Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

The potential deployment of a pan-tuberculosis drug regimen in India: A modelling analysis.

There is increasing interest in future, highly-potent 'pan-TB' regimens against tuberculosis (TB), that may be equally effective in both drug-susceptible and rifampicin-resistant (RR) forms of TB. Taking the example of India, the country with the world's largest burden of TB, we show that adoption of these regimens could be: (i) epidemiologically impactful, and (ii) cost-saving to the national TB programme, even if the regimen itself is more costly than current TB treatment. Mathematical modelling suggests that deployment of a pan-TB regimen in 2022 would reduce the annual incidence of TB in 2030 by 23.9% [95% Bayesian credible intervals [CrI] 17.6-30.8%] if used to treat all TB cases, and by 2.30% [95% CrI 1.57-3.48%] if used to treat only RR-TB. Notably, with a regimen costing less than USD 359 (95% CrI 287-441), treating all diagnosed TB cases with the pan-TB regimen yielded greater cost-savings than treating just those diagnosed with RR-TB. One limitation of our approach is that it does not capture the risk of resistance to the new regimen. We discuss ways in which this risk could be mitigated using modern adherence support mechanisms, as well as drug sensitivity testing at the point of TB diagnosis, to prevent new resistant forms from becoming established. A combination of such approaches would be important for maximising the useful lifetime of any future regimen.

The impact of the COVID-19 epidemic on tuberculosis control in China.

BACKGROUND: In response to the COVID-19 epidemic, China implemented a series of interventions that impacted tuberculosis (TB) control in the country. METHODS: Based on routine surveillance data and questionnaires, the study analyzed TB notification, follow-up examinations, and treatment outcomes. The data were split into three phases in relation to outbreak, lockdown and reopen when the nationwide COVID-19 response started in 2020: control (11 weeks prior), intensive (11 weeks during and immediately after), and regular (4 additional weeks). Data from 2017-2019 were used as baseline. FINDINGS: The notified number of TB patients decreased sharply in the 1st week of the intensive period but took significantly longer to rebound in 2020 compared with baseline. The percentages of TB patients undergoing sputum examination within one week after 2 months treatment and full treatment course in the intensive period were most affected and decreased by 8% in comparison with control period. 75•2% (221/294) of counties reallocated CDC and primary health care workers to fight the COVID-19 epidemic, 26•9% (725/2694) of TB patients had postponed or missed their follow-up examinations due to travel restrictions and fear of contracting COVID-19. INTERPRETATION: In the short term, the COVID-19 epidemic mostly affected TB notification and follow-up examinations in China, which may lead to a surge of demand for TB services in the near future. To cope with this future challenge, an emergency response mechanism for TB should be established. FUNDING: National Health Commission of China-Bill & Melinda Gates Foundation TB Collaboration project (OPP1137180).

Temporal Factors and Missed Doses of Tuberculosis Treatment. A Causal Associations Approach to Analyses of Digital Adherence Data.

Rationale: Tuberculosis treatment lasts for 6 months or more. Treatment adherence is critical; regimen length, among other factors, makes this challenging. Globally, analyses mapping common types of nonadherence are lacking. For example, is there a greater challenge resulting from early treatment cessation (discontinuation) or intermittent missed doses (suboptimal dosing implementation)? This is essential knowledge for the development of effective interventions and more "forgiving" regimens, as well as to direct national tuberculosis programs.Objectives: To granularly describe how patients take their tuberculosis medication and the temporal factors associated with missed doses.Methods: The present study included patients with pulmonary tuberculosis enrolled in the control arm of a pragmatic, cluster-randomized trial in China of electronic reminders to improve treatment adherence. Treatment was the standard 6-month course (180 d), dosed every other day (90 doses). Medication monitor boxes recorded adherence (box opening) without prompting reminders. Patterns of adherence were visualized and described. Mixed-effects logistic regression models examined the temporal factors associated with per-dose suboptimal dosing implementation, adjusting for clustering within a participant. Cox regression models were used to examine the association between early suboptimal dosing implementation and permanent discontinuation.Results: Across 780 patients, 16,794 (23.9%) of 70,200 doses were missed, 9,487 of which were from suboptimal dosing implementation (56.5%). By 60 days, 5.1% of participants had discontinued, and 14.4% had discontinued by 120 days. Most participants (95.9%) missed at least one dose. The majority of gaps were of a single dose (71.4%), although 22.6% of participants had at least one gap of 2 weeks or more. In adjusted models, the initiation-continuation phase transition (odds ratio, 3.07 [95% confidence interval, 2.68-3.51]) and national holidays (1.52 [1.39-1.65]) were associated with increased odds of suboptimal dosing implementation. Early-stage suboptimal dosing implementation was associated with increased discontinuation rates.Conclusions: Digital tools provide an unprecedented step change in describing and addressing nonadherence. In our setting, nonadherence was common; patients displayed a complex range of patterns. Dividing nonadherence into suboptimal dosing implementation and discontinuation, we found that both increased over time. Discontinuation was associated with early suboptimal dosing implementation. These apparent causal associations between temporal factors and nonadherence present opportunities for targeted interventions.Clinical trial registered with the ISRCTN Registry (ISRCTN46846388).

