Acylcarnitines and Genetic Variation in Fat Oxidation Genes in HIV-infected, Antiretroviral-treated Children With and Without Myopathy.

BACKGROUND: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO). METHODS: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated. RESULTS: Abnormal ACP was 73% (95% CI: 56%-86%) and 62% (95% CI: 45%-78%) in the myopathic and nonmyopathic groups, respectively. No significant association was found between myopathy and having an abnormal ACP (OR = 2.10, P = 0.22). In univariate analysis, a 1-year increase in NRTI use was associated with a 20% increase in odds of at least 1 ACP abnormality [OR (95% CI) = 1.20 (1.03-1.41); P = 0.02), and a 1-year increase in protease inhibitor use was associated with 28% increase in the odds of having at least 1 ACP abnormality [OR (95% CI) = 1.28 (1.07-1.52); P = 0.006). Three SNPs, all in the gene for the carnitine transporter ( SLC22A5 ), were associated with the cardiomyopathy phenotype. CONCLUSION: FAO appears to be altered in HIV-infected children with and without myopathy, but abnormal FAO does not fully explain myopathy in ARV-exposed children. Further study of SLC22A5 variation in ARV-exposed people is warranted carnitine transporter dysfunction-related cardiomyopathy may be treatable.

Disease Progression in Children With Perinatal Human Immunodeficiency Virus Correlates With Increased PD-1+ CD8 T Cells That Coexpress Multiple Immune Checkpoints.

BACKGROUND: PD-1 marks exhausted T cells, with weak effector functions. Adults living with human immunodeficiency virus (HIV) have increased levels of PD-1+ CD8 T cells that correlate with HIV disease progression, yet little is known about the role of PD-1+ CD8 T cells in children with perinatal HIV. METHODS: We enrolled 76 Kenyan children with perinatal HIV and 43 children who were HIV unexposed and quantified PD-1 levels on CD8 T cells; their coexpression with immune checkpoints (ICs) 2B4, CD160, and TIM3; correlates with immune activation and HIV disease progression; and HIV-specific and -nonspecific proliferative responses. RESULTS: PD-1+ CD8 T-cell frequencies are elevated in children with perinatal HIV and associated with disease progression. The majority of PD-1+ CD8 T cells coexpress additional ICs. ART initiation lowers total PD-1 levels and coexpression of multiple ICs. The frequency of PD-1+2B4+CD160+TIM3- in PD-1+ CD8 T cells predicts weaker HIV-specific proliferative responses, suggesting that this subset is functionally exhausted. CONCLUSIONS: Children with perinatal HIV have high levels of PD-1+ CD8 T cells that are a heterogeneous population differentially coexpressing multiple ICs. Understanding the complex interplay of ICs is essential to guide the development of PD-1-directed immunotherapies for pediatric HIV remission and cure.

COVID-19 in Children: A Review and Parallels to Other Hyperinflammatory Syndromes.

During the COVID-19 pandemic, children have had markedly different clinical presentations and outcomes compared to adults. In the acute phase of infection, younger children are relatively spared the severe consequences reported in adults. Yet, they are uniquely susceptible to the newly described Multisystem Inflammatory Syndrome in Children (MIS-C). This may result from the developmental "immunodeficiency" resulting from a Th2 polarization that starts in utero and is maintained for most of the first decade of life. MIS-C may be due to IgA complexes in a Th2 environment or a Th1-like response to COVID-19 antigens that developed slowly. Alternatively, MIS-C may occur in vulnerable hosts with genetic susceptibilities in other immune and non-immune pathways. Herein, we present a brief overview of the host immune response, virologic and genetic factors, and comparable inflammatory syndromes that may explain the pathophysiology leading to drastic differences in clinical presentation and outcomes of COVID-19 between children and adults.

Determinants of Malaria Protective Immunity in Mice Immunized with Live Sporozoites during Trimethoprim-Sulfamethoxazole Prophylaxis.

HIV and malaria geographically overlap. Trimethoprim-sulfamethoxazole (TMP-SMX) is a drug widely used in HIV-exposed uninfected and infected children in malaria-endemic areas, and is known to have antimalarial effects. Further study in terms of antimalarial impact and effect on development of malaria-specific immunity is therefore essential. Using rodent malaria models, we previously showed that repeated Plasmodium exposure during TMP-SMX administration, or chemoprophylaxis vaccination (CVac), induces CD8 T-cell-dependent preerythrocytic immunity. However, humoral immune responses have been shown to be important in models of preerythrocytic immunity. Herein, we demonstrate that antibody-mediated responses contribute to protective immunity induced by CVac immune sera using TMP-SMX in models of homologous, but not heterologous, parasite species. Clinical studies must account for potential anti-Plasmodium antibody induced during TMP-SMX prophylaxis.

Fractures in children and adolescents living with perinatally acquired HIV.

BACKGROUND: Across numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS). METHODOLOGY: Lifetime history of fracture events from birth up to age 20 years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6 yr). RESULTS: PHIV (N = 412) were older (median 17.5 vs 16.7 yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N = 206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6 yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6 years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis. CONCLUSIONS: Among children/adolescents ≥6 yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood. SUMMARY: Lifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20 years. Fracture incidence was higher in PHIV compared to PHEU among children <6 years old, but not among older children/adolescents.

A Comparison of Metabolic Outcomes Between Obese HIV-Exposed Uninfected Youth From the PHACS SMARTT Study and HIV-Unexposed Youth From the NHANES Study in the United States.

BACKGROUND: Metabolic perturbations in HIV-exposed uninfected (HEU) obese youth may differ from those in the general obese pediatric population. METHODS: Metabolic parameters of obese (body mass index Z-score >95th percentile) HEU youth in the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study were compared with a matched sample of obese youth from the US National Health and Nutrition Examination Survey (NHANES). We evaluated systolic and diastolic hypertension (blood pressure ≥90th percentile for age, sex, and height), total cholesterol >200 mg/dL, high-density lipoprotein cholesterol <35 mg/dL, low-density lipoprotein cholesterol >130 mg/dL, triglycerides (TGs) >150 mg/dL, and Homeostatic Model Assessment-Insulin Resistance >4.0. Modified Poisson regression models were fit to quantify the prevalence ratio (PR) of each outcome comparing the 2 cohorts, adjusting for confounders. RESULTS: The blood pressure outcome analytic subgroup included 1096 participants (n = 304 HEU), the total cholesterol and high-density lipoprotein cholesterol subgroup 1301 participants (n = 385 HEU), and the low-density lipoprotein cholesterol, TG, and Homeostatic Model Assessment-Insulin Resistance subgroup 271 (n = 83 HEU). After adjustment, obese HEU youth had a higher prevalence of systolic and diastolic hypertension [PR = 3.34, 95% confidence interval (CI): 2.48 to 4.50; PR = 2.04, 95% CI: 1.18 to 3.52, respectively], but lower prevalence of insulin resistance (PR = 0.67, 95% CI: 0.54 to 0.85) and hypercholesterolemia (PR = 0.67, 95% CI: 0.44 to 1.01) compared with obese NHANES youth. CONCLUSIONS: In the United States, obese HEU youth seem to have an increased risk of hypertension, but lower risk of insulin resistance and hypercholesterolemia, compared with a general obese pediatric population. Monitoring for cardiovascular morbidity in adulthood may be warranted in HEU children.

Low Peripheral T Follicular Helper Cells in Perinatally HIV-Infected Children Correlate With Advancing HIV Disease.

