work and this analysis offers a way to consider HIV-related stigma within rehabilitation in an organized and theoretically-informed way. The insights from this study are important for the field of HIV and for advancing understanding of the complexities of stigma in the context of rehabilitation more broadly. This analysis offers guidance to rehabilitation providers about the nuanced and multi-faceted ways that stigma can occur in the context of rehabilitation, including within their own clinical practice. [ABSTRACT FROM AUTHOR]

Background The Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) study is a prospective, multicenter, Canadian cohort study investigating human immunodeficiency virus–1 (HIV-1) reservoirs, chronic inflammation, and immune responses in children with perinatally acquired HIV-1 infection. The focus of this report is HIV-1 reservoirs and correlates in the peripheral blood of children who achieved sustained virologic suppression (SVS) for ≥5 years. Methods HIV-1 reservoirs were determined by measuring HIV-1 DNA in peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+ T-cells by a prostratin analogue stimulation assay. HIV serology was quantified by signal-to-cutoff ratio (S/CO). Results Of 228 enrolled participants, 69 achieved SVS for ≥5 years. HIV-1 DNA, inducible cell-free HIV-1 RNA, and S/COs correlated directly with the age of effective combination antiretroviral therapy (cART) initiation (P <.001, P =.036, and P <.001, respectively) and age when SVS was achieved (P =.002, P =.038, and P <.001, respectively) and inversely with the proportion of life spent on effective cART (P <.001, P =.01, and P <.001, respectively) and proportion of life spent with SVS (P <.001, P =.079, and P <.001, respectively). Inducible cell-free HIV-1 RNA correlated with HIV-1 DNA, most particularly in children with SVS, without virologic blips, that was achieved with the first cART regimen initiated prior to 6 months of age (rho = 0.74; P =.037) or later (rho = 0.87; P <.001). S/COs correlated with HIV-1 DNA (P =.003), but less so with inducible cell-free HIV-1 RNA (P =.09). Conclusions The prostratin analogue stimulation assay, with its lower blood volume requirement, could be a valuable method for evaluating inducible HIV-1 reservoirs in children. Standard commercial HIV serology may be a practical initial indirect measure of reservoir size in the peripheral blood of children with perinatally acquired HIV-1 infection. [ABSTRACT FROM AUTHOR]

Stigma theory is concerned with inclusion and opportunities that influence well-being. Rehabilitation is also concerned with social inclusion and well-being. This is a central concern in one of the leading rehabilitation theories, the World Health Organization's International Classification of Functioning, Disability and Health. Despite these shared concerns, the relationship between the fields of stigma and rehabilitation has not been well theorized to date. Using human immunodeficiency virus (HIV) as an example, this article presents an analysis of three ways that stigma may be conceptualized within the context of the International Classification of Functioning, Disability and Health. Three broad spheres of stigma are described: enacted, self, and structural stigma. These three forms of stigma are then aligned in unique ways with three particular constructs of the International Classification of Functioning, Disability and Health: participation restrictions, environmental, and personal contextual factors. This conceptualization illustrates how rehabilitation professionals and other practitioners, policy makers and researchers can better understand the dynamic and nuanced forms of stigma and how they relate to rehabilitation. Implications for rehabilitation: This article enables rehabilitation professionals to better understand stigma as it relates to rehabilitation and human immunodeficiency virus. Rehabilitation professionals have the important job of allies and advocates for persons experiencing restrictions in these domains as a result of stigma. [ABSTRACT FROM AUTHOR]

Background: Exposure to discarded needles or other objects put children at risk for infection with blood-borne pathogens (BBP), including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C. Objective: The purpose of this study was to retrospectively analyze the epidemiology, management and outcome of children following such exposures in the greater Toronto community setting. Methods: A retrospective study of children <19 years of age who had community-based exposure to objects that could contain BBP between January 2001 and December 2014. Sexual and hospital inpatient exposures were excluded. Patients were identified by medical record review of all children who had HIV testing performed. Results: Sixty-six community-based exposures to objects potentially contaminated with BBP were identified (71.2% needlesticks). The median age was 6.3 years (interquartile range 3.8, 7.8). Exposures occurred outdoors in the community (45.5%), in schools (30.3%), homes (15.2%) and community/outpatient clinics (9.0%). Of 11 (16.7%) identified source subjects, 7 were known to be HIV infected. HIV post-exposure prophylaxis was prescribed to 22 (33.3%) children; 15 (71.4%) completed the course. Only 41.2% of previously unvaccinated children were documented to have completed a full HBV vaccine series post-exposure. No blood-borne infections were documented, but only 60.6% had documentation of adequate follow-up testing. Conclusions: Enhanced public health interventions in schools and other community settings are needed to reduce childhood risk of exposure to needlesticks or other objects potentially contaminated with BBP. [ABSTRACT FROM AUTHOR]

Introduction: The optimal management of infants born to HIV-positive mothers who are untreated or have detectable viral load prior to delivery remains controversial. Despite the increasing use of combination antiretroviral therapy (cART) for post-exposure prophylaxis (PEP) of neonates at high risk of HIV infection, there is little safety and pharmacokinetic data to support this approach. The objective of this study was to evaluate the safety and tolerability of cART for PEP in HIV-exposed neonates. Methods: Retrospective study on 148 cART and 145 Zidovudine (ZDV) monotherapy-exposed infants identified from four Canadian centres where cART for PEP has routinely been prescribed in high-risk situations. Physician-reported adverse events and clinical outcomes were extracted by chart review. Haematological and growth parameters at birth, one and six months of age were compared between cART and ZDV-exposed infants using multivariate mixed effects modelling. Results: Non-specific signs and symptoms were reported in 10.2% of cART recipients versus none of the ZDV recipients. Treatment was discontinued prematurely in 9.5% of cART recipients versus 2.1% of ZDV recipients (p=0.01). In the multivariate model, cART recipients had lower mean haemoglobin (decrease of 2.07 g/L) over the 6-month period compared with ZDV recipients (p=0.04), but no effect was seen on absolute neutrophil count. cART recipients had lower weight and smaller head circumference at birth and one month of age compared with ZDV-exposed infants; these differences were no longer significant at six months of age. Conclusions: cART administered at treatment doses for PEP in neonates was generally well tolerated, though a higher incidence of non-specific signs and symptoms and early treatment discontinuation occurred among cART recipients. [ABSTRACT FROM AUTHOR]

We studied a cohort of children initiated on treatment doses of combination antiretroviral therapy within 72 hours of birth. In children who achieved sustained virologic suppression, measures of HIV-1 reservoir size in peripheral blood were very low.Background. A human immunodeficiency virus type 1 (HIV-1)–infected infant started on combination antiretroviral therapy (cART) at 30 hours of life was recently reported to have no detectable plasma viremia after discontinuing cART. The current study investigated the impact of early cART initiation on measures of HIV-1 reservoir size in HIV-1–infected children with sustained virologic suppression.Methods. Children born to HIV-1–infected mothers and started on cART within 72 hours of birth at 3 Canadian centers were assessed. HIV serology, HIV-1–specific cell-mediated immune responses, plasma viremia, cell-associated HIV-1 DNA and RNA, presence of replication-competent HIV-1, and HLA genotype were determined for HIV-1–infected children with sustained virologic suppression.Results. Of 136 cART-treated children, 12 were vertically infected (8.8%). In the 4 who achieved sustained virologic suppression, HIV serology, HIV-1–specific cell-mediated immune responses (Gag, Nef), and ultrasensitive viral load were negative. HIV-1 DNA was not detected in enriched CD4+ T cells of the 4 children (<2.6 copies/106 CD4+ T cells), whereas HIV-1 RNA was detected (19.5–130 copies/1.5 µg RNA). No virion-associated HIV-1 RNA was detected following mitogenic stimulation of peripheral blood CD4+ T cells (5.4–8.0 million CD4+ T cells) in these 4 children, but replication competent virus was detected by quantitative co-culture involving a higher number of cells in 1 of 2 children tested (0.1 infectious units/106 CD4+ T cells).Conclusions. In perinatally HIV-1–infected newborns, initiation of cART within 72 hours of birth may significantly reduce the size of the HIV-1 reservoirs. Cessation of cART may be necessary to determine whether functional HIV cure can be achieved in such children. [ABSTRACT FROM AUTHOR]

Background: HIV infected children are at increased risk of TB disease and require annual TB screening. Data on use of IGRA for TB screening in them are limited. We retrospectively evaluated the usefulness of Quantiferon Gold-in-tube test (QFT), an IGRA in screening for LTBI in relatively healthy, immunologically stable HIV infected children. Methods: HIV infected children with no prior history of TB were screened for latent TB as part of routine care. They underwent risk of TB assessment, TST and QFT. QFT was repeated twice or three times depending on the quantitative values. Independent test validation was also performed. Results: Eighty one children had 109 QFT tests. All had adequate mitogen responses. The initial QFT was positive in 15 (18.5%) children; quantitative IGRA responses were 0.35-1.0 IU/mL in 9 (60%), 1.0-10 IU/mL in 5 (33.3%) and >10 IU/mL in 1 (6.7%). None that tested positive had documented TB exposure or TB disease. Baseline characteristics in the QFT positive and negative groups were similar. Repeat testing within 17 weeks demonstrated reversion to negative in 79% of cases. Repeat blinded independent testing of all QFT positive results and a random selection of initial negative tests demonstrated concordance in 96% of cases. Seven children (QFT > 1.0 IU/mL or positive TST) were offered INH preventive therapy. In no case has TB disease developed in 2 years of close follow-up. Conclusions: QFT is a valid method for LTBI screening relatively healthy, immunologically stable HIV infected children. However, reversion to negative on repeat testing and lack of correlation with TST results and risk of TB exposure makes interpretation difficult. [ABSTRACT FROM AUTHOR]

Background. The effects of perinatal antiretroviral therapy (ART) on infant mitochondrial function are not well known. We compared blood mitochondrial DNA (mtDNA) levels and mtDNA gene expression (mtRNA) in human immunodeficiency virus (HIV)-uninfected, ART-exposed infants born to HIV-positive mothers with mtDNA levels and mtDNA gene expression in control infants born to uninfected women. Methods. In this prospective cohort study, longitudinal mtDNA:nuclearDNAand mtRNA: β-actin mRNA ratios were compared in blood samples obtained at various time points from birth to 8 months, using generalized estimating equation linear regression models. Results. Log10 mtDNA levels at birth were higher in ART-exposed infants, compared with levels in control infants, although the difference did not reach statistical significance (P = .07 for comparison of samples obtained 0-3 days after birth). ART-exposed infants' mtDNA levels increased further during the zidovudine prophylaxis period-from age 4 days to age 6 weeks-(P = .001) and remained significantly higher than the levels observed in control infants until the end of the study. In contrast, log10 mtRNA levels at birth were lower in ART-exposed infants than in control infants (P = .03), but were not statistically different later. Conclusions. When control infants and ART-exposed infants were compared, the mtDNA level was increased but mitochondrial gene expression was decreased in ART-exposed infants. These differences persisted after zidovudine was discontinued, suggesting that changes in mitochondrial proliferation and/or expression take place during and after ART exposure. These changes are likely the effects of the antiretroviral drugs on mitochondria. The clinical relevance and long-term impact of these alterations must be studied. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Half of new HIV infections worldwide occur among young people. Youth, particularly young women aged 15–29 years, represent a growing population to experience HIV. This study investigated HIV-positive youths’ perceptions of, and experiences with, antiretroviral treatment. Methods: A community-based, participatory approach was used to conduct a mixed methods research study. Thirty-four qualitative, in-depth, semi-structured interviews were conducted with HIV-positive youth (ages 12–24 years) in Ontario, Canada. Brief structured demographic surveys were also administered. A research team of HIV-positive youth, professionals, and researchers collaboratively analyzed the data for emerging themes. Results: Four major themes emerged: Treatment knowledge: confusion and skepticism. Many participants did not understand, or believe in, antiretroviral treatment. Some youth on treatment did not understand why they were taking medications. Treatment decision-making: lack of choice and feeling emotionally unprepared. Some youth did not feel that they had choices about treatment, and others did not feel ready to make treatment decisions. Difficulties taking medications. Youth had problems with social routine disruption, feeling “different” and side effects. Many viewed costs of medications as a barrier to treatment. Inconsistent treatment adherence and treatment interruptions, which were common amongst participants. Conclusions: Youth may need support for managing difficulties with treatments, such as side effects, social impacts, and adherence. Developmentally appropriate, empowerment-based treatment education may be helpful for HIV-positive youth. The availability of social programs to provide treatment access does not guarantee that youth will be aware of them. This may indicate a need for youth-specific outreach. [Copyright &y& Elsevier]

Objective: To investigate the association between African ancestry and neutrophil counts among children living with HIV (CLWH). We also examined whether medications, clinical conditions, hospitalization, or HIV virologic control were associated with low neutrophil counts or African ancestry. Design: We conducted a secondary analysis of the Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) Study, a multicenter prospective cohort study of CLWH across 8 Canadian pediatric HIV care centers. Methods: We classified CLWH according to African ancestry, defined as "African," "Caribbean," or "Black" maternal race. Longitudinal laboratory data (white blood cells, neutrophils, lymphocytes, viral load, and CD4 count) and clinical data (hospitalizations, AIDS-defining conditions, and treatments) were abstracted from medical records. Results: Among 217 CLWH (median age 14, 55% female), 145 were of African ancestry and 72 were of non-African ancestry. African ancestry was associated with lower neutrophil counts, white blood cell counts, and neutrophil-lymphocyte ratios. Neutrophil count <1.5 x 109/L was detected in 60% of CLWH of African ancestry, compared with 31% of CLWH of non-African ancestry (P < 0.0001), representing a 2.0-fold higher relative frequency (95% CI: 1.4-2.9). Neutrophil count was on average 0.74 x 109/L (95% CI: 0.45 to 1.0) lower in CLWH of African ancestry (P < 0.0001). Neither neutrophil count<1.5 x 109/L nor African ancestry was associated with medications, hospitalizations, AIDS-defining conditions, or markers of virologic control (viral load, sustained viral suppression, and lifetime nadir CD4). Conclusions: In CLWH, African ancestry is associated with lower neutrophil counts, without clinical consequences. A flexible evaluation of neutrophil counts in CLWH of African ancestry may avoid unnecessary interventions. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation, platelet dysfunction, and endothelial activation persist in people living with HIV despite sustained virologic suppression (SVS) with combined antiretroviral therapy (cART) and may lead to complications such as atherosclerosis and cardiovascular disease. Angiopoietin-1 (Ang-1) is a key regulator of angiogenesis and endothelial activation and has been studied as an objective biomarker in disease states such as atherosclerosis, sepsis, and severe malaria. Setting: Eight pediatric HIV care centers across Canada. Methods: Cross-sectional study of 61 children living with vertically acquired HIV on cART with undetectable RNA viral load. Plasma levels of Ang-1 were measured by ELISA and analyzed in relation to clinical characteristics abstracted from medical records. Results: Ang-1 levels were directly correlated with clinical indices of virologic control: cumulative proportion of life on effective cART (ρ = +0.35, P = 0.0078) and cumulative proportion of life with SVS (ρ = +0.36, P = 0.0049). Furthermore, higher Ang-1 levels were associated with younger age at SVS (ρ = −0.56, P < 0.0001). These associations remained statistically significant in multivariable linear regression models adjusting for potential confounders (P < 0.05 for all associations). Conclusions: Early effective cART and SVS were associated with higher Ang-1 levels in children living with vertically acquired HIV-1. [ABSTRACT FROM AUTHOR]