Added Value of Comprehensive Program to Provide Universal Access to Care for Sputum Smear-Negative Drug-Resistant Tuberculosis, China.

The increase in drug-resistant tuberculosis in China calls for scaling up rapid diagnosis. We evaluated introduction of rapid resistance testing by line-probe assay for all patients with a diagnosis of pulmonary tuberculosis in 2 prefectures in middle and eastern China. We analyzed sputum samples for smear-positive patients and cultures for smear-negative patients. We used a before-after comparison of baseline and intervention periods (12 months each) and analyzed data for 5,222 baseline period patients and 4,364 intervention period patients. The number of patients with rifampin resistance increased from 30 in the baseline period to 97 in the intervention period for smear-positive patients and from 0 to 13 for smear-negative patients, reflecting a low proportion of positive cultures (410/2,844, 14.4%). Expanding rapid testing for drug resistance for smear-positive patients resulted in a 3-fold increase in patients with diagnoses of rifampin-resistant tuberculosis. However, testing smear-negative patients had limited added value because of a low culture-positive rate.

Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.

BACKGROUND: In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. METHODS: Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. FINDINGS: Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87-94) for rpoB (rifampicin resistance), 86% (74-93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39-68) for pncA (pyrazinamide resistance), 85% (77-91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81-92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. INTERPRETATION: Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Conducting Patient-Pathway Analysis to Inform Programming of Tuberculosis Services: Methods.

Patient-centered care is a central pillar of the World Health Organization's End TB Strategy. Understanding where patients access health services is a first step to planning for the placement of services to meet patient needs and preferences. The patient-pathway analysis (PPA) methodology detailed in this article was developed to better understand the alignment between patient care seeking and tuberculosis service availability. A PPA describes the steps that people with tuberculosis take from the initial care visit to cure. The results of a PPA reveal programmatic gaps in care seeking, diagnosis, treatment initiation, and continuity of care. They can be used as inputs to an evidence-based process of identifying and developing interventions to address the gaps in patient care. This paper summarizes the steps to conduct a PPA and serves as the basis for understanding country case studies that profile the use of PPA.

Finding the Missing Patients With Tuberculosis: Lessons Learned From Patient-Pathway Analyses in 5 Countries.

Background: Despite significant progress in diagnosis and treatment of tuberculosis over the past 2 decades, millions of patients with tuberculosis go unreported every year. The patient-pathway analysis (PPA) is designed to assess the alignment between tuberculosis care-seeking patterns and the availability of tuberculosis services. The PPA can help programs understand where they might find the missing patients with tuberculosis. Methods: This analysis aggregates and compares the PPAs from case studies in Kenya, Ethiopia, Indonesia, the Philippines, and Pakistan. Results: Across the 5 countries, 24% of patients with tuberculosis initiated care seeking in a facility with tuberculosis diagnostic capacity. Forty-two percent of patients sought care at level 0 facilities, where there was generally no tuberculosis diagnostic capacity; another 42% of patients sought care at level 1 facilities, of which 39% had diagnostic capacity. Sixty-six percent of patients initially sought care in private facilities, which had considerably less tuberculosis diagnostic capacity than public facilities; only 7% of notified cases were from the private sector. The GeneXpert system was available in 14%-41% of level 2 facilities in the 3 countries for which there were data. Tuberculosis treatment capacity tracked closely with the availability of diagnostic capacity. There were substantial subnational differences in care-seeking patterns and service availability. Discussion: The PPA can be a valuable planning and programming tool to ensure that diagnostic and treatment services are available to patients where they seek care. Patient-centered care will require closing the diagnostic gap and engaging the private sector. Extensive subnational differences in patient pathways to care call for differentiated approaches to patient-centered care.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

BACKGROUND: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. METHODS: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. FINDINGS: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. INTERPRETATION: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. FUNDING: Bill and Melinda Gates Foundation.

Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models.

BACKGROUND: The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS: We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. FINDINGS: Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. INTERPRETATION: Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. FUNDING: Bill & Melinda Gates Foundation.

Multicenter evaluation of a real-time loop-mediated isothermal amplification (RealAmp) test for rapid diagnosis of Mycobacterium tuberculosis.

The real-time loop-mediated isothermal amplification (RealAmp) test is a novel technology for rapid diagnosis of Mycobacterium tuberculosis (MTB) from sputum samples. This test has not previously been effectively evaluated. In this study, we assessed the performance of the RealAmp test for tuberculosis (TB) detection among TB suspected patients from three provincial hospitals in China. Each eligible TB suspected patients in Shanghai, Guangzhou, and Shandong provided one sputum specimen each, smear microscopy, liquid culture, and the RealAmp test were performed per patient. A total of 1583 TB suspected patients were enrolled in the study, and 1519 were used for the performance analysis. The sensitivity and specificity of the RealAmp test for MTB detection were calculated using liquid culture as reference method. The sensitivity of RealAmp test in smear-negative and culture-positive patients was 60.08%; the sensitivity in smear-positive and culture-positive patients was 97.09%; and the overall sensitivity in culture-positive patients was 74.88%. The specificity of RealAmp test for MTB detection was 86.50%.

Access to and affordability of healthcare for TB patients in China: issues and challenges.

This paper introduces the background, aim and objectives of the project entitled "China-the Gates Foundation Collaboration on TB Control in China" that has been underway for many years. It also summarizes the key findings of the nine papers included in this special issue, which used data from the baseline survey of Phase II of the project. Data were collected from the survey of TB and MDR-TB patients, from designated hospitals, health insurance agencies and the routine health information systems, as well as key informant interviews and focus group discussions with relevant key stakeholders. Key issues discussed in this series of papers include the uses of TB services and anti-TB medicines and their determining factors related to socio-economic and health systems development; expenditures on TB care and the financial burden incurred on TB patients; and the impact of health insurance schemes implemented in China on financial protection.

Cost-effectiveness of a comprehensive programme for drug-resistant tuberculosis in China.

OBJECTIVE: To investigate the cost-effectiveness of a comprehensive programme for drug-resistant tuberculosis launched in four sites in China in 2011. METHODS: In 2011-2012, we reviewed the records of 172 patients with drug-resistant tuberculosis who enrolled in the comprehensive programme and we collected relevant administrative data from hospitals and China's public health agency. For comparison, we examined a cohort of 81 patients who were treated for drug-resistant tuberculosis in 2006-2009. We performed a cost-effectiveness analysis, from a societal perspective, that included probabilistic uncertainty. We measured early treatment outcomes based on three-month culture results and modelled longer-term outcomes to facilitate estimation of the comprehensive programme's cost per disability-adjusted life-year (DALY) averted. FINDINGS: The comprehensive programme cost 8837 United States dollars (US$) per patient treated. Low enrolment rates meant that some fixed costs were higher, per patient, than expected. Although the comprehensive programme appeared 30 times more costly than the previous one, it resulted in greater health benefits. The comprehensive programme, which cost US$ 639 (95% credible interval: 112 to 1322) per DALY averted, satisfied the World Health Organization's criterion for a very cost-effective intervention. CONCLUSION: The comprehensive programme, which included rapid screening, standardized care and financial protection, improved individual outcomes for MDR tuberculosis in a cost-effective manner. To support post-2015 global heath targets, the comprehensive programme should be expanded to non-residents and other areas of China.

Tuberculosis control in China: use of modelling to develop targets and policies.

