Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis

Abstract

BackgroundMultidrug-resistant tuberculosis (MDR-TB) can be acquired through de novo mutation during TB treatment or through transmission from other individuals with active MDR-TB. Understanding the balance between these two mechanisms is essential when allocating resources for MDR-TB.MethodsWe constructed a dynamic transmission model of an MDR-TB epidemic, allowing for both treatment-related acquisition and person-to-person transmission of resistance. We used national TB notification data to inform Bayesian estimates of the fraction of each country’s 2013 MDR-TB incidence that resulted from MDR transmission rather than treatment-related MDR acquisition.FindingsGlobal estimates of 3·5% MDR-TB prevalence among new TB notifications and 20·5% among retreatment notifications translate into an estimate that resistance transmission rather than acquisition accounts for a median 96% (95% UR: 68–100%) of all incident MDR-TB, and 61% (16–95%) of incident MDR-TB in previously-treated individuals. The estimated percentage of MDR-TB resulting from transmission varied substantially with different countries’ notification data; for example, we estimated this percentage at 48% (30–75%) of MDR-TB in Bangladesh, versus 99% (91–100%) in Uzbekistan. Estimates were most sensitive to estimates of the transmissibility of MDR strains, the probability of acquiring MDR during tuberculosis treatment, and the responsiveness of MDR TB to first-line treatment.InterpretationNotifications of MDR prevalence from most high-burden settings are most consistent with the vast majority of incident MDR-TB resulting from transmission rather than new treatment-related acquisition of resistance. Merely improving the treatment of drug-susceptible TB is unlikely to greatly reduce future MDR-TB incidence. Improved diagnosis and treatment of MDR-TB – including new tests and drug regimens – should be highly prioritized.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…40,41 One study examined the estimated incidence of new and retreatment cases in countries with a high tuberculosis burden, and concluded that more than 95% of MDR tuberculosis is due to primary transmission of resistant strains. 42 Consistent with the results described above, these findings suggest that a focus on early detection and improved treatment of MDR tuberculosis is needed to curtail future incidence.…”

“…49,82,[99][100][101] In most regions of the world, drug-resistant tuberculosis is now predominantly caused by transmission rather than acquisition of resistance, with an estimated 95·9% of MDR tuberculosis in new tuberculosis cases and 61·3% in previously treated cases being due to transmission. 42 Even the epidemiology of XDR tuberculosis-defined as resistance to isoniazid, rifampicin, a fluoroquinolone, and an injectable agent-is now better understood as reflecting endemics rather than epidemics, 48,95,102,103 and population migration is recognised as a vehicle for spread beyond the region of the strain's origin. Indeed, molecular epidemiological studies have documented the spread of drug-resistant strains within countries, between countries, and even across con tinents (figure 3).…”

“…42,69,128 Indeed, some settings-from Estonia 129,130 to New York 131 -have seen steeper declines in the incidence of drug-resistant tuberculosis than in tuberculosis as a whole after adopting interventions to control the transmission of drug-resistant tuberculosis. Typically, these measures included universal DST, 132 individualised treatment, 133 access to tuberculosis care, 134 and sustained efforts to improve treatment completion, which is only achieved in two-thirds of cases, even in well functioning programmes.…”

“…460 Some previously treated patients assumed to be due to acquired drug resistance, would likely be attributed to transmission if molecular typing were more widely available. Furthermore, a recent mechanistic mathematical modelling approach 42 based on WHO prevalence data estimated the proportion of MDR tuberculosis due to transmission in different settings. 42 Although the transmission-attributable fraction varied widely from 48% in Bangladesh to 99% in Uzbekistan, with the remainder probably being driven by acquired resistance, this model furthers underscores the importance of interrupting MDR tuberculosis trans mission to prevent new cases.…”

“…Furthermore, a recent mechanistic mathematical modelling approach 42 based on WHO prevalence data estimated the proportion of MDR tuberculosis due to transmission in different settings. 42 Although the transmission-attributable fraction varied widely from 48% in Bangladesh to 99% in Uzbekistan, with the remainder probably being driven by acquired resistance, this model furthers underscores the importance of interrupting MDR tuberculosis trans mission to prevent new cases. For several years, it has been established that only 20% of patients with MDR tuberculosis are given The Lancet Respiratory Medicine Commission effective treatment (and less than half of these successfully treated), and thus the infectious pool of patients with undiagnosed, often unsuspected, drug resistance will continue to grow unabated.…”