The Role of Maternal Secretor Status and Human Milk Oligosaccharides on Early Childhood Development: A Systematic Review and Meta-Analysis.

Background: Breast milk is the gold standard of infant nutrition, delivering nutrients and bioactive molecules as needed to support optimal infant growth and cognitive development. Increasing evidence links human milk oligosaccharides (HMOs) to these early childhood development milestones. Aims: To summarize and synthesize the evidence relating to HMOs and infant brain development, physical growth, and cognitive development. In addition, HMO concentrations in secretor and nonsecretor mothers were compared via a meta-analysis. Study Design: A systematic review and meta-analysis were carried out in accordance with the PRISMA statement. This review used three databases (PubMed, Scopus, and Web of Science) and was limited to English-language articles published between 2000 and June 30, 2023. Results: The initial searches yielded 245 articles, 27 of which were included in the systematic review and 12 in the meta-analysis. The meta-analysis revealed a substantial between-study heterogeneity, I2 = 97.3%. The pooled effect was 0.21 (95% CI: -0.41 to 0.83; p = 0.484), indicating that secretors had higher HMO concentrations, although this difference was not statistically significant. At one month of age, 2'FL, 3FL, and 3'SL play an important role in brain maturation and thus play a critical role in cognitive development. Secretors produce higher concentrations of 2'FL and 3'SL, explaining the benefits to infants of secretor mothers. Growth velocity was correlated to fucosylated and sialylated HMO concentrations, with lower concentrations linked to stunting. Conclusions: According to evidence from the systematically reviewed articles, HMOs are essential for a child's early development, but the extent to which they have an impact depends on maternal secretor status.

Factors associated with viral load non-suppression among treatment-experienced pre-teenage children living with HIV in Kenya: a nationwide population-based cohort study, 2015-2021.

Background: Viral load non-suppression (VLNS) in children is a major public health concern because of attendant HIV disease progression and risk of morbidity and mortality. Based on a nationally representative database we present estimates of the prevalence, trends and factors associated with VLNS in Kenyan pre-teenage children between 2015 and 2021. Methods: Kenya National AIDS & STI Control Program's (NASCOP) maintains an early infant diagnosis and viral load (EID/VL) database for all persons living with HIV who are enrolled in the country's primary care clinics for purposes of monitoring progress towards achievement of the 95% viral suppression goals. Participants were eligible if they were children living with HIV (CLHIV), on combination ART (cART) treatment, and ≤12 years old. The modified Mann-Kendall trend test for serially correlated data was used to identify VLNS trends. Generalized estimating equations (GEE) with a logit link was used to assess the effects of covariates on the odds of VLNS (VL ≥1,000 copies/mL) over repeated points in time, allowing for the correlation among the repeated measures. Findings: Between January 2015 and December 2021, 508,743 viral load tests were performed on samples collected from 109,682 pre-teenage children. The prevalence of VLNS decreased from 22.9% (95% CI 22.4-23.3) to 12.5% (95% CI 12.1-12.9), p < 0.0001, and mean age increased from 3.1 (4.2) to 8.0 (3.2) years in 2015 and 2021 respectively. A modified Mann-Kendall trend test for serially correlated data denotes a statistically significant decreasing trend (τ = -0.300, p < 0.0001) over the study period. In the multivariable GEE analysis adjusted for covariates, the odds of VLNS decreased by 11% per year during the study period, (GEE-aOR 0.89, 95% CI 0.88-0.90; p < 0.0001). Factors positively associated with VLNS were EFV/NVP-based first-line cART regimen (GEE-aOR 1.74, 95% CI 1.65-1.84, p < 0.0001), PI-based cART regimen (GEE-aOR 1.82, 95% CI 1.72-1.92, p < 0.0001), and children aged 1-3 years (toddlers) (GEE-aOR: 1.84, 95% CI 1.79-1.90, p < 0.0001). On the contrary, DTG-based cART regimen, were negatively associated with VLNS (GEE-aOR 0.70, 95% CI 0.65-0.75, p < 0.0001). Interpretation: There is a strong evidence of decreasing viremia between 2015 and 2021. To sustain the decreasing trend, accelerating the switch from the suboptimal EVP/NVP first-line regimen to optimised DTG regimen is warranted. Funding: U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and Clinton Health Access Initiative (CHAI).

Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa.

Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population pharmacokinetic (PK) model and assessed drug exposure of LPV/r oral pellets administered twice daily to CLHIV per World Health Organization (WHO) weight bands. The PK analysis included Kenyan and Ugandan children participating in the LIVING studies (NCT02346487) receiving LPV/r pellets (40/10 mg) and ABC/3TC (60/30 mg) dispersible tablets. Population PK models were developed for lopinavir (LPV) and ritonavir (RTV) to evaluate the impact of RTV on the oral clearance (CL/F) of LPV. The data obtained from the study were analyzed using nonlinear mixed-effects modeling approach. Data from 514 children, comprising a total of 2,998 plasma concentrations of LPV/r were included in the analysis. The LPV and RTV concentrations were accurately represented by a one-compartment model with first-order absorption (incorporating a lag-time) and elimination. Body weight influenced LPV and RTV PK parameters. The impact of RTV concentrations on the CL/F of LPV was characterized using a maximum effect model. Simulation-predicted target LPV exposures were achieved in children with this pellet formulation across the WHO weight bands. The LPV/r pellets dosed in accordance with WHO weight bands provide adequate LPV exposures in Kenyan and Ugandan children weighing 3.0 to 24.9 kg.

Adolescent experiences, perceptions, and preferences for the process of HIV status disclosure in Kenya.

Introduction: Disclosure of HIV status to adolescents living with HIV has been associated with improved treatment outcomes. However, there are limited data regarding the experiences of, perceptions of, and preferences for the process of disclosure of HIV status among adolescents and young adults living with HIV (AYLH), especially in sub-Saharan Africa. Methods: Young adults living with HIV from 20 HIV clinics in Kenya who participated in a clinical trial evaluating the effectiveness of a disclosure and transition package completed an anonymous survey in 2019. We described their experiences and preferences using counts and proportions and assessed factors associated with satisfaction with the disclosure process using linear regression, reporting age-adjusted mean differences (aMD), and 95% confidence intervals (95%CIs). Results: Of the 375 enrolled AYLH, 265 (71%) had perinatally acquired HIV, of whom 162 (61%) were female. The median age of the enrolled AYLH was 16 years (IQR: 14-19 years), and all of them were on antiretroviral therapy (ART). For over half (55%) of the participants, caregivers disclosed their HIV status, and 57% preferred that their caregivers disclose the status to them. Most (78%) of the participants preferred full disclosure by 12 years of age. The majority (69%) believed the disclosure was planned, and 11% suspected being HIV positive before the disclosure. Overall, 198 (75%) AYLH reported that they were ready for disclosure when it happened, and 86% were satisfied with the process. During both pre-disclosure (67 and 70%, respectively) and post-disclosure (>75% for each), AYLH felt supported by the clinic and caregivers. Factors associated with higher satisfaction with the disclosure process were pre-disclosure clinic support (aMD: 0.19 [95%CI: 0.05-0.33]) and pre-disclosure (aMD: 0.19 [0.06-0.31]) and post-disclosure (aMD: 0.17 [0.03-0.31]) caregiver support. AYLH who suspected they were HIV positive before they were disclosed to tended to have lower satisfaction when compared to those who never suspected (aMD: -0.37 [-0.74-(-0.01)]). Overall, they reported that disclosure positively influenced their ART adherence (78%), clinic attendance (45%), and communication with caregivers (20%), and 40% reported being happier after disclosure. Conclusion: Young adults living with HIV advocated for an appropriately timed disclosure process with the involvement of caregivers and healthcare workers (HCWs). Support from caregivers and HCWs before and during disclosure is key to improving their disclosure experience.

Abacavir Drug Exposures in African Children Under 14 kg Using Pediatric Solid Fixed Dose Combinations According to World Health Organization Weight Bands.

BACKGROUND: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands. METHODS: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets. RESULTS: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed. CONCLUSIONS: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.

Age and CD4+ T cell counts are inversely associated with HIV drug resistance mutations in treatment naive female sex workers.

