Reply to Moonan and Weis, Seaworth et al, and Nunn and Phillips.
Reply to Moonan and Weis, Seaworth et al, and Nunn and Phillips.
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回复穆南和韦斯、席沃斯等人以及纳恩和菲利普斯。
DOI：
10.1093/cid/cit434
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Gumbo,Tawanda
中科院分区：
文献类型：
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作者：
Pasipanodya,JotamG;Gumbo,Tawanda
致编辑-我们感谢Moonan博士和Weis博士对我们最近出版物的评论[1]。首先，无论其优良的血统，在世界范围内适用的公共卫生政策应该使用最好的科学方法进行审查。因此，我们重申了直接观察治疗（DOT）与自我管理治疗（SAT）对微生物结果的影响作为可证伪的假设，并在实验室中检验了假设。我们发现，除了一过性异烟肼单耐药外，耐多药结核病不会出现任何程度的不依从，而失败仅发生在> 50%的不依从时;其他人对小鼠结核病的研究也证明了这一点[3，4]。接下来，我们使用治疗策略的最高水平的临床证据研究了同样的问题：随机对照临床试验（RCT）。我们根据最佳证据规则（如GRADE标准）对每项研究的质量进行评价，该标准解决了Moonan和Weis提出的随机化和分配问题。4项RCT的评分为4分，1项为3分，5分为最高分。根据GRADE标准，将RCT确定为高质量或中等质量的进一步证据包括偏倚风险、不精确性、不一致性、间接性和发表偏倚[5]。这5个问题都得到了解决。最直接的结果指标是微生物学结果。我们的结果表明，影响分析具有高度一致性，即没有一项研究表明DOT与SAT相比在统计学上具有上级微生物失效，并且没有显示出出版偏倚。最后，在DOT辩护中提出的长期问题是DOTS项目的质量。我们纳入了DOTS计划绩效的衡量标准，并证明依从性得到了改善，正如预期的那样。显然，在所选的研究中，DOTS项目在通过改善依从性来衡量时表现良好。此外，我们的亚组和敏感性分析直接涉及DOTS项目的质量;结果见补充图2 [2]。因此，随机对照试验或观察性研究的质量不太可能导致DOT的非优效性。事实上，如果我们将相同的证据质量规则应用于支持DOTS的“回顾”和准科学研究，则几乎没有质量证据支持。任何影响到数百万人的全球卫生政策，如果被公共卫生当局当作万灵药出售，都应该而且将会在实验室和诊所中根据最佳证据规则进行检验，而不管“专家”是否达成共识。警告审查员。纳恩和菲利普斯[6]提出了一个可能的双重出版的问题。经过仔细的审查，我们确信这些研究有足够的不同，而且是在不同的地方进行的;尽管不能排除一些重叠。然而，在敏感性分析中，无论是从分析中删除每一项研究（补充图1）[2]，还是删除Ormerod等人的研究，都不会改变效应量和结论。此外，DOT监督的类型在表1 [1]中有很好的描述。Seaworth等人[7]提出了一个有趣的问题，即从患者护理中转移资源。我们同意。事实上，我们的论文的主旨是，资源应该集中在其他地方，而不是远离结核病护理，而是远离DOT。将DOT与重症监护相混淆是错误的：大多数传染病护理都是个体化的，没有DOT。更密集的病人护理，包括密切跟踪病人的不良事件，以及测量药物浓度，是资源应该投入的地方。
TO THE EDITOR—We thank Drs Moonan and Weis for their comments [1] on our recent publication [2]. First, regardless of its excellent pedigree, public health policy that is applied worldwide should be examined using the best scientific methods available. Thus, we restated the effect of directly observed therapy (DOT) versus self-administered therapy (SAT) on microbiological outcome as falsifiable hypotheses, and tested the hypotheses in the laboratory. We found that multidrugresistant tuberculosis was not encountered with any degree of nonadherence, except transient isoniazid monoresistance, whereas failure occurred only at> 50% nonadherence; studies in murine tuberculosis by others have demonstrated the same [3, 4]. Next, we investigated the same question using the highest level of clinical evidence for therapeutic maneuvers: randomized controlled clinical trials (RCTs). We rated the quality of each study based on best rules of evidence, such as GRADE criteria, that address the randomization and allocation concerns Moonan and Weis raise. Four of the RCTs had a score of 4, and one had 3, with 5 as the highest possible score. According to GRADE criteria, further evidence to identify RCTs as high or moderate quality are risk of bias, imprecision, inconsistency, indirectness, and publication bias [5]. All 5 of these were addressed. The most direct outcome measure is microbiologic outcome. Our results demonstrated high consistency in influence analyses; that is, no one study demonstrated statistically superior microbiologic failure with DOT versus SAT, and showed no publication bias. Finally, the perennial issue raised in defense of DOT is quality of DOTS programs. We included measures of DOTS program performance and demonstrate that adherence was improved, as intended. Clearly, the DOTS programs in the studies selected performed well when measured by improved adherence. Moreover, our subgroup and sensitivity analysis directly addressed quality of DOTS programs; results were shown in Supplementary Figure 2 [2]. Thus, it is very unlikely that the quality of the RCTs or even the observational studies could be blamed for the nonsuperiority of DOT. In fact, if we applied the same quality of evidence rules to the “lookback” and quasi-scientific studies that have been used to support DOTS, there would be little to no quality evidence in support. Any global health policy that has an impact on millions of people, and is sold by public health authorities as a panacea, should be, and will be, tested in the laboratory and in the clinic based on the best rules of evidence regardless of consensus by “experts.” Caveat venditor. Nunn and Phillips [6] raise the issue of a possible double publication. A close review convinced us that the studies were sufficiently different and took place in different locales; although some overlap could not be ruled out. However, in the sensitivity analysis, neither the omission of each one of the studies from the analysis (Supplementary Figure 1)[2], nor the omission of Ormerod et al’s study, changed the effect size and conclusion. Moreover, the type of DOT supervision was well described in Table 1 [1]. Seaworth et al [7] raise the interesting issue of moving away resources from patient care. We agree. Indeed, the thrust of our paper was that resources should be concentrated elsewhere, not away from tuberculosis care, but away from DOT. It is a mistake to confuse DOT for intensive care: most infectious disease care is individualized and intensive without DOT. More intensive patient care, including close follow-up of patients for adverse events, among others, and measurement of drug concentrations, is where resources should …