Background:Cytomegalovirus (CMV) is a major unrecognised cause of morbidity and mortality in infants living with HIV. Valganciclovir, an oral prodrug of ganciclovir, treats CMV in immunocompromised patients, but pharmacokinetic data in infants living with HIV are lacking. This study evaluated exploratory valganciclovir pharmacokinetic and pharmacodynamic outcomes in infants with severe HIV-associated pneumonia. Methods:As part of the EMPIRICAL clinical trial (ClinicalTrials.gov: NCT03915366, recruitment closed), infants living with HIV aged 1-12 months received valganciclovir 16 mg/kg twice daily. Pharmacokinetic sampling occurred on day 3 after enrolment at 2- and 5 h post-morning dose. Plasma CMV viral load was measured on days 0 and 15. The area-under-the-curve for ganciclovir over a 12-h interval (AUC0-12 h) was estimated using a limited sampling equation. Geometric mean AUC0-12 h and the proportion of participants within the adult AUC0-12 h target range (40-60 h mg/L) were calculated. Associations of ganciclovir AUC0-12 h with covariates and log-change in plasma CMV viraemia were evaluated using linear regression. Infants were enrolled in this study between August 2020 and August 2022. Findings:Of 98 participants, 87 had evaluable pharmacokinetic profiles. Geometric mean AUC0-12h (%CV) was 38.5 (54.8) h·mg/L. Only 35% achieved the adult AUC0-12 h target; 47% were below, and 18% above it. Reduced renal function was the only covariate associated with higher ganciclovir AUC0-12 h. Ganciclovir AUC0-12 h did not correlate with plasma CMV viral load reduction. Interpretation:Approximately two-thirds of infants was not within adult pharmacokinetic targets at 16 mg/kg/dose of valganciclovir. However, ganciclovir exposure was not predictive for virologic response or toxicity, suggesting lower exposures did not affect treatment efficacy in the EMPIRICAL trial. Funding:This project is funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2) program supported by the European Union (RIA2017MC-2013).

BACKGROUND:Mortality among infants with severe HIV-associated pneumonia remains high. This trial (EMPIRICAL) tested whether empirical valganciclovir treatment for cytomegalovirus improves survival in infants in Africa. METHODS:This multicentre, open-label, group-sequential designed, 2 × 2 factorial, randomised, controlled, superiority trial was conducted in 19 hospitals across Côte d'Ivoire, Malawi, Mozambique, Uganda, Zambia, and Zimbabwe. Infants aged 28-365 days admitted with severe HIV-associated pneumonia were centrally and individually randomly assigned (1:1:1:1) using a secure web-based system stratified by site and severity to receive standard of care (SOC) comprising treatment for bacterial (WHO-recommended antibiotics) and Pneumocystis jirovecii (cotrimoxazole and steroids) pneumonia, SOC plus 15 days of oral valganciclovir (16 mg/kg per 12 h), or SOC plus 6 months of tuberculosis treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months, plus isoniazid and rifampicin for 4 subsequent months), or both interventions combined. The primary endpoint was all-cause mortality, assessed at day 15 and over 1-year follow-up in the intention-to-treat population. In this Article, we report results for the valganciclovir comparison groups. The trial is registered with ClinicalTrials.gov, NCT03915366 and is complete. FINDINGS:From March 15, 2020, to Jan 31, 2024, 563 participants were enrolled; 558 were included in the analyses, with 276 allocated to valganciclovir groups (140 valganciclovir; 136 valganciclovir plus tuberculosis treatment) and 282 to groups without valganciclovir (142 SOC; 140 tuberculosis treatment). The median patient age was 4·4 months (IQR 3·2-7·4), and 274 (49%) were female. There was no evidence of interaction between valganciclovir and tuberculosis treatment (adjusted hazard ratio 1·19 [95% CI 0·73-1·95], heterogeneity p=0·48). At day 15, 64 (23%) of 276 participants in the valganciclovir group and 76 (27%) of 282 in groups without valganciclovir died (rate ratio 0·81 [95% CI 0·61-1·08], p=0·15). 24 (9%) of 276 participants and 13 (5%) of 282, respectively, were lost to follow-up. After 12 months, 119 (43%) of 276 participants in the valganciclovir groups and 134 (48%) of 282 in the groups without valganciclovir died (0·88 [95% CI 0·74-1·05] p=0·15). In a time-varying effects model, at day 15, the adjusted hazard ratio of death was 0·60 (95% CI 0·41-0·87, p=0·0063), and their hazard of death over 1 year was 0·79 (0·62-1·01; p=0·068), or 0·76 (0·58-1·00; p=0·0500) when excluding deaths within 48 h of treatment. Severe adverse events during follow-up were not more common in the valganciclovir treatment groups (odds ratio 0·64 [95% CI 0·35-1·16]). INTERPRETATION:Empirical valganciclovir treatment appeared to be associated with a lower hazard of death in infants with severe HIV-associated pneumonia than SOC alone or SOC plus empirical tuberculosis treatment, and there was little evidence of associated harms. FUNDING:European and Developing Countries Clinical Trials Partnership.

BACKGROUND:The EMPIRICAL trial aims to assess safety and efficacy of an empirical treatment against cytomegalovirus (CMV) and tuberculosis (TB) compared to standard of care (SoC), on adverse events and 15-day and 1-year mortality among infants living with HIV hospitalized with severe pneumonia in Africa. METHODS AND DESIGN:The EMPIRICAL trial (NCT03915366) is an international multicenter phase II-III, open-label randomized factorial clinical trial conducted in six African countries. The trial has four randomization arms in a 1:1:1:1 fashion with patients allocated to (i) TB-Treatment plus SoC, (ii) valganciclovir plus SoC, (iii) both TB-Treatment and valganciclovir plus SoC, and (iv) SoC only. DISCUSSION:This paper describes the statistical analysis plan (SAP) for the trial which, per the study publication plan, needs to be published prior to the database lock and final analysis results. The SAP includes details of the analyses to be undertaken and unpopulated tables that will be reported to address primary and secondary endpoints. The database will be locked on 31st January 2025. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03915366 (registered on April 16, 2019), Universal Trial Number: U111-1231-4736, Pan African Clinical Trial Registry: PACTR201994797961340.

INTRODUCTION:This study aimed to evaluate in detail the short- and long-term humoral responses to the BNT162b2 (BioNTech, SE, Mainz, Germany/Pfizer Inc, New York, NY) vaccine in immunosuppressed children 5-11 years old compared with healthy children. METHODS:A prospective cohort study was conducted with immunosuppressed and healthy children 5-11 years of age following complete vaccination, defined as 3 doses of the BNT162b2 vaccine for immunosuppressed participants and 2 doses for healthy participants. The primary endpoints included IgG antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and receptor-binding domain, as well as neutralizing capacity, 1- and 6-months postvaccination. Secondary endpoints included evaluations of breakthrough infections and cellular immune responses against SARS-CoV-2. RESULTS:Thirty-five participants (20 healthy and 15 immunosuppressed) were included in the study. We could not demonstrate a different serological response in healthy children compared with immunosuppressed children in levels of anti-Spike IgG, anti-receptor-binding domain IgG, or neutralizing antibody at 1- and 6-months postvaccination. Humoral responses declined significantly by 6 months in healthy children; we could not demonstrate a significant decline in immunosuppressed children. Cellular immunity at 6 months showed a strong correlation with humoral response ( R ≥ 0.74). Overall, the immunological response appeared protective for up to 6 months in both healthy and immunosuppressed participants, with only 1 breakthrough infection in a healthy child. CONCLUSIONS:After 3 vaccine doses, immunosuppressed children demonstrate 6-month immune comparable to healthy children who received 2 doses. Despite a decline in humoral responses over time, there were no infections, supporting the effectiveness of current coronavirus disease 2019 vaccination strategies.

In this prospective cohort study with 2326 hospitalized children and young people with coronavirus disease 2019 in Spain and Colombia, 36.4% had comorbidities. Asthma, recurrent wheezing, chronic neurological, cardiac and pulmonary diseases significantly increased the risk of severe outcomes such as death, mechanical ventilation and intensive care unit admission. The incremental risk with additional comorbidities underscores the importance of targeted vaccination strategies for vulnerable children and young people populations.

Background: We evaluated the prevalence and characteristics of persistent signs and/or symptoms in children and young people (CYP) one year after hospitalization for acute COVID-19 compared with a control group of CYP hospitalized for other conditions. Methods: We conducted an observational study in three hospitals in Madrid, which included a group of children aged between 1 month and 18 years who were hospitalized due to acute COVID-19 from March 2020 to December 2021. We also selected a comparison group of patients hospitalized for other, unrelated conditions within the same month. Eligible participants had no history of COVID-19 at recruitment or during follow-up. Data were collected from clinical records and a standardized questionnaire completed by the patients’ families. The primary outcome was the presence of persistent symptoms one year after hospitalization. Results: A total of 96 patients were enrolled and analyzed (50 acute COVID-19 patients and 46 non-COVID-19 participants). Of these, 34/96 (35%) met the criteria for persistent symptoms (CYP: 17/50 (34%) COVID-19 participants and 17/46 (37%) non-COVID-19 participants (p = 0.767)). Symptoms persisted ≥12 months in 14/50 (28%) COVID-19 participants and in 7/46 (15%) non-COVID-19 participants (p = 0.140). Both before and after admission, all of the participants provided similar ratings for all of the specific items related to emotional welfare, social relationships, and current activities. Readmissions occurred in 11/50 (22%) COVID-19 participants and in 6/46 (13%) non-COVID-19 participants (p = 0.267). Conclusions: We identified a non-significant difference in the prevalence of persistent symptoms 1 year after hospitalization between children and young people (CYP) with acute COVID-19 and those hospitalized for non-COVID-19-related conditions.

Background Even with increasing access to rapid HIV diagnosis and early antiretroviral therapy (ART) initiation, infants living with HIV seem to have adverse outcomes. We assessed the probability of death, viral suppression, and other HIV-related events in the fi rst three years of life among early-treated children with perinatally-acquired HIV in South Africa, Mozambique, and Mali. Methods We enrolled a cohort of infants who initiated ART within the initial 6 months of life and within 3 months of diagnosis. These children were monitored 2, 6, 12 and 24 weeks after enrolment, followed by biannual check-ups up to 4 years after enrolment. We assessed the probability of death, viral load (VL) suppression, severe immunosuppression (according to WHO guidelines), and engagement in care using Kaplan-Meier - Meier plots, and hazard ratios for these outcomes using multivariable Cox regression models. Findings Two hundred and fi fteen infants were enrolled and monitored for a median of 34 months [IQR, 16.3; 44.1]. ART initiation occurred at a median of 34 days of age [IQR, 26.0; 73.0]. The probability of death at 1 year of ART was 10% (95% CI, 6-14), - 14), increased to 12% (95% CI, 8-17) - 17) at 2 and remained in 12% at 3 years. The main risk factor for HIV/AIDS-related mortality was baseline viral load [HR: 2.98 (95% CI, 1.25-7.12)]. - 7.12)]. Sixty-one of 146 (42%) children achieved sustained virological control below lower limit of detection for any >= 1 year period between enrolment and 4 years after enrolment. Viral suppression during follow-up was inversely associated with baseline viral load [Hazard Ratio (HR): 0.72 (95% CI, 0.58-0.89] - 0.89] and adverse maternal social events [HR: 0.26 (95% CI, 0.15-0.45)]. - 0.45)]. Adherence to ART was assessed as optimal in 81% of the visits. Female sex at birth, lower age at diagnosis and maternal adverse social life events were risk factors for low adherence [Odds ratio, OR 1.25 (95% CI, 1.00-1.56); - 1.56); 1.12 (95% CI, 1.01-1.27) - 1.27) and 2.52 (95% CI, 2.16-12.37), - 12.37), respectively]. Interpretation Despite early ART, mortality remains high in infants. High baseline VL and adverse maternal social environment increased the risk of poor outcomes. Sustained supportive strategies are essential during and after pregnancy, to achieve better survival.

Purpose We evaluated the prevalence and characteristics of persistent signs and/or symptoms in children and young people (CYP) one year after hospitalization for acute COVID-19 compared with a control group of CYP hospitalized for other conditions. Methods We conducted an observational study in three hospitals in Madrid. We included a group of children who aged 1 month to 18 years of age who were hospitalized for acute COVID-19 from March 2020 to December 2021. We selected a group of patients for comparison among hospitalized patients the same month as the participants with COVID-19, for different reasons, with no history of COVID-19 at recruitment or during follow-up. Data were collected from clinical records and a standardized questionnaire answered by families. The primary outcome was the presence of persistent symptoms one year after hospitalization. Results Ninety-six patients were enrolled and analyzed (50 acute COVID-19 patients and 46 non-COVID-19 participants). The definition of persistent symptoms was met in 34/96 (35%) CYP: 17/50 (34%) COVID-19 participants and 17/46 (37%) non-COVID-19 participants (p=0.767). Symptoms persisted ³12 months in 14/50 (28%) COVID-19 participants and in 7/46 (15%) non-COVID-19 participants (p=0.140). Both groups rated similarly before and after admission on all the specific items related to emotional welfare, social relationships, and current activities. Readmissions occurred in 11/50 (22%) COVID-19 participants and in 6/46 (13%) non-COVID-19 participants (p=0.267). Conclusion: This study found a non-significant difference in the prevalence of persistent symptoms 1 year after hospitalization between children and young people (CYP) with acute COVID-19 and those hospitalized for other reasons.

Background: Community-acquired Pneumonia (CAP) is the most common infectious disease in childhood. Deep learning models have achieved promising results in X-ray interpretation and diagnosis. However, the usual validation workflow of these models found in the state of the art should be extended. The aims of this study are to test the performance, adequacy, and applicability of an already published deep convolutional neural network (CNN)-based model for identifying consolidation in radiographs in an independent subset.Methods: A total of 190 pediatric chest-X-ray (CXRs) images were used to test the CNN model support decision tool (SDT). The performance of the model was estimated using extensions of the two-test Bayesian Latent-Class model (BLCA). The sensitivity, specificity, and accuracy of the model were assessed. The clinical characteristics of the patients were compared according to the model performance. The adequacy of the SDT was assessed by asking two senior physicians the agreement rate with the SDT. The applicability was tested by asking three medical residents before and after using the SDT and the agreement between experts was calculated using the kappa index.Results: The CRXs were labelled by the panel of experts into consolidation (124/176, 70.4%) and no-consolidation/other infiltrates (52/176, 29.5%). A total of 31/176 (17.6%) discrepancies were found between the model and the panel of experts with a kappa index of 0.6. The sensitivity and specificity reached a median of 90.9 (95 % Credible Interval (CrI), 81.2-99.9) and 77.7 (95% CrI, 63.3-98.1) respectively. The senior physicians reported a high agreement rate (70%) with the system in identifying logical consolidation patterns. The three medical residents reached a higher agreement using SDT than alone with experts (0.66±0.1 vs. 0.75±0.2).Conclusions: Augmenting clinicians with automated preliminary read assistants could help expedite their workflows and improve accuracy in identifying consolidation in pediatric CXRs images.

Background Tuberculosis (TB) diagnosis is challenging in children, particularly in infants, contributing to high TB-related mortality. Up to 30% of infants with pulmonary TB have concurrent extrapulmonary disease, with findings that can frequently be detected with ultrasound. A protocol of focused assessment with sonography for HIV-associated TB (FASH) at six abdominal and thoracic positions has shown promise for diagnosis in children and adults, but few infants have been included in published studies. Methods EMPIRICAL (#NCT03915366) is a randomized, controlled trial funded by EDCTP (RIA2017MC-2013) recruiting HIV-positive infants <12 months hospitalized with severe pneumonia without current/past TB diagnosis or exposure. All participants have Xpert Ultra (stool, nasopharyngeal aspirate) and urine LAM testing, and in an ongoing blinded diagnostic ancillary study at 5 hospitals in Mozambique, FASH is performed. An interim descriptive analysis was done for participants no longer active in the trial as of April 2023. Results For the 39 participants included, the median age was 3 months (IQR:3.17–5.13), 48.7% were female, and the median CD4% was 13% (IQR:9.90–17.55). There was ≥1 positive FASH finding in 10/39 (25.6%); all had pericardial effusion 10/39 (25.6%), with focal splenic lesions and ascites also noted in 2/39 (5.1%) and 1/39 (2.6%), respectively. No participants had pleural effusion, focal liver lesions, or abdominal lymphadenopathy. In participants with laboratory-confirmed TB, 42.9% (3/7) had ≥1 positive FASH finding. There were 2 positive FASH findings in 7.6% (3/39) participants, of whom 66.7% (2/3) had laboratory-confirmed TB. Conclusion Positive FASH findings were frequent in HIV-positive infants hospitalized with severe pneumonia and even more common in the subset of participants with laboratory-confirmed TB, with pericardial effusion noted on all positive FASH exams. Future analysis will attempt to define which abnormalities on FASH exam are most predictive of TB disease and assess the use of FASH to monitor TB treatment response.

Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants. First-line antituberculosis drug peak concentrations in infants with HIV were low compared with reference values for adults. The percent peak concentrations within adult reference values were 51%, 22%, 76%, and 6% for isoniazid, rifampicin, pyrazinamide, and ethambutol, respectively.

BACKGROUND:Although super-boosted lopinavir/ritonavir (LPV/r; ratio 4:4 instead of 4:1) is recommended for infants living with HIV and receiving concomitant rifampicin, in clinical practice, many different LPV/r dosing strategies are applied due to poor availability of pediatric separate ritonavir formulations needed to superboost. We evaluated LPV pharmacokinetics in infants with HIV receiving LPV/r dosed according to local guidelines in various sub-Saharan African countries with or without rifampicin-based tuberculosis (TB) treatment. METHODS:This was a 2-arm pharmacokinetic substudy nested within the EMPIRICAL trial (#NCT03915366). Infants aged 1-12 months recruited into the main study were administered LPV/r according to local guidelines and drug availability either with or without rifampicin-based TB treatment; during rifampicin cotreatment, they received double-dosed (ratio 8:2) or semisuperboosted LPV/r (adding a ritonavir 100 mg crushed tablet to the evening LPV/r dose). Six blood samples were taken over 12 hours after intake of LPV/r. RESULTS:In total, 14/16 included infants had evaluable pharmacokinetic curves; 9/14 had rifampicin cotreatment (5 received double-dosed and 4 semisuperboosted LPV/r). The median (IQR) age was 6.4 months (5.4-9.8), weight 6.0 kg (5.2-6.8), and 10/14 were male. Of those receiving rifampicin, 6/9 infants (67%) had LPV Ctrough <1.0 mg/L compared with 1/5 (20%) in the control arm. LPV apparent oral clearance was 3.3-fold higher for infants receiving rifampicin. CONCLUSION:Double-dosed or semisuperboosted LPV/r for infants aged 1-12 months receiving rifampicin resulted in substantial proportions of subtherapeutic LPV levels. There is an urgent need for data on alternative antiretroviral regimens in infants with HIV/TB coinfection, including twice-daily dolutegravir.

Background.We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin. Methods. Infants living with HIV aged 1-12 months, weighing >= 3kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported. Results. Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)(0-24h) 0.91 (95% confidence interval, .59-1.42), C-trough 0.95 (0.57-1.59), C-max 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir C-trough <0.32mg/L, and none had C-trough <0.064mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively. Conclusions. Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.

Background Children with advanced HIV disease (AHD) are at an increased risk of morbidity and mortality. We describe mortality rates among infants with AHD hospitalized with severe pneumonia. Methods EMPIRICAL is an ongoing Phase II-III, open-label randomized factorial (2×2) trial supported by EDCTP (GA RIA2017MC_2013/#NCT03915366) to assess the impact of empirical treatment against cytomegalovirus and tuberculosis in infants living with HIV hospitalized with severe pneumonia. The primary endpoint is all-cause mortality at 15-days and 12-months post enrolment. Recruitment is on-going and includes 22 hospitals from 6 African countries (Côte d’Ivoire, Malawi, Mozambique, Uganda, Zambia, Zimbabwe). Results In March 2023, 431 infants had been recruited and 429 were included in analysis. Their median age was 4.36 months (IQR, 3.18–7.08) and 49% were female; 164 (38%) had a history of maternal and/or infant prophylaxis for prevention-mother-to-child-transmission (PMTCT); 306 (71%) were newly diagnosed of HIV during hospitalization; Median HIV viral load and CD4% were 6.3 logs copies/mL (IQR, 5.8–7.0) and 14.4% (IQR, 9.9–21.6) respectively. 196 (46%) of the infants died within a 6 months follow up period (2.16 months (IQR, 0.26–6.16), 110 (56%) in the first admission and 86 (44%) after it. The main register causes of death are pneumonia 91 (46%), sepsis 32 (16%) and gastroenteritis 10 (5%). An in-depth analysis of deaths is ongoing, including minimally invasive tissue sampling, microbiological and histopathological evaluation. Conclusion Children living with HIV and severe pneumonia have a very high mortality, both during the initial hospitalization and after hospital discharge. Measures focused on earlier identification and treatment as well as focused on decreasing post-discharge mortality are urgently needed. EMPIRICAL will report on the survival benefit of cytomegalovirus and tuberculosis treatment at trial conclusion. Emphasis should be put into reducing missed opportunities for PMTCT; strengthening early infant diagnosis and antiretrovirals initiation for those who fail PMTCT.

Background Infants living with HIV are at high risk of tuberculosis and death. Optimal antituberculosis therapy is essential for favourable clinical outcomes particularly in severely ill children. Using WHO-recommended weight-band dosing, younger children weighing <8kg are at risk of suboptimal exposures. We aimed to evaluate plasma concentration of first line antituberculosis drugs in infants with HIV. Methods EMPIRICAL trial (#NCT03915366; EDCTP2-funded (RIA2017MC-2013)) is a randomized controlled trial evaluating empirical antituberculosis and cytomegalovirus treatment in infants with HIV hospitalized for severe pneumonia in 5 African countries. Eligible infants aged <1 year, weighing ≥3kg, on antituberculosis treatment had a blood sample taken 2-hours post-dose at days 30, 90 and 180 in a pharmacokinetic sub-study. Antituberculosis drugs were dosed according to WHO weight-bands using fixed-dose-combination dispersible tablets of rifampicin(15mg/kg)/isoniazid(10mg/kg)/pyrazinamide(35mg/kg) 75/50/150mg with ethambutol(20mg/kg) 100mg. Antiretroviral-naïve infants initiated treatment in accordance with national guidelines. We compared C2hr plasma concentrations for rifampicin, isoniazid, pyrazinamide, and ethambutol with published Cmax references. Results Forty-nine infants of whom 21 were female, median (range) age 6.1(2.5–13.5) months and weighing 5.3(3.4–8.7) kg were included in the analysis of study day 30. The geometric mean (CV%) C2hr for rifampicin, isoniazid, pyrazinamide and ethambutol were 3.66(161) mg/L, 2.80(102) mg/L, 22.27(97) mg/L, and 0.56(101) mg/L, respectively. The C2hr values were substantially below adult reference Cmax for rifampicin [ref in adults (10 mg/kg dose): 8–24 mg/L] and ethambutol [ref: 2–6 mg/L], slightly lower for isoniazid [ref: 3–6 mg/L], and within range for pyrazinamide [ref: 20–60 mg/L]. Conclusion Plasma levels of first-line TB drugs in infants with HIV and severe pneumonia were low compared to adults. This is consistent with other studies showing that infants and younger children do not achieve adult references for first-line TB drugs at current recommended doses. Our data support considerations for optimising dosing of first-line TB drugs for infants.

Background Despite reduction of HIV-associated mortality in children with the implementation of antiretroviral treatment (ART), HIV-associated neurocognitive deficits are still of great concern. These are thought to result mainly from intra-cranial HIV-associated pathology. The contribution of extra-cranial infections like pneumonia is not well described. We compared neurocognitive function between infants living with HIV (ILHIV), with and without severe pneumonia. Methods This EDCTP-funded case-control study (TMA2020CDF-3198) was conducted among ILHIV with severe pneumonia enrolled in the EMPIRICAL trial (#NCT03915366) (cases), and age-matched ILHIV without severe pneumonia (controls). We assessed neurocognitive function using the Bayley’s Scales of Infant and Toddler Development-III within 3weeks of hospital discharge or recruitment among cases and controls respectively. We compared demographic and clinical characteristics as well as neurocognitive mean scaled scores between the two groups. Results Among 66 infants (44 cases and 22 controls) included in the study, 36 (54.5%) were male and the median age was 6 months (IQR = 4.47 - 8.98). There was no difference in age (p = 0.83), sex distribution (p = 0.43), prematurity proportions (p = 0.16), breastfeeding (p = 0.56) proportion on ART and its duration, (p = 0.05, and p = 0.07 respectively), viral load (p = 0.28), or hemoglobin (p = 0.06). The cases had lower weight-for-height z-scores than the controls (-1.73 [IQR = -2.68 – 0.44] vs -0.08 [IQR = -1.85 - 0.85] respectively, p = 0.04). There was no difference in family care indicators between groups. Among infants with complete data, the cases (n=40) scored poorer than the controls (n=18) in all neurocognitive domains; cognitive (p = <0.01), language (p = 0.04), and motor (p = <0.01). Conclusion Severe pneumonia increases the likelihood of neurocognitive deficits among ILHIV. Interventions reducing the risk and severity of pneumonia may be beneficial in reducing neurocognitive decline in this population.

Objectives To evaluate the performance of oral saliva swab (OSS) reverse transcription PCR (RT-PCR) compared with RT-PCR and antigen rapid diagnostic test (Ag-RDT) on nasopharyngeal swabs (NPS) for SARS-CoV-2 in children. Design Cross-sectional multicentre diagnostic study. Setting Study nested in a prospective, observational cohort (EPICO-AEP) performed between February and March 2021 including 10 hospitals in Spain. Patients Children from 0 to 18 years with symptoms compatible with Covid-19 of ≤5 days of duration were included. Two NPS samples (Ag-RDT and RT-PCR) and one OSS sample for RT-PCR were collected. Main outcome Performance of Ag-RDT and RT-PCR on NPS and RT-PCR on OSS sample for SARS-CoV-2. Results 1174 children were included, aged 3.8 years (IQR 1.7–9.0); 73/1174 (6.2%) patients tested positive by at least one of the techniques. Sensitivity and specificity of OSS RT-PCR were 72.1% (95% CI 59.7 to 81.9) and 99.6% (95% CI 99 to 99.9), respectively, versus 61.8% (95% CI 49.1 to 73) and 99.9% (95% CI 99.4 to 100) for the Ag-RDT. Kappa index was 0.79 (95% CI 0.72 to 0.88) for OSS RT-PCR and 0.74 (95% CI 0.65 to 0.84) for Ag-RDT versus NPS RT-PCR. Conclusions RT-PCR on the OSS sample is an accurate option for SARS-CoV-2 testing in children. A less intrusive technique for younger patients, who usually are tested frequently, might increase the number of patients tested. The results from this multi-centre prospective diagnostic test accuracy study suggest that molecular testing of oral saliva samples for SARS-CoV-2 in children is an accurate and less invasive alternative to molecular testing of nasopharyngeal/oropharyngeal swabs.