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Drug-resistant tuberculosis
Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute (Pty) Ltd, University of Cape Town and Groote Schuur Hospital, South Africa
Corresponding author: G L Calligaro (greg.calligaro@uct.ac.za)
The epidemic of drug-resistant tuberculosis (DR-TB) is a public health emergency that threatens to destabilise global TB control. Although TB incidence and mortality are decreasing in several parts of the world, the overall prevalence of multidrug-resistant tuberculosis (MDR-TB) is increasing in many high-burden countries, particularly in Africa.1 World Health Organization (WHO) statistics show that almost half a million new cases of MDR-TB develop every year,2 of which approximately 40 000 (in more than 80 countries) are thought to be extensively drug-resistant tuberculosis (XDR-TB) (Fig. 1). Limited laboratory capacity and lack of widespread drug susceptibility in resource-poor settings mean that only a fraction of that number are correctly diagnosed and started on treatment.2 This reservoir of undiagnosed and/or untreated DR-TB is largely responsible for driving ongoing person-to-person transmission. Treatment defaulters, delays in initiating treatment, inadequate bed capacity, and poor infection control in healthcare facilities are also important contributors. In South Africa, where high transmission rates and HIV co-infection have combined to produce one of the highest incidence rates of TB in the world, the statistics are equally alarming. South Africa has the fifth highest burden of DR-TB globally, with an incidence of ~2% of new patients and ~7% of retreatment cases;3 of these, 5 - 10% have XDR-TB.4 Definitions for DR-TB are shown in Table 1.
Fig. 1. Countries that had notified an XDR-TB case by the end of 2011. 3
Outcomes, challenges and cost of DR-TB treatment
Appropriately identifying and dealing with the threat of DR-TB is critical. Firstly, DR-TB has poorer treatment outcomes when compared with drug-sensitive TB. Of the estimated half a million MDR-TB patients started globally on treatment in 2009, only 48% were treated successfully.2 Outcomes for XDR-TB are even worse; although the overall success rate for XDR-TB in a recent meta-analysis was reported as 44%, a retrospective study from South Africa showed that fewer than 20% of patients with XDR-TB culture converted within 6 months of initiation of treatment, and that this poor outcome was independent of HIV status.5 Secondly, DR-TB involves a longer duration of treatment with less potent but more toxic medications (groups 2 - 5 in Table 2), and higher relapse rates occur.6 Lastly, DR-TB treatment is considerably more expensive than standard TB treatment. Despite only comprising 2.2% of the case burden of TB in South Africa, DR-TB consumes a third of the total estimated national TB budget for the country.7
Diagnosis of DR-TB
The laboratory diagnosis of DR-TB has traditionally relied on the demonstration of Mycobacterium tuberculosis growth in the presence of specific antituberculous drugs – so-called conventional drug-susceptibility testing (DST). A major disadvantage of this method is the long delay (usually several weeks) in obtaining DST results. During this interval, patients may be treated with ineffectual regimens that encourage the development of further drug resistance and allow the disease to spread. Rapid growth- and microscopy-based DST, such as the microscopy-observed drug susceptibility (MODS) method and thin-layer agar (TLA) technique, has shortened the delay to less than 2 weeks, but is limited by the need for laboratory infrastructure and intensive labour.8
New nucleic acid amplification tests (NAATs) promise to reduce the interval between sample acquisition and the DST result from weeks to hours. They provide rapid DST results at the time of TB diagnosis, potentially increasing the number of cases that are diagnosed with DR-TB and started immediately on the correct treatment, and impacting on transmission rates.9 Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is an automated, cartridge-based polymerase chain reaction (PCR) assay that can be performed in decentralised locations, outside of reference laboratories and potentially at a point-of-care by staff with minimal laboratory training. It can deliver simultaneous diagnosis of TB and rifampicin resistance in less than 2 hours. The sensitivity and specificity of the assay for the detection of rifampicin resistance in sputum are 94.1% and 97.0%, respectively.10 It has been strongly endorsed by the WHO as the first investigation in all patients with suspected DR-TB and/or co-infection with HIV.11 Another NAAT, the MTBDRplus assay (Hain Lifesciences, Nehren, Germany), offers similar advantages as Xpert MTB/RIF for MDR-TB detection.12 , 13 Unlike Xpert MTB/RIF, however, it requires formal laboratory infrastructure, but has the advantage of testing for both rifampicin and isoniazid resistance. More recently, the MTBDRsl (second-line) assay was introduced, which tests for drug resistance to second-line injectable drugs, the fluoroquinolones and ethambutol,14 for use on smear-positive or culture-positive specimens.15
Treatment of DR-TB: Novel drugs and adjuvant surgical management
The principles of MDR-TB and XDR-TB treatment are shown in Table 3. Considering the poor treatment outcomes discussed above, the currently available drugs and regimens are clearly inadequate. A number of novel drugs are undergoing clinical testing, but are unlikely to be available for several years yet.16 Bedaquiline, the first novel antituberculous drug to emerge in almost half a century,17 has been cautiously approved by the WHO for patients in whom a regimen containing 4 effective second-line drugs cannot be constructed, or for patients with MDR-TB and documented resistance to a fluoroquinolone (pre-XDR-TB).18 Linezolid added to the regimen of patients failing standard XDR-TB treatment has been shown to improve culture conversion, but longer-term outcomes are unknown, and cost and toxicity are major concerns.19 Neither bedaquiline nor linezolid is currently available as part of the National Treatment Programme in South Africa.
Patients with localised disease and adequate pulmonary reserve
who have either persistently positive sputum smears and/or
cultures despite an adequate trial of appropriate chemotherapy,
or those who have relapsed or are thought to be at high risk of
relapse, should be considered for surgical resection at
specialised centres.
Conclusion
DR-TB has a high mortality, requires complex, lengthy and expensive treatment regimens, and poses a serious threat to TB control in South Africa. NAATs represent important advances in the diagnosis of DR-TB. However, current treatment regimens are far from satisfactory, and more effective, safer, less toxic and cheaper regimens are urgently required.
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