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Background: Identifying determinants of longitudinal HIV viral load (VL) trajectories using group-based trajectory modeling (GBTM) can inform clinical strategies and mechanisms of nonadherence among children., Methods: Children under 12 months old who were newly diagnosed with HIV were enrolled in the Optimizing Pediatric HIV therapy cohort (NCT00428116) from 2007 to 2010. Children initiated antiretroviral therapy at enrollment, and VL was assessed every 3 months for 24 months post-antiretroviral therapy and every 6 months thereafter up to 8 years old. VL trajectory groups were defined using GBTM. Fisher's exact and Kruskal-Wallis tests were used to determine the correlates of each trajectory group compared with the sustained-low VL group., Results: Five VL trajectory groups were identified among 89 children with 522 VL visits from 6 to 24 months: sustained-low (63% of children), sustained-very-high (16%), sustained-high (9%), low-to-high (7%), and high-with-periods-of-low (6%). Children in the sustained-high group were more frequently on a first-line protease inhibitor (PI)-based regimen (63% vs 38%; P = 0.03) and had younger caregivers (median: 22 vs 28 years; P = 0.02). Among 54 children with 560 VL visits followed from 48 to 96 months, 5 trajectory groups were identified: sustained-low (74%), mid-range (4%), periods-of-low (7%), high-to-low (7%), and sustained-high (7%). Those in the high-to-low group had younger caregivers (21 vs 29 years; P = 0.01)., Conclusions: GBTM identified unique VL patterns among children with unsuppressed VL. Caregiver and regimen-related characteristics were associated with patterns of nonsuppression. Younger caregivers may benefit from tailored counseling to help them support child antiretroviral therapy adherence. Palatable regimens are necessary for viral suppression among children with HIV., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Human cathelicidin LL-37 is a salivary antimicrobial peptide (AMP) with broad-spectrum activity against oral diseases, but few studies have assessed its role in children and adolescents living with HIV (CALHIV). We assessed salivary LL-37 levels and correlates in a long-term cohort of Kenyan CALHIV followed since antiretroviral therapy (ART) initiation., Methods: Saliva was collected from 76 CALHIV who were recruited from two ongoing pediatric HIV studies in Nairobi, Kenya. Oral examinations documenting oral manifestations of HIV, dental caries, and gingivitis were completed. Additional variables included age, sex, HIV treatment (initial ART regimen) and disease parameters, caregivers' demographics, and oral pathologies were conducted. Data were statistically analyzed using the independent T test on the log-transformed LL-37., Results: At the oral exam visit, the mean age of participants was 13.3 years (±SD = 3.4), and the median CD4 count was 954 cells/mm 3 . Mean salivary cathelicidin values of the cohort were 23.7 ± 21.1 ng/mL. Children with permanent dentition at time of oral examination, and children who initiated ART at ≥2 years old had higher mean LL-37 concentrations compared to those with mixed dentition and those who initiated ART <2 years old ( p = 0.0042, 0.0373, respectively). LL-37 levels were not found to differ by initial type of ART regimen, CD4 count, or oral disease., Conclusion: Further research and longitudinal studies are necessary to evaluate and improve the innate immunity of CALHIV in Kenya., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: We determined predictors of both intact (estimate of replication-competent) and total (intact and defective) HIV DNA in the reservoir among children with HIV., Design: HIV DNA in the reservoir was quantified longitudinally in children who initiated antiretroviral therapy (ART) at less than 1 year of age using a novel cross-subtype intact proviral DNA assay that measures both intact and total proviruses. Quantitative PCR was used to measure pre-ART cytomegalovirus (CMV) viral load. Linear mixed effects models were used to determine predictors of intact and total HIV DNA levels (log 10 copies/million)., Results: Among 65 children, median age at ART initiation was 5 months and median follow-up was 5.2 years; 86% of children had CMV viremia pre-ART. Lower pre-ART CD4 + percentage [adjusted relative risk (aRR): 0.87, 95% confidence intervals (95% CI): 0.79-0.97; P  = 0.009] and higher HIV RNA (aRR: 1.21, 95% CI: 1.06-1.39; P  = 0.004) predicted higher levels of total HIV DNA during ART. Pre-ART CD4 + percentage (aRR: 0.76, 95% CI: 0.65-0.89; P < 0.001), CMV viral load (aRR: 1.16, 95% CI: 1.01-1.34; P  = 0.041), and first-line protease inhibitor-based regimens compared with nonnucleoside reverse transcriptase-based regimens (aRR: 1.36, 95% CI: 1.04-1.77; P  = 0.025) predicted higher levels of intact HIV DNA., Conclusion: Pre-ART immunosuppression, first-line ART regimen, and CMV viral load may influence establishment and sustainment of intact HIV DNA in the reservoir., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2023. The Author(s).)

Video-based pre-test information is used in high resource settings to increase HIV testing coverage but remains untested in resource-limited settings. We conducted formative and evaluative focus group discussions with healthcare workers (HCWs) and caregivers of children in Kenya to develop and refine a pediatric HIV pre-test informational video. We then assessed HIV knowledge among caregivers sequentially enrolled in one of three pre-test information groups: (1) individual HCW-led (N = 50), (2) individual video-based (N = 50), and (3) group video-based (N = 50) sessions. A brief video incorporating information on national pediatric testing, modes of HIV transmission, and dramatized testimonials of caregivers who tested children was produced in three languages. Compared to individual HCW-led sessions (mean: 7.2/9; standard deviation [SD]: 1.3), both the group video-based (mean: 7.7; SD: 0.9) and individual video-based (mean: 7.6; SD: 0.9) sessions had higher mean knowledge scores. Video-based pre-test information could enhance existing pediatric HIV testing services., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The impact of antiretroviral treatment (ART) on the occurrence of oral diseases among children and adolescents living with HIV (CALHIV) is poorly understood. The aim of this study was to determine the effect of ART timing on vitamin D levels and the prevalence of four oral diseases (dry mouth, dental caries, enamel hypoplasia, and non-herpes oral ulcer) among Kenyan CALHIV from two pediatric HIV cohorts., Methods: This nested cross-sectional study was conducted at the Kenyatta National Hospital, Nairobi, Kenya. CALHIV, 51 with early-ART initiated at <12 months of age and 27 with late-ART initiated between 18 months-12 years of age, were included. Demographics, HIV diagnosis, baseline CD4 and HIV RNA viral load data were extracted from the primary study databases. Community Oral Health Officers performed oral health examinations following standardized training., Results: Among 78 CALHIV in the study, median age at the time of the oral examination was 11.4 years old and median ART duration at the time of oral examination was 11 years (IQR: 10.1, 13.4). Mean serum vitamin D level was significantly higher among the early-ART group than the late-ART group (29.5 versus 22.4 ng/mL, p = 0.0002). Children who received early-ART had a 70% reduction in risk of inadequate vitamin D level (<20 ng/mL), compared to those who received late-ART (p = 0.02). Although both groups had similar prevalence of oral diseases overall (early-ART 82.4%; late-ART 85.2%; p = 0.2), there was a trend for higher prevalence of dry mouth (p = 0.1) and dental caries (p = 0.1) in the early versus late ART groups. The prevalence of the four oral diseases was not associated with vitamin D levels (p = 0.583)., Conclusions: After >10 years of ART, CALHIV with early-ART initiation had higher serum vitamin D levels compared to the late-ART group. The four oral diseases were not significantly associated with timing of ART initiation or serum vitamin D concentrations in this cohort. There was a trend for higher prevalence of dry mouth and dental caries in the early-ART group, probably as side-effects of ART., Competing Interests: The authors have declared that no competing interests exist.

Expanding index and family-based testing (HBT) is a priority for identifying children living with HIV. Our study characterizes predictors that drive testing location choice for children of parents living with HIV. Kenyan adults living with HIV were offered a choice of HBT or clinic-based testing (CBT) for any of their children (0-12 years) of unknown HIV status. Multilevel generalized linear models were used to identify correlates of choosing HBT or CBT for children and testing all versus some children within a family, including caregiver demographics, HIV history, social support, cost, and child demographics and HIV prevention history. Among 244 caregivers living with HIV and their children of unknown HIV status, most (72%) caregivers tested children using CBT. In multivariate analysis, female caregivers [aRR 0.52 (95% CI 0.34-0.80)] were less likely to choose HBT than male caregivers. Caregivers with more children requiring testing [aRR 1.23 (95% CI 1.05-1.44)] were more likely to choose HBT than those with fewer children requiring testing. In subgroup univariate analysis, female caregivers with a known HIV negative spouse were significantly more likely to choose HBT over CBT than those with a known HIV positive spouse [RR 2.57 (95% CI 1.28-5.14), p = 0.008], no association was found for male caregivers. Child demographics and clinical history was not associated with study outcomes. Caregiver-specific factors were more influential than child-specific factors in caregiver choice of pediatric HIV testing location. Home-based testing may be preferable to families with higher child care needs and may encourage pediatric HIV testing if offered as an alternative to clinic testing., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Few oral health studies have been conducted in HIV-exposed uninfected children, who, like their HIV-infected peers, have altered immunity and perinatal drug exposures., Aim: To compare caregiver' self-report of oral diseases, hygiene practices and utilization of routine dental care, between HIV-infected (HIV), HIV-exposed uninfected (HEU), and HIV-unexposed uninfected (HUU) children in Kenya., Design: This nested cross-sectional study was conducted at the Kenyatta National Hospital, Nairobi, Kenya. Caregivers of 196 children (104 HIV-infected, 55 HEU, and 37 HUU) participated in this study. Using a validated questionnaire from the WHO and photographs of HIV-related oral lesions, we collected data on oral diseases and oral health practices., Results: Caregivers of HIV-infected children reported at least one oral disease in their children (42%; HEU [27%]; HUU [17%; P = .008]). Oral candidiasis was the most common disease reported (HIV-infected [24%], HEU [5.5%], and HUU [2.8%; P < .05]). Baseline CD4% was associated with oral candidiasis (OR = 0.93, 95% CI: 0.88-0.98). Only 16% of children had ever visited a dentist, and most initiated brushing after 3 years of age (83%). Nearly all (98%) caregivers desired a follow-up oral examination., Conclusions: HIV infection/exposure and low CD4% were associated with increased odds of oral diseases. Most caregivers desired a follow-up oral examination for their children., (© 2021 BSPD, IAPD and John Wiley & Sons Ltd.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: The authors have no conflicts of interest to disclose.

Identifying determinants of human immunodeficiency virus (HIV) reservoir levels may inform novel viral eradication strategies. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) coinfections were assessed as predictors of HIV proviral DNA level in 26 HIV RNA-suppressed Kenyan children starting antiretroviral therapy before 7 months of age. Earlier acquisition of CMV and EBV and higher cumulative burden of systemic EBV DNA viremia were each associated with higher HIV DNA level in the reservoir after 24 months of antiretroviral therapy, independent of HIV RNA levels over time. These data suggest that delaying or containing CMV and EBV viremia may be novel strategies to limit HIV reservoir formation., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Cytomegalovirus (CMV) is the commonest cause of congenital infection and particularly so among infants born to HIV-infected women. Studies of congenital CMV infection (cCMVi) pathogenesis are complicated by the presence of multiple infecting maternal CMV strains, especially in HIV-positive women, and the large, recombinant CMV genome. Using newly developed tools to reconstruct CMV haplotypes, we demonstrate anatomic CMV compartmentalization in five HIV-infected mothers and identify the possibility of congenitally transmitted genotypes in three of their infants. A single CMV strain was transmitted in each congenitally infected case, and all were closely related to those that predominate in the cognate maternal cervix. Compared to non-transmitted strains, these congenitally transmitted CMV strains showed statistically significant similarities in 19 genes associated with tissue tropism and immunomodulation. In all infants, incident superinfections with distinct strains from breast milk were captured during follow-up. The results represent potentially important new insights into the virologic determinants of early CMV infection., Competing Interests: JP, JS, SR, JB, CA, JC, CF, PG, JK, SM, AR, HT, RW, SG, RG, JB No competing interests declared, (© 2020, Pang et al.)

Introduction: Gaps in HIV testing of children persist, particularly among older children born before the expansion of the prevention of mother-to-child transmission of HIV programs., Methods: The Counseling and Testing for Children at Home study evaluated an index-case pediatric HIV testing approach. Caregivers receiving HIV care at 7 health facilities in Kenya (index cases), who had children of unknown HIV status aged 0-12 years, were offered the choice of clinic-based testing (CBT) or home-based testing (HBT). Testing uptake and HIV prevalence were compared between groups choosing HBT and CBT; linkage to care, missed opportunities, and predictors of HIV-positive diagnosis were identified., Results: Among 493 caregivers, 70% completed HIV testing for ≥1 child. Most caregivers who tested children chose CBT (266/347, 77%), with 103 (30%) agreeing to same-day testing of an untested accompanying child. Overall HIV prevalence among 521 tested children was 5.8% (CBT 6.8% vs HBT 2.4%; P = 0.07). Within 1 month of diagnosis, 88% of 30 HIV-positive children had linked to care, and 54% had started antiretroviral treatment. For 851 children eligible for testing, the most common reason for having an unknown HIV status was that the child's mother was not tested for HIV or had tested HIV negative during pregnancy (82%)., Conclusion: Testing uptake and HIV prevalence were moderate with nonsignificant differences between HBT and CBT. Standardized offer to test children accompanying caregivers is feasible to scale-up with little additional investment. Linkage to care for HIV-positive children was suboptimal. Lack of peripartum maternal testing contributed to gaps in pediatric testing.

Background: A prior randomized control trial showed financial incentives increase HIV testing rates for children of unknown HIV status. Translating evidence-based interventions such as these to scale requires an implementation science approach., Methods: A qualitative study evaluating health care providers' perceptions of barriers and facilitators of a previously completed financial incentives intervention for pediatric HIV testing was conducted at health care facilities in Kisumu, Kenya. Six focus group discussions with 52 providers explored determinants of acceptability, feasibility, and sustainability of financial incentive scale-up for pediatric HIV testing using the Consolidated Framework for Implementation Research to inform question guides and thematic analysis., Results: Providers found the use of financial incentive interventions for pediatric HIV testing to be highly acceptable. First, providers believed financial incentives had a relative advantage over existing strategies, because they overcame cost barriers and provided additional motivation to test; however, concerns about how financial incentives would be implemented influenced perceptions of feasibility and sustainability. Second, providers expressed concern that already overburdened staff and high costs of financial incentive programs would limit sustainability. Third, providers feared that financial incentives may negatively affect further care because of expectations of repeated financial support and program manipulation., Conclusions: Providers viewed financial incentives as an acceptable intervention to scale programmatically to increase uptake of pediatric testing. To ensure feasibility and sustainability of financial incentives in pediatric HIV testing programs, it will be important to clearly define target populations, manage expectations of continued financial support, and establish systems to track testing.

Lack of health care worker (HCW) training is a barrier to implementing youth-friendly services. We examined training coverage and self-reported competence, defined as knowledge, abilities, and attitudes, of HCWs caring for adolescents living with HIV (ALWH) in Kenya. Surveys were conducted with 24 managers and 142 HCWs. Competence measures were guided by expert input and Kalamazoo II Consensus items. Health care workers had a median of 3 (interquartile range [IQR]: 1-6) years of experience working with ALWH, and 40.1% reported exposure to any ALWH training. Median overall competence was 78.1% (IQR: 68.8-84.4). In multivariable linear regression analyses, more years caring for ALWH and any prior training in adolescent HIV care were associated with significantly higher self-rated competence. Training coverage for adolescent HIV care remains suboptimal. Targeting HCWs with less work experience and training exposure may be a useful and efficient approach to improve quality of youth-friendly HIV services.

Background: Gaps persist in HIV testing for children who were not tested in prevention of mother-to-child HIV transmission programs. Oral mucosal transudate (OMT) rapid HIV tests have been shown to be highly sensitive in adults, but their performance has not been established in children., Methods: Antiretroviral therapy-naive children aged 18 months to 18 years in Kenya and Zimbabwe were tested for HIV using rapid OraQuick ADVANCE Rapid HIV-1/2 Antibody test on oral fluids (OMT) and blood-based rapid diagnostic testing (BBT). BBT followed Kenyan and Zimbabwean national algorithms. Sensitivity and specificity were calculated using the national algorithms as the reference standard., Results: A total of 1776 children were enrolled; median age was 7.3 years (interquartile range: 4.7-11.6). Among 71 children positive by BBT, all 71 were positive by OMT (sensitivity: 100% [97.5% confidence interval (CI): 94.9% to 100%]). Among the 1705 children negative by BBT, 1703 were negative by OMT (specificity: 99.9% [95% CI: 99.6% to 100.0%]). Due to discrepant BBT and OMT results, 2 children who initially tested BBT-negative and OMT-positive were subsequently confirmed positive within 1 week by further tests. Excluding these 2 children, the sensitivity and specificity of OMT compared with those of BBT were each 100% (97.5% CI: 94.9% to 100% and 99.8% to 100%, respectively)., Conclusions: Compared to national algorithms, OMT did not miss any HIV-positive children. These data suggest that OMTs are valid in this age range. Future research should explore the acceptability and uptake of OMT by caregivers and health workers to increase pediatric HIV testing coverage.

HIV incidence and mortality are high among adolescents and young adults (AYA) in sub-Saharan Africa, but testing rates are low. Understanding how support people (SP), such as peers, partners, or parents, influence AYA may improve HIV testing uptake. AYA aged 14-24 seeking HIV testing at a referral hospital in Nairobi, Kenya completed a post-test survey assessing the role of SP. Among 1062 AYA, median age was 21. Overall, 12% reported their decision to test was influenced by a parent, 20% by a partner, and 22% by a peer. Young adults (20-24 years old) were more likely than adolescents (14-19 years old) to be influenced to test by partners (23% vs. 12%, p < .001), and less likely by parents (6.6% vs. 27%, p < .001), healthcare workers (11% vs. 16%, p < .05), or counselors (9.4% vs. 19%, p < .001). Half of AYA were accompanied for testing (9.9% with parent, 10% partner, 23% peer, 4.3% others, and 2.1% multiple types). Young adults were more likely than adolescents to present alone (58% vs. 32%, p < .001) or with a partner (12% vs. 6.7%, p < .05), and less likely with a parent (1.6% vs. 31%, p < .001). Similar proportions of adolescents and young adults came with a peer or in a group. Correlates of presenting with SP included: younger age (aRR = 1.55 [95%CI = 1.30-1.85]), female sex (aRR = 1.45 [95%CI = 1.21-1.73]), and school enrollment (aRR = 1.41 [95%CI = 1.05-1.88]). SP play an important role in AYAs' HIV testing and varies with age. Leveraging SP may promote uptake of HIV testing and subsequent linkage care for AYA.

Introduction: Index case testing (ICT) to identify HIV-infected children is efficient but has suboptimal uptake. Financial incentives (FI) have overcome financial barriers in other populations by offsetting direct and indirect costs. A pilot study found FI to be feasible for motivating paediatric ICT among HIV-infected female caregivers. This randomised trial will determine the effectiveness of FI to increase uptake of paediatric ICT., Methods and Analysis: The Financial Incentives to Increase Uptake of Pediatric HIV Testing trial is a five-arm, unblinded, randomised controlled trial that determines whether FI increases timely uptake of paediatric ICT. The trial will be conducted in multiple public health facilities in western Kenya. Each HIV-infected adult enrolled in HIV care will be screened for eligibility: primary caregiver to one or more children of unknown HIV status aged 0-12 years. Eligible caregivers will be individually randomised at the time of recruitment in equal 1:1:1:1:1 allocation to one of five arms (US$0 (control), US$1.25, US$2.50, US$5.00 and US$10.00). The trial aims to randomise 800 caregivers. Incentives will be disbursed at the time of child HIV testing using mobile money transfer or cash. Arms will be compared in terms of the proportion of adults who complete testing for at least one child within 2 months of randomisation and time to testing. A cost-effectiveness analysis of FI for paediatric ICT will also be conducted., Ethics and Dissemination: This study was reviewed and approved by the University of Washington Institutional Review Board and the Kenyatta National Hospital Ethics and Research Committee. Trial results will be disseminated to healthcare workers at study sites, regional and national policymakers, and with patient populations at study sites (regardless of enrolment in the trial). Randomised trials of caregiver-child FI interventions pose unique study design, ethical and operational challenges, detailed here as a resource for future investigations., Trial Registration Number: NCT03049917; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cytomegalovirus (CMV) is a ubiquitous infection that causes disease in congenitally infected children and immunocompromised patients. Although nearly all CMV infections remain latent and asymptomatic in immunologically normal individuals, numerous studies have found that systemic viral reactivation is common in immunocompetent critically ill adults, as measured by detection of CMV in the blood (viremia). Furthermore, CMV viremia is strongly correlated with adverse outcomes in the adult intensive care unit (ICU), including prolonged stay, duration of mechanical ventilation, and death. Increasing evidence, including from a randomized clinical trial of antiviral treatment, suggests that these effects of CMV may be causal. Therefore, interventions targeting CMV might improve outcomes in adult ICU patients. CMV may have an even greater impact on critically ill children, particularly in low and middle income countries (LMIC), where CMV is regularly acquired in early childhood, and where inpatient morbidity and mortality are inordinately high. However, to date, there are few data regarding the clinical relevance of CMV infection or viremia in immunocompetent critically ill children. We propose that CMV infection should be studied as a potential modifiable cause of disease in critically ill children, and that these studies be conducted in LMIC. Below, we briefly review the role of CMV in immunologically normal critically ill adults and children, outline age-dependent differences in CMV infection that may influence ICU outcomes, and describe an agenda for future research.

Background: Prompt child HIV testing and treatment is critical; however, children are often not diagnosed until symptomatic. Understanding factors that influence pediatric HIV testing can inform strategies to increase testing., Methods: A mixed-methods study was conducted at a tertiary hospital in Nairobi, Kenya. Three focus group discussions with health care workers (HCWs) and 18 in-depth interviews with HIV-infected adults with children of unknown status were analyzed using thematic analysis. A structured questionnaire was administered to 116 HIV-infected caregivers of children of unknown status to triangulate qualitative findings., Results: Analysis revealed 3 key periods of the pediatric HIV testing process: decision to test, test visit, and posttest. Key issues included: decision to test: inaccurate HIV risk perception for children, challenges with paternal consent, lack of caregiver HIV status disclosure to partners or older children; test experience: poor understanding of child consent/assent and disclosure guidelines, perceived costs of testing and care, school schedules, HCW discomfort with pediatric HIV testing; and posttest: pessimism regarding HIV-infected children's prognosis, caregiver concerns about their own emotional health if their child is positive, and challenges communicating about HIV with children. Concerns about all 3 periods influenced child testing decisions. In addition, 3 challenges were unique to pediatric HIV: inaccurate HIV risk perception for children; disclosure, consent, and permission; and costs and scheduling., Conclusions: Pediatric HIV testing barriers are distinct from adult barriers. Uptake of pediatric HIV testing may be enhanced by interventions to address misconceptions, disclosure services, psychosocial support addressing concerns unique to pediatric testing, child-focused HCW training, and alternative clinic hours.

: Polymorphisms in the Toll-like receptor 9 1635 locus have been associated with HIV-1 acquisition and progression. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) acquisition were compared between Kenyan HIV-exposed infants by 1635 genotype. Having one or more copies of the 1635A allele was associated with increased CMV acquisition in HIV-infected infants (42 vs. 11%, P = 0.03) and increased risk of EBV acquisition in HIV-exposed uninfected infants (hazard ratio = 4.2, P = 0.02) compared with 1635GG. In addition, 1635A was associated with 0.4 log10 copies/ml lower median EBV levels in HIV-infected infants (P = 0.03). These data suggest a potentially important role for this locus in primary herpesvirus infection.

HIV mother-to-child transmission (MTCT) represents a success story in the HIV/AIDS field given the significant reduction in number of transmission events with the scale-up of antiretroviral treatment and other prevention methods. Nevertheless, MTCT still occurs and better understanding of the basic biology and immunology of transmission will aid in future prevention and treatment efforts. MTCT is a unique setting given that the transmission pair is known and the infant receives passively transferred HIV-specific antibodies from the mother while in utero. Thus, infant exposure to HIV occurs in the face of HIV-specific antibodies, especially during delivery and breastfeeding. This review highlights the immune correlates of protection in HIV MTCT including humoral (neutralizing antibodies, antibody-dependent cellular cytotoxicity, and binding epitopes), cellular, and innate immune factors. We further discuss the future implications of this research as it pertains to opportunities for passive and active vaccination with the ultimate goal of eliminating HIV MTCT., (© 2018 Elsevier Inc. All rights reserved.)

Background: Adolescent-friendly policies aim to tailor HIV services for adolescents and young adults aged 10-24 years (AYA) to promote health outcomes and improve retention in HIV care and treatment. However, few interventions focus on improving healthcare worker (HCW) competencies and skills for provision of high-quality adolescent care. Standardized patients (SPs) are trained actors who work with HCWs in mock clinical encounters to improve clinical assessment, communication, and empathy skills. This stepped-wedge randomized controlled trial will evaluate a clinical training intervention utilizing SPs to improve HCW skills in caring for HIV-positive AYA, resulting in increased retention in care., Methods/design: The trial will utilize a stepped-wedge design to evaluate a training intervention using SPs to train HCWs in assessment, communication, and empathy skills for AYA HIV care. We will recruit 24 clinics in Kenya with an active electronic medical record (EMR) system and at least 40 adolescents enrolled in HIV care per site. Stratified randomization by county will be used to assign clinics to one of four waves - time periods when they receive the intervention - with each wave including six clinics. From each clinic, up to 10 HCWs will participate in the training intervention. SP training includes didactic sessions in adolescent health, current guidelines, communication skills, and motivational interviewing techniques. HCW participants will rotate through seven standardized SP scenarios, followed by SP feedback, group debriefing, and remote expert evaluation. AYA outcomes will be assessed using routine clinic data. The primary outcome is AYA retention in HIV care, defined as returning for first follow-up visit within 6 months of presenting to care, or returning for a first follow-up visit after re-engagement in care in AYA with a previous history of being lost to follow-up. Secondary outcomes include HCW competency scores, AYA satisfaction with care, and AYA clinical outcomes including CD4 and viral load. Additional analyses will determine cost-effectiveness of the intervention., Discussion: This trial will contribute valuable information to HIV programs in Kenya and other low-resource settings, providing a potentially scalable strategy to improve quality of care and retention in critical HIV services in this population., Trial Registration: ClinicalTrials.gov, ID: NCT02928900. Registered 26 August 2016.

Objectives: To determine whether continuous quality improvement (CQI) improves quality of HIV testing services for adolescents and young adults (AYA)., Design: CQI was introduced at two HIV testing settings: Youth Centre and Voluntary Counseling and Testing (VCT) Center, at a national referral hospital in Nairobi, Kenya., Methods: Primary outcomes were AYA satisfaction with HIV testing services, intent to return, and accurate HIV prevention and transmission knowledge. Healthcare worker (HCW) satisfaction assessed staff morale. T tests and interrupted time series analysis using Prais-Winsten regression and generalized estimating equations accounting for temporal trends and autocorrelation were conducted., Results: There were 172 AYA (Youth Centre = 109, VCT = 63) during 6 baseline weeks and 702 (Youth Centre = 454, VCT = 248) during 24 intervention weeks. CQI was associated with an immediate increase in the proportion of AYA with accurate knowledge of HIV transmission at Youth Centre: 18 vs. 63% [adjusted risk difference (aRD) 0.42,95% confidence interval (CI) 0.21 to 0.63], and a trend at VCT: 38 vs. 72% (aRD 0.30, 95% CI -0.04 to 0.63). CQI was associated with an increase in the proportion of AYA with accurate HIV prevention knowledge in VCT: 46 vs. 61% (aRD 0.39, 95% CI 0.02-0.76), but not Youth Centre (P = 0.759). In VCT, CQI showed a trend towards increased intent to retest (4.0 vs. 4.3; aRD 0.78, 95% CI -0.11 to 1.67), but not at Youth Centre (P = 0.19). CQI was not associated with changes in AYA satisfaction, which was high during baseline and intervention at both clinics (P = 0.384, P = 0.755). HCW satisfaction remained high during intervention and baseline (P = 0.746)., Conclusion: CQI improved AYA knowledge and did not negatively impact HCW satisfaction. Quality improvement interventions may be useful to improve adolescent-friendly service delivery.

Objectives: Adolescents in Africa have low HIV testing rates. Better understanding of adolescent, provider, and caregiver experiences in high-burden countries such as Kenya could improve adolescent HIV testing programs., Design: We conducted 16 qualitative interviews with HIV-positive and HIV-negative adolescents (13-18 years) and six focus group discussions with Healthcare workers (HCWs) and caregivers of adolescents in Nairobi, Kenya., Methods: Semi-structured interviews and focus groups were recorded and transcribed. Analysis employed a modified constant comparative approach to triangulate findings and identify themes influencing testing experiences and practices., Results: All groups identified that supportive interactions during testing were essential to the adolescent's positive testing experience. HCWs were a primary source of support during testing. HCWs who acted respectful and informed helped adolescents accept results, link to care, or return for repeat testing, whereas HCWs who acted dismissive or judgmental discouraged adolescent testing. Caregivers universally supported adolescent testing, including testing with the adolescent to demonstrate support. Caregivers relied on HCWs to inform and encourage adolescents. Although peers played less significant roles during testing, all groups agreed that school-based outreach could increase peer demand and counteract stigma. All groups recognized tensions around adolescent autonomy in the absence of clear consent guidelines. Adolescents valued support people during testing but wanted autonomy over testing and disclosure decisions. HCWs felt pressured to defer consent to caregivers. Caregivers wanted to know results regardless of adolescents' wishes., Conclusion: Findings indicate that strengthening HCW, caregiver, and peer capacities to support adolescents while respecting their autonomy may facilitate attaining '90-90-90' targets for adolescents.

To evaluate the impact of highly active antiretroviral therapy (HAART) on CMV transmission and breast milk level in the context of maternal HIV. Specimens from a randomized trial conducted in Nairobi, Kenya between 2003-2005 were used to compare CMV transmission and breast milk levels between mother-infant pairs randomized to HAART versus short-course antenatal zidovudine plus single-dose nevirapine (ZDV/sdNVP) for prevention of mother-to-child HIV transmission (PMTCT). Fifty-one antiretroviral-naïve women ≤32 weeks gestation, and CD4 between 200-500 cells/mm 3 were randomized at 34 weeks to begin either antenatal ZDV/sdNVP, or HAART through 6 months postpartum. Mean breast milk CMV levels and transmission were compared between arms. Age, sociodemographics, CD4%, and HIV plasma RNA viral load were similar between arms at baseline. CMV viral loads were measured from 243 infant plasma and 185 breast milk specimens during the first year postpartum. The probability of infant CMV infection at 12 months was 19% lower in the HAART arm compared to ZDV/sdNVP (75% vs. 94%, p = .04). All women had CMV detected in breast milk, with 72%, 98%, and 97% testing positive during the first, second, and third weeks postpartum, respectively. There was a trend for early higher mean breast milk CMV level in the HAART arm at 1 week (p = .08), and there was significantly slower decline in breast milk CMV levels (area under the curve, p = .01). HAART started during the third trimester may decrease infant CMV infections, by mechanisms independent of breast milk CMV levels., Clinical Trials Registration: NCT00167674.

Objectives: Few routine systems exist to test older, asymptomatic children for HIV. Testing all children in the population has high uptake but is inefficient, whereas testing only symptomatic children increases efficiency but misses opportunities to optimize outcomes. Testing children of HIV-infected adults in care may efficiently identify previously undiagnosed HIV-infected children before symptomatic disease., Methods: HIV-infected parents in HIV care in Nairobi, Kenya were systematically asked about their children's HIV status and testing history. Adults with untested children ≤12 years old were actively referred and offered the choice of pediatric HIV testing at home or clinic. Testing uptake and HIV prevalence were determined, as were bottlenecks in pediatric HIV testing cascade., Results: Of 10,426 HIV-infected adults interviewed, 8,287 reported having children, of whom 3,477 (42%) had children of unknown HIV status, and 611 (7%) had children ≤12 years of unknown HIV status. After implementation of active referral, the rate of pediatric HIV testing increased 3.8-fold from 3.5 to 13.6 children tested per month (Relative risk: 3.8, 95% confidence interval: 2.3 to 6.1). Of 611 eligible adults, 279 (48%) accepted referral and were screened, and 74 (14%) adults completed testing of 1 or more children. HIV prevalence among 108 tested children was 7.4% (95% confidence interval: 3.3 to 14.1%) and median age was 8 years (interquartile range: 2-11); 1 child was symptomatic at testing., Conclusions: Referring HIV-infected parents in care to have their children tested revealed many untested children and significantly increased the rate of pediatric testing; prevalence of HIV was high. However, despite increases in pediatric testing, most adults did not complete testing of their children.

Background: Virologic and immunologic responses to antiretroviral treatment (ART) in infants may differ from older children due to immunologic, clinical, or epidemiologic characteristics., Methods: Longitudinal ART responses were modeled and compared in HIV-infected infants and children enrolled in cohorts in Nairobi, Kenya. Participants were enrolled soon after HIV diagnosis, started on ART, and followed for 2 years. Viral load decline was compared between infant and child cohorts using a nonlinear mixed effects model and CD4% reconstitution using a linear mixed effects model., Results: Among 121 infants, median age at ART was 3.9 months; among 124 children, median age was 4.8 years. At baseline, viral load was higher among infants than children (6.47 vs. 5.91 log10 copies/ml, P < 0.001). Infants were less likely than children to suppress viral load to less than 250 copies/ml following 6 months of ART (32% infants vs. 73% children, P < 0.0001). CD4% was higher at baseline in infants than children (19 vs. 7.3%, P < 0.001). Older children had more rapid CD4% reconstitution than infants, but failed to catch up to infant CD4%., Conclusion: Despite substantially higher CD4% at ART initiation, viral suppression was significantly slower among infants than older children. New strategies are needed to optimize infant outcomes on ART., Competing Interests: The authors declare no conflicts of interest.

Background: Human immunodeficiency virus (HIV)-exposed uninfected (HEU) infants are a growing population in sub-Saharan Africa, with higher morbidity and mortality than HIV-unexposed infants. HEU infants may experience increased morbidity due to breastfeeding avoidance., Objectives: We sought to describe the burden and identify predictors of hospitalization among HEU infants in the first year of life., Methods: Using a retrospective cohort of HIV-infected mothers and their HEU infants in Nairobi, Kenya, we identified infants who were HIV-uninfected at birth and were followed monthly until their last negative HIV test, death, loss to follow-up, or study exit at 1 year of age. Incidence, timing, and reason for hospitalization was assessed overall as well as stratified by feeding method. Predictors of first infectious disease hospitalization were identified using competing risk regression, with HIV acquisition and death as competing risks., Results: Among 388 infants, 113 hospitalizations were reported (35/100 infant-years [the combined years of observation contributed by all infants in the study]; 95% confidence interval [CI], 29-42). Ninety hospitalizations were due to 1 or more infectious diseases (26/100 infant-years; 95% CI, 21-32)-primarily pneumonia (n = 40), gastroenteritis (n = 17), and sepsis (n = 14). Breastfeeding was associated with decreased risk of infectious disease hospitalization (subhazard ratio = 0.39; 95% CI, 0.24-0.64), as was time-updated nutrition status (subhazard ratio = 0.73; 95% CI, 0.61-0.89). Incidence of infectious disease hospitalization among formula-fed infants was 51/100 infant-years (95% CI, 37-70) compared to 19/100 infant-years (95% CI, 14-25) among breastfed infants., Conclusion: Among HEU infants, breastfeeding and nutrition status were associated with reduced hospitalization during the first year of life., (© The Author(s) 2015.)

Background: Cytomegalovirus (CMV) is associated with morbidity and mortality in human immunodeficiency virus (HIV)-exposed infants. We assessed the effect of and relative contribution of breastfeeding to CMV acquisition among infants delivered by HIV-infected mothers., Methods: Between 1993 and 1998 pregnant, HIV-infected women in Nairobi, Kenya, were randomly assigned to breastfeed or formula-feed their infants in an HIV transmission study. Women were allocated equally between treatment arms, and the study was not blinded. The primary endpoint of this nested study was time to infant CMV infection., Results: CMV infection was assessed in 138 breastfed and 134 formula-fed infants. Baseline characteristics were similar between arms. Breastfed infants acquired CMV earlier than formula-fed infants (median age of acquisition, 4.26 vs 9.87 months; P < .001) and had a higher 1-year probability of CMV infection (0.89 vs 0.69; P < .001). Breastfeeding was associated with a 1.6-fold increased risk of infant CMV acquisition independent of infant HIV status (multivariable hazard ratio, 1.61; 95% confidence interval, 1.20-2.16; P = .002). Approximately one third of CMV infections occurred during the peripartum period, with 40% acquired through breastfeeding and the remainder acquired through modes other than breast milk., Conclusions: Preventing CMV acquisition may be a priority for HIV-exposed infants, but there is a narrow window of opportunity for intervention. Approaches that reduce maternal cervical and breast milk CMV reactivation may help delay infant infection., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

To identify missed opportunities in HIV prevention, diagnosis, and linkage to care, we enrolled 183 hospitalized, HIV-infected, ART-naïve Kenyan children 0-12 years from four hospitals in Nairobi and Kisumu, and reviewed prevention of mother-to-child transmission of HIV (PMTCT), hospitalization, and HIV testing history. Median age was 1.8 years (IQR = 0.8, 4.5). Most mothers received HIV testing during pregnancy (77%). Among mothers tested, 60% and 40% reported HIV-negative and positive results, respectively; 33% of HIV-diagnosed mothers did not receive PMTCT antiretrovirals. First missed opportunities for pediatric diagnosis and linkage were due to failure to test mothers (23.1%), maternal HIV acquisition following initial negative test (45.7%), no early infant diagnosis (EID) or provider-initiated testing (PITC) (12.7%), late breastfeeding transmission (8.7%), failure to collect child HIV test results (1.2%), and no linkage to care following HIV diagnosis (8.7%). Among previously hospitalized children, 38% never received an HIV test. Strengthening initial and repeat maternal HIV testing and PITC are key interventions to prevent, detect, and treat pediatric HIV infections.

Effective biomedical and structural HIV prevention approaches are being implemented throughout sub-Saharan Africa. A "lifecycle approach" to HIV prevention recognizes the interconnectedness of the health of women, children and adolescents, and prioritizes interventions that have benefits across these populations. We review new biomedical prevention strategies for women, adolescents and children, structural prevention approaches, and new modalities for eliminating infant HIV infection, and discuss the implications of a lifecycle approach for the success of these methods. Some examples of the lifecycle approach include evaluating education and HIV prevention strategies among adolescent girls not only for their role in reducing risk of HIV infection and early pregnancy, but also to promote healthy adolescents who will have healthier future children. Similarly, early childhood interventions such as exclusive breastfeeding not only prevent HIV, but also contribute to better child and adolescent health outcomes. The most ambitious biomedical infant HIV prevention effort, Option B+, also represents a lifecycle approach by leveraging the prevention benefits of optimal HIV treatment for mothers; maternal survival benefits from Option B+ may have ultimately more health impact on children than the prevention of infant HIV in isolation. The potential for synergistic and additive benefits of lifecycle interventions should be considered when scaling up HIV prevention efforts in sub-Saharan Africa.

We compared primary Epstein-Barr virus (EBV) infection and suppression between Kenyan human immunodeficiency virus-infected infants starting nevirapine-based vs lopinavir/ritonavir-based antiretroviral regimens. Although the rate of EBV infection was similar between groups, infants receiving lopinavir/ritonavir suppressed EBV more rapidly. Our findings suggest that specific antiretrovirals may potentially impact the risk of future EBV-associated malignancies.

Background: Studies in HIV-1-infected infants and HIV-1-exposed, uninfected infants link early cytomegalovirus (CMV) acquisition with growth delay and cognitive impairment. We investigated maternal valacyclovir to delay infant acquisition of CMV., Methods: Pregnant women with HIV-1, HSV-2 and CD4 count >250 cells/µl were randomized at 34 weeks gestation to 500 mg twice-daily valacyclovir or placebo for 12 months. Maternal CMV DNA was measured in plasma at 34 weeks gestation, in cervical secretions at 34 and 38 weeks gestation, and in breast milk at 7 postpartum timepoints; infant CMV DNA was measured in dried blood spots at 8 timepoints including birth., Results: Among 148 women, 141 infants were compared in intent-to-treat analyses. Maternal and infant characteristics were similar between study arms. Infant CMV acquisition did not differ between study arms, with 46/70 infants (66%) in placebo arm and 47/71 infants (66%) in the valacyclovir arm acquiring CMV; median time to CMV detection did not differ. CMV DNA was detected in 92% of 542 breast milk specimens with no difference in CMV level between study arms. Change in cervical shedding of CMV DNA between baseline and 38 weeks was 0.40-log greater in the placebo arm than the valacyclovir arm (p = 0.05)., Conclusions: In this cohort of HIV-1-seropositive mothers, two-thirds of infants acquired CMV by one year. Maternal valacyclovir had no effect on timing of infant CMV acquisition or breast milk CMV viral loads, although it modestly reduced cervical CMV shedding. Maternal prophylaxis to reduce infant CMV acquisition warrants further evaluation in trials with antiviral agents., Trials Registration: ClinicalTrials.gov NCT00530777.

Background: Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) contribute to neonatal mortality. Maternal HIV-1 infection has been associated with an increased risk of PTB, but mechanisms underlying this association are undefined. We describe correlates and outcomes of PTB, LBW, and SGA in HIV-exposed uninfected infants., Methods: This was a retrospective analysis of cohort study. Between 1999-2002, pregnant, HIV-infected women were enrolled into an HIV-1 transmission study. Logistic regression was used to identify correlates of PTB, LBW and SGA in HIV-negative, spontaneous singleton deliveries. Associations between birth outcomes and mortality were measured using survival analyses., Results: In multivariable models, maternal plasma (OR = 2.1, 95% CI = 1.1-3.8) and cervical HIV-1 RNA levels (OR = 1.6, 95% CI = 1.1-2.4), and CD4 < 15% (OR = 2.4, 95% CI = 1.0-5.6) were associated with increased odds of PTB. Abnormal vaginal discharge and cervical polymorphonuclear leukocytes were also associated with PTB. Cervical HIV-1 RNA level (OR = 2.4, 95% CI = 1.5-6.7) was associated with an increased odds of LBW, while increasing parity (OR = 0.46, 95% CI = 0.24-0.88) was associated with reduced odds. Higher maternal body mass index (OR = 0.75, 95% CI = 0.61-0.92) was associated with a reduced odds of SGA, while bacterial vaginosis was associated with >3-fold increased odds (OR = 3.2, 95% CI = 1.4-7.4). PTB, LBW, and SGA were each associated with a >6-fold increased risk of neonatal death, and a >2-fold increased rate of infant mortality within the first year., Conclusions: Maternal plasma and cervical HIV-1 RNA load, and genital infections may be important risk factors for PTB in HIV-exposed uninfected infants. PTB, LBW, and SGA are associated with increased neonatal and infant mortality in HIV-exposed uninfected infants.

Objective: HIV-exposed uninfected (HEU) infants have higher infectious disease morbidity and mortality than unexposed infants. We determined the incidence and risk factors for pneumonia, a leading cause of infant mortality worldwide, in a cohort of HEU infants. Identifying predictors of pneumonia among HEU infants may enable early identification of those at highest risk., Design: A retrospective cohort of HEU infants participating in a Kenyan perinatal HIV study, enrolled between 1999 and 2002., Methods: Infants were followed monthly from birth to 12 months. Incidence of pneumonia diagnosed at monthly study visits, sick-child visits or by means of averbal autopsy was estimated with a 14-day window for new episodes. Cox proportional hazards regression was used to identify predictors of first pneumonia occurrence., Results: Among 388 HEU infants with 328 person-years of follow-up, the incidence of pneumonia was 900/1000 child-years [95% confidence interval (CI) 800-1000]. Maternal HIV viral load at 32 weeks' gestation [hazard ratio 1.2 (1.0-1.5) per log10 difference] and being underweight (weight-for-age Z-score <-2) at the previous visit [hazard ratio 1.8 (1.1-2.8)] were associated with increased risk of pneumonia. Breastfed infants had a 47% lower risk of pneumonia than those never breastfed [hazard ratio 0.53 (0.39-0.73)], independent of infant growth, maternal viral load and maternal CD4%. Breastfeeding was also associated with a 74% lower risk of pneumonia-related hospitalization [hazard ratio 0.26 (0.13-0.53)]., Conclusions: The incidence of pneumonia in this cohort of HEU infants was high. Our observations suggest that maternal viral suppression and breastfeeding may reduce the burden of pneumonia among HEU infants.

Background: Human immunodeficiency virus (HIV) infection is a risk factor for Epstein-Barr virus (EBV)-associated lymphomas. Characterizing primary infection may elucidate risk factors for malignancy., Methods: To describe clinical and virologic manifestations of primary EBV infection among infants born to HIV-infected women, specimens were utilized from a cohort study conducted in Nairobi, Kenya. HIV and EBV viral loads were measured serially in plasma. EBV serology was performed on EBV DNA-negative infants. Monthly clinical examinations were performed by pediatricians., Results: The probability of EBV infection by 1 year of age was .78 (95% CI, .67-.88) in HIV-infected and .49 (95% CI, .35-.65) in HIV-uninfected infants (P < .0001). At 2 years, probability of EBV infection was .96 (95% CI, .89-.99) in HIV-infected infants. Peak EBV loads were higher in HIV-infected versus HIV-uninfected infants (median 2.6 vs 2.1 log10 copies/mL; P < .0001). The majority of HIV-infected infants had detectable EBV DNA for >3 months (79%). Primary EBV infection was associated with cough, fever, otitis media, pneumonia, hepatomegaly, splenomegaly, and hospitalization in HIV-infected infants; conjunctivitis and rhinorrhea in HIV-uninfected infants., Conclusions: EBV infection occurs early in infants born to HIV-infected women. HIV infection was associated with more frequent and higher quantity EBV DNA detection.

Natural killer (NK) cells play an important role in the containment of HIV replication during primary infection, though their functions are impaired during chronic HIV infection. Infants experience more rapid HIV disease progression than adults, but contributions of infant NK cells to containing HIV infection are unknown. The aim of this study was to determine the impact of HIV infection on infant NK cell phenotype by evaluating samples and data from a cohort study of women and their infants, conducted in Nairobi, Kenya between 1999 and 2003. The percentage and phenotype of NK cells was evaluated longitudinally by multi-parameter flow cytometry over the first year of life in HIV-infected (HIV+, = 16), HIV-exposed uninfected (HIV-EU, n = 6), and healthy unexposed controls (HIV-, n = 4). At birth, NK subset distributions based on expression of CD56 and CD16 did not differ between HIV+, HIV-EU, or HIV- infants. However, HIV infection was associated with a subsequent decline in NK cells as a percentage of total lymphocytes (p < 0.001), and an expanding proportion of CD56-CD16+ NK cells (p < 0.001). Activated CD38(bright)CD69+ NK cells were more frequent in the HIV+ infants, followed by HIV-EU and HIV- infants, in both CD56(dim) (p = 0.005) and CD56(bright) compartments (p = 0.03). HIV infection and exposure was also associated with a significant decline in the percentage of perforin-expressing NK cells in the CD56(dim) compartment over the first year of life, with HIV+ infants losing approximately 2.5% (p < 0.001) and HIV-EU infants losing 3.0% (p = 0.01) of perforin+ cells per month. Thus, infant HIV infection is associated with alterations in NK cell subsets, activation, and cytolytic potential that could contribute to their poor control over HIV infection. Furthermore, exposure to HIV infection in infants who escaped infection is also associated with alterations in NK cells that may contribute to the reduced ability to fight infections that is observed in HIV-EU infants.

Objective: Breast milk is a major route of infant HIV infection, yet the majority of breast-fed, HIV-exposed infants escape infection by unknown mechanisms. This study aimed to investigate the role of HIV-specific breast milk cells in preventing infant HIV infection., Design: A prospective study was designed to measure associations between maternal breast milk HIV-specific interferon-γ (IFN-γ) responses and infant HIV-1 detection at 1 month of age., Methods: In a Kenyan cohort of HIV-infected mothers, blood and breast milk HIV-gag IFN-γ ELISpot responses were measured. Logistic regression was used to measure associations between breast milk IFN-γ responses and infant HIV infection at 1 month of age., Results: IFN-γ responses were detected in breast milk from 117 of 170 (69%) women. IFN-γ responses were associated with breast milk viral load, levels of macrophage inflammatory protein (MIP) 1α, MIP-1β, regulated upon activation, normal T-cell expressed, and secreted and stromal-cell derived factor 1 and subclinical mastitis. Univariate factors associated with infant HIV infection at 1 month postpartum included both detection and breadth of breast milk IFN-γ response (P = 0.08, P = 0.04, respectively), breast milk MIP-1β detection (P = 0.05), and plasma (P = 0.004) and breast milk (P = 0.004) viral load. In multivariate analyses adjusting for breast milk viral load and MIP-1β, breast milk IFN-γ responses were associated with an approximately 70% reduction in infant HIV infection [adjusted odds ratio (aOR) 0.29, 95% confidence interval (CI) 0.092-0.91], and each additional peptide pool targeted was associated with an approximately 35% reduction in infant HIV (aOR 0.65, 95% CI 0.44-0.97)., Conclusion: These data show breast milk HIV-gag-specific IFN-γ cellular immune responses are prevalent and may contribute to protection from early HIV transmission. More broadly, these data suggest breast milk cellular responses are potentially influential in decreasing mother-to-child transmission of viruses.

Cytomegalovirus (CMV) coinfection is associated with infant HIV-1 disease progression and mortality. In a cohort of Kenyan HIV-infected infants, the frequencies of activated (CD38(+) HLA-DR(+)) and apoptosis-vulnerable (CD95(+) Bcl-2(-)) CD4(+) and CD8(+) T cells increased substantially during acute CMV infection. The frequency of activated CD4(+) T cells was strongly associated with both concurrent CMV coinfection (P = 0.001) and HIV-1 viral load (P = 0.05). The frequency of apoptosis-vulnerable cells was also associated with CMV coinfection in the CD4 (P = 0.02) and CD8 (P < 0.001) T cell subsets. Similar observations were made in HIV-exposed uninfected infants. CMV-induced increases in T cell activation and apoptosis may contribute to the rapid disease progression in coinfected infants.

Objectives: Early infant HIV-1 diagnosis and treatment substantially improve survival. Where virologic HIV-1 testing is unavailable, integrated management of childhood illness (IMCI) clinical algorithms may be used for infant HIV-1 screening. We evaluated the performance of the 2008 WHO IMCI HIV algorithm in a cohort of HIV-exposed Kenyan infants., Methods: From 1999 to 2003, 444 infants had monthly clinical assessments and quarterly virologic HIV-1 testing. Using archived clinical data, IMCI sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated using virologic testing as a gold standard. Linear regression and survival analyses were used to determine the effect of age on IMCI performance and timing of diagnosis., Results: Overall IMCI sensitivity, specificity, PPV, and NPV value were 58, 87, 52, and 90%, respectively. Sensitivity (1.4%) and PPV (14%) were lowest at 1 month of age, when 81% of HIV infections already had occurred. Sensitivity increased with age (P < 0.0001), but remained low throughout infancy (range 1.4-35%). Specificity (range 97-100%) was high at each time point and was not associated with age. Fifty-eight percent of HIV-1-infected infants (50 of 86) were eventually diagnosed by IMCI, and use of IMCI was estimated to delay diagnosis in HIV-infected infants by a median of 5.9 months (P < 0.0001)., Conclusion: IMCI had low sensitivity during the first month of life, when the majority of HIV-1 infections had already occurred and initiation of treatment is most critical. Although sensitivity increased with age, the substantial delay in HIV-1 diagnosis using IMCI limits its utility in early infant HIV-1 diagnosis.

Late presentation is common among African HIV-1-infected infants. Incidence and correlates of mortality were examined in 99 infants with HIV-1 diagnosis by 5 months of age. Twelve-month survival was 66.8% (95% confidence interval: 55.9-75.6%). World Health Organization stage 3 or 4, underweight, wasting, microcephaly, low hemoglobin, pneumonia and gastroenteritis predicted mortality. Early HIV-1 diagnosis with antiretroviral therapy before symptomatic disease is critical for infant survival.

Background: The incidence and correlates of breast milk HIV-1 RNA detection were determined in intensively sampled women receiving highly active antiretroviral therapy (HAART) for the prevention of mother-to-child HIV-1 transmission., Methods: Women initiated HAART at 34 weeks of pregnancy. Breast milk was collected every 2-5 days during 1 month postpartum for measurements of cell-associated HIV DNA and cell-free HIV RNA. Plasma and breast milk were also collected at 2 weeks, 1, 3 and 6 months for concurrent HIV-1 RNA and DNA measurements. Regression was used to identify cofactors for breast milk HIV-1 RNA detection., Results: Of 259 breast milk specimens from 25 women receiving HAART, 34 had detectable HIV-1 RNA (13%, incidence 1.4 episodes/100 person-days 95% CI = 0.97-1.9). Fourteen of 25 (56%) women had detectable breast milk HIV-1 RNA [mean 2.5 log(10) copies/ml (range 2.0-3.9)] at least once. HIV-1 DNA was consistently detected in breast milk cells despite HAART, and increased slowly over time, at a rate of approximately 1 copy/10(6) cells per day (p = 0.02). Baseline CD4, plasma viral load, HAART duration, and frequency of breast problems were similar in women with and without detectable breast milk HIV-1 RNA. Women with detectable breast milk HIV-1 RNA were more likely to be primiparous than women without (36% vs 0%, p = 0.05). Plasma HIV-1 RNA detection (OR = 9.0, 95%CI = 1.8-44) and plasma HIV-1 RNA levels (OR = 12, 95% CI = 2.5-56) were strongly associated with concurrent detection of breast milk HIV-1 RNA. However, no association was found between breast milk HIV-1 DNA level and concurrent breast milk HIV-1 RNA detection (OR = 0.96, 95%CI = 0.54-1.7)., Conclusions: The majority of women on HAART had episodic detection of breast milk HIV-1 RNA. Breast milk HIV-1 RNA detection was associated with systemic viral burden rather than breast milk HIV-1 DNA.

Although CD8(+) T cells play an important role in the containment of adult HIV-1 replication, their role in infant HIV-1 infection is not as well understood. Impaired HIV-specific CD8(+) T cell responses may underlie the persistently high viral loads observed in infants. We examined the frequency and phenotype of infant HIV-specific CD8(+) T cells in 7 HIV-infected antiretroviral therapy-naïve infants during the first 2 years of life, using class I HLA tetramers and IFN-γ-ELISPOT. The frequency (0.088-3.9% of CD3(+)CD8(+) cells) and phenotype (CD27(+)CD28(-), CD45RA(+/-), CD57(+/-), HLA-DR(+), CD95(+)) of infant HIV-specific CD8(+) T cells were similar to reports in adults undergoing early infection. Unlike adults, at 23-24 months post-infection a high frequency of HIV-specific CD8(+) T cells expressed HLA-DR (mean 80%, range 68-85%) and CD95 (mean 88%, range 79-96%), suggesting sustained activation and vulnerability to apoptosis. Despite comparable expansion of HIV-specific CD8(+) T cells of a similar phenotype to adults during early infection, infant T cells failed to contain HIV-1 replication, and remained persistently activated and vulnerable to apoptosis during chronic infection.