Efficacy, safety, and pharmacokinetics of isoniazid affected by NAT2 polymorphisms in patients with tuberculosis: A systematic review.

N-acetyltransferase 2 (NAT2) genetic polymorphisms might alter isoniazid metabolism leading to toxicity. We reviewed the impact of NAT2 genotype status on the pharmacokinetics, efficacy, and safety of isoniazid, a treatment for tuberculosis (TB). A systematic search for research articles published in Scopus, PubMed, and Embase until August 31, 2023, was conducted without filters or limits on the following search terms and Boolean operators: "isoniazid" AND "NAT2." Studies were selected if NAT2 phenotypes with pharmacokinetics or efficacy or safety of isoniazid in patients with TB were reported. Patient characteristics, NAT2 status, isoniazid pharmacokinetic parameters, early treatment failure, and the prevalence of drug-induced liver injury were extracted. If the data were given as a median, these values were standardized to the mean. Forty-one pharmacokinetics and 53 safety studies were included, but only one efficacy study was identified. The average maximum concentrations of isoniazid were expressed as supratherapeutic concentrations in adults (7.16 ± 4.85 µg/mL) and children (6.43 ± 3.87 µg/mL) in slow acetylators. The mean prevalence of drug-induced liver injury was 36.23 ± 19.84 in slow acetylators, which was significantly different from the intermediate (19.49 ± 18.20) and rapid (20.47 ± 20.68) acetylators. Subgroup analysis by continent showed that the highest mean drug-induced liver injury prevalence was in Asian slow acetylators (42.83 ± 27.61). The incidence of early treatment failure was decreased by genotype-guided isoniazid dosing in one study. Traditional weight-based dosing of isoniazid in most children and adults yielded therapeutic isoniazid levels (except for slow acetylators). Drug-induced liver injury was more commonly observed in slow acetylators. Genotype-guided dosing may prevent early treatment failure.

Isoniazid use, effectiveness, and safety for treatment of latent tuberculosis infection: a systematic review.

BACKGROUND: The treatment strategy for latent tuberculosis infection is to reduce the number of tuberculosis cases and consequently reduce the transmission of pathogenic bacteria. This study aimed to determine the safety, effectiveness, and adherence of isoniazid use for latent tuberculosis infection treatment. METHODS: To identify studies on isoniazid use for latent tuberculosis infection, five electronic databases were searched. The methods and results are presented in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Most studies (53) used isoniazid for 9 months. The prevalence of use and adherence to treatment varied considerably (18% to 100%), and were evaluated by participant completion of isoniazid treatment for latent tuberculosis infection. The adverse events most frequently reported were hepatotoxicity, gastric intolerance, and neuropathy; the rates of occurrence ranged from < 1% to 48%. In the studies that evaluated the effectiveness of isoniazid for latent tuberculosis infection, the rate varied from 0 to 19.7% for patients who did not have active tuberculosis after the follow-up period. CONCLUSIONS: The importance of maintaining follow up for patients using isoniazid should be emphasized due to the risk of developing adverse events. Despite the treatment challenges, the rates of patients who used isoniazid and developed active tuberculosis during the follow-up period were low. We believe that isoniazid continues to contribute to tuberculosis control worldwide, and better care strategies are required.

Comparison of 3 optimized delivery strategies for completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: A single-center randomized trial.

BACKGROUND: Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies. METHODS AND FINDINGS: In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings. CONCLUSIONS: Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers. TRIAL REGISTRATION: ClinicalTrials.gov NCT03934931.

Efficacy and safety of rifampicin-based triple therapy for non-puerperal mastitis: A single-arm, open-label, prospective clinical trial.

OBJECTIVES: To assess the efficacy and safety of rifampicin-based triple therapy (rifampicin, isoniazid, and ethambutol) for treating NPM. METHODS: This single-center, single-arm, prospective clinical trial was conducted at the Second Hospital of Shandong University (Jinan, China). Patients with pathologically diagnosed granulomatous lobular mastitis and periductal mastitis received triple drugs, i.e., rifampicin (450 mg/day), isoniazid (300 mg/day), and ethambutol (15 mg/kg/day), until complete response or the investigator decided to discontinue treatment. The primary endpoint was the complete response rate (CRR) assessed by the investigator. The secondary endpoints included the overall remission rate (ORR), recurrence rate (RR), and safety. RESULTS: A total of 218 patients were enrolled in the study between January 1, 2013 and October 31, 2020. With a median follow-up time of 48 months, the CRR and the ORR were 78.44% and 94.04%, respectively. While 13 patients (5.96%) demonstrated no response and 19 relapsed (8.72%). Adverse events (AEs) were not common. The most common AEs during treatment were liver dysfunction (1.83%), gastrointestinal reactions (1.83%), fatigue (1.83%), erythema (1.38%), and menstrual disorders (0.92%). CONCLUSION: Rifampicin, isoniazid, and ethambutol demonstrated promising response rates with acceptable safety profiles in patients with NPM. Further confirmatory trial is warranted in the future. TRIAL REGISTRATION: The study was approved by the Ethics Committee of the Second Hospital of Shandong University and retrospectively registered at the China Clinical Trial Registration Center (registration number: ChiCTR2100049591).

The effect of antenatal isoniazid preventive therapy on birth outcomes in Western Kenya.

BACKGROUND: Pregnant women living with HIV (WLHIV) are at high risk for TB. There are limited data to inform whether TB preventive therapy is safe in pregnancy.METHODS: We completed a retrospective study of antenatal and birth records of mother-infant dyads at two health care facilities in Kisumu, Kenya. Among pregnant WLHIV, we assessed the relationship of antenatal isoniazid preventive therapy (IPT) with birth outcomes (preterm birth, low birth weight [LBW], congenital anomalies, and perinatal death).RESULTS: Of 576 mother-infant pairs, most women were on antiretroviral therapy (574, 99.7%) with viral suppression (518, 89.9%) and one-quarter had IPT exposure during pregnancy (152, 26.4%). The prevalence of preterm birth was lower among women with antenatal IPT exposure (21% vs. 30%; P = 0.03). LBW, congenital anomaly and perinatal death were not associated with antenatal IPT; however, we observed a trend toward fewer composite poor birth outcomes among women taking antenatal IPT (26% vs 33%; P = 0.08). Controlling for maternal age and viral load, IPT use during pregnancy was associated with lower odds of preterm birth (aOR 0.62, 95% CI 0.40-0.98; P = 0.04).CONCLUSION: In a programmatic setting in Western Kenya, IPT use was not associated with adverse birth outcomes.

Anti-tubercular therapy (ATT) induced thrombocytopenia: A systematic review.

INTRODUCTION: Drug-induced thrombocytopenia is a known adverse event of several drugs. Antitubercular therapy (ATT) is rarely reported but important cause of thrombocytopenia. The present review aimed to understand the profile of thrombocytopenia caused by first-line ATT i.e. isoniazid, rifampicin, pyrazinamide, and ethambutol. MATERIALS AND METHODS: We screened case reports, case series, and letter-to-editor from databases, like Pubmed/MEDLINE, Ovid, and EMBASE from 1970 to 2021. The PRISMA guidelines were followed in the present systematic review. RESULTS: Categorical data were expressed as n (%) and quantitative data were expressed as median (IQR). After applying the inclusion/exclusion criteria, 17 case reports and 7 letters to the editor were selected for the present review. Rifampicin was most frequently associated with thrombocytopenia (65%). A median (IQR) drop to 20,000 (49,500) platelets/mm3 was observed. Anti-rifampicin associated antibodies and anti-dsDNA positivity were found in six studies. Except for two, all patients responded to symptomatic treatment. DISCUSSION: ATT-induced thrombocytopenia can be life-threatening and require hospitalization. Clinicians should be aware of the association of ATT with thrombocytopenia and should take appropriate measures for patient management. CONCLUSION: This review provides clinicians a comprehensive picture of adverse effects and their management in ATT induced thrombocytopenia.

Financial incentives for reduced alcohol use and increased isoniazid adherence during tuberculosis preventive therapy among people with HIV in Uganda: an open-label, factorial randomised controlled trial.

BACKGROUND: Alcohol use is common among people with HIV and is a risk factor for tuberculosis disease and non-adherence to isoniazid preventive therapy (IPT). Few interventions exist to reduce alcohol use and increase IPT adherence in sub-Saharan Africa. The aim of this study was to test the hypothesis that financial incentives conditional on point-of-care negative urine alcohol biomarker testing and positive urine isoniazid testing would reduce alcohol use and increase isoniazid adherence, respectively, in people with HIV who have latent tuberculosis infection and hazardous alcohol use. METHODS: We conducted an open-label, 2×2 factorial randomised controlled trial in Uganda. Eligible for the study were non-pregnant HIV-positive adults (aged ≥18 years) prescribed antiretroviral therapy for at least 6 months, with current heavy alcohol use confirmed by urine ethyl glucuronide (biomarker of recent alcohol use) and a positive Alcohol Use Disorders Identification Test-Consumption (AUDIT-C; ≥3 for women, ≥4 for men) for the past 3 months' drinking, no history of active tuberculosis, tuberculosis treatment, or tuberculosis preventive therapy, and a positive tuberculin skin test. We randomly assigned participants (1:1:1:1) initiating 6 months of IPT to: no incentives (group 1); or incentives for recent alcohol abstinence (group 2), isoniazid adherence (group 3), or both (group 4). Escalating incentives were contingent on monthly point-of-care urine tests negative for ethyl glucuronide (groups 2 and 4), or positive on IsoScreen (biomarker of recent isoniazid use; groups 3 and 4). The primary alcohol outcome was non-hazardous use by self-report (AUDIT-C <3 for women, <4 for men) and phosphatidylethanol (PEth; past-month alcohol biomarker) <35 ng/mL at 3 months and 6 months. The primary isoniazid adherence outcome was more than 90% bottle opening of days prescribed. We performed intention-to-treat analyses. This trial is registered with ClinicalTrials.gov (NCT03492216), and is complete. FINDINGS: From April 16, 2018, to Aug 2, 2021, 5508 people were screened, of whom 680 were randomly assigned: 169 to group 1, 169 to group 2, 170 to group 3, and 172 to group 4. The median age of participants was 39 years (IQR 32-47), 470 (69%) were male, 598 (90%) of 663 had HIV RNA viral loads of less than 40 copies per mL, median AUDIT-C score was 6 (IQR 4-8), and median PEth was 252 ng/mL (IQR 87-579). Among 636 participants who completed the trial with alcohol use endpoint measures (group 1: 152, group 2: 159, group 3: 161, group 4: 164), non-hazardous alcohol use was more likely in the groups with incentives for alcohol abstinence (groups 2 and 4) versus no alcohol incentives (groups 1 and 3): 57 (17·6%) of 323 versus 31 (9·9%) of 313, respectively; adjusted risk difference (aRD) 7·6% (95% CI 2·7 to 12·5, p=0·0025). Among 656 participants who completed the trial with isoniazid adherence endpoint measures (group 1: 158, group 2: 163, group 3: 168, group 4: 167), incentives for isoniazid adherence did not increase adherence: 244 (72·8%) of 335 in the isoniazid incentive groups (groups 3 and 4) versus 234 (72·9%) of 321 in the no isoniazid incentive groups (groups 1 and 2); aRD -0·2% (95% CI -7·0 to 6·5, p=0·94). Overall, 53 (8%) of 680 participants discontinued isoniazid due to grade 3 or higher adverse events. There was no significant association between randomisation group and hepatotoxicity resulting in isoniazid discontinuation, after adjusting for sex and site. INTERPRETATION: Escalating financial incentives contingent on recent alcohol abstinence led to significantly lower biomarker-confirmed alcohol use versus control, but incentives for recent isoniazid adherence did not lead to changes in adherence. The alcohol intervention was efficacious despite less intensive frequency of incentives and clinic visits than traditional programmes for substance use, suggesting that pragmatic modifications of contingency management for resource-limited settings can have efficacy and that further evaluation of implementation is merited. FUNDING: National Institute on Alcohol Abuse and Alcoholism. TRANSLATION: For the Runyankole translation of the abstract see Supplementary Materials section.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Association of Cytochrome P450 2E1 and N-Acetyltransferase 2 Genotypes with Serum Isoniazid Level and Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Cross-Sectional Study.

Background: Anti-tuberculosis drug-induced hepatotoxicity can result from genetic polymorphism of the isoniazid (INH) metabolizing enzyme. This study aimed to determine the effect of genetic polymorphism of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genes on serum isoniazid level and drug-induced hepatotoxicity. Methods: A cross-sectional study was conducted on 120 patients (with and without hepatotoxicity) with pulmonary tuberculosis from June 2019 to April 2022 in Tehran (Iran). High-performance liquid chromatography was used to measure the serum concentration of INH and acetylisoniazid (AcINH). NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Data were analyzed using SPSS software (version 22.0) with independent two-sample t test, Chi square test, or Fisher's exact test. P<0.05 was considered statistically significant. Results: A total of 40 patients showed hepatotoxicity. The risk of anti-tuberculosis drug-induced hepatotoxicity was significantly higher in patients who are slow acetylator (SA) phenotype than in rapid or intermediate acetylator (P<0.001). NAT2*4/*4 genotypes were not found in patients with hepatotoxicity. The frequency of NAT2*5 and NAT2*6 haplotypes and serum INH concentration was significantly higher in patients with hepatotoxicity than in those without (P=0.003, P<0.001, and P<0.001, respectively). NAT2*4 haplotype was correlated with protection against hepatotoxicity. A combination of SA and CYP2E1 C1/C1 genotype was significantly associated with hepatotoxicity (P<0.001). Conclusion: Hepatotoxicity in Iranian patients with tuberculosis was confirmed due to the presence of NAT2 SA polymorphism. Determining NAT2 and CYP2E1 genotypes and/or INH concentration can be a valuable tool to identify patients susceptible to hepatotoxicity.

Efficacy of anti-tuberculosis drugs for the treatment of latent tuberculosis infection: a systematic review and network meta-analysis.

Despite the availability of three network meta-analyses (NMA) examining the efficacy, treatment completion, and adverse events associated with all latent tuberculosis infection (LTBI) treatments, there is currently no evidence to support the notion that the benefits of these treatments outweigh the potential risks. This NMA aimed to conduct a comprehensive comparison and update of the efficacy, treatment completion rates and adverse events associated with recommended treatment options for LTBI for individuals with confirmed LTBI, as outlined in the 2020 World Health Organization (WHO) Consolidated Guidelines for TB preventive treatment. A comprehensive search of the MEDLINE and Scopus databases was conducted until April 2023. The NMA was applied to estimate the risk difference and corresponding 95% confidence interval (CI) using a combination of direct and indirect evidence. The risk-benefit assessment was employed to evaluate the feasibility of the extra benefits in relation to the extra risks. The primary outcomes of interest in this study were active TB disease, completion rates, and adverse events. The meta-analysis incorporated data from 15 studies, which collectively demonstrated that the administration of a placebo resulted in a significant increase in the risk of developing TB disease by 1.279%, compared to the daily intake of isoniazid for 6 months (6H). Furthermore, treatment completion rates were significantly higher when using isoniazid plus rifapentine weekly for 3 months (3HP) and rifampicin daily for 4 months (4R), as compared to 6H. Considering adverse events, the combination of 3HP, 4R, and isoniazid administered daily for 9 months (referred to as 9H) significantly decreased adverse events by 4.53% in comparison to 6H. The risk-benefit assessment showed that alternative treatment regimens (9H, 4R, 3HR and 3HP) had a lower incidence of adverse events, while demonstrating a higher efficacy in preventing TB, as compared to 6H. This review indicates that there were no significant differences observed among various active treatment options in terms of their efficacy in preventing active TB. Moreover, completion rates were higher in 3HP and 4R, and a reduction in adverse events was observed in 3HP, 4R, and 9H.

Correlation of N-acetyltransferase 2 genotype and acetylation status with plasma isoniazid concentration and its metabolic ratio in ethiopian tuberculosis patients.

Unfavorable treatment outcomes for tuberculosis (TB) treatment might result from altered plasma exposure to antitubercular drugs in TB patients. The present study investigated the distribution of the N-Acetyltransferase 2 (NAT2) genotype, isoniazid acetylation status, genotype-phenotype concordance of NAT2, and isoniazid plasma exposure among Ethiopian tuberculosis patients. Blood samples were collected from newly diagnosed TB patients receiving a fixed dose combination of first-line antitubercular drugs daily. Genotyping of NAT2 was done using TaqMan drug metabolism assay. Isoniazid and its metabolite concentration were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 120 patients (63 male and 57 female) were enrolled in this study. The mean daily dose of isoniazid was 4.71 mg/kg. The frequency of slow, intermediate, and fast NAT2 acetylators genotypes were 74.2%, 22.4%, and 3.3% respectively. The overall median isoniazid maximum plasma concentration (Cmax) was 4.77 µg/mL and the AUC0-7 h was 11.21 µg.h/mL. The median Cmax in slow, intermediate, and fast acetylators were 5.65, 3.44, and 2.47 µg/mL, respectively. The median AUC0-7 h hour in slow, intermediate, and fast acetylators were 13.1, 6.086, and 3.73 mg•h/L, respectively. The majority (87.5%) of the study participants achieved isoniazid Cmax of above 3 µg/mL, which is considered a lower limit for a favorable treatment outcome. There is 85% concordance between the NAT2 genotype and acetylation phenotypes. NAT2 genotype, female sex, and dose were independent predictors of Cmax and AUC0-7 h (p < 0.001). Our finding revealed that there is a high frequency of slow NAT2 genotypes. The plasma Cmax of isoniazid was higher in the female and slow acetylators genotype group. The overall target plasma isoniazid concentrations in Ethiopian tuberculosis patients were achieved in the majority of the patients. Therefore, it is important to monitor adverse drug reactions and the use of a higher dose of isoniazid should be closely monitored.

The Effect of Bergenin on Isonicotinic Acid Hydrazide and Rifampicin-Induced Liver Injury Revealed by RNA Sequencing.

Bergenin (BER), a natural component of polyphenols, has a variety of pharmacological activities, especially in improving drug metabolism, reducing cholestasis, anti-oxidative stress and inhibiting inflammatory responses. The aim of this study was to investigate the effects of BER on liver injury induced by isonicotinic acid hydrazide (INH) and rifampicin (RIF) in mice. The mice model of liver injury was established with INH (100 mg/kg)+RIF (100 mg/kg), and then different doses of BER were used to intervene. The pathological morphology and biochemical indicators of mice were detected. Meanwhile, RNA sequencing was performed to screen the differentially expressed genes and signaling pathways. Finally, critical differentially expressed genes were verified by qRT-PCR and Western blot. RNA sequencing results showed that 707 genes were significantly changed in the INH+RIF group compared with the Control group, and 496 genes were significantly changed after the BER intervention. These differentially expressed genes were mainly enriched in the drug metabolism, bile acid metabolism, Nrf2 pathway and TLR4 pathway. The validation results of qRT-PCR and Western blot were consistent with the RNA sequencing. Therefore, BER alleviated INH+RIF-induced liver injury in mice. The mechanism of BER improving INH+RIF-induced liver injury was related to regulating drug metabolism enzymes, bile acid metabolism, Nrf2 pathway and TLR4 pathway.

Real-world experience of adverse reactions-necessitated rifampicin-sparing treatment for drug-susceptible pulmonary tuberculosis.

Rifampicin is an important agent for tuberculosis treatment; however, it is often discontinued because of adverse reactions. The treatment regimen then can be administered as that for rifampicin-resistant tuberculosis, which can be toxic. We retrospectively reviewed 114 patients with drug-susceptible pulmonary tuberculosis who discontinued rifampicin due to adverse reactions during an 18 year period at a tertiary referral center, of which 92 (80.7%) exhibited favorable response. Hepatotoxicity was the leading cause of intolerance. Patients with a favorable response were younger and less likely to have comorbidities. The majority of patients were administered four medications during the intensive phase and three to four during the consolidative phase. For those with a favorable response, the median duration of treatment was 10.2 months and the most common intensive regimen was a combination of isoniazid, ethambutol, pyrazinamide, and fluoroquinolone (25%). The most common consolidation regimen was a combination of isoniazid, ethambutol, and fluoroquinolone (22.8%). Among the patients with a favorable response, two (2.2%) experienced recurrence after a follow-up of 3.4 (interquartile range 1.8-6.8) years. For patients with drug-susceptible pulmonary tuberculosis who do not tolerate rifampicin owing to its toxicity, a shorter regimen may be a useful alternative.

Safety and tolerability of isoniazid preventive therapy for tuberculosis for persons with HIV with and without alcohol use.

OBJECTIVE: Isoniazid (INH) preventive therapy is recommended to prevent tuberculosis (TB) disease for persons with HIV (PWH), except for those with regular and heavy alcohol consumption, due to hepatotoxicity concerns. We aimed to quantify the incidence of severe INH-related toxicity among PWH with and without recent alcohol consumption. DESIGN: A prospective study of PWH receiving INH. METHODS: We included PWH in southwest Uganda with recent (prior 3 months) ( n  = 200) or no (prior year) self-reported alcohol consumption ( n  = 101), on antiretroviral therapy, TB infected (≥5 mm on tuberculin skin test), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2× or less the upper limit of normal (ULN). Grade 3+ INH-related toxicity was ALT or AST at least 5× the ULN or severe symptoms; we stopped IPT upon detection. Grade 2 INH-related toxicity was ALT or AST 2-5× the ULN or moderate symptoms. RESULTS: The cumulative incidence of Grade 3+ INH-related toxicity was 8.3% [95% confidence interval (95% CI) 5.4-12.0]; all resolved after INH cessation. Incidence was 6.0% (95% CI 3.1-10.2) among those reporting recent alcohol use and 12.9% (95% CI 7.0-21.0) among those reporting no prior year alcohol use. We found no differences by baseline phosphatidylethanol-confirmed alcohol severity. The cumulative incidence of Grade 2 toxicities (without Grade 3+) was 21.7% (95% CI 17.0-27.1); 25.0% (95% CI 19.0-31.8) among those with recent alcohol use and 14.8% (95% CI 8.1-23.9) among those with no prior year alcohol use. CONCLUSION: Alcohol use does not appear to increase risk for serious INH-related toxicity among PWH without significant liver enzyme elevations at baseline (≤2x ULN).

A Systematic Review and Meta-Analysis of Tuberculous Preventative Therapy Adverse Events.

BACKGROUND: Tuberculosis preventative therapy (TPT) is a key part of the World Health Organization's (WHO) end tuberculosis (TB) strategy. However, the occurrence of potentially serious adverse events (AE) is a limitation of TPT regimens. We conducted a systemic review and meta-analysis to estimate the incidence of AE and hepatotoxicity with various TPT regimens to help inform clinical decision making. METHODS: We searched MEDLINE, Cochrane, Health Star, and EMBASE from 1952 to April 2021 for studies reporting AE associated with TPT. Included studies reported AE stratified by regimen and provided the number of participants receiving each regimen. We used a random-effect model to meta-analyze the cumulative incidence of AE. RESULTS: We included 175 publications describing TPT-related AE in 277 cohorts. Among adults, the incidence of any AE, and hepatotoxicity leading to drug discontinuation was 3.7% and 1.1%, respectively, compared to 0.4% and 0.02%, respectively, in children. The highest incidence of any AE, and AE leading to drug discontinuation was with 3 months isoniazid and rifapentine (3HP), and the lowest was with 4 months rifampin (4R). 4R also had the lowest incidence of hepato-toxic AE and drug discontinuation due to hepato-toxic AE. 3HP also had a low incidence of hepato-toxic AE. CONCLUSIONS: Although our study was limited by variability in methods and quality of AE reporting in the studies reviewed, pediatric populations had a very low incidence of AE with all TPT regimens reviewed. In adults, compared to mono-H regimens all rifamycin-based regimens were safer, although 4R had the lowest incidence of TPT-related AE of all types and of hepatotoxicity.

High rate of adverse drug reactions with a novel tuberculosis re-treatment regimen combining triple doses of both isoniazid and rifampicin.

OBJECTIVES: High-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. The primary objective of the TRIple-DOse RE-treatment (TRIDORE) study is to determine whether a 6-month firstline regimen with triple dose of both R and H (intervention arm; 6R3H3ZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with R-susceptible (Rs) recurrent tuberculosis (TB). DESIGN/METHODS: TRIDORE is an ongoing pragmatic open-label multi-stage randomized clinical trial. RESULTS: Between March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6R3H3ZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and the median age (interquartile range) was 37 (30-48) years. The median body mass index at enrollment was 18.1 (16.3-19.7) kg/m2. Drugrelated severe adverse events (AEs) (grade III-V) were significantly more frequent when 6R3H3ZE was used (5/62 vs 0/65, P = 0.03, difference weighted for site 8% [95% confidence interval: 1.0,14.3]). The Data and Safety Monitoring Board recommended publishing our interim safety data analysis. CONCLUSION: We show that the combination of triple-dose R with triple-dose H in a re-treatment regimen for patients with Rs-TB causes excess drug-related AEs.

Screening for Latent Tuberculosis Infection in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Latent tuberculosis infection (LTBI) can progress to active tuberculosis disease, causing morbidity and mortality. Objective: To review the evidence on benefits and harms of screening for and treatment of LTBI in adults to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through December 3, 2021; references; experts; literature surveillance through January 20, 2023. Study Selection: English-language studies of LTBI screening, LTBI treatment, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of LTBI screening and treatment for public health surveillance or disease management were excluded. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when a sufficient number of similar studies were available. Main Outcomes and Measures: Screening test accuracy; development of active tuberculosis disease, transmission, quality of life, mortality, and harms. Results: A total of 113 publications were included (112 studies; N = 69 009). No studies directly evaluated the benefits and harms of screening. Pooled estimates for sensitivity of the TST were 0.80 (95% CI, 0.74-0.87) at the 5-mm induration threshold, 0.81 (95% CI, 0.76-0.87) at the 10-mm threshold, and 0.60 (95% CI, 0.46-0.74) at the 15-mm threshold. Pooled estimates for sensitivity of IGRA tests ranged from 0.81 (95% CI, 0.79-0.84) to 0.90 (95% CI, 0.87-0.92). Pooled estimates for specificity of screening tests ranged from 0.95 to 0.99. For treatment of LTBI, a large (n = 27 830), good-quality randomized clinical trial found a relative risk (RR) for progression to active tuberculosis at 5 years of 0.35 (95% CI, 0.24-0.52) for 24 weeks of isoniazid compared with placebo (number needed to treat, 112) and an increase in hepatotoxicity (RR, 4.59 [95% CI, 2.03-10.39]; number needed to harm, 279). A previously published meta-analysis reported that multiple regimens were efficacious compared with placebo or no treatment. Meta-analysis found greater risk for hepatotoxicity with isoniazid than with rifampin (pooled RR, 4.22 [95% CI, 2.21-8.06]; n = 7339). Conclusions and Relevance: No studies directly evaluated the benefits and harms of screening for LTBI compared with no screening. TST and IGRAs were moderately sensitive and highly specific. Treatment of LTBI with recommended regimens reduced the risk of progression to active tuberculosis. Isoniazid was associated with higher rates of hepatotoxicity than placebo or rifampin.