Evaluation of Risk for Late Language Emergence after In Utero Antiretroviral Drug Exposure in HIV-exposed Uninfected Infants

This is not the published version.BACKGROUND Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected (HEU), particularly for neurodevelopmental problems, such as language delays. METHODS We studied late language emergence (LLE) in HEU children enrolled in a US-based prospective cohort study. LLE was defined as a caregiver-reported score ≤ 10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for one-year-olds and as ≥1 standard deviation below age-specific norms for the Ages and Stages Questionnaire for two-year-olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal, and environmental characteristics. RESULTS 1,129 language assessments were conducted among 792 one- and two-year-olds (50% male, 62% black, and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of one-year-olds and 23% of two-year-olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed one-year-olds, increased odds of LLE was observed for those exposed to atazanavir (aOR=1.83, 95% CI=1.10-3.04), particularly after the first trimester (aOR=3.56, p=0.001), compared to atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among two-year-olds. CONCLUSIONS In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in one-year-old infants with atazanavir exposure

Language Impairment in Children Perinatally Infected with HIV Compared to Children Who Were HIV-Exposed and Uninfected

Objective - To investigate risk for language impairment in children perinatally infected or exposed to HIV. Methods - We evaluated the prevalence of language impairment (LI) in 7–16 year old children with perinatal HIV infection (HIV+) compared to children HIV-exposed and uninfected (HEU), using a comprehensive standardized language test (CELF-4). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease and antiretroviral treatment (ART) factors with LI category were evaluated using univariate and multivariable logistic regression models. Results - Of 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ vs 87.5 (17.9) for HEU. After adjustment, Black children had higher odds of Pri-LI vs no LI (aOR=2.43, p=0.03). Children who were Black, Hispanic, had a caregiver with low education or low IQ, or a non-biological parent as caregiver had higher odds of Con-LI vs no LI. Among HIV+ children, viral load \u3e400 copies/ml (aOR=3.04, pp=0.02) and ART initiation (aOR=2.12, p=0.02) were associated with higher odds of Con-LI vs. no LI. Conclusions - Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI

Language Impairment in Children Perinatally Infected with HIV Compared to Children Who Were HIV-Exposed and Uninfected

OBJECTIVE: To investigate risk for language impairment in children perinatally infected or exposed to HIV. METHOD: We evaluated the prevalence of language impairment (LI) in 7–16 year old children with perinatal HIV infection (HIV+) compared to children HIV-exposed and uninfected (HEU), using a comprehensive standardized language test (CELF-4). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease and antiretroviral treatment (ART) factors with LI category were evaluated using univariate and multivariable logistic regression models. RESULTS: Of 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ vs 87.5 (17.9) for HEU. After adjustment, Black children had higher odds of Pri-LI vs no LI (aOR=2.43, p=0.03). Children who were Black, Hispanic, had a caregiver with low education or low IQ, or a non-biological parent as caregiver had higher odds of Con-LI vs no LI. Among HIV+ children, viral load >400 copies/ml (aOR=3.04, p<0.001), CDC Class C (aOR=2.19, p=0.02) and ART initiation <6 months of age (aOR=2.12, p=0.02) were associated with higher odds of Con-LI vs. no LI. CONCLUSIONS: Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI

Impact of medications prescribed for treatment of attention-deficit hyperactivity disorder on physical growth in children and adolescents with HIV.

OBJECTIVE: To examine the relationships between physical growth and medications prescribed for symptoms of attention-deficit hyperactivity disorder in children with HIV. METHODS: Analysis of data from children with perinatally acquired HIV (N = 2251; age 3-19 years), with and without prescriptions for stimulant and nonstimulant medications used to treat attention-deficit hyperactivity disorder, in a long-term observational study. Height and weight measurements were transformed to z scores and compared across medication groups. Changes in z scores during a 2-year interval were compared using multiple linear regression models adjusting for selected covariates. RESULTS: Participants with (n = 215) and without (n = 2036) prescriptions were shorter than expected based on US age and gender norms (p \u3c .001). Children without prescriptions weighed less at baseline than children in the general population (p \u3c .001) but gained height and weight at a faster rate (p \u3c .001). Children prescribed stimulants were similar to population norms in baseline weight; their height and weight growth velocities were comparable with the general population and children without prescriptions (for weight, p = .511 and .100, respectively). Children prescribed nonstimulants had the lowest baseline height but were similar to population norms in baseline weight. Their height and weight growth velocities were comparable with the general population but significantly slower than children without prescriptions (p = .01 and .02, respectively). CONCLUSION: The use of stimulants to treat symptoms of attention-deficit hyperactivity disorder does not significantly exacerbate the potential for growth delay in children with HIV and may afford opportunities for interventions that promote physical growth. Prospective studies are needed to confirm these findings

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Neurodevelopment and In Utero Antiretroviral Exposure of HIV-Exposed Uninfected Infants

OBJECTIVE: Antiretroviral (ARV) drugs are routinely provided to HIV-infected pregnant women to prevent HIV mother-to-child transmission. Although ARV use has significantly reduced mother-to-child transmission to <2% in the United States, it remains crucial to monitor uninfected infants and children for adverse consequences of in utero ARV exposure. METHODS: We studied neurodevelopmental function in HIV-exposed uninfected children who were enrolled in Pediatric AIDS Clinical Trials Group 219/219C, a multisite, prospective, cohort study. Mental and motor functioning were assessed with the Bayley Scales of Infant Development (BSID), first and second editions. ARV exposure information was collected during pregnancy or within the first years of life. Linear regression methods were used to evaluate the association of in utero ARV exposure on Mental Developmental Index and Psychomotor Developmental Index at 2 years of age, controlling for demographic factors (age, gender, and race/ethnicity) and potential confounders: test version, primary language, primary caregiver, caregiver education level, low birth weight, geographic and urban/rural location, birth year, and maternal illicit drug use. RESULTS: Among 1840 infants who were born between 1993 and 2006, 1694 (92%) were exposed to ARV in utero and 146 (8%) were not exposed. After controlling for confounders, children who were exposed in utero to any ARV did not have lower Mental Developmental Index and Psychomotor Developmental Index scores than unexposed children. Among low birth weight infants, significantly higher BSID scores were observed for prenatally ARV-exposed than unexposed children. Maternal illicit drug use was reported for 17% of mothers but was not associated with BSID scores. CONCLUSIONS: Mental and motor functioning scores were not lower for infants with in utero ARV exposure compared with no exposure. Although these results are reassuring, continued evaluation of uninfected children with in utero ARV exposure for long-term adverse outcomes is important. Pediatrics 2010; 125: e250-e26

Low risk of neurodevelopmental impairment among perinatally acquired HIV-infected preschool children who received early antiretroviral treatment in Thailand

Introduction: Antiretroviral therapy (ART) is recommended in perinatally HIV-infected (PHIV) infants immediately upon diagnosis. We aimed to compare neurodevelopmental outcomes between PHIV children who initiated ART within 12 months of life and perinatally HIV-exposed uninfected (PHEU) children and to assess neurodevelopmental outcomes by timing of ART. Methods: This prospective cohort study included Thai children aged 12 to 56 months who were assessed with the Mullen Scales of Early Learning (MSEL) at enrolment and at 48 weeks. Global Developmental Impairment (GDI) was defined as Early Learning Composite (ELC) ≤ 70 on the MSEL; typical developmental pattern was defined as ELC > 70 at both visits. Logistic regression was used to compare prevalence of any GDI. Predictors of changing ELC scores were analysed with generalized estimating equations linear regression model. Results: From 2016 to 2017, 50 PHIV (twenty-seven early ART within three months and twenty-three standard ART within three to twelve months) and 100 PHEU children were enrolled. Median (IQR) age at first assessment was 28 (19 to 41) months. PHIV children had lower age-relevant Z scores for weight, height and head circumference compared to the PHEU group (p < 0.05). The prevalence of overall GDI was 18% (95% CI 11 to 27) and 32% (95% CI 20 to 47) in PHEU and PHIV children respectively (p = 0.06). In subgroup analysis, 22% (95% CI 9 to 42) of early ART PHIV children and 44% (95% CI 23 to 66) of standard ART PHIV children had overall GDI. There was a higher rate of GDI in standard ART PHIV children (p = 0.01), but not in the early ART group (p = 0.62) when compared with PHEU children. The standard ART PHIV group demonstrated lower typical developmental pattern than both the early ART PHIV group and the PHEU group (57% vs. 77% vs. 82% respectively). Non-attendance at nursery school was associated with changes in ELC score during study participation (adjusted coefficient −3.8; 95% CI −6.1 to −1.6, p = 0.001). Conclusions: Preschool children with HIV who initiated ART in the first three months of life had a similar rate of GDI as PHEU children. Lack of nursery school attendance predicted poor developmental trajectory outcomes among PHIV children