- Email: [email protected]
Tuberculosis eradication versus control
Accepted Manuscript Title: Tuberculosis Eradication versus Control Author: Marco Schito Debra Hanna Alimuddin Zumla PII: DOI: Reference:
S1201-9712(16)31224-3 http://dx.doi.org/doi:10.1016/j.ijid.2016.11.007 IJID 2770
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
5-10-2016 7-11-2016 10-11-2016
Please cite this article as: Schito M, Hanna D, Zumla A, Tuberculosis Eradication versus Control, International Journal of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.ijid.2016.11.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Highlights TB is the number one cause of death worldwide from an infectious disease
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TB control maybe within reach for some countries but not eradication
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Achieving the goal of eradication set by the END TB Strategy is unrealistic
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Impact on global incidence trends require significant funding/political support
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More funder and government commitment is required to alter the current
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Title:
Tuberculosis Eradication versus Control
Authors: Marco Schitoa, Debra Hannaa, Alimuddin Zumlab
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Critical Path Institute, 1730 E. River Rd, Tucson, AZ, USA
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Division of Infection and Immunity, University College London, and NIHR Biomedical
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Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
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Marco Schito
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Scientific Director
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Rapid Drug Susceptibility Testing
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Critical Path to TB Drug Regimens
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Critical Path Institute
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1730 E. River Rd,
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Tucson, AZ 85718
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520-547-3449
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Email: [email protected]
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Corresponding author:
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ABSTRACT
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According to the World Health Organization (WHO), 10.4 million people succumbed to
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tuberculosis (TB) in 2015 and is now the number one cause of death world-wide from a
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preventable infectious disease. Bold vision is needed from global leaders and plans
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have been proposed to end the TB epidemic. However enthusiasm must be matched
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by tangible and achievable goals based on the science and available funding. In order
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to reach the target and goals set by the WHO’s End-TB Strategy, the challenges for TB
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eradication need to be addressed. In order to achieve the targets several areas need to
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be bolstered including the requirement to better identify and treat existing drug
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susceptible and diagnose all the drug resistant forms of the disease. Although
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treatment is available for most TB patients, stock outs and other delays are problematic
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in some settings resulting in ongoing transmission especially for the drug resistant forms
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of the disease. Despite the fact that a majority of multi-drug resistant cases are linked
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to treatment, the cure rate is only 50% which highlights the need for safer, shorter and
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more efficacious drug regimens that are more tolerable to patients. Prospects for a
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more efficacious vaccine are limited with no correlates of protection identified making
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the availability of a vaccine by 2025 highly improbable. Support for instituting infection
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control methods should be prioritized to subvert transmission while patients seek
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treatment and care. Finally, more adequate financial mechanisms should be instituted
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to reduce patient expenditures and support national TB programs. Moreover, funding to
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support basic science, drug development, clinical trial, vaccine, diagnostic and
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implementation research needs to be secured in order to reduce global TB incidence in
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the future.
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Keywords: tuberculosis, End-TB Strategy, vaccination, chemotherapy, drug resistance,
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drug susceptibility testing, diagnostics
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INTRODUCTION On May 19, 2014, the 67th World Health Assembly adopted the World Health Organization’s (WHO) “Global strategy and targets for tuberculosis prevention, care and
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control after 2015”1. The post-2015 global tuberculosis (TB) plan, known as the End-TB
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Strategy2, was formed and developed through consultation with a wide range of
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stakeholders. The strategy sets ambitious goals for the post-2015 agenda. A 90%
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reduction in TB-related mortality, an 80% decline in TB incidence, and the abolition of
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catastrophic expenditures for TB-affected people by 2030 are targeted by this strategy.
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Strong government commitment and adequate financing from all countries together with
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community engagement and appropriate investments in research are necessary in
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order to reach these targets3. The strategy has a vision of making the world free of
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tuberculosis, with zero deaths, disease, and suffering due to the disease. An admirable
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strategy but how realistic is it?
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Mycobacterium tuberculosis (Mtb) can cause a spectrum of clinical manifestations, from latent asymptomatic infection, asymptomatic sub-clinical disease to
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full spectrum of symptomatic clinical disease affecting any organ of the body. Thus the
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true burden of TB remains difficult to quantify. Although there are several commercially
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approved culture and molecular-based diagnostic tests to identify active TB, the tools
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used programmatically in high burden countries still rely on the century old method of
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smear microscopy and in-house culture which is known to miss many cases due to poor
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accuracy and need for specialized culture facilities.
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For latent Mtb infection (LTBI), the accuracy of these assays at predicting TB disease during the lifetime of the individual or identifying previous exposure4,5 remains
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to be seen. Exposure would include those that are colonized as well as those
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individuals who were able to inhibit the establishment of infection. Diagnosis and
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treatment of LTBI is a tool for global TB control, especially in close contacts. However,
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accurate data on this under operational field conditions is scarce from high TB burden
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countries and the benefits of LTBI management remain to be determined. Primary
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healthcare clinics in Sao Paulo reported high proportions of contacts without evaluation,
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incomplete assessment, incorrect records of contraindication for LTBI treatment, lack of
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notes regarding the identification and evaluation of contacts6. This highlights the need
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for on the ground improvement in infrastructure and organization for routine contact
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investigation. The need is global in scope and includes improved coordination
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of TB screening in Europe as well in order to implement the goals outlined by the
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End TB Strategy7.
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In 1998, Dowdle proposed a definition of ‘control’ as a reduction in the incidence,
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prevalence, morbidity or mortality of an infectious disease to a locally acceptable level;
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‘elimination’ as reduction to zero of the incidence of disease or infection in a defined
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geographical area; and ‘eradication’ as permanent reduction to zero of the worldwide
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incidence of infection8. Inherent in these definitions of control and elimination is the
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requirement of continued interventions to prevent re-emergence and re-establishment of
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transmission. It is this need for continued surveillance and intervention after reaching
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control or elimination targets that is essential to sustain disease control. However, most
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countries typically cut budgets in response to declining disease incidence and
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prevalence rates. Neglect or complete cessation of intervention activities can lead to re-
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emergence of the disease in vulnerable populations.
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ERADICATION In theory, if adequate funding, appropriate tools and political commitment were available, all infectious diseases including TB would be eradicable. The important
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indicators of eradicability include the availability of effective interventions including
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practical, affordable and implementable diagnostics, prevention tools, treatment and
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adequate funding8. To date, only smallpox9 and rinderpest10 have been successfully
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eradicated. Both diseases had these tools available coupled with serious political
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commitment to effectively interrupt transmission and reduce prevalence to zero.
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Currently, six ongoing programs (Poliomyelitis, Yaws, Dracunculiasis, Malaria,
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Hookworm and Yellow fever) are in progress. In addition, the International Task Force
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for Disease Eradication at the Carter Center have identified Neonatal tetanus, Leprosy,
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Onchocerciasis, Trachoma and Lymphatic filariasis as additional potential candidates
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for elimination.
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There are three major pre-conditions that make it scientifically more feasible to
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eradicate a disease: 1) epidemiologic vulnerability, 2) effective interventions and 3)
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feasibility of elimination. For TB, the disease is not vulnerable to eradiation because: a)
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it is easily transmitted, b) transmission occurs throughout the year and is not linked to a
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cyclical disease cycle (e.g. like influenza), c) there is no natural immunity to prevent
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reinfection, d) it is not easily diagnosed (current estimates from the WHO suggest nearly
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1/3 of all TB cases are not detected), e) disease relapse is documented in a proportion
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of patients who complete treatment, and f) there is a LTBI reservoir which can re-
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activate at any time in an individual’s lifetime. In addition, TB elimination has never
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been document from any country in the world indicating the likelihood for achieving
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global TB eradication is low.
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PREVENTION TOOLS
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In regards to effective preventive interventions, a safe and effective Mtb vaccine has not been available despite intense research efforts over the past two decades. The
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current BCG vaccine in use today does not prevent infection but may reduce mortality in
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young recipients. BCG has been implemented for nearly a century and despite
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widespread use, TB continues to be a major global problem. A vaccine to prevent Mtb
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infection or disease remains an important tool for elimination but the development of
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such a vaccine is considerably hindered by the complex biology of Mtb and lack of basic
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information on protective immune responses11. There currently is no correlate of
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protection identified for a vaccine, no prospects of what protective host responses the
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vaccine should mount, or what response magnitudes are needed. Furthermore,
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immune responses may need to be elicited at mucosal surfaces to control or prevent
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Mtb infection since the site of infection is the lung. Surprisingly little attention has been
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given to the understanding of Mtb mucosal immune responses in the lung. In the
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absence of this critical information there is no easy path forward and thus one cannot
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put a timeline on developing an effective preventative TB vaccine. Even if a correlate of
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protection is identified and a promising vaccine construct is identified, it will take an
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additional 10 years to complete the required clinical trials. Therefore, as of 2017, it is
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impossible to expect a vaccine by 2025 (Figure 1).
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CHEMOTHERAPY A single tool (such as a vaccine) can impact incidence and prevalence over time but cannot eliminate TB. Disease elimination will require a well-coordinated and long-
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term funded effort. Drugs can help and is another tool in the global health toolkit but as
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we have observed over the past half century since effective TB drugs and treatment
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regimens have been available, it requires a massive coordination and resources to
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scale up to reach a critical level of penetration, with backup for tackling development of
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resistance. A new diagnostic, such as the MTB/RIF GeneXpert assay is important for
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early detection and reducing duration of infectiousness, but by itself it has not been
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shown to affect treatment outcomes12. The lack of adequate funding to develop new
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tools, and for scaling up and implementing existing tools, coupled with the lack of any
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prospect of a preventative vaccine within the next decade, makes it likely that the End
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TB strategy regarding global elimination will not materialize. .
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Current standard TB drug therapy can be effective and affordable but is not well tolerated, toxic and the treatment duration is too long. Moreover, the issue of drug
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resistance has been steadily increasing requiring longer, more toxic, painful treatments
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that are more expensive, steeped in stigma, and requires additional clinical monitoring
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which are not affordable or available to most multi-drug resistant (MDR) TB patients.
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Recent reports of new TB patients with diabetes mellitus at increased risk of drug
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resistant TB disease suggest that new synergies between infectious and non-infectious
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diseases may be important to monitor13,14.
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After many years of financially constrained research, bedaquiline and delamanid
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were recently approved by stringent regulatory authorities to treat MDR-TB in 2012 and
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2014, respectively. As of 2016, no official drug susceptibility test (DST) method has
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been approved to monitor the eventual development of resistance to these new drugs
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despite their availability and use over the past several years to treat patients at a
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programmatic level. Bedaquiline and delamanid may save lives for difficult to treat
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infections but it remains to be determined whether they will have any impact on the
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global epidemiology of TB for which shorter and more effective regimens for both drug-
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susceptible disease and LTBI are necessary3. The development of more potent and
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better-tolerated drug regimens, optimization of drug exposure for the component drugs,
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optimal management of TB in special populations, identification of accurate biomarkers
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of treatment effect, and the assessment of new strategies for implementing regimens in
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the field remain key priority areas for research and are being addressed by the Critical
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Path to TB Drug Regimens (www.cptrinititive.org) along with stakeholder partners.
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Nanotechnology drug delivery systems have considerable potential for the treatment of
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TB. The novel properties of nanotechnology enable the improvement of the
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bioavailability of drugs, can reduce the dosage and frequency of administration, and
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may solve the problem of non-adherence to prescribed therapy, which is a major
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obstacle to the control of TB15.
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DIAGNOSTICS AND DRUG RESISTANCE Many patients do not have access to laboratory facilities that can determine TB-
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DST beyond first-line drugs. New diagnostic tools are particularly needed in order to
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improve the diagnosis of disease and latent infection, the rapid detection of drug-
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resistance, and for use across special (HIV and pediatric) populations. Several new
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diagnostic devices or methods have been endorsed by the WHO since 2007 and many
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others are under investigation. Despite the WHO endorsement of diagnostic tools, the
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reality in the field is that many have not rolled-out or sufficiently scaled-up. As a result
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many TB patients are assessed by sputum smear microscopy and started on treatment
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empirically. Targeted sequencing is being optimized directly from sputum (in the
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absence of culture) to identify mutations within days16 and a global data sharing
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platform (https://platform.reseqtb.org) was recently launched to address the
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bioinformatics need for predicting drug resistance using sequencing technologies17.
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This approach may be potentially useful together with routine diagnostic tests in order to
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quickly build up individualized therapeutic regimens in severe cases of MDR-TB and
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extensively drug-resistant TB (XDR-TB)3 as well as inform surveillance programs.
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Although sequencing is not immediately implementable in all health care settings,
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resources must be developed to support the bioinformatic sequencing needs as the
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technology, cost, turnaround times and clinical outcomes improve.
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Current and future control of MDR-TB significantly relies on the correct and
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optimal use of new diagnostics and new drugs, together with the consistent application
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of the following five core interventions at the programmatic level. First is the need to
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prevent the development of MDR-TB thorough high quality treatment of drug-
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susceptible TB. However, recent modeling suggests that the vast majority of MDR-TB
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is spread through transmission rather than by programmatic mismanagement18
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highlighting the need to bolster infection control efforts. Second, is the need to expand
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rapid testing and detection of drug-resistant TB. This requires significant funding,
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infrastructure and support. Third, provide immediate access to effective treatment and
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proper care. From the 2015 Global WHO TB report, a major success is the fact that
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>90% of MDR-TB patients that are identified are linked to care and put on treatment.
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However, more work needs to address the need to have shorter, safer and more
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effective regimens. Fourth, prevent transmission through infection control which is an
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ongoing need in most settings19-21. Fifth, an increase in political commitment and
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financing (programmatic and research) reportedly in excess of 4 billion dollars22 is
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desperately needed to address the now number one global infectious disease killer.
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Despite more than 1.8 million people succumbing to TB in 2015, funding for TB
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programs through the US Global Health Program account totaled $191 million for 2017,
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a $45 million decrease (19%) below the FY16 level23.
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CONCLUSIONS
Whilst some countries may be able to shift resources to achieve the goal of
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control (defined as <10 TB cases per 100,000), many confounding issues including but
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not limited to increased migration, war, refugee crises, poverty, comorbidities, NTM,
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animal TB and malnutrition together with the identified funding gap thwarts the goal of a
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reducing TB prevalence. This will become apparent as new disease estimates using
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molecular methods begin to trickle in and the size of the MDR-TB population is better
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characterized on a global scale revealing a larger problem than current estimates
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provide. It is essential to increase resources to bolster the support to address the
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issues that have been neglected. For too long the response of the Global Fund and
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other donor agencies for TB investments has been unbalanced resulting in TB
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languishing second rate to HIV and Malaria.
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Until many of these scientific and funding challenges are addressed, the
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likelihood of achieving goals beyond controlling TB is bleak. Even if it was scientifically
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feasible to eradicate TB, there are operational and health systems issues that must be
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considered, such as perceived burden of the disease, expected cost of eradication,
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synergy of eradication efforts with other interventions, and the necessity for eradication
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rather than control8. In addition, since the poorest and socially excluded groups carry
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the largest burden of disease, it essential to properly address the social determinants of
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health through poverty reduction measures and target interventions in high-risk
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populations24 including millions that are displaced. The spread of MDR-TB requires
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special attention and highlights the need to bolster research on new TB drugs, vaccines
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and diagnostics. There is a need to differentiate the development of new technologies
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including the endorsement, adoption, and scale up, from the training, implementation
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and health systems challenges on a global scale. Although significant progress has
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being made in the fight against TB over the last twenty-five years, significant challenges
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remain and much more political and funder investments are still needed to achieve
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global elimination.
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Funding: This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
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Conflict of interest statement: No competing interest declared.
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References:
267 2681. WHO. Documentation for World Health Assembly 67. Published Mar. 2014.
http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_11-en.pdf (accessed Aug 19, 2016).
ip t
269
2702. WHO. The End TB Strategy. Global strategy and targets for tuberculosis prevention,
care and control after 2015. http://www.who.int/tb/strategy/End_TB_Strategy.pdf?ua=1
272
(accessed Aug.24, 2016)
us
cr
271
2733. Raviglione M, Sulis G. Tuberculosis 2015: Burden, Challenges and Strategy for Control
and Elimination. Infect Dis Rep. 2016; 8(2): 6570.
an
274
2754. Ndzi EN, Nkenfou CN, Gwom LC, Fainguem N, Fokam J, Pefura Y. The pros and cons
of the QuantiFERON test for the diagnosis of tuberculosis, prediction of disease
277
progression, and treatment monitoring. Int J Mycobacteriol. 2016; 5(2): 177-84.
M
276
ed
2785. Lamberti M, Uccello R, Monaco MG, Muoio M, Feola D, Sannolo N, et al. Tuberculin
skin test and Quantiferon test agreement and influencing factors in tuberculosis
280
screening of healthcare workers: a systematic review and meta-analysis. J Occup Med
281
Toxicol. 2015; 10:2.
