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Article

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies

by
Wilhelm A. J. W. Vos
1,2,*,
Nadira Vadaq
1,
Vasiliki Matzaraki
1,
Twan Otten
1,
Albert L. Groenendijk
1,3,
Marc J. T. Blaauw
1,4,
Louise E. van Eekeren
1,
Kees Brinkman
2,
Quirijn de Mast
1,
Niels P. Riksen
1,
Anton F. H. Stalenhoef
1,
Jan van Lunzen
1,
Andre J. A. M. van der Ven
1,
Willem L. Blok
2 and
Janneke E. Stalenhoef
2
1
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
2
Department of Internal Medicine and Infectious Diseases, OLVG, 1091 AC Amsterdam, The Netherlands
3
Department of Medical Microbiology and Infectious Diseases, ErasmusMC, Erasmus University, 3015 CN Rotterdam, The Netherlands
4
Department of Internal Medicine and Infectious Diseases, Elizabeth-Tweesteden Ziekenhuis, 5022 GC Tilburg, The Netherlands
*
Author to whom correspondence should be addressed.
Viruses 2024, 16(4), 582; https://doi.org/10.3390/v16040582
Submission received: 8 March 2024 / Revised: 27 March 2024 / Accepted: 9 April 2024 / Published: 10 April 2024
(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)
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Abstract

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 ‘lipid and lipid-like molecules’, ‘organic acids and derivatives’ and ‘organoheterocyclic compounds’. In pathway analysis, perturbed ‘vitamin B1 (thiamin) metabolism’, ‘de novo fatty acid biosynthesis’, ‘bile acid biosynthesis’ and ‘pentose phosphate pathway’ 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.
Keywords: metabolome; lipoproteome; integrase strand transfer inhibitor; non-nucleoside reverse transcriptase inhibitor; combination antiretroviral therapy; lipids metabolome; lipoproteome; integrase strand transfer inhibitor; non-nucleoside reverse transcriptase inhibitor; combination antiretroviral therapy; lipids

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MDPI and ACS Style

Vos, W.A.J.W.; Vadaq, N.; Matzaraki, V.; Otten, T.; Groenendijk, A.L.; Blaauw, M.J.T.; van Eekeren, L.E.; Brinkman, K.; de Mast, Q.; Riksen, N.P.; et al. Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies. Viruses 2024, 16, 582. https://doi.org/10.3390/v16040582

AMA Style

Vos WAJW, Vadaq N, Matzaraki V, Otten T, Groenendijk AL, Blaauw MJT, van Eekeren LE, Brinkman K, de Mast Q, Riksen NP, et al. Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies. Viruses. 2024; 16(4):582. https://doi.org/10.3390/v16040582

Chicago/Turabian Style

Vos, Wilhelm A. J. W., Nadira Vadaq, Vasiliki Matzaraki, Twan Otten, Albert L. Groenendijk, Marc J. T. Blaauw, Louise E. van Eekeren, Kees Brinkman, Quirijn de Mast, Niels P. Riksen, and et al. 2024. "Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies" Viruses 16, no. 4: 582. https://doi.org/10.3390/v16040582

APA Style

Vos, W. A. J. W., Vadaq, N., Matzaraki, V., Otten, T., Groenendijk, A. L., Blaauw, M. J. T., van Eekeren, L. E., Brinkman, K., de Mast, Q., Riksen, N. P., Stalenhoef, A. F. H., van Lunzen, J., van der Ven, A. J. A. M., Blok, W. L., & Stalenhoef, J. E. (2024). Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies. Viruses, 16(4), 582. https://doi.org/10.3390/v16040582

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