Abstract Children recovering from complicated severe acute malnutrition (SAM) have a high risk of infectious mortality and morbidity, which could reflect impaired anti-microbial defence. We used blood samples from a cross-sectional cohort of children under 5 years’ old admitted to hospital with SAM in Zambia and Zimbabwe (cases, n = 125) and adequately nourished non-hospitalised children from the same communities (controls, n = 73) to characterise anti-bacterial innate immune cell function. We did not find evidence that inpatient immune function differed between cases who experienced subsequent adverse clinical outcomes (death, readmission, SAM at 48 weeks) versus those who did not. However, pro-inflammatory cytokine (IL-6, IL-8 and TNF) responses to E. coli lipopolysaccharide and heat-killed Salmonella typhimurium were positively associated with subsequent gains in mid-upper arm circumference, an indicator of nutritional recovery. We then characterised how innate immune cell function changed during post-discharge rehabilitation in a longitudinal sub-cohort of cases who provided repeat blood samples at discharge, 12, 24 and/or 48 weeks post-discharge ( n = 83). Relative to inpatient immune function, bacterial binding capacity declined whilst anti-bacterial pro-inflammatory cytokine secretion increased in the cases over the post-discharge follow-up period with both normalising towards control ranges. These changes were also evident in cases who had recovered to a healthy nutritional status (weight-for-height Z score ≥ −2). Collectively, our data suggest that restoration of anti-bacterial innate immune cell function following complicated SAM lags behind nutritional recovery. Thus, children who are no longer wasted may continue to have deficient anti-bacterial innate immunity months after hospital admission for SAM.

Childhood severe acute malnutrition (SAM) occurs as either classical wasting (non-oedematous-SAM; NO-SAM) or with the presence of oedema (oedematous SAM; O-SAM). Both forms of SAM have distinct mortality and nutritional recovery rates, however, the underlying pathophysiology is poorly understood. We collected stool for whole metagenome shotgun sequencing and plasma for metabolic phenotyping from 238 children (79 NO-SAM, 159 O-SAM) hospitalised with complicated SAM and 141 adequately-nourished controls (ANC) from an observational, prospective cohort in Zimbabwe and Zambia. Children with SAM were followed up at 12-, 24- and 48-weeks post-discharge. During hospitalisation, there were significant alterations in taxonomic and functional microbiome diversity between O-SAM and NO-SAM. Lancefieldella parvula , a potent producer of hydrogen-sulfide from cysteine, was one of three species significantly elevated in O-SAM versus NO-SAM. Metagenomic analysis showed an overabundance of pathways involved in sulfur amino-acid and one-carbon metabolism in O-SAM compared to NO-SAM. Consistently, the sulfur amino acids cysteine and homocysteine were significantly depleted in the plasma of O-SAM versus NO-SAM, while histidine and various phosphatidylcholines were more abundant. During follow-up, O-SAM and NO-SAM microbiomes remained divergent up to 24 weeks post-discharge whilst alpha diversity recovery was delayed in NO-SAM. Plasma metabolomes also remained significantly different between O-SAM, NO-SAM and ANC throughout 48 weeks of follow-up. These findings demonstrate that distinct microbiome profiles may drive disturbance of systemic one-carbon metabolism in O-SAM and highlight persistent microbiome and metabolic dysfunction during nutritional recovery. This work supports further studies targeting the gut microbiome to correct metabolic disturbances and improve long-term clinical outcomes in complicated SAM. One Sentence Summary Children hospitalised with oedematous versus non-oedematous severe acute malnutrition have altered gut microbiomes and disrupted one-carbon metabolism, which remain distinct up to 48 weeks post-discharge. ### Competing Interest Statement RCR is on the scientific advisory board of Biostime Institute Nutrition and Care and declares remittance from Abbott Nutrition Health Institute, Nutricia and Nestle for public conference talks outside the submitted work. All other authors declare that they have no competing interests. ### Clinical Protocols ### Funding Statement HOPE-SAM was funded by the Medical Research Council (MR/K012711/1), Wellcome (107634/Z/15/Z to MB, 206455/Z/17/Z to RCR, and 093768/Z/10/Z and 108065/Z/15/Z to AJP), a joint award from Wellcome and the Royal Society (206225/Z/17/Z to CDB), and UNICEF Zimbabwe (ZIM/PCA201721/PD2019158). JRS is supported by NIHR Southampton Biomedical Research Centre (NIHR203319) and BBSRC (UKRI775; BB/W00139X/1). Funding bodies had no role in the study design, implementation, analysis and interpretation of the data. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Zambia Biomedical Research Ethics Committee (010-02-16) and the Medical Research Council of Zimbabwe (MRCZ/A/2044) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The raw metagenome sequencing data generated in this study have been deposited in the European Bioinformatics Database

