Caregivers of Patients Considering a Destination Therapy Left Ventricular Assist Device and a Shared Decision-Making Intervention: The DECIDE-LVAD Trial.

OBJECTIVES: This study aims to characterize caregivers of patients considering destination therapy left ventricular assist device (DT-LVAD) and evaluate the effectiveness of a shared decision-making (SDM) intervention. BACKGROUND: Caregivers play an integral role in the care of patients with chronic illness. At the extreme, pursuing a DT-LVAD is a major preference-sensitive decision that requires high-level caregiver engagement. Yet, little is known about caregivers of patients considering DT-LVAD, and there is a paucity of research on the involvement of caregivers in medical decision-making. METHODS: A 6-center, stepped-wedge trial was conducted. After varying time in usual care (control), sites were transitioned to an SDM intervention consisting of staff education and pamphlet and video decision aids (DAs). The primary outcome was decision quality, measured by knowledge and values-choice concordance. RESULTS: From 2015 to 2017, 182 caregivers of patients considering DT-LVAD were enrolled (control group, n = 111; intervention group, n = 71). The median age was 61 years, 86.5% were female, and 75.8% were spouses. Caregiver knowledge (0% to 100%) improved from baseline to post-education in both groups: in the control group it improved from 64.2% to 73.3%; in the intervention group it improved from 62.6% to 76.4% (adjusted difference of difference: 4.8%; p = 0.08). At 1 month, correlation between stated values and caregiver-reported treatment choice was stronger in the intervention group (difference in Kendall's tau: 0.36, 95% confidence interval: 0.04 to 0.71; p = 0.03). Caregivers reported decisional conflict (0 to 100) at baseline (control group: 19.0 ± 2.1; intervention group: 21.4 ± 2.6), which decreased post-education more in the control group (control group: 9.0 ± 1.9, intervention group: 18.8 ± 2.4; p = 0.009). Caregivers in the control group were more likely to "definitely recommend" the educational materials than those in the intervention group (93.5% vs. 74.5%, respectively; p = 0.004). CONCLUSIONS: An SDM intervention improved concordance between caregiver values and treatment choice for their loved ones but did not significantly impact knowledge. Caregivers found the DAs less acceptable than more biased educational materials and exposure to DAs led to higher conflict initially. These findings highlight the complexity of SDM involving caregivers of patients with chronic illness. (PCORI-1310-06998 Trial of a Decision Support Intervention for Patients and Caregivers Offered Destination Therapy Heart Assist Device [DECIDE-LVAD]; NCT02344576).

Effects of Education and Experience on Primary Care Providers' Perspectives of Obesity Treatments during a Pragmatic Trial.

OBJECTIVE: To examine the impact of a 1-year pragmatic obesity trial on primary care providers' (PCPs) perspectives of treatment. METHODS: PCPs from four intervention clinics (PCP-I) and five control clinics (PCP-C) completed pre- and postintervention surveys on weight-loss counseling, comfort discussing obesity treatments, and perceived effectiveness of interventions; questions were rated on 0 to 10 Likert scales. Only PCP-I received patient updates and education about obesity management. RESULTS: Eighty PCPs completed preintervention surveys (pre: 71% female, 71% physicians); 82 PCPs completed postintervention surveys (post: 66% female, 70% physicians). PCPs were most comfortable discussing exercise before and after the trial (pre PCP-C: 8.22 [1.44], mean [standard deviation (SD)]; post PCP-C: 8.37 [1.24]; P = 0.8; pre/post PCP-I: 7.88 [1.51] vs. 7.80 [1.71]; P = 0.3). PCPs were initially least comfortable discussing phentermine/topiramate extended release (ER) but developed significantly more comfort after the trial, to a greater degree among PCP-I (pre/post PCP-C: 2.86 [2.66] vs. 3.73 [2.72], P < 0.001; pre/post PCP-I: 4.00 [2.57] vs. 6.17 [2.27], P < 0.001). After the trial, both PCPs rated exercise significantly less effective for weight loss, with a greater decrease in effectiveness rations among PCP-I (pre/post PCP-C: 7.73 [1.94] vs. 6.93 [2.35], P = 0.017; pre/post PCP-I: 6.27 [2.69] vs. 5.15 [2.31], P = 0.001). Both PCPs rated phentermine (pre/post PCP-C: 5.03 [2.05] vs. 5.50 [2.12], P = 0.002; pre/post PCP-I: 5.70 [1.64] vs. 6.83 [1.18], P = 0.001) and phentermine/topiramate ER (pre/post PCP-C: 3.91 [2.33] vs. 5.47 [2.54], P < 0.001; pre/post PCP-I: 5.58 [2.21] vs. 7.02 [1.47], P < 0.001) significantly more effective after the trial, though ratings were higher among PCP-I. CONCLUSIONS: PCPs initially overvalued exercise and undervalued weight-loss medications. PCPs exposed to education and experience gave higher comfort and effectiveness ratings to weight-loss medications.

