Role for Linezolid in drug sensitive tuberculosis.

Tuberculosis (TB) continues to be a global challenge. Reducing the duration of TB treatment for drug-sensitive TB (DSTB) has direct and distinct advantages. We ventured into the aspect of utilizing linezolid as a pivotal drug in shortening therapy in DSTB. Linezolid has gained prominence as it is faring well in resistant TB management. Only a few studies use the strategy of Linezolid in DS-TB but it seems a lucrative approach, the bactericidal effects have been reported favourably in the studies. There have been concerns about the potential adverse drug effects of Linezolid reported but clinical trials have demonstrated safety and tolerability when administered for shorter periods. If the safety and efficacy of giving Linezolid for a shorter period along with standard drugs for DSTB is established it could lead to newer avenues using Linezolid for shortening the duration of treatment for DSTB as an alternative to treat DSTB.

Establishing proof of concept for utility of Trueprep®-extracted DNA in line-probe assay testing.

BACKGROUND AND OBJECTIVES: With an increased demand for rapid, diagnostic tools for TB and drug resistance detection, Truenat® MTB-RIF assay has proven to be a rapid point of care molecular test. The present study aimed to establish a proof of concept of using Trueprep-extracted DNA for line-probe assay (LPA) testing.METHODS: A total of 150 sputum samples (MTB-positive at Truenat sites) were divided into two aliquots. One aliquot was used for DNA extraction using the Trueprep device and MTB testing. The second aliquot of the sample was subjected to GenoLyse® DNA extraction. DNA from both the Trueprep and GenoLyse methods was subjected to first-line (FL) and second-line (SL) LPA testing.RESULTS: Of 139 Trueprep-extracted DNA, respectively 135 (97%) and 105 (75%) had interpretable results by FL and SL-LPA testing. Of 128 GenoLyse-extracted DNA, all 128 (100%) had interpretable FL-LPA results and 114 (89%) had interpretable SL-LPA results.CONCLUSION: The results obtained in this study indicate that Trueprep-extracted DNA can be used in obtaining valid LPA results. However, the study needs to be conducted on a larger sample size before our recommendations can be used for policy-making decisions.

NATCON 2022 Panel discussion: "TB vaccination - Going Forward".

Vaccination is important tuberculosis (TB) preventive strategy that is essential to achieve the goals of the End TB strategy. The BCG vaccination at birth offers protection against TB in young children but not in adolescents and adults. New TB vaccines are the need of the hour. The TB vaccine development pipeline in the past years is encouraging with newer TB vaccines in clinical trials in humans. The focus of the newer TB vaccine is the prevention of infection, disease, and recurrence of TB disease. Therapeutic vaccines focus on better treatment outcomes and prevention of TB recurrence. BCG revaccination is of current interest. Novel, safe, and efficient TB vaccines that prevent TB infection and disease if introduced in 2025 could drastically reduce the rate of TB incidence. However, the development of an effective vaccine for TB is challenging. Engagement of stakeholders, mobilizing funding, and advocacy could accelerate the newer TB vaccine development process.

Newer TB diagnostics: An update.

In recent years, nucleic-acid amplification tests (NAATs), which are highly specific and sensitive, have helped to transform the TB diagnostic landscape. According to the WHO 2021 Guidelines on Diagnostics, the NAATs used in TB diagnosis at the point of care (POC) include Xpert MTB/RIF a cartridge-based test manufactured by Cepheid, and Truenat a chip-based test manufactured by Molbio. Other POC tests that are expected to be implemented in near future include Xpert Omni and Xpert MTB/XDR. The use of line probe assay is involved at the level of reference labs for the detection of MTB and its resistance to first-line (Isoniazid and Rifampicin) and second-line (fluoroquinolones and second-line injectables) drugs. When the currently available NAATs detect mutations for drug resistance at a particular region of MTB sequence, the Whole genome sequencing (WGS) platform demonstrates the exceptional potential for reliable and comprehensive resistance prediction for MTB isolates, by multiple gene regions or whole genome sequence analysis allowing for accurate clinical decisions.

Factors influencing treatment outcomes in patients with isoniazid-resistant pulmonary TB.

INTRODUCTION: Patients with isoniazid (H, INH) resistant pulmonary TB but undetected rifampicin (R, RIF) resistance are treated with a 6-month regimen of levofloxacin-RIF-ethambutol-pyrazinamide (6LvxREZ) under India´s National TB Elimination Programme (NTEP).OBJECTIVE: To describe the profile of and treatment outcomes in patients with pulmonary INH-resistant (INHR) TB initiated on TB treatment, and identify factors associated with unfavourable treatment outcomes (died, failed, treatment changed, lost to follow-up).METHODS: This was a retrospective analysis of NTEP database (Ni-kshay) on pulmonary INHR TB patients initiated on treatment with "H mono/poly regimen" (6LvxREZ) between July 2019 and June 2020 with documented treatment outcomes. Proportions with 95% confidence interval (CI) was calculated and logistic regression analysis was performed.RESULTS: Of the 11,519 patients with pulmonary INHR TB, 9,440 (82%) had treatment success (55.1% cured, 26.9% treatment completed). Unfavourable treatment outcome was observed in 1,901 (16.5%). Male sex, tobacco and alcohol use, HIV reactive status were associated with unfavourable treatment outcome. Patients with katG mutations and resistance to fluoroquinolones were likely to have poor treatment outcomes.CONCLUSION: A levofloxacin-based regimen offers a treatment success rate of 82% in patients with pulmonary INHR TB. Sex-specific strategies, interventions to address smoking and alcohol use, focus on HIV-reactive patients and optimising treatment regimens based on drug susceptibility should be considered for improving treatment outcomes.

Experience on the first national anti-TB drug resistance survey (DRS) in Timor-Leste.

BACKGROUND: A national drug resistance survey (DRS) was implemented for the first time in Timor-Leste (TL) in 2019. The primary objective of the survey was to assess the prevalence of drug resistance among new and previously treated pulmonary TB patients in the country. METHODS: This nation-wide cross-sectional survey was conducted in 2019 targeting all new and previously treated sputum smear-positive pulmonary TB patients. Sputum samples were submitted to the National TB Reference Laboratory for confirmation of TB and to determine resistance to rifampicin by Xpert MTB/RIF. Culture was performed on solid media, and culture isolates of confirmed TB cases were shipped to the WHO Supranational TB Reference Laboratory in Chennai, India for whole genome sequencing (WGS). Survey summary statistics, data cross-tabulations and analysis of potential risk factors of rifampicin-resistant TB (RR-TB) were conducted using R statistical software (version 3.5.2). RESULTS: A total of 953 sputum-smear positive patients were enrolled, of which 917 were confirmed as positive for TB by either Xpert MTB/RIF or culture. An electronic web-based system was used for entry and storage of the data. Rifampicin resistance was detected among 0.6% (95% CI 0.2-1.3) of new cases and 2.7% (95% CI 0.5- 8.2) of previously treated cases. WGS was conducted for validation purposes on 65 randomly selected isolates (29% of RR-TB (2/7) and 7% of RS-TB (63/910) by Xpert MTB/RIF or pDST). The original test results agreed with the WGS validation results for 62/64 isolates (97%). CONCLUSION: The prevalence of RR-TB in Timor-Leste is relatively low compared to the estimated proportions of RR-TB in the WHO South-East Asia Region (2.5% [95% CI 1.9-3.3] among new cases and 14% [95% CI 7.7-21] among previously treated cases). The rapid sputum collection and transportation mechanism implemented in the survey demonstrates its feasibility in low resource settings and should be replicated for routinely transporting TB specimens from microscopy labs to GeneXpert sites. Establishment of in-country capacity for rapid molecular diagnostics for both first- and second-line DST is an immediate need for achieving universal drug susceptibility testing (DST) to guide appropriate patient management.

Trends in rifampicin and isoniazid resistance in patients with presumptive TB.

BACKGROUND: Early diagnosis of drug-resistant TB (DR-TB) is crucial in preventing the spread of the disease in the community. Introduction of upfront decentralised drug susceptibility testing to district-level as part of universal drug susceptibility testing (UDST) policy increased the feasibility of rapid and early testing for drug resistance closer to the patient and has resulted in reduced circumstances for transmission. The introduction of the first-line line-probe assay (FL-LPA), GenoType® MTBDRplus v2, has had an extensive impact on the management of multidrug-resistant TB (MDR-TB) in India.MATERIALS and METHODS: Sputum samples of patients with presumptive TB and DR-TB from selected districts of Tamil Nadu received through National TB Elimination Programme (NTEP) were subjected to FL-LPA as per programme guidelines. In this study, we present trends in genotypic resistance to isoniazid (INH) and rifampicin (RIF) during the 4 years (2016-2019) among these patients. Band patterns were analysed as per the updated GLI (Global Laboratory Initiative) LPA interpretation and reporting guidelines.RESULTS: A total of 26,349 samples were received during the study period. Smear-positive samples (n = 20231) were directly subjected to FL-LPA; smear-negative samples were cultured in liquid media and M. tuberculosis-positive cultures were tested using FL-LPA. A total of 18,441 were MTB-positive on FL-LPA. INH monoresistance, RIF monoresistance and MDR-TB was observed in respectively 8.7%, 1.1% and 3.3% of the samples. There was a decreasing trend in all types of resistance observed particularly after 2017 (P < 0.001). MDR-TB showed a steady decrease from 5.6% to 1.8%. S531L (19.5%) and S315T (61.1%) were the most common mutations identified in the rpoB and katG genes, respectively. The percentage of inhA-c-15t promoter mutation, indicating low-level INH resistance, showed a consistent increase (P < 0.001).CONCLUSION: The impact of the UDST policy on the NTEP may have led to this decreasing trend in RIF and INH resistance observed in the study period. The increase in low-level INH resistance mutation inhA-c-15t may be associated with ethionamide/prothionamide resistance, and this should be taken into account when designing DR-TB regimen.

Concomitant pulmonary disease is common among patients with extrapulmonary TB.

BACKGROUND: Microbiologic screening of extrapulmonary TB (EPTB) patients could inform recommendations for aerosol precautions and close contact prophylaxis. However, this is currently not routinely recommended in India. Therefore, we estimated the proportion of Indian patients with EPTB with microbiologic evidence of pulmonary TB (PTB).METHODS: We characterized baseline clinical, radiological and sputum microbiologic data of 885 adult and pediatric TB patients in Chennai and Pune, India, between March 2014 and November 2018.RESULTS: Of 277 patients with EPTB, enhanced screening led to the identification of 124 (45%) with concomitant PTB, including 53 (19%) who reported a cough >2 weeks; 158 (63%) had an abnormal CXR and 51 (19%) had a positive sputum for TB. Of 70 participants with a normal CXR and without any cough, 14 (20%) had a positive sputum for TB. Overall, the incremental yield of enhanced screening of patients with EPTB to identify concomitant PTB disease was 14% (95% CI 12-16).CONCLUSIONS: A high proportion of patients classified as EPTB in India have concomitant PTB. Our results support the need for improved symptom and CXR screening, and recommends routine sputum TB microbiology screening of all Indian patients with EPTB.

Prime-Boost Vaccination With Covaxin/BBV152 Induces Heightened Systemic Cytokine and Chemokine Responses.

