Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Antenatal Intracellular Concentrations of Tenofovir Diphosphate and Emtricitabine Triphosphate and Associations Between Tenofovir Diphosphate and Severe Adverse Pregnancy Outcomes: IMPAACT-PROMISE (1077BF) Trial.

BACKGROUND: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration. METHODS: Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression. RESULTS: Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively. CONCLUSIONS: TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.

Alendronate Improves Bone Mineral Density in Children and Adolescents Perinatally Infected With Human Immunodeficiency Virus With Low Bone Mineral Density for Age.

BACKGROUND: Children and adolescents with perinatal human immunodeficiency virus (HIV) infection and with low bone mineral density (BMD) may be at higher risk of osteoporosis and fractures in later life than their uninfected peers. Bisphosphonate therapy has been shown to reduce fractures in adults with osteoporosis, but has not been formally studied in youths living with HIV. METHODS: Fifty-two children and adolescents (aged 11-24 years) perinatally infected with HIV with low lumbar spine (LS) BMD (Z score < -1.5) were randomized to receive once-weekly alendronate or placebo in a double-blind cross-over study designed to assess the safety and efficacy of 48 and 96 weeks of alendronate in the United States and Brazil. All participants received daily calcium carbonate and vitamin D supplementation and were asked to engage in regular weight-bearing exercise. Safety and efficacy are summarized for the initial 48 weeks of the trial. RESULTS: Grade 3 or higher abnormal laboratory values, signs, or symptoms developed in 5 of 32 (16%) participants on alendronate and 2 of 18 (11%) on placebo (P > .99). No cases of jaw osteonecrosis, atrial fibrillation, or nonhealing fractures were reported. Mean increases (95% confidence interval) in LS BMD over 48 weeks were significantly larger on alendronate (20% [14%-25%]) than placebo (7% [5%-9%]) (P < .001). Similar improvements were seen for whole body BMD. CONCLUSIONS: In this small study in children and adolescents perinatally infected with HIV with low LS BMD, 48 weeks of alendronate was well-tolerated, showed no safety concerns, and significantly improved LS and whole body BMD compared to participants on vitamin D/calcium supplementation and exercise alone. CLINICAL TRIALS REGISTRATION: NCT00921557.

Advancing HIV Biomedical Prevention Research for At-Risk Adolescents.

Despite significant additions to the HIV prevention toolbox, infection rates across the United States continue to rise among vulnerable adolescents and young adults. Access to these interventions by youth at risk for HIV is limited by the lack of data about their safety and use, compounding the myriad contextual barriers to effectively preventing HIV in this group. The NIH-funded Adolescent Trials Network implemented an innovative approach to the inclusion of adolescents at risk for HIV infection who consented for their own participation in the first adolescent study of HIV pre-exposure prophylaxis (PrEP). This model of mature minor consent was supported by state-based adolescent treatment statutes that extend an adolescent's ability to consent to participation in research with a sufficient prospect of clinical benefit from the intervention to justify the potential risks, and a balance of benefits and risks that is at least as favorable as available evidence-based alternatives. Important data on the safety and patterns of PrEP use by at-risk adolescents prompted the FDA to revise the label. The expanded indication of PrEP for HIV prevention in adolescents is hoped to inform clinical guidelines and provides a powerful tool to reduce new infections in the United States among vulnerable at-risk adolescents. Lessons learned from this years-long iterative endeavor have implications for improving access to the rapidly evolving landscape of HIV prevention modalities, including recently implemented studies of long-acting PrEP formulations designed to reduce the burden of daily adherence required by oral PrEP, a major clinical pitfall for adolescent clinicians and their patients.

Strategies for Identifying and Linking HIV-Infected Infants, Children, and Adolescents to HIV Treatment Services in Resource Limited Settings.

Many children living with HIV in resource-limited settings remain undiagnosed and at risk for HIV-related mortality and morbidity. This article describes 5 key strategies for strengthening HIV case finding and linkage to treatment for infants, children, and adolescents. These strategies result from lessons learned during the Accelerating Children's HIV/AIDS Treatment Initiative, a public-private partnership between the President's Emergency Plan for AIDS Relief (PEPFAR) and the Children's Investment Fund Foundation (CIFF). The 5 strategies include (1) implementing a targeted mix of HIV case finding approaches (eg, provider-initiated testing and counseling within health facilities, optimization of early infant diagnosis, index family testing, and integration of HIV testing within key population and orphan and vulnerable children programs); (2) addressing the unique needs of adolescents; (3) collecting and using data for program improvement; (4) fostering a supportive political and community environment; and (5) investing in health system-strengthening activities. Continued advocacy and global investments are required to eliminate AIDS-related deaths among children and adolescents.

Risk for Speech and Language Impairments in Preschool Age HIV-exposed Uninfected Children With In Utero Combination Antiretroviral Exposure.

BACKGROUND: Perinatally HIV-exposed but uninfected (HEU) children have elevated risk of late language emergence at 1 year of age, with possible links to in utero antiretroviral (ARV) exposure. We investigated possible risks for speech impairments (SIs) and language impairments (LI) in preschool monolingual HEU children in the United States. METHODS: Speech and language assessments were conducted as part of the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities study at ages 3 (N = 208) and 5 (N = 429) years. Domains of speech, overall language, vocabulary and grammar were assessed. SI and LI were defined by standardized scores <15th percentile and categorized as primary (normal nonverbal IQ ≥ 85 without hearing loss) and concomitant (low nonverbal IQ and/or presence of hearing loss). Logistic regression models were used to estimate odds of SI and LI for different ARV exposures, adjusted for confounding variables. RESULTS: The risk for language impairments in HEU children was higher than population norms; risk for SIs was not elevated. Risk factors for impairments included male sex, black race and other socioeconomic measures, although these varied by age, primary (P) versus concomitant (C) impairment and by speech or language measure. Adjusted logistic regression models revealed lower and increased risk for specific ARVs. Tenofovir exposure was associated with increased risk for SI at 3 years of age but was associated with decreased risk for concomitant language impairment at 5 years of age. CONCLUSIONS: Further investigation of combination ARV exposure and speech/language impairment among preschool children is needed to confirm associations.

Impact of Human Immunodeficiency Virus Drug Resistance on Treatment of Human Immunodeficiency Virus Infection in Children in Low- and Middle-Income Countries.

Children living with human immunodeficiency virus (HIV) in low- and middle-income countries (LMICs) experience higher rates of virologic failure than adults. Human immunodeficiency virus drug resistance (HIVDR) plays a major role in pediatric HIV treatment failure because nonsuppressive maternal antiretroviral therapy (ART) during pregnancy and breastfeeding as well as infant antiretroviral prophylaxis lead to high rates of pretreatment drug resistance to regimens most commonly used in children living with HIV. Lack of availability of durable, potent drugs in child-friendly formulations in LMICs and adherence difficulties contribute to acquired drug resistance during treatment. Optimizing drugs available for treating children living with HIV in LMICs, providing robust adherence support, and ensuring virologic monitoring for children receiving ART are essential for reducing HIVDR and improving treatment outcomes for children living with HIV in LMICs.

Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is complicated by cirrhosis and liver cancer. In Thailand, 6-7 % of adults are chronically infected with HBV. The risk of mother-to-child transmission (MTCT) of HBV has been estimated to be about 12 % when mothers have a high hepatitis B viral load, even if infants receive passive-active prophylaxis with HBV immunoglobulin (HBIg) and initiate the hepatitis B vaccine series at birth. We designed a study to assess the efficacy and safety of a short course of maternal tenofovir disoproxil fumarate (TDF) among women with a marker of high viral load for the prevention of MTCT of HBV. METHODS: The study is a phase III, multicenter (17 sites in Thailand), placebo-controlled, double-blind, randomized 1:1, two-arm clinical trial of TDF 300 mg once daily versus placebo among pregnant women from 28 weeks' gestation through 2-month post-partum. All infants receive HBIg at birth, and a hepatitis B (HB) vaccination series according to Thai guidelines: birth, and age 1, 2, 4 and 6 months. Participant women at study entry must be age ≥18 years, hepatitis B surface antigen (HBsAg) and e-antigen (HBeAg) positive, have alanine aminotransferase (ALT) level < 30 IU/L at screening (confirmed < 60 IU/L pre-entry), negative hepatitis C serology, creatinine clearance >50 mL/min, and no history of anti-HBV antiviral treatment. The target sample size of 328 mother/infant pairs assumed 156 evaluable cases per arm to detect a ≥9 % difference in MTCT transmission (3 % experimental arm versus 12 % placebo arm) with 90 % power. Mothers and infants are followed until 12 months after delivery. The primary infant endpoint is detection of HBsAg, confirmed by detection of HBV DNA at six months of age. Secondary endpoints are maternal and infant adverse events, acute exacerbations of maternal hepatitis B disease (ALT >300 IU/L, defined as a "flare") following discontinuation of study treatment, infant HBV infection status and growth up to 12 months of age. DISCUSSION: The results of this randomized trial will clarify the efficacy and safety of a short course of antiviral treatment to prevent mother-to-child transmission of HBV and inform international guidelines. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01745822 .