It is unclear if current programmes in China can achieve the post-2015 global targets for tuberculosis - 50% reduction in incidence and a 75% reduction in mortality by 2025. Chinese policy-makers need to maintain the recent decline in the prevalence of tuberculosis, while revising control policies to cope with an epidemic of drug-resistant tuberculosis and the effects of ongoing health reform. Health reforms are expected to shift patients from tuberculosis dispensaries to designated hospitals. We developed a mathematical model of tuberculosis control in China to help set appropriate targets and prioritize interventions that might be implemented in the next 10 years. This model indicates that, even under the most optimistic scenario - improved treatment in tuberculosis dispensaries, introduction of a new effective regimen for the treatment of drug-susceptible tuberculosis and optimal care of cases of multidrug-resistant tuberculosis - the current global targets for tuberculosis are unlikely to be reached. However, reductions in the incidence of multidrug-resistant tuberculosis should be feasible. We conclude that a shift of patients from tuberculosis dispensaries to designated hospitals is likely to hamper efforts at tuberculosis control if cure rates in the designated hospitals cannot be maintained at a high level. Our results can inform the planning of tuberculosis control in China.

Il est difficile de savoir si les programmes actuellement menés en Chine permettront d'atteindre les objectifs mondiaux pour l'après-2015 concernant la tuberculose, qui consistent à réduire l'incidence de 50% et la mortalité de 75% d'ici à 2025. Les dirigeants chinois doivent confirmer le récent déclin de la prévalence de la tuberculose, mais aussi revoir les politiques de lutte pour faire face à une épidémie de tuberculose pharmacorésistante et les effets de l'actuelle réforme de la santé. La réforme de la santé est censée prévoir le transfert des patients traités dans des dispensaires antituberculeux vers des hôpitaux expressément désignés. Nous avons élaboré un modèle mathématique de lutte contre la tuberculose en Chine qui aide à définir les objectifs appropriés et à hiérarchiser les interventions qui pourraient être réalisées au cours des dix prochaines années. Ce modèle indique que même dans le scénario le plus optimiste ­ amélioration du traitement dans les dispensaires antituberculeux, introduction d'un nouveau schéma thérapeutique efficace pour le traitement de la tuberculose sensible et traitement optimal des cas de tuberculose multirésistante ­, il paraît difficile d'atteindre les objectifs mondiaux actuels pour la tuberculose. Néanmoins, il devrait être possible de réduire l'incidence de la tuberculose multirésistante. Nous en concluons que le transfert des patients traités dans des dispensaires antituberculeux vers des hôpitaux expressément désignés est susceptible d'entraver les efforts de lutte contre la tuberculose s'il est impossible de maintenir des taux de guérison élevés dans ces hôpitaux. Nos résultats peuvent servir de base à la planification de la lutte contre la tuberculose en Chine.

No está claro si los programas actuales en China pueden alcanzar los objetivos globales para la tuberculosis después de 2015, una reducción del 50% de la incidencia y una reducción del 75% de la mortalidad de aquí a 2025. Los responsables políticos de China necesitan mantener el reciente descenso en la prevalencia de la tuberculosis, al mismo tiempo que revisan las políticas de control para hacer frente a una epidemia de tuberculosis farmacorresistente y los efectos en la reforma sanitaria en curso. Se espera que las reformas sanitarias trasladen los pacientes de los dispensarios para tuberculosis a los hospitales designados. Se ha desarrollado un modelo matemático de control de la tuberculosis en China para ayudar a establecer los objetivos apropiados y priorizar las intervenciones que podrían implementarse en los próximos diez años. Este modelo indica que, incluso en el escenario más optimista (una mejora del tratamiento en los dispensarios para tuberculosis, la introducción de un nuevo y efectivo régimen para el tratamiento de la tuberculosis farmacosensible y la atención óptima en casos de la tuberculosis farmacorresistente), es muy poco probable que se cumplan los objetivos actuales globales para la tuberculosis. Sin embargo, las reducciones en la incidencia de la tuberculosis farmacorresistente deberían ser factibles. Se concluye que es posible que un cambio de los pacientes de los dispensarios para tuberculosis a los hospitales designados obstaculice los esfuerzos de un control para la tuberculosis si las tasas de cura en los hospitales designados no pueden mantenerse en un nivel alto. Nuestros resultados pueden dar información sobre la planificación del control de la tuberculosis en China.