The increasing prevalence of human immunodeficiency virus (HIV) drug resistance mutations (HIVDRM) in untreated seropositive persons has consequences for future treatment options. This is extremely important in key populations such as female sex workers (FSWs), where the prevalence of pretreatment drug resistance (PDR) and associated risk factors are unknown. In this study, we analyzed PDR and associated risk factors in recently diagnosed and treatment-naive FSWs in Nairobi, Kenya. In this cross-sectional study, we used 64 HIV-seropositive plasma samples collected from FSWs between November 2020 and April 2021. To identify HIVDRM, the pol gene was amplified and genotyped using sanger sequencing. The effects of age, tropism, CD4+ T cell count, subtype, and location on HIVDRM counts were examined using Poisson regression. Overall, the prevalence of PDR was 35.9% (95% CI: 24.3-48.9), which was strongly influenced by K103N and M184V mutations, which confer resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTI), respectively. Subtype A1 was predominant followed by subtype D with a notable increase in inter-subtype recombinants. We found statistically significant evidence that age was inversely related to HIVDRM. A FSW who is 1 year older had 12% less HIVDRM (incidence rate ratios [IRR]: 0.88; 95% CI: 0.82-0.95; P < .001), after adjusting for CD4+ T cell count, subtype, location, and tropism. Similarly, an increase in CD4+ T cell count by 1 unit, was associated with 0.4% fewer HIVDRM (IRR: 0.996; 95% CI: 0.994-0.998; P = .001), while controlling for the other variables. HIV-1 tropism was not associated with HIVDRM counts. In conclusion, our findings show a high prevalence of NNRTIs. Lower CD4+ T cell counts and younger age were significant risk factors that influenced HIVDRM loads. This finding underscores the relevance of targeted interventions and the importance of continuing to focus on FSWs as a way of addressing the HIV epidemic.

"When they are all grown, I will tell them": Experience and perceptions of parental self-disclosure of HIV status to children in Nairobi, Kenya.

BACKGROUND: There is mixed evidence on the influence of self-disclosure of one's HIV status on mental health, health behaviours and clinical outcomes. We studied the patterns of self-disclosure among parents living with HIV, and factors that influence parental disclosure. METHODS: This mixed-methods study was among adults in HIV care participating in a study assessing the uptake of pediatric index-case testing. They completed a survey to provide demographic and HIV-related health information, and assess self-disclosure to partners, children and others. We ran generalized linear models to determine factors associated with disclosure and reported prevalence ratios (PR). Eighteen participants also participated in in-depth interviews to explore perceived barriers and facilitators of self-disclosure to one's child. A content analysis approach was used to analyze interview transcripts. RESULTS: Of 493 caregivers, 238 (48%) had a child ≥ 6 years old who could potentially be disclosed to about their parent's HIV status. Of 238 participants, 205 (86%) were female, median age was 35 years, and 132 (55%) were in a stable relationship. Among those in a stable relationship, 96 (73%) knew their partner's HIV status, with 79 (60%) reporting that their partner was living with HIV. Caregivers had known their HIV status for a median 2 years, and the median age of their oldest child was 11 years old. Older caregiver age and older first born child's age were each associated with 10% higher likelihood of having disclosed to a child (PR: 1.10 [1.06-1.13] and PR: 1.10 [1.06-1.15], per year of age, respectively). The child's age or perceived maturity and fear of causing anxiety to the child inhibited disclosure. Child's sexual activity was a motivator for disclosure, as well as the belief that disclosing was the "right thing to do". Caregivers advocated for peer and counseling support to gain insight on appropriate ways to disclose their status. CONCLUSIONS: Child's age is a key consideration for parents to disclose their own HIV status to their children. While parents were open to disclosing their HIV status to their children, there is a need to address barriers including anticipated stigma, and fear that disclosure will cause distress to their children.

Tuberculosis Preventative Therapy Initiation and Completion Among Adolescents and Young Adults Living With HIV in Kenya.

BACKGROUND: Tuberculosis is the leading cause of death among adolescents and young adults living with HIV (YWHIV) and their heightened risk warrants deeper understanding of utilization of tuberculosis-prevention measures within HIV care. SETTING: Retrospective study using clinic surveys and medical record data from 86 Kenyan HIV clinics. METHODS: Clinic surveys obtained information on tuberculosis preventive therapy (TPT) services. Medical records of YWHIV were abstracted. Bivariate and multivariate analyses used generalized linear models to determine individual-level and clinic-level cofactors of TPT initiation and completion. RESULTS: Among 10,328 eligible YWHIV, 4337 (42.0%) initiated TPT. Of 3295 with ≥6 months follow-up, 1774 (53.8%) completed TPT. A lower patient-to-staff ratio was a clinic-level cofactor of TPT initiation ( P = 0.044) and completion ( P = 0.004); designated adolescent areas were associated with TPT initiation {prevalence ratio 2.05 [95% confidence interval (CI): 1.46 to -2.88]}. Individual cofactors of TPT initiation included younger age at HIV-care enrollment [relative risk (RR) 0.85 (95% CI: 0.80 to 0.90)] and antiretroviral therapy (ART) duration [1-2 vs. <1 year RR 1.31 (95% CI: 1.18 to 1.45)]. TPT completion was associated with younger age [RR 0.91 (95% CI: 0.85 to 0.98)] and ART duration [2-5 vs. <1 year RR 1.27 (95% CI: 1.03 to 1.57)]. In multivariate models, TPT initiation was associated with younger age and ART duration [1-2 vs. 1 year; adjusted RR 1.30 (95% CI: 1.16 to 1.46)] and TPT completion with ART duration [2-5 vs. 1 year adjusted RR 1.23 (95% CI: 0.99 to 1.52)]. CONCLUSION: Over half of YWHIV did not initiate and >40% did not complete TPT, with distinct clinic-level and individual-level cofactors. Approaches to enhance adolescent-friendly infrastructure and support older YWHIV are necessary to improve TPT use.

Effect of HIV stigma on depressive symptoms, treatment adherence, and viral suppression among youth with HIV.

OBJECTIVE: We estimated the effects of HIV stigma on mental health and treatment outcomes for youth with HIV (YWH). DESIGN: Secondary analysis of data for YWH ages 15-24 years in Western Kenya. METHODS: Participants completed a longitudinal survey (baseline, months 6 and 12) assessing socio-demographics, antiretroviral therapy (ART) adherence, depressive symptoms (PHQ-9), and HIV stigma (10-item Wright scale). First viral load (VL) after enrollment was abstracted from records. We estimated risk of depressive symptoms (score > 4), nonadherence (missing ≥2 days of ART in a month), and detectable VL (≥50 copies/ml) for each standard deviation (SD) increase in HIV stigma score, adjusted for age and sex (and regimen in VL model). The generalizing estimating equation models included measures for the three visits. RESULTS: Median age for the 1011 YWH was 18 years. At baseline, frequency of nonadherence, depressive symptoms and detectable VL was 21%, 21%, and 46%, respectively. Mean stigma score was 25 (SD = 7.0). Each SD stigma score increment was associated with higher risk of depressive symptoms {adjusted relative risk [aRR] 1.31 [95% confidence interval (CI): 1.20-1.44]}, nonadherence [aRR 1.16 (CI: 1.05-1.27)] and detectable VL [aRR 1.20 (CI: 1.08-1.32)]. Experienced and anticipated stigma were associated with detectable VL [aRR 1.16 (CI: 1.10-1.22) and aRR 1.23 (CI: 1.12-1.35), respectively]. Internalized and perceived community stigma were associated with depressive symptoms [aRR 1.31 (CI: 1.21-1.40) and aRR 1.24 (CI: 1.13-1.36), respectively]. CONCLUSIONS: Stigma was associated with depressive symptoms, nonadherence and detectable VL. Interventions to decrease stigma may improve virologic and mental health outcomes in YWH.

Individual-, Interpersonal- and Institutional-Level Factors Associated with HIV Stigma Among Youth in Kenya.

HIV stigma remains a barrier in achieving optimal HIV treatment. We studied the prevalence and predictors of HIV stigma among adolescents and youth with HIV (AYWHIV) ages 15-24 years in Western Kenya. Of 1011 AYWHIV, 69% were female with a median age of 18 years. Most (59%) attended adolescent clinic days, and 40% attended support groups. One-quarter (27%) had experienced physical, 18% emotional, and 7% sexual violence. The majority of AYWHIV (88%) reported disclosure concerns, 48% reported perceived community stigma, 36% experienced, and 24% internalized stigma. Compared to AYWHIV attending adolescent clinics, those in general/adult clinics had higher internalized stigma. Similarly, having dropped out of school was associated with higher internalized stigma. AYWHIV in sexual relationships had higher experienced stigma and disclosure concerns. Lastly, exposure to violence was associated with higher experienced, internalized, perceived community stigma and disclosure concerns. These risk factors can be targeted when developing stigma-prevention interventions.

Early Antiretroviral Therapy Reduces Severity but Does Not Eliminate Neurodevelopmental Compromise in Children With HIV.

BACKGROUND: Early antiretroviral therapy (ART) during infancy reduces cognitive impairment due to HIV, but the extent of benefit is unclear. SETTING: Children were recruited from hospital and health centers providing HIV care and treatment in Nairobi, Kenya. METHODS: Cognitive, behavioral, and motor outcomes were assessed in children with HIV and early ART (<1 year), children with HIV and late ART (1.5-6 years), and children HIV-unexposed uninfected (CHUU). Domain z scores and odds neurobehavioral impairment (≤15th percentile in CHUU) were compared in adjusted analyses. RESULTS: Children with HIV initiated ART at median ages 0.4 (early ART) and 3.5 years (late ART). Children were assessed at median ages 6.9 (CHUU, N = 61), 6.9 (early ART, N = 54), and 13.5 (late ART; N = 27) years. Children with late ART vs. children with early ART had significantly lower z scores in 7 domains, specifically global cognition, short-term memory, visuospatial processing, learning, nonverbal test performance, executive function, and motor skills (adjusted mean differences, -0.42 to -0.62, P values ≤ 0.05), and had higher odds impairment in 7 domains (adjusted odds ratios [aORs], 2.87 to 16.22, P values ≤ 0.05). Children with early ART vs. CHUU had lower z scores in 5 domains (global cognition, short-term memory, delayed memory, processing speed, and behavioral regulation [adjusted mean differences, -0.32 to -0.88, P values < 0.05]) and higher impairment for 2 domains (short-term memory [aOR, 3.88] and behavioral regulation [aOR 3.46], P values < 0.05). Children with late ART vs. CHUU had lower z scores in 8 domains (adjusted mean differences, -0.57 to -1.05, P values ≤ 0.05), and higher impairment in 7 domains (aORs 1.98 to 2.32, P values ≤ 0.05). CONCLUSION: Early ART in the first year of life attenuates but does not eliminate the neurodevelopmental compromise of HIV.

Brief Report: Performance of Tuberculosis Symptom Screening Among Hospitalized ART-Naive Children With HIV in Kenya.

BACKGROUND: The World Health Organization (WHO) recommends tuberculosis (TB) diagnostic evaluation for children with HIV (CHIV) who have history of TB contact, poor weight gain, cough, or fever. These screening criteria were developed based on studies of symptomatic CHIV with incomplete microbiologic confirmation. We performed routine TB microbiologic evaluation of hospitalized CHIV with and without symptoms to develop a data-driven TB symptom screen. METHODS: Among hospitalized antiretroviral therapy-naive Kenyan CHIV enrolled in the Pediatric Urgent Start of Highly Active Antiretroviral Therapy (PUSH) trial, we performed Xpert MTB/RIF and mycobacterial culture of respiratory and stool specimens independent of TB symptoms. We evaluated performance of WHO and other published pediatric TB screening criteria and derived optimized criteria using a combination of symptoms. RESULTS: Of 168 CHIV who underwent TB microbiologic evaluation, 13 (8%) had confirmed TB. WHO TB symptom screening had 100% sensitivity and 4% specificity to detect confirmed TB. Published TB screening criteria that relied on prolonged symptoms missed cases of confirmed TB (sensitivity 85%-92%). An optimized symptom screen including weight loss, cough, anorexia, or TB contact had 100% sensitivity and improved specificity (31%) compared with the WHO pediatric TB symptom screen. CONCLUSIONS: The WHO TB symptom screen was highly sensitive but resulted in a high proportion of hospitalized CHIV who would require TB diagnostic evaluation. Other published TB screening criteria missed CHIV with confirmed TB. Our optimized screening tool increased specificity while preserving sensitivity. Future multicenter studies are needed to improve TB screening tools for CHIV in both inpatient and outpatient settings.

Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples.

Sensitive and specific blood-based assays for the detection of pulmonary and extrapulmonary tuberculosis would reduce mortality associated with missed diagnoses, particularly in children. Here we report a nanoparticle-enhanced immunoassay read by dark-field microscopy that detects two Mycobacterium tuberculosis virulence factors (the glycolipid lipoarabinomannan and its carrier protein) on the surface of circulating extracellular vesicles. In a cohort study of 147 hospitalized and severely immunosuppressed children living with HIV, the assay detected 58 of the 78 (74%) cases of paediatric tuberculosis, 48 of the 66 (73%) cases that were missed by microbiological assays, and 8 out of 10 (80%) cases undiagnosed during the study. It also distinguished tuberculosis from latent-tuberculosis infections in non-human primates. We adapted the assay to make it portable and operable by a smartphone. With further development, the assay may facilitate the detection of tuberculosis at the point of care, particularly in resource-limited settings.

CRISPR detection of circulating cell-free Mycobacterium tuberculosis DNA in adults and children, including children with HIV: a molecular diagnostics study.

BACKGROUND: Tuberculosis remains a leading cause of global mortality, especially for adults and children living with HIV (CLHIV) underdiagnosed by sputum-based assays. Non-sputum-based assays are needed to improve tuberculosis diagnosis and tuberculosis treatment monitoring. Our aim in this study was to determine whether ultrasensitive detection of Mycobacterium tuberculosis cell-free DNA (Mtb-cfDNA) in blood can diagnose tuberculosis and evaluate tuberculosis treatment responses. METHODS: In this molecular diagnostics study we analysed archived serum from two patient populations evaluated for tuberculosis in Eswatini and Kenya to detect Mtb-cfDNA, analysing serum from all individuals who had both sufficient serum volumes and clear diagnostic results. An optimised CRISPR-mediated tuberculosis (CRISPR-TB) assay was used to detect Mtb-cfDNA in serum at enrolment from adults and children with presumptive tuberculosis and their asymptomatic household contacts, and at enrolment and during tuberculosis treatment from a cohort of symptomatic CLHIV at high risk for tuberculosis, who provided longitudinal serum at enrolment and during tuberculosis treatment. FINDINGS: CRISPR-TB identified microbiologically and clinically confirmed tuberculosis cases in the predominantly HIV-negative Eswatini adult cohort with 96% sensitivity (27 [96%] of 28, 95% CI 80-100) and 94% specificity (16 [94%] of 17, 71-100), and with 83% sensitivity (5 [83%] of 6, 36-100) and 95% specificity (21 [95%] of 22, 77-100) in the paediatric cohort, including all six cases of extrapulmonary tuberculosis. In the Kenyan CLHIV cohort, CRISPR-TB detected all (13 [100%] of 13, 75-100) confirmed tuberculosis cases and 85% (39 [85%] of 46, 71-94) of unconfirmed tuberculosis cases diagnosed by non-microbiological clinical findings. CLHIV who were CRISPR-TB positive at enrolment had a 2·4-times higher risk of mortality by 6 months after enrolment. Mtb-cfDNA signal decreased after tuberculosis treatment initiation, with near or complete Mtb-cfDNA clearance by 6 months after tuberculosis treatment initiation. INTERPRETATION: CRISPR-mediated detection of circulating Mtb-cfDNA shows promise to increase the identification of paediatric tuberculosis and HIV-associated tuberculosis, and potential for early diagnosis and rapid monitoring of tuberculosis treatment responses. FUNDING: US Department of Defense, National Institute of Child Health and Human Development, National Institute of Allergy and Infectious Diseases, University of Washington Center for AIDS Research, and the Weatherhead Presidential Endowment fund.

Brief Report: Pediatric Saliva-Based HIV Testing: Health care Worker and Caregiver Acceptability.

BACKGROUND: Pediatric HIV testing remains suboptimal. The OraQuick test [saliva-based test (SBT)] is validated in pediatric populations ≥18 months. Understanding caregiver and health care worker (HCW) acceptability of pediatric SBT is critical for implementation. METHODS: A trained qualitative interviewer conducted 8 focus group discussions (FGDs): 4 with HCWs and 4 with caregivers of children seeking health services in western Kenya. FGDs explored acceptability of pediatric SBT and home- and facility-based SBT use. Two reviewers conducted consensus coding and thematic analyses of transcripts using Dedoose. RESULTS: Most HCWs but few caregivers had heard of SBT. Before seeing SBT instructions, both had concerns about potential HIV transmission through saliva, which were mostly alleviated after kit demonstration. Noted benefits of SBT included usability and avoiding finger pricks. Benefits of facility-based pediatric SBT included shorter client waiting and service time, higher testing coverage, and access to HCWs, while noted challenges included ensuring confidentiality. Benefits of caregivers using home-based SBT included convenience, privacy, decreased travel costs, increased testing, easier administration, and child comfort. Perceived challenges included not receiving counseling, disagreements with partners, child neglect, and negative emotional response to a positive test result. Overall, HCWs felt that SBT could be used for pediatric HIV testing but saw limited utility for caregivers performing SBT without an HCW present. Caregivers saw utility in home-based SBT but wanted easy access to counseling in case of a positive test result. CONCLUSIONS: SBT was generally acceptable to HCWs and caregivers and is a promising strategy to expand testing coverage.

Lower Neurocognitive Functioning in HIV-Exposed Uninfected Children Compared With That in HIV-Unexposed Children.

BACKGROUND: Perinatal HIV and antiretroviral therapy exposure may influence neurocognitive outcomes, although evidence is mixed and most studies are limited to outcomes in the first 24 months. We compared neurocognitive outcomes in school-aged children who were HIV exposed uninfected (CHEU) with those in children who were HIV unexposed uninfected (CHUU). SETTING: Children were recruited from a health center in Nairobi, Kenya. METHODS: Key inclusion criteria were children aged 5-12 years and confirmed child and maternal HIV status; for CHEU, mothers reported knowing HIV-positive status before or at delivery of the index child. Children underwent a detailed battery of neuropsychological tests and behavioral assessment, and comparisons of scores between CHEU and CHUU were conducted using linear regression. RESULTS: Among 56 CHEU and 65 CHUU, the median age and sex distributions were 6.8 and 7.0 years (P = 0.8) and 48% and 60% girls (P = 0.2), respectively. In analyses adjusted for child's age and sex and caregiver's age, education, and household rent, CHEU had significantly lower mean z scores for global cognitive ability than CHUU [-0.35, 95% confidence interval (CI): -0.64 to -0.05; P = 0.02], short-term memory (-0.44, 95% CI: -0.76 to -0.12; P = 0.008), delayed memory (-0.43, 95% CI: -0.79 to -0.08; P = 0.02), attention (-0.41, 95% CI: -0.78 to -0.05; P = 0.03), and processing speed (-0.76, 95% CI: -1.37 to -0.16; P = 0.01). Models adjusted for child nutritional status, household food security, and orphanhood yielded similar results. CONCLUSIONS: Children exposed to HIV had poorer long-term neurocognitive outcomes than CHUU. These data suggest that long-term studies of neurocognitive and educational attainment in CHEU are warranted.

"I Have Actually not Lost any Adolescent Since I Started Engaging Them one on one:" Training Satisfaction and Subsequent Practice among Health Providers Participating in a Standardized Patient Actor Training to Improve Adolescent Engagement in HIV Care.

BACKGROUND: Poor health care worker (HCW) interactions with adolescents negatively influence engagement in HIV care. We assessed the impact of standardized patient actor training on HCW competence in providing adolescent HIV care in Kenya. METHODS: We conducted pre-post cross-sectional surveys and qualitative exit interviews during a stepped wedge randomized trial. Cross-sectional surveys assessed self-rated competence in providing adolescent services before and after the intervention, and training satisfaction. In-depth interviews with a subset of HCW participants one year after training. RESULTS: Over 90% of HCWs reported satisfaction with the training and there was significant improvement in self-rated competence scores (mean = 4.63 [highest possible score of 5] post-training vs 3.86 pre-training, p < 0.001). One-year following training, HCWs reported using skills in patient-centered communication and structuring an adolescent clinical encounter. CONCLUSIONS: This SP training intervention improved self-rated competence and showed sustained perceived impact on HCW skills in adolescent HIV service provision one year later.

Net charge and position 22 of the V3 loop are associated with HIV-1 tropism in recently infected female sex workers in Nairobi, Kenya.

Human immunodeficiency virus (HIV) infection affects around 37 million people worldwide, and in Kenya, key populations especially female sex workers (FSW), are thought to play a substantial role in the wider, mostly heterosexual HIV-1 transmission structure. Notably, HIV tropism has been found to correlate with HIV-1 transmission and disease progression in HIV-infected patients. In this study, recently infected FSWs from Nairobi, Kenya, were assessed for HIV tropism and the factors related to it. We used a cross-sectional study design to analyze 76 HIV-1 positive plasma samples obtained from FSWs enrolled in sex worker outreach program clinics in Nairobi between November 2020 and April 2021. The effects of clinical, demographic, and viral genetic characteristics were determined using multivariable logistic regression. HIV-1 subtype A1 accounted for 89.5% of all cases, with a prevalence of CXCR4-tropic viruses of 26.3%. WebPSSMR5X4 and Geno2Pheno [G2P:10-15% false positive rate] showed high concordance of 88%. Subjects infected with CXCR4-tropic viruses had statistically significant lower baseline CD4+T-cell counts than those infected with CCR5-tropic viruses (P = .044). Using multivariable logistic regression and adjusting for potential confounders, we found that net charge, the amino acid at position 22 of the V3 loop, and the geographic location of the subject were associated with tropism. A unit increase in V3 loop's net-charge increased the odds of a virus being CXCR4-tropic by 2.4 times (OR = 2.40, 95%CI = 1.35-5.00, P = .007). Second, amino acid threonine at position 22 of V3 loop increased the odds of a strain being X4 by 55.7 times compared to the alanine which occurred in CCR5-tropic strains (OR = 55.7, 95%CI = 4.04-84.1, P < .003). The Kawangware sex worker outreach program clinic was associated with CXCR4-tropic strains (P = .034), but there was there was no evidence of a distinct CXCR4-tropic transmission cluster. In conclusion, this study revealed a high concordance of WebPSSMR5X4 and Geno2Pheno in predicting HIV tropism. The most striking finding was that amino acid position 22 of the V3 loop is linked to tropism in HIV-1 subtype A1. Additional studies with a large dataset are warranted to confirm our findings.

Evaluation of a two-way SMS messaging strategy to reduce neonatal mortality: rationale, design and methods of the Mobile WACh NEO randomised controlled trial in Kenya.

INTRODUCTION: Globally, approximately half of the estimated 6.3 million under-5 deaths occur in the neonatal period (within the first 28 days of life). Kenya ranks among countries with the highest number of neonatal deaths, at 20 per 1000 live births. Improved identification and management of neonates with potentially life-threatening illness is critical to meet the WHO's target of ≤12 neonatal deaths per 1000 live births by 2035. We developed an interactive (two-way) short messaging service (SMS) communication intervention, Mobile Solutions for Neonatal Health (Mobile women's and children's health (WACh) NEO), focused on the perinatal period. Mobile WACh NEO sends automated tailored SMS messages to mothers during pregnancy and up to 6 weeks post partum. Messages employ the Information-Motivation-Behaviour Skills framework to promote (1) maternal implementation of essential newborn care (ENC, including early, exclusive breast feeding, cord care and thermal care), (2) maternal identification of neonatal danger signs and care-seeking, and (3) maternal social support and self-efficacy. Participants can also send SMS to the study nurse, enabling on-demand remote support. METHODS AND ANALYSIS: We describe a two-arm unblinded randomised controlled trial of the Mobile WACh NEO intervention. We will enrol 5000 pregnant women in the third trimester of pregnancy at 4 facilities in Kenya and randomise them 1:1 to receive interactive SMS or no SMS (control), and conduct follow-up visits at 2 and 6 weeks post partum. Neonatal mortality will be compared between arms as the primary outcome. Secondary outcomes include care-seeking, practice of ENC and psychosocial health. Exploratory analysis will investigate associations between maternal mental health, practice of ENC, care-seeking and SMS engagement. ETHICS AND DISSEMINATION: This study received ethical approval from the University of Washington (STUDY00006395), Women and Infants Hospital (1755292-1) and Kenyatta National Hospital/University of Nairobi (P310/04/2019). All participants will provide written informed consent. Findings will be published in peer-reviewed journals and international conferences. TRIAL REGISTRATION NUMBER: NCT04598165.

Financial Incentives for Pediatric HIV Testing (FIT): Caregiver Insights on Incentive Mechanisms, Focus Populations, and Acceptability for Programmatic Scale Up.

Children living with HIV experience gaps in HIV testing globally; scaling up evidence-based testing strategies is critical for preventing HIV-related mortality. Financial incentives (FI) were recently demonstrated to increase uptake of pediatric HIV testing. As part of this qualitative follow-up study to the FIT trial (NCT03049917) conducted in Kenya, 54 caregivers participated in individual interviews. Interview transcripts were analyzed to identify considerations for scaling up FI for pediatric testing. Caregivers reported that FI function by directly offsetting costs or nudging caregivers to take action sooner. Caregivers found FI to be feasible and acceptable for broader programmatic implementation, and supported use for a variety of populations. Some concerns were raised about unintended consequences of FI, including caregivers bringing ineligible children to collect incentives and fears about the impact on linkage to care and retention if caregivers become dependent on FI.