European Pregnancy and Paediatric Infections Cohort Collaboration: Paediatric Protocol
European Pregnancy and Paediatric Infections Cohort Collaboration: Paediatric Protocol
Across Europe and worldwide, there are many studies following groups (cohorts) of children
 living with human immunodeficiency virus (HIV) and other infections over time, to monitor
 their long-term health. Some of these infections are rare: for example, few children in
 Western Europe are living with HIV, so the studies often have fairly small numbers of
 participants. This can make it difficult to answer research questions in these cohorts and
 means that doctors and researchers working with these patients in different countries need to
 work together. This is particularly important as children are not often included in clinical
 trials of treatments and other interventions.

 The European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC) is an
 international network of researchers working together in this way. Researchers in the network
 represent cohort studies of pregnant women and children with, or at risk of, infections from
 across Europe and Thailand. The research focuses on infections in pregnant women and
 children, particularly HIV, hepatitis B and C virus, and tuberculosis, and, from 2020, novel
 coronavirus (COVID-19). By combining data from many cohorts, the researchers aim to answer
 questions that could not be answered by one study individually (for example, because a large
 number of pregnant women or children are needed to answer the question).

 This protocol focuses on the paediatric component of EPPICC's research, which focuses on the
 treatment of children at risk of and living with infections. For example, what medicines are
 used most often and how do they affect children's health? EPPICC is an observational study,
 which means that children do not receive any extra treatment as part of the study. Instead,
 children are "observed" during their routine medical care. Each cohort keeps records of the
 children's health collected at routine clinic visits, including information such as date of
 birth and sex, results of diagnostic tests, treatments received, and any illnesses or other
 events that the children have had. The EPPICC study combines and analyses data from all of
 the cohorts that take part, to answer questions about the risks and benefits of different
 diagnosis or treatment strategies, the long-term effects of infection and treatment during
 childhood and young adulthood, and regional variations (e.g. between Western and Eastern
 Europe) in the risk and management of infections.

 All of the data collected through the EPPICC Paediatric Protocol are stored securely at the
 Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. Data collection and storage
 are governed by the General Data Protection Regulation. A Steering Committee guides the
 research to make sure it is relevant and of high quality. Public and patient involvement
 (PPI) may be provided by individual cohorts' own groups, as well as by the interlinked Penta
 organisation, which is a network of paediatricians and researchers working in infections in
 Europe and globally. The PPI groups help with release of the results of the research. The
 results are also published on the Penta Foundation's public website (https://penta-id.org/),
 and presented at conferences and published in Open Access scientific journals.
MAIN AIM OF THE STUDY The overall aim of the EPPICC Paediatric Protocol is to analyse
 individual patient data from across collaborating European and international cohorts on
 infections in children and young people, to inform optimal prevention and treatment
 strategies.

 MAIN AREAS OF FOCUS HIV: prevalence and incidence of immunological and virological failure,
 HIV resistance, AIDS and non-AIDS events, mortality, cascade of care, engagement in care
 (including after transfer to adult care); antiretroviral therapy status and toxicities
 (adverse events, serious adverse events and discontinuation of drug) HCV: disease
 progression, uptake and outcome (effectiveness and safety) of HCV treatment in HCV mono- and
 HCV-HIV co-infected patients TB: incidence (including exploration of different
 diagnostic/screening strategies across regions) of LTBI and TB disease; outcomes of TB
 treatment including treatment of LTBI COVID-19: prevalence and incidence of infection and
 disease among both the general population and specifically among children and adolescents
 living with HIV; admission to hospital/ICU; outcomes (including resolution, death, sequelae
 (e.g. paediatric inflammatory syndrome temporally associated with SARS-CoV-2)) COHORT /
 INVESTIGATOR INCLUSION CRITERIA The study Sponsor has overall responsibility for site and
 investigator selection.

 The Principal Investigators of cohorts which have participated in previous EPPICC data
 mergers will be approached to ascertain their interest in participating in future data
 mergers. New cohorts may also be identified and may be invited to participate. The key
 inclusion criterion for a cohort to participate is enrolment of children and adolescents with
 the infection of interest. All cohorts who are able to commit to submitting and cleaning
 data, obtaining any ethical, regulatory or other approvals required locally, and completion
 of data sharing agreements in accordance with the project timelines will be included.

 DATA COLLECTION Collected data are pseudonymised: no names, initials, hospital numbers,
 national ID or addresses of patients are collected. Core data items included in most EPPICC
 paediatric data mergers include the following; Demographic: Date of birth, sex,
 ethnicity/country of origin, country of residence Therapeutic: Prophylaxis and treatment data
 (HIV, HCV, TB and COVID-19 treatments) including start and stop dates, drug names, doses and
 frequency of administration, and reasons for change/discontinuation Diagnostic: Diagnostic
 tests for infections undertaken, including dates and results Concurrent treatments: Other
 medications Clinical Infection status: (HIV, TB, HCV, HBV, SARS-CoV-2, other infection of
 interest), mode of acquisition of infection, date of diagnosis, disease stage Clinical (other
 events): Adverse events (e.g. severity, causal relation to drugs), AIDS- and non-AIDS-
 defining malignancies, COVID-19 sequelae, weight, height, death, causes of death, pregnancy,
 hospitalisations Laboratory: Absolute CD4 counts and percentage, HIV RNA, HCV RNA
 measurements, other lab markers Other Follow-up status, reason for study drop-out, transfer
 to adult care

 For certain analyses, additional data items may be requested, and may include:

 -  Biochemistry results

 -  Further details of severe adverse events

 -  Outcome of severe events. Data merger methods Individual cohorts collect data from
 medical records in clinics. Cohorts then send electronic datasets to the EPPICC
 Paediatric Data Manager, using a format and method defined in an EPPICC Standard
 Operating Procedure. For the ongoing HIV analyses, data variables are based on HICDEP
 data formats. HICDEP is the HIV Cohorts Data Exchange Protocol (www.hicdep.org) and is
 based on a relational structure, with data presented in a series of tables, together
 with the lookup tables for the codes to be used. For other future cohort collaborations,
 the variables to be collected and the database format will be based on existing data
 collection tools and standards where possible. Transfer of data to the EPPICC Paediatric
 Data Manager takes place using Galaxkey or an equivalent secured method.

 Submitted data are subjected to a range of logic and consistency checks. STATISTICAL
 CONSIDERATIONS EPPICC analyses may cover a wide range of questions, although individual
 Concept Sheets are specific to focussed research questions.

 SAMPLE SIZE Data are collected on all eligible participants enrolled in the participating
 centres who meet the inclusion criteria. Sample size calculations are carried out for
 specific planned analyses to ensure that sufficient participants are available to
 meaningfully answer each research question.

 ANALYSIS PLAN Each Concept Sheet includes a brief analysis plan. Standard statistical methods
 are used in the analysis of different types of exposure and outcome data. Adjustment for
 confounding may be achieved through multivariable modelling or using alternative approaches
 such as propensity scoring. Missing data are to be expected and, depending on the analysis
 and the amount and likely mechanisms of missing data, may be approached using complete case
 analysis or techniques such as multiple imputation. Details of specific analytical approaches
 are included in each Concept Sheet. Previous analyses of EPPICC paediatric data have used
 approaches including Cox regression, linear regression, logistic regression, and propensity
 score matching. Cohorts may be grouped by region (as cohorts within the same region are often
 similar in terms of epidemiology and treatment approaches), and region is then included as a
 covariate in the analysis.

 REGULATORY & ETHICAL ISSUES COMPLIANCE EPPICC is an observational study with no
 study-specific interventions beyond those received in routine care. Nevertheless, it is
 conducted in compliance with the approved protocol, the Declaration of Helsinki 1996, the
 principles of Good Clinical Practice, the General Data Protection Regulation and the UK Data
 Protection Act 2018 (DPA number: Z6364106), and the UK Policy Framework for Health and Social
 Care Research.

 Each cohort is responsible for ensuring compliance with local and national regulatory and
 ethical processes.

 DATA RETENTION

 The paediatric study dataset will be stored at the MRC CTU at UCL, in accordance with
 national data legislation. A final copy will be sent to the study sponsor, the Penta
 Foundation. The dataset will be held for a minimum of 5 years after the end of the study.

 DATA SHARING AGREEMENTS BETWEEN COHORTS AND EPPICC Individual cohorts, the Penta Foundation
 and the MRC CTU at UCL are required to sign a Data Sharing Agreement (DSA), which allows
 transfer of data between cohorts and the Penta Foundation and the MRC CTU at UCL. All data
 will be handled and used in accordance with the DSA. Cohorts should return the DSA, once
 signed, to the project coordinator at the Penta Foundation.

 THIRD PARTY DATA SHARING REQUESTS Extracts of EPPICC data may be requested for other cohort
 collaboration analyses, both nationally and internationally. Requests to access EPPICC data
 will be considered on a case by case basis. Transfer of EPPICC data (partial or complete) to
 third party collaborators requires approval from the PIs of cohorts contributing data (or
 authorised cohort representatives) and is subject to a contract and Data Sharing Agreement,
 if applicable. All data transfer is conducted through a secure process. Any data transferred
 to third parties must be stored by third parties in compliance with all relevant data
 protection regulations.

 Researchers wishing to access EPPICC data should contact the EPPICC Study Team in the first
 instance. A Concept Sheet is then required, which would be circulated to and discussed with
 all potential contributing cohorts.
Children and adolescents diagnosed with HIV and/or chronic HCV are eligible for inclusion
 in this data merger provided they meet one, or both, of the inclusion criteria below:

 Children and young people living with HIV:

 -  Diagnosis of HIV infection at age <18 years

 -  ≥1 visit in paediatric care AND / OR

 -  Children and young people living with HCV:

 -  Diagnosis of chronic HCV infection at age <18 (defined as ≥1 antibody HCV positive
 results at ≥18 months of age or ≥1 HCV RNA positive result at ≥6 months of age) ≥1
 visit in paediatric care