Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant.

BACKGROUND: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1-2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission. METHODS: In this phase 2a-b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)-negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 µg of recombinant spike protein with 50 µg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection. RESULTS: Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, -0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups. CONCLUSIONS: The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399.).

Influence of age and co-medication on dolutegravir glucuronidation in paediatric patients.

Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG-gluc). We described the dolutegravir metabolic ratio (DTG-MR; DTG-gluc AUC0-24h divided by DTG AUC0-24h) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS-4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG-MR. The overall geometric mean (CV%) DTG-MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG-MR (P < .001) in multiple linear regression. DTG-MR geometric mean ratio was 1.81 (95% CI: 1.57-2.08) for children while on vs. off rifampicin. This study showed that overall DTG-MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co-administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data.

Acceptability, feasibility and preliminary effectiveness of the mHealth intervention, InTSHA, on retention in care and viral suppression among adolescents with HIV in South Africa: a pilot randomized clinical trial.

We describe the results of a pilot randomized clinical trial of a mobile phone-based intervention, InTSHA: Interactive Transition Support for Adolescents with HIV, compared to standard care. Encrypted, closed group chats delivered via WhatsApp provided peer support and improved communication between adolescents with HIV, their caregivers, and healthcare providers. We randomized 80 South African adolescents ages 15 to 19 years with perinatally-acquired HIV to receive either the intervention (n=40) or standard of care (n=40). We measured acceptability (Acceptability of Intervention Measure [AIM]) and feasibility (Feasibility of Intervention Measure [FIM]) as primary outcomes. We evaluated impact on retention in care and viral suppression six months after randomization as secondary endpoints. We performed bivariable and multivariable analyses using logistic regression models to assess the effect of the InTSHA intervention compared to standard of care. Among the adolescents randomized to the InTSHA intervention, the median AIM was 4.1/5.0 (82%) and median FIM was 3.9/5.0 (78%). We found no difference in retention in care or in viral suppression comparing intervention and control groups. Among adolescents who attended three or more sessions, retention in care was 100% at 6 months. InTSHA is an acceptable and feasible mHealth intervention warranting further study in a larger population.

Impact of age on antimicrobial prescriptions in hospitalized children at three academic centres in South Africa: a point prevalence survey.

Antimicrobial resistance is a global threat in children, and the emergence of multi-drug-resistant organisms is of concern. This secondary analysis of an antimicrobial point prevalence survey (PPS) in children evaluates the impact of age on antimicrobial use. The mean antimicrobial prescriptions were assessed in neonates, infants, young children (1-5 years), school-going children (6-12 years), and adolescents (13-15 years) from a cross-sectional PPS at three academic hospitals between September 2021 and January 2022. Primary and secondary diagnoses, antibiotic type (World Health Organization AWaRe and Anatomical Therapeutic Chemical classifications), and the incidence of healthcare-associated infections (HAI) were evaluated per age category. Multiple regression models were used to analyse age-related risk factors for HAI. The number of antimicrobials per child (1.7-1.9 per patient) was higher in neonates and infants compared to children 6-12 years old (1.4 per patient). Watch antibiotics, especially carbapenems, were commonly prescribed in neonates (32.5%) and infants (42.2%). Reserve antimicrobial use was notable in neonates (4.7%) and infants (4.1%). The incidence risk ratio (IRR) of HAI was higher in neonates and infants (IRR 2.13; 95% CI 1.23-3.70, IRR 2.20; 95% CI 1.40-3.45, respectively) compared to 6- to 12-year-olds. On multivariate analysis of participants according to age, being HIV infected, length of stay >6 days, high McCabe severity score, having surgery and receipt of blood transfusion were associated with an increased risk of HAI (P < .001 for all) while on univariate analysis only, being premature and/or underweight was associated with an increased risk of HAI in infants (P < .001 for both). Infants with risk factors for HAI significantly influenced antimicrobial prescribing, underscoring the necessity for tailored antimicrobial stewardship and enhanced surveillance. The increased use of Watch antibiotics, particularly carbapenems, in infants warrants closer scrutiny. Further research is required to identify inappropriate antimicrobial use in high-risk hospitalized young children.

Systematic Review of mHealth Interventions for Adolescent and Young Adult HIV Prevention and the Adolescent HIV Continuum of Care in Low to Middle Income Countries.

