{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T10:10:22Z","timestamp":1767175822265,"version":"build-2238731810"},"update-to":[{"DOI":"10.12688\/gatesopenres.12775.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T00:00:00Z","timestamp":1520899200000}}],"reference-count":32,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T00:00:00Z","timestamp":1520899200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1032115"],"award-info":[{"award-number":["OPP1032115"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000200","name":"United States Agency for International Development","doi-asserted-by":"publisher","award":["AID-OAA-A-15-00045"],"award-info":[{"award-number":["AID-OAA-A-15-00045"]}],"id":[{"id":"10.13039\/100000200","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"Medical Research Council of South Africa","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004441","name":"Swedish International Development Cooperation Agency","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004441","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["gatesopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Gates Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    <ns4:italic>In vitro<\/ns4:italic>\n                    , animal, biological and observational clinical studies suggest that some hormonal methods, particularly depot medroxyprogesterone acetate \u2013 DMPA, may increase women\u2019s risk of HIV acquisition. DMPA is the most common contraceptive used in many countries worst affected by the HIV epidemic. To provide robust evidence for contraceptive decision-making among women, clinicians and planners, we are conducting the Evidence for Contraceptive Options and HIV Outcomes (ECHO) study in four countries with high HIV incidence and DMPA use: Kenya, South Africa, Swaziland, and Zambia (Clinical Trials.gov identifier NCT02550067).\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Study design:<\/ns4:bold>\n                    We randomized HIV negative, sexually active women 16-35 years old requesting effective contraception and agreeing to participate to either DMPA, the copper T 380A intrauterine device or levonorgestrel implant. Participants attend a contraception support visit after 1 month and quarterly visits thereafter for up to 18 months. Participants receive a standard HIV prevention package and contraceptive side-effect management at each visit. The primary outcome is HIV seroconversion. Secondary outcomes include pregnancy, serious adverse events and method discontinuation. The sample size of 7800 women provides 80% power to detect a 50% relative increase\u00a0in HIV risk between any of the three method pairs, assuming 250 incident infections per comparison.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Ethical considerations:<\/ns4:bold>\n                    Several WHO consultations have concluded that current evidence on HIV risk associated with DMPA is inconclusive and that a randomized trial is needed to guide policy, counselling and choice. Previous studies suggest that women without a specific contraceptive preference are willing to accept randomization to different contraceptive methods. Stringent performance standards are monitored by an independent data and safety monitoring board approximately every 6 months. The study has been conducted with extensive stakeholder engagement.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    The ECHO study is designed to provide robust evidence on the relative risks (HIV acquisition) and benefits (pregnancy prevention) between three effective contraceptive methods.\n                  <\/ns4:p>","DOI":"10.12688\/gatesopenres.12775.2","type":"journal-article","created":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T08:30:07Z","timestamp":1520929807000},"page":"17","update-policy":"https:\/\/doi.org\/10.12688\/gatesopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Rationale and design of a multi-center, open-label, randomised clinical trial comparing HIV incidence and contraceptive benefits in women using three commonly-used contraceptive methods (the ECHO study)"],"prefix":"10.12688","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3080-1007","authenticated-orcid":false,"given":"G. Justus","family":"Hofmeyr","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9873-3194","authenticated-orcid":false,"given":"Charles S.","family":"Morrison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jared M.","family":"Baeten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsungai","family":"Chipato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0587-7480","authenticated-orcid":false,"given":"Deborah","family":"Donnell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9636-165X","authenticated-orcid":false,"given":"Peter","family":"Gichangi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelly","family":"Mugo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7650-2929","authenticated-orcid":false,"given":"Kavita","family":"Nanda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Rees","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8300-7985","authenticated-orcid":false,"given":"Petrus","family":"Steyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"ECHO 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Ralph","year":"2014","journal-title":"Lancet."},{"key":"ref-31","doi-asserted-by":"publisher","first-page":"303-4","DOI":"10.1016\/S0140-6736(14)60097-0","article-title":"Research on hormonal contraception and HIV.","volume":"383","author":"W Cates","year":"2014","journal-title":"Lancet."},{"key":"ref-32","doi-asserted-by":"publisher","first-page":"354-6","DOI":"10.1016\/j.contraception.2014.08.007","article-title":"DMPA and HIV: why we need a trial.","volume":"90","author":"H Rees","year":"2014","journal-title":"Contraception."}],"container-title":["Gates Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T13:10:15Z","timestamp":1662383415000},"score":1,"resource":{"primary":{"URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,13]]},"references-count":32,"URL":"https:\/\/doi.org\/10.12688\/gatesopenres.12775.2","relation":{},"ISSN":["2572-4754"],"issn-type":[{"value":"2572-4754","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,13]]},"assertion":[{"value":"Indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/gatesopenres.13835.r26174, Audrey E. Pettifor, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 12 Jan 2018, version 1, indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v1#referee-response-26174","order":0,"name":"referee-response-26174","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/gatesopenres.13835.r26178, Sten Vermund, Yale School of Public Health, Yale University, New Haven, CT, USA, 15 Jan 2018, version 1, indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v1#referee-response-26178","order":1,"name":"referee-response-26178","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Charles Morrison<\/b>; \n<i>Posted: 26 Feb 2018<\/i>; The ECHO trial team has produced a highly useful protocol synopsis, along with an ethical rationale for the study itself.&nbsp; This reviewer found it clear and highly informative.  P.3: This sentence is helpful: \u201cThe ECHO Trial has currently completed enrollment and is following up study participants.\u201d&nbsp; However, a timeline for deliverables should be provided, as this will be every reader\u2019s first question! Also, the word \u201ccurrently\u201d won\u2019t play well in the article since readers will read this in 2024 as well as in 2018, so an anchor date should be substituted, e.g., \u201cAs of October 1, 2017, the ECHO Trial had completed enrollment\u2026. (or some such).\u201d  Author response:&nbsp; We have edited the paper as follows: \u201cThe ECHO Trial completed enrollment on 12 September 2017, with completion of participant follow up expected in 2018 and publication of results in 2019.\u201d&nbsp; And under study feasibility: \u201cOn 12 September 2017 ECHO Trial closed recruitment, having randomized 7,830 women with low refusal rates (data not shown).\u201d&nbsp;  Table 1: Can the authors comment how operational metrics are were met in the first year, say, of the trial\u2019s conduct?&nbsp; This could be brief, or even via an additional column in the Table.  Author response: As this is an ongoing randomized trial, our policy is to restrict disclosure of post-randomization data (other than reporting in confidence to the DSMB).&nbsp; Thus, we reported on the number of women enrolled and randomized but no other operational metrics.&nbsp;  P.5 (statistical analysis):&nbsp; This section was exceedingly brief.&nbsp; Given that there are 3 arms, that both intent-to-treat and as-treated analyses are proposed, and that the as-treated analysis will not follow randomization, a bit more analytic detail is warranted.  Because this manuscript focuses on the rationale for the study design and because we include the full study protocol as supplemental material, we have purposefully kept this section short.&nbsp; Nevertheless, we have added several additional sentences describing planned perfect-use and as-used analyses.&nbsp; Additional description can be found in section 8.2 of the study protocol.&nbsp;  P.6 (choice of interventions): While the IUD impact on HIV acquisition is unknown, I think that the authors should mention that its safety for use in HIV-infected women is established with RCT-level evidence (PMID: 17689627).&nbsp; This is important as a rationale for women who seroconvert in the trial to continue IUD use, if they wish.&nbsp;  Author response:&nbsp; Yes, there is limited data suggesting that the copper IUD is safe for HIV-infected women and WHO\u2019s medical eligibility criteria for contraceptive use gives this a \u20182\u2019 rating \u2013 i.e. that the benefits of use generally outweigh the risks for IUD use for women with asymptomatic or mild HIV disease.&nbsp; However, we would also need to then discuss the issue of DMPA and Lng implant use among HIV infected women.&nbsp; Because this issue was not salient to our choice of contraceptives to include in the study, it does not seem necessary or important to include this in this manuscript.  P.6 (sample size):&nbsp; It seems that powering the study to a 47% difference between groups is the study\u2019s principal limitation.&nbsp; Somewhere in the discussion, the prospect that a false negative trial will result if the incidence difference is a 1\/3\n<sup>rd<\/sup> or 2\/5\n<sup>ths<\/sup>, rather than a full 47%.  Author response:&nbsp; First, this was a mistake, the manuscript was changed to reflect the correct amount (45% difference).&nbsp; Secondly, we added under \u2018Questions the ECHO Study will address\u2019 the following: \u201cIt is also not powered to detect smaller effects than provided for by the sample size calculation (see \u2018Study power and effect size\u2019 below).\u201dAdditional note: Since this is a paper about trial methods, the &quot;datasets&quot; question is not really applicable.&nbsp;We agree.","URL":"https:\/\/gatesopenresearch.org\/articles\/1-17\/v2#referee-comment-3068","order":2,"name":"referee-comment-3068","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Bill and Melinda Gates Foundation [OPP1032115], the United States Agency for International Development (USAID) [AIDOAA-A-15-00045], the Swedish International Development Cooperation Agency (SIDA) and the Medical Research Council of South Africa.\n\nThe authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated.\n\nI confirm that the funders had a role in the design of the study, but had no role in the data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}