BACKGROUND:Children living with human immunodeficiency virus (HIV) have limited options for second-line antiretroviral therapy (ART). METHODS:In this open-label trial with a 2-by-4 factorial design, we randomly assigned children with HIV who had first-line treatment failure to receive second-line therapy with tenofovir alafenamide fumarate (TAF)-emtricitabine or standard care (abacavir or zidovudine, plus lamivudine) as the backbone and dolutegravir or ritonavir-boosted darunavir, atazanavir, or lopinavir as the anchor drug. The primary outcome was a viral load of less than 400 copies per milliliter at 96 weeks. We hypothesized that TAF-emtricitabine would be noninferior to standard care, that dolutegravir and ritonavir-boosted darunavir would each be superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination, and that ritonavir-boosted atazanavir would be noninferior to ritonavir-boosted lopinavir. Safety was also assessed. RESULTS:A total of 919 children underwent randomization; 458 were assigned to receive TAF-emtricitabine, and 461 to receive standard care. Assigned anchor drugs were dolutegravir (229 participants), ritonavir-boosted darunavir (232), ritonavir-boosted atazanavir (231), and ritonavir-boosted lopinavir (227). The median age of participants was 10 years, and 497 (54.1%) were male. The median viral load at baseline was 17,573 copies per milliliter. At week 96, TAF-emtricitabine was superior to standard care: the adjusted difference in the percentage of participants with a viral load of less than 400 copies per milliliter was 6.3 percentage points (95% confidence interval [CI], 2.0 to 10.6; P = 0.004). Dolutegravir was superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination (adjusted difference, 9.7 percentage points; 95% CI, 4.8 to 14.5; P<0.001), but ritonavir-boosted darunavir was not (adjusted difference, 5.6 percentage points; 95% CI, 0.3 to 11.0; P = 0.04 [prespecified threshold, P = 0.03]). Ritonavir-boosted atazanavir was noninferior to ritonavir-boosted lopinavir. One child died, and 29 (3.2%) had serious adverse events, with no significant between-group differences. CONCLUSIONS:Second-line ART regimens including TAF-emtricitabine and dolutegravir were effective for children, with no evidence of safety concerns. Ritonavir-boosted darunavir was also effective. (Funded by the European and Developing Countries Clinical Trials Partnership and others; CHAPAS-4 ISRCTN Registry number, ISRCTN22964075.).

Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM ( n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls ( n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children’s outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid–binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.

Background Children living with HIV requiring second-line antiretroviral therapy (ART) have limited options, an unmet need considering children require life-long ART. Methods Children from Uganda, Zambia, Zimbabwe were randomised to one of four second-line anchor drugs: dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r), or lopinavir(LPV/r) in the factorial CHAPAS-4 trial (second randomisation to tenofovir alafenamide fumarate(TAF) or standard-of-care(SOC) backbone, reported elsewhere). Dosing followed WHO weight-bands. The primary endpoint was viral load(VL) <400copies/mL at week-96, analysed using logistic regression, hypothesising that DTG and DRV/r would be superior (threshold p=0.03) to LPV/r and ATV/r arms combined and ATV/r would be non-inferior to LPV/r(12% margin). Secondary endpoints included immunology and safety. Analyses were intention-to-treat. Results 919 children, median(IQR) age 10(8-13) years, 54% male, baseline VL 17,573(5549,55700) copies/mL, CD4 669(413, 971) cells/mm[3][1], weight-for-age Z-score -1.6(-2.4,-0.9), had spent median(IQR) 5.6(3.3,7.8) years on first-line ART. At week-96, DTG was superior (by 9.7%(95% CI 4.8%, 14.5%); p<0.0001) and DRV/r showed a trend to superiority(by 5.6%(0.3%, 11.0%); p=0.04) compared to LPV/r and ATV/r arms combined. ATV/r was non-inferior to LPV/r(+3.4%(-3.4%,+10.2%); p=0.33). CD4 counts increased with no differences between arms. Toxicity was lowest with DTG. All arms except LPV/r showed age-appropriate weight/height gains at week-96. DTG was not associated with excess absolute weight-gain(<1kg) vs. DRV/r or ATZ/r, irrespective of backbone randomisation. Conclusions DTG-based regimens are safe and cost-effective for second-line ART. DRV/r and ATV/r are also good options. Fixed-dose combinations of DTG, DRV/r or ATV/r with nucleoside/nucleotide-reverse-transcriptase-inhibitors(NRTIs) would increase access to robust, essential second-line options for children.([ISRCTN22964075][2]) ### Competing Interest Statement V Musiime declares membership of DSMB/advisory board: ViiV Health Care. The institution of ASW received funding to support a course on Critical Appraisal. ### Clinical Trial ISRCTN22964075 ### Clinical Protocols <http://www.mrcctu.ucl.ac.uk/studies/all-studies/c/chapas-4> ### Funding Statement The CHAPAS-4 Trial is sponsored by University College London (UCL), with central management by the Medical Research Council (MRC) Clinical Trials Unit at UCL supported by MRC core funding (MC\_UU\_00004/03). The main funding for this study is provided by the European and Developing Countries Clinical Trials Partnership. This project is part of the EDCTP programme supported by the European Union (EDCTP; TRIA2015-1078). This publication was produced by CHAPAS-4 which is part of the EDCTP programme supported by the European Union. The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP. Additional funding for the CHAPAS-4 extended follow up was provided by UNIVERSAL project. This project, grant number RIA2019PD- 2882, is part of the EDCTP2 programme supported by the European Union. Additional funding and drug donations were received from Janssen Pharmaceuticals, and Gilead Sciences Inc. Drug donations were also received from Viiv Healthcare and Cipla. Drugs were also purchased from Emcure Pharmaceuticals. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by ethics committees in Uganda (Joint Research Ethics Committee (JREC)), Zambia (University of Zambia Biomedical Research Ethics Committee (UNZABREC)), Zimbabwe (Joint Research Ethics Committee University of Zimbabwe College of Health Sciences (JREC), Research Council Zimbabwe (RCZ)), South Africa (University of Cape Town Human Research Ethics Committee) and United Kingdom (University College London (UCL) Research Ethics Committee). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes MRC CTU at UCL supports a controlled access approach based on completion of a data request proforma available from the corresponding author (mrcctu.ucl.ac.uk/our-research/other-research-policy/data-sharing). [1]: #ref-3 [2]: /external-ref?link_type=ISRCTN&access_num=ISRCTN22964075

Children with severe acute malnutrition (SAM) have high infectious mortality and morbidity, implicating defects in their immune defenses. We hypothesized that circulating innate immune cells from children (0 to 59 months) hospitalized with SAM in Zambia and Zimbabwe ( n = 141) have distinct capacity to respond to bacteria relative to adequately nourished healthy controls ( n = 92). SAM inpatients had higher neutrophil and monocyte Escherichia coli binding capacity but lower monocyte activation and proinflammatory mediator secretion in response to lipopolysaccharide or heat-killed Salmonella typhimurium than controls. Among SAM cases, wasting severity was negatively associated with cytokine secretion, children with HIV had lower monocyte activation, and the youngest children released the least myeloperoxidase upon stimulation. Inpatient bacterial binding capacity and monocyte activation were associated with higher odds of persistent SAM at discharge, a risk factor for subsequent mortality. Thus, SAM shifts innate immune cell function, favoring bacterial containment over proinflammatory activation, which may contribute to health deficits after discharge.

Background Participant information sheets and consent forms (PIS&C) in paediatric/adolescent clinical research are predominantly produced by adults. They are long and complex, meeting ethics, regulatory, and where applicable, pharmaceutical industry requirements, rather than the target audience. Young people report they do not understand much of the information provided, so do not read it, and rely on conversations with trusted Healthcare Providers. LATA (NCT05154747) being conducted by the BREATHER Plus Consortium, is the largest randomised trial of long-acting injectable antiretroviral therapy in virologically suppressed adolescents aged 12–19 years living with HIV-1 (ALWH). LATA has ‘Youth Trials Boards (YTB)’ in the participant countries (Kenya/South Africa/Uganda/Zimbabwe) that consist of supported, structured groups of ALWH who are active partners in the development and delivery of LATA, which started enrolment in May 2023. Methods YTB members attended a global digital meeting to explore what information their peers need to give proper informed consent/assent and what medium would best deliver this. Results The group agreed a short, engaging video would provide core information on how the medicine works, the injection experience and trial requirements. Youth engagement specialists worked with animators to develop a concept and provisional script. The process included ongoing ‘science and youth’ checks. YTB members lent their voices to ensure the video was in local languages. The final video was 5–6 minutes long (u-tube link to follow). All the national ethics committees have approved the video. Conclusion The LATA video compliments the traditional PIS&C and was made through genuine youth engagement. The process allowed the young people to decide the format and content, whilst ensuring it correctly represented the trial. While this video is an adjunct to the PIC&S, in future, videos such as this could replace much of the lengthy complex language provided to trial participants, this merits further discussion with ethics committees and regulators.

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/Objectives Malnutrition underlies 45% of deaths in children under-5 years annually. Children hospitalised with complicated severe acute malnutrition (SAM) have unacceptably high mortality. We aimed to identify variables from early hospital admission (baseline factors) independently associated with inpatient mortality in this cohort to identify those most at risk. Subjects/Methods Observational study of 745 children aged 0–59 months admitted with complicated SAM at three hospitals in Zimbabwe/Zambia. Children underwent anthropometry and clinical assessment by a study physician within 72 h of enrolment, and caregivers provided sociodemographic data. Children were followed-up daily until discharge/death. A multivariable survival analysis identified the baseline factors independently associated with mortality. Results 70/745 (9.4%) children died in hospital. Age between 6–23 months [aHR 6.53, 95%CI 2.24–19.02], higher mid-upper arm circumference [aHR 0.73, 95%CI 0.59–0.89], presence of oedema [aHR 2.22, 95%CI 1.23–4.05], shock [aHR 8.18, 95%CI 3.79–17.65], sepsis [aHR 3.13, 95%CI 1.44–6.80], persistent diarrhoea [aHR 2.27, 95%CI 1.18–4.37], lack of a toilet at home [aHR 4.35, 95%CI 1.65–11.47], and recruitment at one Harare site [aHR 0.38, 95%CI 0.18–0.83] were all independently associated with inpatient mortality. Oedematous children had a significantly higher birthweight [2987 g vs 2757 g, p < 0.001] than those without oedema; higher birthweight was weakly associated with mortality [aHR 1.50 95%CI 0.97–2.31]. Conclusions Children with oedema, low MUAC, baseline infections, shock and lack of home sanitation had a significantly increased risk of inpatient mortality following hospitalisation for complicated SAM. Children with high-risk features may require additional care. A better understanding of the pathophysiology of SAM is needed to identify adjunctive interventions.

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.

Abstract HIV and severe wasting are associated with post-discharge mortality and hospital readmission among children with complicated severe acute malnutrition (SAM); however, the reasons remain unclear. We assessed body composition at hospital discharge, stratified by HIV and oedema status, in a cohort of children with complicated SAM in three hospitals in Zambia and Zimbabwe. We measured skinfold thicknesses and bioelectrical impedance analysis (BIA) to investigate whether fat and lean mass were independent predictors of time to death or readmission. Cox proportional hazards models were used to estimate the association between death/readmission and discharge body composition. Mixed effects models were fitted to compare longitudinal changes in body composition over 1 year. At discharge, 284 and 546 children had complete BIA and skinfold measurements, respectively. Low discharge lean and peripheral fat mass were independently associated with death/hospital readmission. Each unit Z-score increase in impedance index and triceps skinfolds was associated with 48 % (adjusted hazard ratio 0·52, 95 % CI (0·30, 0·90)) and 17 % (adjusted hazard ratio 0·83, 95 % CI (0·71, 0·96)) lower hazard of death/readmission, respectively. HIV-positive v. HIV-negative children had lower gains in sum of skinfolds (mean difference −1·49, 95 % CI (−2·01, −0·97)) and impedance index Z-scores (–0·13, 95 % CI (−0·24, −0·01)) over 52 weeks. Children with non-oedematous v. oedematous SAM had lower mean changes in the sum of skinfolds (–1·47, 95 % CI (−1·97, −0·97)) and impedance index Z-scores (–0·23, 95 % CI (−0·36, −0·09)). Risk stratification to identify children at risk for mortality or readmission, and interventions to increase lean and peripheral fat mass, should be considered in the post-discharge care of these children.

