Publications by authors named "Ruvandhi R Nathavitharana"

35 Publications

Can AI technologies close the diagnostic gap in tuberculosis?

Lancet Digit Health 2021 09;3(9):e535-e536

Division of Infectious Diseases, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address:

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http://dx.doi.org/10.1016/S2589-7500(21)00142-4DOI Listing
September 2021

Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV.

Cochrane Database Syst Rev 2021 08 20;8:CD014641. Epub 2021 Aug 20.

Department of Medicine, Division of Infectious Diseases, John Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Tuberculosis is the primary cause of hospital admission in people living with HIV, and the likelihood of death in the hospital is unacceptably high. The Alere Determine TB LAM Ag test (AlereLAM) is a point-of-care test and the only lateral flow lipoarabinomannan assay (LF-LAM) assay currently commercially available and recommended by the World Health Organization (WHO). A 2019 Cochrane Review summarised the diagnostic accuracy of LF-LAM for tuberculosis in people living with HIV. This systematic review assesses the impact of the use of LF-LAM (AlereLAM) on mortality and other patient-important outcomes.

Objectives: To assess the impact of the use of LF-LAM (AlereLAM) on mortality in adults living with HIV in inpatient and outpatient settings. To assess the impact of the use of LF-LAM (AlereLAM) on other patient-important outcomes in adults living with HIV, including time to diagnosis of tuberculosis, and time to initiation of tuberculosis treatment.

Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); Science Citation Index Expanded (Web of Science), BIOSIS Previews, Scopus, LILACS; ProQuest Dissertations and Theses; ClinicalTrials.gov; and the WHO ICTRP up to 12 March 2021.

Selection Criteria: Randomized controlled trials that compared a diagnostic intervention including LF-LAM with diagnostic strategies that used smear microscopy, mycobacterial culture, a nucleic acid amplification test such as Xpert MTB/RIF, or a combination of these tests. We included adults (≥ 15 years) living with HIV.

Data Collection And Analysis: Two review authors independently assessed trials for eligibility, extracted data, and analysed risk of bias using the Cochrane tool for assessing risk of bias in randomized studies. We contacted study authors for clarification as needed. We used risk ratio (RR) with 95% confidence intervals (CI). We used a fixed-effect model except in the presence of clinical or statistical heterogeneity, in which case we used a random-effects model. We assessed the certainty of the evidence using GRADE.

Main Results: We included three trials, two in inpatient settings and one in outpatient settings. All trials were conducted in sub-Saharan Africa and assessed the impact of diagnostic strategies that included LF-LAM on mortality when the test was used in conjunction with other tuberculosis diagnostic tests or clinical assessment for clinical decision-making in adults living with HIV. Inpatient settings  In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy likely reduces mortality in people living with HIV at eight weeks compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 0.85, 95% CI 0.76 to 0.94; 5102 participants, 2 trials; moderate-certainty evidence). That is, people living with HIV who received LF-LAM had 15% lower risk of mortality. The absolute effect was 34 fewer deaths per 1000 (from 14 fewer to 55 fewer). In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy probably results in a slight increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 1.26, 95% CI 0.94 to 1.69; 5102 participants, 2 trials; moderate-certainty evidence).  Outpatient settings In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality in people living with HIV at six months compared to routine tuberculosis diagnostic testing without LF-LAM (RR 0.89, 95% CI 0.71 to 1.11; 2972 participants, 1 trial; low-certainty evidence). Although this trial did not detect a difference in mortality, the direction of effect was towards a mortality reduction, and the effect size was similar to that in inpatient settings.  In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may result in a large increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (RR 5.44, 95% CI 4.70 to 6.29, 3022 participants, 1 trial; low-certainty evidence). Other patient-important outcomes Assessment of other patient-important and implementation outcomes in the trials varied. The included trials demonstrated that a higher proportion of people living with HIV were able to produce urine compared to sputum for tuberculosis diagnostic testing; a higher proportion of people living with HIV were diagnosed with tuberculosis in the group that received LF-LAM; and the incremental diagnostic yield was higher for LF-LAM than for urine or sputum Xpert MTB/RIF.

Authors' Conclusions: In inpatient settings, the use of LF-LAM as part of a tuberculosis diagnostic testing strategy likely reduces mortality and probably results in a slight increase in tuberculosis treatment initiation in people living with HIV. The reduction in mortality may be due to earlier diagnosis, which facilitates prompt treatment initiation. In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality and may result in a large increase in tuberculosis treatment initiation in people living with HIV. Our results support the implementation of LF-LAM to be used in conjunction with other WHO-recommended tuberculosis diagnostic tests to assist in the rapid diagnosis of tuberculosis in people living with HIV.
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http://dx.doi.org/10.1002/14651858.CD014641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407503PMC
August 2021

"If I've got latent TB, I would like to get rid of it": Derivation of the CARD (Constraints, Actions, Risks, and Desires) Framework informed by South African healthcare worker perspectives on latent tuberculosis treatment.

PLoS One 2021 18;16(8):e0254211. Epub 2021 Aug 18.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa.

Background: Healthcare workers (HWs) have at least twice the risk of tuberculosis (TB) compared to the general population. There is growing emphasis on latent TB infection (LTBI) in high-risk populations. Yet we know little about HWs' perspectives of LTBI testing and treatment to inform implementation in high-incidence settings. We developed a qualitative networked approach to analyze HWs' perspectives on LTBI testing and treatment.

Methods: We conducted 22 in-depth interviews with nurse and physician stakeholders, who had been recruited as part of a larger study evaluating TB transmission risk in HWs at Tygerberg Hospital, Cape Town, South Africa. We performed open coding to identify emergent themes and selective coding to identify relevant text citations. We used thematic analysis to inductively derive the CARD (Constraints, Actions, Risks, Desires) framework.

Results: All HWs desired to avoid developing TB but few felt this was actionable. Despite LTBI knowledge gaps, safety and cost concerns, most HWs reported hypothetical willingness to take LTBI treatment. The CARD framework showed that desire and action related to LTBI testing and treatment was clearly framed by the interactions between constraints, administrative action, and risk. The surprise HWs described on receiving a negative LTBI (Quantiferon-Plus) result suggests LTBI testing may recalibrate HWs' perceptions regarding the futility of actions to reduce their TB risk.

Conclusions: LTBI testing and treatment are acceptable to HWs and could counteract the perceived inevitability of occupational TB infection that currently may limit risk reduction action. This should be coupled with administrative leadership and infrastructural support. The CARD analytic framework is a helpful tool for implementation scientists to understand current practices within complex health systems. Application of CARD could facilitate the development of contextually-relevant interventions to address important public health problems such as occupational TB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254211PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372902PMC
August 2021

Diagnosing active tuberculosis in primary care.

BMJ 2021 07 1;374:n1590. Epub 2021 Jul 1.

Wadhani Institute for Artificial Intelligence, Mumbai, India.

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http://dx.doi.org/10.1136/bmj.n1590DOI Listing
July 2021

Impact of the diagnostic test Xpert MTB/RIF on patient outcomes for tuberculosis.

Cochrane Database Syst Rev 2021 05 6;5:CD012972. Epub 2021 May 6.

University of Basel, Basel, Switzerland.

Background: The World Health Organization (WHO) recommends Xpert MTB/RIF in place of smear microscopy to diagnose tuberculosis (TB), and many countries have adopted it into their diagnostic algorithms. However, it is not clear whether the greater accuracy of the test translates into improved health outcomes.

Objectives: To assess the impact of Xpert MTB/RIF on patient outcomes in people being investigated for tuberculosis.

Search Methods: We searched the following databases, without language restriction, from 2007 to 24 July 2020: Cochrane Infectious Disease Group (CIDG) Specialized Register; CENTRAL; MEDLINE OVID; Embase OVID; CINAHL EBSCO; LILACS BIREME; Science Citation Index Expanded (Web of Science), Social Sciences citation index (Web of Science), and Conference Proceedings Citation Index - Social Science & Humanities (Web of Science). We also searched the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the Pan African Clinical Trials Registry for ongoing trials.

Selection Criteria: We included individual- and cluster-randomized trials, and before-after studies, in participants being investigated for tuberculosis. We analysed the randomized and non-randomized studies separately.  DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data, using a piloted data extraction tool. We assessed the risk of bias using Cochrane and Effective Practice and Organisation of Care (EPOC) tools. We used random effects meta-analysis to allow for heterogeneity between studies in setting and design.  The certainty of the  evidence in the randomized trials was assessed by GRADE.

Main Results: We included 12 studies: eight were randomized controlled trials (RCTs), and four were before-and-after studies. Most included RCTs had a low risk of bias in most domains of the Cochrane 'Risk of bias' tool. There was inconclusive evidence of an effect of Xpert MTB/RIF on all-cause mortality, both overall (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.75 to 1.05; 5 RCTs, 9932 participants, moderate-certainty evidence), and restricted to studies with six-month follow-up (RR 0.98, 95% CI 0.78 to 1.22; 3 RCTs, 8143 participants; moderate-certainty evidence). There was probably a reduction in mortality in participants known to be infected with HIV (odds ratio (OR) 0.80, 95% CI 0.67 to 0.96; 5 RCTs, 5855 participants; moderate-certainty evidence). It is uncertain whether Xpert MTB/RIF has no or a modest effect on the proportion of participants starting tuberculosis treatment who had a successful treatment outcome (OR) 1.10, 95% CI 0.96 to 1.26; 3RCTs, 4802 participants; moderate-certainty evidence). There was also inconclusive evidence of an effect on the  proportion of participants who were treated for tuberculosis (RR 1.10, 95% CI 0.98 to 1.23; 5 RCTs, 8793 participants; moderate-certainty evidence). The proportion of participants treated for tuberculosis who had bacteriological confirmation was probably higher in the Xpert MTB/RIF group (RR 1.44, 95% CI 1.29 to 1.61; 6 RCTs, 2068 participants; moderate-certainty evidence). The proportion of participants with bacteriological confirmation who were lost to follow-up pre-treatment was probably reduced (RR 0.59, 95% CI 0.41 to 0.85; 3 RCTs, 1217 participants; moderate-certainty evidence).

Authors' Conclusions: We were unable to confidently rule in or rule out the effect on all-cause mortality of using Xpert MTB/RIF rather than smear microscopy. Xpert MTB/RIF probably reduces mortality among participants known to be infected with HIV. We are uncertain whether Xpert MTB/RIF has a modest effect or not on the proportion treated or, among those treated, on the proportion with a successful outcome. It probably does not have a substantial effect on these outcomes. Xpert MTB/RIF probably increases both the proportion of treated participants who had bacteriological confirmation, and the proportion with a laboratory-confirmed diagnosis who were treated. These findings may inform decisions about uptake alongside evidence on cost-effectiveness and implementation.
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http://dx.doi.org/10.1002/14651858.CD012972.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208889PMC
May 2021

Progress toward Developing Sensitive Non-Sputum-Based Tuberculosis Diagnostic Tests: the Promise of Urine Cell-Free DNA.

J Clin Microbiol 2021 07 19;59(8):e0070621. Epub 2021 Jul 19.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

A highly accurate, non-sputum-based test for tuberculosis (TB) detection is a key priority for the field of TB diagnostics. A recent study in the by Oreskovic and colleagues (J Clin Microbiol 59:e00074-21, 2021, https://doi.org/10.1128/JCM.00074-21) reports the performance of an optimized urine cell-free DNA (cfDNA) test using sequence-specific purification combined with short-target PCR to improve the accuracy of TB detection. Their retrospective clinical study utilized frozen urine samples ( = 73) from study participants diagnosed with active pulmonary TB in South Africa and compared results to non-TB patients in South Africa and the United States in an early-phase validation study. Overall, this cfDNA technique detected TB with a sensitivity of 83.7% (95% CI: 71.0 to 91.5) and specificity of 100% (95% CI: 86.2 to 100), which meet the World Health Organization's published performance criteria. Sensitivity was 73.3% in people without HIV (95% CI: 48.1 to 89.1) and 76% in people with smear-negative TB (95% CI: 56.5 to 88.5). In this commentary, we discuss the results of this optimized urine TB cfDNA assay within the larger context of TB diagnostics and pose additional questions for further research.
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http://dx.doi.org/10.1128/JCM.00706-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288258PMC
July 2021

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19.

JAMA 2021 04;325(15):1535-1544

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Importance: Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.

Objective: To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.

Design, Setting, And Participants: Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.

Interventions: Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).

Main Outcomes And Measures: Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.

Results: Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.

Conclusion And Relevance: In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.

Trial Registration: ClinicalTrials.gov Identifier: NCT04436276.
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http://dx.doi.org/10.1001/jama.2021.3645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953339PMC
April 2021

Translating scientific discoveries during pandemics: ensuring equity for people affected by COVID-19 and tuberculosis.

ERJ Open Res 2020 Oct 19;6(4). Epub 2020 Oct 19.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Boston, MA, USA.

https://bit.ly/3bTZHS3.
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http://dx.doi.org/10.1183/23120541.00562-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659031PMC
October 2020

Surgical cure of clarithromycin resistant breast implant infection: A case report and review of the literature.

J Clin Tuberc Other Mycobact Dis 2020 Dec 5;21:100183. Epub 2020 Sep 5.

Beth Israel Deaconess Medical Center, Division of Infectious Diseases, Department of Medicine, Boston, MA, United States.

Clusters of patients who obtain cosmetic surgeries abroad have developed surgical site infections due to rapid growing non-tuberculous mycobacteria (NTM). These are usually treated with a combination of surgery and months of anti-mycobacterial therapy, but poor outcomes, including permanent scarring are common. We present a case of a 36-year-old female who developed a clarithromycin-resistant (CRMC) infection after undergoing breast augmentation in the Dominican Republic. She underwent debridement and explant of her silicone implants, but due to a series of complications including discordant antimicrobial susceptibility testing profiles, GI side effects, and then pregnancy, she was unable to receive typical multidrug anti-mycobacterial therapy after surgery. She received close clinical follow up and demonstrated full recovery without any evidence of recurrence of infection at 9 months of follow up. We searched the literature for cases of NTM surgical site infection after breast surgery. To our knowledge, this is the first case report of confirmed NTM breast implant infection being cured with surgery alone, and only the second report of clarithromycin resistant in a patient without disseminated infection or pre-exposure to macrolides. The increasing prevalence of drug resistant NTM infections is an emerging concern for clinicians treating patients with complications related to medical tourism.
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http://dx.doi.org/10.1016/j.jctube.2020.100183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490846PMC
December 2020

Airborne Spread of SARS-CoV-2 and a Potential Role for Air Disinfection.

JAMA 2020 07;324(2):141-142

Beth Israel Deaconess Medical Center, Division of Infectious Diseases, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2020.7603DOI Listing
July 2020

Closing gaps in the tuberculosis care cascade: an action-oriented research agenda.

J Clin Tuberc Other Mycobact Dis 2020 May 11;19:100144. Epub 2020 Jan 11.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA.

The care cascade-which evaluates outcomes across stages of patient engagement in a health system-is an important framework for assessing quality of tuberculosis (TB) care. In recent years, there has been progress in measuring care cascades in high TB burden countries; however, there are still shortcomings in our knowledge of how to reduce poor patient outcomes. In this paper, we outline a research agenda for understanding why patients fall through the cracks in the care cascade. The pathway for evidence generation will require new systematic reviews, observational cohort studies, intervention development and testing, and continuous quality improvement initiatives embedded within national TB programs. Certain gaps, such as pretreatment loss to follow-up and post-treatment disease recurrence, should be a priority given a relative paucity of high-quality research to understand and address poor outcomes. Research on interventions to reduce death and loss to follow-up during treatment should move beyond a focus on monitoring (or observation) strategies, to address patient needs including psychosocial and nutritional support. While key research questions vary for each gap, some patient populations may experience disparities across multiple stages of care and should be a priority for research, including men, individuals with a prior treatment history, and individuals with drug-resistant TB. Closing gaps in the care cascade will require investments in a bold and innovative action-oriented research agenda.
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http://dx.doi.org/10.1016/j.jctube.2020.100144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015982PMC
May 2020

The high-quality health system 'revolution': Re-imagining tuberculosis infection prevention and control.

J Clin Tuberc Other Mycobact Dis 2019 Dec 21;17:100118. Epub 2019 Aug 21.

Department of Public Health and Family Medicine, University of Cape Town, Anzio Rd, Observatory, Cape Town 7925, South Africa.

The Lancet Commission on High-Quality Health Systems called for a 'revolution' in the quality of care provided in low- and middle-income countries. We argue that this provides a helpful framework to demonstrate how effective tuberculosis infection prevention and control (TB IPC) implementation should be linked with health system strengthening, moving it from the silo of the national TB programmes. Using this framework, we identify and discuss links between TB IPC implementation and patient safety, human resources for health, prioritising person-centred care, building trust in health systems and refining the tools used to measure TB IPC implementation. Prioritising patient experience has been a recent addition to the definition of high-quality care. In high TB burden settings, the encounter with TB IPC measures may be a TB patient's initial contact with the healthcare system and may cause feelings of stigmatisation. We advocate for re-imagining the way we implement TB IPC, by drawing on the principles of person-centred care through incorporating the experiences of people using healthcare services. Health workers who developed occupational TB also offer a unique perspective: they have both experienced TB IPC and have played a role in implementing it in their workplace. They can be powerful advocates for person-centred TB IPC implementation. Through framing TB IPC as part of health system strengthening and consciously including person-centred perspectives in TB IPC design, measurement and guidelines, we hope to influence future TB IPC research and practice.
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http://dx.doi.org/10.1016/j.jctube.2019.100118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880133PMC
December 2019

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV.

Cochrane Database Syst Rev 2019 Oct 21;10:CD011420. Epub 2019 Oct 21.

Department of Clinical Research, Research Unit of Infectious Diseases, University of Southern Denmark, Odense, Denmark.

Background: The lateral flow urine lipoarabinomannan (LF-LAM) assay Alere Determine™ TB LAM Ag is recommended by the World Health Organization (WHO) to help detect active tuberculosis in HIV-positive people with severe HIV disease. This review update asks the question, "does new evidence justify the use of LF-LAM in a broader group of people?", and is part of the WHO process for updating guidance on the use of LF-LAM.

Objectives: To assess the accuracy of LF-LAM for the diagnosis of active tuberculosis among HIV-positive adults with signs and symptoms of tuberculosis (symptomatic participants) and among HIV-positive adults irrespective of signs and symptoms of tuberculosis (unselected participants not assessed for tuberculosis signs and symptoms).The proposed role for LF-LAM is as an add on to clinical judgement and with other tests to assist in diagnosing tuberculosis.

Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register; MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, without language restriction to 11 May 2018.

Selection Criteria: Randomized trials, cross-sectional, and observational cohort studies that evaluated LF-LAM for active tuberculosis (pulmonary and extrapulmonary) in HIV-positive adults. We included studies that used the manufacturer's recommended threshold for test positivity, either the updated reference card with four bands (grade 1 of 4) or the corresponding prior reference card grade with five bands (grade 2 of 5). The reference standard was culture or nucleic acid amplification test from any body site (microbiological). We considered a higher quality reference standard to be one in which two or more specimen types were evaluated for tuberculosis diagnosis and a lower quality reference standard to be one in which only one specimen type was evaluated.

Data Collection And Analysis: Two review authors independently extracted data using a standardized form and REDCap electronic data capture tools. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and performed meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and a Bayesian approach. We analyzed studies enrolling strictly symptomatic participants separately from those enrolling unselected participants. We investigated pre-defined sources of heterogeneity including the influence of CD4 count and clinical setting on the accuracy estimates. We assessed the certainty of the evidence using the GRADE approach.

Main Results: We included 15 unique studies (nine new studies and six studies from the original review that met the inclusion criteria): eight studies among symptomatic adults and seven studies among unselected adults. All studies were conducted in low- or middle-income countries. Risk of bias was high in the patient selection and reference standard domains, mainly because studies excluded participants unable to produce sputum and used a lower quality reference standard.Participants with tuberculosis symptomsLF-LAM pooled sensitivity (95% credible interval (CrI) ) was 42% (31% to 55%) (moderate-certainty evidence) and pooled specificity was 91% (85% to 95%) (very low-certainty evidence), (8 studies, 3449 participants, 37% with tuberculosis).For a population of 1000 people where 300 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 189 to be LF-LAM positive: of these, 63 (33%) would not have tuberculosis (false-positives); and 811 to be LF-LAM negative: of these, 174 (21%) would have tuberculosis (false-negatives).By clinical setting, pooled sensitivity was 52% (40% to 64%) among inpatients versus 29% (17% to 47%) among outpatients; and pooled specificity was 87% (78% to 93%) among inpatients versus 96% (91% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count.Unselected participants not assessed for signs and symptoms of tuberculosisLF-LAM pooled sensitivity was 35% (22% to 50%), (moderate-certainty evidence) and pooled specificity was 95% (89% to 96%), (low-certainty evidence), (7 studies, 3365 participants, 13% with tuberculosis).For a population of 1000 people where 100 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 80 to be LF-LAM positive: of these, 45 (56%) would not have tuberculosis (false-positives); and 920 to be LF-LAM negative: of these, 65 (7%) would have tuberculosis (false-negatives).By clinical setting, pooled sensitivity was 62% (41% to 83%) among inpatients versus 31% (18% to 47%) among outpatients; pooled specificity was 84% (48% to 96%) among inpatients versus 95% (87% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count.

Authors' Conclusions: We found that LF-LAM has a sensitivity of 42% to diagnose tuberculosis in HIV-positive individuals with tuberculosis symptoms and 35% in HIV-positive individuals not assessed for tuberculosis symptoms, consistent with findings reported previously. Regardless of how people are enrolled, sensitivity is higher in inpatients and those with lower CD4 cell, but a concomitant lower specificity. As a simple point-of-care test that does not depend upon sputum evaluation, LF-LAM may assist with the diagnosis of tuberculosis, particularly when a sputum specimen cannot be produced.
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http://dx.doi.org/10.1002/14651858.CD011420.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802713PMC
October 2019

Guidance for Studies Evaluating the Accuracy of Tuberculosis Triage Tests.

J Infect Dis 2019 10;220(220 Suppl 3):S116-S125

University Hospital Heidelberg, Division of Tropical Medicine, Centre of Infectious Diseases, Germany.

Approximately 3.6 million cases of active tuberculosis (TB) go potentially undiagnosed annually, partly due to limited access to confirmatory diagnostic tests, such as molecular assays or mycobacterial culture, in community and primary healthcare settings. This article provides guidance for TB triage test evaluations. A TB triage test is designed for use in people with TB symptoms and/or significant risk factors for TB. Triage tests are simple and low-cost tests aiming to improve ease of access and implementation (compared with confirmatory tests) and decrease the proportion of patients requiring more expensive confirmatory testing. Evaluation of triage tests should occur in settings of intended use, such as community and primary healthcare centers. Important considerations for triage test evaluation include study design, population, sample type, test throughput, use of thresholds, reference standard (ideally culture), and specimen flow. The impact of a triage test will depend heavily on issues beyond accuracy, primarily centered on implementation.
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http://dx.doi.org/10.1093/infdis/jiz243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782021PMC
October 2019

A systematic review of the diagnostic accuracy of artificial intelligence-based computer programs to analyze chest x-rays for pulmonary tuberculosis.

PLoS One 2019 3;14(9):e0221339. Epub 2019 Sep 3.

Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada.

We undertook a systematic review of the diagnostic accuracy of artificial intelligence-based software for identification of radiologic abnormalities (computer-aided detection, or CAD) compatible with pulmonary tuberculosis on chest x-rays (CXRs). We searched four databases for articles published between January 2005-February 2019. We summarized data on CAD type, study design, and diagnostic accuracy. We assessed risk of bias with QUADAS-2. We included 53 of the 4712 articles reviewed: 40 focused on CAD design methods ("Development" studies) and 13 focused on evaluation of CAD ("Clinical" studies). Meta-analyses were not performed due to methodological differences. Development studies were more likely to use CXR databases with greater potential for bias as compared to Clinical studies. Areas under the receiver operating characteristic curve (median AUC [IQR]) were significantly higher: in Development studies AUC: 0.88 [0.82-0.90]) versus Clinical studies (0.75 [0.66-0.87]; p-value 0.004); and with deep-learning (0.91 [0.88-0.99]) versus machine-learning (0.82 [0.75-0.89]; p = 0.001). We conclude that CAD programs are promising, but the majority of work thus far has been on development rather than clinical evaluation. We provide concrete suggestions on what study design elements should be improved.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221339PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719854PMC
March 2020

Top Questions in the Diagnosis and Treatment of Pulmonary Disease.

Open Forum Infect Dis 2019 Jul 14;6(7):ofz221. Epub 2019 May 14.

Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

disease is particularly challenging to treat, given the intrinsic drug resistance of this species and the limited data on which recommendations are based, resulting in a greater reliance on expert opinion. We address several commonly encountered questions and management considerations regarding pulmonary disease, including the role of subspecies identification, diagnostic criteria for determining disease, interpretation of drug susceptibility test results, approach to therapy including the need for parenteral antibiotics and the role for new and repurposed drugs, and the use of adjunctive strategies such as airway clearance and surgical resection.
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http://dx.doi.org/10.1093/ofid/ofz221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608938PMC
July 2019

Diagnostic Delays and Treatment Implications for Patients with Isoniazid-Resistant Tuberculosis: A Case Report and Review of the Literature.

Open Forum Infect Dis 2019 Jun 14;6(6):ofz222. Epub 2019 May 14.

Section of Infectious Diseases, Department of Medicine, Boston Medical Center, Boston, Massachusetts.

Drug-resistant tuberculosis (DR-TB) remains a major public health threat. A 23-year-old man presented with fever, dyspnea, and a pleural effusion. After a delay, he was diagnosed with isoniazid (INH)-resistant TB. We review the literature describing the epidemiological and clinical significance of INH-resistant TB and its relevance for low-incidence countries, such as the United States.
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http://dx.doi.org/10.1093/ofid/ofz222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559270PMC
June 2019

Stamping out Tuberculosis: The Importance of Diagnostic Innovation and Effective Implementation.

Ann Am Thorac Soc 2019 09;16(9):1112-1113

Division of Infectious Diseases, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1513/AnnalsATS.201902-173EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812161PMC
September 2019

Constructing care cascades for active tuberculosis: A strategy for program monitoring and identifying gaps in quality of care.

PLoS Med 2019 02 27;16(2):e1002754. Epub 2019 Feb 27.

Department of Epidemiology, Biostatistics and Occupational Health and McGill International TB Centre, McGill University, Montreal, Canada.

The cascade of care is a model for evaluating patient retention across sequential stages of care required to achieve a successful treatment outcome. This approach was first used to evaluate HIV care and has since been applied to other diseases. The tuberculosis (TB) community has only recently started using care cascade analyses to quantify gaps in quality of care. In this article, we describe methods for estimating gaps (patient losses) and steps (patients retained) in the care cascade for active TB disease. We highlight approaches for overcoming challenges in constructing the TB care cascade, which include difficulties in estimating the population-level burden of disease and the diagnostic gap due to the limited sensitivity of TB diagnostic tests. We also describe potential uses of this model for evaluating the impact of interventions to improve case finding, diagnosis, linkage to care, retention in care, and post-treatment monitoring of TB patients.
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http://dx.doi.org/10.1371/journal.pmed.1002754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392267PMC
February 2019

New strategies for inpatients with HIV and tuberculosis.

Lancet 2018 07 20;392(10144):256-258. Epub 2018 Jul 20.

Department of Epidemiology and Biostatistics, McGill University, Montreal, QC H3A 1A2, Canada; McGill International TB Centre, McGill University, Montreal, QC, Canada; Manipal McGill Centre for Infectious Diseases, Manipal Academy of Higher Education, Manipal, India. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(18)31442-9DOI Listing
July 2018

Polyclonal Pulmonary Tuberculosis Infections and Risk for Multidrug Resistance, Lima, Peru.

Emerg Infect Dis 2017 11;23(11):1887-1890

Because within-host Mycobacterium tuberculosis diversity complicates diagnosis and treatment of tuberculosis (TB), we measured diversity prevalence and associated factors among 3,098 pulmonary TB patients in Lima, Peru. The 161 patients with polyclonal infection were more likely than the 115 with clonal or the 2,822 with simple infections to have multidrug-resistant TB.
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http://dx.doi.org/10.3201/eid2311.170077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652442PMC
November 2017

Agents of change: The role of healthcare workers in the prevention of nosocomial and occupational tuberculosis.

Presse Med 2017 Mar 28;46(2 Pt 2):e53-e62. Epub 2017 Feb 28.

TB Proof, Cape Town, South Africa; University College London, and NIHR Biomedical Research Centre, University College London Hospital, Division of Infection and Immunity, London, UK.

Healthcare workers (HCWs) play a central role in global tuberculosis (TB) elimination efforts but their contributions are undermined by occupational TB. HCWs have higher rates of latent and active TB than the general population due to persistent occupational TB exposure, particularly in settings where there is a high prevalence of undiagnosed TB in healthcare facilities and TB infection control (TB-IC) programmes are absent or poorly implemented. Occupational health programmes in high TB burden settings are often weak or non-existent and thus data that record the extent of the increased risk of occupational TB globally are scarce. HCWs represent a limited resource in high TB burden settings and occupational TB can lead to workforce attrition. Stigma plays a role in delayed diagnosis, poor treatment outcomes and impaired well-being in HCWs who develop TB. Ensuring the prioritization and implementation of TB-IC interventions and occupational health programmes, which include robust monitoring and evaluation, is critical to reduce nosocomial TB transmission to patients and HCWs. The provision of preventive therapy for HCWs with latent TB infection (LTBI) can also prevent progression to active TB. Unlike other patient groups, HCWs are in a unique position to serve as agents of change to raise awareness, advocate for necessary resource allocation and implement TB-IC interventions, with appropriate support from dedicated TB-IC officers at the facility and national TB programme level. Students and community health workers (CHWs) must be engaged and involved in these efforts. Nosocomial TB transmission is an urgent public health problem and adopting rights-based approaches can be helpful. However, these efforts cannot succeed without increased political will, supportive legal frameworks and financial investments to support HCWs in efforts to decrease TB transmission.
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http://dx.doi.org/10.1016/j.lpm.2017.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930005PMC
March 2017

Accuracy of line probe assays for the diagnosis of pulmonary and multidrug-resistant tuberculosis: a systematic review and meta-analysis.

