Feasibility and acceptability pilot of video-based direct observed treatment (vDOT) for supporting antitubercular treatment in South India: a cohort study.

OBJECTIVES: The objective of this study was to assess the feasibility and acceptability of video-based anti-tuberculosis (TB) treatment adherence support in patients with TB (PwTB) in South India. DESIGN: An exploratory cohort. SETTING: Participants were recruited at the TB treatment centre (direct observed treatment short centre) of a tertiary-level teaching facility in Bangalore, Karnataka, South India. PARTICIPANTS: The study enrolled 25 PwTB, with replacement. Adult PwTB who were on drug-sensitive treatment regimens were included, while those who had drug resistant TB were excluded from the study. INTERVENTION: Participants received scheduled adherence reminders and were trained to videorecord themselves swallowing their medication via a mobile application. The application was automated to submit these videos for evaluation. Participants were followed up monthly till treatment completion or withdrawal. OUTCOME MEASURES: Adherence rate and acceptability of video-based directly observed treatment (vDOT). RESULTS: The mean±SD age of the participants was 33±14 years, majority were females (16, 64%), residing in urban areas (24,96%), married (17, 68%) and had access to smart phones (23,92%). A total of 3193 person days of follow-up was completed; of the videos submitted within the first 6 months of enrollment (2501), 94% (2354/2501) were considered 'acceptable' and 16 (64%) participants were optimally adherent (ie, ≥80%). Participant videos improved in quality and a higher proportion met acceptability criteria over time. Twenty-one (84%) participants stated that they found the application easy to learn; 13 (52%) preferred vDOT over DOT. Mixed model logistic regression showed that those who are married are more likely have daily adherence to anti-TB treatment. CONCLUSION: Video-based mobile phone interventions are acceptable to PwTB and the ease of using the application increases with time. To provide patient-centred care, vDOT is a promising option that can be offered to patients for treatment support and adherence monitoring.

Role of non-coding RNAs in tuberculosis and their potential for clinical applications.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of mortality due to infectious diseases, only surpassed in 2020 by COVID-19. Despite the development in diagnostics, therapeutics, and evaluation of new vaccines for TB, this infectious disease remains uncontrollable due to the emergence of multidrug-resistant (MDR) and extremely drug-resistant (XDR) TB, among other factors. The development in transcriptomics (RNomics) has enabled the study of gene expression in TB. It is considered that non-coding RNAs (ncRNAs) from host [microRNAs (miRNAs)] and Mtb [small RNAs (sRNAs)] are important elements in TB pathogenesis, immune resistance, and susceptibility. Many studies have shown the importance of host miRNAs in regulating immune response against Mtb via in vitro and in vivo mice models. The bacterial sRNAs play a major role in survival, adaptation, and virulence. Here, we review the characterization and function of host and bacteria ncRNAs in TB and their potential use in clinical applications as diagnostic, prognostic, and therapeutic biomarkers.

[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.

Coinfection of COVID-19 and Tuberculosis in Uganda.

The clinical features and outcomes of tuberculosis (TB) and COVID-19 coinfection are not well established. This short report describes 11 people with TB/COVID-19 coinfection in Uganda. The mean age was 46.9 ± 14.5 years; eight (72.7%) were male and two (18.2%) were coinfected with HIV. All patients presented with cough whose median duration was 71.1 (interquartile range, 33.1, 109) days. Eight (72.7%) had mild COVID-19 whereas two (18.2%) died, including one with advanced HIV disease. All patients were treated with first-line anti-TB drugs and adjunct therapy for COVID-19 using national treatment guidelines. This report presents the possibility of the coexistence of the two diseases and calls for more vigilance, screening, and collective prevention measures for both COVID-19 and TB.

A Review of the Development of Multitarget Molecules against HIV-TB Coinfection Pathogens.

The human immunodeficiency virus (HIV) produces the pathologic basis of acquired immunodeficiency syndrome (AIDS). An increase in the viral load in the body leads to a decline in the number of T lymphocytes, compromising the patient's immune system. Some opportunistic diseases may result, such as tuberculosis (TB), which is the most common in seropositive patients. Long-term treatment is required for HIV-TB coinfection, and cocktails of drugs for both diseases are used concomitantly. The most challenging aspects of treatment are the occurrence of drug interactions, overlapping toxicity, no adherence to treatment and cases of resistance. Recent approaches have involved using molecules that can act synergistically on two or more distinct targets. The development of multitarget molecules could overcome the disadvantages of the therapies used to treat HIV-TB coinfection. This report is the first review on using molecules with activities against HIV and Mycobacterium tuberculosis (MTB) for molecular hybridization and multitarget strategies. Here, we discuss the importance and development of multiple targets as a means of improving adherence to therapy in cases of the coexistence of these pathologies. In this context, several studies on the development of structural entities to treat HIV-TB simultaneously are discussed.

Retaining Patients with Drug-Resistant Tuberculosis on Treatment During the COVID-19 Pandemic - Dharavi, Mumbai, India, 2020-2022.

Mumbai, India's second largest city, has one of the highest prevalences of drug-resistant tuberculosis* (DRTB) in the world. Treatment for DRTB takes longer and is more complicated than treatment for drug-susceptible tuberculosis (TB). Approximately 300 persons receive a new DRTB diagnosis each year in Mumbai's Dharavi slum†; historically, fewer than one half of these patients complete DRTB treatment. As nationwide restrictions to mitigate the COVID-19 pandemic were implemented, a program to facilitate uninterrupted DRTB care for patients receiving treatment was also implemented. A comprehensive tool and risk assessment provided support to DRTB patients and linked those who relocated outside of Dharavi during the pandemic to DRTB care at their destination. During May 2020-September 2022, a total of 973 persons received DRTB treatment in Dharavi, including 255 (26%) who relocated during treatment. Overall, 25 (3%) DRTB patients were lost to follow-up, a rate substantially lower than the rate before the pandemic (18%). Proactive planning and implementation of simple tools retained patients on treatment during periods of travel restrictions and relocations, improving programmatic outcomes. This approach might aid public health programs serving migrant populations or patients receiving treatment for DRTB during public health emergencies.

Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets.

Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host's immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB-the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years-reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in M. tb.

Isoniazid preventive therapy completion in children under 5 years old who are contacts of tuberculosis cases in Lima, Peru: study protocol for an open-label, cluster-randomized superiority trial.

BACKGROUND: Children < 5 years old in contact with TB cases are at high risk for developing severe and fatal forms of TB. Contact investigation, BCG vaccination, and isoniazid preventive therapy (IPT) are the most effective strategies to prevent TB among children. However, the implementation of IPT faces challenges at several stages of the cascade of care of TB infection among children, particularly those less than 5 years old. In Peru, a large proportion of children do not complete IPT, which highlights the need to design effective interventions that enhance preventive therapy adherence and completion. Although the body of evidence for such interventions has grown, interventions in medium TB incidence settings are lacking. This study aims to test the effectiveness, acceptability, and feasibility of an intervention package to increase information and motivation to complete IPT among children < 5 who have been prescribed IPT. METHODS: An open-label, cluster-randomized superiority trial will be conducted in two districts in South Lima, Peru. Thirty health facilities will be randomized as clusters, 10 to the intervention and 20 to control (standard of care). We aim to recruit 10 children from different households in each cluster. Participants will be caretakers of children aged < 5 years old who initiated IPT. The intervention consists of educational material, and short message services (SMS) reminders and motivators. The primary outcomes will be the proportion of children who picked up > 90% of the 24 weeks of IPT (22 pick-ups) and the proportion of children who picked up the 24 weeks of IPT. The standard of care is a weekly pick-up with monthly check-ups in a health facility. Feasibility and acceptability of the intervention will be assessed through an interview with the caretaker. DISCUSSION: Unfavorable outcomes of TB in young children, high effectiveness of IPT, and low rates of IPT completion highlight the need to enhance adherence and completion of IPT among children < 5 years old. Testing of a context-adapted intervention is needed to improve IPT completion rates and therefore TB prevention in young children. TRIAL REGISTRATION: ClinicalTrials.gov NCT03881228. Registered on March 19, 2019.

Influence of COVID-19 for delaying the diagnosis and treatment of pulmonary tuberculosis-Tianjin, China.

Background: The COVID-19 pandemic has disrupted the diagnosis, treatment, and care for tuberculosis (TB). Delays in seeking TB care may result in increased community transmission and unfavorable treatment outcomes. We sought to understand the influence of the COVID-19 pandemic on the proportion of patients with TB who delayed seeking the diagnosis and care for TB and explore the reasons for their postponement. Methods: We surveyed a representative sample of outpatients treated for pulmonary TB from June to November 2020 using an anonymous standardized questionnaire. Multivariable logistic regression was used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CIs) of factors associated with the postponement of TB care. We used routinely collected surveillance data to assess trends of TB reports before and after the emergence of COVID-19 (2017-2019 vs. 2020-2022) in Tianjin, China. Results: Among 358 participants who were diagnosed with pulmonary TB during the COVID-19 response, 61 (17%) postponed seeking TB diagnosis due to COVID-19, with 39 (64%) citing fear as the primary reason. Female sex (aOR:2.0; 95% CI: 1.1-3.7), previous antituberculosis treatment (aOR:3.2; 95%CI: 1.4-7.6), and TB diagnosis during the first-level response (aOR = 3.2, 1.7-6.2) were associated with the postponement. Among all 518 participants receiving antituberculosis treatment, 57 (11%) had postponed their regular healthcare visits due to COVID-19, 175 (34%) received no treatment supervision, and 32 (6%) experienced treatment interruption. Compared to 2017-2019, reported pulmonary TB declined by 36.8% during the first-level response to COVID-19, 23.5% during the second-level response, 14% during the third-level response in 2020, and 4.3% in 2021. Conclusion: The COVID-19 response reduced the number of people who sought and received diagnosis, treatment, and care for TB in Tianjin, China. Integrative programs to ensure access and continuity of TB services should be considered and dual testing for SARS-CoV-2 and M. tuberculosis may facilitate finding cases.

Antibiotic resistance acquisition versus primary transmission in the presentation of extensively drug-resistant tuberculosis.

Mycobacterium tuberculosis is the leading cause of mortality worldwide due to a single bacterial pathogen. Of concern is the negative impact that the COVID-19 pandemic has had on the control of tuberculosis (TB) including drug-resistant forms of the disease. Antimicrobial resistance increases the likelihood of worsened outcomes in TB patients including treatment failure and death. Multidrug-resistant (MDR) strains, resistant to first-line drugs isoniazid and rifampin, and extensively drug-resistant (XDR) strains with further resistance to second-line drugs (SLD), threaten control programs designed to lower TB incidence and end the disease as a public health challenge by 2030, in accordance with UN Sustainable Development Goals. Tackling TB requires an understanding of the pathways through which drug resistance emerges. Here, the roles of acquired resistance mutation, and primary transmission, are examined with regard to XDR-TB. It is apparent that XDR-TB can emerge from MDR-TB through a small number of additional resistance mutations that occur in patients undergoing drug treatment. Rapid detection of resistance, to first-line drugs and SLD, at the initiation of and during treatment, and prompt adjustment of regimens are required to ensure treatment success in these patients. Primary transmission is predicted to make an increasing contribution to the XDR-TB caseload in the future. Much work is required to improve the implementation of the World Health Organization-recommended infection control practices and block onward transmission of XDR-TB patients to contacts including health-care workers. Finally, limiting background resistance to fluoroquinolones in pre-XDR strains of M. tuberculosis will necessitate better antimicrobial stewardship in the broader use of this drug class.

Effect of HIV status and antiretroviral treatment on treatment outcomes of tuberculosis patients in a rural primary healthcare clinic in South Africa.

BACKGROUND: Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV) infected individuals in South Africa. Despite the implementation of HIV/TB integration services at primary healthcare facility level, the effect of HIV on TB treatment outcomes has not been well investigated. To provide evidence base for TB treatment outcome improvement to meet End TB Strategy goal, we assessed the effect of HIV status on treatment outcomes of TB patients at a rural clinic in the Ugu Health District, South Africa. METHODS: We reviewed medical records involving a cohort of 508 TB patients registered for treatment between 1 January 2013 and 31 December 2015 at rural public sector clinic in KwaZulu-Natal province, South Africa. Data were extracted from National TB Programme clinic cards and the TB case registers routinely maintained at study sites. The effect of HIV status on TB treatment outcomes was determined by using multinomial logistic regression. Estimates used were relative risk ratio (RRR) at 95% confidence intervals (95%CI). RESULTS: A total of 506 patients were included in the analysis. Majority of the patients (88%) were new TB cases, 70% had pulmonary TB and 59% were co-infected with HIV. Most of HIV positive patients were on antiretroviral therapy (ART) (90% (n = 268)). About 82% had successful treatment outcome (cured 39.1% (n = 198) and completed treatment (42.9% (n = 217)), 7% (n = 39) died 0.6% (n = 3) failed treatment, 3.9% (n = 20) defaulted treatment and the rest (6.6% (n = 33)) were transferred out of the facility. Furthermore, HIV positive patients had a higher mortality rate (9.67%) than HIV negative patients (2.91%)". Using completed treatment as reference, HIV positive patients not on ART relative to negative patients were more likely to have unsuccessful outcomes [RRR, 5.41; 95%CI, 2.11-13.86]. CONCLUSIONS: When compared between HIV status, HIV positive TB patients were more likely to have unsuccessful treatment outcome in rural primary care. Antiretroviral treatment seems to have had no effect on the likelihood of TB treatment success in rural primary care. The TB mortality rate in HIV positive patients, on the other hand, was higher than in HIV negative patients emphasizing the need for enhanced integrated management of HIV/TB in rural South Africa through active screening of TB among HIV positive individuals and early access to ART among HIV positive TB cases.

Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management.

Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through several mechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterial metabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease.