The Role of Adherence and Retreatment in De Novo Emergence of MDR-TB

Abstract

Treatment failure after therapy of pulmonary tuberculosis (TB) infections is an important challenge, especially when it coincides with de novo emergence of multi-drug-resistant TB (MDR-TB). We seek to explore possible causes why MDR-TB has been found to occur much more often in patients with a history of previous treatment. We develop a mathematical model of the replication of Mycobacterium tuberculosis within a patient reflecting the compartments of macrophages, granulomas, and open cavities as well as parameterizing the effects of drugs on the pathogen dynamics in these compartments. We use this model to study the influence of patient adherence to therapy and of common retreatment regimens on treatment outcome. As expected, the simulations show that treatment success increases with increasing adherence. However, treatment occasionally fails even under perfect adherence due to interpatient variability in pharmacological parameters. The risk of generating MDR de novo is highest between 40% and 80% adherence. Importantly, our simulations highlight the double-edged effect of retreatment: On the one hand, the recommended retreatment regimen increases the overall success rate compared to re-treating with the initial regimen. On the other hand, it increases the probability to accumulate more resistant genotypes. We conclude that treatment adherence is a key factor for a positive outcome, and that screening for resistant strains is advisable after treatment failure or relapse.

Distinct MHC class I-like interacting invariant T cell lineage at the forefront of mycobacterial immunity uncovered inXenopus

“…In addition to providing in vivo evidence of the critical roles of multiple MHC-like-interacting iT cells in amphibian immunity, this study places X. laevis tadpoles as an attractive alternative animal model to explore the role of iT cells in establishment and persistence of Mtb, the causative agent of TB in humans. Despite years of research, Mtb remains a leading cause of infectious mortality worldwide and although TB is generally curable, current treatment strategies are complex and of long duration with the emergence of multidrug and extensive drug-resistant TB (35,36). Although it is well established that cellular immunity is critical in controlling mycobacterial growth, there are still major gaps in our understanding of how the early initiation and regulation of the immune response occurs (37).…”

Insight into treatment ofHIVinfection from viral dynamics models

“…The short half‐life and sharp dose‐response curves for these drugs make the time spent in the selection window where resistant strains are favored small. Similar models have now been developed for many different infections, including HCV, HSV, TB, and others have applied similar models to HIV to examine effects such as archiving of transmitted resistant strains in the latent reservoir, tissue compartments with lower drug concentrations, details of intracellular pharmacokinetics of drugs, and host immunity.…”

Quality of DOTS Adherence Counselling among Hospitalized Tuberculosis Patients

“…Several studies such as a study done by Cadosch, et al have investigated the effects of adherence counselling and DOT on treatment outcomes. The results of that study showed that failure to adhere to anti-TB medication directly affects treatment outcomes [22]. Another study done in 2016 looked at the association between DOT and TB treatment outcomes and found that there was no statistical significance [17].…”

“…Moreover, the lack of adherence counselling as well as emotional and psychosocial support to TB patients and their families is linked to poor treatment outcomes including loss to follow-up and development of DR-TB [5] [18] [19]. The occurrence of adverse drug effects is more common among patients medication for DR-TB and DS-TB, which compromises adherence to medication [18] [20] [21] [22]. Thus, the World Health Organisation (WHO) identifies improved quality of adherence counselling as a key intervention under DOTS to improve medication adherence and TB treatment of outcomes [23] [24].…”