{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:26:14Z","timestamp":1784633174291,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010877","name":"ViiV Healthcare","doi-asserted-by":"publisher","award":["A18-1052"],"award-info":[{"award-number":["A18-1052"]}],"id":[{"id":"10.13039\/100010877","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81\/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to \u2018lipid and lipid-like molecules\u2019, \u2018organic acids and derivatives\u2019 and \u2018organoheterocyclic compounds\u2019. In pathway analysis, perturbed \u2018vitamin B1 (thiamin) metabolism\u2019, \u2018de novo fatty acid biosynthesis\u2019, \u2018bile acid biosynthesis\u2019 and \u2018pentose phosphate pathway\u2019 were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.<\/jats:p>","DOI":"10.3390\/v16040582","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T06:07:46Z","timestamp":1712729266000},"page":"582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies"],"prefix":"10.3390","volume":"16","author":[{"given":"Wilhelm A. J. W.","family":"Vos","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Department of Internal Medicine and Infectious Diseases, OLVG, 1091 AC Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadira","family":"Vadaq","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5852-6801","authenticated-orcid":false,"given":"Vasiliki","family":"Matzaraki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2880-9111","authenticated-orcid":false,"given":"Twan","family":"Otten","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2072-2532","authenticated-orcid":false,"given":"Albert L.","family":"Groenendijk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Department of Medical Microbiology and Infectious Diseases, ErasmusMC, Erasmus University, 3015 CN Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc J. T.","family":"Blaauw","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Department of Internal Medicine and Infectious Diseases, Elizabeth-Tweesteden Ziekenhuis, 5022 GC Tilburg, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise E.","family":"van Eekeren","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kees","family":"Brinkman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Infectious Diseases, OLVG, 1091 AC Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quirijn","family":"de Mast","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9197-8124","authenticated-orcid":false,"given":"Niels P.","family":"Riksen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton F. H.","family":"Stalenhoef","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"van Lunzen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre J. A. M.","family":"van der Ven","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem L.","family":"Blok","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Infectious Diseases, OLVG, 1091 AC Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janneke E.","family":"Stalenhoef","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Infectious Diseases, OLVG, 1091 AC Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zicari, S., Sessa, L., Cotugno, N., Ruggiero, A., Morrocchi, E., Concato, C., Rocca, S., Zangari, P., Manno, E.C., and Palma, P. (2019). 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