Silicosis predicts drug resistance and retreatment among tuberculosis patients in India: a secondary data analysis from Khambhat, Gujarat (2006-2022).

BACKGROUND: India, with the highest global burden of tuberculosis (TB) and drug-resistant TB, aims to eliminate TB by 2025. Yet, limited evidence exists on drug resistance patterns and retreatment among patients with silico-tuberculosis. This study explores these patterns and assesses the impact of silicosis on TB retreatment in India. METHODS: This secondary data analysis stems from a larger retrospective cohort study conducted in Khambhat, Gujarat, between January 2006 and February 2022. It included 138 patients with silico-tuberculosis and 2,610 TB patients without silicosis. Data from the Nikshay TB information portal were linked with silicosis diagnosis reports from the Pneumoconiosis Board using the unique Nikshay ID as the linking variable. Drug-resistant TB was defined as resistance to any anti-TB drug recorded in Nikshay. Retreatment refers to TB patients who have previously undergone anti-TB treatment for one month or more and need further treatment. Recurrent TB denotes patients who were previously declared cured or had completed treatment but later tested positive for microbiologically confirmed TB. Multivariable logistic regression was used to determine the impact of co-prevalent silicosis on drug resistance and retreatment. RESULTS: Patients with silico-tuberculosis showed a higher proportion of retreatment compared to those without silicosis (55% vs. 23%, p < 0.001). Notably, 28% of patients with silico-tuberculosis were recurrent TB cases, compared to 11% among those without silicosis. Regarding drug resistance, the silico-tuberculosis group exhibited a higher rate (6% vs. 3%), largely due to rifampicin resistance (5% vs. 2%, p = 0.022). Co-prevalent silicosis was associated with a 2.5 times greater risk of drug-resistant TB (adjusted OR 2.5, 95% CI, 1.1-5.3; p = 0.021). Additionally, patients with silico-tuberculosis had a fourfold increased risk of retreatment for TB (adjusted OR 4, 95% CI, 3-6; p < 0.001). CONCLUSIONS: Co-prevalent silicosis significantly elevates the risk of drug resistance, recurrence, and retreatment among TB patients in India. This study indicates a need for improved treatment protocols and suggests that future research should focus on randomized controlled trials to evaluate appropriate anti-TB regimen and duration of therapy for this high-risk group. Given India's goal to eliminate TB by 2025, addressing the challenges posed by silico-tuberculosis is critical.

Symptoms and Systemic Drug Reactions in Persons Receiving Weekly Rifapentine Plus Isoniazid (3HP) Treatment for Latent Tuberculosis Infection.

BACKGROUND: Three months of weekly rifapentine plus isoniazid (3HP) therapy for latent tuberculosis infection (LTBI) is recommended worldwide. The development of symptoms and systemic drug reactions (SDRs) on 3HP have not been fully characterized. We aimed to determine the patterns of symptom development and identify SDRs and associated factors in patients taking 3HP. METHODS: We analyzed symptoms data in participants receiving 3HP in the Tuberculosis Trials Consortium's iAdhere study (Study 33). We examined the patterns of symptom reporting across participants from baseline and 4 monthly visits. Bivariate analyses and multivariable regression models were used to identify factors associated with SDRs. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Among 1002 participants receiving 3HP, 768 (77%) reported at least 1 symptom; 97% of these symptoms were grade 1 (79%) or grade 2 (18%). Most symptoms developed in the first month and resolved. A total of 111 (11%) participants had symptoms that met criteria for SDRs; however, 53 (48%) of these participants completed therapy. Factors associated with SDRs and discontinuation included female sex (RR: 2.05; 95% CI: 1.19-3.54), age ≥45 years (RR: 1.99; 95% CI: 1.19-3.31), and use of concomitant medications (RR: 2.26; 95% CI: 1.15-4.42). CONCLUSIONS: Although most patients receiving 3HP reported symptoms, most were mild, occurred early, and resolved without stopping treatment. Among patients experiencing SDRs, nearly half were able to complete therapy. Patient and provider education should focus on differentiating severe reactions where 3HP should be stopped from minor symptoms that will resolve. Clinical Trials Registration. NCT01582711.

Factors affecting ability of TB patients to follow treatment guidelines - applying a capability approach.

BACKGROUND: Negotiating anti-Tuberculosis treatment is a complicated process comprising daily consumption of multiple medications at stipulated times and dosages, as well as periodic follow-ups and investigations, may not be uniform for all Tuberculosis (TB) patients and some may perform better than others. In this context, we conducted a study in Thiruvananthapuram district, Kerala to ascertain the ability of those suffering from TB to follow treatment guidelines. METHODS: This study used an embedded mixed methods design. We collected cross-sectional data from 135 drug sensitive pulmonary TB patients aged 18 years or above in Thiruvananthapuram, Kerala using a structured questionnaire to get the proportion of patients following all treatment guidelines. We also did eight in-depth interviews (four men and four women) from within the survey sample. The in-depth interviews were inductively analysed for getting deeper insights about reasons for the choices people made regarding the treatment guidelines. Written informed consent was taken from all participants and the study was implemented after the necessary programmatic and ethical clearances. RESULTS: Of the 105 men and 30 women studied, uninterrupted daily drug consumption was reported by 80 persons (59.3%, 95% Confidence Intervals (CI) 50.8-67.2%). Overall, 38 (28.2%, 95% CI 21.3%-36.3%) persons were able to follow all seven aspects of advised guidelines. Living in an extended/ joint family (Adjusted Odds ratio (AOR) 2.6, 95% CI 1.1-6.0), approximate monthly household expenditure of over rupees 13,500 (AOR 2.9, 95% CI 1.3-6.7) and no perceived delay in seeking initial care (AOR 3.2, 95% CI 1.2-8.7) were significantly associated with following all aspects of treatment guidelines. In-depth interviews revealed reflective treatment related behaviours were influenced by bodily experiences, moral perceptions, social construct of TB, programmatic factors and substance use. Sometimes behaviours were non-reflective also. Programmatic stress was on individual agency for changing behaviour but capability and opportunity for these were influenced social aspects like stigma, gender roles and poverty. CONCLUSION: TB patients live amidst a syndemic of biomedical and social problems. These problems influence the capabilities and opportunities of such TB patients to follow treatment guidelines. Interventions should balance focus on individual agency and social abd economic factors.

Two-stage revision for treatment of tuberculous prosthetic hip infection: an outcome analysis.

OBJECTIVES: Prosthetic joint infections (PJI) and especially tuberculosis (TB) PJI are rare diseases and hard to cure. The effectiveness of treatments for tuberculous PJI still remains a problem. The objective of this research was to indicate the success of two-stage revision replacement and also giving the associated criteria. METHODS: From 2015 to 2020, five patients with tuberculous PJI were treated with two-stage revision at Cho Ray hospital, Vietnam. We collected the dataset which included demographic data, the interval from the time of joint replacement to reported infection, records of tuberculous PJI, administration of anti-TB medications (duration, months), history of operation(s), duration of follow-up, and specific type(s) of antibiotics loaded in bone cement. The approval for this study was made by the institutional review board from Cho Ray Hospital, Vietnam. We conducted a literature review based on the keywords "PJI" and "TB" on PubMed. RESULTS: Five patients [median age 66 years (range 35-84)] had found tuberculous PJI. The median time from arthroplasty to diagnosis was 19 months (range 4-48). The diagnosis was confirmed by joint aspirates or synovial tissue. Positive PCR was also reported in all cases. The average duration of anti-tuberculosis polytherapy administration was 14.4 months. The operative techniques on five patients included debridement and using spacer loaded with 2 g streptomycin (and 2 g vancomycin if they got a coinfection) for 1 pack of bone cement, and revision arthroplasty. In most cases, the outcome of treatment using two-stage revision replacement was 80%. Overall, the auxiliary bacterial infections were recognized in three patients with tuberculous PJI and Staphylococcus aureus. Streptomycin and vancomycin were loaded in a cement spacer to increase the success rate, and tuberculous PJI was controlled for all patients. CONCLUSION: Tuberculous PJI can be controlled with two-stage revision replacement with an antibiotic-loaded cement spacer that is molded intraoperatively with custom mold and prolonged anti-tuberculosis treatment in all cases. LEVEL OF EVIDENCE: IV.

[The problem of formation of new risks of medicinal resistance of patients with tuberculosis in condition of active use of antibiotics by population under COVID-19].

In pandemic conditions, situation of active and uncontrolled use by population of antimicrobial preparations treating COVID-19 occurs. So, new risks of development of medication resistance among patients with various infectious diseases, tuberculosis included, appear. The purpose of the study is to characterize prevalence of antimicrobial preparations use by population in relationship with development of medication resistance in patients with tuberculosis during COVID-19 pandemic. Material and methods. The analysis of sales of antimicrobial medicines was implemented on the basis of published official data from the joint-stock company DSM Group presenting monthly audit of the Russian pharmaceutical market. The determination of primary antibiotic resistance was carried out in 2018-2020 on 3312 patients with tuberculosis. The modified method of proportions on liquid nutrient medium in system with automated accounting of microorganisms growth, the method of absolute concentrations and the method of polymerase chain reaction with real-time detection were applied. The results of the study. It was established that the most demanding antimicrobial medications among population were ceftriaxone, azithromycin, levofloxacin, moxifloxacin, azithromycin. At the same time, the maximum increase in sales in 2020 up to 150% as compared with of 2019 was determined in medications derived from quinolone moxifloxacin, levofloxacin, which began to be used in treatment of coronavirus infection. At the same time, these medications are traditionally used in tuberculosis treatment. But in 2020, alarming trend was established that limits treatment of tuberculosis patients. The primary resistance of mycobacteria was also established in newly diagnosed tuberculosis patients, also for the same antimicrobial medications of quinolone derivatives, and increasing in proportion of patients with primary medication resistance to levofloxacin, moxifloxacin in 2020 as compared to 2018 was 189-480%. At the same time, increasing of resistance to other antibiotics made up to 60.8% on average. Conclusion. The study results imply alarming scenario of medication resistance shifts towards very virulent and highly medication-resistant genotypes. This trend can result in conditions of successful transmission of deadly medication-resistant mutants that can seriously undermine effectiveness of implemented programs of struggle with tuberculosis worldwide.

Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.

BACKGROUND: In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. METHODS: Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L). RESULTS: In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. CONCLUSIONS: Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.

Tuberculosis treatment intermittency in the continuation phase and mortality in HIV-positive persons receiving antiretroviral therapy.

BACKGROUND: Some tuberculosis (TB) treatment guidelines recommend daily TB treatment in both the intensive and continuation phases of treatment in HIV-positive persons to decrease the risk of relapse and acquired drug resistance. However, guidelines vary across countries, and treatment is given 7, 5, 3, or 2 days/week. The effect of TB treatment intermittency in the continuation phase on mortality in HIV-positive persons on antiretroviral therapy (ART), is not well-described. METHODS: We conducted an observational cohort study among HIV-positive adults treated for TB between 2000 and 2018 and after enrollment into the Caribbean, Central, and South America network for HIV epidemiology (CCASAnet; Brazil, Chile, Haiti, Honduras, Mexico and Peru). All received standard TB therapy (2-month initiation phase of daily isoniazid, rifampin or rifabutin, pyrazinamide ± ethambutol) and continuation phase of isoniazid and rifampin or rifabutin, administered concomitantly with ART. Known timing of ART and TB treatment were also inclusion criteria. Kaplan-Meier and Cox proportional hazards methods compared time to death between groups. Missing model covariates were imputed via multiple imputation. RESULTS: 2303 patients met inclusion criteria: 2003(87%) received TB treatment 5-7 days/week and 300(13%) 2-3 days/week in the continuation phase. Intermittency varied by site: 100% of patients from Brazil and Haiti received continuation phase treatment 5-7 days/week, followed by Honduras (91%), Peru (42%), Mexico (7%), and Chile (0%). The crude risk of death was lower among those receiving treatment 5-7 vs. 2-3 days/week (HR = 0.68; 95% CI = 0.51-0.91; P = 0.008). After adjusting for age, sex, CD4, ART use at TB diagnosis, site of TB disease (pulmonary vs. extrapulmonary), and year of TB diagnosis, mortality risk was lower, but not significantly, among those treated 5-7 days/week vs. 2-3 days/week (HR 0.75, 95%CI 0.55-1.01; P = 0.06). After also stratifying by study site, there was no longer a protective effect (HR 1.42, 95%CI 0.83-2.45; P = 0.20). CONCLUSIONS: TB treatment 5-7 days/week was associated with a marginally decreased risk of death compared to TB treatment 2-3 days/week in the continuation phase in multivariable, unstratified analyses. However, little variation in TB treatment intermittency within country meant the results could have been driven by other differences between study sites. Therefore, randomized trials are needed, especially in heterogenous regions such as Latin America.

The role of the genetic variant FECH rs11660001 in the occurrence of anti-tuberculosis drug-induced liver injury.