Long-term postpartum adherence to antiretroviral drugs among women in Latin America.

Antiretroviral adherence in the postpartum period is crucial for maternal health and decreasing the risk of mother-to-child HIV transmission and transmission to sexual partners. Self-reported antiretroviral adherence was examined between 6- to 12-weeks and 30 months postpartum among 270 HIV-infected women enrolled in a prospective cohort study from 2008 to 2010 at multiple sites in Latin America. Adherence data were collected at each study visit to quantify the proportion of prescribed antiretrovirals taken during the previous three days, assess the timing of the last missed dose, and identify predictors of adherence. Mean adherence rates were 89.5% at 6-12 weeks and 92.4% at 30 months; the proportions with perfect adherence were 80.3% and 83.6%, respectively. The overall trend for perfect adherence was not significant (p = 0.71). In adjusted regression modelling, younger age was associated with an increased probability of non-perfect adherence at 18 and 24 months postpartum. Other factors associated with increased probability of non-perfect adherence were higher parity, current use of alcohol and tobacco, and more advanced HIV disease. Women with perfect adherence had lower viral loads. Interventions for alcohol and tobacco use cessation, and support for young women and those with advanced HIV disease should be considered to improve postpartum adherence.

Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.

Undervaccination of perinatally HIV-infected and HIV-exposed uninfected children in Latin America and the Caribbean.

BACKGROUND: Perinatally HIV-infected (PHIV) children may be at risk of undervaccination. Vaccination coverage rates among PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean were compared. METHODS: All PHIV and HEU children born from 2002 to 2007 who were enrolled in a multisite observational study conducted in Latin America and the Caribbean were included in this analysis. Children were classified as up to date if they had received the recommended number of doses of each vaccine at the appropriate intervals by 12 and 24 months of age. Fisher's exact test was used to analyze the data. Covariates potentially associated with a child's HIV status were considered in multivariable logistic regression modeling. RESULTS: Of 1156 eligible children, 768 (66.4%) were HEU and 388 (33.6%) were PHIV. HEU children were significantly (P < 0.01) more likely to be up to date by 12 and 24 months of age for all vaccines examined. Statistically significant differences persisted when the analyses were limited to children enrolled before 12 months of age. Controlling for birth weight, sex, primary caregiver education and any use of tobacco, alcohol or illegal drugs during pregnancy did not contribute significantly to the logistic regression models. CONCLUSIONS: PHIV children were significantly less likely than HEU children to be up to date for their childhood vaccinations at 12 and 24 months of age, even when limited to children enrolled before 12 months of age. Strategies to increase vaccination rates in PHIV are needed.

Bone health in children and adolescents with perinatal HIV infection.

The long-term impact on bone health of lifelong HIV infection and prolonged ART in growing and developing children is not yet known. Measures of bone health in youth must be interpreted in the context of expected developmental and physiologic changes in bone mass, size, density and strength that occur from fetal through adult life. Low bone mineral density (BMD) appears to be common in perinatally HIV-infected youth, especially outside of high-income settings, but data are limited and interpretation complicated by the need for better pediatric norms. The potential negative effects of tenofovir on BMD and bone mass accrual are of particular concern as this drug may be used more widely in younger children. Emphasizing good nutrition, calcium and vitamin D sufficiency, weight-bearing exercise and avoidance of alcohol and smoking are effective and available approaches to maintain and improve bone health in all settings. More data are needed to inform therapies and monitoring for HIV-infected youth with proven bone fragility. While very limited data suggest lack of marked increase in fracture risk for youth with perinatal HIV infection, the looming concern for these children is that they may fail to attain their expected peak bone mass in early adulthood which could increase their risk for fractures and osteoporosis later in adulthood.

Perinatally HIV-infected youth presenting with acute stroke: progression/evolution of ischemic disease on neuroimaging.

BACKGROUND AND PURPOSE: Although HIV infection is decreasing in infants and children, there is a steady cohort of perinatally HIV-infected (PHIV) children that are growing older. Increased risk of acute stroke has been reported in PHIV children. Our goal was to evaluate evolution/progression of neuroimaging findings in PHIV youth initially presenting with acute stroke. MATERIALS AND METHODS: The medical records of PHIV pediatric patients (n = 179) from 1996 to 2010 were reviewed and patients with clinical documentation of acute stroke referred to the neuroradiology service were eligible for the study. Neuroimaging (brain CT, MRI, and MRA) and charts were evaluated; clinical and neuroimaging findings at the initial acute stroke and at the last presentation to the neuroradiology service were documented and analyzed. RESULTS: Eight PHIV patients with clinical findings of acute stroke referred to the neuroimaging were identified. CT and MRI findings of infarction were found in all (8/8) patients in their first and/or last neuroimaging study; including basal ganglia-thalami (BGT) infarction (7/8), focal cortical infarction (4/8), and internal capsule infarction (4/8). Imaging depicted cortical atrophy (5/8), BGT calcification (3/8), and posterior reversible encephalopathy syndrome, wallerian degeneration, and periventricular white matter hyperintense T2 signal each in one patient. No tumors or infectious masses, cysts or abscesses were identified. Subsequent available neuroimaging revealed progression of the cerebrovascular disease in seven patients, 5/7 in the absence of new clinical signs or symptoms. Segmental occlusion, narrowing or narrowing/dilatation in the circle of Willis was found in 6/6 patients who underwent MR angiography and fusiform aneurysms were detected in three of them, a saccular aneurysm in one patient. CONCLUSION: Asymptomatic progression of cerebrovascular disease was found in PHIV adolescents with prior stroke. These findings may have implications for long-term risk and outcomes for this patient population. There should be a low threshold to evaluate for CNS pathology even with minor symptoms in this population. More studies are necessary to determine if there is a benefit from screening of asymptomatic patients.

Institutional prevention policies and rates of Group B Streptococcus infection among HIV-infected pregnant women and their infants in Latin America.

OBJECTIVE: To describe Group B Streptococcus (GBS) prevention policies at 12 Latin American sites participating in the NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development) International Site Development Initiative (NISDI) Longitudinal Study in Latin American Countries (LILAC) and to determine rates of rectovaginal colonization and GBS-related disease among HIV-infected pregnant women and their infants. METHODS: Site surveys were used to assess prevention policies and practices administered cross-sectionally during 2010. Data collected in NISDI from 2008 to 2010 regarding HIV-infected pregnant women were used to determine rates of colonization and GBS-related disease. RESULTS: Of the 9 sites with a GBS prevention policy, 7 performed routine rectovaginal screening for GBS. Of the 401 women included in the NISDI study, 56.9% were at sites that screened. The GBS colonization rate was 8.3% (19/228 women; 95% confidence interval [CI], 5.1%-12.7%). Disease related to GBS occurred in 0.5% of the participants (2/401 women; 95% CI, 0.1%-1.8%); however, no GBS-related disease was reported among the 398 infants (95% CI, 0.0%-0.9%). CONCLUSION: Improved efforts to implement prevention policies and continued surveillance for GBS are needed to understand the impact of GBS among HIV-infected pregnant women and their infants in Latin America.

Cardiac biomarkers in HIV-exposed uninfected children.

OBJECTIVES: To evaluate associations of cardiac biomarkers with in-utero antiretroviral drug exposures and cardiac function/structure measured by echocardiograms in HIV-exposed but uninfected (HEU) children. DESIGN AND METHODS: We analyzed the association of three cardiac biomarkers (cardiac troponin T, cTnT; high sensitivity C-reactive protein, hsCRP; and N-terminal pro-brain natriuretic peptide, NT-proBNP) with prenatal antiretroviral drug exposures, maternal-child characteristics, and echocardiographic parameters. RESULTS: Among 338 HEU children (mean age 4.3 years), 51% had at least one elevated cardiac biomarker. Maternal tobacco use was associated with elevated NT-proBNP [adjusted odds ratio (aOR) 2.28, P=0.02]. Maternal alcohol and abacavir use were associated with elevated cTnT levels (aOR 3.56, P=0.01 and aOR 2.33, P=0.04, respectively). Among 94 children with paired echocardiogram-biomarker measurements, cTnT measurements were correlated with increased left-ventricular thickness-to-dimension ratio (r=0.21, P=0.04); and elevated cTnT was associated with higher mean left-ventricular end-diastolic (LVED) posterior wall thickness (P=0.04). hsCRP measurements were negatively correlated with septal thickness (r=-0.22, P=0.03) and elevated hsCRP was associated with lower mean left-ventricular contractility Z-scores (P=0.04). NT-proBNP measurements were correlated with increased LVED dimension (r=0.20, P=0.05) and elevated NT-proBNP was associated with lower mean end-systolic septal thickness (P=0.03). CONCLUSION: Our findings suggest that cardiac biomarkers may help identify HEU children who require further cardiac evaluation including echocardiography. Potential cardiac effects of prenatal abacavir exposure in this population need further investigation.

Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth.

BACKGROUND: There is limited information on antiretroviral (ARV) regimens and outcomes in perinatally HIV (PHIV)-infected youth. Substantial drug resistance after long-term ARV use and nonadherence hinder efforts to design suppressive regimens for PHIV-infected youth. This study compares clinical outcomes by expected activity of the prescribed ARV regimens. METHODS: A retrospective cohort study of 13- to 24-year-old PHIV-infected youth on stable ARV regimens for ≥6 months was conducted at a pediatric HIV clinic. ARV regimens were retrospectively categorized as optimal or suboptimal based on accumulated genotypic resistance before study regimen initiation. RESULTS: Fifty-two patients with similar baseline characteristics met inclusion criteria (21 optimal and 31 suboptimal regimens). Patients receiving optimal regimens had significantly higher increases in CD4 than those given suboptimal regimens by week 48 of treatment (+62 versus +8 cells/mm, respectively; P = 0.04) and by the end of study period (+93 versus -1 cells/mm, respectively; P = 0.03). There were no significant differences between the groups in decline of viral load, frequency of opportunistic infections or hospitalizations or accumulation of resistance mutations. Overall, 60% of the optimal and 45% of the suboptimal groups had nonadherence during the study regimen (P = 0.3). CONCLUSIONS: PHIV-infected youth receiving optimal regimens had greater CD4 improvements but no difference in virologic outcomes compared with those receiving suboptimal regimens. In a patient population with significant nonadherence, providers must weigh the immunologic benefits of initiating an optimal regimen versus the potential risks of further resistance accumulation limiting future treatment options.

Language impairment in children perinatally infected with HIV compared to children who were HIV-exposed and uninfected.

OBJECTIVE: To investigate the risk for language impairment (LI) in children perinatally infected or exposed to HIV. METHODS: We evaluated the prevalence of LI in 7- to 16-year-old children with perinatal HIV infection (HIV+) compared with HIV-exposed and uninfected children, using a comprehensive standardized language test (Clinical Evaluation of Language Functioning-Fourth Edition [CELF-4]). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease, and antiretroviral treatment factors with LI category were evaluated using univariate and multivariable logistic regression models. RESULTS: Of the 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ versus 87.5 (17.9) for HIV-exposed and uninfected children. After adjustment, black children had higher odds of Pri-LI versus no LI (adjusted odds ratio [aOR] = 2.43, p = .03). Children who were black, Hispanic, had a caregiver with low education or low intelligence quotient, or a nonbiological parent as caregiver had higher odds of Con-LI versus no LI. Among HIV+ children, viral load >400 copies/mL (aOR = 3.04, p < .001), Centers for Disease Control and Prevention Class C (aOR = 2.19, p = .02), and antiretroviral treatment initiation <6 months of age (aOR = 2.12, p = .02) were associated with higher odds of Con-LI versus no LI. CONCLUSIONS: Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI.

A mechanistic role for type III IFN-λ1 in asthma exacerbations mediated by human rhinoviruses.

RATIONALE: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. OBJECTIVES: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. METHODS: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. MEASUREMENTS AND MAIN RESULTS: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). CONCLUSIONS: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ(1) responses mediate exacerbations caused by HRV. Modulation of IFN- λ(1) should be studied as a therapeutic target for exacerbations caused by HRV.