Surveillance of resistance to anti-TB drugs remains a cornerstone of any effective TB control programme worldwide. With the availability of new technologies and new drugs, and the prospect of new regimens for the treatment of TB and MDR-TB, surveillance of drug resistance is evolving and adapting to continue being a critical tool to inform public health actions to fight TB
by Matteo Zignol
and Mario Raviglione
Global Tuberculosis Programme
World Health Organization
Global Surveillance of Resistance to Anti-Tuberculosis Drugs
“Surveillance” is the systematic ongoing collection, collation and analysis of data for public health purposes and their timely dissemination for assessment and response as necessary (from the International Health Regulations, 2005, adopted by the 58th World Health Assembly).
The basis for global surveillance of drug resistance in tuberculosis (TB) was set during internal discussions within the World Health Organization (WHO) in 1993. A global project on anti-TB drug resistance surveillance was initiated in 1994 with the aim of collecting and evaluating data on drug resistance in TB in a systematic way around the world. Surveillance is needed to measure the frequency of drug resistance as an indicator of the effectiveness of prevention and control activities; to accurately forecast the need for drugs and plan accordingly; to design standardized regimens for the treatment of drug-resistant TB; to assess epidemiological trends; and to identify local outbreaks of drug-resistant TB for a timely response.
Within the standardized methodological framework designed by WHO, two main mechanisms of surveillance are used to collect data on drug resistance that are representative of a geographically-defined population allowing comparison across and within settings over time: surveillance based on routine drug susceptibility testing of all TB patients and periodic surveys of sampled TB patients.
A network of 33 WHO Supranational TB Reference Laboratories covering all six WHO regions supports global surveillance of drug resistance in TB.
Since 1994, therefore, data on drug resistance have been systematically collected and analysed from 144 countries worldwide (74% of 194 WHO Member States). Half of them (72 countries) have established continuous surveillance systems based on routine diagnostic drug susceptibility testing (DST) of all TB patients. The remaining 72 countries rely on ad-hoc epidemiological surveys of representative samples of patients. All countries with high burden of TB and/or multidrug-resistant (MDR*) TB (a total of 36 countries) have either established a continuous surveillance system or conducted at least one survey over the past two decades to monitor drug resistance.
* defined as a form of tuberculosis that is resistant to at least isoniazid and rifampicin
Continuous surveillance for MDR-TB, based on routine DST of TB patients and systematic collection, collation and analysis of data, is the most effective approach to monitor trends in drug resistance over time. The number of countries that can rely on data generated by continuous surveillance systems is increasing, due to efforts invested in scaling up the availability of culture and DST services. Among the 36 countries classified by WHO as suffering from a high TB and/or MDR-TB burden, 10 have put in place high quality surveillance systems to monitor drug resistance. All these countries are in Eastern Europe and Central Asia where the burden of MDR among TB cases is the highest world-wide.
Ad-hoc surveys still represent the most common approach to investigating the burden of drug resistance in resource-limited settings where routine DST is not accessible to all TB patients due to lack of laboratory capacity or resources. Of the 36 countries with high TB and/or MDR-TB burden, 26 have generated drug resistance data through special surveys. Half of them (13 countries) have conducted surveys in the most recent years between 2010 and 2013.
Central and Francophone Africa remain the regions of the world where drug resistance surveillance data are the scarcest, largely as a result of the current weak laboratory infrastructure.
Globally, 3.5% (95% CI: 2.2–4.7%) of new TB cases and 20.5% (95% CI: 13.6–27.5%) of previously treated cases are estimated to have MDR-TB. These estimates are essentially unchanged compared with recent years. The highest proportions of MDR-TB are found in countries of Eastern Europe and Central Asia where in some settings up to 50% of all TB cases have MDR-TB.
Globally in 2013, an estimated 480 000 (range: 350 000‒610 000) new cases of MDR-TB emerged worldwide and 210 000 (range: 130 000‒290 000) died from MDR-TB.
Extensively drug-resistant (XDR**) TB had been reported by 100 countries globally by the end of 2013. A total of 80 countries and territories reported representative data from continuous surveillance or ad-hoc surveys regarding the proportion of MDR-TB cases that had XDR-TB. Combining their data, the average proportion of MDR-TB cases with XDR-TB was 9.6% (95% CI: 8.1%–11%). The proportion of MDR-TB cases with resistance to fluoroquinolones was 17.0% (95% CI: 12.0–22.0). A total of 29.8% (24.3%–35.3%) of patients with MDR-TB have resistance to a fluoroquinolone, a second-line injectable agent, or both. These patients would likely be eligible to receive bedaquiline and/or delamanid, the new bactericidal drugs recently approved for use in patients with MDR-TB.
** defined as a form of tuberculosis which is resistant to at least four of the core anti-TB drugs. XDR-TB involves resistance to the two most powerful anti-TB drugs, isoniazid and rifampicin, also known as multidrug-resistance (MDR-TB), in addition to resistance to any of the fluoroquinolones (such as ofloxacin or moxifloxacin) and to at least one of three injectable second-line drugs (amikacin, capreomycin or kanamycin)
Surveillance of drug resistance is gradually expanding from the main first-line anti-TB drugs, rifampicin and isoniazid, to cover novel and repurposed drugs. For example, fluoroquinolones and pyrazinamide are now considered key drugs for future new regimens for the treatment of TB and MDR-TB. In this context, understanding the background prevalence of resistance to fluoroquinolones and pyrazinamide at the population level is critical to assessing the feasibility of the introduction of new drugs and shorter regimens. A new project to measure levels of resistance to fluoroquinolones and pyrazinamide among TB patients is being implemented in 7 countries (Azerbaijan, Belarus, Bangladesh, Pakistan, Philippines, South Africa and Ukraine). Correlation between phenotypic testing and genetic mutations, and levels of cross-resistance between fluoroquinolones are also being assessed. Results of this project will inform laboratory practices for surveillance and diagnosis of drug resistance and provide guidance to the development of diagnostic algorithms and to the introduction of new treatment regimens.
Molecular technologies are being increasingly incorporated into drug resistance surveys to simplify logistics. GenoType® MTBDRplus (Hain Lifescience, Germany) was used in the national survey completed in 2012 in Nigeria and is currently being used in the national survey in Sudan. In Pakistan, Xpert® MTB/RIF (Cepheid, USA) identified additional cases missed by culture in the national survey completed in 2014. In ongoing surveys in Papua New Guinea and Senegal, Xpert MTB/RIF is being used to screen specimens for rifampicin resistance and identify those requiring further testing at national or supranational TB reference laboratories. This approach greatly reduces the workload for laboratories and decreases the cost of national surveys.
In addition, high-throughput sequencing technologies are now increasingly being used for surveillance purposes. In a few years these technologies will likely completely revolutionize the way in which surveillance of drug resistance in TB is currently conducted.
Surveillance of resistance to anti-TB drugs remains a cornerstone of any effective TB control programme worldwide. With the availability of new technologies and new drugs, and the prospect of new regimens for the treatment of TB and MDR-TB, surveillance of drug resistance is evolving and adapting to continue being a critical tool to inform public health actions to fight TB.