A novel blood-based assay for treatment monitoring of tuberculosis

Abstract Objectives A novel 3-gene host transcriptional signature (GBP5, DUSP3 and KLF2) has been validated for tuberculosis (TB) treatment monitoring using laboratory-based RNA sequencing platforms. The signature was recently translated by Cepheid into a prototype cartridge-based test that can be run on the GeneXpert instrument. In this study, we prospectively evaluated the change in the expression of the cartridge-based 3-gene signature following treatment initiation among pulmonary TB patients who were microbiologically cured at the end of treatment. Results The 3-gene signature expression level (TB score) changed significantly over time with respect to baseline among 31 pulmonary TB patients. The greatest increase in TB score occurred within the first month of treatment (median fold-increase in TB score: 1.08 [IQR 0.54–1.52]) and plateaued after 4 months of treatment (median TB score: 1.97 [IQR: 1.03–2.33]). The rapid and substantial increase of the TB score in the first month of treatment holds promise for the early identification of patients that respond to TB treatment. The plateau in TB score at 4 months may indicate early clearance of disease and could direct treatment to be shortened. These hypotheses need to be further explored with larger prospective treatment monitoring studies.

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A Novel Blood-Based Assay for Treatment Monitoring of Tuberculosis

10.21203/rs.3.rs-384297/v1 ◽

2021 ◽

Author(s):

Alexandra Jaye Zimmer ◽

Samuel G Schumacher ◽

Erik Södersten ◽

Anna Mantsoki ◽

Romain Wyss ◽

...

Keyword(s):

Early Identification ◽

Treatment Initiation ◽

Fold Increase ◽

Gene Signature ◽

Treatment Monitoring ◽

Transcriptional Signature ◽

Tb Treatment ◽

End Of Treatment ◽

Baseline Levels ◽

Over Time

Abstract ObjectivesA novel 3-gene host transcriptional signature (GBP5, DUSP3 and KLF2) that has been validated for TB diagnosis. The signature was recently translated by Cepheid into a prototype cartridge-based test that can be run on the GeneXpert instruments. In this study, we prospectively evaluated the change in the expression of the cartridge-based 3-gene signature with time following treatment initiation among pulmonary TB patients who were microbiologically cured at the end of treatment. ResultsOur results show that the 3-gene signature expression level (TB score) changes significantly over time with respect to baseline levels. The greatest increase in TB score occurred within the first month of treatment (median fold-increase in TB score: 1.08 [IQR 0.54-1.52]) and plateaued after 4 months of treatment (median TB score: 1.97 [IQR: 1.03-2.33]. The rapid and substantial increase of the TB score in the first month of treatment holds promise for the early identification of patients that respond to TB treatment. The plateau in TB score at 4 months may indicate early clearance of disease and could direct treatment to be shortened. These hypotheses need to be further explored with large prospective treatment monitoring and test of cure studies.

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Evaluation of implementation and effectiveness of digital adherence technology with differentiated care to support tuberculosis treatment adherence and improve treatment outcomes in Ethiopia: a study protocol for a cluster randomised trial

BMC Infectious Diseases ◽

10.1186/s12879-021-06833-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Amare W. Tadesse ◽

Zemedu Mohammed ◽

Nicola Foster ◽

Matthew Quaife ◽

Christopher Finn McQuaid ◽

...

Keyword(s):

Treatment Initiation ◽

Patient Adherence ◽

Randomised Trial ◽

Standard Of Care ◽

Cluster Randomised Trial ◽

Pulmonary Tb ◽

Tb Treatment ◽

Cluster Randomised ◽

End Of Treatment ◽

Differentiated Care

Abstract Background Digital adherence technologies (DATs) are recommended to support patient-centred, differentiated care to improve tuberculosis (TB) treatment outcomes, but evidence that such technologies improve adherence is limited. We aim to implement and evaluate the effectiveness of smart pillboxes and medication labels linked to an adherence data platform, to create a differentiated care response to patient adherence and improve TB care among adult pulmonary TB participants. Our study is part of the Adherence Support Coalition to End TB (ASCENT) project in Ethiopia. Methods/Design We will conduct a pragmatic three-arm cluster-randomised trial with 78 health facilities in two regions in Ethiopia. Facilities are randomised (1:1:1) to either of the two intervention arms or standard of care. Adults aged ≥ 18 years with drug-sensitive (DS) pulmonary TB are enrolled over 12 months and followed-up for 12 months after treatment initiation. Participants in facilities randomised to either of the two intervention arms are offered a DAT linked to the web-based ASCENT adherence platform for daily adherence monitoring and differentiated response to patient adherence for those who have missed doses. Participants at standard of care facilities receive routine care. For those that had bacteriologically confirmed TB at treatment initiation and can produce sputum without induction, sputum culture will be performed approximately 6 months after the end of treatment to measure disease recurrence. The primary endpoint is a composite unfavourable outcome measured over 12 months from TB treatment initiation defined as either poor end of treatment outcome (lost to follow-up, death, or treatment failure) or treatment recurrence measured 6 months after the scheduled end of treatment. This study will also evaluate the effectiveness, feasibility, and cost-effectiveness of DAT systems for DS-TB patients. Discussion This trial will evaluate the impact and contextual factors of medication label and smart pillbox with a differentiated response to patient care, among adult pulmonary DS-TB participants in Ethiopia. If successful, this evaluation will generate valuable evidence via a shared evaluation framework for optimal use and scale-up. Trial registration: Pan African Clinical Trials Registry PACTR202008776694999, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241, registered on August 11, 2020.

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Multi-country evaluation of RISK6, a 6-gene blood transcriptomic signature, for tuberculosis diagnosis and treatment monitoring

Scientific Reports ◽

10.1038/s41598-021-93059-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rim Bayaa ◽

Mame Diarra Bousso Ndiaye ◽

Carole Chedid ◽

Eka Kokhreidze ◽

Nestani Tukvadze ◽

...

Keyword(s):

Characteristic Curve ◽

Treatment Monitoring ◽

Tb Treatment ◽

Healthy Donors ◽

End Of Treatment ◽

Product Profile ◽

Transcriptomic Signature ◽

Latent Tb ◽

Latent Tb Infection ◽

Nested Case Control

AbstractThere is a crucial need for non-sputum-based TB tests. Here, we evaluate the performance of RISK6, a human-blood transcriptomic signature, for TB screening, triage and treatment monitoring. RISK6 performance was also compared to that of two IGRAs: one based on RD1 antigens (QuantiFERON-TB Gold Plus, QFT-P, Qiagen) and one on recombinant M. tuberculosis HBHA expressed in Mycobacterium smegmatis (IGRA-rmsHBHA). In this multicenter prospective nested case–control study conducted in Bangladesh, Georgia, Lebanon and Madagascar, adult non-immunocompromised patients with bacteriologically confirmed active pulmonary TB (ATB), latent TB infection (LTBI) and healthy donors (HD) were enrolled. ATB patients were followed-up during and after treatment. Blood RISK6 scores were assessed using quantitative real-time PCR and evaluated by area under the receiver-operating characteristic curve (ROC AUC). RISK6 performance to discriminate ATB from HD reached an AUC of 0.94 (95% CI 0.89–0.99), with 90.9% sensitivity and 87.8% specificity, thus achieving the minimal WHO target product profile for a non-sputum-based TB screening test. Besides, RISK6 yielded an AUC of 0.93 (95% CI 0.85–1) with 90.9% sensitivity and 88.5% specificity for discriminating ATB from LTBI. Moreover, RISK6 showed higher performance (AUC 0.90, 95% CI 0.85–0.94) than IGRA-rmsHBHA (AUC 0.75, 95% CI 0.69–0.82) to differentiate TB infection stages. Finally, RISK6 signature scores significantly decreased after 2 months of TB treatment and continued to decrease gradually until the end of treatment reaching scores obtained in HD. We confirmed the performance of RISK6 signature as a triage TB test and its utility for treatment monitoring.

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IP-10 as a Non Sputum Biomarker in TB Treatment Monitoring

Majalah Kedokteran Bandung ◽

10.15395/mkb.v53n1.2161 ◽

2021 ◽

Vol 53 (1) ◽

Author(s):

Yuhpita Indah Efriyani ◽

◽

Ida Parwati ◽

Nina Tristina ◽

Anna Tjandrawati

Keyword(s):

Cohort Study ◽

Inflammatory Cells ◽

Treatment Monitoring ◽

Observational Cohort Study ◽

Inclusion Criteria ◽

Pulmonary Tb ◽

Tb Treatment ◽

Before And After ◽

Observational Cohort ◽

High Level

There are currently still limitations in the diagnosis of tuberculosis (TB). Sputum collection as specimen for diagnosis is not only difficult but also has low sensitivity.In blood, IP-10/CXCL-10 chemokine plays a role in inducing the movements of chemotactic inflammatory cells towards the sites of inflammation. A high level of IP-10 is found in active pulmonary TB patients and significantly decline after the patients have completed the TB treatments. The aim of this study was to analyze the decline of the IP-10 level before and after 2 months of TB treatment. This study was conducted from March toJuni 2020. This was a comparative observational cohort study on active pulmonary TB patients who were >18 years old at the DOTS Clinic of Dr. Hasan Sadikin General Hospital Bandung. Thirty patients who met the inclusion criteria were followed up until 2 months of TB treatment. Serum of these patients were collected and examined for the IP-10 level before and after 2 months of TB treatment. It was demonstrated that the median IP-10 level in new active pulmonary TB patients was 384.1 pg/mL (136.70–779.80) and dropped to 251.85 pg/mL (91.10–698.30) (p<0l001) two months of TB treatment. Thus, the IP-10 level in the active pulmonary TB patients is significantly declined (p<0.001) after 2 months of TB treatment and that serum IP-10 level could be considered as a non-sputum-based marker to monitor TB treatment.

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Six-year trend and risk factors of unsuccessful pulmonary tuberculosis treatment outcomes in Thai Community Hospital

BMC Research Notes ◽

10.1186/s13104-021-05504-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Sakarn Charoensakulchai ◽

Chaiyapun Lertpheantum ◽

Chanapon Aksornpusitpong ◽

Peeranut Trakulsuk ◽

Boonsub Sakboonyarat ◽

...

Keyword(s):

Risk Factors ◽

Community Hospital ◽

Previous History ◽

Treatment Quality ◽

Intensive Phase ◽

Loss To Follow Up ◽

Pulmonary Tb ◽

Tb Treatment ◽

Monitoring Tools ◽

Unsuccessful Treatment

Abstract Objective Tuberculosis (TB) is a major cause of morbidity and mortality globally. Despite efforts to eliminate TB in Thailand, the incidence rate has declined slowly. This study aimed to identify the incidence and risk factors of unsuccessful pulmonary TB treatment (failed, died and loss-to- follow up) in a community hospital in Chachoengsao Province, Thailand from 1st January 2013 to 31st December 2019. Results A total of 487 patients were eligible for the study. The incidence of unsuccessful treatment was 21.67/100 population person year. Risk factors of unsuccessful pulmonary TB treatment were unemployment (adjusted hazard ratio (AHR) 3.12, 95%CI 1.41–6.86), HIV co-infection (AHR 2.85, 95%CI 1.25–6.46), previous history of TB (AHR 2.00, 95%CI 1.04–3.81), positive sputum AFB at the end of the intensive phase (AHR 5.66, 95%CI 2.33–13.74), and sputum AFB was not performed at the end of the intensive phase (AHR 18.40, 95%CI 9.85–34.35). This study can be utilized to improve prevention and intervention of TB treatment by strengthening public health system on treatment quality especially TB patient monitoring tools or methods easy for accessing to patients in communities.

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Should Sputum Smear Examination Be Carried Out at the End of the Intensive Phase and End of Treatment in Sputum Smear Negative Pulmonary TB Patients?

PLoS ONE ◽

10.1371/journal.pone.0049238 ◽

2012 ◽

Vol 7 (11) ◽

pp. e49238 ◽

Cited By ~ 3

Author(s):

Sumit Malhotra ◽

Sanjay P. Zodpey ◽

Shivani Chandra ◽

Ram Pal Vashist ◽

Srinath Satyanaryana ◽

...

Keyword(s):

Sputum Smear ◽

Intensive Phase ◽

Pulmonary Tb ◽

Smear Examination ◽

End Of Treatment ◽

Smear Negative ◽

Sputum Smear Examination

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Uncovering reasons for treatment initiation delays among children with TB in Lima, Peru

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.20.0079 ◽

2020 ◽

Vol 24 (12) ◽

pp. 1254-1260

Author(s):

J. Coit ◽

M. Wong ◽

J. T. Galea ◽

M. Mendoza ◽

H. Marin ◽

...

Keyword(s):

Treatment Initiation ◽

Complex Interventions ◽

Diagnostic Tools ◽

Diagnostic Study ◽

Burden Of Care ◽

Structured Interviews ◽

Tb Treatment ◽

Pediatric Tb ◽

Field Workers ◽

Pediatric Tuberculosis

BACKGROUND: Timely diagnosis and treatment of pediatric tuberculosis (TB) is critical to reducing mortality but remains challenging in the absence of adequate diagnostic tools. Even once a TB diagnosis is made, delays in treatment initiation are common, but for reasons that are not well understood.METHODS: To examine reasons for delay post-diagnosis, we conducted semi-structured interviews with Ministry of Health (MoH) physicians and field workers affiliated with a pediatric TB diagnostic study, and caregivers of children aged 0–14 years who were diagnosed with pulmonary TB in Lima, Peru. Interviews were analyzed using systematic comparative and descriptive content analysis.RESULTS: We interviewed five physicians, five field workers and 26 caregivers with children who initiated TB treatment < 7 days after diagnosis (n = 15) or who experienced a delay of ≥7 days (n = 11). Median time in delay from diagnosis to treatment initiation was 26 days (range 7–117). Reasons for delay included: health systems challenges (administrative hurdles, medication stock, clinic hours), burden of care on families and caregiver perceptions of disease severity.CONCLUSION: Reasons for delay in treatment initiation are complex. Interventions to streamline administrative processes and tools to identify and support families at risk for delays in treatment initiation are urgently needed.

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A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.20.0513 ◽

2021 ◽

Vol 25 (4) ◽

pp. 305-314

Author(s):

C. D. Tweed ◽

G. H. Wills ◽

A. M. Crook ◽

E. Amukoye ◽

V. Balanag ◽

...

Keyword(s):

Primary Outcome ◽

Randomised Trial ◽

Group Differences ◽

Pulmonary Tb ◽

Intention To Treat ◽

Tb Treatment ◽

Grade 3 ◽

To Receive ◽

Ongoing Evaluation ◽

Post Randomisation

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

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Tuberculosis in native Israeli Arabs and Jews: trends and treatment outcomes, 1999–2011

Epidemiology and Infection ◽

10.1017/s0950268815000382 ◽

2015 ◽

Vol 143 (15) ◽

pp. 3203-3210 ◽

Cited By ~ 1

Author(s):

H. BISHARA ◽

D. GOLDBLATT ◽

E. RORMAN ◽

Z. MOR

Keyword(s):

Treatment Outcomes ◽

Clinical Laboratory ◽

Treatment Success ◽

Developed Countries ◽

National Average ◽

Success Rates ◽

Pulmonary Tb ◽

Tb Treatment ◽

Lower Treatment ◽

Israeli Arabs

SUMMARYThe incidence of tuberculosis (TB) in native ethnic minorities remains high in developed countries. Arabs, the major ethnic minority in Israel, comprise 21% of its population. This retrospective study compared TB incidence, demographic, clinical, laboratory, genotyping characteristics and treatment outcomes in all Israeli-born citizens diagnosed with TB between 1999 and 2011 by ethnicity, i.e. Israeli-born Arabs (IA) and Jews (IJ). A total of 831 Israeli-born TB patients were reported. Of those, there were 530 (64%) IJ and 301 (36%) IA, with an average annual TB rate of 1·1 and 1·6 cases/100 000 population, respectively, lower than the national average (7·0 cases/100 000 population). TB rates in IA and IJ declined and converged to 1 case/100 000 residents. IA TB patients were more likely to be older, have more pulmonary TB and have lower treatment success rates than IJ. Older age and HIV co-infection, but not ethnicity, were predictive of non-success in TB treatment. Ten mixed IA–IJ clades were detected by spoligotyping and three mixed IA–IJ clusters were identified by MIRU-VNTR typing. Only one IA–IJ couple recalled mutual contact. In conclusion, TB rate in IA was higher than in IJ, but declined and converged in both to 1 case/100 000. Treatment success was high in both groups, and was unrelated to ethnicity.

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Mobilising community networks for early identification of tuberculosis and treatment initiation in Cambodia: an evaluation of a seed-and-recruit model

ERJ Open Research ◽

10.1183/23120541.00368-2019 ◽

2020 ◽

Vol 6 (2) ◽

pp. 00368-2019

Author(s):

Alvin Kuo Jing Teo ◽

Kiesha Prem ◽

Sovannary Tuot ◽

Chetra Ork ◽

Sothearith Eng ◽

...

Keyword(s):

Early Identification ◽

Proportional Hazards ◽

Treatment Initiation ◽

Prevalence Ratio ◽

Cox Proportional Hazards ◽

Case Finding ◽

Community Networks ◽

Community Based ◽

Time To Treatment ◽

Time To Treatment Initiation

Background and objectivesThe effects of active case finding (ACF) models that mobilise community networks for early identification and treatment of tuberculosis (TB) remain unknown. We investigated and compared the effect of community-based ACF using a seed-and-recruit model with one-off roving ACF and passive case finding (PCF) on the time to treatment initiation and identification of bacteriologically confirmed TB.MethodsIn this retrospective cohort study conducted in 12 operational districts in Cambodia, we assessed relationships between ACF models and: 1) the time to treatment initiation using Cox proportional hazards regression; and 2) the identification of bacteriologically confirmed TB using modified Poisson regression with robust sandwich variance.ResultsWe included 728 adults with TB, of whom 36% were identified via the community-based ACF using a seed-and-recruit model. We found community-based ACF using a seed-and-recruit model was associated with shorter delay to treatment initiation compared to one-off roving ACF (hazard ratio 0.81, 95% CI 0.68–0.96). Compared to one-off roving ACF and PCF, community-based ACF using a seed-and-recruit model was 45% (prevalence ratio (PR) 1.45, 95% CI 1.19–1.78) and 39% (PR 1.39, 95% CI 0.99–1.94) more likely to find and detect bacteriologically confirmed TB, respectively.ConclusionMobilising community networks to find TB cases was associated with early initiation of TB treatment in Cambodia. This approach was more likely to find bacteriologically confirmed TB cases, contributing to the reduction of risk of transmission within the community.

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