Effectiveness of an Intervention Supporting Shared Decision Making for Destination Therapy Left Ventricular Assist Device: The DECIDE-LVAD Randomized Clinical Trial.

Importance: Shared decision making helps patients and clinicians elect therapies aligned with patients' values and preferences. This is particularly important for invasive therapies with considerable trade-offs. Objective: To assess the effectiveness of a shared decision support intervention for patients considering destination therapy left ventricular assist device (DT LVAD) placement. Design, Setting, and Participants: From 2015 to 2017, a randomized, stepped-wedge trial was conducted in 6 US LVAD implanting centers including 248 patients being considered for DT LVAD. After randomly varying time in usual care, sites were transitioned to an intervention consisting of clinician education and use of DT LVAD pamphlet and video patient decision aids. Follow up occurred at 1 and 6 months. Main Outcomes and Measures: Decision quality as measured by knowledge and values-choice concordance. Results: In total, 135 patients were enrolled during control and 113 during intervention periods. At enrollment, 59 (23.8%) participants were in intensive care, 60 (24.1%) were older than 70 years, 39 (15.7%) were women, 45 (18.1%) were racial/ethnic minorities, and 62 (25.0%) were college graduates. Patient knowledge (mean test performance) during the decision-making period improved from 59.5% to 64.9% in the control group vs 59.1% to 70.0% in the intervention group (adjusted difference of difference, 5.5%; P = .03). Stated values at 1 month (scale 1 = "do everything I can to live longer…" to 10 = "live with whatever time I have left…") were a mean of 2.37 in control and 3.33 in intervention (P = .03). Patient-reported treatment choice at 1 month favored LVAD more in the control group (than in the intervention group (47 [59.5%] vs 95 [91.3%], P < .001). Correlation between stated values and patient-reported treatment choice at 1 month was stronger in the intervention group than in the control group (difference in Kendall's τ, 0.28; 95% CI, 0.05-0.45); however, there was no improved correlation between stated values and actual treatment received by 6 months for the intervention compared with the control group (difference in Kendall's τ, 0.01; 95% CI, -0.24 to 0.25). The adjusted rate of LVAD implantation by 6 months was higher for those in the control group (79.9%) than those in the intervention group (53.9%, P = .008), with significant variation by site. There were no differences in decision conflict, decision regret, or preferred control. Conclusions and Relevance: A shared decision-making intervention for DT LVAD modestly improved patient decision quality as measured by patient knowledge and concordance between stated values and patient-reported treatment choice, but did not improve concordance between stated values and actual treatment received. The rate of implantation of LVADs was substantially lower in the intervention compared with the control group. Trial Registration: clinicaltrials.gov Identifier: NCT02344576.

Development and initial validation of primary care provider mental illness management and team-based care self-efficacy scales.

OBJECTIVE: Develop and validate self-efficacy scales for primary care provider (PCP) mental illness management and team-based care participation. STUDY DESIGN AND SETTING: We developed three self-efficacy scales: team-based care (TBC), mental illness management (MIM), and chronic medical illness (CMI). We developed the scales using Bandura's Social Cognitive Theory as a guide. The survey instrument included items from previously validated scales on team-based care and mental illness management. We administered a mail survey to 900 randomly selected Colorado physicians. We conducted exploratory principal factor analysis with oblique rotation. We constructed self-efficacy scales and calculated standardized Cronbach's alpha coefficients to test internal consistency. We calculated correlation coefficients between the MIM and TBC scales and previously validated measures related to each scale to evaluate convergent validity. We tested correlations between the TBC and the measures expected to correlate with the MIM scale and vice versa to evaluate discriminant validity. RESULTS: PCPs (n=402, response rate=49%) from diverse practice settings completed surveys. Items grouped into factors as expected. Cronbach's alphas were 0.94, 0.88, and 0.83 for TBC, MIM, and CMI scales respectively. In convergent validity testing, the TBC scale was correlated as predicted with scales assessing communications strategies, attitudes toward teams, and other teamwork indicators (r=0.25 to 0.40, all statistically significant). Likewise, the MIM scale was significantly correlated with several items about knowledge and experience managing mental illness (r=0.24 to 41, all statistically significant). As expected in discriminant validity testing, the TBC scale had only very weak correlations with the mental illness knowledge and experience managing mental illness items (r=0.03 to 0.12). Likewise, the MIM scale was only weakly correlated with measures of team-based care (r=0.09 to.17). CONCLUSION: This validation study of MIM and TBC self-efficacy scales showed high internal validity and good construct validity.

Long-term pulmonary complications in perinatally HIV-infected youth.

BACKGROUND: Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE: We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD: Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS: Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION: Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

A randomized trial of heart failure disease management in skilled nursing facilities (SNF Connect): Lessons learned.

BACKGROUND/AIMS: Conducting clinical trials in skilled nursing facilities is particularly challenging. This manuscript describes facility and patient recruitment challenges and solutions for clinical research in skilled nursing facilities. METHODS: Lessons learned from the SNF Connect Trial, a randomized trial of a heart failure disease management versus usual care for patients with heart failure receiving post-acute care in skilled nursing facilities, are discussed. Description of the trial design and barriers to facility and patient recruitment along with regulatory issues are presented. RESULTS: The recruitment of Denver-metro skilled nursing facilities was facilitated by key stakeholders of the skilled nursing facilities community. However, there were still a number of barriers to facility recruitment including leadership turnover, varying policies regarding research, fear of litigation and of an increased workload. Engagement of facilities was facilitated by their strong interest in reducing hospital readmissions, marketing potential to hospitals, and heart failure management education for their staff. Recruitment of patients proved difficult and there were few facilitators. Identified patient recruitment challenges included patients being unaware of their heart failure diagnosis, patients overwhelmed with their illness and care, and frequently there was no available proxy for cognitively impaired patients. Flexibility in changing the recruitment approach and targeting skilled nursing facilities with higher rates of admissions helped to overcome some barriers. CONCLUSION: Recruitment of skilled nursing facilities and patients in skilled nursing facilities for clinical trials is challenging. Strategies to attract both facilities and patients are warranted. These include aligning study goals with facility incentives and flexible recruitment protocols to work with patients in "transition crisis."

Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort.

OBJECTIVE: Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome. METHODS: The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ACTH] or oral corticosteroids), vigabatrin, or "other." Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi-square tests and multivariable logistic regression models. RESULTS: One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040). SIGNIFICANCE: Greater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

Targeting heart failure rehospitalizations in a skilled nursing facility: A case report.

OBJECTIVE: We report on a skilled nursing facility (SNF) that added designated heart failure (HF) beds and created a patient registry to track the number and reasons for rehospitalization. BACKGROUND: Targeting the reduction of rehospitalizations from SNFs is an important goal and patients with HF are particularly vulnerable for rehospitalizations as HF disease management programs in SNFs are rare. METHODS: A case study of a local quality improvement initiative. RESULTS: The data from the registry revealed, that compared to patients without HF, patients with HF were more often rehospitalized for cardiopulmonary symptoms and less often for infection. In addition, patients with HF were most often rehospitalized during the first 7 days of their SNF stay and if they had a primary hospital discharge diagnosis of HF. CONCLUSION: We highlight the benefits of a patient registry to guide future quality improvement initiatives to reduce patient rehospitalization rates.

Prevalence of and progression to abnormal noninvasive markers of liver disease (aspartate aminotransferase-to-platelet ratio index and Fibrosis-4) among US HIV-infected youth.

