Introduction Approximately 5%–10% of individuals with untreated latent tuberculosis infection (LTBI) will progress to active tuberculosis (TB). Children are at a higher risk for progression to TB disease than adults. Isoniazid prophylaxis treatment period is long and can cause liver damage. Alternatives to isoniazid, such as rifamycin containing regimens, should be considered for prophylaxis. Previous systematic reviews, with different study designs and data combining results on children and adults, have evaluated the comparative efficacy and harms of LTBI treatment regimens. We aim to determine the effectiveness and safety of all the different regimens available for the treatment of LTBI for children and adolescents less than 18 years of age, contacts of drug-susceptible TB, without HIV infection.
Methods and analysis MEDLINE, Embase and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials without any language or publication date restriction. Screening and extraction will be performed in duplicate. Risk of bias will be performed in duplicate with Cochrane Risk of Bias tool V.2. Pairwise meta-analysis of direct comparisons and network meta-analyses (NMAs) will be performed. Heterogeneity will be assessed using I2 and Cochrane thresholds. Direct and indirect estimates in an NMA will be combined if justifiable. Subgroups analyses will be performed in different mean age and study year groups. Sensitivity analysis based on the risk of bias will be conducted. Publication bias will be investigated using funnel plots and Egger’s regression test. Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria will assess certainty of the evidence for the direct comparisons. GRADE approach for NMA will assess the quality of the evidence from the indirect and NMA.
Ethics and dissemination Ethical approval is not required as no primary data are collected. This systematic review will be disseminated in a peer-reviewed journal.
PROSPERO registration number CRD42021271512.
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Children have a higher risk for progression to tuberculosis disease than adults, due to vaccination, nutritional and immune status, and age.
Isoniazid prophylaxis non-compliance can be due to long treatment duration, hepatotoxicity, adverse events and forgetting to take or administer the tablets by caregivers.
Short-term regimens should also be considered in children.
WHAT THIS STUDY ADDS
There is no evidence synthesis on the best preventive tuberculosis regimens for children and adolescents.
This project aims to provide a summary of the best available evidence on the effectiveness and safety of the available preventive treatment.
If the assumptions of homogeneity, coherence and transitivity are judged to be justifiable, we will determine the relative effectiveness among regimes to highlight the best and the worst ones for our outcomes of interest.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Our project will present an updated synthesis of the best available evidence about preventive treatments in children.
Our findings will be key to inform clinicians, decision-makers, guideline developers from international organizations and patients/caregivers. about the best interventions to implement in different contexts.
Latent tuberculosis infection (LTBI) is a state of persistent bacterial viability, immune control and no evidence of clinically manifested active tuberculosis (TB),1 constituting a public health problem requiring effective interventions. Since up to 2014, nearly 1.7 billion individuals were reported as latently infected with Mycobacterium tuberculosis.2
Most infected individuals are asymptomatic and do not develop active TB. Nevertheless, if untreated, approximately 5%–10% of persons with LTBI will progress to active TB or TB disease.3–5 Moreover, children are at a higher risk for progression to TB disease than adults.6 Several factors appear to influence the balance of risk between LTBI or progression to active disease, including age and nutritional, vaccination and immune status.7 For instance, in the absences of preventive measures, approximately 50% of infants, even those delivered at term, develop active TB after infection.8 Children under 4 years of age have the highest risk of progression with development of severe forms of TB, such as miliary or disseminated and meningeal or central nervous system TB.9 Safe and effective preventive treatment strategies as part of global TB control10 should be targeted to those population groups at highest risk for progression to active disease.
