Wayne van Gemert

Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007-2010

OBJECTIVE To present a global update of drug-resistant tuberculosis (TB) and explore trends in 1994-2010. METHODS Data on drug resistance among new and previously treated TB patients, as reported by countries to the World Health Organization, were analysed. Such data are collected through surveys of a representative sample of TB patients or surveillance systems based on routine drug susceptibility testing. Associations between multidrug-resistant TB (MDR-TB) and human immunodeficiency virus (HIV) infection and sex were explored through logistic regression. FINDINGS In 2007-2010, 80 countries and 8 territories reported surveillance data. MDR-TB among new and previously treated cases was highest in the Russian Federation (Murmansk oblast, 28.9%) and the Republic of Moldova (65.1%), respectively. In three former Soviet Union countries and South Africa, more than 10% of the cases of MDR-TB were extensively drug-resistant. Globally, in 1994 to 2010 multidrug resistance was observed in 3.4% (95% confidence interval, CI: 1.9-5.0) of all new TB cases and in 19.8% (95% CI: 14.4-25.1) of previously treated TB cases. No overall associations between MDR-TB and HIV infection (odds ratio, OR: 1.4; 95% CI: 0.7-3.0) or sex (OR: 1.1; 95% CI: 0.8-1.4) were found. Between 1994 and 2010, MDR-TB rates in the general population increased in Botswana, Peru, the Republic of Korea and declined in Estonia, Latvia and the United States of America. CONCLUSION The highest global rates of MDR-TB ever reported were documented in 2009 and 2010. Trends in MDR-TB are still unclear in most settings. Better surveillance or survey data are required, especially from Africa and India.

Rapid molecular TB diagnosis: evidence, policy making and global implementation of Xpert MTB/RIF

If tuberculosis (TB) is to be eliminated as a global health problem in the foreseeable future, improved detection of patients, earlier diagnosis and timely identification of rifampicin resistance will be critical. New diagnostics released in recent years have improved this perspective but they require investments in laboratory infrastructure, biosafety and staff specialisation beyond the means of many resource-constrained settings where most patients live. Xpert MTB/RIF, a new assay employing automated nucleic acid amplification to detect Mycobacterium tuberculosis, as well as mutations that confer rifampicin resistance, holds the promise to largely overcome these operational challenges. In this article we position Xpert MTB/RIF in today’s TB diagnostic landscape and describe its additional potential as an adjunct to surveillance and surveys, taking into account considerations of pricing and ethics. In what could serve as a model for the future formulation of new policy on diagnostics, we trace the unique process by which the World Health Organization consulted international expertise and systematically assessed published evidence and freshly emerging experience from the field ahead of its endorsement of the Xpert MTB/RIF technology in 2010, summarise subsequent research findings and guidance on who to test and how, and provide perspectives on scaling up the new technology.

Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk

Resistance to anti-tuberculosis (TB) medicines is a major public health threat in most countries of the former Soviet Union. As no representative and quality-assured information on the magnitude of this problem existed in Belarus, a survey was conducted in the capital city of Minsk. Between November 2009 and December 2010, 156 consecutively diagnosed new and 68 previously treated culture-positive TB patients residing in Minsk were enrolled in the survey. Mycobacterium tuberculosis isolates were obtained from each patient and tested for susceptibility to first- and second-line anti-TB drugs. Multidrug-resistant (MDR)-TB was found in 35.3% (95% CI 27.7–42.8) of new patients and 76.5% (95% CI 66.1–86.8) of those previously treated. Overall, nearly one in two patients enrolled had MDR-TB. Extensively drug-resistant TB was reported in 15 of the 107 MDR-TB patients (14.0%, 95% CI 7.3–20.7). Patients <35 yrs of age have shown a two times higher odds ratio of multidrug-resistant TB than those aged >35 yrs. The findings of this survey in Minsk city are alarming and represent the highest proportions of MDR-TB ever recorded in the world. This study greatly contributes to the understanding of the burden of drug-resistant TB in urban areas of Belarus.

Multidrug-resistant tuberculosis in Belarus: the size of the problem and associated risk factors

OBJECTIVE To assess the problem of multidrug-resistant tuberculosis (MDR-TB) throughout Belarus and investigate the associated risk factors. METHODS In a nationwide survey in 2010-2011, 1420 tuberculosis (TB) patients were screened and 934 new and 410 previously treated cases of TB were found to meet the inclusion criteria. Isolates of Mycobacterium tuberculosis from each eligible patient were tested for susceptibility to anti-TB drugs. Sociobehavioural information was gathered in interviews based on a structured questionnaire. FINDINGS MDR-TB was found in 32.3% and 75.6% of the new and previously treated patients, respectively, and, 11.9% of the 612 patients found to have MDR-TB had extensively drug-resistant TB (XDR-TB). A history of previous treatment for TB was the strongest independent risk factor for MDR-TB (odds ratio, OR: 6.1; 95% confidence interval, CI: 4.8-7.7). The other independent risk factors were human immunodeficiency virus (HIV) infection (OR: 2.2; 95% CI: 1.4-3.5), age < 35 years (OR: 1.4; 95% CI: 1.0-1.8), history of imprisonment (OR: 1.5; 95% CI: 1.1-2.0), disability sufficient to prevent work (OR: 1.9; 95% CI: 1.2-3.0), alcohol abuse (OR: 1.3; 95% CI: 1.0-1.8) and smoking (OR: 1.5; 95% CI: 1.1-2.0). CONCLUSION MDR-TB is very common among TB patients throughout Belarus. The numerous risk factors identified for MDR-TB and the convergence of the epidemics of MDR-TB and HIV infection call not only for stronger collaboration between TB and HIV control programmes, but also for the implementation of innovative measures to accelerate the detection of TB resistance and improve treatment adherence.

Twenty Years of Global Surveillance of Antituberculosis-Drug Resistance

The emergence and dissemination of drug-resistant Mycobacterium tuberculosis is a global threat to health. In this report, surveillance of drug-resistant tuberculosis during the past 20 years is described.

How is Xpert MTB/RIF being implemented in 22 high tuberculosis burden countries?

Accurate and rapid diagnosis is crucial for tuberculosis control by ensuring a timely start to treatment and reducing transmission. In 2012, almost one third of tuberculosis cases were not diagnosed and/or reported to national tuberculosis programmes (NTPs), and <25% of estimated incident multidrug-resistant (MDR) cases were diagnosed [1]. Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), a nucleic acid amplification test, was recommended in 2010 by the World Health Organization (WHO) for detection of HIV-associated pulmonary tuberculosis and rifampicin resistance [2]. In 2013, the test was recommended for detection of paediatric tuberculosis and some forms of extrapulmonary tuberculosis (EPTB), as well as an initial test to replace smear microscopy [3]. Xpert MTB/RIF implementation is mainly donor-funded, focused on DST and is not widely used outside South Africa http://ow.ly/CK4NS

Modernizing surveillance of antituberculosis drug resistance: from special surveys to routine testing.

Availability of new diagnostic tools and global commitment towards universal access to tuberculosis care will accelerate capacity of resource-limited countries to monitor anti-tuberculosis drug resistance. Special surveys will be replaced by routine surveillance of drug resistance linked to patient care.

Digital health for the End TB Strategy: developing priority products and making them work

In 2014, the World Health Organization (WHO) developed the End TB Strategy in response to a World Health Assembly Resolution requesting Member States to end the worldwide epidemic of tuberculosis (TB) by 2035. For the strategys objectives to be realised, the next 20 years will need novel solutions to address the challenges posed by TB to health professionals, and to affected people and communities. Information and communication technology presents opportunities for innovative approaches to support TB efforts in patient care, surveillance, programme management and electronic learning. The effective application of digital health products at a large scale and their continued development need the engagement of TB patients and their caregivers, innovators, funders, policy-makers, advocacy groups, and affected communities. In April 2015, WHO established its Global Task Force on Digital Health for TB to advocate and support the development of digital health innovations in global efforts to improve TB care and prevention. We outline the groups approach to stewarding this process in alignment with the three pillars of the End TB Strategy. The supplementary material of this article includes target product profiles, as developed by early 2016, defining nine priority digital health concepts and products that are strategically positioned to enhance TB action at the country level. Priority digital health products will be profiled and developed to support the scale-up of WHOs End TB Strategy http://ow.ly/4mRRjR

Multidrug Resistance among New Tuberculosis Cases: Detecting Local Variation through Lot Quality-Assurance Sampling

Background: Current methodology for multidrug-resistant tuberculosis (MDR TB) surveys endorsed by the World Health Organization provides estimates of MDR TB prevalence among new cases at the national level. On the aggregate, local variation in the burden of MDR TB may be masked. This paper investigates the utility of applying lot quality-assurance sampling to identify geographic heterogeneity in the proportion of new cases with multidrug resistance. Methods: We simulated the performance of lot quality-assurance sampling by applying these classification-based approaches to data collected in the most recent TB drug-resistance surveys in Ukraine, Vietnam, and Tanzania. We explored 3 classification systems— two-way static, three-way static, and three-way truncated sequential sampling—at 2 sets of thresholds: low MDR TB = 2%, high MDR TB = 10%, and low MDR TB = 5%, high MDR TB = 20%. Results: The lot quality-assurance sampling systems identified local variability in the prevalence of multidrug resistance in both high-resistance (Ukraine) and low-resistance settings (Vietnam). In Tanzania, prevalence was uniformly low, and the lot quality-assurance sampling approach did not reveal variability. The three-way classification systems provide additional information, but sample sizes may not be obtainable in some settings. New rapid drug-sensitivity testing methods may allow truncated sequential sampling designs and early stopping within static designs, producing even greater efficiency gains. Conclusions: Lot quality-assurance sampling study designs may offer an efficient approach for collecting critical information on local variability in the burden of multidrug-resistant TB. Before this methodology is adopted, programs must determine appropriate classification thresholds, the most useful classification system, and appropriate weighting if unbiased national estimates are also desired.

Market penetration of Xpert MTB/RIF in high tuberculosis burden countries: A trend analysis from 2014 - 2016

Background: Xpert® MTB/RIF, a rapid tuberculosis (TB) molecular test, was endorsed by the World Health Organization in 2010. Since then, 34.4 million cartridges have been procured under concessional pricing. Although the roll out of this diagnostic is promising, previous studies showed low market penetration. Methods: To assess 3-year trends of market penetration of Xpert MTB/RIF in the public sector, smear and Xpert MTB/RIF volumes for the year 2016 were evaluated and policies from 2014-2016 within 22 high-burden countries (HBCs) were studied. A structured questionnaire was sent to representatives of 22 HBCs. The questionnaires assessed the total smear and Xpert MTB/RIF volumes, number of modules and days of operation of GeneXpert machines in National TB Programs (NTPs). Data regarding the use of NTP GeneXpert machines for other diseases and GeneXpert procurement by other disease control programs were collected. Market penetration was estimated by the ratio of total sputum smear volume for initial diagnosis divided by the number of Xpert MTB/RIF tests procured in the public sector. Results: The survey response rate was 21/22 (95%). Smear/Xpert ratios decreased in 17/21 countries and increased in four countries, since 2014. The median ratio decreased from 32.6 (IQR: 44.6) in 2014 to 6.0 (IQR: 15.4) in 2016. In 2016, the median GeneXpert utilization was 20%, however seven countries (7/19; 37%) were running tests for other diseases on their NTP-procured GeneXpert systems in 2017, such as HIV, hepatitis-C virus (HCV), Chlamydia trachomatis, and Neisseria gonorrhoeae. Five (5/15; 33%) countries reported GeneXpert procurement by HIV or HCV programs in 2016 and/or 2017. Conclusions: Our results show a positive trend for Xpert MTB/RIF market penetration in 21 HBC public sectors. However, GeneXpert machines were under-utilized for TB, and inadequately exploited as a multi disease technology.