Prospects for advancing tuberculosis control efforts through novel therapies

Abstract

Background: Development of new, effective, and affordable tuberculosis (TB) therapies has been identified as a critical priority for global TB control. As new candidates emerge from the global TB drug pipeline, the potential impacts of novel, shorter regimens on TB incidence and mortality have not yet been examined.

Methods and findings: We used a mathematical model of TB to evaluate the expected benefits of shortening the duration of effective chemotherapy for active pulmonary TB. First, we considered general relationships between treatment duration and TB dynamics. Next, as a specific example, we calibrated the model to reflect the current situation in the South-East Asia region. We found that even with continued and rapid progress in scaling up the World Health Organization's DOTS strategy of directly observed, short-course chemotherapy, the benefits of reducing treatment duration would be substantial. Compared to a baseline of continuing DOTS coverage at current levels, and with currently available tools, a 2-mo regimen introduced by 2012 could prevent around 20% (range 13%-28%) of new cases and 25% (range 19%-29%) of TB deaths in South-East Asia between 2012 and 2030. If effective treatment with existing drugs expands rapidly, overall incremental benefits of shorter regimens would be lower, but would remain considerable (13% [range 8%-19%] and 19% [range 15%-23%] reductions in incidence and mortality, respectively, between 2012 and 2030). A ten-year delay in the introduction of new drugs would erase nearly three-fourths of the total expected benefits in this region through 2030.

Conclusions: The introduction of new, shorter treatment regimens could dramatically accelerate the reductions in TB incidence and mortality that are expected under current regimens-with up to 2- or 3-fold increases in rates of decline if shorter regimens are accompanied by enhanced case detection. Continued progress in reducing the global TB burden will require a balanced approach to pursuing new technologies while promoting wider implementation of proven strategies.

Figure 1. Impact of Treatment Duration on TB Dynamics

The horizontal axis in each plot shows monthly default rates, and the three lines represent treatment durations of 6 mo (solid black line), 4 mo (solid grey line), and 2 mo (dashed black line). The three panels show model estimates for: (top graph) the average cumulative duration of infectiousness for a smear-positive case; (middle graph) the effective reproductive number measured 20 years after treatment is introduced; and (bottom graph) the annual rate of decline in the incidence of active TB, averaged over the 20 years following treatment introduction.

Figure 2. Direct and Indirect Reductions in Mortality in Relation to Treatment Duration and Monthly Default Rates

Each bar shows the total reduction in deaths over a 20-year period following treatment introduction, expressed as a percentage of the deaths expected in a steady-state, no treatment counterfactual. The blue area in each bar indicates the reduction that is attributable directly to benefits in treated patients.

Figure 3. Projected Trends in New TB Cases and Deaths in the WHO South-East Asia Region, 2005–2030

(A) Benefits of new drugs and enhanced detection are projected in comparison to the stable-DOTS baseline (constant 42% case detection). (B) The same benefits as in (A) are projected in comparison to the DOTS-target baseline (70% case detection by 2009).

Figure 4. Impact of Alternative Timing for the Introduction of Shorter Drug Regimens

The left graph shows projected new TB cases in the WHO South-East Asia region, while the right graph shows projected deaths. The blue area in each graph represents the additional cases and deaths that would have been averted if a new drug had been available in 2002, compared to availability in 2012. The red area shows the additional cases and deaths that can be averted if the new regimen becomes available in 2012 compared to 2022.