Establishing a framework towards monitoring HCV microelimination among men who have sex with men living with HIV in Germany: A modeling analysis

Lara K. Marquez; Patrick Ingiliz; Christoph Boesecke; Ivanka Krznaric; Knud Schewe; Thomas Lutz; Stefan Mauss; Stefan Christensen; Jürgen K. Rockstroh; Sonia Jain; Feng He; Joel O. Wertheim; Natasha K. Martin

doi:10.1371/journal.pone.0267853

Peer Review History

Original SubmissionFebruary 8, 2022
14 Mar 2022 Decision Letter - Chen-Hua Liu, Editor PONE-D-22-03984Establishing a framework towards monitoring HCV microelimination among HIV-positive men who have sex with men in Germany: A modeling analysisPLOS ONE Dear Dr. Marquez, 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. Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact. For Lab, Study and Registered Report Protocols: These article types are not expected to include results but may include pilot data. ============================== Please submit your revised manuscript by Apr 28 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Chen-Hua Liu Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. 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 https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. Thank you for stating the following in the Competing Interests section: [NKM has received unrestricted research grants and honoraria from Gilead and Merck. CB reports personal fees from AbbVie, Gilead, Johnson & Johnson, Merck Sharp & Dohme (MSD), and ViiV and grants from DZIF (German Center for Infection Research), Deutsche Leberstiftung, and Hector Stiftung. TL reports grants from AbbVie, Gilead Sciences, ViiV, Janssen-Cilag, MSD, Deutsche Leberstiftung, and DAGNÄ for scientific work. SC reports personal fees from Gilead, AbbVie, ViiV, MSD, and Indivior. S. M. reports personal fees from AbbVie, Gilead, and MSD. JKR reports personal fees from Abivax, AbbVie, Gilead, Janssen, Merck, and ViiV, outside the submitted work. PI has received unrestricted research grants from Gilead (IN-DE-987-4637 and IN-FR-980-6332), a research grant from Abott Laboratories, and speaker fees from Gilead, AbbVie, ViiV, MSD, and Bristol-Myers Squibb. JOW receives funding from CDC via contracts to his institution. LKM, FH and SJ have no conflicts to declare.] Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. 4. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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 Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: 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: This manuscript described “Establishing a framework towards monitoring HCV microelimination among HIV-positive men who have sex with men in Germany: A modeling analysis.” The result presents that HCV elimination among HIV+ MSM in Germany requires further DAA scale-up among those newly diagnosed combined with efforts to treat those previously diagnosed but untreated. In general, this is a well-written manuscript. Other points in this manuscript needed to be clarified are listed below: 1. HIV+MSM : I will suggest “MSM living with HIV” in aspect of terminology Minor revisions: 1. Page 4, line 83: the subject is missing, Although “what” often initiated… 2. Page 13, line 202: please make sure the number of confidence interval is correct 2.5% and 97.5% ? 3. References: please unify the standard form of references, such number of authors, doi, PMID, etc…. Reviewer #2: 1. The modeling presumed that all HIV+MSM are well monitored with regular HCV testing. Considering the retention in care, will loss to follow up in HIV care might affect HCV elimination? 2. Is there any reason that scenario 5 choose to treat “15% per year” of previously diagnosed and untreated infections! 3.Recently, some experts use the pool serum to detect the relapse rate of HCV among the groups including previously DAA treatment experiences HCV patients with elevated liver function test, sexual transmitted disease and found some relapses cases! Such results will influence the HCV elimination in future! Does our model can predict or avoid such influences? 4. For HIV infected patients, same day therapy seems to be helpful to reduce the incidence! According to your model, if we further shortening the duration of diagnosis to treatment of HCV, will it be more helpful to achieve the goal of elimination of HCV infection? ****** 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. Reviewer #1: Yes:** CHENG CHIEN-YU Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: PONE-D-22-03984 reviewer comment.docx https://doi.org/10.1371/journal.pone.0267853.r001
Revision 1
13 Apr 2022 Author Response Dear Editor, We would like to submit the following publication “Establishing a framework towards monitoring HCV microelimination among men who have sex with men living with HIV in Germany: A modeling analysis,” (PONE-D-22-03984) for re-consideration as an original research article in PLOS ONE. We have revised the article based on the comments from reviewers. We thank the reviewers for their comments and have responded to the comments point by point below, with the changes tracked in the submitted version. We believe the manuscript has been strengthened with the suggested edits. Additional journal requirements noted in the revision letter for competing interests and financial disclosures have been included in the cover letter. Please let us know if there are any further questions or concerns. Sincerely, Lara Marquez, on behalf of the coauthors --------------------------------------------------------------------------------------------------------------------------- This manuscript described “Establishing a framework towards monitoring HCV microelimination among HIV-positive men who have sex with men in Germany: A modeling analysis.” The result presents that HCV elimination among HIV+ MSM in Germany requires further DAA scale-up among those newly diagnosed combined with efforts to treat those previously diagnosed but untreated. In general, this is a well-written manuscript. Other points in this manuscript needed to be clarified are listed below: Reviewer #1, Comment #1: HIV+MSM: I will suggest “MSM living with HIV” in aspect of terminology Author reply: We thank the reviewer for their comments and agree that this terminology is much improved by this suggestion. We have incorporated this throughout the manuscript, figures, and supplementary information, replacing any occurrence of ‘HIV+ MSM’ with ‘MSM living with HIV.’ Reviewer #1, Minor revisions comment #1: Page 4, line 83: the subject is missing, Although “what” often initiated… Author reply: We have revised this sentence to be more clear. Introduction, page 4, lines 86-88: “Although MSM living with HIV and HCV were often initiated onto treatment with interferon-based regimens in the early phase of infection, cure rates with interferon-based regimens were insufficient and adverse events often limited treatment uptake [5].” Reviewer #1, Minor revisions comment #2: Page 13, line 202: please make sure the number of confidence interval is correct 2.5% and 97.5%? Author reply: We confirm that we have shown the 2.5%-97.5% confidence boundaries but have revised the text slightly to note confidence percentile for these bounds, rather than interval. Results, page 13, lines 210-212: “Diamonds represent mean epidemiological data estimate; whiskers, 95% confidence intervals; solid lines, the mean model trajectories; dashed lines, the 2.5% and 97.5% confidence percentiles of trajectories.” Reviewer #1, Minor revisions comment #3: References: please unify the standard form of references, such number of authors, doi, PMID, etc…. Author reply: We have revised the references (On pages 20-28) to be uniform throughout. Reviewer #2, Comment #1: The modeling presumed that all HIV+MSM are well monitored with regular HCV testing. Considering the retention in care, will loss to follow up in HIV care might affect HCV elimination? Author reply: We appreciate this question from the reviewer. Within this cohort in Germany, between 2014-2020, HCV treatment coverage with direct acting antiviral therapy was >80% among MSM living with HIV who did not spontaneously clear HCV infection and therefore believe dropout rate to be low. However, despite a high proportion of MSM living with HIV receiving antiretroviral therapy (ART; UNAIDS, 2021), recent evidence from two large, multicenter cohort studies among PLHIV in Germany showed that 93% of people living with diagnosed HIV were on ART (an der Heiden et al., 2019) and further nearly 2/3 of PLHIV initiated onto ART have experienced a gap (median time per gap in Germany: 223 days; Schmidt et al. 2021). Given this high proportion of PLHIV experiencing at least one gap in HIV care and in receiving ART, HCV diagnosis and treatment could be delayed if an individual is infected with HCV during this gap period. As such, this could delay HCV elimination efforts and have added new text in the discussion section highlighting this. Discussion, page 17, lines 300-308: “We note that retention in care strategies remain important in the HCV elimination era. Retention to HCV care appears high among MSM living with diagnosed HIV/HCV (with >80% of MSM living with HIV initiated onto HCV treatment). Further, timely diagnosis of HCV among MSM living with diagnosed HIV is facilitated by high retention in HIV care (>93% of PLHIV are on ART [an der Heiden et al., 2019]). Nevertheless, a high proportion of individuals living with diagnosed HIV experience gaps in care (roughly 2/3 have experienced a gap, with a median time per gap of 223 days in Germany [Schmidt et al. 2021]). If MSM are infected during one of these gap periods, this could delay HCV diagnosis and treatment and be an obstacle to HCV elimination.” Reference: 1. UNAIDS. Germany HIV and AIDS Estimates. 2021. Accessed on 04 April 2022 from https://www.unaids.org/en/regionscountries/countries/germany 2. an der Heiden M, Marcus U, Kollan C, Schmidt D, Gunsenheimer-Bartmeyer B, Bremer V. Schätzung der Zahl der HIV-Neuinfektionen und der Gesamtzahl von Menschen mit HIV in Deutschland, Stand Ende 2018. Epidemiologisches Bulletin. 2019;(46):483–92. 3. Schmidt, D., Kollan, C., Stoll, M. et al. Everything counts - a method to determine viral suppression among people living with HIV using longitudinal data for the HIV care continuum - results of two large, German, multi-center real-life cohort studies over 20 years (1999–2018). BMC Public Health 21, 200 (2021). https://doi.org/10.1186/s12889-020-10088-7 Reviewer #2, Comment #2: Is there any reason that scenario 5 choose to treat “15% per year” of previously diagnosed and untreated infections! Author reply: We selected to treat 15% of previously diagnosed and untreated infections per year based on what was feasible and achievable in this setting. This was informed by data from the NoCo Cohort of MSM living with HIV and HCV in Germany. We have added further clarification in text for this. Discussion, Limitations, page 19, lines 364-367: “Finally, our study explored treating 15% of previously diagnosed and untreated infections per year, based on expected feasibility. Though this was informed by data from the NoCo cohort of MSM living with HIV and HCV in Germany, further research could explore feasibility of treating more than 15% of previously diagnosed and untreated infections per year.” Reviewer #2, Comment #3: Recently, some experts use the pool serum to detect the relapse rate of HCV among the groups including previously DAA treatment experiences HCV patients with elevated liver function test, sexual transmitted disease and found some relapses cases! Such results will influence the HCV elimination in future! Does our model can predict or avoid such influences? Author reply: Our model accounts for both acute infection and reinfections (including those previously treated with DAAs). As such, we incorporate the potential impact of reinfections on reducing the cost-effectiveness of testing and treatment. Due to the risk of reinfection, MSM with HIV are recommended for routine testing after SVR. We agree with the reviewer that pooled testing could be used for surveillance in this group, however we note that pooled testing is most useful in situations where the prevalence of infection is low and therefore it is more efficient and cost-effective to pool. Because incidence of reinfection can be high among MSM previously infected with HCV (Ingiliz et al., 2017), pooling could unnecessarily delay timely identification of infection in this group and may not be more efficient than unpooled testing. Analyses examining the value of pooled testing in relation to prevalence of infection in a subgroup and time to pool would be useful to assess the relative benefits of this strategy among MSM. References: 1. Ingiliz P, Martin TC, Rodger A, Stellbrink H-J, Mauss S, Boesecke C, et al. HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe. J Hepatol. 2017;66(2):282–7. Available from: https://doi.org/10.1016/j.jhep.2016.09.004 2. Aguilera A, Pereira S, Fuentes A, de Salazar A, Trastoy R, Navarro D, Picchio CA, Lazarus JV, García F. Pooling samples for hepatitis C RNA detection. Lancet Gastroenterol Hepatol. 2021 Aug;6(8):608-609. doi: 10.1016/S2468-1253(21)00217-X. PMID: 34246354; PMCID: PMC8266286. Reviewer #2, Comment #4: For HIV infected patients, same day therapy seems to be helpful to reduce the incidence! According to your model, if we further shortening the duration of diagnosis to treatment of HCV, will it be more helpful to achieve the goal of elimination of HCV infection? Author reply: Yes, we agree that our results support that further shortening the duration between time to diagnosis and treatment adds additional prevention benefits. As such, this strategy could be a useful tool to achieving HCV elimination. We further highlight this benefit in the Discussion section. Discussion, page 17, lines 298-300; 308-310: “However, reaching the HCV incidence elimination target is possible through the implementation of combination strategies which shorten the time between diagnosis and treatment and treat previously diagnosed and untreated. This underscores the importance of exploring strategies which do not solely rely on treatment alone but may require programmatic changes which has also been explored in other settings...” Attachments Attachment Submitted filename: ResponsetoReviewers.docx https://doi.org/10.1371/journal.pone.0267853.r002
18 Apr 2022 Decision Letter - Chen-Hua Liu, Editor Establishing a framework towards monitoring HCV microelimination among men who have sex with men living with HIV in Germany: A modeling analysis PONE-D-22-03984R1 Dear Dr. Marquez, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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. Kind regards, Chen-Hua Liu Academic Editor PLOS ONE Reviewers' comments: 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: I fully accept author's revision of manuscript and responses to my comments. Also, the author reply my comments with adequate references. ****** 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: Yes:** Cheng Chien-Yu https://doi.org/10.1371/journal.pone.0267853.r003
Formally Accepted
3 May 2022 Acceptance Letter - Chen-Hua Liu, Editor PONE-D-22-03984R1 Establishing a framework towards monitoring HCV microelimination among men who have sex with men living with HIV in Germany: A modeling analysis Dear Dr. Marquez: I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Chen-Hua Liu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0267853.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .