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Despite considerable reduction of mother-to-child transmission (MTCT) of HIV through use of maternal and infant antiretroviral therapy (ART), over 150,000 infants continue to become infected with HIV annually, falling far short of the World Health Organization goal of reaching, Author summary Despite widespread, effective use of ART among HIV infected pregnant women, new pediatric HIV infections increase by about 150,000 every year. Thus, alternative strategies will be required to reduce MTCT and eliminate pediatric HIV infections. Interestingly, in the absence of ART, less than half of HIV-infected pregnant women will transmit HIV, suggesting natural immune protection of infants from virus acquisition. To understand the impact of maternal plasma autologous virus neutralization responses on MTCT, we compared the plasma and bnAb neutralization sensitivity of the circulating viral population present at the time of delivery in untreated, HIV-infected transmitting and non-transmitting mothers. While there was no significant difference in the ability of transmitting and non-transmitting women to neutralize their own circulating virus strains, specific genetic motifs enriched in variants from transmitting mothers were associated with resistance to bnAbs, suggesting that acquired bnAb resistance is a common feature of vertically-transmitted variants. This work suggests that enhancement of plasma neutralization responses in HIV-infected mothers through passive or active vaccination could further drive selection of variants that could be vertically transmitted, and cautions the use of passive bnAbs for HIV-1 prophylaxis or therapy during pregnancy.

OBJECTIVES To quantify the rate of change in epigenetic age compared with chronological age over time in youth with perinatally acquired HIV (YPHIV) and youth who are perinatally HIV-exposed uninfected (YPHEU). DESIGN Longitudinal study of 32 YPHIV and 8 YPHEU with blood samples collected at two time points at least 3 years apart. METHODS DNA methylation was measured using the Illumina MethylationEPIC array and epigenetic age was calculated using the Horvath method. Linear mixed effects models were fit to estimate the average change in epigenetic age for a 1-year change in chronological age separately for YPHIV and YPHEU. RESULTS Median age was 10.9 and 16.8 years at time 1 and 2, respectively. Groups were balanced by sex (51% male) and race (67% black). Epigenetic age increased by 1.23 years (95% CI 1.03--1.43) for YPHIV and 0.95 years (95% CI 0.74--1.17) for YPHEU per year increase in chronological age. Among YPHIV, in a model with chronological age, a higher area under the curve (AUC) viral load was associated with an increase in epigenetic age over time [2.19 years per log10 copies/ml, (95% CI 0.65--3.74)], whereas a higher time-averaged AUC CD4+ T-cell count was associated with a decrease in epigenetic age over time [-0.34 years per 100 cells/μl, (95% CI -0.63 to -0.06)] in YPHIV. CONCLUSION We observed an increase in the rate of epigenetic aging over time in YPHIV, but not in YPHEU. In YPHIV, higher viral load and lower CD4+ T-cell count were associated with accelerated epigenetic aging, emphasizing the importance of early and sustained suppressive treatment for YPHIV, who will receive lifelong ART.

Objectives To estimate birth prevalence of congenital cytomegalovirus (cCMV) in HIV-exposed uninfected children born in the current era of combination antiretroviral therapy and describe cCMV-related neurodevelopmental and hearing outcomes. Study design The Surveillance Monitoring for ART Toxicities cohort study follows HIV-exposed uninfected children at 22 sites in the US and Puerto Rico. Birth cCMV prevalence was estimated in a subset of participants who had blood pellets collected within three weeks of birth and underwent ≥1 of 6 assessments evaluating cognitive and language development including an audiologic examination between 1 and 5 years of age. Detection of CMV DNA by polymerase chain reaction testing of peripheral blood mononuclear cells was used to diagnose cCMV. Proportions of suboptimal assessment scores were compared by cCMV status using Fisher exact test. Results Mothers of 895 eligible HIV-exposed uninfected children delivered between 2007 and 2015. Most (90%) were on combination antiretroviral therapy, 88% had an HIV viral load of ≤400 copies/mL, and 93% had CD4 cell counts of ≥200 cells/μL. Eight infants were diagnosed with cCMV, yielding an estimated prevalence of 0.89% (95% CI, 0.39%-1.75%). After adjusting for a sensitivity of 70%-75% for the testing method, projected prevalence was 1.2%-1.3%. No differences were observed in cognitive, language and hearing assessments by cCMV status. Conclusions Although birth cCMV prevalence in HIV-exposed uninfected children born to women with well-controlled HIV is trending down compared with earlier combination antiretroviral therapy-era estimates, it is above the 0.4% reported for the general US population. HIV-exposed uninfected children remain at increased risk for cCMV.

BACKGROUND Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration. METHODS In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks. FINDINGS At the data cutoff of Sept 16, 2015, 182 747 children with HIV were included in the CIPHER dataset, of whom 93 351 were eligible, with 83 984 (90·0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3·9 years (IQR 1·6-6·9) and 82 885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9-52). 3883 (4·2%) patients switched to second-line ART after a median of 35 months (IQR 20-57) of ART. The cumulative incidence of switching at 3 years was 3·1% (95% CI 3·0-3·2), but this estimate varied widely depending on the cohort monitoring strategy, from 6·8% (6·5-7·2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0·8% (0·6-1·0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p

The benefits of early combination antiretroviral therapy (cART) in HIV-infected children are well described and include improvement in virologic and immunologic parameters and reductions in mortality, hospital admissions and comorbidities such as HIV encephalopathy and cardiomyopathy [1–6]. The WHO recommends initiation of cART in all HIV-infected children under 5 years of age [1,7]. However, sustaining the benefits of early treatment requires lifelong adherence to cART, which is hampered by dependence on caregivers for cART administration, poor palatability of drugs, pill burden and frequency of administration, drug toxicities and developmental changes, especially during adolescence [8–10]. Globally, excellent virologic suppression rates in children receiving cART have been described with over 80% viral suppression at 36-month follow-up [11,12]. However, 30–40% of children develop virologic failure over time [13]. In children who develop virologic failure, switching to a new cART regimen on the basis of viral drug resistance testing can lead to virologic suppression. Success of this approach relies on overcoming adherence barriers and on the availability of potent drugs to construct a new cART regimen to which the child's virus is susceptible. In resourced settings, highly treatment-experienced children with prior exposure to numerous antiretroviral drugs are presented with the challenges of multiresistant HIV and lack of active drugs [14]. In resource-limited settings, in which financial and structural constraints limit access to new drugs, it is often difficult to access potent new cART regimens for children with virologic failure on first-line therapy. As more children access cART globally, challenges around optimal management of virologic failure are likely to intensify. Treatment options explored by various studies include optimizing therapy with a new CART regimen [15]; continuing with a failing regimen [16]; switching to a simplified, non-cART drug-sparing regimen [17]; and treatment interruption [18]. No studies to date have directly compared immunological and virologic outcomes with these treatment options in children with virologic failure. We used observational data from two large US-based prospective cohorts of perinatally infected children and adolescents (PHIV) to address this question. Among PHIV with virologic failure after at least 6 months of cART, we compared immunological and virologic outcomes 12 months after virologic failure in children managed with the following treatment options: continue with current failing cART; switch to a new cART; switch to a non-cART, drug-sparing regimen and discontinue all ART.

Background Pregnancy outcomes of perinatally human immunodeficiency virus-infected women (PHIV) are poorly defined. Methods We compared preterm delivery and birth weight (BW) outcomes (low BW [LBW]

Background. Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown. Methods. We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1-infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were

APOL1 renal risk alleles are associated with chronic kidney disease (CKD) in adults, with the strongest effect being for HIV-associated nephropathy. Their role in youth with perinatal HIV-1 infection (PHIV) has not been studied. In a nested case-control study of 451 PHIV participants in the Pediatric HIV/AIDS Cohort Study, we found a 3.5-fold increased odds of CKD in those carrying high-risk APOL1 genotypes using a recessive model [95% confidence interval (CI): 1.2 to 10.0]. We report an unadjusted incidence of 1.2 CKD cases/100 person-years (95% CI: 0.5 to 2.5) in PHIV youth carrying APOL1 high-risk genotypes, with important implications for sub-Saharan Africa.

John J Hawkshead III,1 Russell B Van Dyke,2 Susan E Hassig,3 Larry S Webber,4 Rodolfo E Begue5 1Merck & Co, CORE Hospital Specialty Group, Rahway, NJ, 2Department of Pediatrics, Tulane University School of Medicine, 3Department of Epidemiology, 4Department of Biostatistics, Tulane University School of Public Health and Tropical Medicine, 5Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, USA Background: Pediatric Candida infections are associated with worse clinical outcomes and increased costs. Yet, it is not definitively known if particular species are associated with more severe illness. Differential risk factor exposures among the species group may also exist. We aimed to determine whether certain Candida species are more strongly associated with worse outcomes, and whether certain risk factors more strongly predispose patients to infection with certain species. Methods: Microbiology lab records from patients seen from 2003 to 2010 at an urban children's hospital were reviewed for invasive or disseminated Candida infections. Data on measures of disease severity/outcome and risk factors were abstracted and analyzed to determine differences associated with various Candida species. Results: Exactly 106 cases of infection were analyzed. Non-albicans species were associated with a significantly longer length of stay postdiagnosis (P=0.03), as well as longer treatment (P=0.02). Candida albicans was associated with a higher number of antihypotensive medications required (P=0.03) and length of mechanical ventilation postdiagnosis (P=0.05). Candida tropicalis was associated with the highest mortality (45.5%). Hypotension, which was found to be significantly associated with concurrent infection, was significantly associated with increased risk of mortality (odds ratio =5.85, P=0.005). Initial choice of antifungal therapy was not associated with differences in eventual patient mortality. Multivariate logistic regression modeling revealed a trend toward C. albicans infection in patients receiving antineoplastic chemotherapy and non-albicans infection in patients with >96 hours mechanical ventilation. Conclusion: Interspecies differences may exist for Candida in terms of disease severity and risk factors. Underlying morbidity and the role of concurrent infections may play a key role in poor outcomes. Keywords: Candida, disseminated, pediatric, severity, risk factors, fungemia, antifungal, coinfection

