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1. Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels compared to protease inhibitor-based therapy

Author

Alexander O Pasternak, Jelmer Vroom, Neeltje A Kootstra, Ferdinand WNM Wit, Marijn de Bruin, Davide De Francesco, Margreet Bakker, Caroline A Sabin, Alan Winston, Jan M Prins, Peter Reiss, Ben Berkhout, and The Co-morBidity in Relation to Aids (COBRA) Collaboration

Subjects
HIV, virus infection, antiviral drugs, Medicine, Science, Biology (General), QH301-705.5
Abstract

Background: It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Methods: CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART. Results: In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals. Conclusions: All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size. Funding: This work was supported by ZonMw (09120011910035) and FP7 Health (305522).

Published
2021
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2. Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell- associated HIV RNA and DNA levels compared to protease inhibitor-based therapy

Author

O Erlwein, A Winston, Peter Reiss, J Villaudy, B Berkhout, M. van der Valk, DP Benschop, A Kalsbeek, Ben Berkhout, M Martens, C Kingsley, T Booiman, Neeltje A. Kootstra, M Wezel, M Moreno-Villanueva, Paolo Garagnani, N Doyle, S Salvioli, BC Elsenga, JA ter Stege, T van der Kuyl, T Su, FR Janssen, BA Schmand, MM Mangas Ruiz, T Sindlinger, I Maurer, A Bürkle, M Capri, W Zikkenheiner, C Libert, M Chiricolo, Robert Leech, Ferdinand Wnm Wit, J Pothof, Caroline A. Sabin, Cblm Majoie, M Gisslén, A Lovell, Mmj Hillebregt, S Zaheri, I Visser, Claudio Franceschi, M de Graaff-Teulen, Alexander O. Pasternak, S Kovalev, M Prins, M Totté, NA Kootstra, H Zetterberg, D de Francesco, JH Cole, K Legg, Mwa Caan, J Schouten, M Klein Twennaar, Jelmer Vroom, J Berkel, AF Girigorie, P Reiss, S Moll, S Dewaele, K Weijer, D Fuchs, Marijn de Bruin, Alan Winston, Chiara Pirazzini, R.A. van Zoest, F Dall'Olio, Davide De Francesco, David J. Sharp, A Keller, AM Harskamp-Holwerda, J Underwood, F. W. Wit, GJ Geurtsen, P Portegies, Ymc Ruijs, M Stott, Margreet Bakker, M Heidenrijk, KW Kooij, Phlt Bisschop, G Guaraldi, L McDonald, C Sabin, AO Pasternak, J Hoeijmakers, Jan M. Prins, HG Ruhé, E Frankin, D Burger, Commission of the European Communities, National Institute for Health Research, and Pasternak AO, Vroom J, Kootstra NA, Wit FW, de Bruin M, De Francesco D, Bakker M, Sabin CA, Winston A, Prins JM, Reiss P, Berkhout B. Collaboratori C Franceschi, P Garagnani, C Pirazzini, M Capri, F Dall'Olio, M Chiricolo, S Salvioli

Subjects
Life Sciences & Biomedicine - Other Topics, DYNAMICS, Male, PROVIRUSES PRODUCE, medicine, Time Factors, Co-morBidity in Relation to Aids (COBRA) Collaboration, HIV Infections, Virus Replication, 0601 Biochemistry and Cell Biology, Nucleoside Reverse Transcriptase Inhibitor, chemistry.chemical_compound, Transcription (biology), virus infection, Biology (General), Randomized Controlled Trials as Topic, INFECTED PATIENTS, Reverse-transcriptase inhibitor, General Neuroscience, virus diseases, General Medicine, Middle Aged, Viral Load, Europe, Treatment Outcome, viru, RNA, Viral, Reverse Transcriptase Inhibitors, Drug Therapy, Combination, Female, Life Sciences & Biomedicine, medicine.drug, Adult, antiviral drug, Nevirapine, Efavirenz, QH301-705.5, RALTEGRAVIR INTENSIFICATION, Science, infectious disease, VIREMIA, virus, General Biochemistry, Genetics and Molecular Biology, Virus, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], antiviral drugs, All institutes and research themes of the Radboud University Medical Center, Humans, Protease inhibitor (pharmacology), Biology, Science & Technology, General Immunology and Microbiology, business.industry, PERSISTENCE, microbiology, RNA, HIV, HIV Protease Inhibitors, Virology, IMMUNE ACTIVATION, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Cross-Sectional Studies, chemistry, REPLICATION, DNA, Viral, RESERVOIR, business, DECAY
Abstract

Background:It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).Methods:CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART.Results:In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.Conclusions:All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.Funding:This work was supported by ZonMw (09120011910035) and FP7 Health (305522).

Published
2021

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