Priority-Setting for Novel Drug Regimens to Treat Tuberculosis: An Epidemiologic Model

<div><p>Background</p><p>Novel drug regimens are needed for tuberculosis (TB) treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen’s ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective.</p><p>Methods and Findings</p><p>We developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis), South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS) or rifampicin-resistant (RR) TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1) efficacy, (2) duration, (3) ease of adherence, (4) medical contraindications, (5) barrier to resistance, and (6) baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care.</p><p>For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113–187) and 16 (95% UR: 9–23) per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4–10) and 0.6 (95% UR: 0.3–1.1) per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%–20%) and 11% (95% UR: 6%–20%), respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%–46%) and RR TB mortality by 30% (95% UR: 18%–44%). Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%–13%, half the impact of a fully optimized regimen), and increasing the efficacy against RR TB from 76% to 94% lowered RR TB mortality by 13% (95% UR: 6%–23%). Reducing treatment duration or improving ease of adherence had smaller but still substantial impact: shortening RS TB treatment duration from 6 to 2 mo lowered TB mortality by 3% (95% UR: 1%–6%), and shortening RR TB treatment from 20 to 6 mo reduced RR TB mortality by 8% (95% UR: 4%–13%), while reducing nonadherence to the corresponding regimens by 50% reduced TB and RR TB mortality by 2% (95% UR: 1%–4%) and 6% (95% UR: 3%–10%), respectively. Limitations include sparse data on key model parameters and necessary simplifications to model structure and outcomes.</p><p>Conclusions</p><p>In designing clinical trials of novel TB regimens, investigators should consider that even small changes in treatment efficacy may have considerable impact on TB-related incidence and mortality. Other regimen improvements may still have important benefits for resource allocation and outcomes such as patient quality of life.</p></div

Model structure.

<p>The model (panel A) includes infection, rapid or slow progression to active TB, and initiation of treatment with a standard regimen or novel regimen (the transition from Active TB to Treatment, shown in more detail in panels B and C). (Also included in model but not shown in Fig 1: parallel structure for eight different drug resistance phenotypes; parallel structure for HIV infected/uninfected and treatment naïve/experienced; and death/spontaneous resolution.) Six novel drug regimen characteristics were evaluated within this transmission model; improved novel regimen (a) efficacy increases the probability of durable cure. A high barrier to resistance (b) prevents acquisition of resistance to drugs in the novel regimen. Less preexisting resistance to components of the novel regimen (c) and fewer medication contraindications or treatment-limiting toxicities associated with the novel regimen (d) increase the number of patients for whom the novel regimen is prescribed. Shorter regimen duration (e) and greater ease of adherence (f) both increase treatment completion, and shortened duration also reduces the probability of cure after loss to follow-up at any given time point.</p

Relative mortality impact of different individual characteristics of novel regimens for the treatment of RS or RR TB.

<p>Characteristics and levels are defined in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002202#pmed.1002202.t001" target="_blank">Table 1</a>. Impact is measured as a relative change in TB mortality (RS TB regimen, A and B) or RR TB mortality (RR TB regimen, C and D) 10 y after introduction of the novel regimen, as illustrated in Fig 3. In A and C, the benefit of partially (striped bars) or fully (solid bars) optimizing only one aspect of a regimen, with the remaining characteristics meeting only minimal targets, is compared to the impact of a regimen that is fully optimized in all aspects. In B and D, the mortality reduction achievable by a regimen that fails to meet only one optimistic target (relative to mortality projections using standard regimens) is compared to mortality reduction with a regimen that meets all optimistic targets. Percentages need not sum to 100% due to synergy between multiple characteristics of the regimen. Error bars show the 95% UR for the impact of each fully optimized characteristic.</p

Illustration of resulting mortality trends and comparisons for different novel RS and RR TB regimens.

<p>Trajectories illustrate the median impact of novel regimens on the median projections of TB mortality. The impact of variation in each individual characteristic (such as efficacy, illustrated here) was evaluated as a fraction of the total impact of regimen optimization (distance between solid red and green trend lines). This evaluation was performed by optimizing the characteristic in question with an otherwise minimal baseline (difference between solid and dashed red lines, corresponding to the results shown in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002202#pmed.1002202.g003" target="_blank">Fig 3A and 3C</a>) and then by removing the characteristic from an otherwise optimized novel regimen (difference between solid and dashed green lines, corresponding to <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002202#pmed.1002202.g003" target="_blank">Fig 3B and 3D</a>). Scale-up of the novel regimen was assumed to occur over 3 y following regimen introduction, and analyses were performed over the 10 y following the novel regimen’s introduction (including the 3 y of scale-up).</p

Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens.

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens