Bridging dolutegravir clinical viral response across doses and formulations using model-based exposure-response analysis in pediatrics.

OBJECTIVE: Dolutegravir (DTG) is a once-daily HIV-1 integrase inhibitor approved for the treatment of HIV-1 infection in adults and children from 4 weeks of age. The posology of DTG in children has been driven by exposure-matching relative to the adult dose for efficacy and safety. However, higher variability in pediatric exposures raises concern that efficacy may not be reliably extrapolated from adult trials. Therefore, we evaluated the relationship between DTG exposure and virologic response in children. DESIGN/METHODS: A population exposure-response analysis using logistic regression for virologic response was undertaken based on DTG exposure and covariate data from 146 pediatric participants with HIV-1 from age at least 4 weeks to less than 18 years treated for up to 48 weeks with DTG in IMPAACT P1093 study. RESULTS: None of the DTG exposure metrics were predictive of virologic response over the range of exposures in this analysis. Of the covariates tested, viral load at least 100 000 copies/ml at enrolment was a significant predictor of virologic response showing a lower probability of achieving a virologic response of HIV-1 RNA less than 50 copies/ml compared with participants with viral load less than 100 000 copies/ml at enrolment. Baseline viral load was also a significant predictor at week 48 whereby the probability of achieving a virologic response at week 48 decreased with increasing baseline viral load. CONCLUSION: This exposure-response analysis suggests that DTG exposures in children are all above the plateau of the exposure-response relationship. These results suggest that matching pediatric pharmacokinetic exposure parameters to those in adults is a reasonable approach for dose determination of DTG-containing formulations in pediatrics.

Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children.

BACKGROUND: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined. METHODS: Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. RESULTS: The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 ; 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts. CONCLUSIONS: Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.

Community-Wide Universal HIV Test and Treat Intervention Reduces Tuberculosis Transmission in Rural Uganda: A Cluster-Randomized Trial.

BACKGROUND: Human immunodeficiency virus (HIV) treatment reduces tuberculosis (TB) disease and mortality; however, the population-level impact of universal HIV-test-and-treat interventions on TB infection and transmission remain unclear. METHODS: In a sub-study nested in the SEARCH trial, a community cluster-randomized trial (NCT01864603), we assessed whether a universal HIV-test-and-treat intervention reduced population-level incident TB infection in rural Uganda. Intervention communities received annual, population-level HIV testing and patient-centered linkage. Control communities received population-level HIV testing at baseline and endline. We compared estimated incident TB infection by arms, defined by tuberculin skin test conversion in a cohort of persons aged 5 and older, adjusting for participation and predictors of infection, and accounting for clustering. RESULTS: Of the 32 trial communities, 9 were included, comprising 90 801 participants (43 127 intervention and 47 674 control). One-year cumulative incidence of TB infection was 16% in the intervention and 22% in the control; SEARCH reduced the population-level risk of incident TB infection by 27% (adjusted risk ratio = 0.73; 95% confidence interval [CI]: .57-.92, P = .005). In pre-specified analyses, the effect was largest among children aged 5-11 years and males. CONCLUSIONS: A universal HIV-test-and-treat intervention reduced incident TB infection, a marker of population-level TB transmission. Investments in community-level HIV interventions have broader population-level benefits, including TB reductions.

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents.

BACKGROUND AND OBJECTIVE: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. METHODS: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure-safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. RESULTS: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure-safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. CONCLUSIONS: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization.

A multilevel health system intervention for virological suppression in adolescents and young adults living with HIV in rural Kenya and Uganda (SEARCH-Youth): a cluster randomised trial.

BACKGROUND: Social and cognitive developmental events can disrupt care and medication adherence among adolescents and young adults living with HIV in sub-Saharan Africa. We hypothesised that a dynamic multilevel health system intervention helping adolescents and young adults and their providers navigate life-stage related events would increase virological suppression compared with standard care. METHODS: We did a cluster randomised, open-label trial of young individuals aged 15-24 years with HIV and receiving care in eligible clinics (operated by the government and with ≥25 young people receiving care) in rural Kenya and Uganda. After clinic randomisation stratified by region, patient population, and previous participation in the SEARCH trial, participants in intervention clinics received life-stage-based assessment at routine visits, flexible clinic access, and rapid viral load feedback. Providers had a secure mobile platform for interprovider consultation. The control clinics followed standard practice. The primary, prespecified endpoint was virological suppression (HIV RNA <400 copies per mL) at 2 years of follow-up among participants who enrolled before Dec 1, 2019, and received care at the study clinics. This trial is registered with ClinicalTrials.gov, NCT03848728, and is closed to recruitment. FINDINGS: 28 clinics were enrolled and randomly assigned (14 control, 14 intervention) in January, 2019. Between March 14, 2019, and Nov 26, 2020, we recruited 1988 participants at the clinics, of whom 1549 were included in the analysis (785 at intervention clinics and 764 at control clinics). The median participant age was 21 years (IQR 19-23) and 1248 (80·6%) of 1549 participants were female. The mean proportion of participants with virological suppression at 2 years was 88% (95% CI 85-92) for participants in intervention clinics and 80% (77-84) for participants in control clinics, equivalent to a 10% beneficial effect of the intervention (risk ratio [RR] 1·10, 95% CI 1·03-1·16; p=0·0019). The intervention resulted in increased virological suppression within all subgroups of sex, age, and care status at baseline, with greatest improvement among those re-engaging in care (RR 1·60, 95% CI 1·00-2·55; p=0·025). INTERPRETATION: Routine and systematic life-stage-based assessment, prompt adherence support with rapid viral load testing, and patient-centred, flexible clinic access could help bring adolescents and young adults living with HIV closer towards a goal of universal virological suppression. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health.

Antiretroviral postnatal prophylaxis to prevent HIV vertical transmission: present and future strategies.

INTRODUCTION: Maternal antiretroviral therapy (ART) with viral suppression prior to conception, during pregnancy and throughout the breastfeeding period accompanied by infant postnatal prophylaxis (PNP) forms the foundation of current approaches to preventing vertical HIV transmission. Unfortunately, infants continue to acquire HIV infections, with half of these infections occurring during breastfeeding. A consultative meeting of stakeholders was held to review the current state of PNP globally, including the implementation of WHO PNP guidelines in different settings and identifying the key factors affecting PNP uptake and impact, with an aim to optimize future innovative strategies. DISCUSSION: WHO PNP guidelines have been widely implemented with adaptations to the programme context. Some programmes with low rates of antenatal care attendance, maternal HIV testing, maternal ART coverage and viral load testing capacity have opted against risk-stratification and provide an enhanced PNP regimen for all infants exposed to HIV, while other programmes provide infant daily nevirapine antiretroviral (ARV) prophylaxis for an extended duration to cover transmission risk throughout the breastfeeding period. A simplified risk stratification approach may be more relevant for high-performing vertical transmission prevention programmes, while a simplified non-risk stratified approach may be more appropriate for sub-optimally performing programmes given implementation challenges. In settings with concentrated epidemics, where the epidemic is often driven by key populations, infants who are found to be exposed to HIV should be considered at high risk for HIV acquisition. All settings could benefit from newer technologies that promote retention during pregnancy and throughout the breastfeeding period. There are several challenges in enhanced and extended PNP implementation, including ARV stockouts, lack of appropriate formulations, lack of guidance on alternative ARV options for prophylaxis, poor adherence, poor documentation, inconsistent infant feeding practices and in inadequate retention throughout the duration of breastfeeding. CONCLUSIONS: Tailoring PNP strategies to a programmatic context may improve access, adherence, retention and HIV-free outcomes of infants exposed to HIV. Newer ARV options and technologies that enable simplification of regimens, non-toxic potent agents and convenient administration, including longer-acting formulations, should be prioritized to optimize the effect of PNP in the prevention of vertical HIV transmission.

Tilting the Scale: Current Provider Perspectives and Practices on Breastfeeding with HIV in the United States.

The risk of vertical transmission from breastfeeding with HIV (BFHIV) has been found to be very low in optimal scenarios with sustained maternal viral suppression during pregnancy and postpartum. Medical providers must account for the risk of this serious adverse event alongside parental autonomy, breastfeeding benefits, and patient values. To assess provider practices, comfort, and challenges with BFHIV, an online mixed-method survey was sent to breastfeeding and HIV provider listservs from June to July 2021. The target population was US medical professionals from diverse practice settings with experience in clinical issues associated with BFHIV, including physicians, advanced practice providers, nurses, and lactation consultants. Data analysis utilized nonparametric hypothesis testing, ordinal regression, and reflexive thematic analysis. Most providers reported counseling pregnant people with HIV on infant feeding choices, but fewer specifically endorsed counseling about breastfeeding. Of 84 unique institutions identified by 100 included respondents, 10% had an institutional protocol supporting BFHIV. Institutional protocols were associated with higher degrees of provider comfort with BFHIV in optimal scenario clinical vignettes. Providers perceived that White patients faced fewer BFHIV barriers than patients with other racial identities. Discomfort balancing the goals to protect infants from infection risk and support the parent's role in infant feeding decisions was a key theme in free text responses; this manifested in a spectrum of management styles ranging from patient's informed choice to paternalism. This study highlights the tension providers navigate regarding BFHIV discussions, calling for patient care guidelines and protocols grounded in risk reduction and respect of patient autonomy.

Two or more significant life-events in 6-months are associated with lower rates of HIV treatment and virologic suppression among youth with HIV in Uganda and Kenya.

Youth living with HIV in sub-Saharan Africa have poor HIV care outcomes. We determined the association of recent significant life-events with HIV antiretroviral treatment (ART) initiation and HIV viral suppression in youth aged 15-24 years living with HIV in rural Kenya and Uganda. This was a cross-sectional analysis of 995 youth enrolled in the SEARCH Youth study. At baseline, providers assessed recent (within 6 months) life-events, defined as changes in schooling/employment, residence, partnerships, sickness, incarceration status, family strife or death, and birth/pregnancy, self-reported alcohol use, being a parent, and HIV-status disclosure. We examined the frequencies of events and their association with ART status and HIV viral suppression (<400 copies/ul). Recent significant life-events were prevalent (57.7%). Having >2 significant life-events (aOR = 0.61, 95% CI:0.45-0.85) and consuming alcohol (aOR = 0.61, 95% CI:0.43-0.87) were associated with a lower odds of HIV viral suppression, while disclosure of HIV-status to partner (aOR = 2.39, 95% CI:1.6-3.5) or to family (aOR = 1.86, 95% CI:1.3-2.7), being a parent (aOR = 1.8, 95% CI:1.2-2.5), and being single (aOR = 1.6, 95% CI:1.3-2.1) had a higher odds. This suggest that two or more recent life-events and alcohol use are key barriers to ART initiation and achievement of viral suppression among youth living with HIV in rural East Africa.Trial registration: ClinicalTrials.gov identifier: NCT03848728..

Infants Receiving Very Early Antiretroviral Therapy Have High CD4 Counts in the First Year of Life.

We followed 54 infants with in utero HIV after initiating very early antiretroviral treatment. At weeks 24 and 48, ≥80% had CD4 ≥1500 cells/mm3 and CD4% ≥25%. Routine Pneumocystis jirovecii pneumonia prophylaxis in the first year of life may not be necessary for all very early treated infants. CLINICAL TRIALS REGISTRATION: NCT02140255.

Potential of Long-Acting Products to Transform the Treatment and Prevention of Human Immunodeficiency Virus (HIV) in Infants, Children, and Adolescents.

Long-acting antiretroviral products have the potential to transform human immunodeficiency virus (HIV) prevention and treatment approaches in pediatric populations. Broadly neutralizing antibodies and/or long-acting antiretroviral formulations by injection could dramatically improve provision of HIV prophylaxis and/or early treatment to newborns and infants at risk of HIV infection. Challenges in daily oral antiretroviral administration to toddlers and school age children living with HIV may be relieved by use of long-acting formulations, but the pharmacokinetics and safety of these products in children must be studied before they can enter routine clinical use. Although some initial studies of broadly neutralizing antibodies and injectable long-acting agents in infants and young children are underway, more studies of these and other long-acting products are needed. For many adolescents, compliance with daily medication administration is especially challenging. Long-acting products hold particular promise for adolescents living with HIV as well as those at high risk of HIV acquisition, and adolescents can usually be included in the drug development pipeline simultaneously with adults. Long-acting products have the potential to provide alternatives to lifelong daily oral drug administration across the pediatric age spectrum, leading to more effective prevention and treatment of HIV infection in infants, children, and adolescents.

Advancing the prevention and treatment of HIV in children: priorities for research and development.

Safe and effective paediatric formulations of the most promising antiretroviral drugs are crucial to advance the treatment and prevention of HIV in neonates, infants, children, and adolescents. The WHO Paediatric Drug Optimization for HIV (PADO-HIV) group brings together stakeholders and experts every 2-3 years to identify priority products and define research gaps in the development of new HIV drugs and formulations for children in low-income and middle-income countries. PADO-HIV 5 met from Sept 27 to Oct 15, 2021. The group evaluated HIV agents from known and novel drug classes, oral and parenteral long-acting formulations, and developments in broadly neutralising antibodies, and included focused sessions on neonates and new delivery technologies. A list of medium-term and long-term priorities was generated, and research questions were defined. This forward-looking analysis is intended to provide guidance to funders, drug developers, and researchers, and to accelerate access for children to the best HIV drugs and formulations.

What babies need: accelerating access to current and novel antiretroviral drugs in neonates through pharmacokinetic studies.

Although 23 antiretroviral drugs are approved for use in adults, only six are approved by regulatory authorities for use in term neonates born to women with HIV, with even fewer options for preterm neonates. A major hurdle for approvals is the delay in the generation of pharmacokinetic and safety data for antiretrovirals in neonates. The median time between the year of approval from the US Food and Drug Administration of an antiretroviral agent for adults and the first publication date for pharmacokinetic data in neonates less than 4 weeks old is 8 years (range 2-23 years). In this Viewpoint, we address pharmacokinetic research gaps and priorities for current and novel antiretroviral use in neonates. We also consider the challenges and provide guidance on neonatal clinical pharmacology research on antiretroviral agents with the goal of stimulating research and expediting the availability of safe medications for the prevention and treatment of HIV in this vulnerable population.

"I was still very young": agency, stigma and HIV care strategies at school, baseline results of a qualitative study among youth in rural Kenya and Uganda.

INTRODUCTION: Adolescents and young adults living with HIV (AYAH) have the lowest rates of retention in HIV care and antiretroviral therapy (ART) adherence, partly due to the demands of school associated with this life stage, to HIV-related stigma and to fears of serostatus disclosure. We explore the implications of school-based stigma and disclosure on the development of agency during a critical life stage in rural Kenya and Uganda. METHODS: We conducted a qualitative study in the baseline year of the SEARCH Youth study, a combination intervention using a life-stage approach among youth (15-24 years old) living with HIV in western Kenya and southwestern Uganda to improve viral load suppression and health outcomes. We conducted in-depth, semi-structured interviews in 2019 with three cohorts of purposively selected study participants (youth [n = 83], balanced for sex, life stage and HIV care status; recommended family members of youth [n = 33]; and providers [n = 20]). Inductive analysis exploring contextual factors affecting HIV care engagement revealed the high salience of schooling environments. RESULTS: Stigma within school settings, elicited by non-consensual serostatus disclosure, medication schedules and clinic appointments, exerts a constraining factor around which AYAH must navigate to identify and pursue opportunities available to them as young people. HIV status can affect cross-generational support and cohort formation, as AYAH differ from non-AYAH peers because of care-related demands affecting schooling, exams and graduation. However, adolescents demonstrate a capacity to overcome anticipated stigma and protect themselves by selectively disclosing HIV status to trusted peers and caregivers, as they develop a sense of agency concomitant with this life stage. Older adolescents showed greater ability to seek out supportive relationships than younger ones who relied on adult caregivers to facilitate this support. CONCLUSIONS: School is a potential site of HIV stigma and also a setting for learning how to resist such stigma. School-going adolescents should be supported to identify helpful peers and selectively disclose serostatus as they master decision making about when and where to take medications, and who should know. Stigma is avoided by fewer visits to the clinic; providers should consider longer refills, discreet packaging and long-acting, injectable ART for students.

Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial.

BACKGROUND: Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing. FINDINGS: We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir. INTERPRETATION: In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare-GlaxoSmithKline.

Targeted newborn metabolomics: prediction of gestational age from cord blood.

OBJECTIVE: Our study sought to determine whether metabolites from a retrospective collection of banked cord blood specimens could accurately estimate gestational age and to validate these findings in cord blood samples from Busia, Uganda. STUDY DESIGN: Forty-seven metabolites were measured by tandem mass spectrometry or enzymatic assays from 942 banked cord blood samples. Multiple linear regression was performed, and the best model was used to predict gestational age, in weeks, for 150 newborns from Busia, Uganda. RESULTS: The model including metabolites and birthweight, predicted the gestational ages within 2 weeks for 76.7% of the Ugandan cohort. Importantly, this model estimated the prevalence of preterm birth <34 weeks closer to the actual prevalence (4.67% and 4.00%, respectively) than a model with only birthweight which overestimates the prevalence by 283%. CONCLUSION: Models that include cord blood metabolites and birth weight appear to offer improvement in gestational age estimation over birth weight alone.

Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study.

P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to <18 years with HIV-1. Most participants were highly treatment experienced. We report the mechanisms of emergent integrase strand transfer inhibitor (INSTI) resistance among adolescents and children receiving dolutegravir. Plasma was collected at screening and near protocol-defined virologic failure (PDVF) for population-level and, for some samples, clonal-level integrase genotyping, phenotyping, and replication capacity. HIV-1 RNA was assessed in all available plasma samples. Phylogenetic analysis of clonal integrase sequences and homology modeling of HIV-1 intasome complexes containing resistance-associated substitutions were performed. Treatment-emergent INSTI resistance was detected in 8 participants who met PDVF criteria. The rare INSTI resistance-associated substitution G118R or R263K developed in 6 participants. The on-study secondary integrase substitution E157Q or L74I was observed in 2 participants. G118R reduced dolutegravir susceptibility and integrase replication capacity more than R263K and demonstrated greater reduction in susceptibility and integrase replication capacity when present with specific secondary integrase substitutions, including L74M, T66I, and E138E/K. Continuing evolution after R263K acquisition led to reduced dolutegravir susceptibility and integrase replication capacity. Structural examination revealed potential mechanisms for G118R- and R263K-mediated INSTI resistance. G118R and R263K INSTI resistance substitutions, which are distinct to second-generation INSTIs, were detected in adolescents and children with prior virologic failure who received dolutegravir. This study provides additional molecular and structural characterization of integrase to aid in the understanding of INSTI resistance mechanisms in antiretroviral-experienced populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01302847.).

A Mobile Health App (WYZ) for Engagement in Care and Antiretroviral Therapy Adherence Among Youth and Young Adults Living With HIV: Single-Arm Pilot Intervention Study.

BACKGROUND: Youth are globally recognized as being vulnerable to HIV. Younger age has been correlated with worse health outcomes. Mobile health (mHealth) interventions have the potential to interact with youth where they are, using a device they already access. OBJECTIVE: Using predefined benchmarks, we sought to evaluate the feasibility and acceptability of WYZ, an mHealth app, for improved engagement in care and antiretroviral therapy (ART) adherence among youth and young adults living with HIV. WYZ was designed and developed with input from youth and young adults living with HIV using a human-centered design approach and was based on the information, motivation, and behavioral skills framework to address common barriers to care and ART adherence among youth and young adults living with HIV. METHODS: We recruited youth and young adults living with HIV (18-29 years old) from the San Francisco Bay Area to take part in a 6-month pilot trial. Their participation included completing baseline and exit surveys, and participating in seven phone check-ins about their use of WYZ. RESULTS: Youth and young adults living with HIV (N=79) reported high levels of feasibility and acceptability with WYZ use. We met predefined benchmarks for recruitment (79/84, 94%), mean logins per week (5.3), tracking ART adherence (5442/9393, 57.9%), posting chat topics per week (4.8), and app crashes reported per week (0.24). The ease of app download, install, and setup, and comfort with security, privacy, and anonymity were highly rated (all over 91%). Additionally, participants reported high satisfaction for a research project that was remotely conducted. Participants used the app for shorter timeframes compared to the predefined benchmark. CONCLUSIONS: We noted high feasibility and acceptability with WYZ. Further research to examine the efficacy of WYZ will enable youth and young adults living with HIV and their providers to make informed decisions when using, recommending, and prescribing the app for improved engagement in HIV care and ART adherence. TRIAL REGISTRATION: ClinicalTrials.gov NCT03587857; https://clinicaltrials.gov/ct2/show/NCT03587857.

Implementation of a Newborn Clinical Decision Support Software (NoviGuide) in a Rural District Hospital in Eastern Uganda: Feasibility and Acceptability Study.

BACKGROUND: Lack of trained health care workers and nonadherence to national guidelines are key barriers to achieving high-quality newborn care in health care facilities in low- and middle-income countries. Traditional didactic approaches addressing these barriers fail to account for high staff turnover rates and result in temporary behavior change. NoviGuide, a clinical decision support software designed to standardize neonatal care through point-of-care assessments, has the potential to align bedside practice to national guidelines in settings lacking subspecialty neonatal providers. OBJECTIVE: This study aims to determine the adaptation, adoption, feasibility, acceptability, and sustainability of NoviGuide and its impact on nurse-midwives' knowledge in a rural hospital in eastern Uganda. METHODS: This mixed methods observational study was guided by the Proctor framework. Experts reviewed the clinical content of NoviGuide to ensure fidelity to Uganda guidelines. We enrolled nurses and midwives providing newborn care at Tororo District Hospital, trained them on NoviGuide use, and followed them for 12 months. We assessed adoption, feasibility, acceptability, and sustainability by analyzing NoviGuide use data, comparing it with maternity registry data and administering the System Usability Scale (SUS) and the Center for Health Care Evaluation Provider Satisfaction Questionnaire. We compared the mean knowledge assessment score at baseline, 6 months, and 12 months using a two-tailed t test. RESULTS: Five Ugandan experts suggested two minor changes to NoviGuide: the inclusion of an unsterile birth environment as an indication for empiric antibiotics and the addition of a reminder to follow-up with newborns with temperatures between 37.7°C and 37.9°C. Of the 19 nurse-midwives enrolled in February 2017, 74% (n=14) completed the follow-up in March 2018. The participants entered a total of 1705 assessments of varying newborn characteristics into NoviGuide throughout the day, evening, and night nursing shifts. The SUS score at the end of the study was very high (93.5, above the average of 68). Participants had a positive perception about NoviGuide, reporting that NoviGuide saved time (mean 5, SD 0) and prevented mistakes (mean 5, SD 0), and that they felt more confident in taking care of newborns when they used NoviGuide (mean 5, SD 0). Participants were highly satisfied with NoviGuide (mean 4.86, SD 0.36), although they lacked medical supplies and materials needed to follow NoviGuide recommendations (mean 3.3, SD 1.22). The participants' knowledge scores improved by a mean change of 3.7 (95% CI 2.6-4.8) at 6 months and 6.7 (95% CI 4.6-8.2) at 12 months (P<.001). CONCLUSIONS: NoviGuide was easily adapted to the Uganda guidelines. Nurse-midwives used NoviGuide frequently and reported high levels of satisfaction despite challenges with medical supplies and high staff turnover. NoviGuide improved knowledge and confidence in newborn care without in-person didactic training. NoviGuide use has the potential to scale up quality newborn care by facilitating adherence to national guidelines.