Abstract
Coordinated effort in the fight against MDR-TB is needed to develop new drugs and better use existing ones http://ow.ly/bsxD306sPsw
The 2016 World Health Organization (WHO) tuberculosis (TB) report, published after the approval of the End TB Strategy, shows that, because of the improved surveillance/survey figures from India, the global 2015 TB incidence and mortality reached 10.4 and 1.4 million, respectively [1–5]. Together with India, China, Nigeria, Pakistan, Indonesia, Pakistan and South Africa contribute most to the global TB burden.
In 2015, 1.2 million individuals were estimated to be TB/HIV co-infected and 580 000 patients were affected by multidrug-resistant (MDR)-TB (half of the global cases being in China, the Russian Federation and India), of whom, ∼125 000 were treated with a success rate <60%. Although about 49 million lives have been saved between 2000 and 2015 as a result of the enormous effort by WHO and its partners, much work is ahead us in the future if the United Nations Sustainable Development and End TB Strategy goals are to be reached.
The present prevalence of resistance to the available anti-TB drugs plays a crucial role in fighting the MDR-TB epidemic. A systematic review and individual patient data meta-analysis by Dick Menzies and colleagues, published in the recent past, demonstrated that cases harbouring Mycobacterium tuberculosis strains with an extensively drug-resistant (XDR)-TB profile (i.e. resistance to isoniazid, rifampicin, any fluoroquinolones, and at least one of the second-line injectable drugs, amikacin, capreomycin and kanamycin) or with resistance patterns beyond XDR achieve a suboptimal treatment success rate (40% and 20%, respectively) [6–8]. Given the difficulty of ensuring, in these severe cases, the minimum number of anti-TB drugs recommended by WHO to design an effective regimen, important discussions are presently taking place on both new and repurposed drugs [9, 10].
The article by Fox et al. [11] in this issue of the European Respiratory Journal (ERJ) highlights the role of the anti-TB drugs belonging to the (so-called) Group 5; at the time, the 2011 MDR-TB guidelines were still in force. In May of this year, in fact, new WHO guidelines were released, which modified the grouping of second-line anti-TB drugs [12, 13].
Fox et al. [11] focuses on the so-called repurposed drugs, such as the antibiotics approved for infections other than TB (e.g. linezolid, carbapenems (imipenem, meropenem and ertapenem), terizidone, thioacetazone, clarithromycin and amoxicillin/clavulanate). They are used “off label” to treat difficult TB cases, although their efficacy/effectiveness and safety are not well known; few clinical trials and observational analytical studies are presently available, and the evidence is often anecdotal or contains methodological biases (e.g. missing random treatment allocation, absence of a comparable control group, etc.). These drugs are frequently administered when the therapeutic options are scarce in cases of complicated drug resistance patterns, and the option of the new drugs bedaquiline and delamanid has been explored.
Recently, the ERJ has published the results of innovative studies on drugs repurposed for MDR-TB (e.g. on linezolid, mefloquine, imipenem, meropenem, ertapenem and co-trimoxazole) [14–25]. Some of these observational studies were important. A group of them provided the first evidence on carbapenems in the literature [19, 20, 24]. Furthermore, the results a systematic review and meta-analysis on the observational studies on linezolid were confirmed by the first clinical trial on linezolid among XDR-TB patients, published in the New England Journal of Medicine [15, 16, 26].
Fox et al. [11] performed an important systematic review and individual patient data meta-analysis on the former Group 5 drugs. For the first time, a methodologically appropriate quantitative assessment has been made available on this heterogeneous group of drugs.
The authors selected 31 studies (9282 patients) including 24 studies in which 2191 patients were prescribed ex-Group 5 drugs. These studies mainly focused on thioacetazone, clofazimine, macrolides and amoxicillin/clavulanic acid. About half of the recruited cohort included MDR-TB patients with resistance to fluoroquinolones and/or second-line injectable agents.
The median exposure to anti-TB drugs was significantly higher than in the control group not exposed to ex-Group 5 drugs. The treatment success was 74%, almost that observed in the control group (73%). In the analysis, cases lost to follow-up were included. When thioacetazone was used, the treatment success rate improved. This finding needs to be evaluated cautiously, as the majority of data were from a single country (Latvia).
According to the study results, outcomes were less good when macrolides, clofazimine and amoxicillin/clavulanic acid were used. As it was published after the acceptance of the article by Fox et al. [11], the results of a promising study on clarithromycin were not considered [27].
Interestingly, as underlined by the authors, the study results showed that clofazimine seems to perform less well than reported elsewhere [28]. The findings of this study are relevant to providing further guidance on MDR-TB treatment. The study is methodologically strong, being based on individual patient data meta-analysis of a large cohort, where confounding background noise was adequately managed (i.e. hierarchical multivariable logistic regression analysis and propensity score base matching were used).
As frequently observed in these studies, when cases are very complicated, repurposed drugs are prescribed, such that the real effect of these drugs can be underestimated. The study by Fox et al. [11] has the merit of having looked comprehensively at the heterogeneous group of repurposed drugs, some of which were not even included in the last WHO treatment classification [12].
New methodological approaches to conducting TB clinical trials (e.g. multiarm multistage design and evaluating several regimens in one clinical trial) [29] and the recent attempt to shorten treatment durations [30, 31] are likely to provide new evidence in the coming future.
A coordinated effort of all stakeholders committed to the fight against MDR-TB is necessary to develop new drugs and to learn how better to use the existing ones. New opportunities are emerging, such as the Cape Town agreement signed in 2001 (where several stakeholders agreed to improve research and development in the TB field [32, 33]) or the recent plan of the United Nations on antimicrobial resistance (focused on a global strategy to mitigate the antimicrobial resistance burden [34]) to impact the MDR-TB epidemic.
Footnotes
Conflict of interest: None declared.
- Received November 18, 2016.
- Accepted November 18, 2016.
- Copyright ©ERS 2017