Background: T follicular helper (Tfh) cells are crucial for B cell differentiation and antigen-specific antibody production. Dysregulation of Tfh-mediated B cell help weakens B cell responses in HIV infection. Moreover, Tfh cells in the lymph node and peripheral blood comprise a significant portion of the latent HIV reservoir. There is limited data on the effects of perinatal HIV infection on Tfh cells in children. We examined peripheral Tfh (pTfh) cell frequencies and phenotype in HIV-infected children and their associations with disease progression, immune activation, and B cell differentiation. Methods: In a Kenyan cohort of 76 perinatally HIV-infected children, comprised of 43 treatment-naïve (ART-) and 33 on antiretroviral therapy (ART+), and 42 healthy controls (HIV-), we identified memory pTfh cells, T cell activation markers, and B cell differentiation states using multi-parameter flow cytometry. Soluble CD163 and intestinal fatty acid-binding protein plasma levels were quantified by ELISA. Results: ART- children had reduced levels of pTfh cells compared with HIV- children that increased with antiretroviral therapy. HIV+ children had higher programmed cell death protein 1 (PD-1) expression on pTfh cells, regardless of treatment status. Low memory pTfh cells with elevated PD-1 levels correlated with advancing HIV disease status, indicated by increasing HIV viral loads and T cell and monocyte activation, and decreasing %CD4 and CD4:CD8 ratios. Antiretroviral treatment, particularly when started at younger ages, restored pTfh cell frequency and eliminated correlations with disease progression, but failed to lower PD-1 levels on pTfh cells and their associations with CD4 T cell percentages and activation. Altered B cell subsets, with decreased naïve and resting memory B cells and increased activated and tissue-like memory B cells in HIV+ children, correlated with low memory pTfh cell frequencies. Last, HIV+ children had decreased proportions of CXCR5+ CD8 T cells that associated with low %CD4 and CD4:CD8 ratios. Conclusion: Low memory pTfh cell frequencies with high PD-1 expression in HIV+ children correlate with worsening disease status and an activated and differentiated B cell profile. This perturbed memory pTfh cell population may contribute to weak vaccine and HIV-specific antibody responses in HIV+ children. Restoring Tfh cell capacity may be important for novel pediatric HIV cure and vaccine strategies.

Development and application of a multiplex assay for the simultaneous measurement of antibody responses elicited by common childhood vaccines.

Because vaccine co-administration can affect elicited immune responses, it is important to evaluate new vaccines in the context of pre-existing vaccination schedules. This is particularly necessary for new pediatric vaccines, as the World Health Organization's infant immunization program already schedules several vaccines to be administered during the first months of life. To facilitate the assessment of inter-vaccine interference, we developed a pediatric vaccine multiplex assay (PVMA) to simultaneously measure antibodies against vaccines commonly administered to infants, including hepatitis B, Haemophilus influenzae type B, diphtheria, tetanus, pertussis, rubella, and respiratory syncytial virus (RSV). Comparison of antibody concentrations determined by enzyme-linked immunosorbent assays (ELISAs) and the PVMA demonstrated that the PVMA is highly sensitive, specific, reproducible, and accurate. Moreover, the PVMA requires half the time to assess a cohort compared to ELISAs, and only costs marginally more. Demonstrating the utility of the assay, we employed the PVMA to assess vaccine interference in the setting of a candidate vaccine, using the infant HIV vaccines from the completed Pediatric AIDS Clinical Trials Group (PACTG) protocols 230 and 326 as examples. There was no substantial difference in antibody concentrations between vaccine and placebo recipients, which suggests that HIV vaccination did not disrupt antibody responses elicited by routine pediatric vaccines. Thus, the PVMA is a reliable, high-throughput technique that requires minimal sample volume to measure multiple antibody concentrations concurrently, and is an efficient alternative to ELISAs for the measurement of vaccine-elicited antibody responses in large cohorts.

Prevalence of Asymptomatic Parasitemia and Gametocytemia in HIV-Infected Children on Differing Antiretroviral Therapy.

Laboratory data and prior pediatric reports indicate that HIV protease inhibitor (PI)-based antiretroviral therapy (ARV) kills gametocytes and reduces rates of gametocytemia, but not asymptomatic parasitemia, in a high malaria-transmission area. To determine whether ARV regimen impacts these rates in areas with less-intense malaria transmission, we compared asymptomatic parasitemia and gametocytemia rates in HIV-infected children by ARV regimen in Lilongwe, Malawi, an area of low-to-moderate transmission intensity. HIV PI lopinavir-ritonavir (LPV-rtv) ARV- or non-nucleoside reverse transcriptase inhibitor nevirapine ARV-treated children did not differ in the rates of polymerase chain reaction-detected asymptomatic parasitemia (relative risk [RR] 0.43 95% confidence interval [CI] [0.16, 1.18], P value 0.10) or microscopically detected gametocytemia with LPV-rtv ARV during symptomatic malaria (RR 0.48 95% CI [0.22,1.04] P value 0.06). LPV-rtv ARV was not associated with reduced rates of asymptomatic parasitemia, or gametocytemia on days of symptomatic malaria episodes, in HIV-infected children. Larger studies should evaluate whether ARV impacts transmission.

