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.

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.

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.

Effectiveness of Electronic Reminders to Improve Medication Adherence in Tuberculosis Patients: A Cluster-Randomised Trial.

BACKGROUND: Mobile text messaging and medication monitors (medication monitor boxes) have the potential to improve adherence to tuberculosis (TB) treatment and reduce the need for directly observed treatment (DOT), but to our knowledge they have not been properly evaluated in TB patients. We assessed the effectiveness of text messaging and medication monitors to improve medication adherence in TB patients. METHODS AND FINDINGS: In a pragmatic cluster-randomised trial, 36 districts/counties (each with at least 300 active pulmonary TB patients registered in 2009) within the provinces of Heilongjiang, Jiangsu, Hunan, and Chongqing, China, were randomised using stratification and restriction to one of four case-management approaches in which patients received reminders via text messages, a medication monitor, combined, or neither (control). Patients in the intervention arms received reminders to take their drugs and reminders for monthly follow-up visits, and the managing doctor was recommended to switch patients with adherence problems to more intensive management or DOT. In all arms, patients took medications out of a medication monitor box, which recorded when the box was opened, but the box gave reminders only in the medication monitor and combined arms. Patients were followed up for 6 mo. The primary endpoint was the percentage of patient-months on TB treatment where at least 20% of doses were missed as measured by pill count and failure to open the medication monitor box. Secondary endpoints included additional adherence and standard treatment outcome measures. Interventions were not masked to study staff and patients. From 1 June 2011 to 7 March 2012, 4,292 new pulmonary TB patients were enrolled across the 36 clusters. A total of 119 patients (by arm: 33 control, 33 text messaging, 23 medication monitor, 30 combined) withdrew from the study in the first month because they were reassessed as not having TB by their managing doctor (61 patients) or were switched to a different treatment model because of hospitalisation or travel (58 patients), leaving 4,173 TB patients (by arm: 1,104 control, 1,008 text messaging, 997 medication monitor, 1,064 combined). The cluster geometric mean of the percentage of patient-months on TB treatment where at least 20% of doses were missed was 29.9% in the control arm; in comparison, this percentage was 27.3% in the text messaging arm (adjusted mean ratio [aMR] 0.94, 95% CI 0.71, 1.24), 17.0% in the medication monitor arm (aMR 0.58, 95% CI 0.42, 0.79), and 13.9% in the combined arm (aMR 0.49, 95% CI 0.27, 0.88). Patient loss to follow-up was lower in the text messaging arm than the control arm (aMR 0.42, 95% CI 0.18-0.98). Equipment malfunction or operation error was reported in all study arms. Analyses separating patients with and without medication monitor problems did not change the results. Initiation of intensive management was underutilised. CONCLUSIONS: This study is the first to our knowledge to utilise a randomised trial design to demonstrate the effectiveness of a medication monitor to improve medication adherence in TB patients. Reminders from medication monitors improved medication adherence in TB patients, but text messaging reminders did not. In a setting such as China where universal use of DOT is not feasible, innovative approaches to support patients in adhering to TB treatment, such as this, are needed. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN46846388.

Tuberculosis prevalence in China, 1990-2010; a longitudinal analysis of national survey data.

BACKGROUND: China scaled up a tuberculosis control programme (based on the directly observed treatment, short-course [DOTS] strategy) to cover half the population during the 1990s, and to the entire population after 2000. We assessed the effect of the programme. METHODS: In this longitudinal analysis, we compared data from three national tuberculosis prevalence surveys done in 1990, 2000, and 2010. The 2010 survey screened 252,940 eligible individuals aged 15 years and older at 176 investigation points, chosen by stratified random sampling from all 31 mainland provinces. All individuals had chest radiographs taken. Those with abnormal radiographs, persistent cough, or both, were classified as having suspected tuberculosis. Tuberculosis was diagnosed by chest radiograph, sputum-smear microscopy, and culture. Trained staff interviewed each patient with tuberculosis. The 1990 and 2000 surveys were reanalysed and compared with the 2010 survey. FINDINGS: From 1990 to 2010, the prevalence of smear-positive tuberculosis decreased from 170 cases (95% CI 166-174) to 59 cases (49-72) per 100,000 population. During the 1990s, smear-positive prevalence fell only in the provinces with the DOTS programme; after 2000, prevalence decreased in all provinces. The percentage reduction in smear-positive prevalence was greater for the decade after 2000 than the decade before (57% vs 19%; p<0.0001). 70% of the total reduction in smear-positive prevalence (78 of 111 cases per 100,000 population) occurred after 2000. Of these cases, 68 (87%) were in known cases-ie, cases diagnosed with tuberculosis before the survey. Of the known cases, the proportion treated by the public health system (using the DOTS strategy) increased from 59 (15%) of 370 cases in 2000 to 79 (66%) of 123 cases in 2010, contributing to reduced proportions of treatment default (from 163 [43%] of 370 cases to 35 [22%] of 123 cases) and retreatment cases (from 312 [84%] of 374 cases to 48 [31%] of 137 cases; both p<0.0001). INTERPRETATION: In 20 years, China more than halved its tuberculosis prevalence. Marked improvement in tuberculosis treatment, driven by a major shift in treatment from hospitals to the public health centres (that implemented the DOTS strategy) was largely responsible for this epidemiological effect. FUNDING: Chinese Ministry of Health.

