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In individuals with tuberculosis-infection – until recently referred to as latent tuberculosis infection – the risk of progression to active tuberculosis (reactivation) varies strongly. Among those at increased risk of reactivation are patients with an impaired immune system, e.g. due to immunosuppressive therapy. Therefore, prior to planned immunosuppression, patients are screened for tuberculosis-infection and subsequently treated in case of infection. Current screening methods include the Mantoux test, Interferon-γ release assays (i.e., the QuantiFERON-TB Gold Plus and T-SPOT.TB) and chest X-ray. However, despite screening, cases of reactivation continue to occur – in part due to the lack of a gold standard test for tuberculosis-infection. Therefore, the aims of this thesis were to increase the diagnostic sensitivity for tuberculosis-infection prior to immunosuppression. Using various (novel) methods we showed that approximately two-thirds of all QuantiFERON-TB Gold Plus results just below the manufacturer’s cut-off (in the borderline range) are caused by Mycobacterium tuberculosis-infection, which now warrants preventive treatment in patients with such a result. Furthermore, we quantified the diagnostic accuracy of chest X-ray for tuberculosis-infection and showed that using a novel ultra-low dose CT scanning technique, sensitivity for tuberculosis-infection could be significantly increased by three-fold compared to chest X-ray.

In the thesis entitled “ Tuberculosis in Vietnam: New and renewed insights ” written by Hai Viet Nguyen, data from the second national tuberculosis (TB) prevalence survey in Vietnam conducted in 2017, with additions from the first national TB prevalence and tuberculin surveys conducted in 2007, were analysed to provide answers to several research questions that can affect the strategic planning of TB control efforts. By comparing the results from the two surveys, a substantial decline in TB burden from 2007 to 2017 was observed. However, as it used state-of-art diagnostic tools, many more TB patients were found in the second TB prevalence survey, implying that the current prevalence of TB in Vietnam remains high. When used for community TB screening, GeneXpert MTB/Rif, a WHO-endorsed molecular TB diagnostic tool, and MGIT liquid culture, a widely accepted reference standard for TB diagnosis, have a low diagnostic agreement. There is evidence to suggest there are actual biological factor(s) that render men more vulnerable to TB than women, and subclinical TB patients, who have no prolonged cough and either no TB symptoms or only atypical symptoms while still having radiological and microbiological features suggesting TB, likely transmit Mycobacterium tuberculosis to their household members. The empirical chapters of this thesis highlight the need for effective, comprehensive active case finding interventions to promptly find and treat all missing TB cases, in order to end the TB disease in Vietnam by 2035, and provide clues for improved measurement and control of TB worldwide.

Achieving higher degree of equity in healthcare has been a challenge for countries all over the world. Improving the equity in healthcare service use and financing are important pathways to elevate the health status of the overall population, especially for socially vulnerable groups. In China, the healthcare system has also been undergoing constant reforms. This thesis evaluates the impacts of several policy interventions on the healthcare service use and financial burden of these patients, with a focus on the disadvantaged patient groups such as tuberculosis/drug-resistant tuberculosis patients. Results show that the healthcare service use among the general population has achieved a good level of equity across income groups in some areas. For disadvantaged groups like tuberculosis patients, equity in healthcare service use can also be greatly improved through policy interventions such as improving the reimbursement rate and cash transfer. However, the level of equity in financing of healthcare remained relatively low despite the policy interventions, as indicated by the high out-of-pocket health expenditure and high likelihood of incurring catastrophic health expenditure for socially vulnerable patients. Besides, some disadvantaged groups such as internal migrants have not equally enjoyed the improved benefits from healthcare policy reforms. Based on these findings, policy recommendations are proposed that the health insurance structures and payment approach should be reformed to mitigate the benefit gaps across insurance types. Specialized policies should also be developed that include improving reimbursement and cash transfer to provide additional support for tuberculosis/drug-resistant tuberculosis patients, especially for those who are internal migrants.

Diagnosis of Tuberculosis and its susceptibility to anti-tuberculosis drugs from laboratory perspective was still the weakness for Tuberculosis control in China. The objective of this thesis was to provide scientific evidence on new diagnostic assays in intended laboratory settings and the potential effect of specific drugs for composing MDR-TB treatment regimens from a national perspective. The performance of two smear microscopy technologies for detection of acid-fast bacilli against the Ziehl-Neelson method, the domestic Genechip assay designed for rifampin and isoniazid resistance detection and commercial phenotypic MIC assay compared with reference method were assessed. The resistance prevalence of moxifloxacin and pyrazinamid were explored among national representative MDR-TB samples. Two smear microscopy assays increased 2.6% and 9% positive detection rate, respectively. The performance of Genechip for rifampin (sensitivity: 87.6%, 95% CI 83.0%-92.1%; specificity: 98.0%, 95% CI 97.3%-98.6%) and isoniazid (sensitivity: 80.3%, 95% CI 75.3%-85.4%; specificity: 95.8%, 95%CI 94.8%-96.8%) resistance detection was acceptable compared with phenotypic susceptibility testing with reduced turn-around time. The categorical agreement for the twelve drugs between MIC assay and reference method ranged 88.6%-100%. 40.7% of MDR-TB strains isolated in 2007 showed pyrazinamide resistance. 12.9% and 41.4% MDR-TB strains were resistant to moxifloxacin at 0.5μg/ml in 2007 and 2013, while the prevalence were 3.1% and 23.4% at 2.0μg/ml, respectively. The new technologies should be introduced and scaled-up in China. The high resistance prevalence of two specific drugs indicates the challenge of composing effective regimens containing these drugs.

Tuberculose (tbc) is een infectieziekte die in Nederland nog dagelijks gediagnosticeerd wordt. Driekwart van de Nederlandse tbc-patiënten is in een land geboren waar tbc nog veel voorkomt. Immigranten en asielzoekers die in Nederland komen wonen worden verplicht onderzocht op tbc-ziekte (door middel van een longfoto). Velen van hen zijn echter wel besmet met tbc als zij Nederland binnenkomen, maar ontwikkelen pas tbc als zij al langer in Nederland zijn. De ontwikkeling tot tbc-ziekte kan voorkomen worden door screening en behandeling van deze latente tuberculose infectie (LTBI). Deze thesis presenteert studies die de implementatie van LTBI-screening en behandelingsprogramma bij immigranten (als binnenkomstscreening), asielzoekers (als vervolgscreening), en Eritreeërs (als community-screening) onderzochten. De eerste vijf hoofdstukken van deze thesis laten zien dat een LTBI-screening en behandelprogramma’s in de genoemde doelgroepen haalbaar is, mits met een cultuur sensitieve werkwijze, inclusief goede voorlichting in eigen taal, waarbij de persoonlijke behoeften van de cliënt centraal staan. De kosteneffectiviteit studie laat zien dat LTBI-screening bij alle groepen meer gezondheidswinst oplevert vergeleken met de huidige röntgenscreening, maar alleen kosteneffectief is voor immigranten en asielzoekers uit landen met een tbc-incidentie van meer dan 200 per 100.000 inwoners. Ondanks beperkte kosteneffectiviteit is LTBI-screening en behandeling onder hoog tbc-risico migranten een haalbare interventie om de tbc-incidentie in Nederland te laten dalen en te streven naar de beoogde eliminatie van tbc in de toekomst.

Malaria remains a major public health problem in malaria endemic countries despite a global reduction in the burden of the disease over the last two decades. The malaria control program has been threatened with the emergence and spread of multidrug resistant P. falciparum across the Greater Mekong Subregion (GMS). To achieve the goal of malaria elimination by 2030, mass drug administration with three monthly rounds of 3 day course of dihydroartemisinin-piperaquine plus single dose of primaquine was assessed in the four countries of GMS including Lao PDR. This thesis shows that asymptomatic malaria infections are prevalent in Lao PDR. Mass drug administration with the aim to eliminate P. falciparum was safe, feasible and acceptable by community in the Lao context with a significant reduction of P. falciparum for at least one year follow-up. However, it had a transient impact on P. vivax infections with the rebound in prevalence by month 6. A single low dose of primaquine used in MDA is to clear P. falciparum gametocytes but has no effect on the hypnozoites of P. vivax. MDA to eliminate all malarias should include both schizontocaidal and hypnozoitocidal drugs. A subset study to assess the efficacy of 14 day primaquine following three rounds of MDA in the prevention of recurrent of P. vivax infections showed that the strategy was safe and effective in the prevention of recurrence of asymptomatic P. vivax infections.

Bridging diagnostic gaps may help reduce the global burden of rifampicin-resistant tuberculosis (RR-TB) transmission. Inaccurate diagnoses result in false RR-TB patients receiving toxic and less effective drugs, while false rifampicin-susceptible-TB patients continue to transmit RR-TB in the community which may lead to RR-TB outbreaks. Early detection of RR-TB outbreaks entails rapid and systematic analysis of RR data at the population level. The increasing use of Xpert MTB/RIF as a frontline diagnostic test for all presumptive TB patients provides an opportunity to utilize routinely produced RR-TB data for timely detection of RR-TB clusters. Currently, there is no system in place capable of performing this analysis. The PhD thesis of Kamela Charmaine S. Ng entitled “Utilization of molecular resistance test results as tools to support public health efforts for improved control of RR-TB” has improved the understanding of routine diagnostic data and provided policy implications on addressing diagnostic challenges that affect interruption of RR-TB transmission. Furthermore, this thesis developed an early warning tool which harnessed the full potential of routine Xpert data for improved RR-TB surveillance. This tool utilizes both projected site-specific numbers of RR-TB diagnoses and frequency of Xpert probe(s) which represents circulating RR-TB mutations in the setting. The National TB Control Program is then prompted to investigate further on Xpert site(s) with unusual RR-TB clusters, and tailor active case finding and initiate effective treatment to reduce the transmissibility of TB. This thesis demonstrates as a proof-of-concept, that routine Xpert data contain actionable information that could improve country surveillance of RR-TB.

Tuberculosis (TB) continues to remain a major public health problem globally. WHO’s End TB Strategy has set a goal to end the epidemic with ambitious targets for 2035. About 27% of the global TB cases occur in India which poses a challenge to global TB control. This is mainly because majority of patients in India approach the private sector, which is usually diverse, disorganized, unregulated and often disconnected from the national TB control programme (NTP). The quality of care is not consistent across the private sector and completion of treatment is not ensured. Non-standard treatment leads to the emergence of drug-resistant TB. Public-private collaborations in India have shown promising results in improving the situation. This research analyzed the manner and conditions for private sector engagement to increase the chances of ending TB. For this, India will have to improve and scale up public-private partnerships. This will need heavy investments and adoption of newer and innovative approaches, tools and technology aiming Universal Health Coverage. This research used selected publications and reviewed relevant research in the background of the global approaches for ending TB by 2035. The findings originate from research done mostly in India which is relevant for other developing countries.

Despite being one of the most ancient diseases affecting humans, tuberculosis (TB) remains as one of the 21st century’s the major global health concerns. The World Health Organization estimated that TB caused around 1,6 millions deaths in 2017. Assessing TB associated mortality is relevant because it helps to understand the true magnitude of TB compared to other diseases, and thus, it is critical for planning and prioritization of health interventions and allocating resources. It is also fundamental for assessing progress on TB control efforts, which will contribute to the assessment of the End-TB and SDG indicators. However, there is much uncertainty on the true mortality burden attributable to TB, and different institutions provide different burden estimates for a given country. The central aim of this thesis is to evaluate different strategies and approaches related to TB mortality measurement through different study designs. Most of the data presented in this thesis has been collected in Southern Mozambique, a low-income setting with a high TB and HIV burden.