Abstract Nutritional recovery and hospital readmission following inpatient management of complicated severe acute malnutrition (SAM) are poorly characterised. We aimed to ascertain patterns and factors associated with hospital readmission, nutritional recovery and morbidity, in children discharged from hospital following management of complicated SAM in Zambia and Zimbabwe over 52‐weeks posthospitalization. Multivariable Fine‐Gray subdistribution hazard models, with death and loss to follow‐up as competing risks, were used to identify factors associated with hospital readmission; negative binomial regression to assess time to hospitalisation and ordinal logistic regression to model factors associated with nutritional recovery. A total of 649 children (53% male, median age 18.2 months) were discharged to continue community nutritional rehabilitation. All‐cause hospital readmission was 15.4% (95% CI 12.7, 18.6) over 52 weeks. Independent risk factors for time to readmission were cerebral palsy (adjusted subhazard ratio (aSHR): 2.96, 95% CI 1.56, 5.61) and nonoedematous SAM (aSHR: 1.64, 95%CI 1.03, 2.64). Unit increases in height‐for‐age Z‐score (HAZ) (aSHR: 0.82, 95% CI 0.71, 0.95) and enrolment in Zambia (aSHR: 0.52, 95% CI 0.28, 0.97) were associated with reduced subhazard of time to readmission. Young age, SAM at discharge, nonoedematous SAM and cerebral palsy were associated with poor nutritional recovery throughout follow‐up. Collectively, nonoedematous SAM, ongoing SAM at discharge, cerebral palsy and low HAZ are independent risk factors for readmission and poor nutritional recovery following complicated SAM. Children with these high‐risk features should be prioritised for additional convalescent care to improve long‐term outcomes.

Children who initiate antiretroviral therapy (ART) before age 5 years can recover height and weight compared to uninfected peers, but growth outcomes are unknown for children initiating ART at older ages. We investigated factors associated with growth failure at ART initiation and modelled growth by age on ART. We conducted secondary analysis of cohort of children aged 6–15 years late-diagnosed with HIV in Harare, Zimbabwe, with entry at ART initiation in 2013–2015. Factors associated with height-for-age (HAZ), weight-for-age (WAZ) and BMI-for-age (BAZ) z-scores <− 2 (stunting, underweight and wasting respectively) at ART initiation were assessed using multivariable logistic regression. These outcomes were compared at ART initiation and 12 month follow-up using paired t-tests. HAZ and BAZ were modelled using restricted cubic splines. Participants (N = 302; 51.6% female; median age 11 years) were followed for a median of 16.6 months (IQR 11.0–19.8). At ART initiation 34.8% were stunted, 34.5% underweight and 15.1% wasted. Stunting was associated with age ≥ 12 years, CD4 count < 200 cells/μl, tuberculosis (TB) history and history of hospitalisation. Underweight was associated with older age, male sex and TB history, and wasting was associated with older age, TB history and hospitalisation. One year post-initiation, t-tests showed increased WAZ (p = 0.007) and BAZ (p = 0.004), but no evidence of changed HAZ (p = 0.85). Modelling showed that HAZ and BAZ decreased in early adolescence for boys on ART, but not girls. Stunting and underweight were prevalent at ART initiation among late-diagnosed children, and HAZ did not improve after 1 year. Adolescent boys with perinatally acquired HIV and late diagnosis are particularly at risk of growth failure in puberty.

Background: During February 25-March 4, 2019, Zimbabwe's Ministry of Health and Child Care conducted an emergency campaign using 342,000 doses of typhoid conjugate vaccine (TCV) targeting individuals 6 months-15 years of age in eight high-risk suburbs of Harare and up to 45 years of age in one suburb of Harare. The campaign represented the first use of TCV in Africa outside of clinical trials. Methods: Three methods were used to capture adverse events during the campaign and for 42 days following the last dose administered: (1) active surveillance in two Harare hospitals, (2) national passive surveillance, and (3) a post-campaign coverage survey. Results: Thirty-nine adverse events were identified during active surveillance, including 19 seizure cases (16 were febrile), 16 hypersensitivity cases, 1 thrombocytopenia case, 1 anaphylaxis case, and two cases with two conditions. Only 21 (54%) of 39 patients were hospitalized and 38 recovered without sequelae. Attack rates per 100,000 TCV doses administered were highest for seizures (6.27) and hypersensitivity (5.02). Only 6 adverse events were reported through passive surveillance by facilities other than the two active surveillance hospitals. A total of 177 (10%) of 1,817 vaccinees surveyed reported experiencing an adverse event during the post-campaign coverage survey, of which 25 (14%) sought care. Conclusions: In line with previous evaluations of TCV, enhanced adverse event monitoring during an emergency campaign supports the safety of TCV. The majority of reported events were minor or resulted in recovery without long-term sequelae. Attack rates for seizures and hypersensitivity were low compared with previous active surveillance studies conducted in Kenya and Burkina Faso. Strengthening adverse event monitoring in Zimbabwe and establishing background rates of conditions of interest in the general population may improve future safety monitoring during new vaccine introductions. (C) 2022 Published by Elsevier Ltd.

Background Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. Methods ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing >= 14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (>= 14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127. Findings Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1.4 years (IQR 0.6-2.0) and median weight 8.1 kg (5.4-10.0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0.020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0.057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1.08 [95% CI 0.47-2.49]; p=0.86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0.93 [0.50-1.74]; p=0.83). No events were considered related to dolutegravir. Interpretation Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

Objective methods of measuring antiretroviral adherence are limited. We assessed the relationship between tenofovir disoproxil fumarate (TDF) hair concentrations, self-reported adherence, and virological outcomes in HIV-infected adolescents in Harare, Zimbabwe. HIV-infected adolescents on atazanavir/ritonavir-based second-line treatment for >6 months with viral load (VL) >= 1,000 copies/mL were randomized to either modified directly administered antiretroviral therapy (mDAART) or standard of care. Hair and VL samples were collected at baseline and after 90 days. Treatment outcome was defined as TDF concentrations in hair. Virological suppression was defined as VL <1,000 copies/mL. Thirty-four adolescents had TDF concentrations measured at baseline and follow-up. Mean (median); range age was 16 (16); 13-18 years and 53% were females. Nineteen (56%) were randomized to mDAART. Mean (SD); range TDF concentrations were 0.03 (0.04); 0-0.17 ng/mg hair and 0.06 (0.06); 0-0.3 ng/mg hair at baseline and follow-up, respectively. Higher TDF concentrations were associated with decreased VL [regression coefficient (RC) 0.8; 95% confidence interval (CI) 0.7-1.0; p = .008] and mDAART (RC 0.5; 95% CI 0.3-1.0; p = .04), but were not associated with self-reported adherence and virological suppression (VL <1,000 copies/mL). Higher TDF hair concentrations were observed with virological decrease and an adherence intervention. Hair antiretroviral concentrations could be useful in triggering adherence interventions among adolescents with second-line virological failure.

Background: Children discharged from hospital following management of complicated severe acute malnutrition (SAM) have a high risk of mortality, especially HIV-positive children. Few studies have examined mortality in the antiretroviral therapy (ART) era. Objectives: Our objectives were to ascertain 52-wk mortality in children discharged from hospital for management of complicated SAM, and to identify independent predictors of mortality. Methods: A prospective cohort study was conducted in children enrolled from 3 hospitals in Zambia and Zimbabwe between July 2016 and March 2018. The primary outcome was mortality at 52 wk. Univariable and multivariable Cox regression models were used to identify independent risk factors for death, and to investigate whether HIV modifies these associations. Results: Of 745 children, median age at enrolment was 17.4 mo (IQR: 12.8. 22.1 mo), 21.7% were HIV-positive, and 64.4% had edema. Seventy children (9.4%; 95% CI: 7.4, 11.7%) died and 26 exited during hospitalization; 649 were followed postdischarge. At discharge, 43.9% had ongoing SAM and only 50.8% of HIV-positive children were receiving ART. Vital status was ascertained for 604 (93.1%), of whom 55 (9.1%; 95% CI: 6.9, 11.7%) died at median 16.6 wk (IQR: 9.4, 21.9 wk). Overall. 20.0% (95% CI: 13.5. 27.9%) and 5.6% (95% CI: 3.8, 7.9%) of HIV-positive and IIW-negative children, respectively, died [adjusted hazard ratio (aHR): 3.83; 95% CI: 2.15, 6.82]. Additional independent risk factors for mortality were ongoing SAM (aHR: 2.28; 95% CI: 1.22, 4.25), cerebral palsy (aHR: 5.60; 95% CI: 2.72, 1150) and nonedematous SAM (aHR: 2.23: 95% Cl: 1.24, 4.01), with no evidence of interaction with HIV status. Conclusions: HIV-positive children have an almost 4-fold higher mortality than HIV-negative children in the year following hospitalization for complicated SAM. A better understanding of causes of death, an improved continuum of care for HIV and SAM, and targeted interventions to improve convalescence are needed.

BACKGROUND:Suboptimal adherence to antiretroviral therapy (ART) is responsible for most virologic failure among adolescents with HIV. Methods for objectively measuring adherence to ART are limited. This study assessed the association between ritonavir concentrations in hair and self-reported adherence and modified directly administered ART on virologic outcomes among HIV-infected adolescents who were virologically failing second-line ART in Harare, Zimbabwe. METHODS:HIV-infected adolescents on atazanavir-based or ritonavir-based second-line treatment for >6 months with viral load ≥1000 copies/mL were randomized to either modified directly administered ART (mDAART) plus standard of care (intervention) or standard of care alone (control). Questionnaires were administered; viral load and hair samples were collected at baseline and after 90 days. Virological suppression was defned as <1000 copies/mL after follow-up. RESULTS:Fifty adolescents (13-19 years) were enrolled in the study, and 42 adolescents had ritonavir concentrations measured in hair at baseline and at 90 days. Twenty-three participants (46%) were randomized to mDAART. Viral load suppression at follow-up [regression coefficient (standard error): -0.3 (0.1); 95% confidence interval (CI): -0.5 to -0.06; P = 0.01], self-reported adherence at follow-up [regression coefficient (standard error): 0.01 (0.005); 95% CI: 0.004 to 0.02; P = 0.006], and being male sex [regression coefficient (standard error): 0.3 (0.1); 95% CI: 0.08 to 0.5; P = 0.008] were associated with ritonavir concentrations in hair. The intervention, mDAART, was not associated with ritonavir concentrations [regression coefficient (standard error) 0.2 (0.1); 95% CI: -0.07 to 0.4; P = 0.2]. CONCLUSIONS:Ritonavir concentrations in hair predicted virological suppression and were associated with self-reported adherence and being male in this cohort of adolescents with treatment failure to atazanavir-based or ritonavir-based second-line ART. Measuring ritonavir concentrations in hair in adolescents on protease inhibitor-based regimens could assess adherence in this vulnerable group to avert subsequent virologic failure.

Background: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. Materials and methods: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC 0–12h ) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. Results: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) −3.4 (IQR −4.0, −3.0) and 27 non-SAM had median WHZ −1.0 (IQR −1.8, −0.1). No significant differences in mean AUC 0–12h or CL/F were observed ( P ≥ 0.09) except for lower 3TC AUC 0–12h (GMR, 0.60; 95% CI, 0.4–1.0; P = 0.047) at week 12, higher ZDV AUC 0–12h (GMR, 1.52; 1.2–2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). Conclusion: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.