***TASK*** the task is to summarize an input biomedical literature in six sentences 
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    Input: Introduction St and ard treatment duration for drug-susceptible tuberculosis ( TB ) treatment is 6 months . Treatment duration is often extended— and for various different reasons . The aim of this study was to determine the prevalence and to assess risk factors associated with extended TB treatment . Methods A cross-sectional study was conducted . Data including demographic , clinical , radiological and microbiological information from the Netherl and s TB Register ( NTR ) of 90 patients with smear and culture positive pulmonary TB of the region Haagl and en , The Netherl and s , was eligible for analysis . Results Treatment was extended to ≥ 200 days by 46 ( 51 % ) patients . Extended TB treatment was associated with a higher frequency of symptoms , presumed to be due to adverse drug reactions ( ADR ; OR 2.39 95 % CI : 1.01–5.69 ) , drug-induced liver injury ( DILI ) ( OR : 13.51 ; 95 % CI : 1.66–109.82 ) and longer than 2 month smear and culture conversion rate ( OR : 11.00 ; 95 % CI : 1.24–97.96 and OR : 8.56 ; 95 % CI : 1.53–47.96 ) . In the multivariable logistic analysis , development of DILI emerged as the single statistically strong risk factor necessitating extension of TB treatment . Conclusion This finding will need further confirmation in a prospect i ve study , exploring the possible mutual role of pharmacokinetic and pharmacogenetic determinants of DILI among TB patients Background The available pharmacokinetic data on  anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when doses extrapolated from adult studies are used . Also , there is lack of consensus regarding the effect of malnutrition on pharmacokinetics of  anti-tubercular drugs in children . We conducted this study with the aims of determining the plasma concentrations of isoniazid , rifampicin , pyrazinamide and ethambutol achieved with different dosage of the anti-tubercular drugs so as to provide supportive evidence to the revised dosages and to evaluate the effects of malnutrition on the pharmacokinetics of these drugs in children . We also attempted to correlate the plasma concentrations of these drugs with clinical outcome of therapy . Method Prospect i ve drug estimation study was conducted in two groups of children , age 6 months to 15 years , with tuberculosis , with or without severe malnutrition , receiving different dosage of daily anti- tubercular therapy .  The dosage ( range ) of isoniazid was 5 ( 4 - 6 ) and 10 ( 7 - 15 ) mg/kg in the two groups , respectively , that of rifampicin-10 ( 8–12 ) and 15 ( 10–12 ) mg/kg , respectively , both the groups received same dose of pyrazinamide ( 30–35 mg/kg ) and ethambutol ( 20–25 mg/kg ) . All four drugs were simultaneously estimated by liquid chromatography-mass spectrometry ( LC-MS/MS ) . Results and conclusion The median ( IQR ) Cmax of isoniazid  increased significantly from 0.6 ( 0.3,1.2 ) μg/mL to 3.4 ( 1.8 , 5.0 ) μg/mL with increase in the dose . Plasma rifampicin concentrations increased only marginally on increasing the dose [ median ( IQR ) Cmax : 10.4 ( 7.2 , 13.9 ) μg/mL vs. 12.0 ( 6.1 , 24.3 ) μg/mL , p = 0.08 ] . For ethambutol , 55.9 % of the children had inadequate 2-hour concentrations . Two-hour plasma concentrations of at least one drug were low in 59 ( 92.2 % ) and 54 ( 85.7 % ) children in the two dosing regimen , respectively . We did not observe any effect of malnutrition on pharmacokinetic parameters of the drugs studied . We did not observe an association between low plasma drug concentrations and poor outcome . We may have to be cautious while increasing the doses and strive to asses other factors influencing the drug concentrations and treatment outcomes in children ABSTRACT Although human immunodeficiency virus ( HIV ) coinfection is the most important risk factor for a poor antituberculosis ( anti-TB ) treatment response , its effect on the pharmacokinetics of the first-line drugs in children is understudied . This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection . Ghanaian children with TB on isoniazid , rifampin , pyrazinamide , and ethambutol for at least 4 weeks had blood sample s collected predose and at 1 , 2 , 4 , and 8 hours postdose . Drug concentrations were determined by vali date d liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis . The area under the concentration-time curve from 0 to 8 h ( AUC0–8 ) , maximum concentration ( Cmax ) , and apparent oral clearance divided by bioavailability ( CL/F ) for each drug were compared between children with and without HIV coinfection . Of 113 participants , 59 ( 52.2 % ) had HIV coinfection . The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores ( P < 0.05 ) .  Rifampin , pyrazinamide , and ethambutol median body weight-normalized CL/F values were significantly higher , whereas the plasma AUC0–8 values were lower , in the coinfected children than in those with TB alone . In the multivariate analysis , drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC0–8 for rifampin , pyrazinamide , and ethambutol . Isoniazid pharmacokinetics were not different by HIV coinfection status . HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children . Whether TB/HIV-coinfected children need higher dosages of rifampin , pyrazinamide , and ethambutol requires further investigation . ( This study has been registered at Clinical Trials.gov under identifier NCT01687504 . To determine the risk of active tuberculosis associated with human immunodeficiency virus ( HIV ) infection , we prospect ively studied 520 intravenous drug users enrolled in a methadone-maintenance program .  Tuberculin skin testing and testing for HIV antibody  were performed in all subjects . Forty-nine of 217 HIV-seropositive subjects ( 23 percent ) and 62 of 303 HIV-seronegative subjects ( 20 percent ) had a positive response to skin testing with purified protein derivative ( PPD ) tuberculin before entry into the study . The rates of conversion from a negative to a positive PPD test were similar for seropositive subjects ( 15 of 131 ; 11 percent ) and seronegative subjects ( 26 of 202 ; 13 percent ) who were retested during the follow-up period ( mean , 22 months ) . Active tuberculosis developed in eight of the HIV-seropositive subjects ( 4 percent ) and none of the seronegative subjects during the study period ( P less than 0.002 ) . Seven of the eight cases of tuberculosis occurred in HIV-seropositive subjects with a prior positive PPD test ( 7.9 cases per 100 person-years , as compared with 0.3 case per 100 person-years among seropositive subjects without a prior positive PPD test ; rate ratio , 24.0 ; P less than 0.0001 ) . We conclude that , although the prevalence and incidence of tuberculous infection were similar for both HIV-seropositive and HIV-seronegative intravenous drug users , the risk of active tuberculosis was elevated only for seropositive subjects . These data also suggest that in HIV-infected persons tuberculosis most often results from the reactivation of latent tuberculous infection ; our results lend support to recommendations for the aggressive use of chemoprophylaxis against tuberculosis in patients with HIV infection and a positive PPD test BACKGROUND The occurrence of acquired rifamycin resistance despite use of directly observed therapy for tuberculosis is associated with advanced human immunodeficiency virus ( HIV ) disease and highly intermittent administration of antituberculosis drugs . Beyond these associations , the pathogenesis of acquired rifamycin resistance is unknown . METHODS We performed a pharmacokinetic sub study of patients in a trial of treatment with twice-weekly rifabutin and isoniazid .  RESULTS A total of 102 ( 60 % ) of 169 patients in the treatment trial participated in the pharmacokinetic sub study , including 7 of 8 patients in whom tuberculosis treatment failure or relapse occurred in association with acquired rifamycin-resistant mycobacteria ( hereafter , " ARR failure or relapse " ) . The median rifabutin area under the concentration-time curve ( AUC(0 - 24 ) ) was lower for patients with than for patients without ARR failure or relapse ( 3.3 vs. 5.2 microg*h/mL ; P = .06 , by the Mann-Whitney exact test ) . In a multivariate analysis adjusted for CD4 + T cell count , the mean rifabutin AUC(0 - 24 ) was significantly lower for patients with ARR failure or relapse than for other patients ( 3.0 microg*h/mL [ 95 % confidence interval { CI } , 1.9 - 4.5 ] vs. 5.2 microg*h/mL [ 95 % CI , 4.6 - 5.8 ] ; P = .02 , by analysis of covariance ) . The median isoniazid AUC(0 - 12 ) was not significantly associated with ARR failure or relapse ( 20.6 vs. 28.0 microg*h/mL ; P = .24 , by the Mann-Whitney exact test ) . However , in a multivariate logistic regression model that adjusted for the rifabutin AUC(0 - 24 ) , a lower isoniazid AUC(0 - 12 ) was associated with ARR failure or relapse ( OR , 10.5 ; 95 % CI , 1.1 - 100 ; P = .04 ) . CONCLUSIONS Lower plasma concentrations of rifabutin and , perhaps , isoniazid were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly therapy To test the hypothesis that antituberculous drug disposition is altered in patients with AIDS , we studied the steady-state pharmacokinetics of isoniazid ( 300 mg/d ) , rifampin ( 600 mg/d ) , and pyrazinamide ( 1,500 mg/d ) in 29 adults ( 14 patients infected with human immunodeficiency virus [ HIV ] and 15 non-HIV-infected patients ) with tuberculosis in Nairobi , Kenya . Intestinal integrity was assessed with xylose . Neither HIV infection nor diarrhea accounted for the interpatient variability in the area-under-the-plasma concentration vs. time curve ( AUC ) , the maximum concentration , or the terminal half-life ( t1/2 ) of isoniazid , rifampin , and pyrazinamide .  No significant association between HIV infection or diarrhea and pharmacokinetics was seen for any of the compounds . In addition , neither the AUC nor the t1/2 of any of these drugs reflected interpatient differences in CD4 lymphocyte counts . Xylose absorption was uniformly low . We did not demonstrate that HIV infection , diarrhea , or CD4 lymphocyte counts contributed significantly to the variability in pharmacokinetics of isoniazid , rifampin , and pyrazinamide  in TB patients in Nairobi BACKGROUND It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis ( MDR-tuberculosis ) emergence . The level of nonadherence associated with emergence of MDR-tuberculosis is unknown . Performance of a r and omized controlled trial in which some patients are r and omized to nonadherence would be unethical ; therefore , other study design s should be utilized . METHODS We performed hollow fiber studies for both bactericidal and sterilizing effect , with inoculum spiked with 0.5 % rifampin- and isoniazid-resistant isogenic strains in some experiments . St and ard therapy was administered daily for 28 - 56 days , with extents of nonadherence varying between 0 % and 100 % . Sizes of drug-resistant population s were compared using analysis of variance . We also explored the effect of pharmacokinetic variability on MDR-tuberculosis emergence using computer-aided clinical trial simulations of 10 000 Cape Town , South Africa , tuberculosis patients . RESULTS Therapy failure was only encountered at extents of nonadherence ≥60 % . Surprisingly , isoniazid- and rifampin-resistant population s did not achieve ≥1 % proportion in any experiment and did not achieve a higher proportion with nonadherence . However , clinical trial simulations demonstrated that approximately 1 % of tuberculosis patients with perfect adherence would still develop MDR-tuberculosis due to pharmacokinetic 
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Conclusions HIV infection may be one of several factors that reduce FLD exposure .