Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.
Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Am J Respir Crit Care Med. 2023 Jan 15;207(2):193-205. doi: 10.1164/rccm.202201-0144OC.
"Forgiveness" charts the ability of a drug or regimen to withstand nonadherence without negative clinical consequences. We aimed to determine the influence of regimen length, regimen drugs, and dosing, and when during treatment nonadherence occurs on the forgiveness of antituberculosis regimens. Using data from three randomized controlled trials comparing experimental 4-month regimens for drug-sensitive tuberculosis with the standard 6-month regimen, we used generalized linear models to examine how the risk of a negative composite outcome changed as dose-taking decreased. The percentage of doses taken and the absolute number of doses missed were calculated during the intensive and continuation phases of treatment, and overall. A mediation analysis was undertaken to determine how much the association between intensive phase dose-taking and the negative composite outcome was mediated through continuation phase dose-taking. Forgiveness of the 4- and 6-month regimens did not differ for any treatment period. Importantly, 4-month regimens were no less forgiving of small numbers of absolute missed doses than the 6-month regimen (e.g., for 3-7 missed doses vs. no missed doses [baseline], 6-month regimen adjusted risk ratio 1.65 [95% confidence interval, 0.80-3.41] and 4-month regimens 1.80 [1.33-2.45]). No 4-month regimen was conclusively more forgiving than another. We found evidence of mediation by continuation phase dose-taking on the intensive phase dose-taking and negative composite outcome relationship. With the current appetite for, and progress toward, shorter drug-sensitive tuberculosis regimens worldwide, we offer reassurance that shorter regimens are not necessarily less forgiving of nonadherence. Given the importance of continuation phase adherence, patient support during this period should not be neglected.
“宽容性”描述了药物或方案在不产生负面临床后果的情况下抵抗不依从的能力。我们旨在确定方案的长度、方案中的药物和剂量，以及不依从发生在治疗的哪个阶段，对治疗结核病的方案宽容性的影响。使用来自三项比较实验性 4 个月药物敏感结核病方案与标准 6 个月方案的随机对照试验的数据，我们使用广义线性模型来检查随着剂量减少，不良复合结局的风险如何变化。在强化期和继续期治疗期间以及整个治疗期间，计算了服用的剂量百分比和错过的剂量绝对值。进行了中介分析，以确定强化期剂量与不良复合结局之间的关联有多少是通过继续期剂量来介导的。对于任何治疗期，4 个月和 6 个月方案的宽容性都没有差异。重要的是，4 个月方案在错过的绝对剂量较少的情况下并不比 6 个月方案宽容性差（例如，与无错过剂量相比，错过 3-7 个剂量，6 个月方案调整后的风险比为 1.65 [95%置信区间，0.80-3.41]，4 个月方案为 1.80 [1.33-2.45]）。没有一个 4 个月方案明显比另一个更宽容。我们发现，继续期剂量服用在强化期剂量服用与不良复合结局关系中存在中介作用。鉴于目前全球对更短的药物敏感结核病方案的需求和进展，我们可以放心，较短的方案不一定对不依从性的宽容性较差。考虑到继续期依从性的重要性，在此期间不应忽视对患者的支持。
