Criteria for the control of drug-resistant tuberculosis

Abstract

Antibiotic resistance is a growing impediment to the control of infectious diseases worldwide, tuberculosis (TB) being among them. TB kills two million people each year and foci of multidrug-resistant TB (MDR-TB) have been identified in Eastern Europe, Africa, Asia, and Latin America. A critical question for health policy is whether standardized short-course chemotherapy for TB, based on cheap first-line drugs, can prevent and reverse the spread of drug resistance. Here we use mathematical modeling, in conjunction with treatment results from six countries, to show that best-practice short-course chemotherapy is highly likely to bring strains resistant to either of the two key drugs isoniazid and rifampicin under control and to prevent the emergence of MDR-TB. However, it is not certain to contain MDR-TB once it has emerged, partly because cure rates are too low. We estimate that approximately 70% of prevalent, infectious MDR-TB cases should be detected and treated each year, and at least 80% of these cases should be cured, in order to prevent outbreaks of MDR-TB. Poor control programs should aim to increase case detection and cure rates together for three reasons: (i) these variables act synergistically; (ii) when either is low, the other cannot succeed alone; and (iii) the second-line drugs needed to raise MDR-TB cure rates are few and extremely costly. We discuss the implications of these results for World Health Organization policy on the management of antibiotic resistance.

Figure 1

Flow chart of the mathematical model for MDR-TB. Each box represents a state variable of the model (see Methods). The population is followed from the point at which infected and uninfected individuals join the adult population. DS and DR refer to drug-susceptible and drug-resistant (but not MDR) strains of M. tuberculosis, respectively. Individuals in all states may die of causes unrelated to TB (data not shown). Infections leading to MDR-TB are transmitted from new cases, I, and treatment failures, F_i.

Figure 2

Criteria for the control of MDR-TB. (a) Case reproduction numbers of MDR-TB, R_θm, for combinations of cure rate and duration infectiousness (months until first treatment, or between the start of first and subsequent treatments). Contours join lines of equal R_θm. The contour for R_θm = 1 separates MDR-TB persistence from decline. (b) Probability that R_θm ≤ 1 for various combinations of treatment interval and cure rate. Contours join lines of equal probability. Horizontal lines mark the best (Hong Kong) and worst (Ivanovo Oblast, Russian Federation) outcomes of treatment for MDR-TB cases using standard SCC (5). Countries with intermediate results were the Dominican Republic, the Republic of Korea, Italy, and Peru. The vertical line marks the interval between treatment corresponding to an annual detection rate of 70% of prevalent cases. (c) Three-dimensional surface showing the number of years required for a 10-fold reduction in the incidence of MDR-TB, with different combinations of cure rate and months of infectiousness. Some solutions >120 years are generated by combinations of case detection and cure that cause incidence to rise instead of fall.

Figure 3

Interactions between case detection and cure rates in the control of MDR-TB. Initial values of the reproduction number, R_θm, have been scaled to 1 on the vertical axis to aid comparison of different strategies. Horizontal axes explore the impact of improving case detection (a) and cure rates (b). In a, R_θm is more effectively reduced by improving the case detection rate of new cases rather than of retreatment cases (previous failures). The impact of detecting and treating new cases is greater when the cure rate is higher (thick lines), and so is the relative advantage of treating new cases over retreatment cases (bigger gap between thick lines than between thin lines). In b, R_θm is more effectively reduced by improving the cure rate of new cases rather than of retreatment cases. The impact is greater when the detection rate is higher (0.75 instead of 0.5), and this applies to both new and retreatment cases (same gap between thick lines as between thin lines).