A Schematic of the Postulated Correlation between Bacterial Load, T Cell Response, and Clinical Outcome

<div><p>Initial infection might be controlled at its onset with minimal bacterial replication (measured as colony-forming units [CFU]) and induction of ESAT-6 responses (A and D). In such cases, the T cell response may be below the diagnostic cut-off. However, in most cases, initial bacterial replication reaches a point at which it induces an ESAT-6-specific IFNγ response to increase above the established cut-off value (infection threshold), enabling the diagnosis of an individual as latently infected (B and E). In most cases, individuals control the infection, resulting in latent infection, but some develop active TB disease associated with progressive bacterial replication. This is accompanied by increasing and strong ESAT-6 responses and, as hypothesized here, an incipient (higher) disease cut-off value may predict subsequent development of progressive disease (C and F).</p> <p>Reproduced with permission from [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0040208#pmed-0040208-b013" target="_blank">13</a>].</p></div

Low-Cost LED-Based Fluorescence Microscopy Being Evaluated at a TDR/WHO Trial Site in Abuja, Nigeria

<p>Photographer: Andrew Ramsay (Courtesy of TDR, Geneva)</p

A Simplified NAAT Being Evaluated at a FIND Trial Site in India

<p>Photographer: Ralf Linke (Courtesy of FIND, Geneva)</p

Estimates for Model Parameters.

<p>¹ TB, Tuberculosis</p><p>² In the absence of any TB-specific microbiological test</p><p>³ IGRA, Interferon-Gamma Release Assay</p><p>⁴ MTB/RIF, <i>Mycobacterium tuberculosis</i> and Rifampin Resistance Testing</p><p>⁵ Excludes studies not performed in developing countries</p><p>⁶ HIV, Human Immunodeficiency Virus</p><p>⁷ ART, antiretroviral therapy</p><p>⁸ MDR, Multi-drug resistant</p><p>⁹ DALY, Disability-Adjusted Life Year</p><p>Estimates for Model Parameters.</p

Impact of resistance testing on multi-drug and isoniazid resistance.

<p>Projected trajectories for multi-drug resistant (MDR) (A, C) and INH-resistance (INHr) (B, D) cases with TB detection, TB+RIF and TB+RIF/INH over ten years. Results are shown as the absolute number of MDR or INHr cases per 100,000 (A, B) and as a proportion of all cases (new cases and relapse/default cases) detected (C, D).</p

Select Two-Way Sensitivity Analyses.

<p>Left) Two-way sensitivity analysis of the effects of changes in IGRA sensitivity and specificity parameters within pre-specified ranges on DALYs averted, demostrating the most effective diagnostic strategy, irrespective of cost. Right) Two-way sensitivity analysis of the effects of changes in IGRA and Xpert MTB/Rif prices within pre-specified ranges on the cost of each diagnostic approach, demostrating the least costly diagnostic strategy, irrespective of effectiveness.</p

Study decision tree.

<p>Depicted is a simplified version of the analytic framework for this decision analysis. The square represents a decision node, circles chance nodes, and triangles terminal nodes. The branch of the decision node (sputum smear + serology) is compared to similar branches corresponding to scenarios of no TB-specific diagnosis, sputum smear only, and sputum smear plus TB culture (commercial liquid media), as described in the text. Probabilities, costs, and DALYs are calculated at each terminal node according to the parameters described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001074#pmed-1001074-t002" target="_blank">Table 2</a>. ARV, antiretroviral therapy; +, positive; −, negative.</p

Impact of resistance testing on incidence and mortality.

<p>Trajectory of overall TB incidence (solid lines, left axis) and mortality (dotted lines, right axis) over 10 years with introduction of a molecular test for diagnosis and detection of rifampin (RIF) resistance, with or without a molecular test for isoniazid (INH) resistance. Grey lines correspond to the high-coverage scenario (i.e. 50%, 80% and 100% coverage among new, previously treated and failure cases, respectively, excluding those with no access to care), green lines to an alternative lower-coverage scenario (15%, 25%, and 30% among new, previously treated and failure). The curves for TB+RIF versus TB+RIF/INH are indistinguishable on the graph because the projected outcomes are so similar (see inset with incidence from year 8–10 for high coverage scenarios).</p

Projected tuberculosis outcomes.

<p>Projected tuberculosis outcomes.</p

Do We Need to Detect Isoniazid Resistance in Addition to Rifampicin Resistance in Diagnostic Tests for Tuberculosis?

<div><p>Background</p><p>Multidrug-resistant tuberculosis (MDR-TB) is resistant to both rifampicin (RIF) and isoniazid (INH). Whereas many TB diagnostics detect RIF-resistance, few detect INH-monoresistance, which is common and may increase risk of acquired MDR-TB. Whether inclusion of INH-resistance in a first-line rapid test for TB would have an important impact on MDR-TB rates remains uncertain.</p><p>Methods</p><p>We developed a transmission model to evaluate three tests in a population similar to that of India: a rapid molecular test for TB, the same test plus RIF-resistance detection (“TB+RIF”), and detection of RIF and INH-resistance (“TB+RIF/INH”). Our primary outcome was the prevalence of INH-resistant and MDR-TB at ten years.</p><p>Results</p><p>Compared to the TB test alone and assuming treatment of all diagnosed MDR cases, the TB+RIF test reduced the prevalence of MDR-TB among all TB cases from 5.5% to 3.8% (30.6% reduction, 95% uncertainty range, UR: 17–54%). Despite using liberal assumptions about the impact of INH-monoresistance on treatment outcomes and MDR-TB acquisition, expansion from TB+RIF to TB+RIF/INH lowered this prevalence only from 3.8% to 3.6% further (4% reduction, 95% UR: 3–7%) and INH-monoresistant TB from 15.8% to 15.1% (4% reduction, 95% UR: (-8)-19%).</p><p>Conclusion</p><p>When added to a rapid test for TB plus RIF-resistance, detection of INH-resistance has minimal impact on transmission of TB, MDR-TB, and INH-monoresistant TB.</p></div