Preventing emergence of drug resistant tuberculosis in Myanmar's transitioning health system.

Multidrug-resistant tuberculosis (MDR-TB) is a particular threat to the populations of resource-limited countries. Although inadequate treatment of TB has been identified as a major underlying cause of drug resistance, essential information to inform changes in health service delivery and policy is missing. We investigate factors that may be driving the emergence of MDR-TB in Myanmar, a country where investment and health system reforms are ongoing to address the unexplained, high occurrence of MDR-TB. We conducted a multi-centre, retrospective case-control study in 10 townships across Yangon. Cases were 202 GeneXpert-confirmed MDR-TB patients with a history of prior first-line treatment for TB. Controls were 404 previously untreated smear-microscopy confirmed TB patients who had no evidence of resistance to anti-TB drugs. Information on patient and health service factors was collected through face-to-face patient interviews and hospital record reviews. Multivariable logistic regression analysis indicated that the following TB patient groups are at higher risk of developing MDR-TB after initial TB treatment: those who have diabetes (aOR 2.10; 95% CI 1.17-3.76), those who missed taking drugs during the initial treatment more than once weekly (aOR 2.35; 95% CI 1.18-4.65) and those with a higher socioeconomic (aOR 1.99; 95% CI 1.09-3.63) or educational status (aOR 1.78; 95% CI1.01-3.13). Coinciding with a surge in funding to improve health in Myanmar, this study identifies practices of patients and healthcare organizations that can be addressed, and high-risk TB patient groups that can be prioritized for treatment support. Specifically, the study shows that TB patients who experience frequent, short interruptions in treatment and those with diabetes may require enhanced treatment support and monitoring by health services in order to prevent further generation of drug resistance.

Risk factors that may be driving the emergence of drug resistance in tuberculosis patients treated in Yangon, Myanmar.

BACKGROUND: The majority of new tuberculosis cases emerging every year occur in low and middle-income countries where public health systems are often characterised by weak infrastructure and inadequate resources. This study investigates healthcare seeking behaviour, knowledge and treatment of tuberculosis patients in Myanmar-which is facing an acute drug-resistant tuberculosis epidemic-and identifies factors that may increase the risk of emergence of drug-resistant tuberculosis. METHODS: We randomly selected adult smear-positive pulmonary tuberculosis patients diagnosed between September 2014 and March 2015 at ten public township health centres in Yangon, the largest city in Myanmar. Data on patients' healthcare seeking behaviour, treatment at the township health centres, co-morbidities and knowledge was collected through patient interviews and extraction from hospital records. A retrospective descriptive cross-sectional analysis was conducted. RESULTS: Of 404 TB patients selected to participate in the study, 11 had died since diagnosis, resulting in 393 patients being included in the final analysis. Results indicate that a high proportion of patients (16%; 95% CI = 13-20) did not have a treatment supporter assigned to improve adherence to medication, with men being more likely to have no treatment supporter assigned. Use of private healthcare providers was very common; 59% (54-64) and 30.3% (25.9-35.0) of patients reported first seeking care at private clinics and pharmacies respectively. We found that 8% (6-11) of tuberculosis patients had confirmed diabetes. Most patients had some knowledge about tuberculosis transmission and the consequences of missing treatment. However, 5% (3-8) stated that they miss taking tuberculosis medicines at least weekly, and patients with no knowledge of consequences of missing treatment were more likely to miss doses. CONCLUSIONS: This study analysed healthcare seeking behaviour and treatment related practices of tuberculosis patients being managed under operational conditions in a fragile health system. Findings indicate that ensuring that treatment adherence support is arranged for all patients, monitoring of response to treatment among the high proportion of tuberculosis patients with diabetes and engagement with private healthcare providers could be strategies addressed to reduce the risk of emergence of drug-resistant tuberculosis.

Evidence to inform resource allocation for tuberculosis control in Myanmar: a systematic review based on the SYSRA framework.

Myanmar represents an extreme example of the difficulties in optimally allocating resources for maximum public health benefit, on the basis of limited information. At the recent Myanmar Health Forum 'Investing in Health' much of the discussion revolved around what to invest in, how health systems could be strengthened, and what research and capacity building areas the international donor community should prioritise for support. Funding for infectious disease control, particularly HIV and tuberculosis, is being channelled to the country at an unprecedented rate, but very little research has been conducted in recent years, and existing information has not yet been synthesised. This paper presents findings of the first systematic literature review on tuberculosis control and the health system in Myanmar, with the aim of informing the development of optimal research priorities and strategies. Medline and grey literature were searched for relevant papers. Inclusion criteria and analyses were structured to capture data on the Myanmar health system, healthcare delivery, financing, tuberculosis control indicators and information systems. A total of 77 papers were included in the analysis. The results indicate that there has been a large increase in the number of peer-reviewed articles published on tuberculosis in Myanmar over the past decade, although the absolute number of studies remains small. We identified several areas in which evidence to inform policy and resource allocation decisions is lacking, including research focused on rural and/or vulnerable populations, analyses of risk factors for TB and drug resistance that can inform prevention strategies and economic analyses for optimising resource allocation. The gaps in research to inform policy identified through this study may be relevant to other low resource settings with extremely limited research capacity.

Economic interventions to improve population health: a scoping study of systematic reviews.

BACKGROUND: Recognizing the close relationship between poverty and health, national program managers, policy-makers and donors are increasingly including economic interventions as part of their core strategies to improve population health. However, there is often confusion among stakeholders about the definitions and operational differences between distinct types of economic interventions and financial instruments, which can lead to important differences in interpretation and expectations. METHODS: We conducted a scoping study to define and clarify concepts underlying key economic interventions - price interventions (taxes and subsidies), income transfer programs, incentive programs, livelihood support programs and health-related financial services - and map the evidence currently available from systematic reviews. RESULTS: We identified 195 systematic reviews on economic interventions published between 2005 and July 2015. Overall, there was an increase in the number of reviews published after 2010. The majority of reviews focused on price interventions, income transfer programs and incentive programs, with much less evidence available from systematic reviews on livelihood support programs and health-related financial services. We also identified a lack of evidence on: health outcomes in low income countries; unintended or perverse outcomes; implementation challenges; scalability and cost-effectiveness of economic interventions. CONCLUSIONS: We conclude that while more research is clearly needed to assess suitability and effectiveness of economic interventions in different contexts, before interventions are tested and further systematic reviews conducted, a consistent and accurate understanding of the fundamental differences in terminology and approaches is essential among researchers, public health policy makers and program planners.

Do mixed infections matter? Assessing virulence of mixed-clone infections in experimental human and murine malaria.

BACKGROUND: Malaria parasites within an individual infection often consist of multiple strains (clonal populations) of a single species, which have the potential to interact both with one another, and with the host immune system. Several effects of these interactions have been measured in different parasite systems including competition and mutualism; however, direct observation of these effects in human malaria has been limited by sampling complexities and inherent ethical limitations. METHODS: Using multiple complementary epidemiological models, we propose a suite of analyses to more fully utilize data from challenge experiments, and re-examine historical human challenge studies with mixed-strain Plasmodium vivax inocula. We then compare these results with murine model systems using mixed-strain Plasmodium yoelii or Plasmodium chabaudi, to explore the utility of these methods in fully utilizing these data, including the first quantitative estimates of effect sizes for mixed-strain parasitemia. These models also provide a method to assess consistency within these animal model systems. RESULTS: We find that amongst a limited set of P. vivax (incubation time) and P. yoelii infections (time-to-mortality), survival times at a study population-level are intermediate between each single-clone infection, and are not dominated by the more virulent clone; in P. vivax relapses, mixed clone infections also show intermediate survival curves. In these infections, the results strongly suggest that highly virulent clones have their virulence attenuated by the presence of less-virulent clones. The analysis of multiple experiments with P. chabaudi suggests greater nuances in the interactions between strains, and that mortality and time-to-event in mixed-strain infections are both indistinguishable from single infections with the more virulent strain. CONCLUSIONS: These divergent dynamics support earlier work that suggested drivers of virulence may differ in fundamental ways between malaria species that are reticulocyte-specific and those that readily infect all red blood cell stages which should be studied in greater detail. The effect sizes (magnitude of biological effects) from these analyses are significant, and suggest the potential for important gains in malaria control by greater incorporation of evolutionary epidemiology theory. Moreover, we suggest that using these epidemiological models may generally allow fuller use of data from experimentally challenging animal model experiments.

Pilgrims and MERS-CoV: what's the risk?

The risk of Middle East Respiratory Syndrome Coronavirus spreading globally is worrying, given the annual mass gathering of the Hajj and the year-long influx of pilgrims undertaking the Umrah. Based on the incidence in Saudi Arabia since June 2012, the most likely scenario given recent pilgrim numbers is estimated to be one case per Hajj, and three Umrah pilgrims per year, but which could plausibly reach seven and ten pilgrims respectively. In addition to the 2015 Hajj, national surveillance systems should be on the alert for the low but long-lasting risk of infected pilgrims returning from the Umrah throughout the year.

Communicable disease control programmes and health systems: an analytical approach to sustainability.

There is renewed concern over the sustainability of disease control programmes, and re-emergence of policy recommendations to integrate programmes with general health systems. However, the conceptualization of this issue has remarkably received little critical attention. Additionally, the study of programmatic sustainability presents methodological challenges. In this article, we propose a conceptual framework to support analyses of sustainability of communicable disease programmes. Through this work, we also aim to clarify a link between notions of integration and sustainability. As a part of development of the conceptual framework, we conducted a systematic literature review of peer-reviewed literature on concepts, definitions, analytical approaches and empirical studies on sustainability in health systems. Identified conceptual proposals for analysis of sustainability in health systems lack an explicit conceptualization of what a health system is. Drawing upon theoretical concepts originating in sustainability sciences and our review here, we conceptualize a communicable disease programme as a component of a health system which is viewed as a complex adaptive system. We propose five programmatic characteristics that may explain a potential for sustainability: leadership, capacity, interactions (notions of integration), flexibility/adaptability and performance. Though integration of elements of a programme with other system components is important, its role in sustainability is context specific and difficult to predict. The proposed framework might serve as a basis for further empirical evaluations in understanding complex interplay between programmes and broader health systems in the development of sustainable responses to communicable diseases.

Pandemic influenza and health system resource gaps in Bali: an analysis through a resource transmission dynamics model.

The failure to contain pandemic influenza A(H1N1) 2009 in Mexico has shifted global attention from containment to mitigation. Limited surveillance and reporting have, however, prevented detailed assessment of mitigation during the pandemic, particularly in low- and middle-income countries. To assess pandemic influenza case management capabilities in a resource-limited setting, the authors used a health system questionnaire and density-dependent, deterministic transmission model for Bali, Indonesia, determining resource gaps. The majority of health resources were focused in and around the provincial capital, Denpasar; however, gaps are found in every district for nursing staff, surgical masks, and N95 masks. A relatively low pathogenicity pandemic influenza virus would see an overall surplus for physicians, antivirals, and antimicrobials; however, a more pathogenic virus would lead to gaps in every resource except antimicrobials. Resources could be allocated more evenly across Bali. These, however, are in short supply universally and therefore redistribution would not fill resource gaps.

The distribution of incubation and relapse times in experimental human infections with the malaria parasite Plasmodium vivax.

BACKGROUND: The distributions of incubation and relapse periods are key components of infectious disease models for the malaria parasite Plasmodium vivax; however, detailed distributions based upon experimental data are lacking. METHODS: Using a range of historical, experimental mosquito-transmitted human infections, Bayesian estimation with non-informative priors was used to determine parametric distributions that can be readily implemented for the incubation period and time-to-first relapse in P. vivax infections, including global subregions by parasite source. These analyses were complemented with a pooled analysis of observational human infection data with infections that included malaria chemoprophylaxis and long-latencies. The epidemiological impact of these distributional assumptions was explored using stochastic epidemic simulations at a fixed reproductive number while varying the underlying distribution of incubation periods. RESULTS: Using the Deviance Information Criteria to compare parameterizations, experimental incubation periods are most closely modeled with a shifted log-logistic distribution; a log-logistic mixture is the best fit for incubations in observational studies. The mixture Gompertz distribution was the best fit for experimental times-to-relapse among the tested parameterizations, with some variation by geographic subregions. Simulations suggest underlying distributional assumptions have critically important impacts on both the time-scale and total case counts within epidemics. CONCLUSIONS: These results suggest that the exponential and gamma distributions commonly used for modeling incubation periods and relapse times inadequately capture the complexity in the distributions of event times in P. vivax malaria infections. In future models, log-logistic and Gompertz distributions should be utilized for general incubation periods and relapse times respectively, and region-specific distributions should be considered to accurately model and predict the epidemiology of this important human pathogen.

Re-assessing the relationship between sporozoite dose and incubation period in Plasmodium vivax malaria: a systematic re-analysis.

Infections with the malaria parasite Plasmodium vivax are noteworthy for potentially very long incubation periods (6-9 months), which present a major barrier to disease elimination. Increased sporozoite challenge has been reported to be associated with both shorter incubation and pre-patent periods in a range of human challenge studies. However, this evidence base has scant empirical foundation, as these historical analyses were limited by available analytic methods, and provides no quantitative estimates of effect size. Following a comprehensive literature search, we re-analysed all identified studies using survival and/or logistic models plus contingency tables. We have found very weak evidence for dose-dependence at entomologically plausible inocula levels. These results strongly suggest that sporozoite dosage is not an important driver of long-latency. Evidence presented suggests that parasite strain and vector species have quantitatively greater impacts, and the potential existence of a dose threshold for human dose-response to sporozoites. Greater consideration of the complex interplay between these aspects of vectors and parasites are important for human challenge experiments, vaccine trials, and epidemiology towards global malaria elimination.

Quantifying effect of geographic location on epidemiology of Plasmodium vivax malaria.

Recent autochthonous transmission of Plasmodium vivax malaria in previously malaria-free temperate regions has generated renewed interest in the epidemiology of this disease. Accurate estimates of the incubation period and time to relapse are required for effective malaria surveillance; however, this information is currently lacking. By using historical data from experimental human infections with diverse P. vivax strains, survival analysis models were used to obtain quantitative estimates of the incubation period and time to first relapse for P. vivax malaria in broad geographic regions. Results show that Eurasian strains from temperate regions have longer incubation periods, and Western Hemisphere strains from tropical and temperate regions have longer times to relapse compared with Eastern Hemisphere strains. The diversity in these estimates of key epidemiologic parameters for P. vivax supports the need for elucidating local epidemiology to inform clinical follow-up and to build an evidence base toward global elimination of malaria.

Understanding and managing zoonotic risk in the new livestock industries.

BACKGROUND: In many parts of the world, livestock production is undergoing a process of rapid intensification. The health implications of this development are uncertain. Intensification creates cheaper products, allowing more people to access animal-based foods. However, some practices associated with intensification may contribute to zoonotic disease emergence and spread: for example, the sustained use of antibiotics, concentration of animals in confined units, and long distances and frequent movement of livestock. OBJECTIVES: Here we present the diverse range of ecological, biological, and socioeconomic factors likely to enhance or reduce zoonotic risk, and identify ways in which a comprehensive risk analysis may be conducted by using an interdisciplinary approach. We also offer a conceptual framework to guide systematic research on this problem. DISCUSSION: We recommend that interdisciplinary work on zoonotic risk should take into account the complexity of risk environments, rather than limiting studies to simple linear causal relations between risk drivers and disease emergence and/or spread. In addition, interdisciplinary integration is needed at different levels of analysis, from the study of risk environments to the identification of policy options for risk management. CONCLUSION: Given rapid changes in livestock production systems and their potential health implications at the local and global level, the problem we analyze here is of great importance for environmental health and development. Although we offer a systematic interdisciplinary approach to understand and address these implications, we recognize that further research is needed to clarify methodological and practical questions arising from the integration of the natural and social sciences.

Communicable diseases and governance: a tale of two regions.

Regional policies and programmes on communicable disease prevention and control are becoming an important component of global public health. In a comparative fashion, we examined the situation in the European and Southeast Asian contexts, with a focus on the underlying institutional and political backgrounds underpinning the regionalisation of planning and interventions. Our findings document the emergence of two distinctive models of regional integration. While in Europe there is a process of institutionalisation and centralisation, in Southeast Asia the landscape of regional cooperation is characterised by the proliferation of many provisional projects, based on loose agreements and a decentralised structure that emphasises the initiative and sense of ownership of member countries. These two approaches, we conclude, reflect wider differences of political culture between supranational integration in Europe and intergovernmental agreements in Southeast Asia.

Emerging infectious diseases in southeast Asia: regional challenges to control.

Southeast Asia is a hotspot for emerging infectious diseases, including those with pandemic potential. Emerging infectious diseases have exacted heavy public health and economic tolls. Severe acute respiratory syndrome rapidly decimated the region's tourist industry. Influenza A H5N1 has had a profound effect on the poultry industry. The reasons why southeast Asia is at risk from emerging infectious diseases are complex. The region is home to dynamic systems in which biological, social, ecological, and technological processes interconnect in ways that enable microbes to exploit new ecological niches. These processes include population growth and movement, urbanisation, changes in food production, agriculture and land use, water and sanitation, and the effect of health systems through generation of drug resistance. Southeast Asia is home to about 600 million people residing in countries as diverse as Singapore, a city state with a gross domestic product (GDP) of US$37,500 per head, and Laos, until recently an overwhelmingly rural economy, with a GDP of US$890 per head. The regional challenges in control of emerging infectious diseases are formidable and range from influencing the factors that drive disease emergence, to making surveillance systems fit for purpose, and ensuring that regional governance mechanisms work effectively to improve control interventions.

Using a decision support systems computer simulation model to examine HIV and tuberculosis: the Russian Federation.

The aim of this paper is to describe the development and use of a computer simulation model that can be used as a Decision Support System (DSS) to tackle the critical public health issues of HIV and HIV-related tuberculosis in the Russian Federation. This country has recently witnessed an explosion of HIV infections and a worrying spread of the Multi-Drug Resistant form of Tuberculosis (MDRTB). The conclusions drawn are that a high population coverage with Highly Active Anti-Retroviral Treatment (HAART) (75% or higher), allied with high MDRTB cure rates, reduces cumulative deaths by 60%, with limited impact below this level. This research offers a simulation model that can be applied as a DSS by public health officials to inform policy making. By doing so, ways of controlling the spread of HIV and MDRTB and reduce mortality from these serious public health threats is provided.

High coverage with HAART is required to substantially reduce the number of deaths from tuberculosis: system dynamics simulation.

We used a system dynamics simulation model of the transmission dynamics of drug-sensitive tuberculosis (DSTB), multidrug-resistant tuberculosis (MDRTB) and HIV to estimate the impact of coverage with highly active antiretroviral therapy (HAART) and different cure rates for MDRTB in settings of explosive HIV epidemics and high MDRTB levels. Population coverage levels at 0%, 25%, 50%, 75% and 100% for HAART, and 5% and 80% of MDRTB treatment cure rates were simulated over a 10-year period and cumulative deaths from tuberculosis and HIV-associated tuberculosis were estimated for populations with latent tuberculosis, DSTB, MDRTB, HIV and HIV-associated tuberculosis. Depending on levels of HAART population coverage, increasing MDRTB cure rates from 5% to 80% reduces cumulative tuberculosis deaths by 1% and 13%. High population coverage with HAART (75% or higher), allied with high MDRTB cure rates, reduces cumulative deaths by 60%, with limited impact below this level. High coverage with HAART is required to substantially reduce the number of deaths from tuberculosis.