Among first-line antituberculous medication, isoniazid is also used as a single drug to prevent M. tuberculosis infection and progression from latent infection to active TB.11 Isoniazid prophylaxis has traditionally been used for decades; it has showed high efficacy and proved risk reduction for TB among children.12 However, the treatment period with isoniazid is long, can cause liver damage and only approximately 50% of patients complete the treatment.10 Compliance to isoniazid regimen can be a challenge, especially in high-risk populations. Non-compliance has been reported due to forgetting to take or administer the tablets by caregivers, adverse events, migration or travelling, among others.13
Alternatives to isoniazid, such as rifamycin containing regimens (rifampicin and rifapentine), should be considered for prophylaxis. Trials comparing short-term rifampicin alone with long regimes of isoniazid, mostly in adults, have not shown higher rates of active TB, and compliance is probably higher and adverse events rates may be lower.10 Furthermore, a combination of rifapentine and isoniazid supervised weekly for 3 months has demonstrated to be as effective in preventing TB as self-administered isoniazid for 9 months, increased treatment completion and caused less liver toxicity, though treatment-limiting adverse events were more frequent.10
Previous systematic reviews and network meta-analyses have evaluated the comparative efficacy and harms of LTBI treatment regimens. However, these studies have combined data from both, adults and children, to estimate the comparative effectiveness of several regimes.14 Other previous reviews have included different study types, such as non-randomised studies and trials, to answer one structured clinical question about LTBI treatment options in children.15 Moreover, a meta-analysis of randomised controlled trials (RCTs) has exclusively evaluated the efficacy of isoniazid, compared with placebo or no prophylaxis, in the prevention of TB morbidity and mortality in children.12 As a result, to date, there is not a systematic review that had synthesised all the available evidence from RCTs comparing all the available prophylaxis regimes in children to determine whether there are differences among them. We aim to evaluate the effectiveness and safety of all the different regimens available for the treatment of LTBI for children and adolescents less than 18 years of age, contacts of drug-susceptible TB and without HIV infection.
Methods and analysis
The protocol of this systematic review was developed based on Participants, Interventions, Comparators and Outcomes components of the review method and prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines.16 The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (Registration No. CRD42021271512) on 2 August 2021. The final report of this review will follow the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for systematic reviews incorporating network meta-analyses (NMAs).17
We are interested in RCT studies including children and/or adolescents under 18 years of age, with LTBI and who are contacts of individuals with drug-susceptible TB, regardless of the definition the authors used for LTBI. We will exclude studies with combined results for adults and children/adolescents, from which the information on children could not be extracted, and studies with HIV-infected children/adolescents.
Interventions and comparators
We will not include pyrazinamide regimens due to the known risk of severe hepatotoxicity as recommended by the Centers for Disease Control and Prevention (CDC) and the American Thoracic Society, since 2003.18 On the basis of multiple reports and investigations from 2000 to 2002, the entities recommended in 2003 that rifampin and pyrazinamide regimens should generally not be offered to persons with LTBI for either HIV-negative or HIV-infected persons, which is also endorsed by the Infectious Diseases Society of America.18 Clinicians are advised to use the preferred or alternative regimens for treatment of LTBI and only can be considered in carefully selected patients.18 We will include studies that compared all the mentioned regimens among them, or with placebo.
The primary outcomes are incidence of active TB at 2 years of follow-up and treatment compliance/adherence. We defined active TB as the disease caused by being infected with M. tuberculosis,19 confirmed bacteriologically or diagnosed clinically based on the TB diagnostic criteria of the American Thoracic Society/Infectious Diseases Society of America/CDC Clinical Practice Guidelines.20 Treatment adherence/compliance is included as used and reported by the authors of the primary studies.
Our secondary outcomes are incidence of active TB at 1 year and 5 years of follow-up, bacteriological confirmation of TB within the first 2 years after exposure, adverse reactions, hepatotoxicity, discontinuation of treatment due to adverse event and mortality at 5 years of follow-up. Bacteriological confirmation is obtained when TB is diagnosed in a biological specimen by smear microscopy, culture or molecular test (such as Xpert MTB/RIF).19
Adverse events, as defined by the study authors, include all signs and symptoms that can be expressions of organic or physiological alteration in the child/adolescent, as a result of the administration of the medication at indicated doses. These events can be detected during questioning of the children and/or their caregivers, during medical evaluations (clinically) or through laboratory test, and can lead to treatment discontinuation according to the seriousness of the event. Serious adverse events can result in death, are life threatening, require or prolong hospitalisation, result in persistent or significant disability or incapacity, or result in a congenital anomaly.21 While unexpected adverse events are previously unobserved or undocumented, expected events typically do not require expedited reporting to the regulatory authorities.21 Related adverse events indicate a reasonable possibility of an event being related to exposure to the product, based on biological plausibility, prior experience, temporal relationship between product exposure and onset of the event, as well as dechallenge and rechallenge.21 Even though there is no standard nomenclature to describe the degree of causality, terms such as certainly, definitely, probably, possibly or likely related or not related have been used.21
Information sources and search strategy
We will search MEDLINE via Ovid, Embase via Ovid and the Cochrane Central Register of Controlled Trials (The Cochrane Library – current) without any language or publication date restriction and limited to human studies. The MEDLINE strategy was developed with input from the project team. To build the search strategy, MEDLINE and Embase via Ovid were used to identify an extensive list of keywords and MeSH terms related to “latent tuberculosis”, “children”, and “isoniazid” or “rifampin” or “rifamycins”. The search strategy was revised and approved by all authors. A draft MEDLINE search strategy is available in online supplemental appendix 1. The MEDLINE strategy will be adapted to the syntax and subject subheadings of the other databases. PROSPERO database was also searched for ongoing or recently completed systematic reviews. The search will be updated towards the end of the review, after being validated to ensure that the MEDLINE strategy retrieves a high proportion of eligible studies found through any means but indexed in MEDLINE. The full search strategies and study selection process will be presented in a PRISMA flow diagram.
Citations retrieved from the searches from all the databases will be merged using EndNote V.X9.1 software, and duplicate records will be removed. References will be then exported to a Microsoft Excel (V.14.1.0, Redmond, Washington, USA: Microsoft, 2011) spreadsheet to continue the selection process. Title and abstract screening will be performed in duplicate by two reviewers (VS-J and YHM). We will obtain full-text articles for all titles identified as potentially eligible by at least one of the reviewers, which appear to meet the inclusion criteria or when there is any uncertainty.
The potentially eligible full-text articles will also be reviewed independently and in duplicate by two reviewers (VS-J and YHM) to determine their inclusion. We will seek additional information and contact the corresponding authors to resolve questions about eligibility when needed. Studies considered eligible by both reviewers will be included. Data extraction of included will also be performed independently and in duplicate (VS-J, YHM and AFE-B). Disagreements in the full-text or the data extraction stages will be resolved by consensus discussion or by seeking adjudication from a third reviewer (JA-R). Extracted data will include information on study design (title, author information, year of publication, recruitment stage, country in which the study was conducted, language, study design, sample size and funding), population characteristics (age, percentage of children less than 5 years old, body weight/body mass index, sex, case source identification, intrafamilial infection, TB incidence, endemicity and population type), trial characteristics (tuberculin skin testing cut-off point for inclusion, interferon gamma release assay result and type as inclusion criteria, number of patients per trial arms, allocation and information of interventions (dose, details and duration)), risk of bias assessment and outcome measurements (number of events, per arms, for dichotomous outcomes).
Risk of bias (RoB) in individual studies
The RoB of each randomised control trial will be performed with the Cochrane Risk of Bias tool V.2.22 The following domains will be assessed per outcome (primary and secondary outcomes): RoB in randomisation process, deviations from the intended intervention (effect of assignment and adhering to intervention), missing outcome data, measurement of the outcome and selection of the reported result. Each domain will be assigned an RoB judgement of ‘low risk of bias’, ‘high risk of bias’ or ‘some concerns’. The overall risk of bias domain will be classified as: ‘low risk of bias’ when all domains are judged as low risk, ‘some concerns’ when at least one domain is some concern but was not high risk for any domain and ‘high risk’ if at least one domain was high risk or if multiple domains were judged as some concerns.22 Two independent reviewers (VS-J, YHM and AFE-B) will perform the RoB assessment. Possible discrepancies between the two reviewers regarding bias appraisal will be solved by consensus. Nevertheless, if consensus cannot be reached, a third reviewer will resolve it (IDF).
We will first describe the results narratively and using tables. If possible, we will conduct a pairwise meta-analysis of the available direct comparisons and network meta-analyses. Since we expect clinical and methodological heterogeneity among the studies, we plan to pool direct evidence for each treatment comparison using a frequentist random-effects model, applying the Hartung-Knapp-Sidik-Jonkman method.23 Effect estimates along with 95% CIs will be estimated using OR for dichotomous outcomes. Heterogeneity will be assessed using the I2 statistic to quantify the percentage of variability that is due to true differences between studies rather than sampling error.24 25 The I2 will be interpreted following the Cochrane thresholds.26
NMA synthesises both direct and indirect evidence, estimates the relative effectiveness among pairs of interventions, even if specific interventions have never been compared directly in RCTs, and provides a ranking of interventions.27 When direct evidence for a given comparison is not available, an indirect comparison will provide an effect estimate. In the presence of direct evidence, the NMA will provide a combined estimate (ie, the statistical combination of direct and indirect evidence).28 We will combine direct and indirect estimates in an NMA if the coherence and transitivity assumptions across treatment comparisons are judged to be justifiable. By combining direct and indirect evidence, we may obtain estimates with increased precision. We will present the network geometry and the results in probability statements as well as forest plots. We will calculate the surface under the cumulative ranking curve values for each intervention, per outcome. The NMA will be performed in Statistical Software for Data Science (STATA) V.15.0.
We will conduct additional analyses to investigate potential reasons for heterogeneity. We plan to conduct subgroups analyses based on potential effect modifiers if sufficient data are available. We have identified age as a potential effect modifier, as well as study year (the year the recruitment began), due to the likelihood of TB infection. We will also conduct a sensitivity analysis based on the risk of bias, excluding articles with high risk of bias to assess the robustness of results. Lastly, we will conduct network meta-regression to evaluate the potential impact of age on the effect estimates. Publication bias will be investigated using funnel plots, and Egger’s regression test will be applied to statistics when the funnel plots show asymmetry and there are five or more studies available.29
Certainty of the evidence
The confidence in the estimates for each reported outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group approach.30 We will assess the certainty of the evidence for the direct available comparisons following the traditional GRADE criteria: risk of bias, inconsistency, imprecision, indirectness and publication bias.31 The assessment of the quality of the evidence from the indirect and NMA will be performed using the specific GRADE approach for NMA. This approach considers, in addition to the traditional GRADE criteria, the assessment of intransitivity and incoherence criteria.32 33 Lastly, to optimise the results interpretation, we will present a summary using a novel approach recommended by GRADE to draw conclusions from the NMA using a minimally contextualised framework.34
Patient and public involvement
There was no patient or public involvement in the development of the systematic review protocol.
Ethics and dissemination
Ethical approval is not required for this study; this review is based on the analysis of published evidence. No personal data of patients were required. The results of the review will be disseminated by the publication of the manuscript in a peer-reviewed journal focusing on infectious diseases and paediatrics for publication.
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
Patient consent for publication
Twitter @BenjumeaDione, @anfesbo, @jotacosta104, @ivand_florez
Contributors IDF, DB-B and YHM conceptualised and designed the study; VS-J, AFE-B and IDF developed the search strategy. VS-J wrote the manuscript under the supervision of DB-B, JA-R and IDF. VS-J, YHM, DB-B, AFE-B, JA-R and IDF critically reviewed the protocol and manuscript submitted. All authors provided substantive feedback on the manuscript and have read and approved the final version. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding This work was supported by Ministerio de Ciencia, Tecnología e Innovación (MinCiencias) with grants number 902-2019 and 088-2021.
Competing interests VS-J attended a Master Class on Reproductive and Evidenced-Based Medicine financed by Abbott Laboratories, a Medical Health Update Conference financed by Sanofi Aventis, and was a speaker for Virtual Training in Primary Healthcare financed by Lafrancol S.A.S. The other authors certify that they have no affiliations with or involvement in any organisation or entity with any financial or non-financial interest in the subject matter or materials discussed.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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