Publications

19

Feb, 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

Authors: Cecilia L. Moore, Anna Turkova , Hilda Mujuru , Adeodata Kekitiinwa, Abbas Lugemwa, Cissy M. Kityo, Linda N. Barlow-Mosha, et al, ODYSSEY trial team

Published in: BMC Infectious Diseases

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 ARTnaïve 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 substudies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children.

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21

Jan, 2021

Harmonising regulatory approval for antibiotics in children

Authors: Phoebe C M Williams, John Bradley, Emmanuel Roilides, Linus Olson, Sheldon Kaplan, Irja Lutsar, Carlo Giaquinto, Daniel K Benjamin, Mike Sharland

Published in: The Lancet

Introduction: Antimicrobial resistance represents a substantial threat to the Sustainable Development Goals (SDGs), with a large impact on the health of children worldwide. However, very few paediatric trials for new antibiotics have been done to inform the optimal treatment of multidrug-resistant infections in children.

The current drug regulatory framework has evolved from a system that rightly aimed to protect children, yet remains governed by interpretation of laws established in response to historical incidents involving agents that caused harm. This approach, particularly for medicines from well established classes with a long experience of safe use in children (such as β-lactam penicillins), now unnecessarily complicates the process of paediatric antibiotic development, and is one of the many barriers to children with multidrug-resistant infections being appropriately treated with licensed drugs.

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12

Jan, 2021

Zika virus infection in pregnancy: a protocol for the join analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia

Tags: ZIKA, Pregnancy

Authors: A E Ades, Elizabeth B Brickley, Neal Alexander, David Brown, Thomas Jaenisch, Demócrito de Barros Miranda-Filho, Moritz Pohl, Kerstin D Rosenberger, Antoni Soriano-Arandes , Claire Thorne et al.

Published in: BMJ Journals

Abstract:

Introduction Zika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean.

Methods and analysis We will carry out a centre-by- centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach.

Ethics and dissemination Ethical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities.

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29

Dec, 2020

A population pharmacokinetics analysis assessing the exposure of raltegravir once‐daily 1200mg in pregnant women living with HIV

Authors: Vera E. Bukkems, Teun M. Post, Angela P. Colbers, David M. Burger, Elin M. Svensson

Published in: American Society for Clinical Pharmacology and Therapeutics

Abstract: Once‐daily two 600mg tablets (1200mg QD) raltegravir offers an easier treatment option compared to the twice‐daily regimen of one 400mg tablet. No pharmacokinetic, efficacy or safety data of the 1200mg QD regimen have been reported in pregnant women to date as it is challenging to collect these clinical data.

This study aimed to develop a population pharmacokinetic (popPK) model to predict the pharmacokinetic profile of raltegravir 1200mg QD in pregnant women and to discuss the expected pharmacodynamic properties of raltegravir 1200mg QD during pregnancy based on previously reported concentration‐effect relationships. Data from 11 pharmacokinetic studies were pooled (n=221).

A two‐compartment model with first‐order elimination and absorption through three sequential transit compartments best described the data. We assessed that the bio‐availability of the 600mg tablets was 21% higher as the 400mg tablets, and the bio‐availability in pregnant women was 49% lower. Monte‐Carlo simulations were performed to predict the pharmacokinetic profile of 1200mg QD in pregnant and non‐pregnant women.

The primary criteria for efficacy was that the lower bound of the 90% confidence interval (CI) of the concentration before next dose administration (C_trough) geometric mean ratio (GMR) of simulated pregnant/non‐pregnant women had to be >0.75. The simulated raltegravir C_trough GMR (90%CI) was 0.51 (0.41‐0.63), hence not meeting the primary target for efficacy. Clinical data from two pregnant women using 1200mg QD raltegravir showed a similar C_trough ratio pregnant/non‐pregnant.

Our pharmacokinetic results support the current recommendation of not using the raltegravir 1200mg QD regimen during pregnancy until more data on the exposure‐response relationship becomes available.

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22

Dec, 2020

Clinical Charateristrics of 58 Children with a Pediatric Inflmmatory Multisystem Syndrome Temporally Associated with SARS-CoV-2

Tags: Coronavirus, COVID-19

Authors: Elizabeth Whittaker, Alasdair Bamford, Julia Kenny, Myrsini Kaforou, Christine E Jones, Priyen Shah, Padmanabhan Ramnarayan, Alain Fraisse, Owen Miller, Patrick Davies, Filip Kucera, Joe Brierley, Marilyn McDougall, Michael Carter, Adriana Tremoulet, Chisato Shimizu, Jethro Herberg, Jane C Burns, Hermione Lyall, Michael Levin, PIMS-TS Study Group and EUCLIDS and PERFORM Consortia

Published in: JAMA Network

Abstract: Importance: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation.

Objectives:To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders.

Design, setting, and participants:Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019.

Exposures:Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization.

Main outcomes and measures:Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders.

Results:Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 μg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively).

Conclusions and relevance:In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.

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10

Dec, 2020

Cascade of care in children and adolescents with HIV in Russian Federation

Tags: HIV, Paediatric Medicines

Author: Anna Turkova, Evgeny Voronin, Yulia Plotnikova, Anna Samarina, Edith Milanzi, Vladimir Rozenberg, Liubov Okhonskaia, Inga Latysheva, Aleksey Plynsky, Elena Fertikh, Siobhan Crichton, Charlotte Jackson, Ali Judd, Intira J Collins, on behalf of the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC)

Published in: 12th International Workshop on HIV Pediatrics

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Background:

The cascade of care summarises the 90-90-90 UNAIDS targets, of 90% of HIV+ people knowing their status, of whom 90% receive antiretroviral treatment (ART), of whom 90% are virally suppressed

By 2019, there were 1,068,839 people diagnosed with HIV in Russia, of whom 50% were on ART, and of those 76% were virally suppressed1.

However, there is less data on the HIV care continuum in children and adolescents with HIV in Russia

Objective:

To summarise the cascade of care in children and adolescents living with HIV in three Russian clinics.

Method:

We included data on children/adolescents aged <18 years at HIV diagnosis from three Russian clinics within the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC).

Follow-up data from first presentation to HIV care until death, loss to follow-up, transfer to adult care or last visit (data cut-off 1/10/2016) were included.

As all patients were already diagnosed with HIV, we adapted the cascade of care as follows: (a) initiated ART, (b) virally suppressed (VS) ≤1000 copies/ml and (c) having good WHO immune status* at last visit. The analysis was restricted to patients in active paediatric follow-up (FU) in 2015-2016 and had ≥12 months of FU.

Characteristics of patients and cascade results were stratified by age of HIV diagnosis:

i.Diagnosed during “childhood” (age <10) and

ii.Diagnosed during “adolescence” (age ≥10)

The proportion with VS and good immune status* at 12(±3) months after ART start was also summarized overall and by calendar year of ART start.

Results:

Of 922 patients followed in the 3 centres, 703 had ≥12 months FU and were in care in 2015/16 and included in this analysis. Of these:
655 (93%) were diagnosed in childhood, of whom 94% had perinatally acquired HIV (Table 1)
48 (7%) were diagnosed in adolescence, of whom 27% had perinatally acquired HIV, 25% sexually-acquired, and 48% had other or unknown mode of transmission
94% (618/655) in the childhood group initiated ART compared to 81% (39/48) in the adolescent group.
At ART initiation, the median age was 2.2 years and 16.1 years in the childhood and adolescence group, respectively. 52% and 58% had advanced or severe WHO immunosuppression at ART start, respectively (Table 1).

4

Dec, 2020

Pediatric dolutegravir (DTG) dosing recommendations derived from combined P1093 and ODYSSEY Population Pharmacokinetic analysis

Tags: HIV, Paediatric Medicines

Authors: Singh R, Baker M, Thapar M, Gibb D, Turkova A, Ford D, Ruel T, Wiznia A, Farhad M, Alvero C, Green J, Bollen P, Colbers A, Burger D, Acosta E

Published in: 12th International Workshop on HIV Pediatrics

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Background: HIV treatment options remain limited in children. The recent Tivicay (dolutegravir, DTG) pediatric regulatory submissions propose WHO weight-band based recommendations for once-daily dosing in children ≥4 weeks of age using combined datasets from two pediatric studies: IMPAACT P1093 and ODYSSEY (PENTA20). These doses were informed by the Population PK (PopPK) analysis described below.

Methods: P1093 is a Phase I/II, non-comparative pharmacokinetic (PK) and safety study in HIV-1 infected children (≥4 weeks to <18 years of age). ODYSSEY is a non-inferiority, phase II/III study comparing the efficacy and toxicity of DTG plus 2 NRTIs vs. standard of care in infants and children. Intensive and sparse PK samples following dosing with film coated tablets (FCT), granules and dispersible tablet (DT) formulations in the fasted state and without regard to food were collected in P1093; intensive PK samples using FCTs and DTs in fasted state were collected in ODYSSEY. A PopPK model was developed with data from P1093 (1711 concentrations from n=151 participants) and ODYSSEY (939 concentrations from n=88 participants) to characterize PK, covariates, and associated variability. The final PopPK model simulated exposures across weight bands, doses, and formulations which were compared with established adult reference data.

Results: Of N=239 participants included, baseline age ranged from 0.17-17.5 years and weight from 3.9-91 kg, 50% were male and 80% were black. The model described study data and associated variability well with estimated mean (interindividual variability) CL/F=1.03L/h (29%) and V/F=13.6 L (107%). Based on observed and simulated data, dose stratification by age (<6 months and ≥6 months) in the 6 to <10 kg weight band (10 and 15 mg DTG DT, respectively) was proposed to account for metabolic enzyme maturation. The proposed doses are 5mg DT in 3 to <6kg; 10 mg DT in 6 to<10kg and <6 months, 15mg DT in 6 to <10kg and ≥6months, 20mg DT in 10 to <14kg, 25mg DT in 14 to <20kg and 30mg DT or 50 mg FCT in >20kg. At these doses, the simulated 24- hour concentration (C24h) was consistent across weight bands, similar to observed data, and met the minimum target concentrations of 0.697μg/mL. Similarly, simulated 24-hour area-under-the-curve (AUC24h) met the minimum target (46 h*μg/mL) across weight bands. Simulated maximum concentration (Cmax) results were 0.96 to 1.79- fold those observed historically in adults at the approved dose of DTG 50 mg BID (4.15 μg/mL). The safety exposure-response analysis demonstrated no relationships between PK parameters and adverse events.

Conclusions: Using FCT and DT formulations, DTG dosing in children ≥4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed PK variability was higher in this pediatric population and no additional safety concerns were observed.

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19

Nov, 2020

Tools for Healthcare Workers to measure Health Research Capacity Development at an Individual Level

Tags: Research

Author: Bilardi D, Rapa E, Bernays S, & Lang T

Published in: European Academy of Pediatric Societies

Background: Despite health research capacity development (HRCD) in low and middle-income countries (LMICs) being recognised as a critical element to overcoming global health challenges, insufficient actions have been taken to tackle major barriers to HRCD. A key barrier in supporting HRCD is the lack of empirical measurement of competencies to assess skills and identify gaps in research activities. An effective tool to measure HRCD would help drive more capable teams to undertake more locally-led research.

Aims: Primary aim: Systematically search the existing literature to investigate the nature, the scope and the extensiveness of existing tools created to measure HRCD at personal level in healthcare workers (HCW) working in LMICs. Secondary aims: identify a tool using a global evidence- based competency framework suitable for a comparable, standardised and consistent analyses of long term research competency acquisition in HCW in LMICs.

Methodology: Eleven databases were searched from inception to 16 January 2020. The first 10 pages of results from Google Scholar were also considered. The search was limited to English language publications. Two authors independently screened and reviewed studies using Covidence, extracted data and performed quality assessments using the extraction log validated against the CASP qualitative checklist. The content method was used to define a meta-narrative analysis.

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2

Nov, 2020

Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies

Tags: ZIKAction, ZIKA

Authors: A E Ades, Antoni Soriano-Arandes, Ana Alarcon, Francesco Bonfante, Claire Thorne, Catherine S Peckham, Carlo Giaquinto

Published in: The Lancet

Abstract
Background: Prospective studies of Zika virus in pregnancy have reported rates of congenital Zika syndrome and other adverse outcomes by trimester. However, Zika virus can infect and damage the fetus early in utero, but clear before delivery. The true vertical transmission rate is therefore unknown. We aimed to provide the first estimates of underlying vertical transmission rates and adverse outcomes due to congenital infection with Zika virus by trimester of exposure.

Methods: This was a Bayesian latent class analysis of data from seven prospective studies of Zika virus in pregnancy. We estimated vertical transmission rates, rates of Zika-virus-related and non-Zika-virus-related adverse outcomes, and the diagnostic sensitivity of markers of congenital infection. We allowed for variation between studies in these parameters and used information from women in comparison groups with no PCR-confirmed infection, where available.

Funding: European Union Horizon 2020 programme.

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30

Oct, 2020

COVID and HIV: Psychological impact and awareness of COVID-19 in young people with HIV

Tags: HIV, COVID19

Authors: S. Bernardi1, E. Mozzo, M. Di Pastena, F. Leone, C. Novello, A. Oletto, N. Cotugno, P. Zangari, P. Palma, V. Santilli, P. Palma, O. Rampon, C. Giaquinto

Published in: 12th National Congress of Italian Conference on AIDS and Antiviral Research

Background: Public health emergencies may affect the health, safety, and well-being of both individuals and communities. These effects may translate into a range of emotional reactions and unhealthy behaviours. Some people may be more vulnerable than others to the psychosocial effects of pandemics. Young people living with HIV can experience solitude, depression and anxiety as a consequence of the stigma that continues to surround HIV and the daily challenge of living with a chronic infection. We investigated the psychological impact of the current COVID-19 pandemic among a group of HIV-infected young people and assessed their knowledge on HIV and COVID-19 infections.

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