National survey of drug-resistant tuberculosis in China.

BACKGROUND: The available information on the epidemic of drug-resistant tuberculosis in China is based on local or regional surveys. In 2007, we carried out a national survey of drug-resistant tuberculosis in China. METHODS: We estimated the proportion of tuberculosis cases in China that were resistant to drugs by means of cluster-randomized sampling of tuberculosis cases in the public health system and testing for resistance to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and streptomycin and the second-line drugs ofloxacin and kanamycin. We used the results from this survey and published estimates of the incidence of tuberculosis to estimate the incidence of drug-resistant tuberculosis. Information from patient interviews was used to identify factors linked to drug resistance. RESULTS: Among 3037 patients with new cases of tuberculosis and 892 with previously treated cases, 5.7% (95% confidence interval [CI], 4.5 to 7.0) and 25.6% (95% CI, 21.5 to 29.8), respectively, had multidrug-resistant (MDR) tuberculosis (defined as disease that was resistant to at least isoniazid and rifampin). Among all patients with tuberculosis, approximately 1 of 4 had disease that was resistant to isoniazid, rifampin, or both, and 1 of 10 had MDR tuberculosis. Approximately 8% of the patients with MDR tuberculosis had extensively drug-resistant (XDR) tuberculosis (defined as disease that was resistant to at least isoniazid, rifampin, ofloxacin, and kanamycin). In 2007, there were 110,000 incident cases (95% CI, 97,000 to 130,000) of MDR tuberculosis and 8200 incident cases (95% CI, 7200 to 9700) of XDR tuberculosis. Most cases of MDR and XDR tuberculosis resulted from primary transmission. Patients with multiple previous treatments who had received their last treatment in a tuberculosis hospital had the highest risk of MDR tuberculosis (adjusted odds ratio, 13.3; 95% CI, 3.9 to 46.0). Among 226 previously treated patients with MDR tuberculosis, 43.8% had not completed their last treatment; most had been treated in the hospital system. Among those who had completed treatment, tuberculosis developed again in most of the patients after their treatment in the public health system. CONCLUSIONS: China has a serious epidemic of drug-resistant tuberculosis. MDR tuberculosis is linked to inadequate treatment in both the public health system and the hospital system, especially tuberculosis hospitals; however, primary transmission accounts for most cases. (Funded by the Chinese Ministry of Health.).

Tuberculosis control strategies to reach the 2035 global targets in China: the role of changing demographics and reactivation disease.

BACKGROUND: In the last 20 years, China ramped up a DOTS (directly observed treatment, short-course)-based tuberculosis (TB) control program with 80% population coverage, achieving the 2015 Millennium Development Goal of a 50% reduction in TB prevalence and mortality. Recently, the World Health Organization developed the End TB Strategy, with an overall goal of a 90% reduction in TB incidence and a 95% reduction in TB deaths from 2015-2035. As the TB burden shifts to older individuals and China's overall population ages, it is unclear if maintaining the current DOTS strategy will be sufficient for China to reach the global targets. METHODS: We developed an individual-based computational model of TB transmission, implementing realistic age demographics and fitting to country-level data of age-dependent prevalence over time. We explored the trajectory of TB burden if the DOTS strategy is maintained or if new interventions are introduced using currently available and soon-to-be-available tools. These interventions include increasing population coverage of DOTS, reducing time to treatment, increasing treatment success, and active case finding among elders > 65 years old. We also considered preventative therapy in latently infected elders, a strategy limited by resource constraints and the risk of adverse events. RESULTS: Maintenance of the DOTS strategy reduces TB incidence and mortality by 42% (95% credible interval, 27-59%) and 41% (5-64%), respectively, between 2015 and 2035. A combination of all feasible interventions nears the 2035 mortality target, reducing TB incidence and mortality by 59% (50-76%) and 83% (73-94%). Addition of preventative therapy for elders would enable China to nearly reach both the incidence and mortality targets, reducing incidence and mortality by 84% (78-93%) and 92% (86-98%). CONCLUSIONS: The current decline in incidence is driven by two factors: maintaining a low level of new infections in young individuals and the aging out of older latently infected individuals who contribute incidence due to reactivation disease. While further reducing the level of new infections has a modest effect on burden, interventions that limit reactivation have a greater impact on TB burden. Tools that make preventative therapy more feasible on a large scale and in elders will help China achieve the global targets.

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.

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.

Multicenter Evaluation of the Molecular Line Probe Assay for Multidrug Resistant Mycobacterium Tuberculosis Detection in China.

In order to evaluate the performance of a molecular Hain line probe assay (Hain LPA) for rapid detection of rifampicin and isoniazid resistance of Mycobacterium tuberculosis in China, 1612 smear positive patients were consecutively enrolled in this study. Smear positive sputum specimens were collected for Hain LPA and conventional drug susceptibility testing (DST). The sensitivity and specificity of Hain LPA were analyzed by using conventional DST as golden reference. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for rifampicin resistance detection were 88.33%, 97.66%, 81.54%, and 98.62%, respectively. The sensitivity, specificity, PPV and NPV for isoniazid resistance detection were 80.25%, 98.07%, 87.25%, and 96.78%, respectively. These findings suggested that Hain LPA can be an effective method worthy of broader use in China.

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.

Multicenter evaluation of genechip for detection of multidrug-resistant Mycobacterium tuberculosis.

Drug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), is still one of the most serious threats to TB control worldwide. Early diagnosis of MDR-TB is important for effectively blocking transmission and establishing an effective protocol for chemotherapy. Genechip is a rapid diagnostic method based on molecular biology that overcomes the poor biosafety, time consumption, and other drawbacks of traditional drug sensitivity testing (DST) that can detect MDR-TB. However, the Genechip approach has not been effectively evaluated, especially in limited-resource laboratories. In this study, we evaluated the performance of Genechip for MDR-TB in 1,814 patients in four prefectural or municipal laboratories and compared its performance with that of traditional DST. The results showed that the sensitivity and specificity of Genechip were 87.56% and 97.95% for rifampin resistance and 80.34% and 95.82% for isoniazid resistance, respectively. In addition, we found that the positive grade of the sputum smears influenced the judgment of results by Genechip. The test judged only 75% of the specimens of "scanty" positive grade. However, the positive grade of the specimens showed no influence on the accuracy of Genechip. Overall, the study suggests that, in limited-resource laboratories, Genechip showed high sensitivity and specificity for rifampin and isoniazid resistance, making it a more effective, rapid, safe, and cost-beneficial method worthy of broader use in limited-resource laboratories in China.

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.

A strategy to control transmission of Schistosoma japonicum in China.

BACKGROUND: Schistosoma japonicum causes an infection involving humans, livestock, and snails and is a significant cause of morbidity in China. METHODS: We evaluated a comprehensive control strategy in two intervention villages and two control villages along Poyang Lake in the southeastern province of Jiangxi, where annual synchronous chemotherapy is routinely used. New interventions, implemented from 2005 through 2007, included removing cattle from snail-infested grasslands, providing farmers with mechanized farm equipment, improving sanitation by supplying tap water and building lavatories and latrines, providing boats with fecal-matter containers, and implementing an intensive health-education program. During the intervention period, we observed changes in S. japonicum infection in humans, measured the rate of infection in snails, and tested the infectivity of lake water in mice. RESULTS: After three transmission seasons, the rate of infection in humans decreased to less than 1.0% in the intervention villages, from 11.3% to 0.7% in one village and from 4.0% to 0.9% in the other (P<0.001 for both comparisons). The rate of infection in humans in control villages fluctuated but remained at baseline levels. In intervention villages, the percentage of sampling sites with infected snails decreased from 2.2% to 0.1% in one grassland area and from 0.3% to no infection in the other (P<0.001 for both comparisons). The rate of infection in mice after exposure to lake water decreased from 79% to no infection (P<0.001). CONCLUSIONS: A comprehensive control strategy based on interventions to reduce the rate of transmission of S. japonicum infection from cattle and humans to snails was highly effective. These interventions have been adopted as the national strategy to control schistosomiasis in China.

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).

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).

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.

Emergence and control of infectious diseases in China.

Infectious diseases remain the major causes of morbidity and mortality in China despite substantial progress in their control. China is a major contributor to the worldwide infectious disease burden because of its population size. The association of China with the rest of the world through travel and trade means that events in the country can affect distant populations. The ecological interaction of people with animals in China favours the emergence of new microbial threats. The public-health system has to be prepared to deal with the challenges of newly emerging infectious diseases and at the same time try to control existing diseases. To address the microbial threats, such as severe acute respiratory syndrome, the government has committed substantial resources to the implementation of new strategies, including the development of a real-time monitoring system as part of the infectious-disease surveillance. This strategy can serve as a model for worldwide surveillance and response to threats from infectious diseases.