Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases

Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD

Most Early-Treated Children With Perinatally Acquired HIV Have Preserved Lung Function at School Age

Background: Impaired lung function is common among older children with perinatally acquired HIV (PHIV) who initiated antiretroviral therapy (ART) late in childhood. We determined the prevalence of abnormal spirometry and cofactors for impaired lung function among school-age children with PHIV who initiated ART when aged 12 months or younger. Setting: Children who received early ART in the Optimizing Pediatric HIV-1 Therapy study in Kenya and underwent spirometry at school age. Methods: Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured. Abnormal spirometry was defined as follows: obstructive (FEV1/FVC <1.64 z score [zFEV1/FVC]) and restricted (zFVC <1.64 with zFEV1/FVC ≥1.64). Characteristics, including anthropometric and HIV-related data, were ascertained in infancy and at school age. Caregiver carbon monoxide exposure served as a proxy for school-age child exposure. Linear regression determined associations of cofactors with lung function. Results: Among 40 children, the median age was 5 months at ART initiation and 8.5 years at spirometry. The mean zFEV1, zFVC, and zFEV1/FVC (SD) were 0.21 (1.35), 0.31 (1.22), and −0.24 (0.82), respectively. Five (13%) children had abnormal spirometry. Spirometry z scores were significantly lower among children with pre-ART pneumonia, WHO HIV stage 3/4, higher HIV RNA at 6 months after ART initiation, low anthropometric z scores, and higher carbon monoxide exposure. Conclusions: Most of the children with PHIV who initiated ART at age 12 months or younger had normal spirometry, suggesting that ART in infancy preserved lung function. However, 13% had abnormal spirometry despite early ART. Modifiable factors were associated with impaired lung function, providing potential targets for interventions to prevent chronic lung disease

Implications of Combined Exposure to Household Air Pollution and HIV on Neurocognition in Children

Air pollution exposure and HIV infection can each cause neurocognitive insult in children. The purpose of this study was to test whether children with combined high air pollution exposure and perinatal HIV infection have even greater risk of neurocognitive impairment. This was a cross-sectional study of HIV-uninfected unexposed (HUU) and HIV-infected children and their caregivers in Nairobi, Kenya. We used a detailed neuropsychological battery to evaluate neurocognitive functioning in several domains. We measured caregiver 24-h personal CO exposure as a proxy for child CO exposure and child urinary 1-hydroxypyrene (1-OHP), a biomarker for exposure to polycyclic aromatic hydrocarbons (PAHs). Median 24-h caregiver CO exposure was 6.1 and 3.7 ppm for 45 HIV-infected (mean age 6.6 years) and 49 HUU (mean age 6.7 years), respectively; 48.5% of HIV-infected and 38.6% of HUU had caregiver 24-h CO levels exceeding the WHO recommended level. Median 1-OHP exposure was 0.6 and 0.7 µmol/mol creatinine among HIV-infected and HUU children, respectively. HIV-infected children with high urinary 1-OHP (exceeding 0.68 µmol/mol creatinine) had significantly lower global cognition (p = 0.04), delayed memory (p = 0.01), and attention scores (p = 0.003). Among HUU children, urinary 1-OHP and caregiver 24-h caregiver CO were not significantly associated with neurocognitive function. Our findings suggest that combined chronic exposure to air pollutants and perinatal HIV infection may be associated with poorer neurocognitive outcomes. High prevalence of air pollution exposure highlights the need to reduce these exposures

Risk‐based versus universal PrEP delivery during pregnancy: a cluster randomized trial in Western Kenya from 2018 to 2019

Abstract Introduction Integrating pre‐exposure prophylaxis (PrEP) delivery for pregnant and postpartum women within maternal and child health (MCH) clinics is feasible and acceptable. It is unknown whether a risk‐guided model would facilitate appropriate PrEP use among MCH attendees better than universally offering PrEP. Methods The PrEP Implementation for Mothers in Antenatal Care (PrIMA) study was a cluster randomized trial to assess two models for PrEP delivery among pregnant women seeking routine MCH care at 20 public clinics in Kenya between January 2018 and July 2019 (NCT03070600). In the Universal arm, all participants received PrEP counselling and self‐selected whether to initiate PrEP. In the Targeted arm, participants underwent an HIV risk assessment, including an objective risk‐scoring tool and an offer of HIV self‐tests for at‐home partner testing; those determined to be at high risk received a PrEP offer. Participants were followed through 9 months postpartum. Primary outcomes included incident HIV and appropriate PrEP use (defined as PrEP uptake among those at high risk and no PrEP uptake for those not at risk). Outcomes were compared using intention‐to‐treat analyses, adjusting for baseline HIV risk and marital status. Results Among 4447 women enrolled, the median age was 24.0 years (interquartile range [IQR]: 20.9, 28.3), and most were married (84.8%). The median gestational age at enrolment was 24 weeks (IQR: 20, 30). Women in the Targeted arm were more likely to be at high risk for HIV acquisition at baseline (51.6% vs. 33.3%). During 4638 person‐years (p‐yr) of follow‐up, there were 16 maternal HIV infections with no difference in maternal HIV incidence between arms: 0.31/100 p‐yr (95% CI: 0.15, 0.65) Targeted and 0.38/100p‐yr (95% CI: 0.20, 0.73) Universal (adjusted relative risk [aRR]: 0.85 [CI: 0.28, 2.55]). There was no significant difference in the frequency of appropriate PrEP use between the arms (68.2% vs. 59.1% in Targeted vs. Universal, respectively) (aRR: 1.03 [CI: 0.96, 1.10]). Conclusions Given comparable maternal HIV incidence and PrEP uptake in Universal and Targeted approaches, and the simplicity that universal PrEP offers, our findings suggest that universal PrEP counselling is optimal for integrating PrEP in MCH systems