{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T21:57:37Z","timestamp":1774562257242,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/f1000research.15995.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T00:00:00Z","timestamp":1554249600000}}],"reference-count":47,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T00:00:00Z","timestamp":1554249600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PZ00P3_154730"],"award-info":[{"award-number":["PZ00P3_154730"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["32FP30-174281"],"award-info":[{"award-number":["32FP30-174281"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["33IC30_166819"],"award-info":[{"award-number":["33IC30_166819"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p><ns4:bold>Background: <\/ns4:bold>Dolutegravir-containing maintenance therapy is a promising simplification strategy for virologically suppressed HIV-infected individuals. However, most of the available data to inform this strategy come from small, uncontrolled studies. We estimated the proportion of HIV-infected patients experiencing virological failure (VF) and developing drug resistance on dolutegravir (DTG)-based maintenance therapy.<\/ns4:p><ns4:p> <ns4:bold>Methods: <\/ns4:bold>We searched Medline, Embase, Cochrane Central, Web of Science, and conference abstracts for studies assessing VF on DTG-based maintenance therapy. Studies including \u22655 adults with an undetectable viral load on antiretroviral therapy (ART) who switched to a DTG-based mono- or dual therapy were included. Pooled proportions of VF were estimated using random-intercept logistic meta-regression and acquired drug resistance mutations described for each strategy.<\/ns4:p><ns4:p> <ns4:bold>Results<\/ns4:bold>: Of 1719 studies considered, 21 met our selection criteria, including seven interventional and 14 observational studies. Eight studies including 251 patients assessed VF on DTG monotherapy and fourteen studies including 1670 participants VF on dual therapy. The participant\u2019s median age ranged from 43 to 63 years, their median nadir CD4 count from 90 to 399 cells\/\u00b5l, and 27.6% were female. The proportion of participants experiencing VF on DTG-monotherapy was 3.6% (95% confidence interval [CI] 1.9-6.7) at 24 weeks and 8.9% (95% CI 4.7-16.2) at 48 weeks. Resistance mutations developed in seven (3.6%) participants on DTG-monotherapy. Among patients on dual therapy, ten (0.7%, 95% CI 0.4-1.3) experienced VF by 48 weeks and none developed resistance to DTG. In adjusted analyses, VF at 24 weeks was less likely on dual therapy than on monotherapy (adjusted odds ratio: 0.10, 95% CI 0.03-0.30).<\/ns4:p><ns4:p> <ns4:bold>Conclusions:<\/ns4:bold> Whereas VF is relatively common on DTG maintenance monotherapy, DTG-based dual therapy appears to be a promising simplification strategy for individuals with a suppressed HIV viral load on triple-ART.<\/ns4:p>","DOI":"10.12688\/f1000research.15995.2","type":"journal-article","created":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T13:40:12Z","timestamp":1554298812000},"page":"1359","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis"],"prefix":"10.12688","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5278-8763","authenticated-orcid":false,"given":"Gilles","family":"Wandeler","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Buzzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanina","family":"Anderegg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delphine","family":"Sculier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"B\u00e9guelin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Egger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1137-6826","authenticated-orcid":false,"given":"Alexandra","family":"Calmy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2019,4,3]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"734-9","DOI":"10.1056\/NEJM199709113371102","article-title":"Treatment 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When including this variable, the tau-squared were reduced from 1.17 (95% CI 0.33-2.19) to 0.00 (95% CI 0.00-1.11) in the 24 week analysis and from 1.37 (95% CI 0.54-2.15) to 0.00 (95% CI 0.00-1.00) in the 48 week analysis. The inclusion of other variables did not impact the estimates of tau-squared.\u201d \n<i>The first sentence says explicitly that only the treatment strategy was found to contribute to heterogeneity, and we are not sure how to make the conclusion more explicit.<\/i> \n<i>The second sentence quantifies the statement.<\/i>  (page 9) Please provide some references (at least one) for the impact of M184V on viral fitness (this one is of interest for DTG-based regimen: doi: 10.1097\/QAD.0000000000001191) \n<i>We included references in the new version of the paper (see 2<sup>nd<\/sup> paragraph in the discussion section).<\/i>&nbsp;  (page 9) I think authors should provide some data on VF (%, emerging mutations) during switch from a triple therapy to another one (in order to have an \u201chistorical comparator\u201d for dual therapy) \n<i>We added a comment in the 1st paragraph of the discussion section.<\/i> \n<i>&laquo; We performed a comprehensive systematic review of studies that reported on VF among patients switched to DTG-based maintenance therapy. Our meta-analysis shows that DTG-based dual therapy is successful in sustaining virological control in ART-experienced HIV-infected patients: only 12 of 1670 (0.7%) experienced a VF and none of them developed resistance mutations to DTG. For comparison, recent trials testing InSTI-based triple maintenance combinations showed a similar virological failure rate (ref ci dessous 1-4). On the contrary, 16 of 251 (6.4%) individuals switched to DTG monotherapy had a VF, of which more than one-half developed resistance to DTG. &raquo;<\/i>  (page 10) \u201cIn addition, more data on the activity of DTG-based simplified regimens in compartments other than blood are needed.\u201d There are some references for mono- or dual-therapy in the genital tract (Hocqueloux et al.1&nbsp;and Gianella et al.2) and CNS (Doco Lecompte et al.3) \n<i>We modified the text in the new version of the paper (see 4<sup>th<\/sup> paragraph of the discussion section).<\/i> &laquo; In addition, more data on the activity of DTG-based simplified regimens in compartments other than blood are needed. Letendre et al. Showed that DTG achieved therapeutic concentrations in the central nervous system (CNS), with a CNS penetration effectiveness score of four. In the MONODO study, all patients had an undetectable plasma HIV viral load at week 24 on DTG maintenance monotherapy, whereas only one had a detectable viral load in the cerebrospinal fluid (\n<i>ref 21 by Sculier et al<\/i>). Moreover, levels of HIV-1 RNA in the genital tract on DTG-monotherapy \n<i>(nouvelle ref 1 )<\/i> and under DTG-3TC \n<i>(nouvelle ref 2) <\/i>were comparable to those under standard cART. However, these results were based on a very small sample of patients and data from individuals on simplified, DTG-based therapies are lacking. &raquo;  \n<i>(<\/i>page 10) Authors should cite recent reports (all communicated at the IAS 2018 in Amsterdam) confirming their conclusions, even though they cannot include them in the analyses: two randomized-controlled clinical trials on DTG monotherapy (Braun et al.4 and Hocqueloux et al.5), the extended follow-up of the SWORD trials at week 100 (Aboud et al.6) and results of the GEMINI trials (Cahn et al.7). \n<i>In accordance&nbsp; with the pre-specified analysis plan described in our study protocol, we decided not to include these results as they had not been presented at the time of the last version of our analyses.<\/i>  References: (references 25 and 28) I think two references (Gantner and Bonijoly) are duplicates (as they are based on the analyze of the same database; Bonijoly et al. have included more patients \/ with longer duration of follow-up than Gantner). \n<i>We agree with the reviewer. However, as one study reported 24 weeks and the other 48 weeks outcomes, we decided to keep both estimates. Furthermore, we did not combine them as the study populations were not exactly the same.<\/i>","URL":"https:\/\/f1000research.com\/articles\/7-1359\/v2#referee-comment-4393","order":3,"name":"referee-comment-4393","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.17470.r37756, Omar Sued, Fundaci\u00f3n Hu\u00e9sped, Buenos Aires, Argentina, 10 Sep 2018, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/7-1359\/v1#referee-response-37756","order":4,"name":"referee-response-37756","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Gilles Wandeler<\/b>; \n<i>Posted: 03 Feb 2019<\/i>; Note that reference 9 is for naive patients, and not for switching. \n<i>We agree with the comment. However, we prefer to keep this unchanged as we used the reference in a generic sentence.<\/i>  REPRODUCIBILITY: Risk of bias checklist is not available. It could be good idea to include as supplementary material a sample of the checklist of assessment of bias. \n<i>We used the Cochrane Collaboration list to assess risk of bias among the two RCT included in the meta-analysis. For observational studies, it was not appropriate to use the ROBINS-I tool, as we only considered data from the group of patients maintenance therapy. Thus, we assessed the population characteristics and missing outcome data for each study. This is explained in detail in the methods section of the published manuscript.<\/i>  The number of reviewed studies is 21, but the authors reported 8 for monotherapy and 14 for dual therapy without clarifying that some are focused on both strategies. \n<i>We explained this in the text (see data analysis section).<\/i>  Similarly, in figure 2, the name of the author is followed by the (n) of participants. This makes the reader think this is the reference. Please consider to add the reference number in this place, and an additional column for &quot;n&quot; \n<i>The reference is indicated differently in the text and we decided to keep the figure 2 unchanged.<\/i>  Regarding the phrase (page 9) &quot;These three patients did not have a history of previous VF and had a suppressed HIV viral load for several years before switching to DTG-monotherapy&quot;. Please comment if patients experiencing INSTI resistance in monotherapy were previously exposed to INSTI. \n<i>We included this information in the new version of the paper (see drug resistance section).<\/i>  Please review Table 2, because some INSTI mutations are not in bold, and the $ symbol is not explained in notes \n<i>We adapted the table 2 in the new version of the paper.<\/i>  In discussion you mention &quot;For instance, no virological failures were noted among patients on DTG\/3TC despite the presence of a 184V mutation at the time of simplification in several studies.&quot; but you are not showing this result. Given the potential clinical importance of this issue, consider show how many participants had this mutation and show the outcomes. \n<i>As this information was missing from most studies, we described cases where reported but could not formally evaluate the association between specific mutations and treatment failure.<\/i>  In the discussion, these phrases look similar: First Paragraph: &quot;Although the proportion of patients experiencing a confirmed viral rebound on DTG-monotherapy does not seem to be higher than in patients on PI-monotherapy, the risk of losing future treatment options is higher with DTG-monotherapy&quot; Second Paragraph &quot;Although the proportion of patients experiencing a confirmed viral rebound on DTG-monotherapy does not seem to be higher than in patients on PI-monotherapy, their chances of losing future treatment options is higher than reported in most PI-monotherapy trials&quot; \n<i>Adapted in the text (doubled sentence cancelled from the 2nd paragraph of the discussion section).<\/i>  Why to mention DTG-XTC if no study was presented with FTC?. I would suggest to stick to the presented data, therefore to discuss about 3TC. \n<i>Adapted in the new version of the paper (see discussion section): XTC canceled and FTC used in reference to study using FTC.<\/i>  \n<i>The phrase &quot;In addition to the studies on maintenance therapy39,40, clinical trials are also assessing the efficacy of DTG\/XTC in treatment-na&iuml;ve patients&quot; should be updated based on the results of GEMINI1&amp;2.<\/i> \n<i>Adapted in the new version of the paper (see discussion section)<\/i> &nbsp; It could be good to try to explain the higher rate of failure in those three trials in dual therapy (Blanco, and Navarro). \n<i>This is an important comment. However, available data within these studies did not allow us to make specific conclusions.<\/i> \n<i>Blanco dual: 3.45% VF at W24. Bonijoly: 1.49% VF at W48. Navarro: 3.70% of VF at W48. Taiwo: 2.27% VF at W 24 and W48 All others dual &lt; 1% of VF both at 24 and 48 weeks.<\/i>  Please check the failure rate in figure 2 for Taiwo (44 patients with failure 2.7%). \n<i>We checked again data and did not find any error in the figure.<\/i> \n<i>Only one of the 44 patients exposed to dual therapy had a rel VF (1\/44 0 2.7%). with the FDA snapshot algorithm 2 other patients (one lost to FUP and one switching therapy because AE) were considered as failure by authors at W24.<\/i>","URL":"https:\/\/f1000research.com\/articles\/7-1359\/v2#referee-comment-4392","order":5,"name":"referee-comment-4392","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This study was supported by the Swiss National Science Foundation (Ambizione-PROSPER fellowship PZ00P3_154730 to GW, grant 32FP30-174281 to ME, and grant 33IC30_166819 to AC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":6,"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.Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).","order":0,"name":"copyright-info","label":"Copyright"}]}}