Presentation and outcomes of post-transplant lymphoproliferative disorder at a single institution pediatric transplant center.

BACKGROUND: This study aimed to characterize features present at the time of diagnosis and describe outcomes in patients with post-transplant lymphoproliferative disorder (PTLD) following pediatric solid organ transplantation. METHODS: We performed a retrospective review of solid organ transplant patients who developed pathologically confirmed PTLD at our center from 2006 to 2016. RESULTS: Of 594 patients included in this study, 41(6.9%) were diagnosed with PTLD. Median age at transplant was 5.6(IQR 1.7-16.1) years. Proportion of PTLD cases by organ transplanted and median time (IQR) to disease onset were: heart 11/144(7.6%) at 13.6(8.5-55.6) months, lung 7/52(13.5%) at 9.1(4.9-35) months, kidney 8/255(3.1%) at 39.5(13.9-57.1) months, liver 12/125(9.6%) at 7.7(5.5-22) months, intestine 0/4(0%), and multi-visceral 3/14(21.4%) at 5.4(5.4-5.6) months. No significant correlation was seen between recipient EBV status at transplant and timing of development of PTLD. There were six early lesions, 15 polymorphic, 19 monomorphic, and one uncharacterizable PTLD. Following immunosuppression reduction, 30 patients received rituximab, and 14 required chemotherapy. At median 25(IQR 12-53) months follow-up from the onset of PTLD, eight patients died secondary to transplant related complications, three are alive with active disease, and 30 have no evidence of disease. CONCLUSION: PTLD is a significant complication following pediatric solid organ transplantation. EBV levels in conjunction with symptomatic presentation following transplant may assist in detection of PTLD. Most patients can achieve long-term disease-free survival through immunosuppression reduction, anti-CD20 treatment, and chemotherapy in refractory cases.

Birth Weight and Preterm Delivery Outcomes of Perinatally vs Nonperinatally Human Immunodeficiency Virus-Infected Pregnant Women in the United States: Results From the PHACS SMARTT Study and IMPAACT P1025 Protocol.

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], <2500 g), small-for-gestational-age [SGA], and BW z scores [BWZ]) in HIV-exposed uninfected infants of PHIV vs nonperinatally HIV-infected (NPHIV) pregnant women in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities or International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 studies. Mixed effects models and log binomial models were used to assess the association of maternal PHIV status with infant outcomes. Age-stratified analyses were performed. RESULTS: From 1998 to 2013, 2270 HIV-infected pregnant women delivered 2692 newborns (270 born to PHIV and 2422 to NPHIV women). PHIV women were younger, (mean age 21 vs 25 years, P < .01) and more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs 11%, P = .01). No associations between maternal PHIV status and preterm delivery, SGA, or LBW were observed. After adjustment, BWZ was 0.12 lower in infants of PHIV vs NPHIV women (adjusted mean, -0.45 vs -0.33; P = .04). Among women aged 23-30 years (n = 1770), maternal PHIV was associated with LBW (aRR = 1.74; 95% confidence interval, 1.18, 2.58; P < .01). CONCLUSION: The overall lack of association between maternal PHIV status and preterm delivery or infant BW outcomes is reassuring. The higher rates of LBW observed in PHIV women aged 23-30 years warrants further mechanism-based investigations as this is a rapidly growing and aging population worldwide. CLINICAL TRIALS REGISTRATION: PHACS SMARTT study, NCT01310023. CLINICAL TRIALS REGISTRATION: IMPAACT 1025, NCT00028145.

Prevalence and Persistence of Varicella Antibodies in Previously Immunized Children and Youth With Perinatal HIV-1 Infection.

BACKGROUND: Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)-infected children with CD4% ≥ 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status. METHODS: The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics. RESULTS: Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at <3 years (both), 73% and 100% at 3-<7 years (P < .05), and 77% and 97% at ≥ 7 years (P < .01), respectively. Seropositivity among recipients of 2 vaccine doses was >94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on ≥ 3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P < .001 for overall dose effect), and in those vaccinated ≥ 3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02). CONCLUSIONS: Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose ≥ 3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use.

Immunity to Measles, Mumps, and Rubella in US Children With Perinatal HIV Infection or Perinatal HIV Exposure Without Infection.

BACKGROUND: Children with perinatal human immunodeficiency virus (HIV) infection (PHIV) may not be protected against measles, mumps, and rubella (MMR) because of impaired initial vaccine response or waning immunity. Our objectives were to estimate seroimmunity in PHIV-infected and perinatally HIV-exposed but uninfected (HEU) children and identify predictors of immunity in the PHIV cohort. METHODS: PHIV and HEU children were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) at ages 7-15 years from 2007 to 2009. At annual visits, demographic, laboratory, immunization, and clinical data were abstracted and serologic specimens collected. Most recent serologic specimen was used to determine measles seroprotection by plaque reduction neutralization assay and rubella seroprotection and mumps seropositivity by enzyme immunoassay. Sustained combination antiretroviral therapy (cART) was defined as taking cART for at least 3 months. RESULTS: Among 428 PHIV and 221 HEU PHACS participants, the prevalence was significantly lower in PHIV children for measles seroprotection (57% [95% confidence interval {CI}, 52%-62%] vs 99% [95% CI, 96%-100%]), rubella seroprotection (65% [95% CI, 60%-70%] vs 98% [95% CI, 95%-100%]), and mumps seropositivity (59% [95% CI, 55%-64%] vs 97% [95% CI, 94%-99%]). On multivariable analysis, greater number of vaccine doses while receiving sustained cART and higher nadir CD4 percentage between last vaccine dose and serologic testing independently improved the cumulative prediction of measles seroprotection in PHIV. Predictors of rubella seroprotection and mumps seropositivity were similar. CONCLUSIONS: High proportions of PHIV-infected children, but not HEU children, lack serologic evidence of immunity to MMR, despite documented immunization and current cART. Effective cART before immunization is a strong predictor of current seroimmunity.

The impact of RSV, adenovirus, influenza, and parainfluenza infection in pediatric patients receiving stem cell transplant, solid organ transplant, or cancer chemotherapy.

RVIs are a significant cause of morbidity and mortality in immunocompromised children. We analyzed the characteristics and outcomes of infection by four respiratory viruses (RSV, adenovirus, influenza, and parainfluenza) treated at a pediatric tertiary care hospital in a retrospective cohort of patients who had received cancer chemotherapy, hematopoietic stem cell, or SOT. A total of 208 infections were studied among 166 unique patients over a time period of 1993-2006 for transplant recipients, and 2000-2005 for patients with cancer. RSV was the most common respiratory virus identified. There were 17 (10% of all patients) deaths overall, of which 12 were at least partly attributed to the presence of a RVI. In multivariate models, LRT symptoms in the absence of upper respiratory symptoms on presentation (OR 10.2 [2.3, 45.7], p = 0.002) and adenoviral infection (OR 3.7 [1.1, 12.6], p = 0.034) were significantly associated with poor outcome, defined as death or disability related to RVI. All of the deaths occurred in patients who had received either solid organ or HSCT. There were no infections resulting in death or disability in the cancer chemotherapy group.

Maternal cytomegalovirus-specific immune responses and symptomatic postnatal cytomegalovirus transmission in very low-birth-weight preterm infants.

INTRODUCTION: Transmission of cytomegalovirus (CMV) via breast milk can lead to severe acute illness in very low-birth-weight (VLBW) preterm infants. Although the majority of CMV-seropositive women shed CMV in milk, symptomatic postnatal infection of VLBW infants occurs infrequently, suggesting that virologic or immunologic factors in milk may be associated with the risk and severity of postnatal CMV infection. METHODS: We investigated the magnitude of CMV-specific cellular and humoral immune responses in milk of 30 seropositive mothers of VLWB preterm infants and assessed their relationship to milk CMV load and symptomatic CMV transmission. RESULTS: Milk immunoglobulin G (IgG) avidity was inversely correlated to milk CMV load (r = -0.47; P = .009). However, milk CMV load and CMV-specific cellular and humoral immune responses were similar in mothers of VLBW infants with and those without symptomatic postnatal CMV infection. CONCLUSIONS: Similar immunologic parameters in milk of CMV-seropositive mothers of VLBW infants with and without symptomatic postnatal CMV infection indicate that screening milk by these parameters may not predict disease risk. However, the inverse correlation between milk CMV IgG avidity and CMV load may suggest that enhancement of maternal CMV-specific IgG responses could aid in reduction of CMV shedding into breast milk.

A Digital Platform to Support HIV Case Management for Youth and Young Adults: Mixed Methods Feasibility Study.

BACKGROUND: Advances in medical treatments in recent years have contributed to an overall decline in HIV-related opportunistic infections and deaths in youth; however, mortality and morbidity rates in perinatally and nonperinatally infected adolescents and young adults (AYA) living with HIV remain relatively high today. OBJECTIVE: The goal of this project was to assess the use, utility, and cost-effectiveness of PlusCare, a digital app for HIV case management in AYA living with HIV. The app supports routine case management tasks, such as scheduling follow-up visits, sharing documents for review and signature, laboratory test results, and between-visit communications (eg, encouraging messages). METHODS: We conducted a single-group mixed methods pre-post study with HIV case management programs in 2 large urban hospitals in the Boston metro area. Case management staff (case managers [CMs], N=20) and AYA living with HIV participants (N=45) took part in the study with access to PlusCare for up to 15 and 12 months, respectively. RESULTS: The CMs and AYA living with HIV reported mean System Usability Scale scores of 51 (SD 7.9) and 63 (SD 10.6), respectively. Although marginally significant, total charges billed at 1 of the 2 sites compared with the 12 months before app use (including emergency, inpatient, and outpatient charges) decreased by 41% (P=.046). We also observed slight increases in AYA living with HIV self-reported self-efficacy in chronic disease management and quality of life (Health-Related Quality of Life-4) from baseline to the 12-month follow-up (P=.02 and P=.03, respectively) and increased self-efficacy from the 6- to 12-month follow-up (P=.02). There was no significant change in HIV viral suppression, appointment adherence, or medication adherence in this small-sample pilot study. CONCLUSIONS: Although perceived usability was low, qualitative feedback from CMs and use patterns suggested that direct messaging and timely, remote, and secure sharing of laboratory results and documents (including electronic signatures) between CMs and AYA living with HIV can be particularly useful and have potential value in supporting care coordination and promoting patient self-efficacy and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT03758066; https://clinicaltrials.gov/ct2/show/NCT03758066.

Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza A antibodies.

BACKGROUND: Lack of life-long immunity against influenza viruses represents a major global health care problem with profound medical and economic consequences. A greater understanding of the broad-spectrum "heterosubtypic" neutralizing human antibody (BnAb) response to influenza should bring us closer toward a universal influenza vaccine. METHODS: Serum samples obtained from 77 volunteers in an H5N1 vaccine study were analyzed for cross-reactive antibodies (Abs) against both subtype hemagglutinins (HAs) and a highly conserved pocket on the HA stem of Group 1 viruses. Cross-reactive Abs in commercial intravenous immunoglobulin were affinity purified using H5-coupled beads followed by step-wise monoclonal antibody competition or acid elution. Enzyme-linked immunosorbent assays were used to quantify cross-binding, and neutralization activity was determined with HA-pseudotyped viruses. RESULTS: Prevaccination serum samples have detectable levels of heterosubtypic HA binding activity to both Group 1 and 2 influenza A viruses, including subtypes H5 and H7, respectively, to which study subjects had not been vaccinated. Two different populations of Broadly neutralizing Abs (BnAbs) were purified from intravenous immunoglobulin by H5 beads: ~0.01% of total immunoglobulin G can bind to HAs from both Group 1 and 2 and neutralize H1N1 and H5N1 viruses; ~0.001% is F10-like Abs directed against the HA stem pocket on Group 1 viruses. CONCLUSION: These data--to our knowledge, for the first time--quantitatively show the presence, albeit at low levels, of two populations of heterosubtypic BnAbs against influenza A in human serum. These observations warrant further investigation to determine their origin, host polymorphism(s) that may affect their expression levels and how to boost these BnAb responses by vaccination to reach sustainable protective levels.

Immune response to influenza vaccine in children with inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) frequently receive immunosuppressive therapy. The immune response in these patients to vaccines has not been well studied. We conducted a prospective, open label study to evaluate the serologic response to influenza vaccine in children with IBD. METHODS: Serum was obtained from 146 children and young adults with IBD (96 Crohn's disease, 47 ulcerative colitis, and 3 indeterminate colitis) for baseline influenza titer, immediately followed by immunization with trivalent (A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (B)) inactivated influenza vaccine. Patients returned for repeat titers 3-9 weeks later. Seroprotection against each influenza strain was defined as hemagglutination inhibition titer > or = 40. Patients were categorized as nonimmunosuppressed (NIS; aminosalicylates only, antibiotics only, or no therapy) or immunosuppressed (IS; any immunosuppressive agent). IS patients were further subcategorized as: (i) tacrolimus, (ii) tumor necrosis factor-alpha (TNF-alpha) inhibitor, (3) immunomodulator, and (4) corticosteroids only. RESULTS: More patients were seroprotected against strains A/H1N1 and A/H3N2 than B strain (P<0.02), regardless of immunosuppression status. The proportion of seroprotected patients and geometric mean titers at post-vaccination were similar between NIS and IS groups for all three strains. Subanalysis of patients not seroprotected at baseline showed that those receiving anti-TNF therapy were less likely to be seroprotected against strain B (14%) compared to patients in the NIS group (39%, P=0.025). There were no serious vaccine-associated adverse events. CONCLUSIONS: Influenza vaccination produces a high prevalence of seroprotection in IBD patients, particularly against A strains. The vaccine is well tolerated. Routine influenza vaccination in IBD patients is recommended, irrespective of whether patients receive immunosuppressive medications.

CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children.

BACKGROUND: Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. METHODS: In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. RESULTS: NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). CONCLUSIONS: The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Association of Risk of Viremia, Immunosuppression, Serious Clinical Events, and Mortality With Increasing Age in Perinatally Human Immunodeficiency Virus-Infected Youth.

Importance: As perinatally human immunodeficiency virus-infected youth (PHIVY) in the United States grow older and more treatment experienced, clinicians need updated information about the association of age, CD4 cell count, viral load (VL), and antiretroviral (ARV) drug use with risk of opportunistic infections, key clinical events, and mortality to understand patient risks and improve care. Objective: To examine the incidence or first occurrence during follow-up of key clinical events (including Centers for Disease Control and Prevention stage B [CDC-B] and stage C [CDC-C] events) and mortality among PHIVY stratified by age, CD4 cell count, and VL and ARV status. Design, Setting, and Participants: Combining data from the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 multicenter cohort studies (March 2007 through April 2015), we estimated event rates during person-time spent in key strata of age (7-12, 13-17, and 18-30 years), CD4 cell count (<200, 200-499, and ≥500/µL), and a combined measure of VL and ARV status (VL <400 or ≥400 copies/mL; ARV therapy or no ARV therapy). A total of 1562 participants in the PHACS Adolescent Master Protocol and IMPAACT P1074 were eligible, and 1446 PHIVY from 41 ambulatory sites in the 12 US states, including Puerto Rico were enrolled. The dates of analysis were March 2015 through January 2017. Main Outcomes and Measures: Clinical event rates stratified by person-time in age, CD4 cell count, and VL and ARV categories. Results: A total of 1446 PHIVY participated in the study (mean [SD] age, 14.6 [4.6] years; 759 female [52.5%]; 953 black [65.9%]). During a mean (SD) follow-up of 4.9 (1.3) years, higher incidences of CDC-B events, CDC-C events, and mortality were observed as participants aged. Older PHIVY (aged 13-17 and 18-30 years) spent more time with a VL of 400 copies/mL or more and with a CD4 cell count of less than 200/µL compared with 7- to 12-year-old participants (30% and 44% vs 22% of person-time with a VL≥400 copies/mL; 5% and 18% vs 2% of person-time with CD4 cell count <200/µL; P < .001 for each comparison). We observed higher rates of CDC-B events, CDC-C events, bacterial infections, and mortality at lower CD4 cell counts, as expected. The mortality rate among older PHIVY was 6 to 12 times that among the general US population. Higher rates of sexually transmitted infections were also observed at lower CD4 cell counts after adjusting for age. Conclusions and Relevance: Older PHIVY were at increased risk of viremia, immunosuppression, CDC-B events, CDC-C events, and mortality. Interventions to improve ARV therapy adherence and optimize models of care for PHIVY as they age are urgently needed to improve long-term outcomes among PHIVY.

Reduced lopinavir exposure during pregnancy.

BACKGROUND: Optimal antiretroviral exposure during pregnancy is critical for prevention of mother-to-child HIV transmission and for maternal health. Pregnancy can alter antiretroviral pharmacokinetics. Our objective was to describe lopinavir/ritonavir (LPV/r) pharmacokinetics during pregnancy. METHODS: We performed intensive steady-state 12-h pharmacokinetic profiles of lopinavir and ritonavir (three capsules: LPV 400 mg/r 100 mg) at 30-36 weeks gestation and 6-12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured LPV and ritonavir by reverse-phase high-performance liquid chromatography. Target LPV area under concentration versus time curve (AUC) was > or = 52 microg h/ml, the estimated 10th percentile LPV AUC in non-pregnant historical controls (mean AUC = 83 microg h/ml). RESULTS: Seventeen women completed antepartum evaluations; average gestational age was 35 weeks. Geometric mean antepartum LPV AUC was 44.4 microg h/ml [90% confidence interval (CI), 38.7-50.9] and 12-h post-dose concentration (C12h) was 1.6 microg/ml (90% CI, 1.1-2.5). Twelve women completed postpartum evaluations; geometric mean LPV AUC was 65.2 microg h/ml (90% CI, 49.7-85.4) and C12h was 4.6 microg/ml (90% CI, 3.7-5.7). The geometric mean ratio of antepartum/postpartum LPV AUC was 0.72 (90% CI, 0.54-0.96). Fourteen of 17 (82%) pregnant and three of 12 (25%) postpartum women did not meet our target LPV AUC. The ratio of cord blood/maternal LPV concentration in ten paired detectable samples was 0.2 +/- 0.13. CONCLUSIONS: LPV/r exposure during late pregnancy was lower compared to postpartum and compared to non-pregnant historical controls. Small amounts of lopinavir cross the placenta. The pharmacokinetics, safety, and effectiveness of increased LPV/r dosing during the third trimester of pregnancy should be investigated.

Impact of pregnancy on abacavir pharmacokinetics.

OBJECTIVE: To describe abacavir pharmacokinetics during pregnancy and postpartum; physiological changes during pregnancy are known to affect antiretroviral drug disposition. DESIGN: The Pediatric AIDS Clinical Trials Group P1026s study is an on-going, prospective, non-blinded pharmacokinetic study of pregnant women receiving one or more antiretroviral drugs for routine clinical care, including a cohort receiving abacavir 300 mg twice daily. METHODS: Serial plasma samples (predose, 1, 2, 4, and 6 h postdose) obtained antepartum (30-36 weeks of gestation) and again postpartum (6-12 weeks after delivery) were assayed for abacavir concentration by reversed-phase high-performance liquid chromatography. RESULTS: Antepartum evaluations were available for 25 women [mean age, 28.6 years (SD, 6); mean third-trimester weight 92 kg (SD, 35.4); and race/ethnicity 52% black, 28% Hispanic, 16% white, 4% Asian], with geometric mean abacavir area under the concentration-time curve (AUC) of 5.9 mg.h/l [90% confidence interval (CI), 5.2-6.8] and maximum plasma concentration (Cmax) of 1.9 mg/l (90% CI, 1.6-2.2). Seventeen women completed postpartum sampling, and the ratios of antepartum to postpartum AUC and Cmax were 1.04 (90% CI, 0.91-1.18) and 0.79 (90% CI, 0.65-0.98), respectively. CONCLUSIONS: Abacavir AUC during pregnancy was similar to that at 6-12 weeks postpartum and to that for non-pregnant historical controls (5.8 mg.h/l). Consequently, pregnancy does not appear to affect overall abacavir exposure significantly or to necessitate dose adjustments.

Phenotypic Coreceptor Tropism in Perinatally HIV-infected Youth Failing Antiretroviral Therapy.

BACKGROUND: Perinatally HIV-infected (PHIV) children and youth are often heavily treatment-experienced, with resultant antiretroviral resistance and limited treatment options. For those with virologic failure (VF), new agents such as CCR5 (R5) antagonists may be useful; however, reports of R5 antagonist susceptibility in children have mostly relied on genotypic testing, which may not accurately reflect the phenotypic tropism of the viral populations. We characterized phenotypic coreceptor usage among PHIV children and youth with VF on antiretroviral treatment to identify predictors of CXCR4 (X4) tropism which preclude R5 antagonist use. METHODS: Plasma samples with >1000 HIV RNA copies/mL were obtained from 73 PHIV antiretroviral treatment-treated children and youth (age 9-21 years) enrolled in the multicenter Pediatric HIV/AIDS Cohort Study. Samples were analyzed using the Trofile phenotypic assay. Multiple logistic regression was performed to identify factors associated with detectable X4 tropism. RESULTS: Tropism results were obtained for 59 (81%) of the 73 children and youth; 32 (54%) had X4-tropism. Persistent viremia (≥80% of HIV RNA measurements >400 copies/mL) was associated with detectable X4 tropism (adjusted odds ratio: 6.6, 95% confidence interval: 1.4, 31.4), while longer cumulative nucleoside reverse transcriptase inhibitor use was associated with lower risk of X4 tropism (adjusted odds ratio: 0.6, 95% confidence interval: 0.5, 0.9). CONCLUSIONS: Using a phenotypic assay, >50% of PHIV children and youth with VF had X4 tropism, similar to that in experienced adults, and higher than the 30% reported for children using genotypic assays. Persistent viremia and shorter nucleoside reverse transcriptase inhibitor exposure are associated with X4-tropism in children and youth and may help target phenotypic testing to those most likely to benefit from R5 antagonist.

Case Report of a Child after Hematopoietic Cell Transplantation with Acute Aspergillus Tracheobronchitis as a Cause for Respiratory Failure.

Rapid respiratory failure due to invasive mycosis of the airways is an uncommon presentation of Aspergillus infection, even in immunocompromised patients, and very few pediatric cases have been reported. Patients with Aspergillus tracheobronchitis present with nonspecific symptoms, and radiologic studies are often noninformative, leading to a delay in diagnosis. Prompt initiation of adequate antifungal therapies is of utmost importance to improve outcome. We report the case of a 9-year-old girl with chronic myelogenous leukemia who developed respiratory distress 41 days after hematopoietic cell transplantation and rapidly deteriorated despite multiple interventions and treatment modalities.

Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women.

BACKGROUND: Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL. RESULTS: Median (range) AUC0-24 were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37-225, n = 17), 56 (<10-181, n = 30), and 81 (<10-299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3-0.8, n = 21). Delivery HIV-1 RNA was ≤50 copies per milliliter in 70% and ≤400 copies per milliliter in 90% of women. Cmin were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10-93) vs 63 (15-200) ng/mL (P = 0.0001). Cmin was below the protein binding-adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10%). CONCLUSIONS: Rilpivirine exposure is lower during pregnancy compared with postpartum and highly variable. Ninety percent of women had minimum concentrations above the protein binding-adjusted EC90 for rilpivirine.

Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents.

BACKGROUND: There is limited evidence about longer-term effects of combination antiretroviral therapy that includes protease inhibitors (PIs) on the immunological status of HIV-1-infected children. Better understanding might help to resolve questions on when to initiate treatment. METHODS: The change in percentage of CD4-positive T lymphocytes (CD4%) was investigated in 1012 previously treated HIV-1-infected children (aged 0-17 years) who were enrolled in research clinics in the USA before 1996 and followed up to 2000. 702 started PI-based combination therapy. Data analyses ignored subsequent treatment changes. FINDINGS: Among the 1012 children, the median CD4% increased from 22% to 28% between 1996, when PIs were first prescribed, and 2000. For the 702 who started PI-based therapy, the mean CD4% increase after 3 years was largest among participants with the greatest immunosuppression (15.7%, 10.6%, 5.1%, and 2.0% for participants with CD4% before therapy of <5%, 5-14%, 15-24%, and >25%; p<0.0001). After adjustment for pre-PI CD4%, the mean increase was largest among the youngest participants (9.2%, 8.0%, and 4.3% for ages <5 years, 5-9 years, and >10 years; p=0.001). However, only a minority of significantly immunocompromised participants (33%, 26%, and 49% of those with pre-PI CD4% of <5%, 5-14%, or 15-24%) achieved CD4% values above 25%, whereas 84% of those with pre-PI values above 25% maintained such values. INTERPRETATION: Although PI-based therapy was associated with substantial improvements in CD4%, initiation before severe immunosuppression and at younger ages may be more effective for recovery or maintenance of normal CD4%. Randomised investigation of when to start combination therapy in children, particularly infants, is needed.