OBJECTIVE: To longitudinally characterize noninvasive markers of liver disease in HIV-infected youth. DESIGN: HIV infection, without viral hepatitis coinfection, may contribute to liver disease. Noninvasive markers of liver disease [FIB-4 (Fibrosis-4) and APRI (aspartate aminotransferase-to-platelet ratio index)] have been evaluated in adults with concomitant HIV and hepatitis C, but are less studied in children. METHODS: In prospective cohorts of HIV-infected and HIV-uninfected youth, we used linear regression models to compare log-transformed FIB-4 and APRI measures by HIV status based on a single visit at ages 15-20 years. We also longitudinally modeled trends in these measures in HIV-infected youth with two or more visits to compare those with behavioral vs. perinatal HIV infection (PHIV) using mixed effect linear regression, adjusting for age, sex, body mass index, and race/ethnicity. RESULTS: Of 1785 participants, 41% were men, 57% black non-Hispanic, and 27% Hispanic. More HIV-infected than uninfected youth had an APRI score more than 0.5 (13 vs. 3%, P < 0.001). Among 1307 HIV-infected participants with longitudinal measures, FIB-4 scores increased 6% per year (P < 0.001) among all HIV-infected youth, whereas APRI scores increased 2% per year (P = 0.007) only among PHIV youth. The incidence rates (95% confidence interval) of progression of APRI to more than 0.5 and more than 1.5 were 7.5 (6.5-8.7) and 1.4 (1.0-1.9) cases per 100 person-years of follow-up, respectively. The incidence of progression of FIB-4 to more than 1.5 and more than 3.25 were 1.6 (1.2-2.2) and 0.3 (0.2-0.6) cases per 100 person-years, respectively. CONCLUSION: APRI and FIB-4 scores were higher among HIV-infected youth. Progression to scores suggesting subclinical fibrosis or worse was common.

Long-Term Effects of In Utero Antiretroviral Exposure: Systolic and Diastolic Function in HIV-Exposed Uninfected Youth.

The aim of this study was to evaluate the association of in utero exposure to highly active antiretroviral therapy (HAART) with left ventricular (LV) function and structure in HIV-exposed uninfected (HEU) children. A prospective, multisite cohort study in HEU children was conducted by the Pediatric HIV/AIDS Cohort Study (PHACS). Echocardiographic measures of LV systolic and diastolic function and cardiac structure were obtained from HEU subjects aged ≥6 years enrolled in the PHACS Surveillance Monitoring of ART Toxicities study. Echocardiographic Z-scores were calculated using normative data from an established reference cohort. We used adjusted linear regression models to compare Z-scores for echocardiographic measures from HEU children exposed in utero to HAART with those exposed to non-HAART, adjusting for demographic and maternal health characteristics. One hundred seventy-four HEU subjects with echocardiograms and maternal ARV information were included (mean age 10.9 years; 48% male, 56% black non-Hispanic). Among 156 HEU youth with any ARV exposure, we observed no differences in Z-scores for LV systolic function measures between youth exposed in utero to HAART (39%) and HAART-unexposed youth in either unadjusted or adjusted models. In adjusted models, those exposed to HAART had significantly lower mitral late diastolic inflow velocities (adjusted mean Z-score = 0.00 vs. 0.52, p = .04) and significantly higher adjusted mean LV mass-to-volume ratio Z-scores (adjusted mean Z-score = 0.47 vs. 0.11, p = .03) than HAART-unexposed youth. Uninfected children with perinatal exposure to HAART had no difference in LV systolic function. However, small but significant differences in LV diastolic function and cardiac structure were observed, suggesting that continued monitoring for cardiac outcomes is warranted in this population.

Risk of congenital cytomegalovirus infection among HIV-exposed uninfected infants is not decreased by maternal nelfinavir use during pregnancy.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is common among infants born to HIV-infected women. Nelfinavir (NFV), an antiretroviral drug that is safe during pregnancy, inhibits CMV replication in vitro at concentrations that standard doses achieve in plasma. We hypothesized that infants born to women receiving NFV for prevention of mother-to-child transmission of HIV (PMTCT) would have a reduced prevalence of cCMV infection. METHODS: The prevalence of cCMV infection was compared among HIV-uninfected infants whose HIV-infected mothers either received NFV for >4 weeks during pregnancy (NFV-exposed) or did not receive any NFV in pregnancy (NFV-unexposed). CMV PCR was performed on infant blood samples collected at <3 weeks from birth. RESULTS: Of the 1,255 women included, 314 received NFV for >4 weeks during pregnancy and 941 did not receive any NFV during pregnancy. The overall prevalence of cCMV infection in the infants was 2.2%, which did not differ by maternal NFV use. Maternal CD4 T cell counts were inversely correlated with risk of cCMV infection, independent of the time NFV was initiated during gestation. Infants with cCMV infection were born 0.7 weeks earlier (P = 0.010) and weighed 170 g less (P = 0.009) than uninfected infants. CONCLUSION: Among HIV-exposed uninfected infants, cCMV infection was associated with adverse perinatal outcomes. NFV use in pregnancy was not associated with protection against cCMV. Safe and effective strategies to prevent cCMV infection are needed.

Response to treatment in a prospective national infantile spasms cohort.

OBJECTIVE: Infantile spasms are seizures associated with a severe epileptic encephalopathy presenting in the first 2 years of life, and optimal treatment continues to be debated. This study evaluates early and sustained response to initial treatments and addresses both clinical remission and electrographic resolution of hypsarrhythmia. Secondarily, it assesses whether response to treatment differs by etiology or developmental status. METHODS: The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of infantile spasms. Children were considered responders if there was clinical remission and resolution of hypsarrhythmia that was sustained at 3 months after first treatment initiation. Standard treatments of adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin were considered individually, and all other nonstandard therapies were analyzed collectively. Developmental status and etiology were assessed. We compared response rates by treatment group using chi-square tests and multivariate logistic regression models. RESULTS: Two hundred thirty infants were enrolled from 22 centers. Overall, 46% of children receiving standard therapy responded, compared to only 9% who responded to nonstandard therapy (p < 0.001). Fifty-five percent of infants receiving ACTH as initial treatment responded, compared to 39% for oral corticosteroids, 36% for vigabatrin, and 9% for other (p < 0.001). Neither etiology nor development significantly modified the response pattern by treatment group. INTERPRETATION: Response rate varies by treatment choice. Standard therapies should be considered as initial treatment for infantile spasms, including those with impaired development or known structural or genetic/metabolic etiology. ACTH appeared to be more effective than other standard therapies.

Relationship between viral load and behavioral measures of adherence to antiretroviral therapy in children living with human immunodeficiency virus in Latin America

Few studies have examined antiretroviral therapy adherence in Latin American children. Standardized behavioral measures were applied to a large cohort of human immunodeficiency virus-infected children in Brazil, Mexico, and Peru to assess adherence to prescribed antiretroviral therapy doses during the three days prior to study visits, assess timing of last missed dose, and evaluate the ability of the adherence measures to predict viral suppression. Time trends in adherence were modeled using a generalized estimating equations approach to account for possible correlations in outcomes measured repeatedly in the same participants. Associations of adherence with human immunodeficiency virus viral load were examined using linear regression. Mean enrollment age of the 380 participants was 5 years; 57.6% had undetectable' viral load (<400 copies/mL). At enrollment, 90.8% of participants were perfectly (100%) adherent, compared to 87.6% at the 6-month and 92.0% at the 12-month visit; the proportion with perfect adherence did not differ over time (p = 0.1). Perfect adherence was associated with a higher probability of undetectable viral load at the 12-month visit (odds ratio = 4.1, 95% confidence interval: 1.8-9.1; p < 0.001), but not at enrollment or the 6-month visit (p > 0.3). Last time missed any antiretroviral therapy dose was reported as "never" for 52.0% at enrollment, increasing to 60.7% and 65.9% at the 6- and 12-month visits, respectively (p < 0.001 for test of trend). The proportion with undetectable viral load was higher among those who never missed a dose at enrollment and the 12-month visit (p ≤ 0.005), but not at the 6-month visit (p = 0.2). While antiretroviral therapy adherence measures utilized in this study showed some association with viral load for these Latin American children, they may not be adequate for reliably identifying non-adherence and consequently children at risk for viral resistance. Other strategies are needed to improve the evaluation of adherence in this population.

Relationship between viral load and behavioral measures of adherence to antiretroviral therapy in children living with human immunodeficiency virus in Latin America.

Few studies have examined antiretroviral therapy adherence in Latin American children. Standardized behavioral measures were applied to a large cohort of human immunodeficiency virus-infected children in Brazil, Mexico, and Peru to assess adherence to prescribed antiretroviral therapy doses during the three days prior to study visits, assess timing of last missed dose, and evaluate the ability of the adherence measures to predict viral suppression. Time trends in adherence were modeled using a generalized estimating equations approach to account for possible correlations in outcomes measured repeatedly in the same participants. Associations of adherence with human immunodeficiency virus viral load were examined using linear regression. Mean enrollment age of the 380 participants was 5 years; 57.6% had undetectable' viral load (<400 copies/mL). At enrollment, 90.8% of participants were perfectly (100%) adherent, compared to 87.6% at the 6-month and 92.0% at the 12-month visit; the proportion with perfect adherence did not differ over time (p=0.1). Perfect adherence was associated with a higher probability of undetectable viral load at the 12-month visit (odds ratio=4.1, 95% confidence interval: 1.8-9.1; p<0.001), but not at enrollment or the 6-month visit (p>0.3). Last time missed any antiretroviral therapy dose was reported as "never" for 52.0% at enrollment, increasing to 60.7% and 65.9% at the 6- and 12-month visits, respectively (p<0.001 for test of trend). The proportion with undetectable viral load was higher among those who never missed a dose at enrollment and the 12-month visit (p≤0.005), but not at the 6-month visit (p=0.2). While antiretroviral therapy adherence measures utilized in this study showed some association with viral load for these Latin American children, they may not be adequate for reliably identifying non-adherence and consequently children at risk for viral resistance. Other strategies are needed to improve the evaluation of adherence in this population.

Factors associated with lack of viral suppression at delivery among highly active antiretroviral therapy-naive women with HIV: a cohort study.

BACKGROUND: A high delivery maternal plasma HIV-1 RNA level (viral load [VL]) is a risk factor for mother-to-child transmission and poor maternal health. OBJECTIVE: To identify factors associated with detectable VL at delivery despite initiation of highly active antiretroviral therapy (HAART) during pregnancy. DESIGN: Multicenter observational study. (ClinicalTrial.gov: NCT00028145). SETTING: 67 U.S. AIDS clinical research sites. PATIENTS: Pregnant women with HIV who initiated HAART during pregnancy. MEASUREMENTS: Descriptive summaries and associations among sociodemographic, HIV disease, and treatment characteristics; pregnancy-related risk factors; and detectable VL (>400 copies/mL) at delivery. RESULTS: Between 2002 and 2011, 671 women met inclusion criteria and 13.1% had detectable VL at delivery. Factors associated with detectable VL included multiparity (16.4% vs. 8.0% nulliparity; P = 0.002), black ethnicity (17.6% vs. 6.6% Hispanic and 6.6% white; P < 0.001), 11th grade education or less (17.6% vs. 12.1% had a high school diploma; P = 0.013), initiation of HAART in the third trimester (23.9% vs. 12.3% and 8.6% in the second and trimesters, respectively; P = 0.003), having an HIV diagnosis before the current pregnancy (16.1% vs. 11.0% during the current pregnancy; P = 0.051), and having the first prenatal visit in the third trimester (33.3% vs. 14.3% and 10.5% in the second and third trimesters, respectively; P = 0.002). Women who had treatment interruptions or reported poor medication adherence were more likely to have detectable VL at delivery. LIMITATION: Data on many covariates were incomplete because women entered the study at varying times during pregnancy. CONCLUSION: A total of 13.1% of women who initiated HAART during pregnancy had detectable VL at delivery. The timing of HAART initiation and prenatal care, along with medication adherence during pregnancy, were associated with detectable VL at delivery. Social factors, including ethnicity and education, may help identify women who could benefit from focused efforts to promote early HAART initiation and adherence. PRIMARY FUNDING SOURCE: U.S. Department of Health and Human Services.

Biomarkers and neurodevelopment in perinatally HIV-infected or exposed youth: a structural equation model analysis.

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.

Relationship between viral load and self-report measures of medication adherence among youth with perinatal HIV infection.

Poor adherence to antiretroviral therapy (ART) contributes to disease progression and emergence of drug-resistant HIV in youth with perinatally acquired HIV infection (PHIV +), necessitating reliable measures of adherence. Although electronic monitoring devices have often been considered the gold-standard assessment in HIV research, they are costly, can overestimate nonadherence and are not practical for routine care. Thus, the development of valid, easily administered self-report adherence measures is crucial for adherence monitoring. PHIV+youth aged 7-16 (n = 289) and their caregivers, enrolled in a multisite cohort study, were interviewed to assess several reported indicators of adherence. HIV-1 RNA viral load (VL) was dichotomized into >/≤ 400 copies/mL. Lower adherence was significantly associated with VL >400 copies/mL across most indicators, including ≥ 1 missed dose in past seven days [youth report: OR = 2.78 (95% CI, 1.46-5.27)]. Caregiver and combined youth/caregiver reports yielded similar results. Within-rater agreement between various adherence indicators was high for both youth and caregivers. Inter-rater agreement on adherence was moderate across most indicators. Age ≥ 13 years and living with biological mother or relative were associated with VL >400 copies/mL. Findings support the validity of caregiver and youth adherence reports and identify youth at risk of poor adherence.

Biomarkers from late pregnancy to 6 weeks postpartum in HIV-infected women who continue versus discontinue antiretroviral therapy after delivery.

BACKGROUND: Women who use antiretroviral therapy (ART) solely for the prevention of mother-to-child transmission of HIV discontinue postpartum. We hypothesized that women discontinuing ART by 6 weeks postpartum ("discontinuers") would have elevated postpartum inflammatory biomarker levels relative to women remaining on ART postpartum ("continuers"). METHODS: Data from HIV-infected pregnant women enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1025 with CD4 counts >350 cells per cubic millimeter before initiating ART or first pregnancy CD4 counts >400 cells per cubic millimeter after starting ART and with available stored plasma samples at >20 weeks of gestation, delivery, and 6 weeks postpartum were analyzed. Plasma samples were tested for highly sensitive C-reactive protein, D-dimer, and interleukin-6. We used longitudinal linear spline regression to model biomarkers over time. RESULTS: Data from 128 women (65 continuers and 63 discontinuers) were analyzed. All biomarkers increased from late pregnancy to delivery, then decreased postpartum (slopes different from 0, P < 0.001). Continuers had a steeper decrease in log D-dimer between delivery and 6 weeks postpartum than discontinuers (P = 0.002). CONCLUSIONS: In contrast to results from treatment interruption studies in adults, both ART continuers and ART discontinuers had significant decreases in the levels of D-dimer, highly sensitive C-reactive protein, or interleukin-6 postpartum. Continuation was associated with a more rapid decline in D-dimer levels compared with discontinuation.

Cardiac status of children infected with human immunodeficiency virus who are receiving long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the Multicenter Pediatric HIV/AIDS Cohort Study.

IMPORTANCE: Prior to contemporary antiretroviral therapies (ARTs), children infected with human immunodeficiency virus (HIV) were more likely to have heart failure. This study suggests that highly active ART (HAART) does not appear to impair heart function. OBJECTIVE: To determine the cardiac effects of prolonged exposure to HAART on HIV-infected children. DESIGN: In the National Institutes of Health-funded Pediatric HIV/AIDS Cohort Study's Adolescent Master Protocol (AMP), we used linear regression models to compare echocardiographic measures. SETTING: A total of 14 US pediatric HIV clinics. PARTICIPANTS: Perinatally HIV-infected children receiving HAART (n = 325), HIV-exposed but uninfected children (n = 189), and HIV-infected (mostly HAART-unexposed) historical pediatric controls from the National Institutes of Health-funded Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2-HIV) Study (n = 70). EXPOSURE Long-term HAART. MAIN OUTCOMES AND MEASURES: Echocardiographic measures of left ventricular (LV) function and structure. RESULTS: The 325 AMP HIV-infected children had lower viral loads, higher CD4 counts, and longer durations of ART than did the 70 HIV-infected children from the P2C2-HIV Study (all P < .001). The z scores for LV fractional shortening (a measure of cardiac function) were significantly lower among HIV-infected children from the P2C2-HIV Study than among the AMP HIV-infected group or the 189 AMP HIV-exposed but uninfected controls (P < .05). For HIV-infected children, a lower nadir CD4 percentage and a higher current viral load were associated with significantly lower cardiac function (LV contractility and LV fractional shortening z scores; all P = .001) and an increased LV end-systolic dimension z score (all P < .03). In an interaction analysis by HIV-infected cohort, the HIV-infected children from the P2C2-HIV Study with a longer ART exposure or a lower nadir CD4 percentage had lower mean LV fractional shortening z scores, whereas the mean z scores were relatively constant among AMP HIV-infected children (P < .05 for all interactions). CONCLUSIONS AND RELEVANCE: Long-term HAART appears to be cardioprotective for HIV-infected children and adolescents.