WHAT IS KNOWN AND OBJECTIVE: The pathogenic mechanism of anti-tuberculosis drug-induced liver injury (AT-DILI) is still largely unknown. Recent studies have indicated that rifampicin and isoniazid cotreatment causes the accumulation of endogenous protoporphyrin IX in the liver through the haem biosynthesis pathway. Alanine synthase 1 (ALAS1) and ferrochelatase (FECH) are the rate-limiting enzymes in the production of haem. The present study aimed to investigate the genetic contribution of the ALAS1 and FECH genes to the risk of AT-DILI in an Eastern Chinese Han population. METHODS: A 1:4 matched case-control study was conducted, and eight SNPs in the ALAS1 and FECH genes were detected and assessed. A multivariate conditional logistic regression model was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking and drinking history as covariates. RESULTS AND DISCUSSION: Overall, 202 AT-DILI cases and 808 controls were included in this study. The female patients carrying polymorphisms of rs11660001 in FECH had an increased risk of AT-DILI under the dominant and additive models (OR = 1.831, 95% CI: 1.014-3.307, p = 0.045; OR = 1.673, 95% CI: 1.015-2.760, p = 0.044, respectively). The peak aspartate transaminase level was significantly higher in female patients carrying the GA+AA genotype of rs11660001 than in those with the GG genotype during anti-TB treatment (p = 0.032). WHAT IS NEW AND CONCLUSION: Based on this 1:4 individual matched case-control study, SNP rs11660001 in the FECH gene may be associated with susceptibility to AT-DILI in Chinese female anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

Increased Healthcare Delays in Tuberculosis Patients During the First Wave of COVID-19 Pandemic in Korea: A Nationwide Cross-Sectional Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused disruptions to healthcare systems, consequently endangering tuberculosis (TB) control. We investigated delays in TB treatment among notified patients during the first wave of the COVID-19 pandemic in Korea. METHODS: We systemically collected and analyzed data from the Korea TB cohort database from January to May 2020. Groups were categorized as 'before-pandemic' and 'during-pandemic' based on TB notification period. Presentation delay was defined as the period between initial onset of symptoms and the first hospital visit, and healthcare delay as the period between the first hospital visit and anti-TB treatment initiation. A multivariate logistic regression analysis was performed to evaluate factors associated with delays in TB treatment. RESULTS: Proportion of presentation delay > 14 days was not significantly different between two groups (48.3% vs. 43.7%, P = 0.067); however, proportion of healthcare delay > 5 days was significantly higher in the during-pandemic group (48.6% vs. 42.3%, P = 0.012). In multivariate analysis, the during-pandemic group was significantly associated with healthcare delay > 5 days (adjusted odds ratio = 0.884, 95% confidence interval = 0.715-1.094). CONCLUSION: The COVID-19 pandemic was associated with healthcare delay of > 5 days in Korea. Public health interventions are necessary to minimize the pandemic's impact on the national TB control project.

Diagnostic pitfalls of urogenital tuberculosis.

OBJECTIVES: To describe characteristics, details of diagnosis and outcomes of urogenital tuberculosis (UGTB) in a low-prevalence country. METHODS: We conducted a retrospective observational study of 37 consecutive patients diagnosed with UGTB between 1st January 2014 and 31st October 2019 in an East London hospital. RESULTS: 68% (25/37) of patients were male and the median age was 42 years (IQR 34-55). 89% (33/37) of patients were born outside the United Kingdom with 65% (24/37) born in the South Asian region. Renal (32.4%), epididymal (24.3%) and endometrial TB (21.6%) were the most prevalent forms of UGTB. Only 13.5% of UGTB patients had concurrent pulmonary TB. The median length of time from symptom onset to treatment was 163 days, while endometrial TB had an average delay to diagnosis of 564 days. Approximately half of patients with UGTB were culture positive (51.4%). However, 70% of early morning urines (EMUs) sent in urinary TB were culture positive. 11 patients (30.6%) underwent two or more invasive procedures, such as biopsy to obtain specimen samples. The mean treatment length for all UGTB cases was 7.3 months (SD 3.1). Notably, 25% of patients with endometrial TB required surgery despite antituberculous treatment. CONCLUSIONS: UGTB is challenging to diagnose as early disease is often asymptomatic. Clinicians faced with non-specific symptoms, or features suggestive of urogenital malignancy amongst patients from TB-endemic areas, should maintain a high suspicion of UGTB.

An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study.

BACKGROUND: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. METHODS: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. RESULTS: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. CONCLUSION: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. TRIAL REGISTRATION: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

Discontinuation of tuberculosis treatment among children in the Kampala Capital City Authority health facilities: a mixed-methods study.

INTRODUCTION: Discontinuation of tuberculosis treatment (DTT) among children in sub-Saharan Africa is a major obstacle to effective tuberculosis (TB) control and has the potential to worsen the emergence of multi-drug resistant TB and death. DTT in children is understudied in Uganda. We examined the level and factors associated with DTT among children at four large health facilities in Kampala Capital City Authority and documented the reasons for DTT from treatment supporters and healthcare provider perspectives. METHODS: We conducted a retrospective analysis of records for children < 15 years diagnosed and treated for TB between January 2018 and December 2019. We held focus group discussions with treatment supporters and key informant interviews with healthcare providers. We defined DTT as the stoppage of TB treatment for 30 or more consecutive days. We used a stepwise generalized linear model to assess factors independently associated with DTT and content analysis for the qualitative data reported using sub-themes. RESULTS: Of 312 participants enrolled, 35 (11.2%) had discontinued TB treatment. The reasons for DTT included lack of privacy at healthcare facilities for children with TB and their treatment supporters, the disappearance of TB symptoms following treatment initiation, poor implementation of the community-based directly observed therapy short-course (CB-DOTS) strategy, insufficient funding to the TB program, and frequent stock-outs of TB drugs. DTT was more likely during the continuation phase of TB treatment compared to the intensive phase (Adjusted odds ratio (aOR), 5.22; 95% Confidence Interval (CI), 1.76-17.52) and when the treatment supporter was employed compared to when the treatment supporter was unemployed (aOR, 3.60; 95% CI, 1.34-11.38). CONCLUSION: Many children with TB discontinue TB treatment and this might exacerbate TB morbidity and mortality. To mitigate DTT, healthcare providers should ensure children with TB and their treatment supporters are accorded privacy during service provision and provide more information about TB symptom resolution and treatment duration versus the need to complete treatment. The district and national TB control programs should address gaps in funding to TB care, the supply of TB drugs, and the implementation of the CB-DOTS strategy.

Putting Crohn's on the MAP: Five Common Questions on the Contribution of Mycobacterium avium subspecies paratuberculosis to the Pathophysiology of Crohn's Disease.

For decades, Mycobacterium avium subspecies paratuberculosis (MAP) has been linked to the pathogenesis of Crohn's disease. Despite many investigations and research efforts, there remains no clear unifying explanation of its pathogenicity to humans. Proponents argue Crohn's disease shares many identical features with a granulomatous infection in ruminants termed Johne's disease and similarities with ileo-cecal tuberculosis. Both are caused by species within the Mycobacterium genus. Sceptics assert that since MAP is found in individuals diagnosed with Crohn's disease as well as in healthy population controls, any association with CD is coincidental. This view is supported by the uncertain response of patients to antimicrobial therapy. This report aims to address the controversial aspects of this proposition with information and knowledge gathered from several disciplines, including microbiology and veterinary medicine. The authors hope that this discussion will stimulate further research aimed at confirming or refuting the contribution of MAP to the pathogenesis of Crohn's disease and ultimately lead to advanced targeted clinical therapies.

Impact of socio-economic factors on Tuberculosis treatment outcomes in north-eastern Uganda: a mixed methods study.

BACKGROUND: Tuberculosis (TB) is a major public health problem and at 48%, Karamoja in North-Eastern Uganda has the lowest treatment success rate nationally. Addressing the social determinants of TB is crucial to ending TB. This study sought to understand the extent and ways in which socio-economic factors affect TB treatment outcomes in Karamoja. METHODS: We conducted a convergent parallel mixed methods study in 10 TB Diagnostic and Treatment Units. The study enrolled former TB patients diagnosed with drug-susceptible TB between April 2018 and March 2019. Unit TB and laboratory registers were reviewed to identify pre-treatment losses to follow-up. Four focus group discussions with former TB patients and 18 key informant interviews with healthcare workers were conducted. Principle component analysis was used to generate wealth quintiles that were compared to treatment outcomes using the proportion test. The association between sociodemographic characteristics and TB treatment outcomes was evaluated using the chi-square test and multiple logistic regression. RESULTS: A total of 313 participants were randomly selected from 1184 former TB patients recorded in the unit TB registers. Of these, 264 were contacted in the community and consented to join the study: 57% were male and 156 (59.1%) participants had unsuccessful treatment outcomes. The wealthiest quintile had a 58% reduction in the risk of having an unsuccessful treatment outcome (adj OR = 0.42, 95% CI 0.18-0.99, p = 0.047). People who were employed in the informal sector (adj OR = 4.71, 95% CI 1.18-18.89, p = 0.029) and children under the age of 15 years who were not in school or employed (adj OR = 2.71, 95% CI 1.11-6.62, p = 0.029) had significantly higher odds of unsuccessful treatment outcome. Analysis of the pre-treatment loss to follow-up showed that 17.2% of patients with pulmonary bacteriologically confirmed TB did not initiate treatment with a higher proportion among females (21.7%) than males (13.5%). Inadequate food, belonging to migratory communities, stigma, lack of social protection, drug stock-outs and transport challenges affected TB treatment outcomes. CONCLUSIONS: This study confirmed that low socio-economic status is associated with poor TB treatment outcomes emphasizing the need for multi- and cross-sectoral approaches and socio-economic enablers to optimise TB care.

A validation study of the UGT1A4 rs2011404 variant and the risk of anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population.

WHAT IS KNOWN AND OBJECTIVE: Anti-tuberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. A recent study found that the rs2011404 variant of uridine 5'-diphospho-glucuronosyl-transferase 1A4 (UGT1A4) is a marker of susceptibility to ATDH. The present study aimed to validate this relationship in an Eastern Chinese Han anti-TB treatment population. METHODS: A 1:4 matched case-control study was conducted among anti-TB treatment patients in four regions of Jiangsu. ATDH was diagnosed based on the criteria from the Chinese Society of Hepatology and the updated Roussel Uclaf Causality Assessment Method. A conditional logistic regression model was used to estimate the association between rs2011404 genotypes and the risk of ATDH using odds ratios (ORs) with 95% confidence intervals (95% CIs) and smoking, drinking, hepatoprotectant use and liver diseases as covariates. RESULTS AND DISCUSSION: A total of 202 ATDH cases and 808 controls were matched according to age, sex and treatment history. After correcting for potential confounding factors, conditional logistic regression analysis indicated no significant differences in genotypes between the two groups (CC vs. TC: OR = 0.933, 95% CI: 0.457-1.905, p = 0.849). Subgroup analysis suggested that patients carrying the CC genotype at rs2011404 in UGT1A4 were at a reduced risk of moderate or severe liver injury (OR = 0.293, 95% CI: 0.093-0.921, p = 0.036). WHAT IS NEW AND CONCLUSION: Based on a 1:4 individual matched case-control study, possessing the CC genotype at rs2011404 of the UGT1A4 gene reduces the risk of moderate or severe liver injury in Eastern Chinese Han patients receiving anti-TB treatment. Further research is warranted to explain the role of the UGT1A4 gene and its contribution to individual differences in susceptibility to ATDH.

The clinical presentation and treatment outcomes of ocular tuberculosis: a 5-year experience in an endemic area.

PURPOSE: To report the clinical presentations of ocular tuberculosis infection (OTB) and the treatment regimen and outcome in an endemic area. METHODS: This is a retrospective case series of patients with presumed OTB treated in a tertiary teaching hospital in Hong Kong in 2014-2019. RESULTS: Among the nineteen patients recruited, the most common clinical presentation of OTB was retinal vasculitis (42.1%), followed by scleritis, intermediate uveitis, and choroidal tuberculoma (15.8% respectively). 94.7% and 94.4% of the subjects were treated with ATT and steroid, respectively, and 31.6% were put on systemic immunosuppressant prior to the initiation of ATT. Apart from those suffering from intermediate uveitis, most demonstrated good clinical response within 8 weeks of ATT initiation. CONCLUSION: Ocular involvement of TB has been increasingly recognized, especially in endemic regions like Hong Kong. High index of suspicion is recommended for OTB in typical clinical phenotypes or recurrent/resistant ocular inflammation unresponsive to conventional therapy. TB retinal vasculitis was the most common presentation of OTB in this study and OTB generally requires treatment with either regional or systemic steroid together with ATT.

[Evaluation of the quality of public health nurses' community DOTS practices and its relationship with individual and organizational factors].

Objectives　By targeting the public health nurses (PHNs) who are expected to be actively involved in the implementation of community DOTS practices, we evaluated the quality of the regional DOTS practices based on the three aspects of "enhancing tuberculosis (TB) treatment adherence," "patient-centered support other than treatment," and "coordination with related organizations." We examined the individual and organizational factors that affect the quality of these practices. Further, we clarified the challenges related to the abilities of PHNs.Methods　A self-report questionnaire survey of 958 PHNs from local governments with a TB incidence rate of 15 or more was administered in 2015. This resulted in there being 410 valid responses with a valid response rate of 42.8%.　The quality of the community DOTS practices was evaluated based on the three aspects by reviewing the literature on expert PHNs for TB patient support. After a preliminary survey, each was evaluated based on a scale of 10 points. A multiple regression analysis was conducted to understand the relationship between these and the TB control implementation system (organizational factors), the experience and motivation of PHNs to support tuberculosis patients, and the learning situation (individual factors).Results　The quality of the community DOTS practices was 7.54±1.69 for "enhancing TB treatment adherence," was 6.91±1.63 for "coordination with related organizations," and was 6.68±1.53 for "patient-centered support." The scores for the first factor were higher than those for the latter two factors (P<0.05). With regard to "patient-centered support," one-fourth of the surveyed PHNs rated their practices as low. Each predictor showed a strong relationship with the quality of community DOTS practices, especially "coordination with related organizations" and "patient-centered support" (r=0.787). The significant organizational factors associated with the quality of the community DOTS practices in terms of each aspect were "making an individual support plan for TB patients" (ß=0.112-0.270), "reporting own practices at the DOTS conference as a responsible PHN" (ß=0.113-0.173), "attending cohort study meetings" (ß=0.129-0.167), and the individual factor of "many years of experience as a PHN" (ß=0.210-0.316). Additionally, in the model of "coordination with related organizations," "reading specialized books and journals" (ß=0.108) was found to be significant and positively related.Conclusion　To improve the quality of the community DOTS practices based on the self-evaluation of PHNs, "patient-centered support" with a low score and high relevance to other aspects is a priority. It was also suggested that it would be useful if the PHNs participated in DOTS evaluations, developed individual patient support plans, presented support plans, and participated in performance evaluations to improve the quality of DOTS practices.

High Rates of Drug-induced Liver Injury in People Living With HIV Coinfected With Tuberculosis (TB) Irrespective of Antiretroviral Therapy Timing During Antituberculosis Treatment: Results From the Starting Antiretroviral Therapy at Three Points in TB Trial.

BACKGROUND: New onset or worsening drug-induced liver injury challenges coinfected patients on antiretroviral therapy (ART) initiation during antituberculosis (TB) treatment. METHODS: Post hoc analysis within a randomized trial, the Starting Antiretroviral Therapy at Three Points in Tuberculosis trial, was conducted. Patients were randomized to initiate ART either early or late during TB treatment or after TB treatment completion. Liver enzymes were measured at baseline, 6-month intervals, and when clinically indicated. RESULTS: Among 642 patients enrolled, the median age was 34 years (standard deviation, 28-40), and 17.6% had baseline CD4+ cell counts <50 cells/mm3. Overall, 146/472 patients (52, 47, and 47: early, late, and sequential arms) developed new-onset liver injury following TB treatment initiation. The incidence of liver injury post-ART initiation in patients with CD4+ cell counts <200 cells/mm3 and ≥200 cells/ mm3 was 27.4 (95% confidence interval [CI], 18.0-39.8), 19.0 (95% CI, 10.9-30.9), and 18.4 (95% CI, 8.8-33.8) per 100 person-years, and 32.1 (95% CI, 20.1-48.5), 11.8 (95% CI, 4.3-25.7), and 28.2 (95% CI, 13.5-51.9) per 100 person-years in the early, late integrated, and sequential treatment arms, respectively. Severe and life-threatening liver injury occurred in 2, 7, and 3 early, late, and sequential treatment arm patients, respectively. Older age and hepatitis B positivity predicted liver injury. CONCLUSIONS: High incidence rates of liver injury among cotreated human immunodeficiency virus (HIV)-TB coinfected patients were observed. Clinical guidelines and policies must provide guidance on frequency of liver function monitoring for HIV-TB coinfected patients.

Clinical Impact of Rapid Drug Susceptibility Testing to Accompany Fluoroquinolone-Containing Universal Tuberculosis Regimens: A Markov Model.

BACKGROUND: To appropriately treat tuberculosis (TB) with regimens that combine novel and older drugs, evidence-based, context-specific strategies for drug-susceptibility testing (DST) will be required. METHODS: We created a Markov state-transition model of 100 000 adults with TB receiving a novel, fluoroquinolone (FQ)-containing regimen. We estimated clinical outcomes and resource utilization with no FQ-DST, universal FQ-DST, or FQ-DST only for patients with rifampin-resistant TB ("targeted FQ-DST"). We considered scenarios of stronger (South Africa) and weaker (Southeast Asia) correlation of fluoroquinolone resistance with rifampin resistance, with sensitivity analysis for other setting and regimen characteristics. RESULTS: Relative to no FQ-DST, targeted FQ-DST increased cure of FQ-resistant TB by 7.5% (interquartile range [IQR], 6.7%-9.2%) in South Africa and 1.7% (IQR, 0.7%-2.5%) in Southeast Asia. However, rare FQ resistance among the more prevalent rifampin-susceptible TB accounted for 50% of FQ-resistant TB in South Africa and 83% in Southeast Asia. As a result, universal FQ-DST further increased cure of FQ-resistant TB by 3.4% (IQR, 2.3%-5.4%) in South Africa and 5.8% (IQR, 5.1%-6.3%) in Southeast Asia. With targeted FQ-DST, 1 additional patient was cured per 50 (IQR, 42-70) tests in South Africa and 44 (IQR, 37-51) in Southeast Asia. When expanding from targeted to universal FQ-DST, 1 additional cure required 3500 (IQR, 2300-5500) tests in South Africa and 410 (IQR, 370-450) in Southeast Asia. CONCLUSIONS: FQ-DST improved patient outcomes and was particularly important for high-risk patient groups and less robust regimens. A universal strategy was favored in generalized epidemics of fluoroquinolone resistance.

Tuberculosis treatment outcomes and associated factors in two states in Nigeria.

OBJECTIVE: To determine the treatment success rate among TB patients and associated factors in Anambra and Oyo, the two states with the largest burden of tuberculosis in Nigeria. METHODS: A health facility record review for 2016 was conducted in the two states (Anambra and Oyo). A checklist was used to extract relevant information from the records kept in each of the selected DOTS facilities to determine TB treatment success rates. Treatment success rate was defined as the proportion of new smear-positive TB cases registered under DOTS in a given year that successfully completed treatment, whether with bacteriologic evidence of success ('cured') or without ('treatment completed'). Treatment success rate was classified into good (≥85%) and poor (<85%) success rates using the 85% national target for TB treatment outcome. Data were analysed using descriptive statistics and chi-square at P < 0.05. RESULTS: There were 1281 TB treatment enrollees in 2016 in Anambra and 3809 in Oyo (total = 4835). An overall treatment success rate of 75.8% was achieved (Anambra-57.5%; Oyo-82.0%). The percentage cure rates were 61.5% for Anambra and 85.2% for Oyo. Overall, only 28.6% of the facilities in both states (Anambra-0.0%; Oyo-60.0%) had a good treatment success rate. More facilities in Anambra (100.0%) than Oyo (40.0%) had a poor treatment success rate (p < 0.001), as did more private/FBO (100.0%) than public health facilities (60.0%) (p = 0.009). All tertiary facilities had a poor treatment success rate followed by 87.5% of secondary health facilities and 56.5% of primary healthcare facilities (P = 0.035). CONCLUSION: Treatment success and cure rates in Anambra state were below the 85.0% of the recommended target set by the WHO. Geographical location, and level/tier and type of facility were factors associated with this. Interventions are recommended to address these problems.

OBJECTIF: Déterminer le taux de succès du traitement chez les patients TB et les facteurs associés à Anambra et Oyo, les deux Etats avec la plus grande charge de TB au Nigéria. MÉTHODES: Un examen des dossiers des établissements de santé pour 2016 a été réalisé dans les deux Etats (Anambra et Oyo). Une liste de contrôle a été utilisée pour extraire les informations pertinentes des registres conservés dans chacun des établissements DOTS sélectionnés afin de déterminer les taux de succès du traitement antituberculeux. Le taux de succès du traitement a été défini comme la proportion de nouveaux cas de TB à frottis positif enregistrés dans le cadre du DOTS au cours d'une année donnée qui ont terminé le traitement avec succès, que ce soit avec des preuves bactériologiques de succès («guéri¼) ou sans («traitement terminé¼) . Le taux de succès du traitement a été classé en bons (≥ 85%) et mauvais (<85%) taux de réussite en utilisant l'objectif national de 85% pour l'issue du traitement de la TB. Les données ont été analysées à l'aide de statistiques descriptives et du Chi carré à p <0,05. RÉSULTATS: Il y avait 1.281 personnes inscrites au traitement antituberculeux en 2016 à Anambra et 3.809 à Oyo (total = 4835). Un taux de succès global du traitement de 75,8% a été atteint (Anambra, 57,5%; Oyo, 82,0%). Les taux de guérison en pourcentage étaient de 61,5% pour Anambra et de 85,2% pour Oyo. Dans l'ensemble, seuls 28,6% des établissements des deux Etats (Anambra, 0,0%; Oyo, 60,0%) avaient un bon taux de réussite du traitement. Plus d'établissements à Anambra (100,0%) qu'à Oyo (40,0%) avaient un faible taux de réussite du traitement (p <0,001), tout comme plus d'établissements de santé privés/FBO (100,0%) que publics (60,0%) (p = 0,009). Tous les établissements tertiaires avaient un faible taux de réussite du traitement, suivis de 87,5% des établissements de santé secondaires et 56,5% des établissements de soins de santé primaires (p = 0,035). CONCLUSION: Le succès du traitement et les taux de guérison dans l'Etat d'Anambra étaient inférieurs aux 85,0% de l'objectif recommandé fixé par l'OMS. L'emplacement géographique, le niveau et le type d'établissement étaient des facteurs associés à cela. Des interventions sont recommandées pour résoudre ces problèmes.