Background Our recent study showed significantly lower bone mineral content (BMC) in HIV-exposed uninfected (HEU) neonates born to HIV-infected (HIV+) mothers who took tenofovir disoproxil fumarate (TDF) in late pregnancy compared with no TDF use. In this cohort we sought to understand possible mechanisms for lower BMC by comparing markers of bone metabolism and renal function with TDF exposure in HEU neonates. Methods Among a subset of HEU children in the multicenter (United States and Puerto Rico) observational Surveillance Monitoring for ART Toxicities (SMARTT) Cohort study, we enrolled neonates (≥36 weeks gestational age) of HIV+ mothers who took TDF for ≥8 weeks in the third trimester (TDF+) or no TDF in pregnancy (TDF-). In addition to BMC measures, we collected a blood and urine sample on each child ≤30 days of birth to measure serum creatinine, phosphate, 25-OH vitamin D, parathyroid hormone and urine creatinine, phosphate and N-terminal telopeptide. Standard equations were used to estimate proximal tubular phosphate reabsorption and glomerular filtration rate (eGFR). Comparisons were made by TDF exposure using Wilcoxon and Fisher’s exact tests. We fit linear models to compare TDF+ and TDF− for each assay by age in days at sample collection (slope), stratified by age group at sample collection time (0–3 days, 4–30 days). Results Of 160 HEU neonates (Black 71%, Hispanic 31%), 82 were TDF+ and 78 TDF−. Sociodemographic and anthropometric characteristics did not differ by TDF exposure in each age group. Within 0–3 days of life, TDF+ had a greater decline in serum creatinine (P = 0.04) and a greater increase in eGFR compared with TDF− (P = 0.06), but no difference in slope by TDF exposure within 4–30 days of life, nor in serum phosphate in either age group. Proximal tubular phosphate reabsorption was similar for both groups within the first 3 days of life, with a significantly greater decline in phosphate reabsorption between 4 and 30 days of life in the TDF+ compared with the TDF− group (P = 0.006, Figure 1). Bone markers did not differ by TDF exposure for either age group. Conclusion Urinary phosphate loss was increased among HEU neonates of mothers who took TDF in late pregnancy. This suggests proximal tubular dysfunction and may explain, at least in part, the decrease in BMC previously described. Disclosures R. Van Dyke, Giliad Sciences: Grant Investigator, Research grant.

Mitochondrial abnormalities may lead to metabolic complications in HIV-infected children who have been receiving long-term antiretroviral treatment. We conducted a matched, case-control study comparing 21 HIV-infected children with insulin resistance (cases) to 21 HIV-infected children without insulin resistance (controls) to assess differences in mitochondrial DNA (mtDNA) copies/cell and oxidative phosphorylation NADH dehydrogenase (C1) and cytochrome c oxidase (C4) enzyme activities in peripheral blood mononuclear cells. MtDNA copies/cell tended to be lower in cases, and fasting serum glucose levels were inversely and significantly correlated with C1 enzyme activity, more so in cases. Larger pediatric studies should evaluate mitochondrial etiologies of insulin resistance and determine the role of antiretroviral therapies or HIV infection on mitochondrial dysfunction.

Background/Aims: Because of prior inconsistent findings, we studied a large cohort of HIV-infected children to determine: (1) prevalence of insulin resistance (IR); (2) anthropometric and clinical correlates of IR, and (3) concomitant abnormalities of glucose tolerance. Methods: The study population consisted of 451 children from the Pediatric HIV/AIDS Cohort Study. The outcome of interest was HOMA-IR. Covariates included demographic, metabolic, growth, body composition, HIV laboratory tests, and treatment characteristics. Children meeting triggers for IR underwent oral glucose tolerance tests and hemoglobin A1c (HbA1c) measurements. Results: Among 402 children with glucose and insulin measurements, 15.2% had IR of whom 79% were pubertal. IR was associated with higher alanine aminotransferase, body mass index, and nadir CD4%, Tanner stage 5, and ever having received amprenavir. Of those with IR, three had impaired fasting glucose (IFG), three impaired glucose tolerance (IGT), one IFG and IGT, none diabetic glucose tolerance, and three HbA1c between 6.1 and 6.5%. Conclusion: In our cohort of HIV-infected adolescents, we observed a 15.2% prevalence of IR more closely linked to obesity than any other variable. This finding mirrors the high prevalence of obesity-mediated IR in American youth. However, associations with CD4 count and use of protease inhibitors may indicate some effect of HIV and/or its treatment.

In a sample of perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, uninfected (PHEU) adolescents, we examined the co-occurrence of behavioral health risks including mental health problems, onset of sexual and drug use behaviors, and (in PHIV+ youth) nonadherence to antiretroviral therapy (ART). Participants, recruited from 2007 to 2010, included 349 youth, ages 10-16 years, enrolled in a cohort study examining the impact of HIV infection and ART. Measures of the above behavioral health risks were administered to participants and primary caregivers. Nearly half the participants met study criteria for at least one behavioral health risk, most frequently, mental health problems (28%), with the onset of sexual activity and substance use each reported by an average of 16%. Among the sexually active, 65% of PHIV+ and 50% of PHEU youth reported unprotected sex. For PHIV +youth, 34% reported recent ART nonadherence, of whom 45% had detectable HIV RNA levels. Between 16% (PHIV+) and 11% (PHEU) of youth reported at least two behavioral health risks. Older age, but not HIV status, was associated with having two or more behavioral health risks versus none. Among PHIV+ youth, living with a birth mother (versus other caregivers) and detectable viral load were associated with co-occurrence of behavioral health risks. In conclusion, this study suggests that for both PHIV+ and PHEU youth, there are multiple behavioral health risks, particularly mental health problems, which should be targeted by service systems that can integrate prevention and treatment efforts.

Lopinavir (LPV) exposure is reduced during the third trimester of pregnancy. We report the pharmacokinetics of standard LPV-ritonavir dosing (400/100 mg twice daily) in the immediate and early postpartum period when initiated during labor. In 16 human immunodeficiency virus-infected Thai women, the median (range) LPV area under the concentration-time curve and maximum and minimum concentrations in plasma were 99.7 (66.1 to 180.5) μg·h/ml, 11.2 (8.0 to 17.5) μg/ml, and 4.6 (1.7 to 12.5) μg/ml, respectively, at 41 (12 to 74) h after delivery. All of the women attained adequate LPV levels through 30 days postpartum. No serious adverse events were reported.

Background The impact of extended use of ART in developing countries has been enormous. A thorough understanding of all factors contributing to the success of antiretroviral therapy is required. The current study aims to investigate the value of cross-sectional drug resistance monitoring using DNA and RNA oligonucleotide ligation assays (OLA) in treatment cohorts in low-resource settings. The study was conducted in the first cohort of children gaining access to structured ART in Peru. Methods Between 2002–5, 46 eligible children started the standard regimen of AZT, 3TC and NFV Patients had a median age of 5.6 years (range: 0.7-14y), a median viral load of 1.7·105 RNA/ml (range: 2.1·103 – 1.2·106), and a median CD4-count of 232 cells/μL (range: 1–1591). Of these, 20 patients were classified as CDC clinical category C and 31/46 as CDC immune category 3. At the time of cross-sectional analysis in 2005, adherence questionnaires were administered. DNA OLAs and RNA OLAs were performed from frozen PBMC and plasma, RNA genotyping from dried blood spots. Results During the first year of ART, 44% of children experienced virologic failure, with an additional 9% failing by the end of the second year. Virologic failure was significantly associated with the number of resistance mutations detected by DNA-OLA (p < 0.001) during cross-sectional analysis, but also with low immunologic CDC-scores at baseline (p < 0.001). Children who had been exposed to unsupervised short-term antiretrovirals before starting structured ART showed significantly higher numbers of resistance mutations by DNA-OLA (p = 0.01). Detection of M184V (3TC resistance) by RNA-OLA and DNA-OLA demonstrated a sensitivity of 0.93 and 0.86 and specificity of 0.67 and 0.7, respectively, for the identification of virologic failure. The RT mutations N88D and L90M (NFV resistance) detected by DNA-OLA correlated with virologic failure, whereas mutations at RT position 215 (AZT resistance) were not associated with virologic failure. Conclusions Advanced immunosuppression at baseline and previous exposures to unsupervised brief cycles of ART significantly impaired treatment outcomes at a time when structured ART was finally introduced in his cohort. Brief maternal exposures to with AZT +/− NVP for the prevention of mother-to-child transmission did not affect treatment outcomes in this group of children. DNA-OLA from frozen PBMC provided a highly specific tool to detect archived drug resistance. RNA consensus genotyping from dried blood spots and RNA-OLA from plasma consistently detected drug resistance mutations, but merely in association with virologic failure.