Ac ce
pt
279
2826. Wysocki AD, Villa TC, Arakawa T, Brunello ME, Vendramini SH, Monroe AA, et al. 283
Latent Tuberculosis Infection Diagnostic and Treatment Cascade among Contacts in
284
Primary Health Care in a City of Sao Paulo State, Brazil: Cross-Sectional Study. PLoS
285
One. 2016; 11(6): e0155348.
2867. Dara M, Solovic I, Sotgiu G, D'Ambrosio L, Centis R, Tran R, et al. Tuberculosis care 287
among refugees arriving in Europe: a ERS/WHO Europe Region survey of current
288
practices. Eur Respir J. 2016: 48(3): 808-17
14
Page 14 of 19
2898. Dowdle WR. The principles of disease elimination and eradication. Bull World Health 290
Organ 1998; 76 Suppl 2: 23-5.
2919. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID, et al. Smallpox and its
Eradication, WHO, Geneva, 1988
ip t
292
29310. Moutou F. The second eradication: rinderpest. Bull Soc Pathol Exot. 2014; 107(3): 135-
6, 137-8.
cr
294
us
29511. Moliva JI, Turner J, Torrelles JB. Prospects in Mycobacterium bovis Bacille Calmette et
Guérin (BCG) vaccine diversity and delivery: why does BCG fail to protect against
297
tuberculosis? Vaccine. 2015; 33(39): 5035-41.
an
296
29812. Churchyard GJ, Stevens WS, Mametja LD, McCarthy KM, Chihota V, Nicol MP,et al.
Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis:
300
a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF. Lancet
301
Glob Health. 2015; 3(8): e450-7
ed
M
299
30213. Baghaei P, Tabarsi P, Javanmard P, Farnia P, Marjani M, Moniri A, et al. Impact of
diabetes mellitus on tuberculosis drug resistance in new cases of tuberculosis. J Glob
304
Antimicrob Resist. 2016; 4: 1-4.
Ac ce
pt
303
30514. Bates M, Marais BJ, Zumla A. Tuberculosis Comorbidity with Communicable and 306
Noncommunicable Diseases. Cold Spring Harb Perspect Med. 2015; 5(11). pii:
307
a017889.
30815. da Silva PB, de Freitas ES, Bernegossi J, Gonçalez ML, Sato MR, Leite CQ, et al. 309
Nanotechnology-Based Drug Delivery Systems for Treatment of Tuberculosis-A
310
Review. J Biomed Nanotechnol. 2016;12(2): 241-60.
15
Page 15 of 19
31116. Colman RE, Anderson J, Lemmer D, Lehmkuhl E, Georghiou SB, Heaton H, et al.
Rapid Drug Susceptibility Testing of Drug-Resistant Mycobacterium tuberculosis
313
Isolates Directly from Clinical Samples by Use of Amplicon Sequencing: a Proof-of-
314
Concept Study. J Clin Microbiol. 2016; 54(8): 2058-67.
ip t
312
31517. Starks AM, Avilés E, Cirillo DM, Denkinger CM, Dolinger DL, Emerson C, et al.
Collaborative Effort for a Centralized Worldwide Tuberculosis Relational Sequencing
317
Data Platform. Clin Infect Dis. 2015; 61Suppl 3: S141-6.
us
cr
316
31818. Kendall EA, Fofana MO, Dowdy DW. Burden of transmitted multidrug resistance in
epidemics of tuberculosis: a transmission modelling analysis. Lancet Respir Med. 2015;
320
3(12): 963-72.
an
319
M
32119. Godfrey C, Tauscher G, Hunsberger S, Austin M, Scott L, Schouten JT, et al. A survey
of tuberculosis infection control practices at the NIH/NIAID/DAIDS-supported clinical
323
trial sites in low and middle income countries. BMC Infect Dis. 2016; 16:269.
ed
322
32420. von Delft A, Dramowski A, Sifumba Z, Mosidi T, Xun Ting T, von Delft D, et al. Exposed,
but Not Protected: More Is Needed to Prevent Drug-Resistant Tuberculosis in
326
Healthcare Workers and Students. Clin Infect Dis. 2016; 62 Suppl 3: S275-80.
Ac ce
pt
325
32721. Verkuijl S, Middelkoop K. Protecting Our Front-liners: Occupational Tuberculosis 328
Prevention Through Infection Control Strategies. Clin Infect Dis. 2016; 62 Suppl 3:
329
S231-7.
33022. WHO. Global Tuberculosis Report 2016. WHO/HTM/TB/2016.13. 33123. Kaiser Family Foundation analysis of data from the President’s FY2017 Budget 332
Request, and the “Consolidated Appropriations Act, 2016” (P.L. 114-113) and
333
accompanying explanatory reports. http://kff.org/global-health-policy/issue-brief/the-u-s-
16
Page 16 of 19
334
global-health-budget-analysis-of-the-fiscal-year-2017-budget-request/ (accessed August
335
19, 2016).
33624. Matteelli A, Centis R, D'Ambrosio L, Sotgiu G, Tadolini M, Pontali E, et al. WHO
strategies for the programmatic management of drug-resistant tuberculosis. Expert Rev
338
Respir Med. 2016; 22: 1-12.
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Our reference: IJID 2770 Article reference: IJID_IJID-D-16-00798
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Article title: Tuberculosis Eradication versus Control To be published in: International Journal of Infectious Diseases
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Figure caption:
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Figure 1. Projected decline in global TB incidence based on the deployment and optimization of new emerging tools and challenges associated in their successful introduction. Reproduced and modified with permission by the World Health Organization.
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Dr. Marco Schito Rapid Drug Susceptibility Testing Critical Path Institute Critical Path to TB Drug Regimens 1730 E. River Rd Tucson, AZ 85718 United States Phone: +1520-547-3449 Fax: +1520-547-3456 E-mail: [email protected]
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Contact details:
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S1201-9712(16)31224-3 http://dx.doi.org/doi:10.1016/j.ijid.2016.11.007 IJID 2770
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
5-10-2016 7-11-2016 10-11-2016
Please cite this article as: Schito M, Hanna D, Zumla A, Tuberculosis Eradication versus Control, International Journal of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.ijid.2016.11.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Highlights TB is the number one cause of death worldwide from an infectious disease
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TB control maybe within reach for some countries but not eradication
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Achieving the goal of eradication set by the END TB Strategy is unrealistic
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Impact on global incidence trends require significant funding/political support
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More funder and government commitment is required to alter the current
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Title:
Tuberculosis Eradication versus Control
Authors: Marco Schitoa, Debra Hannaa, Alimuddin Zumlab
11 a
Critical Path Institute, 1730 E. River Rd, Tucson, AZ, USA
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Division of Infection and Immunity, University College London, and NIHR Biomedical
14
Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
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Marco Schito
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Scientific Director
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Rapid Drug Susceptibility Testing
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Critical Path to TB Drug Regimens
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Critical Path Institute
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1730 E. River Rd,
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Tucson, AZ 85718
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520-547-3449
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Email: [email protected]
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Corresponding author:
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ABSTRACT
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According to the World Health Organization (WHO), 10.4 million people succumbed to
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tuberculosis (TB) in 2015 and is now the number one cause of death world-wide from a
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preventable infectious disease. Bold vision is needed from global leaders and plans
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have been proposed to end the TB epidemic. However enthusiasm must be matched
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by tangible and achievable goals based on the science and available funding. In order
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to reach the target and goals set by the WHO’s End-TB Strategy, the challenges for TB
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eradication need to be addressed. In order to achieve the targets several areas need to
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be bolstered including the requirement to better identify and treat existing drug
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susceptible and diagnose all the drug resistant forms of the disease. Although
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treatment is available for most TB patients, stock outs and other delays are problematic
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in some settings resulting in ongoing transmission especially for the drug resistant forms
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of the disease. Despite the fact that a majority of multi-drug resistant cases are linked
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to treatment, the cure rate is only 50% which highlights the need for safer, shorter and
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more efficacious drug regimens that are more tolerable to patients. Prospects for a
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more efficacious vaccine are limited with no correlates of protection identified making
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the availability of a vaccine by 2025 highly improbable. Support for instituting infection
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control methods should be prioritized to subvert transmission while patients seek
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treatment and care. Finally, more adequate financial mechanisms should be instituted
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to reduce patient expenditures and support national TB programs. Moreover, funding to
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support basic science, drug development, clinical trial, vaccine, diagnostic and
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implementation research needs to be secured in order to reduce global TB incidence in
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the future.
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Keywords: tuberculosis, End-TB Strategy, vaccination, chemotherapy, drug resistance,
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drug susceptibility testing, diagnostics
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INTRODUCTION On May 19, 2014, the 67th World Health Assembly adopted the World Health Organization’s (WHO) “Global strategy and targets for tuberculosis prevention, care and
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control after 2015”1. The post-2015 global tuberculosis (TB) plan, known as the End-TB
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Strategy2, was formed and developed through consultation with a wide range of
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stakeholders. The strategy sets ambitious goals for the post-2015 agenda. A 90%
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reduction in TB-related mortality, an 80% decline in TB incidence, and the abolition of
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catastrophic expenditures for TB-affected people by 2030 are targeted by this strategy.
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Strong government commitment and adequate financing from all countries together with
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community engagement and appropriate investments in research are necessary in
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order to reach these targets3. The strategy has a vision of making the world free of
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tuberculosis, with zero deaths, disease, and suffering due to the disease. An admirable
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strategy but how realistic is it?
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Mycobacterium tuberculosis (Mtb) can cause a spectrum of clinical manifestations, from latent asymptomatic infection, asymptomatic sub-clinical disease to
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full spectrum of symptomatic clinical disease affecting any organ of the body. Thus the
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true burden of TB remains difficult to quantify. Although there are several commercially
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approved culture and molecular-based diagnostic tests to identify active TB, the tools
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used programmatically in high burden countries still rely on the century old method of
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smear microscopy and in-house culture which is known to miss many cases due to poor
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accuracy and need for specialized culture facilities.
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For latent Mtb infection (LTBI), the accuracy of these assays at predicting TB disease during the lifetime of the individual or identifying previous exposure4,5 remains
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to be seen. Exposure would include those that are colonized as well as those
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individuals who were able to inhibit the establishment of infection. Diagnosis and
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treatment of LTBI is a tool for global TB control, especially in close contacts. However,
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accurate data on this under operational field conditions is scarce from high TB burden
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countries and the benefits of LTBI management remain to be determined. Primary
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healthcare clinics in Sao Paulo reported high proportions of contacts without evaluation,
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incomplete assessment, incorrect records of contraindication for LTBI treatment, lack of
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notes regarding the identification and evaluation of contacts6. This highlights the need
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for on the ground improvement in infrastructure and organization for routine contact
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investigation. The need is global in scope and includes improved coordination
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of TB screening in Europe as well in order to implement the goals outlined by the
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End TB Strategy7.
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In 1998, Dowdle proposed a definition of ‘control’ as a reduction in the incidence,
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prevalence, morbidity or mortality of an infectious disease to a locally acceptable level;
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‘elimination’ as reduction to zero of the incidence of disease or infection in a defined
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geographical area; and ‘eradication’ as permanent reduction to zero of the worldwide
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incidence of infection8. Inherent in these definitions of control and elimination is the
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requirement of continued interventions to prevent re-emergence and re-establishment of
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transmission. It is this need for continued surveillance and intervention after reaching
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control or elimination targets that is essential to sustain disease control. However, most
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countries typically cut budgets in response to declining disease incidence and
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prevalence rates. Neglect or complete cessation of intervention activities can lead to re-
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emergence of the disease in vulnerable populations.
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ERADICATION In theory, if adequate funding, appropriate tools and political commitment were available, all infectious diseases including TB would be eradicable. The important
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indicators of eradicability include the availability of effective interventions including
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practical, affordable and implementable diagnostics, prevention tools, treatment and
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adequate funding8. To date, only smallpox9 and rinderpest10 have been successfully
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eradicated. Both diseases had these tools available coupled with serious political
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commitment to effectively interrupt transmission and reduce prevalence to zero.
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Currently, six ongoing programs (Poliomyelitis, Yaws, Dracunculiasis, Malaria,
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Hookworm and Yellow fever) are in progress. In addition, the International Task Force
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for Disease Eradication at the Carter Center have identified Neonatal tetanus, Leprosy,
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Onchocerciasis, Trachoma and Lymphatic filariasis as additional potential candidates
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for elimination.
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There are three major pre-conditions that make it scientifically more feasible to
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eradicate a disease: 1) epidemiologic vulnerability, 2) effective interventions and 3)
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feasibility of elimination. For TB, the disease is not vulnerable to eradiation because: a)
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it is easily transmitted, b) transmission occurs throughout the year and is not linked to a
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cyclical disease cycle (e.g. like influenza), c) there is no natural immunity to prevent
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reinfection, d) it is not easily diagnosed (current estimates from the WHO suggest nearly
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1/3 of all TB cases are not detected), e) disease relapse is documented in a proportion
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of patients who complete treatment, and f) there is a LTBI reservoir which can re-
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activate at any time in an individual’s lifetime. In addition, TB elimination has never
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been document from any country in the world indicating the likelihood for achieving
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global TB eradication is low.
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PREVENTION TOOLS
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In regards to effective preventive interventions, a safe and effective Mtb vaccine has not been available despite intense research efforts over the past two decades. The
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current BCG vaccine in use today does not prevent infection but may reduce mortality in
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young recipients. BCG has been implemented for nearly a century and despite
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widespread use, TB continues to be a major global problem. A vaccine to prevent Mtb
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infection or disease remains an important tool for elimination but the development of
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such a vaccine is considerably hindered by the complex biology of Mtb and lack of basic
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information on protective immune responses11. There currently is no correlate of
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protection identified for a vaccine, no prospects of what protective host responses the
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vaccine should mount, or what response magnitudes are needed. Furthermore,
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immune responses may need to be elicited at mucosal surfaces to control or prevent
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Mtb infection since the site of infection is the lung. Surprisingly little attention has been
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given to the understanding of Mtb mucosal immune responses in the lung. In the
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absence of this critical information there is no easy path forward and thus one cannot
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put a timeline on developing an effective preventative TB vaccine. Even if a correlate of
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protection is identified and a promising vaccine construct is identified, it will take an
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additional 10 years to complete the required clinical trials. Therefore, as of 2017, it is
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impossible to expect a vaccine by 2025 (Figure 1).
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CHEMOTHERAPY A single tool (such as a vaccine) can impact incidence and prevalence over time but cannot eliminate TB. Disease elimination will require a well-coordinated and long-
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term funded effort. Drugs can help and is another tool in the global health toolkit but as
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we have observed over the past half century since effective TB drugs and treatment
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regimens have been available, it requires a massive coordination and resources to
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scale up to reach a critical level of penetration, with backup for tackling development of
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resistance. A new diagnostic, such as the MTB/RIF GeneXpert assay is important for
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early detection and reducing duration of infectiousness, but by itself it has not been
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shown to affect treatment outcomes12. The lack of adequate funding to develop new
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tools, and for scaling up and implementing existing tools, coupled with the lack of any
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prospect of a preventative vaccine within the next decade, makes it likely that the End
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TB strategy regarding global elimination will not materialize. .
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Current standard TB drug therapy can be effective and affordable but is not well tolerated, toxic and the treatment duration is too long. Moreover, the issue of drug
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resistance has been steadily increasing requiring longer, more toxic, painful treatments
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that are more expensive, steeped in stigma, and requires additional clinical monitoring
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which are not affordable or available to most multi-drug resistant (MDR) TB patients.
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Recent reports of new TB patients with diabetes mellitus at increased risk of drug
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resistant TB disease suggest that new synergies between infectious and non-infectious
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diseases may be important to monitor13,14.
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After many years of financially constrained research, bedaquiline and delamanid
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were recently approved by stringent regulatory authorities to treat MDR-TB in 2012 and
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2014, respectively. As of 2016, no official drug susceptibility test (DST) method has
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been approved to monitor the eventual development of resistance to these new drugs
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despite their availability and use over the past several years to treat patients at a
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programmatic level. Bedaquiline and delamanid may save lives for difficult to treat
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infections but it remains to be determined whether they will have any impact on the
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global epidemiology of TB for which shorter and more effective regimens for both drug-
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susceptible disease and LTBI are necessary3. The development of more potent and
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better-tolerated drug regimens, optimization of drug exposure for the component drugs,
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optimal management of TB in special populations, identification of accurate biomarkers
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of treatment effect, and the assessment of new strategies for implementing regimens in
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the field remain key priority areas for research and are being addressed by the Critical
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Path to TB Drug Regimens (www.cptrinititive.org) along with stakeholder partners.
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Nanotechnology drug delivery systems have considerable potential for the treatment of
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TB. The novel properties of nanotechnology enable the improvement of the
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bioavailability of drugs, can reduce the dosage and frequency of administration, and
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may solve the problem of non-adherence to prescribed therapy, which is a major
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obstacle to the control of TB15.
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DIAGNOSTICS AND DRUG RESISTANCE Many patients do not have access to laboratory facilities that can determine TB-
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DST beyond first-line drugs. New diagnostic tools are particularly needed in order to
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improve the diagnosis of disease and latent infection, the rapid detection of drug-
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resistance, and for use across special (HIV and pediatric) populations. Several new
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diagnostic devices or methods have been endorsed by the WHO since 2007 and many
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others are under investigation. Despite the WHO endorsement of diagnostic tools, the
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reality in the field is that many have not rolled-out or sufficiently scaled-up. As a result
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many TB patients are assessed by sputum smear microscopy and started on treatment
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empirically. Targeted sequencing is being optimized directly from sputum (in the
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absence of culture) to identify mutations within days16 and a global data sharing
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platform (https://platform.reseqtb.org) was recently launched to address the
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bioinformatics need for predicting drug resistance using sequencing technologies17.
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This approach may be potentially useful together with routine diagnostic tests in order to
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quickly build up individualized therapeutic regimens in severe cases of MDR-TB and
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extensively drug-resistant TB (XDR-TB)3 as well as inform surveillance programs.
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Although sequencing is not immediately implementable in all health care settings,
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resources must be developed to support the bioinformatic sequencing needs as the
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technology, cost, turnaround times and clinical outcomes improve.
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Current and future control of MDR-TB significantly relies on the correct and
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optimal use of new diagnostics and new drugs, together with the consistent application
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of the following five core interventions at the programmatic level. First is the need to
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prevent the development of MDR-TB thorough high quality treatment of drug-
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susceptible TB. However, recent modeling suggests that the vast majority of MDR-TB
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is spread through transmission rather than by programmatic mismanagement18
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highlighting the need to bolster infection control efforts. Second, is the need to expand
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rapid testing and detection of drug-resistant TB. This requires significant funding,
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infrastructure and support. Third, provide immediate access to effective treatment and
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proper care. From the 2015 Global WHO TB report, a major success is the fact that
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>90% of MDR-TB patients that are identified are linked to care and put on treatment.
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However, more work needs to address the need to have shorter, safer and more
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effective regimens. Fourth, prevent transmission through infection control which is an
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ongoing need in most settings19-21. Fifth, an increase in political commitment and
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financing (programmatic and research) reportedly in excess of 4 billion dollars22 is
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desperately needed to address the now number one global infectious disease killer.
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Despite more than 1.8 million people succumbing to TB in 2015, funding for TB
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programs through the US Global Health Program account totaled $191 million for 2017,
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a $45 million decrease (19%) below the FY16 level23.
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CONCLUSIONS
Whilst some countries may be able to shift resources to achieve the goal of
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control (defined as <10 TB cases per 100,000), many confounding issues including but
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not limited to increased migration, war, refugee crises, poverty, comorbidities, NTM,
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animal TB and malnutrition together with the identified funding gap thwarts the goal of a
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reducing TB prevalence. This will become apparent as new disease estimates using
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molecular methods begin to trickle in and the size of the MDR-TB population is better
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characterized on a global scale revealing a larger problem than current estimates
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provide. It is essential to increase resources to bolster the support to address the
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issues that have been neglected. For too long the response of the Global Fund and
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other donor agencies for TB investments has been unbalanced resulting in TB
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languishing second rate to HIV and Malaria.
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Until many of these scientific and funding challenges are addressed, the
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likelihood of achieving goals beyond controlling TB is bleak. Even if it was scientifically
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feasible to eradicate TB, there are operational and health systems issues that must be
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considered, such as perceived burden of the disease, expected cost of eradication,
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synergy of eradication efforts with other interventions, and the necessity for eradication
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rather than control8. In addition, since the poorest and socially excluded groups carry
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the largest burden of disease, it essential to properly address the social determinants of
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health through poverty reduction measures and target interventions in high-risk
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populations24 including millions that are displaced. The spread of MDR-TB requires
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special attention and highlights the need to bolster research on new TB drugs, vaccines
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and diagnostics. There is a need to differentiate the development of new technologies
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including the endorsement, adoption, and scale up, from the training, implementation
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and health systems challenges on a global scale. Although significant progress has
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being made in the fight against TB over the last twenty-five years, significant challenges
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remain and much more political and funder investments are still needed to achieve
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global elimination.
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Funding: This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
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Conflict of interest statement: No competing interest declared.
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References:
267 2681. WHO. Documentation for World Health Assembly 67. Published Mar. 2014.
http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_11-en.pdf (accessed Aug 19, 2016).
ip t
269
2702. WHO. The End TB Strategy. Global strategy and targets for tuberculosis prevention,
care and control after 2015. http://www.who.int/tb/strategy/End_TB_Strategy.pdf?ua=1
272
(accessed Aug.24, 2016)
us
cr
271
2733. Raviglione M, Sulis G. Tuberculosis 2015: Burden, Challenges and Strategy for Control
and Elimination. Infect Dis Rep. 2016; 8(2): 6570.
an
274
2754. Ndzi EN, Nkenfou CN, Gwom LC, Fainguem N, Fokam J, Pefura Y. The pros and cons
of the QuantiFERON test for the diagnosis of tuberculosis, prediction of disease
277
progression, and treatment monitoring. Int J Mycobacteriol. 2016; 5(2): 177-84.
M
276
ed
2785. Lamberti M, Uccello R, Monaco MG, Muoio M, Feola D, Sannolo N, et al. Tuberculin
skin test and Quantiferon test agreement and influencing factors in tuberculosis
280
screening of healthcare workers: a systematic review and meta-analysis. J Occup Med
281
Toxicol. 2015; 10:2.
Ac ce
pt
279
2826. Wysocki AD, Villa TC, Arakawa T, Brunello ME, Vendramini SH, Monroe AA, et al. 283
Latent Tuberculosis Infection Diagnostic and Treatment Cascade among Contacts in
284
Primary Health Care in a City of Sao Paulo State, Brazil: Cross-Sectional Study. PLoS
285
One. 2016; 11(6): e0155348.
2867. Dara M, Solovic I, Sotgiu G, D'Ambrosio L, Centis R, Tran R, et al. Tuberculosis care 287
among refugees arriving in Europe: a ERS/WHO Europe Region survey of current
288
practices. Eur Respir J. 2016: 48(3): 808-17
14
Page 14 of 19
2898. Dowdle WR. The principles of disease elimination and eradication. Bull World Health 290
Organ 1998; 76 Suppl 2: 23-5.
2919. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID, et al. Smallpox and its
Eradication, WHO, Geneva, 1988
ip t
292
29310. Moutou F. The second eradication: rinderpest. Bull Soc Pathol Exot. 2014; 107(3): 135-
6, 137-8.
cr
294
us
29511. Moliva JI, Turner J, Torrelles JB. Prospects in Mycobacterium bovis Bacille Calmette et
Guérin (BCG) vaccine diversity and delivery: why does BCG fail to protect against
297
tuberculosis? Vaccine. 2015; 33(39): 5035-41.
an
296
29812. Churchyard GJ, Stevens WS, Mametja LD, McCarthy KM, Chihota V, Nicol MP,et al.
Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis:
300
a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF. Lancet
301
Glob Health. 2015; 3(8): e450-7
ed
M
299
30213. Baghaei P, Tabarsi P, Javanmard P, Farnia P, Marjani M, Moniri A, et al. Impact of
diabetes mellitus on tuberculosis drug resistance in new cases of tuberculosis. J Glob
304
Antimicrob Resist. 2016; 4: 1-4.
Ac ce
pt
303
30514. Bates M, Marais BJ, Zumla A. Tuberculosis Comorbidity with Communicable and 306
Noncommunicable Diseases. Cold Spring Harb Perspect Med. 2015; 5(11). pii:
307
a017889.
30815. da Silva PB, de Freitas ES, Bernegossi J, Gonçalez ML, Sato MR, Leite CQ, et al. 309
Nanotechnology-Based Drug Delivery Systems for Treatment of Tuberculosis-A
310
Review. J Biomed Nanotechnol. 2016;12(2): 241-60.
15
Page 15 of 19
31116. Colman RE, Anderson J, Lemmer D, Lehmkuhl E, Georghiou SB, Heaton H, et al.
Rapid Drug Susceptibility Testing of Drug-Resistant Mycobacterium tuberculosis
313
Isolates Directly from Clinical Samples by Use of Amplicon Sequencing: a Proof-of-
314
Concept Study. J Clin Microbiol. 2016; 54(8): 2058-67.
ip t
312
31517. Starks AM, Avilés E, Cirillo DM, Denkinger CM, Dolinger DL, Emerson C, et al.
Collaborative Effort for a Centralized Worldwide Tuberculosis Relational Sequencing
317
Data Platform. Clin Infect Dis. 2015; 61Suppl 3: S141-6.
us
cr
316
31818. Kendall EA, Fofana MO, Dowdy DW. Burden of transmitted multidrug resistance in
epidemics of tuberculosis: a transmission modelling analysis. Lancet Respir Med. 2015;
320
3(12): 963-72.
an
319
M
32119. Godfrey C, Tauscher G, Hunsberger S, Austin M, Scott L, Schouten JT, et al. A survey
of tuberculosis infection control practices at the NIH/NIAID/DAIDS-supported clinical
323
trial sites in low and middle income countries. BMC Infect Dis. 2016; 16:269.
ed
322
32420. von Delft A, Dramowski A, Sifumba Z, Mosidi T, Xun Ting T, von Delft D, et al. Exposed,
but Not Protected: More Is Needed to Prevent Drug-Resistant Tuberculosis in
326
Healthcare Workers and Students. Clin Infect Dis. 2016; 62 Suppl 3: S275-80.
Ac ce
pt
325
32721. Verkuijl S, Middelkoop K. Protecting Our Front-liners: Occupational Tuberculosis 328
Prevention Through Infection Control Strategies. Clin Infect Dis. 2016; 62 Suppl 3:
329
S231-7.
33022. WHO. Global Tuberculosis Report 2016. WHO/HTM/TB/2016.13. 33123. Kaiser Family Foundation analysis of data from the President’s FY2017 Budget 332
Request, and the “Consolidated Appropriations Act, 2016” (P.L. 114-113) and
333
accompanying explanatory reports. http://kff.org/global-health-policy/issue-brief/the-u-s-
16
Page 16 of 19
334
global-health-budget-analysis-of-the-fiscal-year-2017-budget-request/ (accessed August
335
19, 2016).
33624. Matteelli A, Centis R, D'Ambrosio L, Sotgiu G, Tadolini M, Pontali E, et al. WHO
strategies for the programmatic management of drug-resistant tuberculosis. Expert Rev
338
Respir Med. 2016; 22: 1-12.
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Our reference: IJID 2770 Article reference: IJID_IJID-D-16-00798
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Article title: Tuberculosis Eradication versus Control To be published in: International Journal of Infectious Diseases
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Figure caption:
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Figure 1. Projected decline in global TB incidence based on the deployment and optimization of new emerging tools and challenges associated in their successful introduction. Reproduced and modified with permission by the World Health Organization.
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Dr. Marco Schito Rapid Drug Susceptibility Testing Critical Path Institute Critical Path to TB Drug Regimens 1730 E. River Rd Tucson, AZ 85718 United States Phone: +1520-547-3449 Fax: +1520-547-3456 E-mail: [email protected]
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Contact details:
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