HIV-Exposed Infants Vaccinated with an MF59/Recombinant gp120 Vaccine Have Higher-Magnitude Anti-V1V2 IgG Responses than Adults Immunized with the Same Vaccine.

In the RV144 vaccine trial, IgG responses against the HIV envelope variable loops 1 and 2 (V1V2) were associated with decreased HIV acquisition risk. We previously reported that infants immunized with an MF59-adjuvanted rgp120 vaccine developed higher-magnitude anti-V1V2 IgG responses than adult RV144 vaccinees. To determine whether the robust antibody response in infants is due to differences in vaccine regimens or to inherent differences between the adult and infant immune systems, we compared Env-specific IgG responses in adults and infants immunized with the same MF59- and alum-adjuvanted HIV envelope vaccines. At peak immunogenicity, the magnitudes of the gp120- and V1V2-specific IgG responses were comparable between adults and infants immunized with the alum/MNrgp120 vaccine (gp120 median fluorescence intensities [FIs] in infants = 7,118 and in adults = 11,510, P = 0.070; V1V2 median MFIs of 512 [infants] and 804 [adults], P = 0.50), whereas infants immunized with the MF59/SF-2 rgp120 vaccine had higher-magnitude antibody levels than adults (gp120 median FIs of 15,509 [infants] and 2,290 [adults], P < 0.001; V1V2 median FIs of 23,926 [infants] and 1,538 [adults]; P < 0.001). Six months after peak immunogenicity, infants maintained higher levels Env-specific IgG than adults. Anti-V1V2 IgG3 antibodies that were associated with decreased HIV-1 risk in RV144 vaccinees were present in 43% of MF59/rgp120-vaccinated infants but only in 12% of the vaccinated adults (P = 0.0018). Finally, in contrast to the rare vaccine-elicited Env-specific IgA in infants, rgp120 vaccine-elicited Env-specific IgA was frequently detected in adults. Our results suggest that vaccine adjuvants differently modulate gp120-specific antibody responses in adults and infants and that infants can robustly respond to HIV Env immunization.IMPORTANCE More than 150,000 pediatric HIV infections occur yearly, despite the availability of antiretroviral prophylaxis. A pediatric HIV vaccine could reduce the number of these ongoing infant infections and also prime for long-term immunity prior to sexual debut. We previously reported that immunization of infants with an MF59-adjuvanted recombinant gp120 vaccine induced higher-magnitude, potentially protective anti-V1V2 IgG responses than in adult vaccinees receiving the moderately effective RV144 vaccine. In the present study, we demonstrate that the robust response observed in infants is not due to differences in vaccine regimen or vaccine dose between adults and infants. Our results suggest that HIV vaccine adjuvants may differentially modulate immune responses in adults and infants, highlighting the need to conduct vaccine trials in pediatric populations.

The Effect of Complete Blood Count Timing on Lumbar Puncture Rates in Asymptomatic Infants Born to Mothers with Chorioamnionitis.

Background Maternal chorioamnionitis is a risk factor for sepsis but, often, these infants are asymptomatic at birth. Different markers for infections, such as the immature to total (I/T) white blood cell (WBC) ratio, are used to help determine which infants require lumbar punctures (LPs), in addition to blood cultures and antibiotics. The timing of when the complete blood count (CBC) is obtained may have some effect on the length of antibiotic treatment. Aims The purpose of this proof-of-concept study was to assess if obtaining a CBC at greater than four hours of life as compared to less than four hours of life has an impact on the incidence of LPs performed in asymptomatic, full-term infants undergoing evaluation for sepsis secondary to maternal chorioamnionitis. Methods We performed a retrospective study of full-term, asymptomatic infants admitted for sepsis evaluation secondary to maternal chorioamnionitis. Subjects were grouped based upon the timing of their initial CBC (early = < four hours of life or late = > four hours of life). The incidence of LPs, duration of antibiotic treatment, and length of hospitalization were compared between the groups. Results A total of 230 subjects were included in the study (early group = 124, late group = 106). Subjects in the late group underwent significantly fewer LPs than subjects in the early group, 5.7% vs. 22.6% (p<0.001). There was no difference in length of treatment or hospitalization. Conclusions Asymptomatic full-term infants undergoing evaluation for sepsis secondary to maternal chorioamnionitis are less likely to undergo an LP if their initial CBC is obtained at greater than four hours of life.

Immune activation despite preserved CD4 T cells in perinatally HIV-infected children and adolescents.

BACKGROUND: HIV disease progresses more rapidly in children than adults with mortality rates exceeding 50% by 2 years of age without antiretroviral therapy (ART) in sub-Saharan Africa. Recent World Health Organization (WHO) guidelines recommend universal treatment for all living persons with HIV, yet there is limited supporting evidence in pediatric populations. The objective of this study was to determine whether CD4 cell counts reflect immunological markers associated with disease progression in ART naïve perinatally-infected HIV+ children and adolescents and their response to ART. METHODS: PBMC and plasma samples were collected from 71 HIV negative and 132 HIV+ children (65 ART naïve and 67 on ART) between ages 1-19 years from Mombasa, Kenya. Untreated HIV+ subjects were sub-categorized by high or low CD4 T cell counts. Immune activation markers CD38, HLA-DR and Ki67 were analyzed by flow cytometry. Plasma soluble CD14 (sCD14) was quantified by ELISA. RESULTS: HIV-infected children and adolescents with preserved CD4 cell counts had depleted CD4 percentages and CD4:CD8 ratios, and high immune activation levels. ART initiation rapidly and persistently reversed T cell activation, but failed to normalize CD4:CD8 ratios and plasma sCD14 levels. CONCLUSIONS: Diminished CD4 percentages and CD4:CD8 ratios along with profound immune activation occur independent of CD4 cell count thresholds in ART naïve HIV+ children and adolescents. Immediate ART initiation, as recommended in the most recent WHO guidelines may protect them from pathologic sequelae associated with persistent inflammation.

HIV-Infected Children Have Elevated Levels of PD-1+ Memory CD4 T Cells With Low Proliferative Capacity and High Inflammatory Cytokine Effector Functions.

Background: During human immunodeficiency virus (HIV) disease, chronic immune activation leads to T-cell exhaustion. PD-1 identifies "exhausted" CD8 T cells with impaired HIV-specific effector functions, but its role on CD4 T cells and in HIV-infected children is poorly understood. Methods: In a Kenyan cohort of vertically HIV-infected children, we measured PD-1+ CD4 T-cell frequencies and phenotype by flow cytometry and their correlation with HIV disease progression and immune activation. Second, in vitro CD4 T-cell proliferative and cytokine responses to HIV-specific and -nonspecific stimuli were assessed with and without PD-1 blockade. Results: HIV-infected children have increased frequencies of PD-1+ memory CD4 T cells that fail to normalize with antiretroviral treatment. These cells are comprised of central and effector memory subsets and correlate with HIV disease progression, measured by viral load, CD4 percentage, CD4:CD8 T-cell ratio, and immune activation. Last, PD-1+ CD4 T cells predict impaired proliferative potential yet preferentially secrete the Th1 and Th17 cytokines interferon-γ and interleukin 17A, and are unresponsive to in vitro PD-1 blockade. Conclusions: This study highlights differences in PD-1+ CD4 T-cell memory phenotype and response to blockade between HIV-infected children and adults, with implications for potential immune checkpoint therapies.

CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3-36 months with HIV infection.

OBJECTIVES: To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. DESIGN: IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). METHODS: CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35-180 µg*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. RESULTS: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 µg*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. CONCLUSION: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.

Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge.

Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used in malaria-endemic areas in human immunodeficiency virus (HIV)-infected children and HIV-uninfected, HIV-exposed children as opportunistic infection prophylaxis. Despite the known effects that TMP-SMX has in reducing clinical malaria, its impact on development of malaria-specific immunity in these children remains poorly understood. Using rodent malaria models, we previously showed that TMP-SMX, at prophylactic doses, can arrest liver stage development of malaria parasites and speculated that TMP-SMX prophylaxis during repeated malaria exposures would induce protective long-lived sterile immunity targeting pre-erythrocytic stage parasites in mice. Using the same models, we now demonstrate that repeated exposures to malaria parasites during TMP-SMX administration induces stage-specific and long-lived pre-erythrocytic protective anti-malarial immunity, mediated primarily by CD8+ T-cells. Given the HIV infection and malaria coepidemic in sub-Saharan Africa, clinical studies aimed at determining the optimum duration of TMP-SMX prophylaxis in HIV-infected or HIV-exposed children must account for the potential anti-infection immunity effect of TMP-SMX prophylaxis.

