Forgiveness Is the Attribute of the Strong: Nonadherence and Regimen Shortening in Drug-sensitive Tuberculosis

Thompson, Jennifer A.; Lipman, Marc; Sloan, Derek J.; Flook, Mary; Fielding, Katherine

doi:10.1164/rccm.202201-0144oc

Cited by 5 publications

(4 citation statements)

References 23 publications

(29 reference statements)

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“…For Gap 4, given the rich and variable findings by patient population, we highlight key additional high-level points here. First, consistent with findings from clinical trials [20,180,181], non-adherence to TB medications was independently associated with increased risk of unfavorable treatment outcomes (Gap 4) [81,84,93,97,98,121] and TB recurrence (Gap 5) [158] across multiple Indian studies, which suggests that adherence is a mediator of outcomes in programmatic care. However, measuring TB medication adherence in routine care is challenging, with recent studies from India showing that 99DOTS (a digital adherence technology used in the NTEP) and patient self-report have suboptimal accuracy [182][183][184].…”

Section: Findings Specific To Each Care Cascade Gapsupporting

confidence: 57%

Barriers to engagement by people with active tuberculosis in the care cascade in India: a systematic review of two decades of quantitative research

Jhaveri,

Galivanche

et al. 2023

Preprint

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Background. India has the highest burden of tuberculosis (TB), accounting for more than one-quarter of people with active TB and nearly one-third of TB deaths globally. Most people contracting active TB in India do not successfully navigate all stages of the care cascade to receive treatment and achieve TB recurrence-free survival. Understanding reasons for losses across the care cascade is critical to improve outcomes. In this paper, guided by a PECO (population/exposure/comparison/outcome) framework, we describe quantitative findings of a systematic review aimed at identifying factors contributing to unfavorable outcomes experienced by people with TB at each care cascade gap in India. Methods and findings. We defined care cascade gaps as comprising people with confirmed or presumptive TB who did not: start the TB diagnostic workup (Gap 1), complete the diagnostic workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches were conducted to identify 147 unique articles published from 2000 to 2021 that evaluated factors associated with unfavorable outcomes for each gap (reported as odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons reported for these outcomes (reported as proportions). Findings were organized into patient-, family-, society-, or health system-related factors, using a social-ecological framework. Some factors were common and associated with unfavorable outcomes across multiple care cascade stages. These included male sex, older age (variably defined across studies), a broad array of poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) local government health services. People who had been previously treated for TB were more likely to seek care and engage in the TB diagnostic workup (Gaps 1 and 2) but were also more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable outcomes during TB treatment (Gap 4), especially those who had been lost to follow-up during their prior treatment episode. For individual care cascade gaps, multiple studies highlighted the importance of lack of TB knowledge and structural barriers to care (e.g., transport or financial challenges in reaching clinics) in contributing to lack of care-seeking for TB symptoms (Gap 1, 15 studies or analyses); lack of access to diagnostics (e.g., chest X-ray), non-identification of eligible patients for testing, and failure of providers to communicate concern for TB to patients in contributing to non-completion of the diagnostic workup (Gap 2, 20 studies or analyses); TB stigma, poor recording of patient contact information by providers, and early death due to diagnostic delays in contributing to pretreatment loss to follow-up (Gap 3, 25 studies); and medication adverse effects, TB stigma, and lack of TB knowledge in contributing to unfavorable treatment outcomes (Gap 4, 104 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and post-treatment TB recurrence (Gap 5, 15 studies). Conclusions. This extensive systematic review illuminates common patterns of risk that shape outcomes for people with TB in India, while also highlighting gaps in knowledge, particularly with regard to TB care for children or in the private sector, that can help to guide future research. These findings may help inform targeting of additional support services to people with TB who are at higher risk of poor outcomes and inform development of multi-component interventions to close gaps in India′s TB care cascade.

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Section: Findings Specific To Each Care Cascade Gapsupporting

confidence: 57%

Barriers to engagement by people with active tuberculosis in the care cascade in India: a systematic review of two decades of quantitative research

Jhaveri,

Galivanche

et al. 2023

Preprint

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“…For instance, using fractional polynomials or generalized propensity score methods. 36,37 Future work should assess the additional benefits of these approaches. In addition, further research should compare the performance of different statistical methods for handling treatment non-adherence in non-inferiority trials with active control regimens and time-to-event outcomes (where treatment crossovers are often not permitted).…”

Section: Discussionmentioning

confidence: 99%

“…It is plausible that utilizing a continuous functional form of adherence may improve the ability of the more sophisticated methods to eliminate bias due to treatment non‐adherence. For instance, using fractional polynomials or generalized propensity score methods 36,37 . Future work should assess the additional benefits of these approaches.…”

Section: Discussionmentioning

confidence: 99%

Assessing efficacy in non‐inferiority trials with non‐adherence to interventions: Are intention‐to‐treat and per‐protocol analyses fit for purpose?

Dodd,

Carpenter,

Thompson

et al. 2024

Statistics in Medicine

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BackgroundNon‐inferiority trials comparing different active drugs are often subject to treatment non‐adherence. Intention‐to‐treat (ITT) and per‐protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non‐adherence.MethodsThe REMoxTB trial evaluated two 4‐month experimental regimens compared with a 6‐month control regimen for newly diagnosed drug‐susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post‐randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non‐adherence in non‐inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse‐probability‐of‐treatment weighting (IPTW), and a doubly‐robust (DR) estimator.ResultsWhen non‐adherence differed between trial arms, ITT, and PP analyses often resulted in non‐trivial bias in the estimated treatment effect, which consequently under‐ or over‐inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non‐adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power.ConclusionsWhen non‐adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

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“…Despite a number of options for the treatment of both drug-sensitive and drug-resistant TB, there are large gaps between the proportion of individuals cured when allocated to standard of care in clinical trials ( 5 – 8 ) and comparable figures published annually in the World Health Organization global surveillance reports ( 9 ). How robust a new treatment regimen is likely to perform in a programmatic setting in the presence of nonadherence is a critical aspect of drug development; in this issue of the Journal , the work by Stagg and colleagues (p. 193–205 ) to compare the forgiveness of 6- and 4-month regimens using data from clinical trials is welcome ( 10 ).…”

mentioning

confidence: 99%

To Err Is Human, to Forgive Is Pharmacodynamic

Phillips

Stout

2023

Am J Respir Crit Care Med

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Forgiveness Is the Attribute of the Strong: Nonadherence and Regimen Shortening in Drug-sensitive Tuberculosis

Cited by 5 publications

References 23 publications

Barriers to engagement by people with active tuberculosis in the care cascade in India: a systematic review of two decades of quantitative research

Barriers to engagement by people with active tuberculosis in the care cascade in India: a systematic review of two decades of quantitative research

Assessing efficacy in non‐inferiority trials with non‐adherence to interventions: Are intention‐to‐treat and per‐protocol analyses fit for purpose?

To Err Is Human, to Forgive Is Pharmacodynamic

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