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This percentage is higher than the overall national rate &#40;9&#46;2&#37;&#41; as well as that of the Northeast region &#40;8&#46;2&#37;&#41; <a class="elsevierStyleCrossRef" href="#bib0185">&#91;2&#93;</a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The occurrence of hepatotoxicity during the treatment of TB in people living with HIV&#47;AIDS &#40;PLWHA&#41;&#44; who experience difficulties inherent to a combination of the two diseases&#44; may cause a negative effect on the therapeutic regimen and in most cases&#44; lead to the discontinuation of treatment <a class="elsevierStyleCrossRef" href="#bib0190">&#91;3&#93;</a>&#46; In Brazil&#44; the incidence rate of hepatotoxicity following the use of drugs for TB treatment amongst those infected with HIV range between 31&#37; and 44&#37; <a class="elsevierStyleCrossRefs" href="#bib0195">&#91;4&#44;5&#93;</a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Isoniazid is one of the major drugs used to treat TB&#44; as recommended by the Brazilian Health Ministry&#44; and is a recognized cause of liver toxicity <a class="elsevierStyleCrossRef" href="#bib0205">&#91;6&#93;</a>&#46; The N-acetiltransferase2 enzyme &#40;<span class="elsevierStyleItalic">NAT2</span>&#41;&#44; encoded by the <span class="elsevierStyleItalic">NAT2</span> gene&#44; initiates the metabolism mechanism of isoniazid in the liver by biochemical acetylation&#44; which produces acetylisoniazid and isonicotinic acid&#46; Curiously&#44; the acetylation rate of isoniazid varies and depends on the genetic component of each individual&#44; which may be classified into rapid and slow acetylators <a class="elsevierStyleCrossRef" href="#bib0210">&#91;7&#93;</a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">There are reports in the literature describing various polymorphisms in genes that encode enzymes associated with hepatic metabolism&#44; such as cytochrome P450 2E1 &#40;<span class="elsevierStyleItalic">CYP2E1</span>&#41;&#44; glutathione S-transferase &#40;<span class="elsevierStyleItalic">GST</span>&#41; and manganese superoxide dismutase &#40;<span class="elsevierStyleItalic">MnSOD&#44; SOD2</span>&#41;&#44; and that are predisposed to hepatotoxicity induced by several substances <a class="elsevierStyleCrossRef" href="#bib0215">&#91;8&#93;</a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In effect&#44; <span class="elsevierStyleItalic">NAT2</span> polymorphism explains the bimodal frequency distribution after administrating identical doses of isoniazid to different individuals&#44; i&#46;e&#46; one group of rapid acetylators and another of slow acetylators <a class="elsevierStyleCrossRef" href="#bib0220">&#91;9&#93;</a>&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Despite considerable evidence from within several populations demonstrating that the relationship between developing hepatotoxicity and the distribution of <span class="elsevierStyleItalic">NAT2</span> encoding alleles differs according to ethnicity&#44; there are few studies that address this issue in Brazil&#44; and involve in their entirety&#44; PLWHA and the diagnosis of active tuberculosis <a class="elsevierStyleCrossRefs" href="#bib0225">&#91;10&#8211;13&#93;</a>&#46; The aim of this study was to investigate <span class="elsevierStyleItalic">NAT2</span> functional polymorphisms &#91;<span class="elsevierStyleItalic">NAT2&#42;5D&#44; NAT2&#42;6B&#44; NAT2&#42;7A&#44; NAT2&#42;11A&#44; NAT2&#42;12A&#44; NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;14A</span>&#93; associated with the development of hepatotoxicity after initiating treatment for TB in PLWHA in the state of Pernambuco&#44; Northeast Brazil&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0045">Design&#44; site and study population</span><p id="par0035" class="elsevierStylePara elsevierViewall">This was a prospective cohort study with 173 PLWHA diagnosed with active tuberculosis&#44; of both sexes&#44; aged between 20 and 67 years&#44; treated at the Hospital Correia Pican&#231;o&#44; in a specialized service for PLWHA in the state of Pernambuco&#44; Northeast Brazil&#46; In addition&#44; a further 80 healthy individuals without HIV infection or tuberculosis were used as a control group&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0050">Ethical aspects</span><p id="par0040" class="elsevierStylePara elsevierViewall">This study was approved by the Research Ethics Committee at the Universidade Federal de Pernambuco&#44; Brazil&#44; under protocol No&#46; 254&#47;05&#46; All participants in the study signed an Informed Consent Form&#44; as required by the statement on ethics contained in Resolution N&#176;466&#47;12 of the Brazilian National Health Council&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0055">Biological samples</span><p id="par0045" class="elsevierStylePara elsevierViewall">Peripheral vein blood samples &#40;10<span class="elsevierStyleHsp" style=""></span>mL&#41; were obtained from all studied patients at baseline and at the end of the first and second months on the follow-up visits to the health service&#44; irrespective of whether or not they presented symptoms of hepatitis&#44; to measure the aspartate aminotransferase &#40;AST&#41; and alanine aminotransferase &#40;ALT&#41; enzymes&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Healthy individuals&#44; enrolled on the National Register of Bone Marrow Voluntary Donors&#44; were randomly selected&#46; This group was composed of consanguineously unrelated individuals&#44; matched by geographic region&#44; so as to demonstrate that <span class="elsevierStyleItalic">NAT2</span> allele and genotype frequencies are present irrespective of HIV infection&#44; tuberculosis or hepatotoxicity&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0060">Defining the study variables</span><p id="par0055" class="elsevierStylePara elsevierViewall">Hepatotoxicity was defined as elevated aminotransferase levels and identified as being three times higher than before initiating TB treatment&#44; 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eutrophic &#40;18&#46;5<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>24&#46;9<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41; and overweight&#47;obese &#40;BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>25&#46;0<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The treatments for TB&#44; according to the Brazilian Ministry of Health&#44; were categorized as the RIP regimen &#40;consisting of three drugs&#58; rifampicin&#44; isoniazid and pyrazinamide&#41;&#44; and the newly recommended RIPE regimen &#40;consisting of four drugs&#58; rifampicin&#44; isoniazid&#44; pyrazinamide and ethambutol&#41; and others <a class="elsevierStyleCrossRef" href="#bib0245">&#91;14&#93;</a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The use of antiretroviral drugs at the time of initiating TB treatment was confirmed through medical records and categorized as&#58; not using HAART&#44; initiated HAART before TB treatment and initiated HAART during the first two months of TB treatment&#46; For the analysis&#44; we considered a CD4 count measured in the six months prior to initiating TB treatment&#44; and the variable was categorized as &#60;200<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span> and &#8805;200<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Patients were considered HIV-seropositive when they tested positive in two sequential tests&#44; in accordance with the recommendations of the Ministry of Health in Brazil&#46; The results of all the 346 tests for HIV antibodies conducted on the 173 PLWHA patients included in this study were positive&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">All patients who had initiated TB treatment due to clinical diagnosis or after a bacteriological test confirmation were said to have TB infection&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0065">Laboratory procedures</span><p id="par0085" class="elsevierStylePara elsevierViewall">The serological test used for the detection of HIV infection was the Rapid-check HIV1 &#38; 2 &#40;NDI-N&#250;cleo de Doen&#231;as Infecciosas&#44; Vit&#243;ria&#44; ES&#44; Brasil&#41; and the rapid test &#8211; HIV-1&#47;2 Bio-Manguinhos &#40;Funda&#231;&#227;o Oswaldo Cruz&#47;Biomanguinhos&#44; Rio de Janeiro&#44; Brasil&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T lymphocyte count was performed by flow cytometry using anti-CD4 antibodies labeled with fluorescent dyes through the BD FACSCalibur&#8482; system&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0070"><span class="elsevierStyleItalic">NAT2</span> polymorphism analysis</span><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">NAT2</span> genotypes were defined by direct sequencing&#44; comprising two <span class="elsevierStyleItalic">loci</span>&#46; Genomic DNA isolation was performed using the Biopur Extraction Kit &#8211; Mini Cent &#40;Biometrix&#174;&#44; Brazil&#41; according to the manufacturer&#39;s specifications&#46; After extraction&#44; DNA samples were stored at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C until use&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">PCRs were performed with two independent reactions&#44; as follows&#58; 36&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;l H<span class="elsevierStyleInf">2</span>O&#44; 5<span class="elsevierStyleHsp" style=""></span>&#956;l 10&#215; PCR buffer&#44; 2<span class="elsevierStyleHsp" style=""></span>&#956;l MgCl<span class="elsevierStyleInf">2</span> 50<span class="elsevierStyleHsp" style=""></span>mM&#44; 1<span class="elsevierStyleHsp" style=""></span>&#956;l 10<span class="elsevierStyleHsp" style=""></span>mM dNTP&#44; 2<span class="elsevierStyleHsp" style=""></span>&#956;l of each 10<span class="elsevierStyleHsp" style=""></span>mM primer&#44; 1<span class="elsevierStyleHsp" style=""></span>&#956;l DNA&#44; and also 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;l <span class="elsevierStyleItalic">Taq</span> &#40;5<span class="elsevierStyleHsp" style=""></span>U&#47;&#956;l&#41; to 50<span class="elsevierStyleHsp" style=""></span>&#956;l final volume&#46; The single nucleotide polymorphisms &#40;SNPs&#41; G191A &#40;<span class="elsevierStyleItalic">NAT2&#42;14A</span>&#41;&#44; C282T &#40;<span class="elsevierStyleItalic">NAT2&#42;13A</span>&#41; and T341C &#40;<span class="elsevierStyleItalic">NAT2&#42;5D</span>&#41; were evaluated using the 5&#8242;-CCTTACAGGGTTCTGAGACTAC-3&#8242; and 5&#8242;-GGTGCCTTGCATTTTCTGCT-3&#8242; pair primers and the following cycling parameters&#58; initial denaturation &#40;94<span class="elsevierStyleHsp" style=""></span>&#176;C&#47;3<span class="elsevierStyleHsp" style=""></span>min&#41;&#44; 35 cycles &#40;94<span class="elsevierStyleHsp" style=""></span>&#176;C&#47;1<span class="elsevierStyleHsp" style=""></span>min&#44; 50<span class="elsevierStyleHsp" style=""></span>&#176;C&#47;1<span class="elsevierStyleHsp" style=""></span>min&#44; and 72<span class="elsevierStyleHsp" style=""></span>&#176;C&#47;1<span class="elsevierStyleHsp" style=""></span>min&#41;&#44; and final extension at 72<span class="elsevierStyleHsp" style=""></span>&#176;C&#47;5<span class="elsevierStyleHsp" style=""></span>min&#46; On the other hand&#44; the SNPs C481T &#40;<span class="elsevierStyleItalic">NAT2&#42;11A</span>&#41;&#44; G590A &#40;<span class="elsevierStyleItalic">NAT2&#42;6B</span>&#41;&#44; A803G &#40;<span class="elsevierStyleItalic">NAT2&#42;12A</span>&#41; and G857A &#40;<span class="elsevierStyleItalic">NAT2&#42;7A</span>&#41; were evaluated using 5&#8217;-CATTGTCGATGCTGGGTCTG-3 and 5&#8217;-TCATCCATAAAAATGTCAGCATTT-3&#8242; primers with the same cycling parameters listed above&#44; except for the annealing temperature &#40;55<span class="elsevierStyleHsp" style=""></span>&#176;C&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The 667<span class="elsevierStyleHsp" style=""></span>bp and 665<span class="elsevierStyleHsp" style=""></span>bp amplicons were amplified respectively and analyzed by electrophoresis in 1&#37; agarose gel&#46; Direct sequencing was performed using the ABI PRISM BigDye Terminator v&#46;3&#46;1 Sequencing Kit &#40;PE Applied Biosystems&#41;&#46; Genotyping and sequence analysis were performed using the ApE-A-plasmid-Editor v2&#46;0&#46;45 with the GenBank accession n&#176; AY331807 sequence as a reference &#40;&#60;<a href="http://www.ncbi.nlm.nih.gov/nuccore/AY331807">www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;nuccore&#47;AY331807</a>&#62;&#41;&#44; following the International Committee for Gene Nomenclature NAT2 &#40;&#60;<a href="http://nat.mbg.duth.gr/">http&#58;&#47;&#47;nat&#46;mbg&#46;duth&#46;gr</a>&#62;&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">From amongst the 7 SNPs commonly found in the human population&#44; for predicting genotypes and phenotypes&#44; four SNPs&#44; which result in amino acid substitution and the consequent decrease in the acetylation capacity&#44; were analyzed&#46; Individuals who presented at least two variant alleles in any of the SNPs at positions 191A &#40;<span class="elsevierStyleItalic">NAT2&#42;14A</span>&#41;&#44; 341C &#40;<span class="elsevierStyleItalic">NAT2&#42;5D</span>&#41;&#44; 590A &#40;<span class="elsevierStyleItalic">NAT2&#42;6B</span>&#41; and 857A &#40;<span class="elsevierStyleItalic">NAT2&#42;7A</span>&#41; were classified as slow acetylators <a class="elsevierStyleCrossRef" href="#bib0250">&#91;15&#93;</a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The reference SNPs &#40;rs&#41; for the alleles <span class="elsevierStyleItalic">NAT2</span> studied were&#44; respectively&#58; rs1801280 &#40;<span class="elsevierStyleItalic">NAT2&#42;5D</span>&#41;&#44; rs1799930 &#40;<span class="elsevierStyleItalic">NAT2&#42;6B</span>&#41;&#44; rs1799931 &#40;<span class="elsevierStyleItalic">NAT2&#42;7A</span>&#41;&#44; rs1799929 &#40;<span class="elsevierStyleItalic">NAT2&#42;11A</span>&#41;&#44; rs1208 &#40;<span class="elsevierStyleItalic">NAT2&#42;12A</span>&#41;&#44; rs1041983 &#40;<span class="elsevierStyleItalic">NAT2&#42;13A</span>&#41; and rs1801279 &#40;<span class="elsevierStyleItalic">NAT2&#42;14A</span>&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0120" class="elsevierStylePara elsevierViewall">Data were stored in a database created for this research&#46; All data were double entered &#40;validated in EPI-INFO 6&#46;04&#41;&#44; and were subsequently compared to identify any possible typing errors&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The analysis was performed using STATA 12&#46;0 &#40;Statistical Software for Professionals&#44; StataCorp LP&#44; UK&#41;&#46; To check the statistical significance of differences in the frequency distribution of variables and the Hardy&#8211;Weinberg equilibrium&#44; the chi-square test was used&#44; or when necessary&#44; the Fisher exact test&#46; The bivariate logistic regression analysis was performed and the magnitude of the associations was expressed by the odds ratio &#40;OR&#41; as an estimate of relative risk&#44; with a confidence interval of 95&#37; regression and a significance level of 5&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Estimation for haplotypes frequency was based on the maximum likelihood method using Arlequin 3&#46;5&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0130" class="elsevierStylePara elsevierViewall">Amongst the 173 patients enrolled in this study&#44; 53 &#40;30&#46;6&#37;&#41; presented symptoms consistent with hepatitis and high aminotransferase levels&#44; three times higher than those recorded before initiating TB treatment&#46; These were the cases of hepatotoxicity&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> demonstrates the frequency distribution of biological and clinical variables of PLWHA with tuberculosis&#46; This cohort was predominantly male &#40;67&#37;&#41;&#44; just over half &#40;52&#37;&#41; were aged under 40&#44; with a greater proportion of eutrophic &#40;61&#37;&#41; and non-white &#40;79&#37;&#41; individuals&#46; It was found that the most commonly used therapeutic regimen for TB &#40;61&#37;&#41; was that of three drugs &#40;i&#46;e&#46;&#44; RIP &#8211; Rifampicin&#44; Isoniazid and Pyrazinamide&#41;&#44; and HAART &#40;Highly active antiretroviral therapy&#41; was being used by 78&#46;6&#37;&#44; the majority of whom had initiated HAART before treatment for TB &#40;49&#37;&#41;&#46; The antiretroviral regimen containing two NRTIs &#40;nucleoside reverse transcriptase inhibitors&#41; and one NNRTI &#40;non-nucleoside reverse transcriptase inhibitor&#41; was the most commonly used by HAART users &#40;60&#37;&#41;&#46; Slightly more than half &#40;59&#37;&#41; the population presented a CD4 level of less than 200<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span> and this was statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;022&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">Seven different SNPs&#44; previously known to be determinants of the acetylator phenotype were identified using <span class="elsevierStyleItalic">NAT2</span> sequencing in the study population and control group &#40;healthy individuals&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> describes the frequencies of these seven main mutations and their respective alleles related to the <span class="elsevierStyleItalic">NAT2</span> acetylator phenotype profile&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Thirteen alleles derived from these 7 common SNPs were verified&#44; the majority of which &#40;7&#47;13&#41; were classified phenotypically as slow acetylators&#46; The others &#40;5&#47;13&#41; were classified as rapid acetylators&#46; There was no statistically significant difference between the groups studied&#46; The most frequent allele observed with rapid acetylation was <span class="elsevierStyleItalic">NAT2&#42;4</span> &#40;86&#37;&#41;&#44; followed by <span class="elsevierStyleItalic">NAT2&#42;11A</span> &#40;7&#37;&#41;&#46; With regard to slow acetylation&#44; the most frequent allele was <span class="elsevierStyleItalic">NAT2&#42;5B</span> &#40;38&#37;&#41;&#44; followed by <span class="elsevierStyleItalic">NAT2&#42;5D</span> &#40;25&#37;&#41; and <span class="elsevierStyleItalic">NAT2&#42;6A</span> &#40;21&#37;&#41;&#46; The <span class="elsevierStyleItalic">NAT2</span> allele frequencies of both the healthy control subjects and PLWHA&#47;TB were very similar and were in Hardy-Weinberg equilibrium &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In the <span class="elsevierStyleItalic">NAT2&#42;14A</span>&#44; an absence was observed of the AA genotype variant&#44; both in the studied population and the control population&#46; Within this <span class="elsevierStyleItalic">locus&#44;</span> the most frequent genotype was GG &#40;89&#46;6&#37;&#41;&#46; For the <span class="elsevierStyleItalic">NAT2&#42;13A</span>&#44; the frequency of genotypes CC &#40;43&#46;3&#37;&#41; and CT &#40;46&#46;3&#37;&#41; was similar between the healthy and control groups&#46; In the <span class="elsevierStyleItalic">NAT2&#42;6B</span>&#44; there was a genotypic frequency of 58&#46;4&#37; GG&#44; GA 35&#46;3&#37; and 6&#46;3&#37; AA&#46; Amongst the 173 individuals analyzed&#44; only one individual presented the AA genotype variant in the <span class="elsevierStyleItalic">NAT2&#42;7A&#46;</span></p><p id="par0160" class="elsevierStylePara elsevierViewall">The frequencies of the variant <span class="elsevierStyleItalic">NAT2</span> allele amongst individuals from different Brazilian regions are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; In this cohort&#44; the allele frequencies of the study population were different to those encountered in the Par&#225; and Bahia populations&#46; The main difference in the Par&#225; population was in variant allele <span class="elsevierStyleItalic">NAT2&#42;6B</span>&#46; The frequency of this allele in the present study was 24&#37;&#44; while in the Par&#225; population the frequency of the same allele was 3&#46;2&#37;&#46; Another allele&#44; <span class="elsevierStyleItalic">NAT2&#42;5D</span>&#44; was more frequent in the Par&#225; population &#40;52&#37;&#41; when compared to the frequency of same allele in our population &#40;40&#37;&#41;&#44; with a statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;020&#41;&#46; The frequency of the variant allele <span class="elsevierStyleItalic">NAT2&#42;12A</span> in the Bahia population was lower &#40;21&#46;6&#37;&#41; than that observed in this population &#40;41&#46;1&#37;&#41;&#44; also with a statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">The hypothesis that PLWHA and TB patients encoding <span class="elsevierStyleItalic">NAT2</span> variant alleles would be more likely to develop hepatotoxicity during TB treatment was tested&#46; In order to perform such an analysis&#44; the PLWHA and TB group was stratified taking into account the clinical outcomes of hepatotoxicity and the potential correlation was observed between the seven SNPs and the clinical outcome&#46; It was found that the presence of the variant allele of both <span class="elsevierStyleItalic">NAT2&#42;13A</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;98&#44; 95&#37;CI &#40;1&#46;0&#8211;3&#46;9&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41; and <span class="elsevierStyleItalic">NAT2&#42;6B</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;93&#44; 95&#37;CI &#40;1&#46;0&#8211;3&#46;7&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41; constituted isolated risk factors for developing hepatotoxicity during TB treatment in PLWHA &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">In the population studied&#44; it was possible to define four haplotypes&#44; &#91;<span class="elsevierStyleItalic">NAT2&#42;4</span> &#40;GC&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;13A</span> &#40;GT&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;6B</span> &#40;AC&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;6A</span> &#40;AT&#41;&#93;&#44; with 8 genotype variants&#44; &#91;<span class="elsevierStyleItalic">NAT2&#42;4</span>&#47;<span class="elsevierStyleItalic">NAT2</span>&#42;<span class="elsevierStyleItalic">13A</span> &#40;GC&#47;GT&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;4</span>&#47;<span class="elsevierStyleItalic">NAT2&#42;6B</span> &#40;GC&#47;AC&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;13A</span> &#40;GT&#47;GT&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;13A</span>&#47;<span class="elsevierStyleItalic">NAT2&#42;6A</span> &#40;GT&#47;AT&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;13A</span>&#47;<span class="elsevierStyleItalic">NAT2&#42;6B</span> &#40;GT&#47;AC&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;6B</span>&#47;<span class="elsevierStyleItalic">NAT2&#42;6B</span> &#40;AC&#47;AC&#41;&#44; <span class="elsevierStyleItalic">NAT2&#42;6B</span>&#47;<span class="elsevierStyleItalic">NAT2&#42;6A</span> &#40;AC&#47;AT&#41; and <span class="elsevierStyleItalic">NAT2&#42;6A&#47;NAT2&#42;6A</span> &#40;AT&#47;AT&#41;&#93;&#44; and one wild type &#91;<span class="elsevierStyleItalic">NAT2&#42;4</span>&#47;<span class="elsevierStyleItalic">NAT2&#42;4</span> &#40;GC&#47;GC&#41;&#93; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In turn&#44; the individual comparison between the wild type and each genotype containing allele variants indicated that the risk of developing hepatotoxicity during TB treatment in individuals with HIV&#47;AIDS and signatures <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;13A</span> &#40;GT&#47;GT&#41; and <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;6B</span> &#40;GT&#47;AC&#41; was 4&#46;4 times greater&#44; and was statistically significant &#91;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#59; &#40;95&#37; CI 1&#46;1&#8211;18&#46;8&#41; and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#59; &#40;95&#37; CI 1&#46;5&#8211;12&#46;7&#41;&#44; respectively&#93;&#46; A borderline association of a risk for developing hepatotoxicity was demonstrated in the analysis between combined haplotypes involving the variant group and the wild type &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;3 &#40;95&#37; CI 1&#46;0&#8211;5&#46;4&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;052&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0180" class="elsevierStylePara elsevierViewall">The metabolic pathway of isoniazid has been the basis for most of the recent studies seeking to explain the pathogenic mechanism of liver damage induced by the use of antituberculosis drugs&#44; and the <span class="elsevierStyleItalic">NAT2</span> slow acetylator phenotype has been documented as a strong risk factor for the occurrence of such liver damage <a class="elsevierStyleCrossRefs" href="#bib0255">&#91;16&#44;17&#93;</a>&#46; In effect&#44; although some studies have indicated different opinions&#44; i&#46;e&#46;&#44; that rapid acetylators would be more vulnerable to liver damage induced by antituberculosis drugs due to the increased production of hepatotoxins&#44; resulting from the rapid <span class="elsevierStyleItalic">NAT2</span> enzyme activity&#44; and that there is no relationship between the acetylation profile and the hepatotoxicity induced by these drugs <a class="elsevierStyleCrossRefs" href="#bib0265">&#91;18&#44;19&#93;</a>&#44; it is nonetheless believed that individuals phenotypically classified as slow acetylators accumulate more acetyl hydrazine&#44; since it competes with the toxic metabolite of isoniazid by acetylation <a class="elsevierStyleCrossRef" href="#bib0275">&#91;20&#93;</a>&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">NAT2</span> is located on chromosome 8&#44; region 8p22&#44; where seven SNPs are commonly identified in its coding region&#44; in different world populations &#40;&#60;<a href="http://nat.mbg.duth.gr/">http&#58;&#47;&#47;nat&#46;mbg&#46;duth&#46;gr</a>&#62;&#41;&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The distribution and frequency of the alleles that encode the <span class="elsevierStyleItalic">NAT2</span> may vary considerably between different ethnic groups&#46; The <span class="elsevierStyleItalic">NAT2&#42;14A</span> is more common in native African populations and African Americans&#46; However&#44; it is virtually absent in the East&#46; The frequencies of the <span class="elsevierStyleItalic">NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;6B</span> are similar in most populations studied throughout the world&#46; In the case of <span class="elsevierStyleItalic">NAT2&#42;5D</span> and <span class="elsevierStyleItalic">NAT2&#42;7A</span>&#44; there was a greater frequency amongst Moroccans&#44; Amerindians and Asians&#46; <span class="elsevierStyleItalic">NAT2&#42;11A</span> and <span class="elsevierStyleItalic">NAT2&#42;12A</span> are rare in most populations <a class="elsevierStyleCrossRefs" href="#bib0215">&#91;8&#44;13&#44;21&#8211;24&#93;</a>&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The Brazilian population is made up of an extensive mix of three different ancestral roots&#58; Amerindians&#44; Europeans and Africans&#44; which makes it one of the most heterogeneous populations in the world <a class="elsevierStyleCrossRefs" href="#bib0300">&#91;25&#44;26&#93;</a>&#46; The first Brazilian studies describing the genotypic profile of <span class="elsevierStyleItalic">NAT2</span> were conducted in the states of Rio de Janeiro and Goi&#225;s where degrees of variation in the genotypic profile of <span class="elsevierStyleItalic">NAT2</span> were demonstrated <a class="elsevierStyleCrossRefs" href="#bib0230">&#91;11&#8211;27&#93;</a>&#46; The allele frequencies observed in our cohort were similar to those found in the populations of Rio de Janeiro and Goi&#225;s&#44; although they were different from the populations of the states of Par&#225; and Bahia <a class="elsevierStyleCrossRefs" href="#bib0310">&#91;27&#8211;29&#93;</a>&#46; These data reinforce the need for further studies in order to address this issue throughout the different regions of the country so that the genotypic profile of the <span class="elsevierStyleItalic">NAT2</span> in Brazil may be better explained&#46; In other Brazilian studies the data were restricted to reporting the acetylation phenotypic profile and therefore&#44; the allele and genotype frequencies were not presented <a class="elsevierStyleCrossRefs" href="#bib0195">&#91;4&#44;5&#44;30&#44;31&#93;</a>&#46; In this present approach&#44; for all the studied SNPs&#44; were observed that the allele and genotype frequencies of the healthy control population were similar to those observed in the test population &#40;PLWHA&#41;&#46; Thus&#44; we may affirm the good representation of the cohort for the state of Pernambuco&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">The presence of the variant allele in the <span class="elsevierStyleItalic">NAT2&#42;13A</span> &#40;282T&#41; and <span class="elsevierStyleItalic">NAT2&#42;6B</span> &#40;590A&#41; <span class="elsevierStyleItalic">loci</span> was an independent factor associated with elevated aminotransferase levels after initiating antituberculosis drugs in PLWHA &#91;&#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;98&#44; 95&#37;CI 1&#46;0&#8211;3&#46;9&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41; and &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;93&#44; 95&#37;CI 1&#46;0&#8211;3&#46;7&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41;&#44; respectively&#93;&#46; The <span class="elsevierStyleItalic">NAT2&#42;6B</span> is a non-synonymous polymorphism that involves the replacement of amino acid residue 197 Arg-Gln &#40;arginine-glutamine&#41; with a consequent decrease in the acetylation capacity&#44; due to a change in the catalytic site&#44; and which therefore justifies our findings <a class="elsevierStyleCrossRef" href="#bib0335">&#91;32&#93;</a>&#46; Poor individual metabolizers present low enzymatic efficiency of <span class="elsevierStyleItalic">NAT</span> acetyltransferase&#95;2&#44; and thereby allow more time for the drug to circulate in the body&#46; As a result&#44; the toxicity produced by the drug also becomes higher <a class="elsevierStyleCrossRef" href="#bib0340">&#91;33&#93;</a>&#46; In contrast to this&#44; the <span class="elsevierStyleItalic">NAT2&#42;13A</span> is a synonymous polymorphism&#44; i&#46;e&#46;&#44; its presence alone does not prompt a change in the peptide composition&#44; and is also unable to change the slow&#47;rapid molecular phenotype acetylator in patients <a class="elsevierStyleCrossRef" href="#bib0345">&#91;34&#93;</a>&#44; diverging from the risk association for hepatotoxicity associated with the <span class="elsevierStyleItalic">NAT2&#42;13A</span> in PLWHA&#44; as observed in the present study&#46; One recent publication on genetic context&#44; could be a key element in explaining the phenotype definition in genetically influenced diseases and the contradictory effects of individual genetic markers &#40;SNPs&#41; that have been observed in different populations <a class="elsevierStyleCrossRef" href="#bib0350">&#91;35&#93;</a>&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">The special conditions concerning two different coinfecting pathogens&#44; with concomitant treatment against HIV and TB&#44; and the potential interaction between them&#44; represent important confounding factors for the outcome of hepatotoxicity&#46; Indeed&#44; it has recently been described that the properties of using fluconazole&#44; being malnourished and the presence of a <span class="elsevierStyleItalic">NAT2</span> slow acetylator profile were each isolated risk factors for developing hepatotoxicity&#46; It is suspected that hepatitis B and C viruses and alcohol consumption may be associated with increased hepatotoxicity in PLWHA during tuberculosis therapy&#44; although in this previous study this association was not observed <a class="elsevierStyleCrossRef" href="#bib0195">&#91;4&#93;</a>&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">In the present study&#44; it has been verified that the BMI &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; and CD4 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;022&#41; were statistically associated with hepatotoxicity&#44; suggesting that these two variables were likely to be confounding factors&#46; Thus&#44; the analysis was undertaken of these two variables with the SNPs and it was verified that they presented no statistically significant difference&#46; This fact interferes with the definition of confounding factor&#46; It is therefore our belief that these two variables should not be used to adjust the model in logistic regression analysis&#46; It is a fact that drug interactions modify the response to pharmacotherapy and are also a risk for drug toxicity&#46; While on the one hand&#44; the use of HAART is associated with a higher risk of hepatotoxicity&#44; because it potentiates the hepatotoxic effect of the antituberculosis drugs&#44; on the other&#44; we also believe that the interaction between anti-HIV and antituberculosis drugs probably has no influence over the association between <span class="elsevierStyleItalic">NAT2</span> variants and hepatotoxicity&#46; Although most of the study population &#40;78&#46;6&#37;&#41; used HAART&#44; of whom 33&#46;9&#37; presented with hepatotoxicity during the first 60 days of TB treatment&#44; no statistically significant difference was observed between the use of HAART and the occurrence of hepatotoxicity&#46; We chose to analyze the combination of ARV classes due to the wide variation in the antiretroviral drugs used by the population studied&#46; Certainly&#44; if we had analyzed the association of each drug with the outcome&#44; the power of the study would have been limited&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Finally&#44; the present study has the limitations of an observational study with PLWHA attending a routine medical care setting&#46; The exposures related to drugs registered by the attending physician were studied&#46; We did not investigate the concomitant use of medicinal herbs in this population&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">The findings of this study have demonstrated that providing greater support for PLWHA undergoing treatment for tuberculosis may well contribute to greater control in managing the drugs used by this population&#44; especially those patients with genotypes <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;6B</span>&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">In conclusion&#44; this study suggests that <span class="elsevierStyleItalic">NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;6B</span> variant alleles are risk factors for developing hepatotoxicity&#44; and that PLWHA with genotypes <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;6B</span> present a higher chance of developing hepatotoxicity during tuberculosis treatment&#46; We believe that in the near future&#44; the treatment of tuberculosis should become individualized&#44; namely&#44; drugs and dosages should be adapted according to the <span class="elsevierStyleItalic">NAT2</span> phenotypic profile of each patient&#46; Further studies with different populations and larger sample sizes are required to verify the universality of our findings&#46;<span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0090">Abbreviations</span><span class="elsevierStyleDefTerm">AIDS</span><span class="elsevierStyleDefDescription"><p id="par0230" class="elsevierStylePara elsevierViewall">acquired immunodeficiency syndrome</p></span><span class="elsevierStyleDefTerm">ALT</span><span class="elsevierStyleDefDescription"><p id="par0235" class="elsevierStylePara elsevierViewall">alanine aminotransferase</p></span><span class="elsevierStyleDefTerm">Arg-Gln</span><span class="elsevierStyleDefDescription"><p id="par0240" class="elsevierStylePara elsevierViewall">arginine glutamine</p></span><span class="elsevierStyleDefTerm">ARV</span><span class="elsevierStyleDefDescription"><p id="par0245" class="elsevierStylePara elsevierViewall">antiretroviral therapy</p></span><span class="elsevierStyleDefTerm">AST</span><span class="elsevierStyleDefDescription"><p id="par0250" class="elsevierStylePara elsevierViewall">aspartate aminotransferase</p></span><span class="elsevierStyleDefTerm">BMI</span><span class="elsevierStyleDefDescription"><p id="par0255" class="elsevierStylePara elsevierViewall">body mass index</p></span><span class="elsevierStyleDefTerm">bp</span><span class="elsevierStyleDefDescription"><p id="par0260" class="elsevierStylePara elsevierViewall">base pairs</p></span><span class="elsevierStyleDefTerm">CD4</span><span class="elsevierStyleDefDescription"><p id="par0265" class="elsevierStylePara elsevierViewall">lymphocyte cell with cell membrane surface protein 4</p></span><span class="elsevierStyleDefTerm">CI</span><span class="elsevierStyleDefDescription"><p id="par0270" class="elsevierStylePara elsevierViewall">confidence interval</p></span><span class="elsevierStyleDefTerm"><span class="elsevierStyleItalic">CYP2E1</span></span><span class="elsevierStyleDefDescription"><p id="par0275" class="elsevierStylePara elsevierViewall">cytochrome P450 2E1</p></span><span class="elsevierStyleDefTerm">DNA</span><span class="elsevierStyleDefDescription"><p id="par0280" class="elsevierStylePara elsevierViewall">deoxyribonucleic acid</p></span><span class="elsevierStyleDefTerm">dNTP</span><span class="elsevierStyleDefDescription"><p id="par0285" class="elsevierStylePara elsevierViewall">deoxynucleotides</p></span><span class="elsevierStyleDefTerm"><span class="elsevierStyleItalic">GST</span></span><span class="elsevierStyleDefDescription"><p id="par0290" class="elsevierStylePara elsevierViewall">glutathione S-transferase</p></span><span class="elsevierStyleDefTerm">HAART</span><span class="elsevierStyleDefDescription"><p id="par0295" class="elsevierStylePara elsevierViewall">highly active antiretroviral therapy</p></span><span class="elsevierStyleDefTerm">HIV</span><span class="elsevierStyleDefDescription"><p id="par0300" class="elsevierStylePara elsevierViewall">human immunodeficiency virus</p></span><span class="elsevierStyleDefTerm">H<span class="elsevierStyleInf">2</span>O</span><span class="elsevierStyleDefDescription"><p id="par0305" class="elsevierStylePara elsevierViewall">water</p></span><span class="elsevierStyleDefTerm">MgCl<span class="elsevierStyleInf">2</span></span><span class="elsevierStyleDefDescription"><p id="par0310" class="elsevierStylePara elsevierViewall">magnesium chloride</p></span><span class="elsevierStyleDefTerm"><span class="elsevierStyleItalic">MnSOD&#44; SOD2</span></span><span class="elsevierStyleDefDescription"><p id="par0315" class="elsevierStylePara elsevierViewall">manganese superoxide dismutase</p></span><span class="elsevierStyleDefTerm"><span class="elsevierStyleItalic">NAT2</span></span><span class="elsevierStyleDefDescription"><p id="par0320" class="elsevierStylePara elsevierViewall">arylamine N-acetyltransferase</p></span><span class="elsevierStyleDefTerm">NNRTI</span><span class="elsevierStyleDefDescription"><p id="par0325" class="elsevierStylePara elsevierViewall">non-nucleoside reverse transcriptase inhibitor</p></span><span class="elsevierStyleDefTerm">NRTI</span><span class="elsevierStyleDefDescription"><p id="par0330" class="elsevierStylePara elsevierViewall">nucleoside reverse transcriptase inhibitor</p></span><span class="elsevierStyleDefTerm">OR</span><span class="elsevierStyleDefDescription"><p id="par0335" class="elsevierStylePara elsevierViewall">odds ratio</p></span><span class="elsevierStyleDefTerm">PCR</span><span class="elsevierStyleDefDescription"><p id="par0340" class="elsevierStylePara elsevierViewall">polymerase chain reaction</p></span><span class="elsevierStyleDefTerm">PLWHA</span><span class="elsevierStyleDefDescription"><p id="par0345" class="elsevierStylePara elsevierViewall">people living with HIV&#47;AIDS</p></span><span class="elsevierStyleDefTerm">PI&#47;r</span><span class="elsevierStyleDefDescription"><p id="par0350" class="elsevierStylePara elsevierViewall">protease inhibitor&#47;ritonavir</p></span><span class="elsevierStyleDefTerm">RIP</span><span class="elsevierStyleDefDescription"><p id="par0355" class="elsevierStylePara elsevierViewall">rifampicin&#44; isoniazid&#44; pyrazinamide</p></span><span class="elsevierStyleDefTerm">RIPE</span><span class="elsevierStyleDefDescription"><p id="par0360" class="elsevierStylePara elsevierViewall">rifampicin&#44; isoniazid&#44; pyrazinamide&#44; ethambutol</p></span><span class="elsevierStyleDefTerm">SNP</span><span class="elsevierStyleDefDescription"><p id="par0365" class="elsevierStylePara elsevierViewall">single nucleotide polymorphisms</p></span><span class="elsevierStyleDefTerm"><span class="elsevierStyleItalic">Taq</span> polymerase</span><span class="elsevierStyleDefDescription"><p id="par0370" class="elsevierStylePara elsevierViewall">thermus aquaticus polymerase</p></span><span class="elsevierStyleDefTerm">TB</span><span class="elsevierStyleDefDescription"><p id="par0375" class="elsevierStylePara elsevierViewall">tuberculosis</p></span><span class="elsevierStyleDefTerm">WHO</span><span class="elsevierStyleDefDescription"><p id="par0380" class="elsevierStylePara elsevierViewall">World Health Organization</p></span></span></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Author contribution</span><p id="par0385" class="elsevierStylePara elsevierViewall">All authors contributed equally to this article and all authors reviewed and approved the manuscript prior to submission&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Financial support</span><p id="par0390" class="elsevierStylePara elsevierViewall">This study received financial support from the <span class="elsevierStyleGrantSponsor" id="gs1">Brazilian Health Ministry&#47;DST&#47;AIDS&#47;UNESCO</span> &#40;CSV Project 182&#47;06&#41; and the <span class="elsevierStyleGrantSponsor" id="gs2">Ministry of Science and Technology CNPq&#47;MSSCTIE-DECIT</span> &#40;Case N&#176;10567&#47;2006-0&#41;&#46; The following authors received partial support from <span class="elsevierStyleGrantSponsor" id="gs3">CNPq</span>&#58; RAAX &#8211; Productivity Grant 308311&#47;2009-4&#59; MFPMA &#8211; Productivity Grant 301779&#47;2009-0&#59; and HRL &#8211; Study Grant <span class="elsevierStyleGrantNumber" refid="gs3">310911&#47;2009-5</span>&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical aspects</span><p id="par0395" class="elsevierStylePara elsevierViewall">This study was approved by the Research Ethics Committee at the Universidade Federal de Pernambuco&#44; Brazil&#44; under protocol No&#46; 254&#47;05&#46; All participants in the study signed an Informed Consent Form&#44; as required by the statement on ethics contained in Resolution N&#176;466&#47;12 of the Brazilian National Health Council&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0400" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            0 => "Arylamine N-acetyltransferase"
            1 => "Liver disease"
            2 => "Toxicity"
            3 => "Antitubercular drugs"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hepatotoxicity during tuberculosis &#40;TB&#41; treatment is frequent and may be related to the Arylamine N-Acetyltransferase &#40;<span class="elsevierStyleItalic">NAT2</span>&#41; acetylator profile&#44; in which allele frequencies differ according to the population&#46; The aim of this study was to investigate functional polymorphisms in <span class="elsevierStyleItalic">NAT2</span> associated with the development of hepatotoxicity after initiating treatment for TB in people living with HIV&#47;AIDS &#40;PLWHA&#41; in Pernambuco&#44; Northeast Brazil&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This was a prospective cohort study that investigated seven single nucleotide polymorphisms located in the <span class="elsevierStyleItalic">NAT2</span> coding region in 173 PLWHA undergoing TB treatment&#46; Hepatotoxicity was defined as elevated aminotransferase levels and identified as being three times higher than it was before initiating TB treatment&#44; with associated symptoms of hepatitis&#46; A further 80 healthy subjects&#44; without HIV infection or TB were used as a control group&#46; All individuals were genotyped by direct sequencing&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The <span class="elsevierStyleItalic">NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;6B</span> variant alleles were significantly associated with the development of hepatotoxicity during TB treatment in PLWHA &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Individual comparisons between the wild type and each variant genotype revealed that PLWHA with signatures <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;13A</span> &#40;OR 4&#46;4&#59; CI95&#37; 1&#46;1&#8211;18&#46;8&#59; <span class="elsevierStyleItalic">p</span> 0&#46;037&#41; and <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;6B</span> &#40;OR 4&#46;4&#59; CI95&#37; 1&#46;5&#8211;12&#46;7&#59; <span class="elsevierStyleItalic">p</span> 0&#46;005&#41; significantly increased the risk of hepatotoxicity&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study suggests that <span class="elsevierStyleItalic">NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;6B</span> variant alleles are risk factors for developing hepatotoxicity&#44; and PLWHA with genotypes <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;13A</span> and <span class="elsevierStyleItalic">NAT2&#42;13A&#47;NAT2&#42;6B</span> should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis&#46;</p></span>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">PLWHA &#40;People living with HIV&#47;AIDS&#41;&#44; BMI &#40;Body mass index&#41;&#44; <span class="elsevierStyleItalic">NAT2</span> &#40;Arylamine N-Acetyltransferase&#41;&#44; TB &#40;Tuberculosis&#41;&#44; RIP &#40;Rifampicin&#44; Isoniazid&#44; Pyrazinamide&#41;&#44; RIPE &#40;Rifampicin&#44; Isoniazid&#44; Pyrazinamide&#44; ethambutol&#41;&#44; HAART &#40;Highly active antiretroviral therapy&#41;&#44; ARV &#40;Antiretroviral therapy&#41;&#44; NRTI &#40;nucleoside reverse transcriptase inhibitor&#41;&#44; NNRTI &#40;Non-nucleoside reverse transcriptase inhibitor&#41;&#44; PI&#47;r &#40;Protease inhibitor&#47;ritonavir&#41;&#46;</p>"
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                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hepatotoxicity</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" colspan="2" style="border-bottom: 2px solid black">Total</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Variables&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Yes</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sex</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">67&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;216&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Age</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#60;40 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;40 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;368&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BMI</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Eutrophic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">105&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Malnourished&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;002</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Overweight&#47;obese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t">0&#46;279<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="8" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Skin color</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>White&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">98&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">79&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;230&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TB regimen</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RIP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">35&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">66&#46;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">71&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">59&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">106&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">61&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RIPE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">33&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">65&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">37&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;465&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">00&#46;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HAART</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Not using HAART&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Initiated HAART before TB treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;584&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Initiated HAART during the first two months of TB treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Rapid acetylator phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2 &#42; 4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;373&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2 &#42; 11A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2 &#42; 12A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2 &#42; 12C</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2 &#42; 13A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2253097.png"
              ]
            ]
            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Slow acetylator phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2 &#42; 5A</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;976&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2 &#42; 5B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">36&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Yes</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">OR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">CI&#40;95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>-Value<a class="elsevierStyleCrossRef" href="#tblfn0055"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>-Value<a class="elsevierStyleCrossRef" href="#tblfn0060"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2&#42;11A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rapid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;CT<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>TT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">108&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;0&#46;4&#8211;1&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;477&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;477&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NAT2&#42;12A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rapid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  """
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              "etiqueta" => "&#91;2&#93;"
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                  "referenciaCompleta" => "Brasil&#46; Boletim epidemiol&#243;gico &#8211; Coinfec&#231;&#227;o TB-HIV no Brasil&#58; panorama epidemiol&#243;gico e atividades colaborativas&#46; Bras&#237;lia&#58; Minist&#233;rio da Sa&#250;de&#59; 2017&#46;"
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