Dataset Information

NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis.

ABSTRACT: BACKGROUND:Tuberculosis (TB) patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions (ADRs) such as hepatotoxicity. Variants of the N-acetyltransferase 2 (NAT2) gene may increase the risk of experiencing such toxicity events. OBJECTIVE:To provide a comprehensive evaluation of the evidence base for associations between NAT2 variants and anti-tuberculosis drug-related toxicity. METHOD:This was a systematic review and meta-analysis. We searched for studies in Medline, PubMed, EMBASE, BIOSIS and Web of Science. We included data from 41 articles (39 distinct cohorts of patients). We pooled effect estimates for each genotype on each outcome using meta-analyses stratified by country. RESULTS:We assessed the quality of the included studies, which was variable, with many areas of concern. Slow/intermediate NAT2 acetylators were statistically significantly more likely to experience hepatotoxicity than rapid acetylators (OR 1.59, 95%CI 1.26-2.01). Heterogeneity was not detected in the overall pooled analysis (I² = 0%). NAT2 acetylator status was significantly associated with the likelihood of experiencing anti-tuberculosis drug-related hepatotoxicity. CONCLUSION:We encountered several challenges in performing robust syntheses of data from pharmacogenetic studies, and we outline recommendations for the future reporting of pharmacogenetic studies to enable high-quality systematic reviews and meta-analyses to be performed.

SUBMITTER: Richardson M

PROVIDER: S-EPMC6421944 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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<i>NAT2</i> variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis.

Richardson M M Kirkham J J Dwan K K Sloan D J DJ Davies G G Jorgensen A L AL

The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 20190301 3

<h4>Background</h4>Tuberculosis (TB) patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions (ADRs) such as hepatotoxicity. Variants of the <i>N</i>-acetyltransferase 2 (<i>NAT2</i>) gene may increase the risk of experiencing such toxicity events.<h4>Objective</h4>To provide a comprehensive evaluation of the evidence base for associations between <i>NAT2</i> variants and anti-tuberculosis drug-related toxicity.<h4>Method</h4>This was a systematic review and m ...[more]

PMID: 30871660

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Project description:BackgroundTreatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes.MethodsWe searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies.ResultsWe included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56-1.00; p = 0.047, I2 = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38-48.68, I2 = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19-3.21, I2 = 0%).ConclusionsGenerally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants' ethnicity was sparsely reported in the included studies.Systematic review registrationPROSPERO registration number: CRD42017068448.

Project description:BackgroundTuberculosis 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.MethodsWe 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.DiscussionOur 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 registrationPROSPERO CRD42017068448.

Project description:BackgroundThe potential role of adjunctive anti-inflammatory therapy to enhance tuberculosis (TB) treatment has recently received increasing interest. There is, therefore, a need to broadly examine current host-directed therapies (HDTs) that could accelerate treatment response and improve TB outcomes.MethodsThis systematic review and meta-analysis included randomised controlled trials of vitamin D and other HDT agents in patients receiving antibiotic treatment for pulmonary TB. Sputum smear conversion rate at 4-8 weeks was the primary outcome. Secondary outcomes included blood indices associated with infectivity and inflammation, chest radiology and incidence of adverse events.ResultsFifty-five studies were screened for eligibility after the initial search, which yielded more than 1000 records. Of the 2540 participants in the 15 trials included in the meta-analysis, 1898 (74.7%) were male, and the age at entry ranged from 18 to 70 years. There was a 38% significantly (RR 1.38, 95% CI = 1.03-1.84) increased sputum smear negativity in patients administered with vitamin D in addition to standard TB treatment than those receiving only the TB treatment. Patients treated with other HDT anti-inflammatory agents in addition to TB treatment also had a 29% significantly increased sputum smear conversion rate (RR 1.29, 95% CI = 1.09-1.563). Lymphocyte to monocyte ratio was significantly higher in the vitamin D treatment groups compared to the controls (3.52 vs 2.70, 95% CI for difference 0.16-1.11, p = 0.009) and (adjusted mean difference 0.4, 95% CI 0.2 -- 0.6; p = 0.001); whilst tumour necrosis factor-alpha (TNF-α) showed a trend towards a reduction in prednisolone (p < 0.001) and pentoxifylline (p = 0.27) treatment groups. Vitamin D and N-acetylcysteine also accelerated radiographic resolution in treatment compared to placebo at 8 weeks. No differences were observed in the occurrence of adverse events among all HDT treatments.ConclusionsVitamin D and other anti-inflammatory HDT medications used as adjunct TB treatment may be well tolerated and effective. They significantly improved sputum smear conversion rate and chest radiological appearance, and also exhibited an inflammation resolution effect.

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NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis.

Publications

<i>NAT2</i> variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis.

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