Efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region: A network meta-analysis

Cho Naing; Maxine A. Whittaker; Norah Htet Htet; Saint Nway Aye; Joon Wah Mak

doi:10.1371/journal.pone.0225882

Peer Review History

Original SubmissionSeptember 24, 2019
5 Nov 2019 Decision Letter - Gordon Langsley, Editor PONE-D-19-26846 Efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region: A network meta-analysis PLOS ONE Dear Cho Naing, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. I would like to apologise for the time taken to come to a decision on your submission. This was due to the many reviewers contacted refusing, or simply not replying, when asked to examine your manuscript. Finally, one expert accepted and his recommendation is minor revision. If you clearly point out in your rebuttal letter how you modified your revision to address each and every one of the comments then I should be able to make a rapid editorial decision without sending your revision back out for review. We would appreciate receiving your revised manuscript by Dec 20 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. 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We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: https://apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf?ua=1 https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-11-153 http://www.ajtmh.org/content/journals/10.4269/ajtmh.2006.74.991#html_fulltext https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-018-3506-x https://aac.asm.org/content/aac/47/3/901.full.pdf In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. 3.Thank you for stating the following financial disclosure: "none". Please provide an amended Funding Statement that declares all the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." * Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Suggest defining “Asian region” in Methods-Study selection (since this definition was used to include studies in the analysis) or the Introduction (since line 84 may suggest to some readers that Asian region is synonymous with GMS). Suggest defining uncomplicated malaria and indicating whether this definition includes patients with hyperparasitemia but without signs or symptoms of severe malaria. Line 45: Suggest assigning abbreviations for all treatments at first use here and using them consistently throughout the manuscript, tables, and figures. Line 57: The conclusion that DHP is superior to AL is not supported by the OR (95% CI) data in line 57 and Table 2. Lines 59, 308, 312: The suggestion to analyze safety information in future studies seems to come out of nowhere. Does it relate to the benefit vs. harm concept mentioned in line 242? In any case, suggest mentioning at least one result in the Abstract to support this statement. Line 100: Suggest providing 1-2 examples of conflicting results in other studies that the present study was designed to address. Line 108: This sentence suggests that ASCQ (mentioned in the Abstract) is currently used in Asian region. Is this true? If so, where? How is “currently” defined? Line 154: Does “preferred” mean that the ITT population analysis was used over another analysis whenever it was available, or that only ITT population analyses were used? Line 191: Suggest indicating that 5043 refers to total number of patients. Line 197: Suggest stating the range of % males as well. Line 302: This statement seems misleading considering that SP and CQ are almost completely ineffective in Southeast Asia due to drug resistance. Suggest revising. In general, the authors should state the caveat that one drug regimen is better than another only if current drug-resistance patterns are at play. For example, AL may be far superior to DHP in areas where both artemisinin and piperaquine resistance are prevalent. Table 1: Funding for Studies 1, 12 and 16 are missing. If information is not available, suggest stating so. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. 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Revision 1
13 Nov 2019 Author Response Q/1 Suggest defining “Asian region” in Methods-Study selection (since this definition was used to include studies in the analysis) or the Introduction (since line 84 may suggest to some readers that Asian region is synonymous with GMS). A/1 We have provided an operational definition of the Asian region.Thank you Methods Selection of study An operational definition of the Asian region for this particular study covers countries in three regions of Southeast Asia, South Asia and East Asia. /2 Suggest defining uncomplicated malaria and indicating whether this definition includes patients with hyperparasitemia but without signs or symptoms of severe malaria. A/2 According to the WHO revised criteria, P. falciparum parasitaemia >5% or > 200,000/μl is one of the feature of severe malaria. In the present meta-analysis study, some studies indicated specific information on parasitemia as less than 200,000/μl. But, not all trials provided such information. All studies had confirmed P. falciparum and excluded patients with clinical features of severe malaria as described by WHO. Hence, we selected the studies if they had indicated patients with uncomplicated malaria (excluding severe malaria) are recruited. As suggested, we now have provided additional information for clarification. Thank you Selection of study Uncomplicated malaria caused by the P. falciparum parasite in this study is defined as patients with the presence of P. falciparum and having symptoms that are non-specific and with no clinical or laboratory findings of severe organ dysfunction. Q/3 Line 45: Suggest assigning abbreviations for all treatments at first use here and using them consistently throughout the manuscript, tables, and figures. A/3 We have updated the abbreviations in consistency manner throughout the manuscript. In the abstract, please allow us to use abbreviations, only if it is necessary to repeat. Thank you Q/4 Line 57: The conclusion that DHP is superior to AL is not supported by the OR (95% CI) data in line 57 and Table 2. A/4 Please, accept our apology for a typing mistake in the previous version. It should be described as (OR 2.5, 95%CI: 1.08 to 5.8) as shown in Table 2 pertinent to ‘Network estimate’ column. We have done the corrections in this revised version Moreover, we have briefly added a caution over drug resistance status of the area. Thank you for giving the valuable inputs. Abstract Results In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8). There is low certainty evidence due to limited number of studies and small trials. Conclusion The findings suggest the superiority of DHP (3–day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only, if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. Text Results Fourteen-node analysis For instance, DHP compared to AL in a single trial and there was a superiority of DHP in cure rate at day 28 (OR 2.5, 95%CI: 1.08 to 5.8) (Table 2) Q/5 Lines 59, 308, 312: The suggestion to analyze safety information in future studies seems to come out of nowhere. Does it relate to the benefit vs. harm concept mentioned in line 242? In any case, suggest mentioning at least one result in the Abstract to support this statement. Q/5 We gratefully agreed on the inputs given. We have recommended future studies to included safety analysis so as to cover the benefit versus harm concept. Thank you A/5 Abstract Conclusions In the light of benefit versus harm concept, future analysis including safety information are recommended. Discussion Implications Moreover, in the light of benefit versus harm concept, a NMA of the relative safety of different antimalarial treatment is needed. Conclusions In the light of benefit versus harm concept, future analysis with safety information is recommended. Q/6 Line 100: Suggest providing 1-2 examples of conflicting results in other studies that the present study was designed to address. A/6 We have added salient examples in brief. Thank you Text Introduction For example, a review by Zani and associates reported that in Africa, there was better efficacy in DHP than AL at day 28. However, such relationship was not shown in Asia [7]. This reflects that efficacy of antimalarial is related to whether the area is with artemisinin-sensitive parasite populations or not [6,9]. Q/7 Line 108: This sentence suggests that ASCQ (mentioned in the Abstract) is currently used in Asian region. Is this true? If so, where? How is “currently” defined? A/7 Our main focus was the currently used 5 ACTs including DHP, AL. These currently used drugs compared with other antimalarials. All comparators are not currently used antimalarials (e.g ASCQ in this case). We have indicated the comparator drugs as available in the trials. For clarity, we have removed this result from abstract. To be more specific, we have added a concern over an issue of drug resistance for an interpretation of the results. We very much appreciated the points provided. Thank you Abstract Results In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8).There is low certainty evidence due to limited number of studies and small trials. Conclusions The findings suggest the superiority of DHP (3–day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only, if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. Q/8 Line 154: Does “preferred” mean that the ITT population analysis was used over another analysis whenever it was available, or that only ITT population analyses were used? A/8 For clarity, we have updated this information. Thank you for the valuable input. Data synthesis We preferred the intention-to-treat (ITT) analysis over another analysis whenever it was available. Q/9 Line 191: Suggest indicating that 5043 refers to total number of patients.We have clarified this information. Thank you A/9 Results After removal of duplicates and screening of titles and abstracts, 34 full-text papers were evaluated and 17 studies, incorporating 5043 total number of patients were finally included in this review [14, 23-38]. Q/10 Line 197: Suggest stating the range of % males as well. A/10 We have updated this information. Thank you The majority of participants in the studies included were males (range from 51% to 96%) with mean age between 5.9 to 29 years. Q/11 Line 302: This statement seems misleading considering that SP and CQ are almost completely ineffective in Southeast Asia due to drug resistance. Suggest revising. We have clarified the statement. Thank you Implications There is evidence that DHP has better treatment outcome than monotherapy such as SP and CQ, which are almost completely ineffective in Southeast Asia due to drug resistance. Q/12 In general, the authors should state the caveat that one drug regimen is better than another only if current drug-resistance patterns are at play. For example, AL may be far superior to DHP in areas where both artemisinin and piperaquine resistance are prevalent. Much appreciated for giving the valuable inputs. A/12 We have updated the conclusion, taking the points provided. Thanking you Abstract Conclusions Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. Text Conclusions The findings suggest the superiority of DHP to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only, if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent [7,9]. Q/13 Table 1: Funding for Studies 1, 12 and 16 are missing. If information is not available, suggest stating so. A/13 Thank you for pointing out the missing information. We have updated the Table 1 accordingly. Table 1 Journal requirements: 1 When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pd A/ We have followed the PLOS One format. Thank you 2 We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: https://apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf?ua=1 https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-11-153 http://www.ajtmh.org/content/journals/10.4269/ajtmh.2006.74.991#html_fulltext https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-018-3506-x https://aac.asm.org/content/aac/47/3/901.full.pdf In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. We have updated the whole text and improved any duplication. A/ We have checked % similarity and it shows 20% similarity (attached as other file). We sincerely feel that this is an acceptable limit for a meta- analysis study. Thank you 3 Thank you for stating the following financial disclosure: “none". a. Please provide an amended Funding Statement that declares all the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. b. Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." * Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4 Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files A/We have placed Tables in the manuscript. Thank you Attachments Attachment Submitted filename: Our reply_ (12112019).doc https://doi.org/10.1371/journal.pone.0225882.r002
15 Nov 2019 Decision Letter - Gordon Langsley, Editor Efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region: A network meta-analysis PONE-D-19-26846R1 Dear Dr. Cho Naing, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With kind regards, Gordon Langsley Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Authors: Thank you for addressing my comments and incorporating revisions into the manuscript, much appreciated. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No https://doi.org/10.1371/journal.pone.0225882.r003
Formally Accepted
21 Nov 2019 Acceptance Letter - Gordon Langsley, Editor PONE-D-19-26846R1 Efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region: A network meta-analysis Dear Dr. Naing: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Gordon Langsley Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0225882.r004

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