Search

CYP genetic variants and hepatotoxicity meta-analyses. (DOCX 38Â kb)

Results of the sensitivity analyses. (DOCX 62Â kb)

Funnel plots for the primary analyses. (DOCX 20Â kb)

PRISMA 2009 Checklist. (DOC 53Â kb)

Table S1. Key characteristics of included studies. (DOCX 40Â kb)

Table S4. Summary of results for other toxicity outcomes. (DOCX 16Â kb)

Search history. (DOCX 22Â kb)

Table S3. Definitions of other toxicity outcomes. (DOCX 15Â kb)

Table S2. Definitions of hepatotoxicity in the included studies. (DOCX 23Â kb)

Background Tuberculosis patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions, such as hepatotoxicity. Genetic risk factors, such as polymorphisms of the NAT2, CYP2E1 and GSTM1 genes, may increase the risk of experiencing such toxicity events. Many pharmacogenetic studies have investigated the association between genetic variants and anti-tuberculosis drug-related toxicity events, and several meta-analyses have synthesised data from these studies, although conclusions from these meta-analyses are conflicting. Many meta-analyses also have serious methodological limitations, such as applying restrictive inclusion criteria, or not assessing the quality of included studies. Most also only consider hepatotoxicity outcomes and specific genetic variants. The purpose of this systematic review and meta-analysis is to give a comprehensive evaluation of the evidence base for associations between any genetic variant and anti-tuberculosis drug-related toxicity. Methods We will search for studies in MEDLINE, EMBASE, BIOSIS and Web of Science. We will also hand search reference lists from relevant studies and contact experts in the field. We will include cohort studies, case–control studies and randomised controlled trials that recruited patients with tuberculosis who were either already established on anti-tuberculosis treatment or were commencing treatment and who were genotyped to investigate the effect of genetic variants on any anti-tuberculosis drug-related toxicity outcome. One author will screen abstracts to identify potentially relevant studies and will then obtain the full text for each potentially relevant study in order to assess eligibility. At each of these stages, a second author will independently screen/assess 10% of studies. Two authors will independently extract data and assess the quality of studies using a pre-piloted data extraction form. If appropriate, we will pool estimates of effect for each genotype on each outcome using meta-analyses stratified by ethnicity. Discussion Our review and meta-analysis will update and add to the existing research in this field. By not restricting the scope of the review to a specific drug, genetic variant, or toxicity outcome, we hope to synthesise data for associations between genetic variants and anti-tuberculosis drug-related toxicity outcomes that have previously not been summarised in systematic reviews, and consequently, add to the knowledge base of the pharmacogenetics of anti-tuberculosis drugs. Systematic review registration PROSPERO CRD42017068448 Electronic supplementary material The online version of this article (doi:10.1186/s13643-017-0533-4) contains supplementary material, which is available to authorized users.

Additional file 7. GRADE summary of findings table, mid-range dose (0.4â 0.5Â mg/kg) PQ compared to placebo in G6PD deficient people.

Search strategy. Outlining the search terms and search strategy that we will use to identify studies to include in our systematic review and meta-analysis. (DOCX 20 kb)

PRISMA-P 2015 checklist. Containing the populated PRISMA-P checklist table, demonstrating how this protocol has been prepared in accordance with the PRISMA-P statement. (DOCX 33 kb)

BACKGROUND\ud A discordant immune response (DIR) is a failure to satisfactorily increase CD4 counts on ART despite successful virological control. Literature on the clinical effects of DIR has not been systematically evaluated. We aimed to summarise the risk of mortality, AIDS and serious non-AIDS events associated with DIR with a systematic review.\ud \ud METHODS\ud The protocol is registered with the Centre for Review Dissemination, University of York (registration number CRD42014010821). Included studies investigated the effect of DIR on mortality, AIDS, or serious non-AIDS events in cohort studies or cohorts contained in arms of randomised controlled trials for adults aged 16 years or older. DIR was classified as a suboptimal CD4 count (as defined by the study) despite virological suppression following at least 6 months of ART. We systematically searched PubMed, Embase, and the Cochrane Library to December 2015. Risk of bias was assessed using the Cochrane tool for assessing risk of bias in cohort studies. Two authors applied inclusion criteria and one author extracted data. Risk ratios were calculated for each clinical outcome reported.\ud \ud RESULTS\ud Of 20 studies that met the inclusion criteria, 14 different definitions of DIR were used. Risk ratios for mortality in patients with and without DIR ranged between 1.00 (95% CI 0.26 to 3.92) and 4.29 (95% CI 1.96 to 9.38) with the majority of studies reporting a 2 to 3 fold increase in risk.\ud \ud CONCLUSIONS\ud DIR is associated with a marked increase in mortality in most studies but definitions vary widely. We propose a standardised definition to aid the development of management options for DIR.