Adolescents and young adults (AYA) in low to middle income countries (LMIC) have poorer outcomes along each step in the HIV continuum of prevention and care compared to younger children or older adults. The use of mHealth technology provides a potentially promising implementation strategy for interventions to remedy these disparities. We therefore conducted a systematic review of the English literature and conference proceedings from January 1, 2000 to April 1, 2021 evaluating mHealth interventions targeting AYA along each step of the HIV continuum of care in LMIC. We identified 27 mHealth interventions across the HIV continuum, with no interventions addressing transition from pediatric to adult care. The majority of studies were single arm, uncontrolled or underpowered, with few randomized trials resulting in mixed and inconclusive outcomes. mHealth interventions have potential to remedy disparities along the HIV continuum of care for AYA in LMIC but larger, powered randomized trials are needed.

RESUMEN: Los adolescentes y adultos jóvenes (AYA) en países de ingresos bajos a medianos (LMIC) tienen peores resultados en cada paso del continuo de prevención y atención del VIH en comparación con los niños más pequeños o los adultos mayores. El uso de la tecnología mHealth proporciona una estrategia de implementación potencialmente prometedora para las intervenciones para remediar estas disparidades. Por lo tanto, realizamos una revisión sistemática de los resúmenes y artículos publicados en inglés desde el 1 de enero de 2000 hasta el 1 de abril de 2021 para evaluar las intervenciones de mHealth dirigidas a AYA a lo largo de cada paso del continuo de atención del VIH en LMIC. Identificamos 27 intervenciones de mHealth en todo el continuo del VIH, sin intervenciones que abordaran la transición de la atención pediátrica a la de adultos. La mayoría de los estudios fueron de un solo brazo, no controlados o con bajo poder estadístico, con pocos ensayos aleatorios que dieron resultados mixtos y no concluyentes. Las intervenciones de mHealth tienen el potencial de remediar las disparidades a lo largo de la continuidad de la atención del VIH para AYA en LMIC, pero se necesitan ensayos aleatorios más grandes y potentes.

Predictors of stunting among children aged 6-59 months, Zimbabwe.

OBJECTIVE: Stunted children have an increased risk of diminished cognitive development, diabetes, degenerative and CVD later in life. Numerous modifiable factors decrease the risk of stunting in children. This study aimed to assess the role of the individual, household and social factors on stunting in Zimbabwean children. DESIGN: A 1:2 unmatched case-control study. SETTING: This study was conducted in two predominantly rural provinces (one with the highest national prevalence of stunting and one with the lowest prevalence) in Zimbabwe. PARTICIPANTS: Data were obtained from the caregivers of 150 children aged between 6 and 59 months with stunting and from the caregivers of 300 children without stunting. RESULTS: Multiple (39) correlates of stunting were identified. Child's age, birth length, birth weight, and weight-for-age outcome (child-related factors), caregiver's age, maternal HIV status, occupation, and education (parental factors), breast-feeding status, number of meals, and dietary quality (dietary factors), child's appetite, diarrhoeal and worm infection (childhood illnesses), income status, access to safe water, access to a toilet, health clubs and maternal support in infant feeding (household, socio-cultural factors) were all found to be significant predictors of childhood stunting. CONCLUSION: Nearly all aspects under review from the individual-, household- to social-level factors were significantly associated with childhood stunting. These findings add to the growing body of evidence supporting the WHO stunting framework and strengthen the need to focus interventions on a multi-sectoral approach to effectively address stunting in high prevalence countries.

Abacavir pharmacokinetics in African children living with HIV: A pooled analysis describing the effects of age, malnutrition and common concomitant medications.

AIMS: Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. METHODS: A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling. RESULTS: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. CONCLUSION: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.

Borrowing information across patient subgroups in clinical trials, with application to a paediatric trial.

BACKGROUND: Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. METHODS: We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. RESULTS: The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing < 14 kg in whom the treatment effect will be estimated separately. Expert clinical opinion was elicited and demonstrated that substantial borrowing is supported. Clinical experts chose on average to allocate a relative weight of 78% (reduced from 90% based on sample size) to data from children weighing ≥ 14 kg in a Bayesian analysis of the children weighing < 14 kg. The total effective sample size in the Bayesian analysis was 386 children, providing 84% predictive power to exclude a difference of more than 10% between arms, whereas the 85 younger children weighing < 14 kg provided only 20% power in a standalone frequentist analysis. CONCLUSIONS: Borrowing information from a larger subgroup or subgroups can facilitate estimation of treatment effects in small subgroups within a clinical trial, leading to improved power and precision. Informative prior distributions for interaction parameters are required to inform the degree of borrowing and can be informed by expert opinion. We demonstrated accessible methods for obtaining opinions.

Development of a transition readiness score for adolescents living with perinatally-acquired HIV and transitioning to adult care.

We created a transition readiness score for adolescents with perinatally-acquired HIV as they transition from pediatric to adult care. Of the 199 adolescents who transitioned to adult care, 84 (42%) had viral suppression (< 200 copies/ml) one year after transition. Adolescents on first-line ART, with documented HIV status disclosure, and higher rating on the HIV Adolescent Readiness to Transition Scale had significantly higher odds of viral suppression after transition. Conversely, females, those with older age at ART initiation, and those with prior alcohol use had significantly lower odds of viral suppression after transition. Using these data, we created a transition readiness score organized into low, intermediate, and high levels of transition readiness. This transition readiness score can be used to identify adolescents who are likely ready to transition to adult care and identify additional areas for intervention to improve the likelihood of successful transition for those with lower transition readiness scores.

"I am not shy anymore": A qualitative study of the role of an interactive mHealth intervention on sexual health knowledge, attitudes, and behaviors of South African adolescents with perinatal HIV.

BACKGROUND: South Africa has one of the highest burdens of adolescents with perinatally-acquired HIV (APHIV) in the world. APHIV in South Africa have limited access to sexual and reproductive health (SRH) education and services specific to their HIV status. When lacking comprehensive SRH education, APHIV are prone to sexual risk behaviors that can lead to unintended pregnancy, sexually transmitted infections, and HIV transmission. The use of mHealth interventions has been shown to deliver information, foster social support, and improve decision-making skills. In this study, we evaluate how an mHealth intervention influences sexual health knowledge and behaviors in APHIV. METHODS: We purposively enrolled adolescents from the intervention arm of a randomized clinical trial assessing a multi-module, moderated WhatsApp-based intervention-Interactive Transition Support for Adolescents Living with HIV (InTSHA)-within a government supported clinic in KwaMashu, an urban township of KwaZulu-Natal, South Africa. We conducted in-depth interviews based on World Health Organization guidelines for asking adolescents about SRH. We thematically analyzed data through an iterative, team-based coding approach combining deductive and inductive elements to contextualize SRH attitudes, knowledge, and behaviors before and after receiving the InTSHA intervention. RESULTS: Of the 21 participants, 13 (61.9%) were female and the mean age was 16.6 years. Most participants reported first learning about SRH as young teenagers in school through non-targeted and negative ways, seeking clarification through peers and the internet rather than clinicians or caregivers. Participants reported that InTSHA provided a holistic perspective on relationships, gender, and sexuality specific to growing up with HIV in South Africa. They praised the ability to give and receive information from peers in a moderated setting through the mHealth intervention, building their confidence, decision-making skills, and communication with partners and caregivers throughout their everyday lives. Despite reporting some technological challenges, adolescents agreed that InTSHA was convenient, confidential, and user-friendly. CONCLUSIONS: South African APHIV receive incomplete and conflicting sexual education from peers, caregivers, teachers, and technology that can be supplemented by mHealth curricula targeted for the unique needs of APHIV. Future, scaled-up mHealth interventions can lower SRH stigma by expanding access to sexual education and peer support, supplementing adolescents' existing SRH education.

South African adolescents with perinatally-acquired HIV (APHIV)­teenagers who were born with HIV­lack access to sexual and reproductive health (SRH) education specific to their HIV status. Ineffective SRH education often leads to risky behaviors (such as unprotected sex), teenage pregnancy, and the spread of HIV. Mobile health (mHealth) interventions, such as phone apps, can help improve adolescent SRH knowledge and decision-making. In this study, we evaluate how a WhatsApp-based intervention­Interactive Transition Support for Adolescents Living with HIV (InTSHA)­influences SRH attitudes and behaviors of APHIV. InTSHA involved long-term, weekly group chats of APHIV, run by trained facilitators, that included two modules discussing SRH. This study analyzes in-depth interviews we conducted with adolescents who completed InTSHA, asking them about their SRH knowledge and behaviors before and after the intervention. The interviews took place in a government-supported clinic in an urban township of KwaZulu-Natal. Interviews were recorded, transcribed, translated, coded, and analyzed. Of 21 participants, 13 were female and the average age was 16.6 years. Most participants reported first learning about SRH as young teenagers in school, through peers, or on the internet, rather than through healthcare workers or family members. Participants reported that InTSHA provided a comfortable platform to discuss relationships, gender, and sexuality as APHIV. Adolescents enjoyed giving and receiving information from peers in a moderated setting. They reported that InTSHA built their confidence, decision-making skills, and communication with partners and caregivers. South African SRH education for APHIV can be supplemented by targeted mHealth interventions.

Early Initiation of Antiretroviral Therapy Following In Utero HIV Infection Is Associated With Low Viral Reservoirs but Other Factors Determine Viral Rebound.

BACKGROUND: Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown. METHODS: Peripheral blood total HIV DNA from 164 early treated (day 0-21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants. RESULTS: Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7-4.8) did not correlate with age at cART initiation (0-21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound. CONCLUSIONS: With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.

Disclosure, Social Support, and Mental Health are Modifiable Factors Affecting Engagement in Care of Perinatally-HIV Infected Adolescents: A Qualitative Dyadic Analysis.

Adolescents living with perinatally acquired HIV in South Africa face significant barriers to successful transition from pediatric to adult care. We performed in-depth qualitative interviews with 41 adolescents living with HIV and 18 of their caregivers to investigate modifiable factors to improve engagement in care prior to transition to adult care. Based on dyadic, inductive content analysis, findings suggest that HIV status disclosure, social support, and mental health are targets for improvement in engagement in care. Early disclosure and a sense of belonging facilitated engagement in care, while barriers included delayed or inadequate disclosure, denial, and lack of disclosure to others. Adherence support improved by having a biological mother as a direct supervisor. Barriers to care included changing caregivers, abandonment, undiagnosed mental health problems and learning difficulties. Despite these factors, the majority of adolescents showed resilience and remained engaged in care despite difficult circumstances.

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.

Population pharmacokinetics of abacavir and lamivudine in severely malnourished human immunodeficiency virus-infected children in relation to treatment outcomes.

AIMS: Describe the pharmacokinetics (PK) of the antiretroviral drugs abacavir and lamivudine in malnourished paediatric patients and relate to viral load outcomes after 12 and 48 weeks of treatment. METHODS: Severely malnourished human immunodeficiency virus-infected children were randomized to early (within 14 days) or delayed (after nutritional recovery) initiation of antiretroviral treatment (ART) using World Health Organization weight-band dosages. Abacavir and lamivudine concentrations were measured as a secondary objective on day 1 and day 14 and patients were followed-up to week 48. Population PK of abacavir and lamivudine were described using NONMEM. RESULTS: In total, 623 abacavir and 627 lamivudine concentrations were collected from 75 paediatric patients aged 0.1-10.8 (median 1.4) years. Abacavir PK was described by a 2-compartment model, patients randomized to early ART showed increased bioavailability of 31%. Apparent clearance (CL/F, L/h/7 kg) of abacavir increased from day 1 to day 14 from 3.33 (95% confidence interval 2.71-4.12) to 5.86 (95% confidence interval 4.78-7.3). A 1-compartment model described lamivudine PK, variability on CL/F was explained by maturation with age, with age at half-matured CL/F being 4 months. For both drugs allometrically scaled total body weight was related to CL/F and apparent volume of distribution. PK exposure did not correlate with virological outcomes or death at 12 or 48 weeks. CONCLUSION: Increases in Abacavir's CL/F between day 1 to day 14, bioavailability and PK variability with early start of ART was found in this cohort of severely malnourished children; however, these changes did not influence virological outcomes. The study supports the use of weight-band dosage tables.

Molecular Characterization of Corynebacterium diphtheriae Outbreak Isolates, South Africa, March-June 2015.

In 2015, a cluster of respiratory diphtheria cases was reported from KwaZulu-Natal Province in South Africa. By using whole-genome analysis, we characterized 21 Corynebacterium diphtheriae isolates collected from 20 patients and contacts during the outbreak (1 patient was infected with 2 variants of C. diphtheriae). In addition, we included 1 cutaneous isolate, 2 endocarditis isolates, and 2 archived clinical isolates (ca. 1980) for comparison. Two novel lineages were identified, namely, toxigenic sequence type (ST) ST-378 (n = 17) and nontoxigenic ST-395 (n = 3). One archived isolate and the cutaneous isolate were ST-395, suggesting ongoing circulation of this lineage for >30 years. The absence of preexisting molecular sequence data limits drawing conclusions pertaining to the origin of these strains; however, these findings provide baseline genotypic data for future cases and outbreaks. Neither ST has been reported in any other country; this ST appears to be endemic only in South Africa.

Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial.

BACKGROUND: The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial. METHODS: Human immunodeficiency virus (HIV)-infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring. RESULTS: As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3-6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37-2.65) but not death alone (aHR, 1.65; 95% CI, .72-3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses. CONCLUSIONS: These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children. CLINICAL TRIALS REGISTRATION: NCT00307151.

Lessons from a school-based vaccination response following a Diphtheria outbreak in eThekwini district, SA.

Diphtheria is a life-threatening respiratory tract infection that causes outbreaks in susceptible populations. Between April and May 2018, an outbreak of diphtheria occurred in the eThekwini district. A school-based outbreak vaccination response was initiated to target vulnerable children and adolescents. Contribution: This study adds to the limited data describing a school-based vaccination in an outbreak response and highlights successes and challenges. School-based outbreak vaccination response can rapidly increase vaccine coverage; however, additional community engagement may be required in vaccine-hesitant populations.

Mimickers of hypoxic-ischaemic brain injury in term neonates: What the radiologist should know.

Patterns of neonatal hypoxic-ischaemic brain injury (HIBI) are fairly well known. There are, however, other diagnoses with imaging patterns that may mimic HIBI. A review of MRI studies was conducted for children with suspected cerebral palsy, correlated with prior imaging, clinical details and laboratory tests where available. In the 63 identified cases, imaging features were, in many cases, very similar to the known patterns of HIBI. The alternative diagnoses can be classified as developmental, vascular, chromosomal, infections, metabolic disorders, and congenital syndromes. These findings are described in this pictorial essay. The potential mimickers of HIBI described in this essay can demonstrate similar imaging appearances to HIBI. Contribution: There are multiple possible causes of neonatal encephalopathy other than hypoxic-ischaemic encephalopathy. Many conditions may mimic HIBI, each of which can be associated with significant morbidity. It is prudent for the reporting radiologist to be aware of these alternate clinico-radiological diagnoses.

Changes in the medical admissions and mortality amongst children in four South African hospitals following the COVID-19 pandemic: A five-year review.

Vulnerable children from poor communities with high HIV and Tuberculosis(TB) burdens were impacted by COVID-19 lockdowns. Concern was raised about the extent of this impact and anticipated post-pandemic surges in mortality. Interrupted time series segmented regression analyses were done using routinely collected facility-level data of children admitted for medical conditions at four South African referral hospitals. Monthly admission and mortality data over 60 months from 01 April 2018 to 31 January 2023 was analysed using models which included dummy lockdown level variables, a dummy post-COVID period variable, Fourier terms to account for seasonality, and excess mortality as a proxy for healthcare burden. Of the 45 015 admissions analysed, 1237(2·75%) demised with significant decreases in admissions during all the lockdown levels, with the most significant mean monthly decrease of 450(95%, CI = 657·3, -244·3) p<0·001 in level 5 (the most severe) lockdown. There was evidence of loss of seasonality on a six-month scale during the COVID periods for all admissions (p = 0·002), including under-one-year-olds (p = 0·034) and under-five-year-olds (p = 0·004). No decreases in mortality accompanied decreased admissions. Post-pandemic surges in admissions or mortality were not identified in children with acute gastroenteritis, acute pneumonia and severe acute malnutrition.During the COVID-19 pandemic, paediatric admissions in 4 hospitals serving communities with high levels of HIV, TB and poverty decreased, similar to global experiences; however, there was no change in in-hospital mortality. No post-pandemic surge in admissions or mortality was documented. Differences in the impact of pandemic control measures on the transmission of childhood infections and access to health care may account for differing outcomes seen in our setting compared to the global experiences. Further studies are needed to understand the impact of pandemic control measures on healthcare provision and transmission dynamics and to better inform future responses amongst vulnerable child populations.