Title: Treatment adherence among sputum smear-positive pulmonary tuberculosis patients in mountainous areas in China

Transcription

1 Author's response to reviews Title: Treatment adherence among sputum smear-positive pulmonary tuberculosis patients in mountainous areas in China Authors: Song Yao Wen-Hui Huang Susan van den Hof Shu-Min Yang Xiao-Lin Wang Wei Chen Xue-Hui Fang Hai-Feng Pan Version: 2 Date: 29 June 2011 Author's response to reviews: see over

2 1 Dear Editor, We are very pleased to learn from your letter about revision for our manuscript entitled Treatment adherence among sputum smear-positive pulmonary tuberculosis patients in mountainous areas in China (MS: ). Thank you for your attention and the reviewers for their helpful comments and advice. We have revised the manuscript according to the comments from you and the reviewers. Response to Reviewers and Editor Reviewer's report Title: Treatment adherence among sputum smear-positive pulmonary tuberculosis patients in mountainous areas in China Version: 1 Date: 28 March 2011 Reviewer: Dong-Qing Ye Reviewer's report: This is an interesting study, Yao and colleagues assessed the treatment adherence and investigated factors associated with low treatment adherence in sputum smear-positive tuberculosis (TB) patients in rural, mountainous areas in five provinces in China. Their results may be used to develop targeted measures to improve patient treatment adherence and hereby improve cure and reduce development of drug resistance and recurrence of TB. I suggest the article be accepted for publication after minor revision. Please provide a brief introduction of the five included Provinces; Vertical lines should not be inserted in the table; Grammar and syntax need some corrections Reply: we included a brief introduction of the five provinces in the methods section, removed vertical lines from the tables, and adjusted grammar and spelling where necessary. Reviewer's report Title: Treatment adherence among sputum smear-positive pulmonary tuberculosis patients in mountainous areas in China Version: 1 Date: 12 April 2011 Reviewer: Yeying Wang Reviewer's report: Major Compulsory Revisions 1. How did you collect the data of patients adherence and what were the methods that you conducted to control the information biases? Reply: Data on patient adherence was collected from patient registers and patient interviews, we added this information to the methods section. We aimed to cross-check information provided by patients by re-interviewing 10% of all patients by provincial level staff. Re-interviews provided very similar information. 2. When did you collect the data? And could you explain that you collected the data among the patients who registered in 2007, however, you held the data collection training workshop from Oct to Jan. 2009?

3 2 Reply: The data were collected from Oct 2008 to Jan Before data collection a workshop was held for data collectors. We adjusted the text to clarify this. 3. What were the patients treatment phases? It is an important issue of adherence. Reply: TB treatment has an intensive phase and a continuation phase. We described these phases in the text. New smear positive TB patients: 2 months of intensive-phase and 4 months of persistent phase Re-treatment smear positive TB patients: 2 months of intensive-phase and 6 months of persistent phase 4. The type of this study might be cross-sectional study because your second aim of this study was not proving adherence influence factors but providing the hits of influence factors which is the function of cross-sectional study. If you accepted this suggestion, you need to change the calculation of sample size. Reply: Indeed, this is a cross-sectional study. This was described in the methods section. The sample size calculation was already based on a cross-sectional study design. 5. What was the multivariable analysis method that you used in this study? And please re-clarified the aim of using Chi-square test. Reply: We used logistic regression for multivariable analysis. We clarified this in the methods section. 6. It will be appreciated if the results of multivariable analysis displayed as single tables. Reply: Thanks for your suggestion, we did the recommended change. 7. Perhaps table 2 and table 3 needs to reorganize as two groups, namely, adherence and non-adherence, hence, you could show the both numbers of adherence and non-adherence patients in each item, as well as the results of OR and statistical tests which used to compare the difference between two groups. Reply (to 6 and 7): we used different logistic regression models to establish factors associated with non-adherence to anti-tb drugs, and with non-adherence to smear examinations. Therefore, the results of these models are displayed in two different tables. We apologize if this was not clear. We have adjusted the text in the methods section under data-analysis to clarify this. 8. More than 100 doctors from five provinces were interviewed. It would be an issue if you combined their attitudes when there were different regional typical attitudes towards non-adherence influence factors among five different provinces. For example, the non-adherence patients in different provinces might have different influence factors. Reply: We agree. However, we aimed to investigate the overall data of the five province, so as to provide evidence for implementation of the Stop TB strategy in China. Moreover, the small sample size likely does not have adequate power to draw reliable results through subgroup analysis.

4 3 9. As the highlight of this manuscript was mountain areas of China, did you detect any adherence influence factor which differed from other types areas? And please discuss more about your highlight detections. 10. It could have been interesting to compare your results with other countries related studies in discussion part. Reply (to 9 and 10): In the introduction and discussion section, we have included a short description of Chinese literature on adherence, and in the discussion section we have compared our results to findings of others. Minor Essential Revisions 1. The part of Study population and sampling was closer to Study sites than Study population. And the part of Data collection mixed too many different types information. Reply: We have combined the paragraphs on study population and sampling and sample size, and moved some text from data collection to this paragraph. 2. The first sentence of Adherence to taking of anti-tb drugs had a mistaken narration, forty-nine (9.4%) and same mistaken could be found at Adherence to sputum smear re-examinations, ninety-two (17.6%). Reply: The percentages correspond to the total number of patients: 49/524=9.4% and 92/524=17.6%. 3. You called table 1 at the first sentence of part of Adherence to taking of anti-tb drugs, I thought it might be table 2. Same mistaken could be found at the first sentence of Adherence to sputum smear re-examinations, it might be table 3. Reply: Thank you for noting this. We have corrected these mistakes. Reviewer's report The paper aims to describe treatment adherence of TB treatment in rural China. It is important in the TB field and would provide evidence on the DOT rate and actual adherence of TB treatment in China. Despite the importance of its topic, the authors have to consider the compulsory major revisions: 1) The review of TB patient adherence has not include some recent and important papers, such as (Sun et al., 2008), (Long et al., 2008), (Wei et al., 2008) and (Hu et al., 2008). As well, the authors did not review enough international literatures either. Reply: Thank you for providing relevant literature. We have added a summary of this literature in the introduction section, and have compared our results to this literature as well as international literature in the discussion section. Sun Q, Meng Q, Yip W, Yin X, Li H.DOT in rural China: experience from a case study in Shandong Province, China. Int J Tuberc Lung Dis Jun;12(6): Long Q, Li Y, Wang Y, Yue Y, Tang C, Tang S, Squire SB, Tolhurst R. Barriers to accessing TB diagnosis for rural-to-urban migrants with chronic cough in Chongqing, China: a mixed methods study. BMC Health Serv Res Oct 2;8:202. Wei X, Liang X, Liu F, Walley JD, Dong B. Decentralising tuberculosis services from county tuberculosis dispensaries to township hospitals in China: an intervention study. Int J Tuberc Lung

5 4 Dis May;12(5): Hu D, Liu X, Chen J, Wang Y, Wang T, Zeng W, Smith H, Garner P.Direct observation and adherence to tuberculosis treatment in Chongqing, China: a descriptive study. Health Policy Plan Jan;23(1): ) Its research method is confusing. I can understand that the study used a purposive sampling with stratification at the provincial level. It is far from a representative sample. However, the sample size of 500 was described in a way as representative sample. What is the indicator used in your sample? Reply: We tried to clarify the sampling method in the methods section of the manuscript. Within each province, mountainous counties were stratified into three groups based on GDP. From each GDP stratum, one county was randomly selected. With this method, we tried to make the sample as representative as possible. Anhui is different from all other four provinces in terms of geography, economy development. Anhui is not listed as a mountainous province in China. Thus, the study can not be called survey from mountainous provinces. Why you chose the five provinces for the study? Second, it will be nice to have at least two counties in one province. Reply: The study was done in these five provinces as a result of a shared interest of the researchers in this topic. We did not select mountainous provinces, we selected mountainous regions within the provinces. We selected three counties from each province. We tried to clarify this further in the methods section The authors used patient cards to measure adherence. In theory, the doctor put X on the date when patient has to take drugs and patients should circle it when swallowing drugs. However, in reality, patients may miss circling it or sometime Doctors just circle all Xs at the end of the treatment. Have the authors considered this as a potential bias? How did you deal with it? Reply: In addition to self-supervising of the patients, doctors or family members are both engaged in supervising the medication compliance of TB patients, they will put X on the date immediately after taking drugs. Furthermore, at the end of every month, doctors or family members will make an inventory of drug use, in order to avoid potential drug missing. 3) The authors should describe what DOT means in China, who conducted DOT, what is defined as DOT. In many cases, the village doctor may only remind patients to take drugs rather than watching them taking drugs, is it DOT or not? Reply: Besides the village doctors remind patients to take drugs, the family members also will watch them taking drugs. 4) The authors failed to do an in-depth interview with patients regarding reasons of non compliance and DOT. Many study has raised the issue of stigma, incontinence of seeing the village doctor and travel costs (Wei et al., 2009, Sun et al., 2008). It is linked with the implications of the paper. If you find DOT is not the case, should the China NTP enforce DOT as you find better association with adherence? This un-thoughtful implication will not only be biased, but also

6 5 have detrimental impact to the practice, because it did not consider the barriers from both patient and health system sides of implementing DOT. Instead, the authors should enrich themselves on the new WHO Stop TB strategy of Patient Support and supervision (Uplekar, 2006). Many RCTs and reviews have questioned the value and barriers of DOT (Walley et al., 2001),(Zwarenstein et al., 2000), (Wright et al., 2004, Newell et al., 2006). Reply: Thank you for providing this important literature. We agree that it is a limitation of this study that we were not able to include qualitative research, using in-depth interviews of patients. We have described this limitation in the discussion. 5) The authors have to understand how to report qualitative analysis. Normally, quality analysis have to report how the analysis was conducted (coding etc), and what themes/codes were identified. Authors here reported the qualitative study using numbers, which is not right. Reply: We do not consider our method a qualitative study method. We used structured questionnaires with open answers, and we counted the number of responses as described. This just provides a first insight into opinions of doctors, but is not qualitative research. 6) Written English is far from satisfactory for publication. Reply: We have adjusted grammar and spelling in the revised manuscript. Minor essential revisions: 1) Authors should be familiar with TB related terms. For example, using intermittent treatment regimen rather than standardized thrice weekly treatment in Para 4, Page 6. Reply: The term intermittent refers to the fact that the treatment is not daily. Intermittent therapy can be twice weekly or thrice weekly. To be as specific as possible, we used the term thrice weekly. This term is used more often, for example see Menzies et al., Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis, PLoS Med, ) It will be nice to describe clearly of DOT and its practice in the revision. Reply: Besides the village doctors remind patients to take drugs, the family members also will watch them taking drugs. 3) The sampling is not representative. So please avoid of being too much assertive in your conclusions. Reply: As explained above, we have tried to make the sample as representative as possible, using stratified sampling. We have adjusted the conclusions nonetheless and made them less assertive. Reviewer's report Title: Treatment adherence among sputum smear-positive pulmonary tuberculosis patients in mountainous areas in China Version: 1 Date: 22 April 2011 Reviewer: Vijay Bhagat Reviewer's report:

7 6 Major compulsory Revisions: 1. Objectives are incomplete and should also include adherence to reexamination of sputum smear. Reply: Treatment adherence refers both to adherence to drug taking and adherence to smear examinations. We have tried to further clarify this in the text. Minor Essential Revision: 2. Word 'rural' should be deleted from objectives. Reply: Done. All counties were rural, but we agree that we did not sample on rurality. 3. Word 'outcome' should be deleted from conclusions. Reply: We do not understand why we would need to remove the word outcome from the conclusions. Poor adherence is known to be associated with poor treatment outcomes. 4. In sample size authors should use study variables instead of 'exposed' and 'unexposed' Reply: The terms exposed and unexposed refer to all study variables. We calculated a sample size that would be able to detect differences in treatment adherence for several variables. 5. Authors should stick to objectives, term 'medical check-ups' should be deleted. Reply: Reply: Treatment adherence refers both to adherence to drug taking and adherence to smear examinations. Smear examinations are done during medical check-ups. We have tried to further clarify this in the text. 6. In study population and characteristics of results section; number and / or proportions should be shown as there is no reference in the table. Reply: We have adjusted numbers in the results section 7. In adherence to taking of anti TB drugs subsection of results second line; reference is not table 1 but table 2. Reply: We have corrected this. 8. In the adherence to sputum smear examination subsection line one; reference should be Table 3 instead of table 1. Reply: We have corrected this. Discretionary Revisions: 9. In the section on data collection broad objectives and contents of training programme may be stated. Reply: We have stated related content in the revised manuscript. 10. In adherence to taking of anti TB drugs subsection of results last line; has no relevance; can be deleted. Reply: We removed the last part of this sentence. 11. In the structured interviews with TB doctors subsection of results; Grass root workers play

8 7 important role in retrieval of TB patients. Directors have very little role in this matter. Reply: Township and village doctors are grass root workers in China TB control..