Publications by authors named "Diana M Gibb"

180 Publications

Incidence and predictors of hospital readmission in children presenting with severe anaemia in Uganda and Malawi: a secondary analysis of TRACT trial data.

BMC Public Health 2021 Jul 29;21(1):1480. Epub 2021 Jul 29.

MRC Clinical Trials Unit at University College London, 90 High Holborn, London, WC1V 6LJ, UK.

Background: Severe anaemia (haemoglobin < 6 g/dL) is a leading cause of recurrent hospitalisation in African children. We investigated predictors of readmission in children hospitalised with severe anaemia in the TRACT trial (ISRCTN84086586) in order to identify potential future interventions.

Methods: Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering.

Results: Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63-3.78), p < 0.001); ≥2 hospital admissions in the preceding 12 months (1.44(1.19-1.74), p < 0.001); history of transfusion (1.48(1.13-1.93), p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21-1.69), p < 0.001). Children with uncomplicated severe anaemia (Hb 4-6 g/dL and no severity features), who never received a transfusion (per trial protocol) during the initial admission had a substantially lower risk of readmission (0.67(0.47-0.96), p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47-0.76), p < 0.001); younger-age (1.07 (1.03-1.10) per 1 year younger, p < 0.001) and known sickle cell disease (0.62(0.46-0.82), p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23-2.44) and 1.46(1.18-1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria.

Conclusions: Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important.

Trial Registration: ISRCTN ISRCTN84086586 .
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http://dx.doi.org/10.1186/s12889-021-11481-6DOI Listing
July 2021

Gastroenteritis Rehydration Of children with Severe Acute Malnutrition (GASTROSAM): A Phase II Randomised Controlled trial: Trial Protocol.

Wellcome Open Res 2021 23;6:160. Epub 2021 Jun 23.

Clinical Trials Facility, KEMRI-Wellcome Trust Research Programme, Kilifi, PO Box 230, Kenya.

Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea ( 3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial is the first step in reappraising current recommendations. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. An open Phase II trial, with a partial factorial design, enrolling Ugandan and Kenyan children aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration.  In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or  WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)).  Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is urine output (mls/kg/hour at 8 hours post-randomisation), and for oral rehydration a change in sodium levels at 24 hours post-randomisation. This trial will also generate feasibility, safety and preliminary data on survival to 28 days. . If current rehydration strategies for non-malnourished children are safe in SAM this could prompt future evaluation in Phase III trials.
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http://dx.doi.org/10.12688/wellcomeopenres.16885.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276193PMC
June 2021

The impact of viraemia on inflammatory biomarkers and CD4+ cell subpopulations in HIV-infected children in sub-Saharan Africa.

AIDS 2021 Aug;35(10):1537-1548

UCL Great Ormond Street Institute of Child Health.

Objective: To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa.

Design: Longitudinal cohort study.

Methods: In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events.

Results: Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression.

Conclusions: As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.
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http://dx.doi.org/10.1097/QAD.0000000000002916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611315PMC
August 2021

Transfusion management of severe anaemia in African children: a consensus algorithm.

Br J Haematol 2021 Jun 6;193(6):1247-1259. Epub 2021 May 6.

Medical Research Council Clinical Trials Unit (MRC CTU), University College London, London, UK.

The phase III Transfusion and Treatment of severe anaemia in African Children Trial (TRACT) found that conservative management of uncomplicated severe anaemia [haemoglobin (Hb) 40-60 g/l] was safe, and that transfusion volume (20 vs. 30 ml/kg whole blood equivalent) for children with severe anaemia (Hb <60 g/l) had strong but opposing effects on mortality, depending on fever status (>37·5°C). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all 3196 children receiving an initial transfusion there was no evidence that nutritional status, presence of shock, malaria parasite burden or sickle cell disease status influenced outcomes or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating three additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practice.
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http://dx.doi.org/10.1111/bjh.17429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611319PMC
June 2021

Defeating Paediatric Tuberculous Meningitis: Applying the WHO "Defeating Meningitis by 2030: Global Roadmap".

Microorganisms 2021 Apr 16;9(4). Epub 2021 Apr 16.

MRC Clinical Trials Unit at UCL, 90 High Holborn, Holborn, London WC1V 6LJ, UK.

Children affected by tuberculous meningitis (TBM), as well as their families, have needs that lie at the intersections between the tuberculosis and meningitis clinical, research, and policy spheres. There is therefore a substantial risk that these needs are not fully met by either programme. In this narrative review article, we use the World Health Organization (WHO) "Defeating Meningitis by 2030: global roadmap" as a starting point to consider key goals and activities to specifically defeat TBM in children. We apply the five pillars outlined in the roadmap to describe how this approach can be adapted to serve children affected by TBM. The pillars are (i) prevention; (ii) diagnosis and treatment; (iii) surveillance; (iv) support and care for people affected by meningitis; and (v) advocacy and engagement. We conclude by calling for greater integration between meningitis and TB programmes at WHO and at national levels.
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http://dx.doi.org/10.3390/microorganisms9040857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073113PMC
April 2021

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.

BMC Infect Dis 2021 Jan 4;21(1). Epub 2021 Jan 4.

Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom.

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.
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http://dx.doi.org/10.1186/s12879-020-05672-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809782PMC
January 2021

Benefits of enhanced infection prophylaxis at antiretroviral therapy initiation by cryptococcal antigen status.

AIDS 2021 03;35(4):585-594

MRC CTU at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK.

Objectives: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial.

Design: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/μl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole).

Methods: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity.

Results: Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratio = 0.36 (95% confidence interval 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratio = 0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneity = 0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneity > 0.3).

Conclusion: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.
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http://dx.doi.org/10.1097/QAD.0000000000002781DOI Listing
March 2021

Brief Report: Cessation of Long-Term Cotrimoxazole Prophylaxis in HIV-Infected Children Does Not Alter the Carriage of Antimicrobial Resistance Genes.

J Acquir Immune Defic Syndr 2020 12;85(5):601-605

School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Cotrimoxazole (CTX) is a broad-spectrum antimicrobial, combining trimethoprim and sulfamethoxazole. CTX prophylaxis reduces mortality and morbidity among people living with HIV in regions with high prevalence of bacterial infections and malaria. The Antiretroviral research for Watoto trial evaluated the effect of stopping versus continuing CTX prophylaxis in sub-Saharan Africa.

Methods: In this study, 72 HIV-infected Zimbabwean children, on antiretroviral therapy, provided fecal samples at 84 and 96 weeks after randomization to continue or stop CTX. DNA was extracted for whole metagenome shotgun sequencing, with sequencing reads mapped to the Comprehensive Antibiotic Resistance Database to identify CTX and other antimicrobial resistance genes.

Results: There were minimal differences in the carriage of CTX resistance genes between groups. The dfrA1 gene, conferring trimethoprim resistance, was significantly higher in the continue group (P = 0.039) and the tetA(P) gene conferring resistance to tetracycline was significantly higher in the stop group (P = 0.013). CTX prophylaxis has a role in shaping the resistome; however, stopping prophylaxis does not decrease resistance gene abundance.

Conclusions: No differences were observed in resistance gene carriage between the stop and continue groups. The previously shown multi-faceted protective effects of CTX in antiretroviral research for Watoto trial clinical outcomes are not outweighed by the risk of multi-drug resistance gene selection due to prophylaxis. These findings are reassuring, given current recommendations for long-term CTX prophylaxis among children living with HIV in sub-Saharan Africa to decrease mortality and morbidity.
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http://dx.doi.org/10.1097/QAI.0000000000002489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654951PMC
December 2020

Comparison of Lymphocyte Subset Populations in Children From South Africa, US and Europe.

Front Pediatr 2020 23;8:406. Epub 2020 Jul 23.

UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

Typically, African healthcare providers use immunological reference intervals adopted from Europe and the United States (US). This may be inappropriate in a setting with many differences including exposure to different environmental stimuli and pathogens. We compared immunological reference intervals for children from Europe and the US with South African children to explore whether healthy children living in settings with high rates of infectious diseases have different baseline immunological parameters. Blood was taken from 381 HIV-uninfected children aged between 2 weeks and 13 years of age from a Child Wellness Clinic in an informal settlement in Cape Town to establish local hematological and lymphocyte reference intervals for South African children. Flow-cytometry quantified percentage and absolute counts of the B-cells, NK-cells, and T-cells including activated, naïve, and memory subsets. These parameters were compared to three separate studies of healthy children in Europe and the US. Increased activated T-cells, and natural killer cells were seen in the younger age-groups. The main finding across all age-groups was that the ratio of naïve/memory CD4 and CD8 T-cells reached a 1:1 ratio around the first decade of life in healthy South African children, far earlier than in resource-rich countries, where it occurs around the fourth decade of life. This is the largest data set to date describing healthy children from an African environment. These data have been used to create local reference intervals for South African children. The dramatic decline in the naïve/memory ratio of both CD4 and CD8 T-cells alongside increased activation markers may indicate that South African children are exposed to a wider range of environmental pathogens in early life than in resource-rich countries. These marked differences illustrate that reference intervals should be relevant to the population they serve. The implications for the developing pediatric immune system requires further investigation.
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http://dx.doi.org/10.3389/fped.2020.00406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390891PMC
July 2020

Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial.

Lancet HIV 2020 08;7(8):e533-e544

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, Netherlands.

Background: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV.

Methods: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (C) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses.

Findings: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) C (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM C of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM C was 0·39 mg/L (48%), which was 54% lower than the GM C in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM C was 0·46 mg/L (63%), which was 45% lower than the GM C in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, C was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir.

Interpretation: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg.

Funding: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.
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http://dx.doi.org/10.1016/S2352-3018(20)30189-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445428PMC
August 2020

Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy.

PLoS One 2020 9;15(7):e0233877. Epub 2020 Jul 9.

MRC Clinical Trials Unit at UCL, UCL Institute for Clinical Trials and Methodology, London, England, United Kingdom.

Background: The impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear.

Methods: In the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications.

Results: In simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction.

Discussion: This study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233877PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347189PMC
September 2020

Accuracy of Xpert Ultra in Diagnosis of Pulmonary Tuberculosis among Children in Uganda: a Substudy from the SHINE Trial.

J Clin Microbiol 2020 08 24;58(9). Epub 2020 Aug 24.

MRC Clinical Trials Unit, University College London, London, United Kingdom.

Childhood tuberculosis (TB) presents significant diagnostic challenges associated with paucibacillary disease and requires a more sensitive test. We evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial. SHINE is a randomized trial evaluating shorter treatment in 1,204 children with minimal TB disease in Africa and India. Among 352 samples and one cervical lymph node fine needle aspirate, one sample was randomly selected per patient and tested with the Xpert MTB/RIF assay (Xpert) and with Lowenstein-Jensen medium (LJ) and liquid mycobacterial growth indicator tube (MGIT) cultures. We selected only uncontaminated stored sample pellets for Ultra testing. We estimated the sensitivity of Xpert and Ultra against culture and a composite microbiological reference standard (any positive result). Of 398 children, 353 (89%) had culture, Xpert, and Ultra results. The median age was 2.8 years (interquartile range [IQR], 1.3 to 5.3); 8.5% (30/353) were HIV infected, and 54.4% (192/353) were male. Of the 353, 31 (9%) were positive by LJ and/or MGIT culture, 36 (10%) by Ultra, and 16 (5%) by Xpert. Sensitivities (95% confidence intervals [CI]) were 58% (39 to 65% [18/31]) for Ultra and 45% (27 to 64% [14/31]) for Xpert against any culture-positive result, with false positives of <1% and 5.5% for Xpert and Ultra. Against a composite microbiological reference, sensitivities were 72% (58 to 84% [36/50]) for Ultra and 32% (20 to 47% [16/50]) for Xpert. However, there were 17 samples that were positive only with Ultra (majority trace). Among children screened for minimal TB in Uganda, Ultra has higher sensitivity than Xpert. This represents an important advance for a condition which has posed a diagnostic challenge for decades.
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http://dx.doi.org/10.1128/JCM.00410-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448651PMC
August 2020

Factors Associated With Nonadherence to Antiretroviral Therapy Among Young People Living With Perinatally Acquired HIV in England.

J Assoc Nurses AIDS Care 2020 Sep-Oct;31(5):574-586

Young people living with perinatally acquired HIV may be at risk of poor adherence to antiretroviral therapy; identification of predictors, using a conceptual framework approach proposed previously by others, is important to identify those at higher risk. In 261 young people with perinatally acquired HIV in England, 70 (27%) reported 3-day nonadherence, 82 (31%) last month nonadherence, and 106 (41%) nonadherence on either measure. Of those reporting nonadherence on both measures, 52% (23/44) had viral load of <50 copies/ml, compared with 88% (127/145) of those reported being fully adherent. In multivariable analysis, young person and medication theme factors were associated with nonadherence. The main predictors of 3-day nonadherence were antiretroviral therapy containing a boosted protease inhibitor and poorer quality of life. Predictors of last month nonadherence were having told more people about one's HIV status, worse self-perception about having HIV, and boosted protease inhibitor-based regimens. The consistency of individual young person and medication factors in predicting nonadherence gives insight into where interventions may best be targeted to improve adherence.
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http://dx.doi.org/10.1097/JNC.0000000000000171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497417PMC
February 2021

Neuroimaging young children and associations with neurocognitive development in a South African birth cohort study.

Neuroimage 2020 10 15;219:116846. Epub 2020 Apr 15.

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, South Africa; Neuroscience Institute, University of Cape Town, South Africa.

Magnetic resonance imaging (MRI) is an indispensable tool for investigating brain development in young children and the neurobiological mechanisms underlying developmental risk and resilience. Sub-Saharan Africa has the highest proportion of children at risk of developmental delay worldwide, yet in this region there is very limited neuroimaging research focusing on the neurobiology of such impairment. Furthermore, paediatric MRI imaging is challenging in any setting due to motion sensitivity. Although sedation and anesthesia are routinely used in clinical practice to minimise movement in young children, this may not be ethical in the context of research. Our study aimed to investigate the feasibility of paediatric multimodal MRI at age 2-3 years without sedation, and to explore the relationship between cortical structure and neurocognitive development at this understudied age in a sub-Saharan African setting. A total of 239 children from the Drakenstein Child Health Study, a large observational South African birth cohort, were recruited for neuroimaging at 2-3 years of age. Scans were conducted during natural sleep utilising locally developed techniques. T1-MEMPRAGE and T2-weighted structural imaging, resting state functional MRI, diffusion tensor imaging and magnetic resonance spectroscopy sequences were included. Child neurodevelopment was assessed using the Bayley-III Scales of Infant and Toddler Development. Following 23 pilot scans, 216 children underwent scanning and T1-weighted images were obtained from 167/216 (77%) of children (median age 34.8 months). Furthermore, we found cortical surface area and thickness within frontal regions were associated with cognitive development, and in temporal and frontal regions with language development (beta coefficient ≥0.20). Overall, we demonstrate the feasibility of carrying out a neuroimaging study of young children during natural sleep in sub-Saharan Africa. Our findings indicate that dynamic morphological changes in heteromodal association regions are associated with cognitive and language development at this young age. These proof-of-concept analyses suggest similar links between the brain and cognition as prior literature from high income countries, enhancing understanding of the interplay between cortical structure and function during brain maturation.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443699PMC
October 2020

The cost-effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa.

J Int AIDS Soc 2020 03;23(3):e25469

Centre for Health Economics, University of York, York, UK.

Introduction: Many HIV-positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced-prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 <100 cells/mm . We investigated the cost-effectiveness of this enhanced-prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4 <200 cells/mm or <100 cells/mm at ART initiation and all individuals regardless of CD4 count.

Methods: The REALITY trial enrolled from June 2013 to April 2015. A decision-analytic model was developed to estimate the cost-effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard-prophylaxis, enhanced-prophylaxis, standard-prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced-prophylaxis (CrAg-positive) or standard-prophylaxis (CrAg-negative), the second to enhanced-prophylaxis (CrAg-positive) or enhanced-prophylaxis without fluconazole (CrAg-negative) and the third to standard-prophylaxis with fluconazole (CrAg-positive) or without fluconazole (CrAg-negative). The model estimated costs, life-years and quality-adjusted life-years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause.

Results: Enhanced-prophylaxis was cost-effective at cost-effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost-effectiveness ratio (ICER) of US$157 per QALY in the CD4 <200 cells/mm population providing enhanced-prophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4 <100 cells/mm population) and increased in all individuals regardless of CD4 count (US$722 per QALY). Results were sensitive to prices of the enhanced-prophylaxis components. Enhanced-prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced-prophylaxis still conveyed health gains in CrAg-negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost-effective unless the price of CrAg testing fell below US$2.30.

Conclusions: The REALITY enhanced-prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost-effective. Efforts should continue to ensure that components are accessed at lowest available prices.
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http://dx.doi.org/10.1002/jia2.25469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099175PMC
March 2020

Mortality risk over time after early fluid resuscitation in African children.

