Short-course Treatment Regimens Research Articles

Treatment Outcomes for Tuberculosis Infection and Disease Among Persons Deprived of Liberty, Uganda, 2020.

We report that unsuccessful treatment outcomes were 11.8% for tuberculosis (TB) disease and 21.8% for TB infection among persons deprived of liberty in Uganda Prisons Service facilities. Remedial efforts should include enhancing referral networks to ensure treatment continuity, strengthening data systems for complete outcome documentation, and prioritizing short-course treatment regimens.

Establishing a protocol to increase racial/ethnic minority enrollment on an active radiation oncology randomized clinical trial.

TPS1638 Background: In the United States (US), underrepresented racial/ethnic groups lack ample enrollment in clinical trials, yielding ungeneralizable trial results. Barriers to increasing minority enrollment include decreased awareness of clinical trials, lack of access, financial burden and toxicity, medical system mistrust, and discordant physician-patient demographics. The ongoing Spine Patient Optimal Radiosurgery Treatment for Symptomatic Metastatic Neoplasms (SPORTSMEN) clinical trial (NCT05617716) has a study design to actively accrue minority patients. We present our protocol addressing key targets to increase minority enrollment on this randomized, phase II clinical trial. Methods: Adults with evidence of symptomatic spine metastases are eligible. Baseline demographics (including race/ethnicity) are reported for statistical analysis. Our protocol seeks to minimize barriers to minority enrollment and targets four key areas. Access to care: SPORTSMEN involves institutions located in zip codes with diverse ethnic populations, presently located in regions 46% and 70% African American. Clinical trial design: SPORTSMEN has a prespecified goal of accruing patients to mirror US census representation. The rate of minority enrollment will be reviewed periodically at the discretion of the Data Safety and Monitoring Board. Community outreach and engagement: The trial team will engage with local health care systems to create an alliance within different oncology specialties to provide the basis and benefit for SPORTSMEN and patient-centered education on eligibility criteria, rationale, and intended outcomes. Our principal focus will be providers in prostate, breast, and lung cancers as minorities with these primary site malignancies have a higher propensity to be trial-eligible. Furthermore, we understand the historical mistrust of minorities for the medical community. Therefore, we will engage local grassroot organizations such as churches, community outreach centers, and social clubs to increase awareness of clinical trials and to help foster trust. Financial burden and toxicity: SPORTSMEN does not have direct enrollment costs. A short-course treatment regimen is used to minimize the number of treatment visits required allowing for decreased resources for travel, time lost at work, and additional childcare or eldercare needs. Financial toxicity will be objectively quantified using the validated COST-Functional Assessment of Chronic Illness Therapy survey. Increasing clinical trial diversity is a challenge that must be addressed with meaningful intent to present robust Level 1 data that broadens the understanding of treatment response in all demographics. Our protocol takes a patient-centered approach to achieve the objective of concordant racial/ethnic representation in a randomized clinical trial. Clinical trial information: NCT05617716 .

Financial burden of tuberculosis diagnosis and treatment for patients in Ethiopia: a systematic review and meta-analysis

BackgroundDespite the diagnosis and treatment of tuberculosis (TB) given free of charge in many high-burden countries, the costs that patients face in the cascade of care remain a major concern. Here, we aimed to investigate the financial burden of TB diagnosis and treatment for people with TB in Ethiopia.MethodFor this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, and Cochrane Center for Clinical Trials from December 1 2022 to 31 June 2023 for articles reporting the cost of diagnosis and treatment for patients regardless of their age with all forms of TB in Ethiopia. Major study outcomes were catastrophic costs, direct (out-of-pocket) pre-diagnosis, medical cost, and post-diagnosis costs, indirect (income loss) costs, coping costs, and total costs. We have used a threshold of 20% to define catastrophic costs. We used random-effects meta-analyses to calculate summary estimates of costs. R-studio software was used for analysis. The study is registered with PROSPERO: CRD42023387687.ResultTwelve studies, with a total of 4792 patients with TB, were included in our analysis. At the 20% threshold of total expenses, 51% of patients (2301 participants from 5 studies, 95% CI: 36-65%, I2 = 97%) faced catastrophic costs due to bacteriologically confirmed drug-sensitive pulmonary TB. Private facility diagnosis, drug-resistance TB, TB-HIV co-infection, hospitalization, and occupation were found to be associated with catastrophic costs. Reduction in the total cost spent by the patients was associated with digital adherence interventions, community-based direct observed therapy, short-course MDR-TB treatment regimens, and active case-finding. Pre-diagnosis costs had a positive correlation with diagnosis delays and the number of facilities visited until diagnosis. Post-diagnosis costs had a positive correlation with rural residence and inpatient treatments.ConclusionIrrespective of a national policy of free TB service, more than half of TB patients are suffering catastrophic costs due to drug-sensitive pulmonary TB in Ethiopia and most of the patients spend a lot of money during the pre-diagnosis period and intensive phase, but declined drastically over time. Active case-finding, digital adherence interventions, community-based treatment, and comprehensive health insurance coverage have the potential to minimize the financial burden of TB diagnosis and treatment.

Simulation of Conditions and Results of Implementation of Short-Course Treatment Regimes in Tuberculosis Patients

The objective: to study the conditions of implementation of short-course (4 and 9 months) treatment regimens in tuberculosis patients and simulate their impact on the frequency of early treatment interruption (ETI) by patients.Subjects and Methods. Data on the treatment duration from enrollment to chemotherapy interruption in 8,029 tuberculosis patients were studied. Data were obtained from the Federal Register of Tuberculosis Cases for 2020. Of these, 3,379 patients were treated with regimens for susceptible or suspected susceptible tuberculous mycobacteria excluding isoniazid resistant tuberculosis, and 4,650 patients received regimens for rifampicin-resistant tuberculous mycobacteria.Results. The median duration of treatment from onset to ETI was 124 (95% CI 120-128) days in 3,379 patients, 224 (95% CI 215-233) days in 4,650 patients, or 170 (95% CI 157-181) days if there was a history of treatment interruption. Simulation of ETI terms when short-course chemotherapy regimens were introduced has shown that we can expect a 2-fold decrease in the proportion of patients who interrupted chemotherapy among patients with preserved/suspected susceptibility of tuberculous mycobacteria, and 1.3-1.7-fold decrease among patients with confirmed/presumed drug resistance of tuberculous mycobacteria at least to rifampicin.

Shortened Treatment Regimens for Drug Sensitive TB.

Tuberculosis (TB) has remained a global health challenge despite the availability of effective anti-tubercular drugs and various treatment strategies. Apart from the complications related to TB disease per se, adverse effects of antitubercular therapy (ATT) also contribute to morbidity. In addition to the adverse effects, the long duration of the treatment regimen also reduces the patient's acceptability of ATT. The available "short-course treatment regimens" are still relatively long, thereby adversely affecting treatment compliance. There is a need for effective, safe, short and intensive regimens for TB which can reduce the treatment cost and adverse effects, thereby improving its acceptance. With the emergence of new evidence, the World Health Organization (WHO) has recently endorsed 4 mo short duration ATT regimen for non-severe, drug-sensitive cases of tuberculosis. Even in severe forms of disease like tubercular meningitis (TBM), trials are underway evaluating efficacy and safety of shorter regimens. Inclusion of fluroquinolones and rifapentine help shorten the regimens. These shortened regimens, however, need more close monitoring for adverse effects and may need to be converted to longer course if there is inadequate clinical response. Thus, shorter regimens for pediatric TB are likely to not only decrease the burden on patients and healthcare but also improve compliance and lower the side effects of the drugs due to prolonged exposure. This article reviews the current evidence and the guidelines pertaining to the shortened, intensive regimens for drug-sensitive tuberculosis.

Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial

BackgroundStandard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs.MethodsORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages.DiscussionThis trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB.Trial registrationThe trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

Introduction of short course treatment for latent tuberculosis infection at a primary care facility for refugees in Winnipeg, Canada: A mixed methods evaluation.

The World Health Organization (WHO) End TB strategy document 'Toward tuberculosis elimination: an action framework for low incidence countries'-like Canada- identifies screening and treatment of latent tuberculosis infection (LTBI) for groups at increased risk for TB disease as a priority, including newcomers from endemic countries. In 2015, the clients-centered model offered at a primary care facility for refugees, BridgeCare Clinic, Winnipeg, Canada was evaluated. The model included LTBI screening, assessment, and treatment, and originally offered 9-months of isoniazid as treatment. This mixed methods evaluation investigates LTBI program outcomes since the introduction of two short-course treatment regimens: 4-months of rifampin, and 3-months of isoniazid and rifapentine. This study combined a retrospective analysis of program administrative data with structured interviews of clinic staff. We included LTBI treatment eligibility, the treatment regimen offered, treatment initiation, and completed treatment from January 1, 2015 to August 6, 2020. Seven hundred and one people were screened, and infection rates varied from 34.1% in 2015 to 53.3% in 2020. Most people living with LTBI came from high TB burden countries in Africa and South-East Asia WHO regions and were younger than 45 years old. Treatment eligibility increased 9% (75% in 2015 to 86% in 2016-2020) and most people diagnosed with LTBI took the short course treatments offered. There was an increase of 14.5% in treatment initiation (75.6 vs. 90.1%), and an increase of 8% in treatment completion (82.4 vs. 90.4%) after short-course regimens were introduced. The final model showed that the treatment regimen tends to affect the frequency of treatment completion, but there are other factors that influence this outcome, in this population. With the new treatments, BridgeCare Clinic achieved the 90% of treatment coverage, and the 90% treatment completion rate targets recommended in the End TB Strategy. Qualitative interviews with clinic staff further affirm the higher acceptability of the new treatments. While these results are limited to government-sponsored refugees in Winnipeg, they highlight the acceptability and value of short-course LTBI treatment as a possibility for reaching End TB targets in primary care settings.

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study.

BackgroundIdentifying host plasma exosome proteins associated with host response to latent tuberculosis infection (LTBI) treatment might promote our understanding of tuberculosis (TB) pathogenesis and provide useful tools for implementing the precise intervention.MethodsBased on an open-label randomized controlled trial (RCT) aiming to evaluate the short-course regimens for LTBI treatment, plasma exosomes from pre- and post-LTBI treatment were retrospectively detected by label-free quantitative protein mass spectrometry and validated by a parallel reaction monitoring method for participants with changed or not changed infection testing results after LTBI treatment. Eligible participants for both screening and verification sets were randomly selected from the based-RCT in a 1:1 ratio by age and gender. Reversion was defined as a decrease in IFN-γ levels from >0.70 IU/ml prior to treatment to 0.20 IU/ml within 1 week of treatment. The predictive ability of the candidate proteins was evaluated by receiver operating characteristic (ROC) analysis.ResultsTotally, two sample sets for screening (n = 40) and validation (n = 60) were included. Each of them included an equal number of subjects with persistent positive or reversed QuantiFERON-TB Gold In-Tube (QFT) results after LTBI. A total of 2,321 exosome proteins were detected and 102 differentially expressed proteins were identified to be associated with QFT reversion. Proteins with high confidence and original values intact were selected to be further verified. Totally, 9 downregulated proteins met the criteria and were validated. After verification, C4BPA and S100A9 were confirmed to be still significantly downregulated (fold change <0.67, p < 0.05). The respective areas under the ROC curve were 0.73 (95% CI: 0.57–0.89) and 0.69 (95% CI: 0.52–0.86) for C4BPA and S100A9, with a combined value of 0.78 (95% CI: 0.63–0.93). The positive and negative predictive values for combined markers were 70.10% (95% CI: 50.22–86.30%) and 55.63% (95% CI: 29.17–61.00%).ConclusionOur findings suggest that downregulated C4BPA and S100A9 in plasma exosomes might be associated with a host positive response to LTBI treatment. Further studies are warranted to verify the findings and potential underlying mechanisms in varied populations with a larger sample size.

National approaches to TB care in adolescents.

BACKGROUND: Adolescents bear a large burden of TB but high-prevalence countries differ significantly in their approach to address the specific needs of adolescent patients. We explore the national approaches to TB care in adolescents and compare them to the recommendations of the WHO.METHODS: We conducted a scoping review to describe the country-level guidelines to TB care in adolescents in high-burden countries. These guidelines were obtained through open sources. Information on TB care in adolescents were extracted from guidelines and compared to WHO recommendations.RESULTS: We found a lack of consensus in defining adolescents and that many national guidelines do not address the special healthcare needs of adolescents nor align with the WHO recommendations. Recently updated country guidelines are more likely to recommend short-course regimens for TB preventive treatment and countries with a higher level of income were more likely to follow WHO guidance for microbiological confirmation of TB disease in adolescents.CONCLUSION: A clear understanding of the burden of TB in adolescents that is reflected in disaggregated data reported at the country level is imperative in order to address the specific challenges to care in this high-risk group.

Is 6 Months of Antitubercular Chemotherapy as Effective as More Than 6 Months Regimen in Spinal Tuberculosis? A Systematic Review and Meta-analysis.

Historically, osteoarticular tuberculosis (TB), including spinal TB, was treated with prolonged course of antitubercular therapy (ATT). Due to various challenges, there has been reluctance to explore the use of short-course ATT in spinal TB. However, with the success of short-course ATT being demonstrated in other forms of extrapulmonary TB, the subject is open for debate again. Therefore, we systematically reviewed various published literature to determine whether short-course treatment regimen (6 months) of ATT provides equivalent results in terms of disease healing as long-course treatment regimen (≥9 months) in the management of spinal TB. Five electronic databases (PubMed, MEDLINE, EMBASE, CENTRAL, and Web of Science) and their reference lists were searched to identify relevant randomized controlled trials with at least 1 year of follow-up that compared short-course with standard-course ATT for treatment of spinal TB. The methodological quality of included studies was assessed, and their data were extracted. A meta-analysis was used to calculate pooled effect sizes and 95% confidence interval (CI). The outcome measure was healed status of the disease at the final follow-up. Of 331 publications identified through literature search, eight publications describing six randomized studies were included. Moreover, 375 of 414 patients (90.58%) who received 6 months of ATT had healed status at their final follow-up compared to 404 of 463 patients (87.26%) who received ≥9 months of ATT. Overall, the healed status of spinal TB was equivalent in patients in both groups (pooled relative risk, 0.98; 95% CI, 0.92-1.04; p =0.439). However, there was considerable heterogeneity among the trials (I2=40.8%, p =0.149). The results suggest that the use of short-course (6 months) chemotherapy may be considered for the treatment of spinal TB in view of the similarity in the healing response achieved compared to treatment regimens of longer duration.

Longitudinal Model-Based Biomarker Analysis of Exposure-Response Relationships in Adults with Pulmonary Tuberculosis.

ABSTRACTThe identification of sensitive, specific, and reliable biomarkers that can be quantified in the early phases of tuberculosis treatment and predictive of long-term outcome is key for the development of an effective short-course treatment regimen. Time to positivity (TTP), a biomarker of treatment outcome against Mycobacterium tuberculosis, measures longitudinal bacterial growth in mycobacterial growth indicator tube broth culture and may be predictive of standard time to stable culture conversion (TSCC). In two randomized phase 2b trials investigating dose-ranging rifapentine (Studies 29 and 29X), 662 participants had sputum collected over 6 months where TTP, TSCC, and time to culture conversion were quantified. The goals of this post hoc study were to characterize longitudinal TTP profiles and to identify individual patient characteristics associated with delayed time to culture conversion. In order to do so, a nonlinear mixed-effects model describing longitudinal TTP was built. Independent variables associated with increased bacterial clearance (increased TTP), assessed by subject-specific and population-level trajectories, were higher rifapentine exposure, lower baseline grade of sputum acid-fast bacillus smear, absence of productive cough, and lower extent of lung infiltrates on radiographs. Importantly, sensitivity analysis revealed that major learning milestones in phase 2b trials, such as significant exposure-response and covariate relationships, could be detected using truncated TTP data as early as 6 weeks from start of treatment, suggesting alternative phase 2b study designs. The TTP model built depicts a novel phase 2b surrogate endpoint that can inform early assessment of experimental treatment efficacy and treatment failure or relapse in patients treated with shorter and novel TB treatment regimens, improving efficiency of phase 2 clinical trials. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT00694629 and NCT01043575.)

Assessing the impacts of short-course multidrug-resistant tuberculosis treatment in the Southeast Asia Region using a mathematical modeling approach.

This study aimed to predict the impacts of shorter duration treatment regimens for multidrug-resistant tuberculosis (MDR-TB) on both MDR-TB percentage among new cases and overall MDR-TB cases in the WHO Southeast Asia Region. A deterministic compartmental model was constructed to describe both the transmission of TB and the MDR-TB situation in the Southeast Asia region. The population-level impacts of short-course treatment regimens were compared with the impacts of conventional regimens. Multi-way analysis was used to evaluate the impact by varying programmatic factors (eligibility for short-course MDR-TB treatment, treatment initiation, and drug susceptibility test (DST) coverage). The model predicted that overall TB incidence will be reduced from 246 (95% credible intervals (CrI), 221–275) per 100,000 population in 2020 to 239 (95% CrI, 215–267) per 100,000 population in 2035, with a modest reduction of 2.8% (95% CrI, 2.7%–2.9%). Despite the slight reduction in overall TB infections, the model predicted that the MDR-TB percentage among newly notified TB infections will remain steady, with 2.4% (95% CrI, 2.1–2.9) in 2020 and 2.5% (95% CrI, 2.3–3.1) in 2035, using conventional MDR-TB treatment. With the introduction of short-course regimens to treat MDR-TB, the development of resistance can be slowed by 38.6% (95% confidence intervals (CI), 35.9–41.3) reduction in MDR-TB case number, and 37.6% (95% CI, 34.9–40.3) reduction in MDR-TB percentage among new TB infections over the 30-year period compared with the baseline using the standard treatment regimen. The multi-way analysis showed eligibility for short-course treatment and treatment initiation greatly influenced the impacts of short-course treatment regimens on reductions in MDR-TB cases and percentage resistance among new infections. Policies which promote the expansion of short-course regimens and early MDR-TB treatment initiation should be considered along with other interventions to tackle antimicrobial resistance in the region.

Short course chemotherapy in children suffering from drug resistant tuberculosis

The objective: to study the effect of short course chemotherapy regimens on treatment outcomes in children with drug resistant tuberculosis.Subjects and methods. In 2017-2019, 31 children at the age from 3 to 17 years old, received short course chemotherapy which lasted for 12-15 months. Children of both genders were enrolled in the study, they all were new pulmonary tuberculosis cases with multiple drug resistance or at risk of MDR, with no history of previous treatment with reserve anti-tuberculosis drugs, and without severe concomitant diseases. Before the treatment was prescribed, all children underwent lung computed tomography additionally to general clinical and laboratory tests.Results. The chemotherapy regimen for each child consisted of 4-6 drugs selected individually with the consideration of resistance pattern of the child or suspected index case. In all cases, the combination of drugs included fluoroquinolones (levofloxacin or moxifloxacin). Amikacin (67.7%), aminosalicylic acid (80.6%) and prothionamide (74.2%) were frequently prescribed. 54.8% of children received pyrazinamide and 48.4% – cycloserine. Given the limited lesions, only 16.1% of children received linezolid and 9.7% of children received bedaquiline. The main chemotherapy course made 13.2 ± 0.5 months (from 12 to 15 months depending on the form of tuberculosis and changes during treatment). The duration of the intensive phase made 4.8 ± 0.3 on the average. 2 (6.5 ± 4.4%) of 31 children developed adverse events requiring the cancellation of the drugs causing them.Conclusion. This study has demonstrated satisfactory tolerability and good efficacy of these short course regimens for treatment of multiple drug resistant tuberculosis. No relapses of tuberculosis were reported.

1653. Estimation of country-specific tuberculosis antibiograms using a wide and deep neural net on a large genomic dataset

BackgroundImproved estimates of drug resistant tuberculosis (TB) burden are needed to aid control efforts. The World Health Organization (WHO) currently reports estimates for rifampin resistance (RR) or multidrug resistance (MDR) at the national level. Resistance rates to other first-line and second-line agents, e.g. ethambutol, pyrazinamide, and aminoglycosides, are rarely available, even at the country level. Our objective was to generate country and drug specific resistance prevalence estimates (antibiograms) using in silico phenotype prediction and curated public and surveillance Mycobacterium tuberculosis (MTB) genomic data.MethodsWe curated MTB genomes either by sequencing or from published literature and excluded genomes that did not meet our quality criteria (i.e. at least 10X depth in >95% of the genome). A machine learning model previously trained to predict phenotypic resistance in MTB with high accuracy, a wide and deep neural net (WDNN), was used to predict resistance to ten drugs. We corrected for resistance oversampling in genomic data by conditioning on RR and using country specific surveillance MDR/RR rates reported by the WHO.ResultsOf the 49,851 MTB genomes curated, 33,873 isolates met quality criteria. Of these, geographic data was available for 22,838 genomes. Antibiograms were generated for nine first- and second-line drugs for 36 countries. Among countries with at least 100 isolates, a high rate of resistance to fluoroquinolones and second line injectables was seen among isolates from the Republic of Moldova (15.4% [CI = 13.7-16.7%] moxifloxacin resistant, 6.3% [CI = 5.5-6.8%] kanamycin resistant, n = 330) and Russian Federation (9.3% [CI = 9.1-9.4] moxifloxacin resistant, 5.4% [CI = 5.3-5.5%] kanamycin resistant, n = 1011) (Figure 1).Figure 1: Antibiograms created using genotypic data for isolates from Republic of Moldova (n=330, rifampin-resistance rate correction: 29%, range 26-31% among new tuberculosis cases);and Russian Federation (n=1011, rifampin-resistance rate correction 35%, range 34-35%, among new tuberculosis cases. rif: rifampin, inh: isoniazid, pza: pyrazinamide, emb: ethambutol, str: streptomycin, cap: capreomycin, amk: amikacin, kan: kanamycin, moxi: moxifloxacin ConclusionThe estimation of antibiotic resistance prevalence in MTB for pyrazinamide, ethambutol and second-line agents can be aided by the use of in silico models of drug resistance. A high rate of resistance to second-line drugs precludes large scale roll out of short-course WHO regimens for treatment of MDR-TB for empiric use in certain countries. The use of whole genome sequencing for resistance surveillance can inform policy on optimal national regimen choice for TB treatment.Disclosures All Authors: No reported disclosures

Patient and health-care worker perspectives on the short-course regimen for treatment of drug-resistant tuberculosis in Karakalpakstan, Uzbekistan.

Standard multidrug-resistant tuberculosis (MDR-TB) treatment is lengthy, toxic, and insufficiently effective. New drugs and a shorter treatment regimen (SCR) are now recommended. However, patient and health-care worker (HCW) perspectives regarding the SCR are unknown. We aimed to determine the views and experiences of patients with MDR-TB and HCW regarding the SCR in Karakalpakstan, Uzbekistan. In a qualitative study, we conducted 48 in-depth interviews with 24 people with MDR-TB and 20 HCW, purposively recruited to include those with a range of treatment-taking experiences and employment positions. Data were analysed thematically using Nvivo 12, to identify emergent patterns, concepts, and categories. Principles of grounded theory were drawn upon to generate findings inductively from participants' accounts. All patients viewed the SCR favourably. The SCR was seen as enabling an expedited return to work, studies, and "normality". This reduced the burden of treatment and difficulties with treatment fatigue. The SCR appeared to improve mental health, ease difficulties with TB-related stigma, and foster improved adherence. While patients wanted shorter treatment, it was also important that treatment be tolerable and effective. However, HCW doubted the appropriateness and effectiveness of the SCR, which influenced their confidence in prescribing the regimen. The SCR was said to benefit treatment completion and patients' lives. HCW concerns about SCR appropriateness and effectiveness may influence who receives the regimen. These are important considerations for SCR implementation and MDR-TB treatment developments, and dissonance between patient and HCW perspectives must be addressed for successful implementation of shorter regimens in the future.

An explainable machine learning platform for pyrazinamide resistance prediction and genetic feature identification of Mycobacterium tuberculosis.

Tuberculosis is the leading cause of death from a single infectious agent. The emergence of antimicrobial resistant Mycobacterium tuberculosis strains makes the problem more severe. Pyrazinamide (PZA) is an important component for short-course treatment regimens and first- and second-line treatment regimens. This research aims for fast diagnosis of M. tuberculosis resistance to PZA and identification of genetic features causing resistance. We use clinically collected genomic data of M. tuberculosis that are resistant or susceptible to PZA. A machine learning platform is built to diagnose PZA resistance using the whole genome sequence data, and to identify resistance genes and mutations. The platform consists of a deep convolutional neural network (DCNN) model for resistance diagnosis and a support vector machine (SVM) model as a surrogate to identify resistance genes and mutations. The DCNN model achieves a PZA resistance diagnosis accuracy of 93%. Each prediction takes less than a second. The SVM has revealed 2 novel genes, embB and gyrA, besides the well-known pncA gene, and 9 mutations that harbor PZA resistance. The DCNN and SVM machine learning platform, if used together with the real-time genome sequencing machines, could allow for rapid PZA diagnosis, allowing for critical time to ensure good patient outcomes, and preventing outbreaks of deadly infections. Furthermore, identifying pertinent resistance genes and mutations will help researchers better understand the biological mechanisms behind resistance. Machine learning can be used to achieve high-accuracy resistance prediction, and identify genes and mutations causing the resistance.

Treatment outcomes of Nigerian patients with tuberculosis: A retrospective 25-year review in a regional medical center.

Tuberculosis (TB) remains a global health challenge and leading infectious killer worldwide. The need for continuous evaluation of TB treatment outcomes becomes more imperative in the midst of a global economic meltdown substantially impacting resource-limited-settings. This study retrospectively reviewed 25-years of treatment outcomes in 3,384 patients who were managed for TB at a tertiary hospital in Nigeria. Confirmed TB cases were given directly observed therapy of a short-course treatment regimen and monitored for clinical response. Out of 1,146,560 patients screened, there were 24,330 (2.1%) presumptive and 3,384 (13.9%) confirmed TB cases. The patients' mean age was 35.8 years (0.33-101 years). There were 1,902 (56.2%) male, 332(9.8%) pediatric, and 2,878 (85%) pulmonary TB cases. The annual mean measured treatment outcomes were as follows: adherence, 91.4(±5.8) %; successful outcome, 75.3(±8.8) % potentially unsatisfactory outcome, 14.8(±7.2) %; and mortality 10.0(±3.6) %. Female, extra-pulmonary TB (EPTB), newly diagnosed, and relapsed patients compliant with treatment had successful outcomes. Adulthood and HIV infection were mortality risk factors. The mean annual successful treatment outcome is 75.3(±8.8) %. Female, pediatric, EPTB, new, and relapsed patients were predisposed to successful treatment outcomes. Lessons learned will guide future program modifications.

Serum level of IL-1ra was associated with the treatment of latent tuberculosis infection in a Chinese population

BackgroundDynamically changed levels of serum cytokines might predict the development of active TB from latent tuberculosis infection (LTBI) and monitor preventive treatment effectiveness. The aim of the study was to identify potential serum cytokines associated with LTBI treatment which might predict active disease development in a Chinese population.MethodsBased on a randomized controlled trial aiming to explore short-course regimens for LTBI treatment, the dynamic changes of serum cytokines determined by bead-based multiplex assays were investigated for the participants who developed active TB during follow-up and age and gender matched controls stayed healthy.ResultsTotally, 21 patients diagnosed with active tuberculosis (TB) during the 2-year follow-up (12 from treated groups and 9 from untreated controls) and 42 age and gender matched healthy controls (24 from treated groups and 18 from untreated controls) were included in the study. Before treatment, serum IL-1ra was statistically higher among those who developed active disease during follow-up as compared with those stayed healthy. As for treated participants, the levels of IL-1ra were significantly lower after treatment in comparison with those before treatment both in active TB group (p = 0.002) and non-TB group (p = 0.009). For untreated participants, the levels of IL-1ra were not statistically different between different time points both in active TB group (p = 0.078) and non-TB group (p = 0.265).ConclusionOur results suggested that declined serum level of IL-1ra was associated with LTBI treatment. Further studies are needed to verify whether it could be used to evaluate LTBI treatment and to predict active disease development.

Advances in the diagnosis and treatment of latent tuberculosis infection.

This review describes the major developments in the rationale for treating latent tuberculosis infection; new approaches to identifying persons with latent infection who are most likely to progress to active disease; and the development of novel short-course regimens for treatment of latent tuberculosis. As many as one-third of the world's population has latent infection with Mycobacterium tuberculosis. Models demonstrate that tuberculosis will not be eliminated without large-scale treatment of persons with latent TB. Current tools for identifying persons at risk for active tuberculosis disease include TST and IGRA, which have poor positive predictive values. Newer approaches using gene expression profiling show promise and are being studied in the ongoing trials. Development of short-course regimens are a major advance in treatment of latent TB. Three months of rifapentine with isoniazid, 4 months of rifampin, and 1 month of rifapentine with isoniazid have been found to be noninferior to the standard 9 months of isoniazid. Progress towards TB elimination can be accelerated by instituting public health measures that take into account new developments in identifying and treating persons with latent tuberculosis infection who are most likely to progress to active disease.

Guidelines for the treatment of latent tuberculosis infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020

Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. Am J Respir Crit Care Med 161:S221-S247, 2000). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens for treatment of LTBI among persons who live in the United States. The systematic literature review included clinical trials of regimens to treat LTBI. Quality of evidence (high, moderate, low, or very low) from clinical trial comparisons was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. In addition, a network meta-analysis evaluated regimens that had not been compared directly in clinical trials. The effectiveness outcome was tuberculosis disease; the toxicity outcome was hepatotoxicity. Strong GRADE recommendations required at least moderate evidence of effectiveness and that the desirable consequences outweighed the undesirable consequences in the majority of patients. Conditional GRADE recommendations were made when determination of whether desirable consequences outweighed undesirable consequences was uncertain (eg with low-quality evidence). These updated 2020 LTBI treatment guidelines include the NTCA- and CDC-recommended treatment regimens that comprise three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily isoniazid. All recommended treatment regimens are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to isoniazid or rifampin. These updated guidelines do not apply when evidence is available that the infecting M tuberculosis strain is resistant to both isoniazid and rifampin; recommendations for treating contacts exposed to multidrug-resistant tuberculosis were published in 2019 (Nahid P, Mase SR Migliori GB, et al Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93-e142). The three rifamycin-based preferred regimens are 3months of once-weekly isoniazid plus rifapentine, 4months of daily rifampin, or 3months of daily isoniazid plus rifampin. Prescribing providers or pharmacists who are unfamiliar with rifampin and rifapentine might confuse the two drugs. They are not interchangeable, and caution should be taken to ensure that patients receive the correct medication for the intended regimen. Preference for these rifamycin-based regimens was made on the basis of effectiveness, safety, and high treatment completion rates. The two alternative treatment regimens are daily isoniazid for 6 or 9months; isoniazid monotherapy is efficacious but has higher toxicity risk and lower treatment completion rates than shorter rifamycin-based regimens. In summary, short-course (3- to 4-month) rifamycin-based treatment regimens are preferred over longer-course (6-9month) isoniazid monotherapy for treatment of LTBI. These updated guidelines can be used by clinicians, public health officials, policymakers, health care organizations, and other state and local stakeholders who might need to adapt them to fit individual clinical circumstances.