The thesis presents studies into the effectiveness of specific tuberculosis (TB) control interventions in the Netherlands aimed at early case finding and prevention of TB. The first study showed screening of new immigrants upon entry met the criteria for risk group screening of more than 50 per 100,000 population. Abnormalities in the chest-X-ray without the presence of active TB was a powerful predictor of the development of TB during the following 2 years. In those with a normal chest X-ray , bi-annual follow-up screening met the criteria for risk group screening only for immigrants from countries with an estimated TB incidence of more than 200 per 100,000 population. The second study showed the added value of interferon gamma release assays (IGRA) for the diagnosis of latent TB infection (LTBI). When used to confirm the diagnosis of LTBI after a tuberculin skin reaction of 5 mm or more, IGRA reduced the number needed to treat to prevent a new TB patient with 60%. The third study showed Dutch TB control effectively detects and prevents TB among children. Improving coverage of BCG-vaccination and screening of immigrant children for LTBI will prevent further TB cases. The final studies describe the trends in target groups for screening, and independent risk factors for acceptance, completion and the occurrence of adverse events of preventive treatment on LTBI. Preventive treatment has the largest impact on TB incidence in the two years after LTBI diagnosis among TB contacts and children younger than 5 years.

Willy Ssengooba’s thesis evaluates the consequences of the genetic diversity of Mycobacterium tuberculosis, the causative agent of tuberculosis, for diagnosis of this disease tuberculosis in Africa, often in HIV co-infected patients. It addresses three main sub-themes around M. tuberculosis genetic diversity; laboratory diagnosis, clinical presentation of tuberculosis disease and resistance to anti-tuberculosis drugs. For the first two sub-themes, he looked at how to best use molecular assays in practice given the various disease presentations especially in HIV-positive patients who often have bloodstream infections (mycobacteremia). He further looked at additional attributes of molecular assays and the extent to which genetic diversity of M. tuberculosis may influence the reliability and interpretation of results of molecular assays. Under the drug resistance theme, he evaluated the extent of variations and risk factors of drug-resistant tuberculosis in sub-Saharan Africa in a systematic review and meta-analysis. Furthermore, he determined the diversity of drug resistance-conferring mutations that could be picked up by molecular tests (existing or under development) in a country with a drug-resistant tuberculosis epidemic that is typical for the African region. Lastly he investigated to what extent this diversity is affected by HIV-coinfection given the fitness cost differences between different resistance-conferring mutations.

Tuberculosis remains the leading cause of death among people living with HIV in sub-Saharan Africa and worldwide. The clinical presentation in such patients is often so non-specific that much tuberculosis remains unsuspected, undiagnosed and is therefore untreated prior to death. Anaemia is one of the most common complications of both HIV and tuberculosis, and is associated with substantial morbidity and mortality. Haemoglobin levels may be a useful biomarker in patients with HIV-associated tuberculosis and anaemia may have predictive value that is under-utilized as an important entry point into the tuberculosis diagnostic algorithm. This thesis found that moderate or severe anaemia was highly predictive of both prevalent and incident tuberculosis among ambulatory outpatients as well as hospitalised in-patients in South Africa and was also a very strong independent predictor of mortality. Therefore, in high tuberculosis incidence areas in sub-Saharan Africa, all HIV-infected patients with moderate or severe anaemia should be suspected of having tuberculosis and be microbiologically tested for tuberculosis using rapid diagnostic assays regardless of symptomatology. Because anaemia of chronic disease, a process driven by elevated hepcidin levels, is the most common mechanism underlying anaemia in these patients, the majority can be expected to have resolution of anaemia with antiretroviral therapy and anti-tuberculosis therapy alone. The impact of such screening and treatment strategies on HIV-associated tuberculosis in sub-Saharan is not yet known and must be evaluated in future research.

This thesis considers investments in infectious disease research awarded to UK institutions between 1997 and 2010. It considers awards by pathogen and disease area, and by the type of science along the R&D pipeline (from pre-clinical and basic science, through clinical trials and product development and into operational and implementation research). It also compares level of investment with the global burden of disease, to identify areas of research strength and funding neglect. The chapters include- analyses of the relative expenditure compared to global disability-adjusted life years (DALYs); descriptions of, and discussions on, mycology infectious disease and the limited range of research taking place in that area; descriptions of investments in antimicrobial resistance, one original research paper describing the research spend across several pathogens and disease areas, and a comment piece briefly outlining some personal views about ways forward, particularly from a global and governance perspective; descriptions of healthcare-associated infections research, which showed significant increases in research funding from around the turn of the century; descriptions of respiratory infectious disease and analyses comparing to the global burdens of disease; descriptions of viral hepatology and analyses comparing to the global burden of disease; concept of measuring research investments against published outputs to identify which diseases and types of science are particularly productive; critical reflections on the portfolio of manuscripts, discussions of the limitations of these approaches, and suggestions for future decision-making by policymakers, funders and global health researchers.

The main aim of this thesis was to describe and assess the efficacy of the Patient-Centred Treatment (PCT) strategy for the delivery and supervision of tuberculosis (TB) treatment as implemented by the National Tuberculosis and Leprosy programme of Tanzania. The studies presented in this thesis show that the PCT strategy is acceptable and effective in TB control in Tanzania. The evidence of the effectiveness of the PCT strategy in a programmatic setting can be of value for areas outside the context of TB (other chronic diseases) and other developing-countries.

The overall objective of this thesis is to assess how guideline implementation and evaluation contribute to health care decision-making and to assess what critical factors contribute to successful or unsuccessful implementation of TB control guidelines through case studies mainly conducted in Mozambique. We specifically evaluate two components of the guideline development process: implementation and evaluation of guidelines. The central research questions of this thesis are: 1. How can assessment of guideline implementation and its evaluation contribute to health care decision-making? Guidelines support health care decision-making at both patient and health care service delivery level. To do so effectively, health care workers and decision-makers should use guidelines and monitor their outcomes. If this occurs either not or incompletely, the decision-making process lacks crucial information. This could lead to poor or no decision-making. In this thesis we evaluate outcomes described in guidelines with the aim to inform health care decision-making. 2. Which factors are critical for failure or success in guideline implementation? Improved health care is one of the objectives of guidelines, however, implementation of these is often challenging. If the desired outcomes of guidelines are not achieved, assessment of the reasons for this need exploration. It seems logical to evaluate guideline implementation or the guideline itself, though this does not happen systematically. In this thesis we assess various aspects of guideline implementation to identify factors that contribute to failure and success of the implementation.

Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide with an estimated 9.0 million people who developed TB in 2013, of whom around one-third remained undiagnosed. The release of global guidance on new TB diagnostics has accelerated since 2007, but there remains a gap in local implementation. This thesis investigated the extent of this gap and generated evidence to support implementation of the most recently recommended test for TB and drug-resistant TB, the Xpert MTB/RIF assay. This thesis showed that by 2009 only half of high-burden TB and multidrug-resistant TB countries had started introduction of new TB diagnostic methods and were aware of recent global guidelines. Also, there was substantial lack of published scientific evidence to support the translation of global TB diagnostic policies into local practice. More operational research was needed to provide evidence on scale-up of new TB diagnostics for both local and global policy-makers. Field studies presented in this thesis found that the introduction of the Xpert MTB/RIF assay was feasible and effective in Indonesia and Kazakhstan, as well as cost-effective in India, South Africa and Uganda. Xpert MTB/RIF helped to start more drug-resistant TB patients on appropriate treatment and initiate treatment earlier than conventional methods. However, under- and over-treatment after diagnosis can undermine the impact of any new test on patient-important outcomes. Future studies should take into account operational aspects that reflect the mismatch between diagnosis and treatment, including patient drop-out rates, diagnostic delays, clinical decision-making processes and rates of empirical treatment.

This thesis reports findings of six studies including two tuberculosis (TB) drug resistance surveys, a comparative study of HIV infection rates among patients enrolled in the survey and those under routine TB/HIV surveillance, two TB molecular epidemiological analyses and a systematic review and meta-analysis of drug-resistant TB in sub-Saharan Africa. It provides a general introduction to anti-tuberculosis drug resistance in the world and associated risk factors. Results from the drug resistance surveys presented show low levels of anti-TB drug resistance (DR) rates considering WHO estimates. Findings from these studies also indicated that anti-TB DR and HIV infection are not associated. From these studies we show consistently lower levels of TB/HIV co-infection among survey participants compared to what is reported under routine TB/HIV surveillance by the National TB/Leprosy Program. Through the molecular epidemiological studies, we confirm and document the predominant MTC lineages in Uganda and the negative association of the predominant lineage with TB DR. We explored anti-TB DR rates in relation to HIV infection elsewhere in sub-Saharan Africa through a systematic review. This analysis showed that pooled estimates of anti-TB DR including MDR-TB in this region are almost half of the global WHO estimates and that MDR-TB is not associated with HIV, despite TB/HIV co-infection rates being highest in this region. Finally, we discuss findings of the studies in general and policy implications to technically recommend to the national TB programs feasible interventions for prevention and control of DR-TB in this region.

Contains fulltext : 124089.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 03 februari 2014 Promotores : Soolingen, D. van, Cobelens, F.G.J. Co-promotores : Tiemersma, E.W., Nguyen, L. Thi Ngoc

In this thesis, we look at the clinical and immunological impact of Mycobacterium tuberculosis (MTB) on HIV-1 infection and disease. We show that, unlike other HIV related opportunistic infections, successful treatment of MTB disease may in some patients be associated with some degree of decrease in HIV-1 load. However this is partial, and not sustained, and does not halt the progress of HIV disease. In fact, active MTB disease is often associated with unrelenting progression of HIV to AIDS thereafter, with death often following within a couple of years without the intervention of highly active antiretroviral treatment (HAART).

This thesis outlines studies that were conducted between 2006 and 2010 in Rwandan clinical and public health settings to respond to some unresolved research priority questions. It describes and analyses sputum completion and conversion rates at two months of treatment and their determinants. It explores determinants of adherence to tuberculosis (TB) treatment, TB mortality and the independent effect of adherence on mortality. It reports and analyses HIV test-uptake before and after the introduction of provider-initiated HIV testing and counselling (PITC), as well as the acceptability of PITC and its barriers towards linkage to HIV care. It also reports patient attrition after HIV diagnosis and analyses factors associated with this. Lastly, it explores the prevalence and determinants of discordant treatment responses in a Rwandan cohort of HIV patients who started combined antiretroviral therapy (cART).

Tran Ngoc Buu vat een aantal onderzoeken samen die recente trends in de epidemiologie van tuberculose (tbc) in Vietnam trachten te verklaren. Ondanks goede bestrijding neemt het aantal patiënten in dat land niet af; er is een stijging onder jongvolwassenen. Dat is volgens Ngoc Buu voor een deel te verklaren door de opkomende hiv-epidemie. Daarnaast lijkt er een rol weggelegd voor het Beijing-genotype, het belangrijkste subtype van de tuberkelbacil Mycobacterium tuberculosis in Zuidoost-Azië en de voormalige Sovjet-Unie. Dit Beijing-genotype komt vaker voor onder jonge patiënten. Ngoc Buu toont dat patiënten met tbc door het Beijing-genotype minder goed reageren op de standaard tbc-behandeling die wereldwijd wordt gegeven. Ook lijkt resistentie tegen streptomycine, een van de oudere tbc-middelen, invloed te hebben op de mate waarin het Beijing-genotype wordt verspreid.