Tuberculosis Clinical Trial
Official title:
Genome Sequencing of MDR TB in Sputum
Drug resistant tuberculosis is a growing problem world wide. The current methods for diagnosis are time consuming and may delay diagnosis and treatment for many weeks. In this study the investigators wish to take sputum samples from patients to see if the investigators can validate a molecular DNA based process for prompt identification of drug resistant tuberculosis. The investigators wish to extract and amplify DNA from drug resistant tuberculosis and identify genes within it that confer resistance.
Drug resistant M. tuberculosis is an increasing problem in the United Kingdom and abroad. In
the United Kingdom (UK) as a whole the number of isolates that were shown to be resistant to
at least one of the first line drugs was nearly 400, with the total number of isolates
approaching 5000. A total of 9040 cases were reported in the UK in 2009 and of these 6.9%
demonstrated resistance to at least one first line drug(1). In certain populations the
incidence of drug resistance is higher: in London, homeless patients, those who have been in
prison and those from certain countries abroad, particularly Eastern Europe.
The difficulty of drug resistant tuberculosis is that the treatment duration, cost and
complexity is increased. Typically the patient will be on treatment for 18 months or more
and the Health Protection Agency (HPA) has estimated the cost of this as being upto £50000.
Current diagnosis rests on the culture of the M. tuberculosis and drug sensitivity testing.
This can take six or eight weeks, meaning that patients may be on ineffective therapy for
some time, leading to further transmission and deterioration of the patient's clinical
condition. In this study the investigators would hope to develop a new test to improve and
expedite the diagnosis of multi- drug resistant or MDR TB.
The predominant mechanism by which resistance occurs in M. tuberculosis is by the
development and selection of mutants containing single nucleotide polymorphisms (SNP's)(2).
Present commercial assays enable only a common subset (5-10) of the (900+) documented
resistance mutations to be detected (www.tbdreamdb.com). It is highly likely that many more
exist particularly in regions of the genome that may modulate sensitivity or resistance.
This complexity is compounded by the requirement to treat TB with cocktails of antibiotics
even for fully drug sensitive M.tuberculosis for which treatment consists of isoniazid (H),
rifampicin (R), pyrazinamide (Z) and ethambutol (E). Multidrug resistant (MDR) and
extensively drug resistant (XDR) TB cases are treated with second line drugs such as
moxifloxacin, amikacin, capreomycin, para-aminosalicylic acid (PAS), thiocetazone and others
for which genotypic markers of resistance are not tested. Such complex treatment
combinations increase the need to screen multiple gene targets with the imperative to treat
immediately with correct combinations of antibiotics.
The large number of mutations makes exhaustive detection of all known SNP's impossible with
existing diagnostic procedures. Whole genome sequencing offers the potential to interrogate
the genome of clinical isolates of M. tuberculosis for all known mutations and from this to
infer an antimicrobial sensitivity pattern.
The extensive cost of treating and managing MDR cases(3) could potentially be reduced by
obtaining a rapid genomic resistance profile early within the patients treatment. Cost
benefit analysis of immediate whole genome sequencing (WGS) on all TB cases would be highly
beneficial financially as well as clinically. The investigators propose to conduct a limited
pilot study to assess the potential to acquire whole genome sequence directly from sputum
specimens, early in a patient's treatment and to retrospectively define the potential impact
of the availability of this data on patient care. This proposal will thus provide an
evidence base for WGS to be developed into a routine diagnostic test/process with medical
potential both at local National Health Service (NHS) level and globally so as to improve
care pathways for MDR and XDR TB.
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Observational Model: Case-Only, Time Perspective: Prospective
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