Safety and Efficacy of Atorvastatin in Human Immunodeficiency Virus-infected Children, Adolescents and Young Adults With Hyperlipidemia.

BACKGROUND: Human immunodeficiency virus (HIV)-infected children receiving antiretroviral therapy (ART) have increased prevalence of hyperlipidemia and risk factors for cardiovascular disease. No studies have investigated the efficacy and safety of statins in this population. METHODS: HIV-infected youth 10 to <24 years of age on stable ART with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL for ≥6 months initiated atorvastatin 10 mg once daily. Atorvastatin was increased to 20 mg if LDL-C efficacy criteria (LDL-C < 110 mg/dL or decreased ≥30% from baseline) were not met at week 4. Primary outcomes were safety and efficacy. RESULTS: Twenty-eight youth initiated atorvastatin; 7 were 10-15 years and 21 were 15-24 years. Mean baseline LDL-C was 161 mg/dL (standard deviation 19 mg/dL). Efficacy criteria were met at week 4 by 17 of 27 (63%) participants. Atorvastatin was increased to 20 mg in 10 participants. Mean LDL-C decreased from baseline by 30% (90% confidence interval: 26%, 35%) at week 4, 28% (90% confidence interval: 23%, 33%) at week 24 and 26% (90% confidence interval: 20%, 33%) at week 48. LDL-C was less than 110 mg/dL in 44% at week 4, 42% at week 12 and 46% at weeks 24 and 48. Total cholesterol, non high-density lipoprotein (non-HDL)-C and apolipoprotein B decreased significantly, but IL-6 and high-sensitivity C-reactive protein did not. Two participants in the younger age group discontinued study for toxicities possibly related to atorvastatin. CONCLUSIONS: Atorvastatin lowered total cholesterol, LDL-C, non HDL-C and apolipoprotein B in HIV-infected youth with ART-associated hyperlipidemia. Atorvastatin could be considered for HIV-infected children with hyperlipidemia, but safety monitoring is important particularly in younger children.

Thirty-year Perspective of the Long-term Survival, CD4 Percentage and Social Achievements of Perinatally HIV-infected Children as a Function of Their Birth Era.

BACKGROUND: Pediatric HIV has evolved from a pre-antiretroviral (ART) era (pre-1989 or pre-ART) to an ART era (1989 to 1996) and to a highly active antiretroviral therapy (HAART) era (post-1996). As we have passed the third decade following these individuals, we thought it useful to review clinical, laboratory and social outcomes. METHODS: A retrospective, cross-sectional study of 399 children infected perinatally. They were divided into pre-ART, ART and HAART groups. A Kaplan-Meier plot was constructed. One hundred seventy-nine have been lost to follow-up at an average of 7.6 (0.3-27.6) years. RESULTS: Approximately 40%, 80% and 90% of individuals in the pre-ART, ART and HAART groups have long-term survival. One hundred twenty-one died at an average of 5.1 (0-26.1) years. Pre-ART, ART and HAART groups had mean most recent CD4% values (±SEM) of 16.74 (1.09), 22.97 (0.96) and 33.07 (2.09), respectively (P < 0.001). Pre-ART RNA is limited in that era and present if they survived to another era. In this group, the median RNA values in those who died (311,300, n = 16) was greater than in survivors (19,402, n = 45). Forty-three percent of the individuals in the ART group and 77% of individuals in the HAART group had most recent HIV RNA <400 copies/mL. Eighteen individuals >18 years of age have only a grade school or no education. Fifty-five have graduated high school or received an equivalency diploma. Twenty-three more have completed college. Nadir and recent CD4% of those who did and did not complete high school was equivalent to college graduates. Sixteen survivors (1/2 male) have had 18 uninfected children. CONCLUSIONS: This first long-term follow-up study demonstrates remarkable survival and social skills of our patients.

Growth at 2 Years of Age in HIV-exposed Uninfected Children in the United States by Trimester of Maternal Antiretroviral Initiation.

BACKGROUND: Abnormal childhood growth may affect future health. Maternal tenofovir (TFV) use was associated with lower body length and head circumference at 1 year of age in HIV-exposed uninfected (HEU) US children. METHODS: We studied 509 HEU children in the US-based Surveillance Monitoring of Antiretroviral Therapy Toxicities cohort whose HIV-infected mothers were not using antiretrovirals at the last menstrual period and began combination antiretroviral therapy (cART) in pregnancy (cART initiators). We examined adjusted associations between antiretrovirals and Centers for Disease Control 2000 growth Z scores at 2 years of age within trimester of cART initiation: weight (weight Z score), length (length Z score), weight-for-length [weight-for-length Z score (WFLZ)], triceps skinfold Z score (TSFZ) and head circumference (head circumference Z score). RESULTS: Mothers mean age was 28.6 years; 57% were black non-Hispanic and 19% delivered at <37 weeks gestation. At 2 years, mean weight Z score, length Z score, WFLZ and head circumference Z score were above average (P < 0.05), whereas TSFZ (P = 0.57) did not differ from average. WFLZ was >1.64 standard deviation (SD) (>95th percentile) in 13%. Among children of first-trimester cART initiators, TFV+emtricitabine-exposed children had slightly higher mean WFLZ (0.45 SD; 95% confidence interval: -0.10 to 1.00) and lower TSFZ (-0.55 SD; 95% confidence interval: -1.07 to -0.02) compared with zidovudine+lamivudine-exposed children. TSFZ was lower in those exposed to boosted protease inhibitors. In contrast, growth in children of second trimester cART initiators did not differ by antiretroviral exposures. CONCLUSION: Growth was above average in HEU; 13% were obese. Maternal TFV use was not associated with lower length or head circumference at 2 years of age, as hypothesized, but may be related to greater weight among those exposed to cART early in pregnancy.

Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060.

BACKGROUND: HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed. METHODS: Thirty-one children from Malawi aged 4-62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor. RESULTS: We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03). CONCLUSIONS: LPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT00719602.

HIV-Infected Children Have Lower Frequencies of CD8+ Mucosal-Associated Invariant T (MAIT) Cells that Correlate with Innate, Th17 and Th22 Cell Subsets.

Mucosal-associated invariant T cells (MAIT) are innate T cells restricted by major histocompatibility related molecule 1 (MR1) presenting riboflavin metabolite ligands derived from microbes. Specificity to riboflavin metabolites confers MAIT cells a broad array of host-protective activity against gram-negative and -positive bacteria, mycobacteria, and fungal pathogens. MAIT cells are present at low levels in the peripheral blood of neonates and gradually expand to relatively abundant levels during childhood. Despite no anti-viral activity, MAIT cells are depleted early and irreversibly in HIV infected adults. Such loss or impaired expansion of MAIT cells in HIV-positive children may render them more susceptible to common childhood illnesses and opportunistic infections. In this study we evaluated the frequency of MAIT cells in perinatally HIV-infected children, their response to antiretroviral treatment and their associations with HIV clinical status and related innate and adaptive immune cell subsets with potent antibacterial effector functions. We found HIV+ children between ages 3 to 18 years have significantly decreased CD8+ MAIT cell frequencies compared to uninfected healthy children. Remarkably, CD8 MAIT levels gradually increased with antiretroviral therapy, with greater recovery when treatment is initiated at a young age. Moreover, diminished CD8+ MAIT cell frequencies are associated with low CD4:CD8 ratios and elevated sCD14, suggesting a link with HIV disease progression. Last, CD8+ MAIT cell levels tightly correlate with other antibacterial and mucosa-protective immune subsets, namely, neutrophils, innate-like T cells, and Th17 and Th22 cells. Together these findings suggest that low frequencies of MAIT cells in HIV positive children are part of a concerted disruption to the innate and adaptive immune compartments specialized in sensing and responding to pathogenic or commensal bacteria.