Applying new tools to control tuberculosis

In this Tuberculosis Updates 2018 series, experts from various parts of the world review important innovations and developments in a global effort to end the tuberculosis (TB) epidemic. Major gaps remain in reaching, diagnosing and effectively managing TB patients in many parts of the world. Social inequities continue to hamper TB control, especially in resource-limited settings. Universal health coverage and social protection are necessary to remove the barriers to the access to quality TB care. Antimicrobial resistance represents a growing threat to public health and economic growth worldwide. Standardized treatment regimens, while having facilitated large-scale programmatic implementation, could have inadvertently accelerated the development of multidrug-resistant (MDR) TB and extensively drugresistant (XDR) TB through drug-specific resistance amplification. Although the End-TB Strategy advocates universal access to drug susceptibility testing (DST), this is not widely available. The slow growth of Mycobacterium tuberculosis complicates phenotypic DST, and the long turn round time severely limits its clinical utility in guiding the initial choice of drugs. Unlike the regular reporting of minimal inhibitory concentration (MIC) for other bacterial infections, the use of a single critical concentration that inhibits the growth of 99% of phenotypically wild-type strains to classify phenotypical susceptibility or resistance to TB drugs may not bear a direct relationship with either achievable serum drug level or clinical response of a mutant strain. Clinical breakpoint, or MIC at or below which the relevant strain is likely to respond to treatment, may be useful for drugs that can be used at higher doses, such as isoniazid, rifampicin and fluoroquinolones. However, with the intrinsic difficulty in delineating the effect of individual drugs in a combination regimen, suggested values for the clinical breakpoint are given only for moxifloxacin in the recently published technical report from the World Health Organization (WHO). Commercial rapid molecular tests are now available for direct application to clinical specimens to detect mutations associated with resistance to key firstand second-line drugs, such as rifampicin, isoniazid, pyrazinamide, fluoroquinolones and second-line injectables, but their drug target coverage is still too limited to guide the formulation of individualized treatment regimens. Whole-genome sequencing holds promise for revolutionizing the coverage and predictive power of genotypical DST, but cost, throughput, facility requirement, background noises and replicative errors still remain important hurdles preventing its direct application to clinical specimens. The preliminary results of the STREAM Stage 1 Trial showed marginally lower favourable outcome (78.1% vs 80.6%) for the standardized 9–12-month shorter MDRTB regimen as compared to the conventional 18–24-month regimen. The difference could neither demonstrate non-inferiority of the shorter regimen nor superiority of the longer regimen. The trial end-point may not fully reflect the operational advantages of the much shorter regimen. Following an expedited review, the WHO continues to conditionally recommend the shorter regimen for adults and children with pulmonary MDR/rifampicin-resistant (RR) TB who were not previously treated with second-line TB drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely. However, no more than 4–50% of patients in some MDR-TB hotspots, such as Eastern Europe, South East Asia, Pakistan and Brazil, are likely to be eligible for the shorter regimen because of the high prevalence of drug resistance to one or more of the drugs used in the regimen, thus raising concern of its longer-term sustainability. TB drugs used in the longer conventional regimen for MDR-TB have been regrouped into three different categories by the WHO in August 2018. Group A drugs, including levofloxacin/moxifloxacin, bedaquiline and linezolid, are to be prioritized. Group B drugs, including clofazimine and cycloserine/terizidone, are to be added next. Group C drugs (ethambutol, delamanid, pyrazinamide, imipenem-cilastatin, meropenem, amikacin/streptomycin, ethionamide/prothionamide, p-aminosalicylic acid) are included when drugs from Groups A and B cannot be used. Judicious use of repurposed and new drugs is essential to avoid the emergence of resistance to these drugs, which would further set global TB control efforts back, in view of the relatively slow rate of TB drug development. With the reasonably favourable outcomes achievable with an optimized background regimen in both the STREAM Stage 1 Trial and Delamanid Trial 213, there may be a valid question as to whether the relatively toxic drug, linezolid, and the expensive new drug, bedaquiline, with very short and incompletely established safety record, are needed in the treatment of MDR-TB in the absence of fluoroquinolone resistance. Kanamycin and capreomycin are no longer recommended by WHO based on their associated risk of treatment failure and relapse in a recent individual data meta-analysis. However, retrospective observational data on treatment