Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Analyzing Longitudinally Collected Viral Load Measurements in Youth With Perinatally Acquired HIV Infection: Problems and Possible Remedies.

Human immunodeficiency virus (HIV) viral load (VL) is an important quantitative marker of disease progression and treatment response in people living with HIV infection, including children with perinatally acquired HIV. Measures of VL are often used to predict different outcomes of interest in this population, such as HIV-associated neurocognitive disorder. One popular approach to summarizing historical viral burden is the area under a time-VL curve (AUC). However, alternative historical VL summaries (HVS) may better answer the research question of interest. In this article, we discuss and contrast the AUC with alternative HVS, including the time-averaged AUC, duration of viremia, percentage of time with suppressed VL, peak VL, and age at peak VL. Using data on youth with perinatally acquired HIV infection from the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, we show that HVS and their associations with full-scale intelligence quotient depend on when the VLs were measured. When VL measurements are incomplete, as can be the case in observational studies, analysis results may be subject to selection bias. To alleviate bias, we detail an imputation strategy, and we present a simulation study demonstrating that unbiased estimation of a historical VL summary is possible with a correctly specified imputation model.

Randomized Controlled Trial of a Remote Coaching mHealth Adherence Intervention in Youth Living with HIV.

Youth living with HIV (YLWH) in the US have low rates of viral suppression (VS). In a prospective randomized clinical trial (ATN152) that enrolled 89 YLWH on antiretroviral therapy (ART) with detectable viral load, we evaluated a 12 week triggered escalating real-time adherence (TERA) intervention with remote coaching, electronic dose monitoring (EDM), and outreach for missed/delayed doses compared to standard of care (SOC). Median [Q1, Q3] percent days with EDM opening was higher in TERA (72% (47%, 89%)) versus SOC (41% (21%, 59%); p < 0.001) and incidence of numbers of 7 day gaps between openings were lower (TERA to SOC ratio: 0.40; 95% CI 0.30, 0.53; p < 0.001). There were no differences in VS at week 12 (TERA 35%; 95% CI 21%, 51% versus SOC 36%; 95% CI 22%, 51%; p > 0.99) or later time-points. The intervention improved adherence but not VS in heavily ART-experienced YLWH. Remote coaching more closely tailored to the unique dosing patterns and duration of need for youth struggling to reach VS warrants further investigation.

Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants.

BACKGROUND: Perinatal human immunodeficiency virus type 1 (HIV-1) continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). METHODS: An extended half-life bNAb, VRC01LS, was administered subcutaneously at 80 mg/dose after birth to HIV-1-exposed, nonbreastfed (cohort 1, n = 10) and breastfed (cohort 2, n = 11) infants. Cohort 2 received a second dose (100 mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. RESULTS: Local reactions (all grade ≤2) occurred in 67% and 20% after dose 1 and dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administered subcutaneously achieved a mean (standard deviation) plasma level of 222.3 (71.6) µg/mL by 24 hours and 44.0 (11.6) µg/mL at week 12, prior to dose 2. The preestablished target of ≥50 µg/mL was attained in 95% and 32% at weeks 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after 1 dose was significantly greater (P <.002) than after a VRC01 dose (20 mg/kg). No infants acquired HIV-1. CONCLUSIONS: VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with antiretrovirals to prevent infant HIV-1 transmission.

Birth Prevalence of Congenital Cytomegalovirus Infection in HIV-Exposed Uninfected Children in the Era of Combination Antiretroviral Therapy.

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.

Human Papillomavirus Antibody Levels and Quadrivalent Vaccine Clinical Effectiveness in Perinatally Human Immunodeficiency Virus-infected and Exposed, Uninfected Youth.

BACKGROUND: Persons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth. METHODS: This is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts. RESULTS: Seroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively. CONCLUSION: Antibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.

Adverse Pregnancy Outcomes Among Women Who Conceive on Antiretroviral Therapy.

Background: Adverse pregnancy outcomes for women who conceive on antiretroviral therapy (ART) may be increased, but data are conflicting. Methods: Human immunodeficiency virus-infected, nonbreastfeeding women with pre-ART CD4 counts ≥400 cells/µL who started ART during pregnancy were randomized after delivery to continue ART (CTART) or discontinue ART (DCART). Women randomized to DCART were recommended to restart if a subsequent pregnancy occurred or for clinical indications. Using both intent-to-treat and as-treated approaches, we performed Fisher exact tests to compare subsequent pregnancy outcomes by randomized arm. Results: Subsequent pregnancies occurred in 277 of 1652 (17%) women (CTART: 144/827; DCART: 133/825). A pregnancy outcome was recorded for 266 (96%) women with a median age of 27 years (interquartile range [IQR], 24-31 years) and median CD4+ T-cell count 638 cells/µL (IQR, 492-833 cells/µL). When spontaneous abortions and stillbirths were combined, there was a significant difference in events, with 33 of 140 (23.6%) in the CTART arm and 15 of 126 (11.9%) in the DCART arm (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.1-3.5]; P = .02). In the as-treated analysis, the RR was reduced and no longer statistically significant (RR, 1.4 [95% CI, .8-2.4]). Conclusions: Women randomized to continue ART who subsequently conceived were more likely to have spontaneous abortion or stillbirth, compared with women randomized to stop ART; however, the findings did not remain significant in the as-treated analysis. More data are needed on pregnancy outcomes among women conceiving on ART, particularly with newer regimens.

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

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

Predictors of Disclosure of Maternal HIV Status by Caregivers to their Children in an Inner-City Community in the United States.

Disclosure of HIV status to children is a challenge parents living with HIV face. To evaluate predictors of maternal HIV disclosure in a low-income clinic in the U.S. that serves an African American, Hispanic and immigrant population with high HIV prevalence, 172 caregivers with 608 children completed a standardized survey. Caregivers were 93 % female, 84 % biological mothers, and 34 % foreign born. Sixty-two (36 %) caregivers had at least one disclosed child, 42 of whom also had other nondisclosed children. Of all children, 581 (96 %) were uninfected and 181 (30 %) were disclosed. Caregiver's U.S. birth (OR: 2.32, 95 % CI 1.20-4.52), child's age (OR: 1.2/year, 95 % CI 1.16-1.24), and increased HIV-stigma perception by caregiver (1.06/point increase, 95 % CI 1.04-1.09) predicted disclosure. Children were more often disclosed if their caregiver was born in the U.S. or reported higher HIV-related stigma. These findings suggest that complex family context may complicate disclosure, particularly among immigrants.

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.

Antiretroviral Drug Resistance Among Children and Youth in the United States With Perinatal HIV.

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load.

Changing Trends in Complications and Mortality Rates Among US Youth and Young Adults With HIV Infection in the Era of Combination Antiretroviral Therapy.

BACKGROUND: Combination antiretroviral therapy (cART) has resulted in a dramatic decrease in human immunodeficiency virus (HIV)-related opportunistic infections and deaths in US youth, but both continue to occur. METHODS: We estimated the incidence of complications and deaths in IMPAACT P1074, a long-term US-based prospective multicenter cohort study conducted from April 2008 to June 2014. Incidence rates of selected diagnoses and trends over time were compared with those from a previous observational cohort study, P219C (2004-2007). Causes of death and relevant demographic and clinical features were reviewed. RESULTS: Among 1201 HIV-infected youth in P1074 (87% perinatally infected; mean [standard deviation] age at last chart review, 20.9 [5.4] years), psychiatric and neurodevelopmental disorders, asthma, pneumonia, and genital tract infections were among the most common comorbid conditions. Compared with findings in P219C, conditions with significantly increased incidence included substance or alcohol abuse, latent tuberculosis, diabetes mellitus, atypical mycobacterial infections, vitamin D deficiency or metabolic bone disorders, anxiety disorders, and fractures; the incidence of pneumonia decreased significantly. Twenty-eight deaths occurred, yielding a standardized mortality rate 31.5 times that of the US population. Those who died were older, less likely to be receiving cART, and had lower CD4 cell counts and higher viral loads. Most deaths (86%) were due to HIV-related medical conditions. CONCLUSIONS: Opportunistic infections and deaths are less common among HIV-infected youth in the US in the cART era, but the mortality rate remains elevated. Deaths were associated with poor HIV control and older age. Emerging complications, such as psychiatric, inflammatory, metabolic, and genital tract diseases, need to be addressed.

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.

Predictors of resolution and persistence of renal laboratory abnormalities in pediatric HIV infection.

BACKGROUND: Among human immunodeficiency virus (HIV)-infected youth, the role of renal disease (RD) and its management has become increasingly important as these children/adolescents mature into young adults. The identification of predictors of abnormal renal laboratory events (RLE) may be helpful in the management of their HIV infection and its associated renal complications. METHODS: Data collected from HIV-infected youth followed for ≥ 48 months were analyzed to identify predictors of resolution versus persistence of RLE and determine the utility of RLE to predict the onset of RD. Analysis included descriptive and inferential methods using a multivariable extended Cox proportional hazards model. RESULTS: Of the 1,874 at-risk children enrolled in the study, 428 (23 %) developed RLE, which persisted in 229 of these (54 %). CD4 percentages of <25 % [hazard ratio (HR) 0.63, p < 0.002) and an HIV viral load of >100,000 copies/ml (HR 0.31, p < 0.01) were associated with reduced rates of resolution, while in most cases exposure to highly active antiretroviral therapy (HAART)/nephrotoxic HAART prior to or subsequent to RLE were not. Persistence of RLE was 88 % sensitive for identifying new RD. Negative predictive values for RD were >95 % for both the at-risk cohort and those with RLE. CONCLUSIONS: Advanced HIV disease predicted persistence of RLE in HIV-infected youth. Persistent RLE were useful for identifying RD.

Phosphaturia in HIV-exposed Uninfected Neonates Associated with Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. Potential mechanisms underlying this observation are unknown. METHODS: The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in third trimester versus none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4-30 days, to compare slopes by TDF exposure. RESULTS: Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 versus -0.08/day (difference -0.50/day [95%CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] versus 26 [22,37] ng/mL). No differences were observed for other biomarkers. CONCLUSIONS: Third trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

Prevalence of detectable HIV-DNA and -RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy.

OBJECTIVE: Central nervous system (CNS) HIV infection can impact cognition and may be an obstacle to cure in adolescents and young adults with perinatal HIV (AYAPHIV). IMPAACT2015 enrolled AYAPHIV on suppressive antiretroviral therapy (ART) with cognitive impairment to detect and quantify HIV in blood and cerebrospinal fluid (CSF). DESIGN: IMPAACT2015 was a U.S.-based multi-site, exploratory, observational study. METHODS: Cognitive impairment was defined as NIH Toolbox Fluid Cognition Composite score (FCCS) > 1 standard deviation below age-adjusted normative group mean. Cell-free HIV-RNA and cell-associated HIV pol/gag -DNA and 10 biomarkers of inflammation/neuronal injury were measured in paired CSF and blood. ART exposure concentrations were quantified in hair. RESULTS: Among 24 participants, 20 had successful CSF collection and 18 also met viral suppression criteria. 9/18 (50%) were female sex-at-birth, 14/18 (78%) were Black. Median (range) age was 20 years (13-27), time on ART 18.3 years (8.0-25.5), and FCCS 68 (53-80). HIV-DNA was detected in PBMCs from all participants. In CSF, 2/18 (11%, 95% CI: 1.4-34.7%) participants had detectable cell-free HIV-RNA, while HIV gag or pol -DNA was detectable in 13/18 (72%, 95% CI: 47-90%). Detectable HIV-DNA in CSF was associated with male sex-at-birth (p = 0.051), lower CD4 count at enrollment (p = 0.016), and higher PBMC HIV pol -DNA copies (p = 0.058). Hair antiretroviral concentrations and biomarkers were not associated with CSF HIV-DNA detection. CONCLUSIONS: We found a high proportion of AYAPHIV with neurocognitive impairment had CSF cells harboring HIV-DNA during long-term virologic suppression. This evidence of persistent HIV-DNA in CSF suggests that the CNS should be considered in treatment and cure studies.

Auditory Function in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol Up Young Adults: A Pilot Study.

BACKGROUND: To collect and compare selected hearing measures in a pilot study of young adults with perinatally acquired HIV (YAPHIV) and those with perinatal HIV exposure who are uninfected young adults with PHEU (YAPHEU). SETTING: Cross-sectional hearing measures in YAPHIV and YAPHEU enrolled in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (AMP) for Participants 18 Years of Age and Older (AMP Up). METHODS: Pure-tone air conduction audiometry and distortion product otoacoustic emission (DPOAE) data were collected in 1 visit. A low-frequency pure-tone average (PTA) (LFPTA, at 0.25, 0.5, 1, and 2 kHz), a speech-frequency PTA (SFPTA, at 0.5, 1, 2, and 4 kHz), and a high-frequency PTA (HFPTA, at 3, 4, 6, and 8 kHz) were calculated. Hearing loss was defined as worse ear SFPTA of ≥20 dB HL. Separate linear regression models were fit for worse ear LFPTA, SFPTA, and HFPTA to assess associations with PHIV status. DPOAE signal-to-noise ratios (SNRs) were obtained at 3 frequencies in each ear. RESULTS: Forty-seven YAPHIV and 9 YAPHEU completed hearing testing. All adjusted mean PTAs were similar between YAPHIV and YAPHEU. Hearing loss occurred more in YAPHIV (7/47, 15.2%; 95% CI: 6.3%-28.9%), compared with YAPHEU (0/9, 0%). No associations were detected between HIV disease severity measures and worse ear SFPTA. DPOAE SNRs were similar between YAPHIV and YAPHEU. CONCLUSIONS: In this pilot study, peripheral hearing (ie, PTAs) and cochlear function (ie, DPOAEs) were similar between YAPHIV and YAPHEU. A larger study is warranted to confirm these findings.

Increased risk of asthma and atopic dermatitis in perinatally HIV-infected children and adolescents.

The incidence of asthma and atopic dermatitis (AD) was evaluated in HIV-infected (n = 451) compared to HIV-exposed (n = 227) but uninfected (HEU) children and adolescents by abstraction from clinical charts. Asthma was more common in HIV-infected compared to HEU children by clinical diagnosis (25% vs. 20%, p = 0.101), by asthma medication use, (31% vs. 22%, p = 0.012), and by clinical diagnosis and/or medication use, (34% vs. 25%, p = 0.012). HIV-infected children had a greater risk of asthma compared to HEU children (HR = 1.37, 95% CI: 1.01 to 1.86). AD was more common in HIV-infected than HEU children (20% vs. 12%, p = 0.009)) and children with AD were more likely to have asthma in both cohorts (41% vs. 29%, p = 0.010). HIV-infected children and adolescents in this study had an increased incidence of asthma and AD, a finding critical for millions of HIV-infected children worldwide.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

Chronic kidney disease associated with perinatal HIV infection in children and adolescents.

BACKGROUND: This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection. METHODS: Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining the long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in the absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria. RESULTS: Questionnaires on 191 out of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and 6 clinical cases of HIVAN, and 7 biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, 3; IgA nephropathy, 2; membranous nephropathy, 2). Incidence rates for CKD associated with HIV in pre-highly active antiretroviral therapy (HAART) (1993-1997) and HAART (1998-2002, 2003-2006) eras were 0.43, 2.84, and 2.79 events per 1,000 person years respectively. In multivariate analysis, black race and viral load ≥100,000 copies/mL (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD. CONCLUSIONS: A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV.