Recent advances in the treatment of tuberculosis.

BACKGROUND: Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances. OBJECTIVES: This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials. SOURCES: A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). CONTENT: This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. IMPLICATIONS: Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centred access to new treatment options for all people affected by TB.

Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes.

Periconceptional antibiotic use and spontaneous abortion: A prospective cohort study.

BACKGROUND: Many reproductive-aged North Americans use antibiotics in the weeks preceding conception or during early pregnancy. Antibiotic use may influence risk of spontaneous abortion (SAB) by disrupting the reproductive tract microbiome or treating harmful infections. However, this association has not been extensively studied. OBJECTIVE: To determine the extent to which periconceptional antibiotic use is associated with the risk of SAB. METHODS: We analysed data from an internet-based preconception cohort study of pregnancy planners. Eligible participants self-identified as female, were aged 21-45 years, resided in the USA or Canada, and conceived during 12 months of follow-up (n = 7890). Participants completed an enrolment questionnaire during June 2013-September 2021 and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever came first. Pregnant participants completed questionnaires in early (~8-9 weeks) and late (~32 weeks) gestation. We assessed antibiotic use, including type (penicillins, nitrofurantoin, cephalosporins and macrolides) and indication for use, during the previous 4 weeks on preconception questionnaires. Participants reported pregnancies and SAB on follow-up and pregnancy questionnaires. We used Cox proportional hazards regression models with gestational weeks as the time scale to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between periconceptional antibiotic use and SAB, controlling for potential demographic, medical, and lifestyle confounders. RESULTS: Nineteen percent (n = 1537) of pregnancies ended in SAB. Participants reported periconceptional antibiotic use in 8% of pregnancies ending in SAB and 7% not ending in SAB. Periconceptional antibiotic use was not appreciably associated with SAB (adjusted HR 1.06, 95% CI 0.88, 1.28). We observed no strong associations between antibiotic type, indication for use, or recency of exposure and SAB risk. CONCLUSIONS: Periconceptional antibiotic use was not appreciably associated with SAB in this study. This association is likely complicated by antibiotic type and dosage, timing of conception, and the individual's overall health.

Predictors of weight loss during the intensive phase of tuberculosis treatment in patients with drug-susceptible pulmonary tuberculosis in South India.

BACKGROUND: Tuberculosis (TB) is well-known for causing wasting. Patients on treatment gain weight and weight loss is associated with unfavorable treatment outcomes. There is limited description of weight loss and its predictors during intensive treatment phase. The objective of this study was to assess the predictors of weight loss during intensive phase and to see if there is any association exists with sputum conversion at the end of intensive phase of treatment. METHODS: Data collected as a part of the prospective TB cohort (Regional Prospective Observational Research for TB India Phase 1) conducted in Pondicherry, Cuddalore and Viluppuram districts of Tamil Nadu were used for this study. Sputum smear and body weight comparison were made in the baseline and at the end of second month of treatment. RESULTS: In all, 726 participants had weight measurements at the two time points and 18.7% had weight loss; mean weight lost being 2.3 kg (SD 3.05). Mean weight loss was more among males (2.4 kg, SD 3.2), diabetics (2.8 kg, SD 3.9) and alcoholics (2.1 kg, SD 2.4). Alcohol consumption was the only predictor of weight loss after adjusting for age, diabetes, marital status and BMI (aRR 1.52, P 0.02). Weight loss was not associated with sputum conversion at the end of second month. CONCLUSIONS: Alcohol use emerged as the major predictor for weight loss during intensive phase.

Development of prognostic scoring system for predicting 1-year mortality among pulmonary tuberculosis patients in South India.

BACKGROUND: Development of a prediction model using baseline characteristics of tuberculosis (TB) patients at the time of diagnosis will aid us in early identification of the high-risk groups and devise pertinent strategies accordingly. Hence, we did this study to develop a prognostic-scoring model for predicting the death among newly diagnosed drug sensitive pulmonary TB patients in South India. METHODS: We undertook a longitudinal analysis of cohort data under the Regional Prospective Observational Research for Tuberculosis India consortium. Multivariable cox regression using the stepwise backward elimination procedure was used to select variables for the model building and the nomogram-scoring system was developed with the final selected model. RESULTS: In total, 54 (4.6%) out of the 1181 patients had died during the 1-year follow-up period. The TB mortality rate was 0.20 per 1000 person-days. Eight variables (age, gender, functional limitation, anemia, leukopenia, thrombocytopenia, diabetes, neutrophil-lymphocyte ratio) were selected and a nomogram was built using these variables. The discriminatory power was 0.81 (95% confidence interval: 0.75-0.86) and this model was well-calibrated. Decision curve analysis showed that the model is beneficial at a threshold probability ~15-65%. CONCLUSIONS: This scoring system could help the clinicians and policy makers to devise targeted interventions and in turn reduce the TB mortality in India.

Effect of treatment adherence on the association between sex and unfavourable treatment outcomes among tuberculosis patients in Puducherry, India: a mediation analysis.

BACKGROUND: A better understanding of the complex interplay between risk factors of tuberculosis (TB) is essential. This study was part of the Regional Prospective Observational Research for Tuberculosis (RePORT) India consortium and includes newly diagnosed TB patients in Puducherry between 2014 and 2018. We employed mediation analysis to identify the effect of treatment adherence on association between sex and unfavourable TB treatment outcomes. METHODS: Required demographic and treatment-related variables were extracted from the RePORT India consortium database and causal mediation analysis using parametric regression models was done. RESULTS: Of the 712 TB patients, ~87 (12.2%) had unfavourable TB treatment outcomes. Total effect of male sex was significantly associated with the unfavourable TB treatment outcomes [adjusted odds ratio (aOR) = 2.48; 95% confidence interval (CI): 1.11-5.55]. However, the overall association between male sex and TB treatment outcomes was dominated by the indirect pathway, as the direct pathway does not show significant association (aOR = 1.67; 95% CI: 0.75-3.75), while the indirect pathway shows significantly higher odds of TB treatment outcomes (aOR = 1.48; 95% CI:1.27-1.73), indicating complete mediation by the treatment adherence. CONCLUSIONS: The study has shown a complete mediation of sexes through TB treatment adherence for unfavourable treatment outcomes. Developing of treatment strategies require better understanding between the biological and social factors related to TB.

Accuracy of Timika X-ray scoring system to predict the treatment outcomes among tuberculosis patients in India.

BACKGROUND: Timika scoring system is a radiographic grading tool, widely employed for grading the severity of tuberculosis (TB). We evaluated the predictive accuracy of this tool for adverse treatment outcomes among TB patients in Indian setting. METHODS: We undertook a longitudinal analysis of cohort data under the RePORT-India consortium. Cohort having participants with active pulmonary TB were included. CXRs were independently scored by chest physicians. Timika scoring system had a total score of 140. The predictive nature of the tool was assessed using the ROC analysis. RESULTS: Around 364 laboratory confirmed TB patients were enrolled. The mean (SD) of overall Timika score was 62.3 (24.9). Sputum conversion was achieved among 218/260 (83.8%) patients available at end of intensive phase. AUC for Timika score was 0.53 (95% CI: 0.43-0.63) and for percent lung affected, was 0.56 (95% CI: 0.46-0.65). Unfavorable treatment outcome was observed among 67/287 (23.3%) at the end of continuation phase. AUC for percent lung affected was 0.62 (95% CI: 0.54-0.70) and for Timika score was 0.59 (95% CI: 0.51-0.67). CONCLUSION: Both Timika scoring system and percent lung affected had poor predictive accuracy, highlighting the inability of a single CXR scoring system to predict the treatment outcome in Indian setting.

Missed Tuberculosis Diagnoses: Analysis of Pediatric Autopsy Data From General Hospitals in Lviv, Ukraine.

We reviewed autopsy data from general hospitals in Lviv, Ukraine to understand pediatric mortality due to tuberculosis (TB). We identified 14 (0.6%) of 2345 autopsied children with unrecognized or untreated TB. More sensitive TB diagnostics for children and improved strategies for identifying which children require TB evaluation are urgently needed.

Development and Validation of a Parsimonious Tuberculosis Gene Signature Using the digital NanoString nCounter Platform.

BACKGROUND: Blood-based biomarkers for diagnosing active tuberculosis (TB), monitoring treatment response, and predicting risk of progression to TB disease have been reported. However, validation of the biomarkers across multiple independent cohorts is scarce. A robust platform to validate TB biomarkers in different populations with clinical end points is essential to the development of a point-of-care clinical test. NanoString nCounter technology is an amplification-free digital detection platform that directly measures mRNA transcripts with high specificity. Here, we determined whether NanoString could serve as a platform for extensive validation of candidate TB biomarkers. METHODS: The NanoString platform was used for performance evaluation of existing TB gene signatures in a cohort in which signatures were previously evaluated on an RNA-seq dataset. A NanoString codeset that probes 107 genes comprising 12 TB signatures and 6 housekeeping genes (NS-TB107) was developed and applied to total RNA derived from whole blood samples of TB patients and individuals with latent TB infection (LTBI) from South India. The TBSignatureProfiler tool was used to score samples for each signature. An ensemble of machine learning algorithms was used to derive a parsimonious biomarker. RESULTS: Gene signatures present in NS-TB107 had statistically significant discriminative power for segregating TB from LTBI. Further analysis of the data yielded a NanoString 6-gene set (NANO6) that when tested on 10 published datasets was highly diagnostic for active TB. CONCLUSIONS: The NanoString nCounter system provides a robust platform for validating existing TB biomarkers and deriving a parsimonious gene signature with enhanced diagnostic performance.

Prevalence and risk factors associated with latent tuberculosis infection among household contacts of smear positive pulmonary tuberculosis patients in South India.

OBJECTIVE: We aimed to determine the prevalence and find the risk factors associated with latent tuberculosis infection (LTBI) among the household contacts (HHC) of pulmonary TB patients. METHODS: This cohort study was conducted from 2014 to 2019. Pretested standardised questionnaires and tools were used for data collection. The prevalence of LTBI among HHCs of TB patients was summarised as proportion with 95% confidence interval (CI). Mixed-effects generalised linear modelling function (meglm) in STATA with family Poisson and log link was performed to find the factors associated with LTBI. RESULTS: In total, 1523 HHC of pulmonary TB patients were included in the study. Almost all HHC shared their residence with the index case (IC) for more than a year; 25% shared the same bed with the IC. The prevalence of LTBI among the HHC of TB patients was 52.6% (95% CI: 50.1-55.1%). In an adjusted model, we found that among HHC belonging to the age group of 19-64 years (aIRR = 1.2; 95% CI: 1.1-1.3; p-value: 0.02), to the age group >65 years (aIRR = 1.4, 95% CI: 1.1-1.9, p-value: 0.02) and sharing the same bed with the IC (aIRR = 1.2, 95% CI: 1.1-1.3, p value: 0.04) were independent determinants of LTBI among the HHC. CONCLUSION: One in two household contacts of TB patients have latent tuberculosis infection. This underscores the need of targeted contact screening strategies, effective contact tracing and testing using standardised methods in high TB burden settings.

Comparison of profile and treatment outcomes between elderly and non-elderly tuberculosis patients in Puducherry and Tamil Nadu, South India.

The rising geriatric population and the increased susceptibility of this age group to tuberculosis (TB), the deadliest single infectious agent, is bothersome for India. This study tried to explore the demographic and treatment outcome differences between the elderly (aged 60 years and above) and non-elderly TB (<60 years) patients from South India. This study was part of a large ongoing cohort study under the RePORT India consortium. Newly diagnosed TB patients recruited into the cohort between 2014 and 2018 were included in this study. Pretested and standardized questionnaire and tools were used to collect data and were stored securely for the entire cohort. Required demographic, anthropometric and treatment related variables were extracted from this database and analyzed using Stata version 14.0. Prevalence of elderly TB was summarized as percentage with 95% confidence interval (CI). Generalized linear modelling was attempted to find the factors associated with elderly TB. A total of 1,259 eligible TB patients were included into this present study. Mean (SD) of the participants in the elderly and non-elderly group was 65.8 (6.2) and 40.2 (12.0) respectively. Prevalence of elderly TB was 15.6% (95%CI: 13.6%-17.6%) with nearly 71% belonging to 60-69 age category. Male sex, OBC caste, poor education, unemployment, marriage, alcohol consumption and unable to work as per Karnofsky score were found to be significantly associated with an increased prevalence of elderly TB. Unfavorable outcomes (12% vs 6.5%, p value: 0.018), including death (9.3% vs 3.4%, p value: 0.001) were significantly higher among the elderly group when compared to their non-elderly counterparts. The current TB programme should have strategies to maintain follow up with due attention to adverse effects, social support and outcomes. Additional research should focus on predictors for unfavorable outcomes among the elderly TB group and explore ways to handle the same. Rendering adequate social support from the health system side and family side would be a good start.

Antibiotics and fecundability among female pregnancy planners: a prospective cohort study.

STUDY QUESTION: To what extent is female preconception antibiotic use associated with fecundability? SUMMARY ANSWER: Preconception antibiotic use overall was not appreciably associated with fecundability. WHAT IS KNOWN ALREADY: Antibiotics are commonly used by women and are generally thought to be safe for use during pregnancy. However, little is known about possible effects of antibiotic use on fecundability, the per-cycle probability of conception. Previous research on this question has been limited to occupational rather than therapeutic exposure. STUDY DESIGN, SIZE, DURATION: We analyzed data from an Internet-based preconception cohort study of 9524 female pregnancy planners aged 21-45 years residing in the USA and Canada who had been attempting to conceive for six or fewer cycles at study entry. Participants enrolled between June 2013 and September 2020 and completed baseline and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever came first. The questions pertaining to antibiotic type and indication were added to the PRESTO questionnaires in March 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed antibiotic use in the previous 4 weeks at baseline and on each follow-up questionnaire. Participants provided the name of the specific antibiotic and the indication for use. Antibiotics were classified based on active ingredient (penicillins, macrolides, nitrofurantoin, nitroimidazole, cephalosporins, sulfonamides, quinolones, tetracyclines, lincosamides), and indications were classified by type of infection (respiratory, urinary tract, skin, vaginal, pelvic, and surgical). Participants reported pregnancy status on follow-up questionnaires. We used proportional probabilities regression to estimate fecundability ratios (FR), the per-cycle probability of conception comparing exposed with unexposed individuals, and 95% confidence intervals (CI), adjusting for sociodemographics, lifestyle factors, and reproductive history. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, women who used antibiotics in the past 4 weeks at baseline had similar fecundability to those who had not used antibiotics (FR: 0.98, 95% CI: 0.89-1.07). Sulfonamides and lincosamides were associated with slightly increased fecundability (FR: 1.39, 95% CI: 0.90-2.15, and FR: 1.58 95% CI: 0.96-2.60, respectively), while macrolides were associated with slightly reduced fecundability (FR: 0.70, 95% CI: 0.47-1.04). Analyses of the indication for antibiotic use suggest that there is likely some confounding by indication. LIMITATIONS, REASONS FOR CAUTION: Findings were imprecise for some antibiotic classes and indications for use owing to small numbers of antibiotic users in these categories. There are likely heterogeneous effects of different combinations of indications and treatments, which may be obscured in the overall null results, but cannot be further elucidated in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: There is little evidence that use of most antibiotics is associated with reduced fecundability. Antibiotics and the infections they treat are likely associated with fecundability through differing mechanisms, resulting in their association with increased fecundability in some circumstances and decreased fecundability in others. STUDY FUNDING/COMPETING INTEREST(S): This study was supported through funds provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (R01-HD086742, R21-HD072326). L.A.W. has received in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, Fertility Friend, and Kindara for primary data collection in PRESTO. The other authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Alcohol and Tobacco Use in a Tuberculosis Treatment Cohort during South Africa's COVID-19 Sales Bans: A Case Series.

BACKGROUND: South Africa temporarily banned alcohol and tobacco sales for about 20 weeks during the COVID-19 lockdown. We described changes in alcohol and tobacco consumption after implementation of these restrictions among a small number of participants in a tuberculosis treatment cohort. METHOD: The timeline follow-back procedure and Fägerstrom test for nicotine dependence was used to collect monthly alcohol and tobacco use information. We report changes in heavy drinking days (HDD), average amount of absolute alcohol (AA) consumed per drinking day, and cigarettes smoked daily during the alcohol and tobacco ban compared to use prior to the ban. RESULTS: Of the 61 participants for whom we have pre-ban and within-ban alcohol use information, 17 (27.9%) reported within-ban alcohol use. On average, participants reported one less HDD per fortnight (interquartile range (IQR): -4, 1), but their amount of AA consumed increased by 37.4 g per drinking occasion (IQR: -65.9 g, 71.0 g). Of 53 participants who reported pre-ban tobacco use, 17 (32.1%) stopped smoking during the ban. The number of participants smoking >10 cigarettes per day decreased from 8 to 1. CONCLUSIONS: From these observations, we hypothesize that policies restricting alcohol and tobacco availability seem to enable some individuals to reduce their consumption. However, these appear to have little effect on the volume of AA consumed among individuals with more harmful patterns of drinking in the absence of additional behavior change interventions.

Directly Observed Therapy to Measure Adherence to Tuberculosis Medication in Observational Research: Protocol for a Prospective Cohort Study.

BACKGROUND: A major challenge for prospective, clinical tuberculosis (TB) research is accurately defining a metric for measuring medication adherence. OBJECTIVE: We aimed to design a method to capture directly observed therapy (DOT) via mobile health carried out by community workers. The program was created specifically to measure TB medication adherence for a prospective TB cohort in Western Cape Province, South Africa. METHODS: Community workers collect daily adherence data on mobile smartphones. Participant-level adherence, program-level adherence, and program function are systematically monitored to assess DOT program implementation. A data dashboard allows for regular visualization of indicators. Numerous design elements aim to prevent or limit data falsification and ensure study data integrity. RESULTS: The cohort study is ongoing and data collection is in progress. Enrollment began on May 16, 2017, and as of January 12, 2021, a total of 236 participants were enrolled. Adherence data will be used to analyze the study's primary aims and to investigate adherence as a primary outcome. CONCLUSIONS: The DOT program includes a mobile health application for data collection as well as a monitoring framework and dashboard. This approach has potential to be adapted for other settings to improve the capture of medication adherence in clinical TB research. TRIAL REGISTRATION: Clinicaltrials.gov NCT02840877; https://clinicaltrials.gov/ct2/show/NCT02840877.

Evaluation of factors influencing Mycobacterium tuberculosis complex recovery and contamination rates in MGIT960.

BACKGROUND: Tuberculosis (TB) is a major public health problem worldwide. Contamination rate and poor recovery of Mycobacterium tuberculosis complex (MTBC) in MGIT960 culture may affect the early diagnosis of TB. Evidence is needed to determine the factors associated with contamination rates and MTBC recovery in MGIT960. Hence, we undertook this study to compare the factors influencing MTBC culture positivity and contamination rates in MGIT960 in patients with Pulmonary tuberculosis (PTB). METHODS: A total of 849 sputum samples from newly diagnosed smear-positive TB cases enrolled into the Regional Prospective Observational Research for Tuberculosis India cohort between May 2014 to March 2017 were analyzed. Samples were inoculated into MGIT960 and positive cultures were examined for the presence of MTBC by immunochromatographic test for detection of MPT64 antigen. RESULTS: Of the 849 cases, 811 (95.5%) were culture positive for MTBC, 23 (2.7%) were culture negative and 15 (1.8%) were contaminated. Salivary sputum showed significantly less culture yield compared to mucopurulent/blood stained samples (p = 0.021). Sputum from individuals <20 or ≥60 years showed lower culture yield of 93.9%, compared to those aged 20-59years (98.2%) (p = 0.002). Based on smear grading, culture isolation of MTBC by MGIT960 was 86.1%, 93.6% and 99.5% for negative, scanty and positive (1+/2+/3+) samples, respectively (p ≤ 0.0001). Sputum from HIV negative patients showed higher culture yield, compared to HIV positive patients (p ≤ 0.0001). Chest X-Ray revealed that patient with cavity showed higher culture isolation of MTBC compared to patients without cavity (p = 0.035). Contamination rates were higher in smear negatives (6.0%), compared to scanty (2.1%) and smear positives (1.1%) (p = 0.007). However, delay in transport of the specimen to the laboratory was the only independent factor significantly associated with increase in culture contamination. CONCLUSION: Our results highlight that extremes of age, smear negativity, HIV infection, sputum quality and cavitation significantly influence the culture yield of MTBC, whereas transport duration and smear grading affected the contamination rates in MGIT960. Hence, addressing these factors may improve the diagnostic performance of MGIT960.

Using Cure Models to Estimate the Serial Interval of Tuberculosis With Limited Follow-up.

Serial interval (SI), defined as the time between symptom onset in an infector and infectee pair, is commonly used to understand infectious diseases transmission. Slow progression to active disease, as well as the small percentage of individuals who will eventually develop active disease, complicate the estimation of the SI for tuberculosis (TB). In this paper, we showed via simulation studies that when there is credible information on the percentage of those who will develop TB disease following infection, a cure model, first introduced by Boag in 1949, should be used to estimate the SI for TB. This model includes a parameter in the likelihood function to account for the study population being composed of those who will have the event of interest and those who will never have the event. We estimated the SI for TB to be approximately 0.5 years for the United States and Canada (January 2002 to December 2006) and approximately 2.0 years for Brazil (March 2008 to June 2012), which might imply a higher occurrence of reinfection TB in a developing country like Brazil.

Pediatric Multidrug-resistant Tuberculosis in Kyiv City, Ukraine.

Few reports have described pediatric Multidrug-resistant Tuberculosis (MDR-TB) in the former Soviet republics, despite the fact that these countries have the highest proportion of TB cases that are MDR. We aimed to examine pediatric MDR-TB in Ukraine. This retrospective cohort study included all children <18 years of age who started undergoing MDR-TB treatment between January 1, 2011 and July 31, 2016 at Kyiv City Pediatric TB Hospital. From each child's clinical chart, we abstracted demographic and clinical data. Using Fisher's exact test, we compared characteristics between children with microbiologically confirmed vs. probable (i.e., clinically diagnosed) MDR-TB. The study population included 20 children with a median age of 5 years. At diagnosis, 12 (60%) had intrathoracic lymphadenopathy as their only radiographic abnormality, and two (10%) were asymptomatic. Children with confirmed MDR-TB were more likely to be adolescents or have radiologic abnormalities in addition to intrathoracic lymphadenopathy. Median treatment duration was 20 months. Eighteen (90%) children were treated successfully. The remaining two were transferred to another facility, and their final outcomes were unknown. The excellent outcomes in this cohort are consistent with high treatment success rates for pediatric MDR-TB reported in other parts of the world.

Brief Report: Assessing the Association Between Changing NRTIs When Initiating Second-Line ART and Treatment Outcomes.

BACKGROUND: After first-line antiretroviral therapy failure, the importance of change in nucleoside reverse transcriptase inhibitor (NRTI) in second line is uncertain due to the high potency of protease inhibitors used in second line. SETTING: We used clinical data from 6290 adult patients in South Africa and Zambia from the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa cohort. METHODS: We included patients who initiated on standard first-line antiretroviral therapy and had evidence of first-line failure. We used propensity score-adjusted Cox proportional-hazards models to evaluate the impact of change in NRTI on second-line failure compared with remaining on the same NRTI in second line. In South Africa, where viral load monitoring was available, treatment failure was defined as 2 consecutive viral loads >1000 copies/mL. In Zambia, it was defined as 2 consecutive CD4 counts <100 cells/mm. RESULTS: Among patients in South Africa initiated on zidovudine (AZT), the adjusted hazard ratio for second-line virologic failure was 0.25 (95% confidence interval: 0.11 to 0.57) for those switching to tenofovir (TDF) vs. remaining on AZT. Among patients in South Africa initiated on TDF, switching to AZT in second line was associated with reduced second-line failure (adjusted hazard ratio = 0.35 [95% confidence interval: 0.13 to 0.96]). In Zambia, where viral load monitoring was not available, results were less conclusive. CONCLUSIONS: Changing NRTI in second line was associated with better clinical outcomes in South Africa. Additional clinical trial research regarding second-line NRTI choices for patients initiated on TDF or with contraindications to specific NRTIs is needed.

Latent Tuberculosis Infection Testing Practices in Long-Term Care Facilities, Boston, Massachusetts.

OBJECTIVES: To describe latent tuberculosis infection (LTBI) testing practices in long-term care facilities (LTCFs). DESIGN: Retrospective cohort study. SETTING: Three Boston-area LTCFs. PARTICIPANTS: Residents admitted between January 1 and December 31, 2011. MEASUREMENTS: Resident demographic characteristics, comorbidities, LTCF stay, and LTBI testing and treatment. RESULTS: Data for 291 LTCF residents admitted in 2011 were reviewed. Of the 257 without a history of LTBI and with documentation of testing, 162 (63%) were tested; 114 of 186 (61%) with a stay less than 90 days and 48 of 71 (68%) with a stay of 90 days or longer were tested. Of 196 residents with data on prior LTBI testing, 39 (19.9%) had LTBI; 12 of these (30.8%) were diagnosed at the LTCF. Hispanic participants were more likely than black participants to undergo LTBI testing (adjusted odds ratio (aOR) = 2.4, P = .003). Having a length of stay of less than 90 days (aOR = 0.7, P < .001) and history of illicit drug use (aOR = 0.7, P < .001) were associated with lower odds of LTBI testing. CONCLUSION: One-fifth of LTCF residents had LTBI, but testing was not always performed. The high prevalence of LTBI in older adults combined with the risk of an outbreak if a case of tuberculosis occurs in a LTCF make LTBI testing and treatment an important prevention opportunity. The importance of LTBI testing in LTCFs needs to be reinforced.

Increased risk of active tuberculosis after cancer diagnosis.

BACKGROUND: Cancer may increase risk of active tuberculosis but evidence is sparse. We therefore examined tuberculosis risk in patients with incident cancer using Danish nationwide medical databases. METHODS: We conducted a matched follow-up study comparing risk of active tuberculosis in cancer-exposed individuals to that in a general population comparison cohort, matched on gender, age, and country of origin, in different follow-up intervals using Cox regression. FINDINGS: We identified 290,944 patients with incident cancer and 871,147 matched comparison cohort members during 1 January, 2004-30 November, 2013. After adjusting for comorbidities, the overall adjusted hazard ratio (aHR) for tuberculosis among cancer patients was 2.48 (95% confidence interval [CI]: 1.99-3.10). The highest tuberculosis risks were observed following cancers of the aerodigestive tract (aHR = 8.12; 95% CI: 4.33-15.22), tobacco-related cancers (aHR = 5.01; 95% CI: 3.37-7.44), and hematological cancers (aHR = 4.88; 95% CI: 2.27-10.48). Tuberculosis risk was highly elevated within the first year after cancer diagnosis (aHR = 4.14; 95% CI: 2.88-5.96), with a 6.78-fold increased aHR for cancer patients receiving cytostatics or radiotherapy. Beyond five years of observation, the overall aHR for tuberculosis remained at 2.66 (95% CI: 1.22-5.81). INTERPRETATION: Cancer is a clinical predictor for increased risk of active tuberculosis, probably related to decreased infection barriers, immunosuppression, and shared risk factors.