Eur Respir J 2017 01 18;49(1). Epub 2017 Jan 18.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Only 25% of multidrug-resistant tuberculosis (MDR-TB) cases are currently diagnosed. Line probe assays (LPAs) enable rapid drug-susceptibility testing for rifampicin (RIF) and isoniazid (INH) resistance and Mycobacterium tuberculosis detection. Genotype MTBDRplusV1 was WHO-endorsed in 2008 but newer LPAs have since been developed.This systematic review evaluated three LPAs: Hain Genotype MTBDRplusV1, MTBDRplusV2 and Nipro NTM+MDRTB. Study quality was assessed with QUADAS-2. Bivariate random-effects meta-analyses were performed for direct and indirect testing. Results for RIF and INH resistance were compared to phenotypic and composite (incorporating sequencing) reference standards. M. tuberculosis detection results were compared to culture.74 unique studies were included. For RIF resistance (21 225 samples), pooled sensitivity and specificity (with 95% confidence intervals) were 96.7% (95.6-97.5%) and 98.8% (98.2-99.2%). For INH resistance (20 954 samples), pooled sensitivity and specificity were 90.2% (88.2-91.9%) and 99.2% (98.7-99.5%). Results were similar for direct and indirect testing and across LPAs. Using a composite reference standard, specificity increased marginally. For M. tuberculosis detection (3451 samples), pooled sensitivity was 94% (89.4-99.4%) for smear-positive specimens and 44% (20.2-71.7%) for smear-negative specimens.In patients with pulmonary TB, LPAs have high sensitivity and specificity for RIF resistance and high specificity and good sensitivity for INH resistance. This meta-analysis provides evidence for policy and practice.
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http://dx.doi.org/10.1183/13993003.01075-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898952PMC
January 2017

Mortality in children diagnosed with tuberculosis: a systematic review and meta-analysis.

Lancet Infect Dis 2017 03 8;17(3):285-295. Epub 2016 Dec 8.

Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.

Background: Case fatality ratios in children with tuberculosis are poorly understood-particularly those among children with HIV and children not receiving tuberculosis treatment. We did a systematic review of published work to identify studies of population-representative samples of paediatric (ie, <15 years) tuberculosis cases.

Methods: We searched PubMed and Embase for reports published in English, French, Portuguese, or Spanish before Aug 12, 2016, that included terms related to tuberculosis, children, mortality, and population representativeness. We also reviewed our own files and reference lists of articles identified by this search. We screened titles and abstracts for inclusion, excluding studies in which outcomes were unknown for 10% or more of the children and publications detailing non-representative samples. We used random-effects meta-analysis to produce pooled estimates of case fatality ratios from the included studies, which we divided into three eras: the pre-treatment era (ie, studies before 1946), the middle era (1946-80), and the recent era (after 1980). We stratified our analyses by whether or not children received tuberculosis treatment, age (0-4 years, 5-14 years), and HIV status.

Findings: We identified 31 papers comprising 35 datasets representing 82 436 children with tuberculosis disease, of whom 9274 died. Among children with tuberculosis included in studies in the pre-treatment era, the pooled case fatality ratio was 21·9% (95% CI 18·1-26·4) overall. The pooled case fatality ratio was significantly higher in children aged 0-4 years (43·6%, 95% CI 36·8-50·6) than in those aged 5-14 years (14·9%, 11·5-19·1). In studies in the recent era, when most children had tuberculosis treatment, the pooled case fatality ratio was 0·9% (95% CI 0·5-1·6). US surveillance data suggest that the case fatality ratio is substantially higher in children with HIV receiving treatment for tuberculosis (especially without antiretroviral therapy) than in those without HIV.

Interpretation: Without adequate treatment, children with tuberculosis, especially those younger than 5 years, are at high risk of death. Children with HIV have an increased mortality risk, even when receiving tuberculosis treatment.

Funding: US National Institutes of Health, Janssen Global Public Health.
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http://dx.doi.org/10.1016/S1473-3099(16)30474-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330933PMC
March 2017

Tuberculosis prevention must integrate technological and basic care innovation.

Eur Respir J 2016 11;48(5):1531-1532

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

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http://dx.doi.org/10.1183/13993003.01601-2016DOI Listing
November 2016

The Tuberculosis Cascade of Care in India's Public Sector: A Systematic Review and Meta-analysis.

PLoS Med 2016 Oct 25;13(10):e1002149. Epub 2016 Oct 25.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.

Background: India has 23% of the global burden of active tuberculosis (TB) patients and 27% of the world's "missing" patients, which includes those who may not have received effective TB care and could potentially spread TB to others. The "cascade of care" is a useful model for visualizing deficiencies in case detection and retention in care, in order to prioritize interventions.

Methods And Findings: The care cascade constructed in this paper focuses on the Revised National TB Control Programme (RNTCP), which treats about half of India's TB patients. We define the TB cascade as including the following patient populations: total prevalent active TB patients in India, TB patients who reach and undergo evaluation at RNTCP diagnostic facilities, patients successfully diagnosed with TB, patients who start treatment, patients retained to treatment completion, and patients who achieve 1-y recurrence-free survival. We estimate each step of the cascade for 2013 using data from two World Health Organization (WHO) reports (2014-2015), one WHO dataset (2015), and three RNTCP reports (2014-2016). In addition, we conduct three targeted systematic reviews of the scientific literature to identify 39 unique articles published from 2000-2015 that provide additional data on five indicators that help estimate different steps of the TB cascade. We construct separate care cascades for the overall population of patients with active TB and for patients with specific forms of TB-including new smear-positive, new smear-negative, retreatment smear-positive, and multidrug-resistant (MDR) TB. The WHO estimated that there were 2,700,000 (95%CI: 1,800,000-3,800,000) prevalent TB patients in India in 2013. Of these patients, we estimate that 1,938,027 (72%) TB patients were evaluated at RNTCP facilities; 1,629,906 (60%) were successfully diagnosed; 1,417,838 (53%) got registered for treatment; 1,221,764 (45%) completed treatment; and 1,049,237 (95%CI: 1,008,775-1,083,243), or 39%, of 2,700,000 TB patients achieved the optimal outcome of 1-y recurrence-free survival. The separate cascades for different forms of TB highlight different patterns of patient attrition. Pretreatment loss to follow-up of diagnosed patients and post-treatment TB recurrence were major points of attrition in the new smear-positive TB cascade. In the new smear-negative and MDR TB cascades, a substantial proportion of patients who were evaluated at RNTCP diagnostic facilities were not successfully diagnosed. Retreatment smear-positive and MDR TB patients had poorer treatment outcomes than the general TB population. Limitations of our analysis include the lack of available data on the cascade of care in the private sector and substantial uncertainty regarding the 1-y period prevalence of TB in India.

Conclusions: Increasing case detection is critical to improving outcomes in India's TB cascade of care, especially for smear-negative and MDR TB patients. For new smear-positive patients, pretreatment loss to follow-up and post-treatment TB recurrence are considerable points of attrition that may contribute to ongoing TB transmission. Future multisite studies providing more accurate information on key steps in the public sector TB cascade and extension of this analysis to private sector patients may help to better target interventions and resources for TB control in India.
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http://dx.doi.org/10.1371/journal.pmed.1002149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079571PMC
October 2016

Re-Treatment With Ethambutol After Toxic Optic Neuropathy.

J Neuroophthalmol 2017 03;37(1):40-42

Department of Neurology (MAB, NT), Beth Israel Deaconess Medical Center, Boston, Massachusetts; Division of Infectious Disease (RRN, DY), Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and Division of Ophthalmology (NT), Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

There are no data in the literature regarding the safety of re-treatment with ethambutol for recurrent mycobacterial infection after prior ethambutol-induced optic neuropathy. We describe a patient who developed optic neuropathy attributed to ethambutol, recovered fully after drug withdrawal, and tolerated a 14-month long re-treatment 10 years later without developing recurrent optic neuropathy.
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http://dx.doi.org/10.1097/WNO.0000000000000445DOI Listing
March 2017

Engaging health-care workers to reduce tuberculosis transmission.

Lancet Infect Dis 2016 08;16(8):883-5

Division of Global Health Equity, Brigham and Women's' Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1016/S1473-3099(16)30199-2DOI Listing
August 2016

Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better?

Eur Respir J 2016 08 13;48(2):516-25. Epub 2016 Jul 13.

FIND, Geneva, Switzerland.

The global roll-out of Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) has changed the diagnostic landscape of tuberculosis (TB). More than 16 million tests have been performed in 122 countries since 2011, and detection of multidrug-resistant TB has increased three- to eight-fold compared to conventional testing. The roll-out has galvanised stakeholders, from donors to civil society, and paved the way for universal drug susceptibility testing. It has attracted new product developers to TB, resulting in a robust molecular diagnostics pipeline. However, the roll-out has also highlighted gaps that have constrained scale-up and limited impact on patient outcomes. The roll-out has been hampered by high costs for under-funded programmes, unavailability of a complete solution package (notably comprehensive training, quality assurance, implementation plans, inadequate service and maintenance support) and lack of impact assessment. Insufficient focus has been afforded to effective linkage to care of diagnosed patients, and clinical impact has been blunted by weak health systems. In many countries the private sector plays a dominant role in TB control, yet this sector has limited access to subsidised pricing. In light of these lessons, we advocate for a comprehensive diagnostics implementation approach, including increased engagement of in-country stakeholders for product launch and roll-out, broader systems strengthening in preparation for new technologies, as well as quality impact data from programmatic settings.
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http://dx.doi.org/10.1183/13993003.00543-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967565PMC
August 2016
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