Emerging Therapeutics, Technologies, and Drug Development Strategies to Address Patient Nonadherence and Improve Tuberculosis Treatment

Abstract

Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient phenotypes, population pharmacokinetics, resistance development, drug distribution to tuberculosis lesions, and pharmacodynamics at the site of infection is necessary to fully measure the impact of adherence on patient outcomes. To decrease the impact of expected variability in drug intake on tuberculosis outcomes, an improvement in patient adherence and new forgiving regimens that protect against missed doses are needed. In this review, we summarize emerging technologies to improve medication adherence in clinical practice and provide suggestions on how digital adherence technologies can be incorporated in clinical trials and practice and the drug development pipeline that will lead to more forgiving regimens and benefit patients suffering from tuberculosis. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Can digital adherence technologies reduce inequity in tuberculosis treatment success? Evidence from a randomised controlled trial

“…The WHO currently promotes digital adherence technologies (DATs)-such as feature or smart phone-bases strategies, electronic pillboxes or ingestible sensors-as possible facilitators for improving TB treatment adherence in resource-limited settings. [7][8][9] However, little research has investigated whether DATs are more likely to benefit high-risk patients or, alternatively, whether these technologies may be ineffective for such patients or even create intervention-generated inequality (IGI) by disproportionately benefiting patients who already have a low probability of an unsuccessful outcome (ie, low-risk patients). 10 Some researchers have argued that technology-based health interventions may disproportionately benefit low-risk patients and create IGI, because such individuals may be more advantaged, and therefore, have higher baseline access to these technologies (eg, mobile phones) or greater ability to use them.…”

“…The WHO currently promotes digital adherence technologies (DATs)—such as feature or smart phone-bases strategies, electronic pillboxes or ingestible sensors—as possible facilitators for improving TB treatment adherence in resource-limited settings 7–9. However, little research has investigated whether DATs are more likely to benefit high-risk patients or, alternatively, whether these technologies may be ineffective for such patients or even create intervention-generated inequality (IGI) by disproportionately benefiting patients who already have a low probability of an unsuccessful outcome (ie, low-risk patients) 10.…”

No action is without its side effects: Adverse drug reactions and missed doses of antituberculosis therapy, a scoping review

“…Additionally in this review, we noted a lack of standardized language in defining missed doses. As our knowledge increases as to the most detrimental patterns of missed doses, 18 knowing their causes will be critical to building interventions to better support patients who miss doses of therapy due to ADRs. 7 We present detailed data as to whether specific ADRs were associated with missed doses in the underlying studies.…”

Pharmacokinetic analysis across studies to drive knowledge‐integration: A tutorial on individual patient data meta‐analysis (IPDMA)

“…All information from study protocols, clinical trial reports, and publications must be reviewed, and clinical trials, sponsors, and researchers of original studies should be contacted to attempt to resolve any missingness in the dosing histories. If missingness can be resolved, then, nonadherence, which impacts the PK analysis, 35 can be handled by simply not including drug administration at the time of the missing data. However, for a missing dosing record, we do not know whether a patient took a dose or not and different approaches to control missing information and to assess reliability can be explored 36 .…”