Crit Care 2019 11 27;23(1):377. Epub 2019 Nov 27.

Medical Research Council Clinical Trials Unit (MRC CTU) at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK.

Background: African children hospitalised with severe febrile illness have a high risk of mortality. The Fluid Expansion As Supportive Therapy (FEAST) trial (ISCRTN 69856593) demonstrated increased mortality risk associated with fluid boluses, but the temporal relationship to bolus therapy and underlying mechanism remains unclear.

Methods: In a post hoc retrospective analysis, flexible parametric models were used to compare change in mortality risk post-randomisation in children allocated to bolus therapy with 20-40 ml/kg 5% albumin or 0.9% saline over 1-2 h or no bolus (control, 4 ml/kg/hour maintenance), overall and for different terminal clinical events (cardiogenic, neurological, respiratory, or unknown/other).

Results: Two thousand ninety-seven and 1041 children were randomised to bolus vs no bolus, of whom 254 (12%) and 91 (9%) respectively died within 28 days. Median (IQR) bolus fluid in the bolus groups received by 4 h was 20 (20, 40) ml/kg and was the same at 8 h; total fluids received in bolus groups at 4 h and 8 h were 38 (28, 43) ml/kg and 40 (30, 50) ml/kg, respectively. Total fluid volumes received in the control group by 4 h and 8 h were median (IQR) 10 (6, 15) ml/kg and 10 (10, 26) ml/kg, respectively. Mortality risk was greatest 30 min post-randomisation in both groups, declining sharply to 4 h and then more slowly to 28 days. Maximum mortality risk was similar in bolus and no bolus groups; however, the risk declined more slowly in the bolus group, with significantly higher mortality risk compared to the no bolus group from 1.6 to 101 h (4 days) post-randomisation. The delay in decline in mortality risk in the bolus groups was most pronounced for cardiogenic modes of death.

Conclusions: The increased risk from bolus therapy was not due to a mechanism occurring immediately after bolus administration. Excess mortality risk in the bolus group resulted from slower decrease in mortality risk over the ensuing 4 days. Thus, administration of modest bolus volumes appeared to prevent mortality risk declining at the same rate that it would have done without a bolus, rather than harm associated with bolus resulting from a concurrent increased risk of death peri-bolus administration.

Trial Registration: ISRCTN69856593. Date of registration 15 December 2008.
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http://dx.doi.org/10.1186/s13054-019-2619-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882199PMC
November 2019

Growth and Neurodevelopment of HIV-Exposed Uninfected Children: a Conceptual Framework.

Curr HIV/AIDS Rep 2019 12;16(6):501-513

Blizard Institute, Queen Mary University of London, London, UK.

Purpose Of Review: The population of HIV-exposed uninfected (HEU) children is expanding rapidly, and over one million HEU infants are born each year globally. Several recent studies have reported that HEU children, particularly in low- and middle-income countries, are at risk of poor outcomes, including impaired growth and neurodevelopment. However, the reasons for poor clinical outcomes amongst HEU children remain unclear.

Recent Findings: We summarise the findings from recent large studies that have characterised growth and neurodevelopment in HEU children, identified risk factors and explored underlying mechanistic pathways. We propose a conceptual framework to explain how exposure to HIV and antiretroviral therapy (ART) may lead to adverse growth and neurodevelopment in uninfected children, and review the available evidence and research gaps. We propose that HEU children are affected both indirectly, through the augmentation of universal risk factors underlying poor growth and neurodevelopment, and directly through HIV/ART-specific pathways, which ultimately may converge through a series of common pathogenic mechanisms. In the era of universal ART, a better understanding of these pathways is crucial to inform future prevention and intervention strategies.
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http://dx.doi.org/10.1007/s11904-019-00459-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920255PMC
December 2019

Changes over time in creatinine clearance and comparison of emergent adverse events for HIV-positive adults receiving standard doses (300 mg/day) of lamivudine-containing antiretroviral therapy with baseline creatinine clearance of 30-49 vs ≥50 mL/min.

PLoS One 2019 14;14(11):e0225199. Epub 2019 Nov 14.

Medical Affairs, ViiV Healthcare, Research Triangle Park, NC, United States of America.

A retrospective analysis of the randomized controlled DART (Development of AntiRetroviral Therapy in Africa; ISRCTN13968779) trial in HIV-1-positive adults initiating antiretroviral therapy with co-formulated zidovudine/lamivudine plus either tenofovir, abacavir, or nevirapine was conducted to evaluate the safety of initiating standard lamivudine dosing in patients with impaired creatinine clearance (CLcr). Safety data collected through 96 weeks were analyzed after stratification by baseline CLcr (estimated using Cockcroft-Gault) of 30-49 mL/min (n = 168) versus ≥50 mL/min (n = 3,132) and treatment regimen. The Grade 3-4 adverse events (AEs) and serious AEs (for hematological, hepatic and gastrointestinal events), maximal toxicities for liver enzymes, serum creatinine and bilirubin and maximum treatment-emergent hematology toxicities were comparable for groups with baseline CLcr 30-49 versus CLcr≥50 mL/min. No new risks or trends were identified from this dataset. Substantial and similar increases in the mean creatinine clearance (>25 mL/min) were observed from baseline though Week 96 among participants who entered the trial with CLcr 30-49 mL/min, while no increase or smaller median changes in creatinine clearance (<7 mL/min) were observed for participants who entered the trial with CLcr ≥50 mL/min. Substantial increases (> 150 cells/ mm3) in mean CD4+ cells counts from baseline to Week 96 were also observed for participants who entered the trial with CLcr 30-49 mL/min and those with baseline CLcr ≥50 mL/min. Though these results are descriptive, they suggest that HIV-positive patients with CLcr of 30-49 mL/min would have similar AE risks in comparison to patients with CLcr ≥50 mL/min when initiating antiretroviral therapy delivering doses of 300 mg of lamivudine daily through 96 weeks of treatment. Overall improvements in CLcr were observed for patients with baseline CLcr 30-49 mL/min.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225199PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855468PMC
March 2020

Secondary re-analysis of the FEAST trial.

Lancet Respir Med 2019 10;7(10):e29

Medical Research Council Clinical Trials Unit at University College London, London, UK.

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http://dx.doi.org/10.1016/S2213-2600(19)30272-3DOI Listing
October 2019

Co-trimoxazole or multivitamin multimineral supplement for post-discharge outcomes after severe anaemia in African children: a randomised controlled trial.

Lancet Glob Health 2019 10;7(10):e1435-e1447

Medical Research Council Clinical Trials Unit at University College London.

Background: Severe anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes.

Methods: Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second non-sequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete.

Findings: From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79-1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86-1·32; p=0·56). We found no evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180, 489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate group (HR 0·95, 95% CI 0·84-1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children in the no co-trimoxazole group (1·01, 0·89-1·15; p=0·85) had had one or more serious adverse events. Most serious adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions).

Interpretation: Neither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa.

Funding: Medical Research Council and Department for International Development.
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http://dx.doi.org/10.1016/S2214-109X(19)30345-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024999PMC
October 2019

Neurodevelopment of HIV-exposed uninfected children in South Africa: outcomes from an observational birth cohort study.

Lancet Child Adolesc Health 2019 11 9;3(11):803-813. Epub 2019 Sep 9.

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.

Background: HIV infection is known to cause developmental delay, but the effects of HIV exposure without infection during pregnancy on child development are unclear. We compared the neurodevelopmental outcomes of HIV-exposed uninfected and HIV-unexposed children during their first 2 years of life.

Methods: Pregnant women (>18 years of age) at 20-28 weeks' gestation were enrolled into the Drakenstein Child Health cohort study while attending routine antenatal appointments at one of two peri-urban community-based clinics in Paarl, South Africa. Livebirths born to enrolled women during follow-up were included in the birth cohort. Mothers and infants received antenatal and postnatal HIV testing and antiretroviral therapy per local guidelines. Developmental assessments on the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), were done in a subgroup of infants at 6 months of age, and in the full cohort at 24 months of age, with assessors masked to HIV exposure status. Mean raw scores and the proportions of children categorised as having a delay (scores <-2 SDs from the reference mean) on BSID-III were compared between HIV-exposed uninfected and HIV-unexposed children.

Findings: 1225 women were enrolled between March 5, 2012, and March 31, 2015. Of 1143 livebirths, 1065 (93%) children were in follow-up at 6 months and 1000 (87%) at 24 months. Two children were diagnosed with HIV infection between birth and 24-month follow-up and were excluded from the analysis. BSID-III assessments were done in 260 (24%) randomly selected children (61 HIV-exposed uninfected, 199 HIV-unexposed) at 6 months and in 732 (73%) children (168 HIV-exposed uninfected, 564 HIV-unexposed) at 24 months. All HIV-exposed uninfected children were exposed to antiretrovirals (88% to maternal triple antiretroviral therapy). BSID-III outcomes did not significantly differ between HIV-exposed uninfected and HIV-unexposed children at 6 months. At 24 months, HIV-exposed uninfected children scored lower than HIV-unexposed for receptive language (adjusted mean difference -1·03 [95% CI -1·69 to -0·37]) and expressive language (-1·17 [-2·09 to -0·24]), whereas adjusted differences in cognitive (-0·45 [-1·32 to 0·43]), fine motor (0·09 [-0·49 to 0·66]), and gross motor (-0·41 [-1·09 to 0·27]) domain scores between groups were not significant. Correspondingly, the proportions of HIV-exposed uninfected children with developmental delay were higher than those of HIV-unexposed children for receptive language (adjusted odds ratio 1·96 [95% CI 1·09 to 3·52]) and expressive language (2·14 [1·11 to 4·15]).

Interpretation: Uninfected children exposed to maternal HIV infection and antiretroviral therapy have increased odds of receptive and expressive language delays at 2 years of age. Further long-term work is needed to understand developmental outcomes of HIV-exposed uninfected children, especially in regions such as sub-Saharan Africa that have a high prevalence of HIV exposure among children.

Funding: Bill & Melinda Gates Foundation, SA Medical Research Council, Wellcome Trust.
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http://dx.doi.org/10.1016/S2352-4642(19)30250-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876655PMC
November 2019

Self-harm in young people with perinatal HIV and HIV negative young people in England: cross sectional analysis.

BMC Public Health 2019 Aug 27;19(1):1165. Epub 2019 Aug 27.

Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL), 90 High Holborn, WC1V 6LJ, London, UK.

Background: Self-harm in adolescents is of growing concern internationally but limited evidence exists on the prevalence of self-harm in those living with HIV, who may be at higher risk of poor mental health outcomes. Therefore our aim was to determine the prevalence and predictors of self-harm among young people with perinatally-acquired HIV (PHIV) and HIV negative (with sibling or mother living with HIV) young people living in England.

Methods: 303 PHIV and 100 HIV negative young people (aged 12-23 years) participating in the Adolescents and Adults Living with Perinatal HIV cohort study completed an anonymous self-harm questionnaire, as well as a number of standardised mental-health assessments. Logistic regression investigated predictors of self-harm.

Results: The median age was 16.7 years in both groups, and 40.9% of the PHIV and 31.0% of the HIV negative groups were male. In total 13.9% (56/403) reported having ever self-harmed, with no difference by HIV status (p = 0.089). Multivariable predictors of self-harm were female sex (adjusted odds ratio (AOR) 5.3, (95% confidence interval 1.9, 14.1), p = 0.001), lower self-esteem (AOR 0.9 (0.8, 0.9) per 1 point increase, p < 0.001) and having ever used alcohol (AOR 3.8 (1.8, 7.8), p < 0.001). Self-esteem z-scores for both PHIV and HIV negative participants were 1.9 standard deviations below the mean for population norms.

Conclusions: Self-harm is common among PHIV and HIV negative adolescents in England. Reassuringly however, they do not appear to be at an increased risk compared to the general adolescent population (15-19% lifetime prevalence). The low level of self-esteem (compared to available normative data) in both groups is worrying and warrants further attention.
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http://dx.doi.org/10.1186/s12889-019-7424-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712658PMC
August 2019

Review article: direct-acting antivirals for the treatment of HCV during pregnancy and lactation - implications for maternal dosing, foetal exposure, and safety for mother and child.

Aliment Pharmacol Ther 2019 10 25;50(7):738-750. Epub 2019 Aug 25.

Department of Pharmacy, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct-acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended.

Aim: To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation METHODS: A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation.

Results: Exposure to all DAAs studied is likely to be altered during pregnancy, mostly related to pregnancy-induced effects on drug absorption and metabolism. Although animal studies show that most DAAs are reported to cross the placenta and transfer into breast milk, most DAA combinations show a favourable safety profile. Because of the rapid viral decline after treatment initiation, and to avoid the critical period of organogenesis, treatment may be started at the end of the second trimester or early third trimester.

Conclusions: Treatment of HCV infection during pregnancy is realistic, as DAAs are highly effective and treatment duration is relatively short. There is an urgent need to study DAAs during pregnancy and lactation to contribute to the goal of HCV elimination.
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http://dx.doi.org/10.1111/apt.15476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773363PMC
October 2019

Transfusion Volume for Children with Severe Anemia in Africa.

N Engl J Med 2019 08;381(5):420-431

From the Department of Medicine (K.M., T.N.W.) and Nutrition Research Section (G.F.), Imperial College London, and the Medical Research Council Clinical Trials Unit at University College London (E.C.G., D.M.G., A.S.W.), London, the School of Medicine, Dentistry, and Biomedical Science, Queen's University, Belfast (N.K.), the Liverpool School of Tropical Medicine and Hygiene, Liverpool (I.B.), the Department of Pediatrics, University Hospital of Wales, Cardiff (J.A.E.), and the Centre for Health Economics, University of York, York (P.S.G.) - all in the United Kingdom; Busitema University Faculty of Health Sciences, Mbale Campus, Mbale Regional Referral Hospital (P.O.-O., J.N., C.N.), and the Mbale Blood Transfusion Services (B.W.), Mbale, the Department of Pediatrics, Makerere University and Mulago Hospital (S.K., R.O.O., J.K.), and the Uganda Blood Transfusion Services, National Blood Transfusion Services (D.K.B.), Kampala, and Soroti Regional Referral Hospital, Soroti (F.A., C.E., M.N.) - all in Uganda; the Kenya Medical Research Institute-Wellcome Trust Research Program, Kilifi (K.M., A.M., S.U., T.N.W.); and the College of Medicine and the Malawi-Liverpool-Wellcome Trust Clinical Research Program (G.C., M.M., N.K.) and the Malawi Blood Transfusion Services (B.M.) - all in Blantyre, Malawi.

Background: Severe anemia (hemoglobin level, <6 g per deciliter) is a leading cause of hospital admission and death in children in sub-Saharan Africa. The World Health Organization recommends transfusion of 20 ml of whole-blood equivalent per kilogram of body weight for anemia, regardless of hemoglobin level.

Methods: In this factorial, open-label trial, we randomly assigned Ugandan and Malawian children 2 months to 12 years of age with a hemoglobin level of less than 6 g per deciliter and severity features (e.g., respiratory distress or reduced consciousness) to receive immediate blood transfusion with 20 ml per kilogram or 30 ml per kilogram. Three other randomized analyses investigated immediate as compared with no immediate transfusion, the administration of postdischarge micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole. The primary outcome was 28-day mortality.

Results: A total of 3196 eligible children (median age, 37 months; 2050 [64.1%] with malaria) were assigned to receive a transfusion of 30 ml per kilogram (1598 children) or 20 ml per kilogram (1598 children) and were followed for 180 days. A total of 1592 children (99.6%) in the higher-volume group and 1596 (99.9%) in the lower-volume group started transfusion (median, 1.2 hours after randomization). The mean (±SD) volume of total blood transfused per child was 475±385 ml and 353±348 ml, respectively; 197 children (12.3%) and 300 children (18.8%) in the respective groups received additional transfusions. Overall, 55 children (3.4%) in the higher-volume group and 72 (4.5%) in the lower-volume group died before 28 days (hazard ratio, 0.76; 95% confidence interval [CI], 0.54 to 1.08; P = 0.12 by log-rank test). This finding masked significant heterogeneity in 28-day mortality according to the presence or absence of fever (>37.5°C) at screening (P=0.001 after Sidak correction). Among the 1943 children (60.8%) without fever, mortality was lower with a transfusion volume of 30 ml per kilogram than with a volume of 20 ml per kilogram (hazard ratio, 0.43; 95% CI, 0.27 to 0.69). Among the 1253 children (39.2%) with fever, mortality was higher with 30 ml per kilogram than with 20 ml per kilogram (hazard ratio, 1.91; 95% CI, 1.04 to 3.49). There was no evidence of differences between the randomized groups in readmissions, serious adverse events, or hemoglobin recovery at 180 days.

Conclusions: Overall mortality did not differ between the two transfusion strategies. (Funded by the Medical Research Council and Department for International Development, United Kingdom; TRACT Current Controlled Trials number, ISRCTN84086586.).
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http://dx.doi.org/10.1056/NEJMoa1900100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610610PMC
August 2019

Immediate Transfusion in African Children with Uncomplicated Severe Anemia.

N Engl J Med 2019 08;381(5):407-419

From the Department of Pediatrics (K.M., T.N.W.) and Nutrition Research Section (G.F.), Imperial College London, and the Medical Research Council Clinical Trials Unit at University College London (E.C.G., D.M.G., A.S.W.), London, the Centre for Health Economics, University of York, York (P.S.G.), the School of Medicine, Dentistry, and Biomedical Science, Queen's University, Belfast (N.K.), Liverpool School of Tropical Medicine and Hygiene, Liverpool (I.B.), and the Department of Pediatrics, University Hospital of Wales, Cardiff (J.A.E.) - all in the United Kingdom; the Department of Pediatrics, Makerere University and Mulago Hospital (S.K., R.O.O., E.N.), and the Uganda Blood Transfusion Services (BTS), National BTS (D.K.B.), Kampala, Busitema University Faculty of Health Sciences, Mbale Campus and Mbale Regional Referral Hospital (P.O.-O., J.N., C.N.), and Mbale BTS (B.W.), Mbale, and the Soroti Regional Referral Hospital, Soroti (C.E., F.A., M.N.) - all in Uganda; the College of Medicine and Malawi-Liverpool-Wellcome Trust Clinical Research Program (M.M., G.C.). and Malawi BTS (B.M.), Blantyre, Malawi; and the Kenya Medical Research Institute-Wellcome Trust Research Program, Kilifi, Kenya (K.M., A.M. S.U., T.N.W.).

Background: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes.

Methods: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole.

Results: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group.

Conclusions: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).
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http://dx.doi.org/10.1056/NEJMoa1900105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611152PMC
August 2019

Gastroenteritis aggressive versus slow treatment for rehydration (GASTRO): a phase II rehydration trial for severe dehydration: WHO plan C versus slow rehydration.

BMC Med 2019 07 1;17(1):122. Epub 2019 Jul 1.

Department of Paediatrics, Faculty of Medicine, St Mary's Campus, Norfolk Place, Imperial College, London, W2 1PG, UK.

Background: World Health Organization rehydration management guidelines (plan C) for severe dehydration are widely practiced in resource-poor settings, but never formally evaluated in a trial. The Fluid Expansion as a Supportive Therapy trial raised concerns regarding the safety of bolus therapy for septic shock, warranting a formal evaluation of rehydration therapy for gastroenteritis.

Methods: A multi-centre open-label phase II randomised controlled trial evaluated two rehydration strategies in 122 Ugandan/Kenyan children aged 60 days to 12 years with severe dehydration secondary to gastroenteritis. We compared the safety and efficacy of standard rapid rehydration using Ringer's lactate (100 ml/kg over 3 h (6 h if < 1 year), incorporating 0.9% saline boluses for children with shock (plan C) versus slower rehydration: 100 ml/kg Ringer's lactate over 8 h (all ages) without boluses (slow: experimental). The primary outcome was the frequency of serious adverse events (SAE) within 48 h including cardiovascular, respiratory and neurological complications. Secondary outcomes included clinical, biochemical and physiological measures of response to treatment by intravenous rehydration.

Results: One hundred twenty-two eligible children (median (IQR) age 8 (6-12) months) were randomised to plan C (n = 61) or slow (n = 61), with two (2%) lost to follow-up at day 7). Following randomisation mean (SD) time to start intravenous rehydration started was 15 min (18) in both arms. Mean (SD) fluid received by 1 hour was greater in plan C (mean 20.2 ml/kg (12.2) and 33.1 ml/kg (17) for children < 1 year and >- 1 year respectively) versus 10.4 ml/kg (6.6) in slow arm. By 8 hours volume received were similar mean (SD) plan C: 96.3 ml/kg (15.6) and 97.8 ml/kg (10.0) for children < 1 and ≥ 1 year respectively vs 93.2 ml/kg (12.2) in slow arm. By 48-h, three (5%) plan C vs two (3%) slow had an SAE (risk ratio 0.67, 95% CI 0.12-3.85, p = 0.65). There was no difference in time to the correction of dehydration (p = 0.9) or time to discharge (p = 0.8) between groups. Atrial natriuretic peptide levels rose substantially by 8 hours in both arms, which persisted to day 7. Day 7 weights suggested only 33 (29%) could be retrospectively classified as severely dehydration (≥ 10% weight loss).

Conclusion: Slower rehydration over 8 hours appears to be safe, easier to implement than plan C. Future large trials with mortality as the primary endpoint are warranted.

Trial Registration: ISRCTN67518332 . Date applied 31 August 2016.
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http://dx.doi.org/10.1186/s12916-019-1356-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600884PMC
July 2019

Efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with Community-Acquired Pneumonia: a protocol for a randomIsed controlled Trial (CAP-IT).

BMJ Open 2019 05 22;9(5):e029875. Epub 2019 May 22.

Paediatric Infectious Diseases Research Group, MRC Clinical Trial Unit at UCL, Institute for Infection and Immunity, St George's University of London, London, UK.

Introduction: Community-acquired pneumonia (CAP) is a common indication for antibiotic treatment in young children. Data are limited regarding the ideal dose and duration of amoxicillin, leading to practice variation which may impact on treatment failure and antimicrobial resistance (AMR). Community-Acquired Pneumonia: a randomIsed controlled Trial (CAP-IT) aims to determine the optimal amoxicillin treatment strategies for CAP in young children in relation to efficacy and AMR.

Methods And Analysis: The CAP-IT trial is a multicentre, randomised, double-blind, placebo-controlled 2×2 factorial non-inferiority trial of amoxicillin dose and duration. Children are enrolled in paediatric emergency and inpatient environments, and randomised to receive amoxicillin 70-90 or 35-50 mg/kg/day for 3 or 7 days following hospital discharge. The primary outcome is systemic antibacterial treatment for respiratory tract infection (including CAP) other than trial medication up to 4 weeks after randomisation. Secondary outcomes include adverse events, severity and duration of parent-reported CAP symptoms, adherence and antibiotic resistance. The primary analysis will be by intention to treat. Assuming a 15% primary outcome event rate, 8% non-inferiority margin assessed against an upper one-sided 95% CI, 90% power and 15% loss to follow-up, 800 children will be enrolled to demonstrate non-inferiority for the primary outcome for each of duration and dose.

Ethics And Dissemination: The CAP-IT trial and relevant materials were approved by the National Research Ethics Service (reference: 16/LO/0831; 30 June 2016). The CAP-IT trial results will be published in peer-reviewed journals, and in a report published by the National Institute for Health Research Health Technology Assessment programme. Oral and poster presentations will be given to national and international conferences, and participating families will be notified of the results if they so wish. Key messages will be constructed in partnership with families, and social media will be used in their dissemination.

Trial Registration Number: ISRCTN76888927, EudraCT2016-000809-36.
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http://dx.doi.org/10.1136/bmjopen-2019-029875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538022PMC
May 2019

Inflammatory biomarkers in HIV-infected children hospitalized for severe malnutrition in Uganda and Zimbabwe.

AIDS 2019 07;33(9):1485-1490

MRC Clinical Trials Unit at UCL.

Objectives: A proportion of HIV-infected children with advanced disease develop severe malnutrition soon after antiretroviral therapy (ART) initiation. We tested the hypothesis that systemic inflammation underlies the pathogenesis of severe malnutrition in HIV-infected children.

Design: Cross-sectional laboratory substudy in 613 HIV-infected children initiating ART in Uganda and Zimbabwe.

Methods: We measured C-reactive protein (CRP), TNFα, IL-6 and soluble CD14 by ELISA in cryopreserved plasma at baseline (pre-ART) and week-4 (children with severe malnutrition only). Independent associations between baseline biomarkers and subsequent hospitalization for severe malnutrition were identified using multivariable fractional polynomial logistic regression.

Results: Compared with children without severe malnutrition (n = 574, median age 6.3 years, median baseline weight-for-age Z-score -2.2), children hospitalized for severe malnutrition post-ART (n = 39, median age 2.3 years, median baseline weight-for-age Z-score -4.8) had higher baseline CRP [median 13.5 (interquartile range 5.5, 41.1) versus 4.1 (1.4, 14.4) mg/l; P = 0.003] and IL-6 [median 9.2 (6.7, 15.6) versus 5.9 (4.6, 9.3) pg/ml; P < 0.0001], but similar overall TNFα, soluble CD14 and HIV viral load (all P > 0.06). In a multivariable model, higher pre-ART IL-6, lower TNFα and lower weight-for-age were independently associated with subsequent hospitalization for severe malnutrition. Between weeks 0 and 4, there was a significant rise in CRP, IL-6 and soluble CD14, and fall in TNFα and HIV viral load in children hospitalized for severe malnutrition (all P < 0.02).

Conclusion: Pre-ART IL-6 and TNFα were more strongly associated with hospitalization for severe malnutrition than CD4 cell count or viral load, highlighting the importance of inflammation at the time of ART initiation in HIV-infected children.
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http://dx.doi.org/10.1097/QAD.0000000000002231DOI Listing
July 2019

Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation.

Sci Transl Med 2019 04;11(486)

Blizard Institute, Queen Mary University of London, London E1 2AT, UK.

Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue ( = 144) versus stop ( = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing ( = 36) versus stopping ( = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive ( = 16) and HIV-negative ( = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa.
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http://dx.doi.org/10.1126/scitranslmed.aav0537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783302PMC
April 2019

Haematological quality and age of donor blood issued for paediatric transfusion to four hospitals in sub-Saharan Africa.

Vox Sang 2019 May 5;114(4):340-348. Epub 2019 Mar 5.

KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya.

Background And Objectives: Paediatric blood transfusion for severe anaemia in hospitals in sub-Saharan Africa remains common. Yet, reports describing the haematological quality of donor blood or storage duration in routine practice are very limited. Both factors are likely to affect transfusion outcomes.

Materials And Methods: We undertook three audits examining the distribution of pack types, haematological quality and storage duration of donor blood used in a paediatric clinical trial of blood at four hospitals in Africa (Uganda and Malawi).

Results: The overall distribution of whole blood, packed cells (plasma-reduced by centrifugation) and red cell concentrates (RCC) (plasma-reduced by gravity-dependent sedimentation) used in a randomised trial was 40·7% (N = 1215), 22·4% (N = 669) and 36·8% (N = 1099), respectively. The first audit found similar median haematocrits of 57·0% (50·0,74·0), 64·0% (52·0,72·5; P = 0·238 vs. whole blood) and 56·0% (48·0,67·0; P = 0·462) in whole blood, RCC and packed cells, respectively, which resulted from unclear pack labelling by blood transfusion services (BTS). Re-training of the BTS, hospital blood banks and clinical teams led to, in subsequent audits, significant differences in median haematocrit and haemoglobins across the three pack types and values within expected ranges. Median storage duration time was 12 days (IQR: 6, 19) with 18·2% (537/2964) over 21 days in storage. Initially, 9 (2·8%) packs were issued past the recommended duration of storage, dropping to 0·3% (N = 7) in the third audit post-training.

Conclusion: The study highlights the importance of close interactions and education between BTS and clinical services and the importance of haemovigilance to ensure safe transfusion practice.
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http://dx.doi.org/10.1111/vox.12764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563499PMC
May 2019
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