Covaxin/BBV152 is a whole virion inactivated SARS-CoV-2 vaccine. The effect of prime-boost vaccination with Covaxin on systemic immune responses is not known. We investigated the effect of Covaxin on the plasma levels of a wide panel of cytokines and chemokines at baseline (M0) and at months 1 (M1), 2 (M2) and 3 (M3) following prime-boost vaccination in healthy volunteers. Our results demonstrate that Covaxin induces enhanced plasma levels of Type 1 cytokines (IFNγ, IL-2, TNFα), Type 2/regulatory cytokines (IL-4, IL-5, IL-10 and IL-13), Type 17 cytokine (IL-17A), other pro-inflammatory cytokines (IL-6, IL-12, IL-1α, IL-1ß) and other cytokines (IL-3 and IL-7) but diminished plasma levels of IL-25, IL-33, GM-CSF and Type 1 IFNs. Covaxin also induced enhanced plasma levels of CC chemokine (CCL4) and CXC chemokines (CXCL1, CXCL2 and CX3CL1) but diminished levels of CXCL10. Covaxin vaccination induces enhanced cytokine and chemokine responses as early as month 1, following prime-boost vaccination, indicating robust activation of innate and adaptive immune responses in vaccine recipients.

Antibody responses to the BBV152 vaccine in individuals previously infected with SARS-CoV-2: A pilot study.

Background & objectives: Vaccination against SARS-CoV-2 is a recommendation from the World Health Organization as the foremost preference in the current situation to control the COVID-19 pandemic. BBV152 is one of the approved vaccines against SARS-CoV-2 in India. In this study, we determined SARS-CoV-2-specific antibody levels at day 0 (baseline, before vaccination), day 28 ± 2 post-first dose (month 1) and day 56 ± 2 post-first dose (month 2) of BBV152 whole-virion-inactivated SARS-CoV-2 recipients, and compared the antibody responses of individuals with confirmed pre-vaccination SARS-CoV-2 infection to those individuals without prior evidence of infection. Methods: Blood samples were collected from 114 healthcare professionals and frontline workers who received BBV152 vaccine from February to May & June 2021. Prior infection with SARS-CoV-2 was determined at baseline. Serum samples were used to estimate SARS-CoV-2 nucleoprotein-specific IgG [IgG (N)], spike protein-specific IgG [IgG (S)] and neutralizing antibodies (NAb). Results: Participants with previous SARS-CoV-2 infection after a single vaccine dose elicited IgG (N) and IgG (S) antibody levels along with NAb binding inhibition responses levels were similar to infection-naïve vaccinated participants who had taken two doses of vaccine. Interpretation & conclusions: Our preliminary data suggested that a single dose of BBV152-induced humoral immunity in previously infected individuals was equivalent to two doses of the vaccine in infection-naïve individuals. However, these findings need to be confirmed with large sized cohort studies.

Recent developments in the diagnosis and treatment of extrapulmonary non-tuberculous mycobacterial diseases.

Diseases due to pathogenic mycobacteria cause significant health and economic impact on humans worldwide. Although mycobacterial diseases primarily affect the lungs, the involvement of extrapulmonary organs has also gained ground, particularly among individuals with co-existing medical conditions. Besides Mycobacterium tuberculosis complex organisms, non-tuberculous mycobacteria (NTM) are also known to cause pulmonary and extrapulmonary diseases. Primary and disseminated extrapulmonary mycobacterial infections affect the brain, eye, mouth, tongue, lymph nodes of the neck, spine, bones, muscles, skin, pleura, pericardium, gastro-intestinal, peritoneum and genito-urinary system. The clinical presentation of extrapulmonary mycobacterial diseases, including systemic symptoms, of M. tuberculosis-infected cases and NTM-infected cases is similar. Moreover, extrapulmonary mycobacterial diseases are complicated by the involvement of diverse bacterial species as aetiological agents. Culture and molecular techniques are used to differentiate NTM from Mycobacterium tuberculosis and to classify sub-species of the pathogens. As sub-speciation and drug susceptibility profiling are critical factors in treating extrapulmonary NTM diseases, there are often significant delays in initiating treatment and customising the therapeutic regimen. Here, we summarise the clinical symptoms of NTM diseases in various extrapulmonary organs, and discuss the recent trends in diagnosing and treating these diseases. We also highlight the complications associated with the management of extrapulmonary NTM disease.

Unhealthy alcohol use independently associated with unfavorable TB treatment outcomes among Indian men.

BACKGROUND: Approximately 10% of incident TB cases worldwide are attributable to alcohol. However, evidence associating alcohol with unfavorable TB treatment outcomes is weak.METHODS: We prospectively evaluated men (≥18 years) with pulmonary TB in India for up to 24 months to investigate the association between alcohol use and treatment outcomes. Unhealthy alcohol use was defined as a score of ≥4 on the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) scale at entry. Unfavorable TB treatment outcomes included failure, recurrence, and all-cause mortality, analyzed as composite and independent endpoints.RESULTS: Among 751 men, we identified unhealthy alcohol use in 302 (40%). Median age was 39 years (IQR 28-50); 415 (55%) were underweight (defined as a body mass index [BMI] <18.5 kg/m²); and 198 (26%) experienced an unfavorable outcome. Unhealthy alcohol use was an independent risk factor for the composite unfavorable outcome (adjusted incidence rate ratio [aIRR] 1.47, 95% CI 1.05-2.06; P = 0.03) and death (aIRR 1.90, 95% CI 1.08-3.34; P = 0.03), specifically. We found significant interaction between AUDIT-C and BMI; underweight men with unhealthy alcohol use had increased risk of unfavorable outcomes (aIRR 2.22, 95% CI 1.44-3.44; P < 0.001) compared to men with BMI ≥18.5 kg/m² and AUDIT-C <4.CONCLUSION: Unhealthy alcohol use was independently associated with unfavorable TB treatment outcomes, highlighting the need for integrating effective alcohol interventions into TB care.

Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis.

BACKGROUND: India accounts for a quarter of the world's multidrug-resistant tuberculosis (MDR-TB); with less than 50% having successful treatment outcomes. Bedaquiline (BDQ) was approved for use under conditional access program in India in 2015. OBJECTIVE: We evaluate the effectiveness, safety, and tolerability of a BDQ containing regimen used under field settings in India. METHOD: Interim analysis of a prospective cohort of MDR-TB patients on a BDQ containing regimen at six sites in the country. RESULTS: Six hundred and twenty MDR-TB patients [349 (56%) males; 554 (89%) between 18 and 50 years and 240 (39%) severely malnourished] were started on BDQ containing regimen between June 2016 and August 2017. There 354 (57%) patients had MDR-TB with additional drug resistance to fluoroquinolone (MDRFQ); 31 (5%) with additional resistance to second-line injectable (MDRSLI) and 101 (16%) extensively drug-resistant TB. After 6 months of treatment, culture conversion was achieved in 513 of 620 (83%) patients. The median time to culture conversion was 60 days. Higher body mass index was the only factor associated with faster culture conversion (HR 1.97; 95% CI 1.24-2.9). Around 100 patients (16.3%) experienced a ≥60-ms increase in QTc interval during the treatment. Seventy-three (12%) deaths were reported, the majority of them (56%) occurring within the first 6 months of treatment. CONCLUSIONS: BDQ with a background regimen has the potential to achieve higher and faster culture conversion rates with a lower toxicity profile among DR-TB patients. Use of BDQ with additional monitoring may be safe and effective even in the field settings.

Effectiveness of isoniazid preventive therapy on incidence of tuberculosis among HIV-infected adults in programme setting.

BACKGROUND & OBJECTIVES: As India and other developing countries are scaling up isoniazid preventive therapy (IPT) for people living with HIV (PLHIV) in their national programmes, we studied the feasibility and performance of IPT in terms of treatment adherence, outcome and post-treatment effect when given under programmatic settings. METHODS: A multicentre, prospective pilot study was initiated among adults living with HIV on isoniazid 300 mg with pyridoxine 50 mg after ruling out active tuberculosis (TB). Symptom review and counselling were done monthly during IPT and for six-month post-IPT. The TB incidence rate was calculated and risk factors were identified. RESULTS: Among 4528 adults living with HIV who initiated IPT, 4015 (89%) successfully completed IPT. IPT was terminated in 121 adults (3%) due to grade 2 or above adverse events. Twenty five PLHIVs developed TB while on IPT. The incidence of TB while on IPT was 1.17/100 person-years (p-y) [95% confidence interval (CI) 0.8-1.73] as compared to TB incidence of 2.42/100 p-y (95% CI 1.90-3.10) during the pre-IPT period at these centres (P=0.017). The incidence of TB post-IPT was 0.64/100 p-y (95% CI 0.04-1.12). No single factor was significantly associated with the development of TB. INTERPRETATION & CONCLUSIONS: Under programmatic settings, completion of IPT treatment was high, adverse events minimal with good post-treatment protection. After ruling out TB, IPT should be offered to all PLHIVs, irrespective of their antiretroviral therapy (ART) status. Scaling-up of IPT services including active case finding, periodic counselling on adherence and re-training of ART staff should be prioritized to reduce the TB burden in this community.

Profile of patients with pulmonary non-tuberculous mycobacterial disease mimicking pulmonary tuberculosis.

INTRODUCTION: With the introduction of newer molecular diagnostic tools, an increasing number of Non-tuberculous Mycobacteria (NTM) affecting the respiratory system and mimicking symptoms of pulmonary tuberculosis (PTB) are being identified. They may be misdiagnosed and treated as PTB, often categorized as treatment failures if they do not respond to treatment. This manuscript aims to characterize patients with pulmonary NTM disease. METHODS: Patient characteristics of bacteriologically confirmed pulmonary NTM disease, attending the ICMR-National Institute for Research in Tuberculosis, Chennai were prospectively compiled over a two-year period (2017-2018). RESULTS: A total of 122 patients with recurrent chest symptoms and not responding to anti-tuberculosis treatment were screened for NTM. Thirty-nine cases (26 males and 13 females) of symptomatic pulmonary NTM were diagnosed. The mean (SD) patient age and body mass index were 48.6 ± 11 years and 16.3 ± 3. All male participants were smokers, had at least one episode of previous ATT. Mycobacterium kansasii (48.7%) was the most frequently isolated species followed by Mycobacterium intracellulare (20.5%), Mycobacterium abscessus (7.6%) followed by Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium kyorinense, and Mycobacterium simiae. Infection with multiple NTMs was seen in four patients. Isoniazid resistance was identified in 20 patients. Based on species identified, treatment was initiated as per American Thoracic Society guidelines and continued up to 12 months of culture negativity. CONCLUSIONS: M. kansasii is the commonest pulmonary NTM isolated in Tamilnadu with a higher prevalence in males and elderly. Sensitization of both patients and providers is essential to avoid misdiagnosis and delay in diagnosis of pulmonary NTM disease as pulmonary TB.

Is Chemoprophylaxis for Child Contacts of Drug-Resistant TB Patients Beneficial? A Systematic Review.

BACKGROUND: Preventive therapy for child contacts of multidrug-resistant tuberculosis (MDR-TB) patients is poorly studied, and no consensus about the role and the rationale of chemoprophylaxis has been reached. OBJECTIVE: To conduct systematic review with an aim to determine the effectiveness of TB preventive therapy in reducing the incidence of TB disease in pediatric contacts of MDR-TB patients. METHODS: We conducted a literature search for randomized control trials, cohort studies, and case reports of chemoprophylaxis for pediatric contacts of MDR-TB patients in PubMed, EMBASE, Cochrane Databases of Systematic Reviews, metaRegister of Controlled Trials, and other clinical registries through March 2017, using appropriate search strategy. In addition we searched abstracts from international conferences and references of published articles and reviews. RESULTS: Of the 153 references assessed from various databases, seven studies were identified as relevant after adaption of eligibility criteria and assessed for systematic review. Of these, only two studies contributed data for the pooled meta-analysis. CONCLUSIONS: Though the available evidences suggest that the chemoprophylaxis for child contacts of MDR-TB patients is beneficial, data to support or reject preventive therapy is very limited. Further clinical research, in Tb endemic settings like India, needs to be performed to prove the beneficial effect of chemoprophylaxis for pediatric contacts of MDR-TB.