Abstract
Integrase-strand-transfer inhibitors (INSTIs) are known to rapidly reduce HIV-1 plasma viral load, replication cycles, and new viral integrations, thus potentially limiting viral evolution. Here, we assessed the role of INSTIs on HIV-1 V3 evolution in a cohort of 89 HIV-1-infected individuals starting an INSTI- (N = 41, [dolutegravir: N = 1; elvitegravir: N = 3; raltegravir: N = 37]) or a non-INSTI-based (N = 48) combined antiretroviral therapy (cART), with two plasma RNA V3 genotypic tests available (one before [baseline] and one during cART). V3 sequences were analysed for genetic distance (Tajima-Nei model) and positive selection (dN/dS ratio). Individuals were mainly infected by B subtype (71.9%). Median (interquartile-range, IQR) plasma viral load and CD4 + T cell count at baseline were 4.8 (3.5–5.5) log10 copies/mL and 207 (67–441) cells/mm3, respectively. Genetic distance (median, IQR) between the V3 sequences obtained during cART and those obtained at baseline was 0.04 (0.01–0.07). By considering treatment, genetic distance was significantly lower in INSTI-treated than in non-INSTI-treated individuals (median [IQR]: 0.03[0.01–0.04] vs. 0.05[0.02–0.08], p = 0.026). In line with this, a positive selection (defined as dN/dS ≥ 1) was observed in 36.6% of V3 sequences belonging to the INSTI-treated group and in 56.3% of non-INSTI group (p = 0.05). Multivariable logistic regression confirmed the independent correlation of INSTI-based regimens with a lower probability of both V3 evolution (adjusted odds-ratio: 0.35 [confidence interval (CI) 0.13–0.88], p = 0.027) and positive selection (even if with a trend) (adjusted odds-ratio: 0.46 [CI 0.19–1.11], p = 0.083). Overall, this study suggests a role of INSTI-based regimen in limiting HIV-1 V3 evolution over time. Further studies are required to confirm these findings.
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Acknowledgements
We thank: Massimiliano Bruni and Marzia Romani for data entry; Andrea Biddittu and Alberto Giannetti for data management. Moreover, we wish to thank all the clinicians and virologists throughout Italy who contribute with their work to develop, expand and maintain the ARCA database.
Funding
This work was financially supported by the European Commission Framework 7 Programme (CHAIN, the Collaborative HIV and Anti-HIV Drug Resistance Network, Integrated Project no. 223131), the Italian Ministry of Health (Progetto Ricerca Corrente 2016, line n. 2, project n.2, sub-project n.2d), the Italian Ministry of Education, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1°) and an unrestricted grant from AVIRALIA foundation.
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C.A. conceived the presented idea and wrote the manuscript. R.S. developed and performed the statistical analyses. D.A. and M.M.S. contributed to perform and interpret the statistical analyses. A.B., C.G., and I.V. determined the V3 sequences. G.F., C.M.M., C.C., A.C., B.B., M.A., and A.A. provided samples. R.S. and M.M.S. contributed to the writing of the manuscript. M.Z., V.S., F.C.S. and C.F.P. contributed to the interpretation of the results and revised the manuscript. All authors reviewed and approved the manuscript.
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The authors have no competing interests that might be perceived to influence the results and/or discussion reported in this paper. However, Francesca Ceccherini-Silberstein reports personal fees from Gilead Sciences, Bristol-Myers Squibb, Abbvie, Roche Diagnostics, Janssen-Cilag, Abbott Molecular, ViiV Healthcare; grants and personal fees from Merck Sharp & Dohme; grants from Italian Ministry of Education, University and Research (MIUR). Carlo Federico Perno reports grants from Italian Ministry of Instruction, University and Research (MIUR), and from Aviralia Foundation; personal fees from Gilead Sciences, Abbvie, Roche Diagnostics, Janssen-Cilag, Abbott Molecular, and grants and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, and ViiV Healthcare. All other authors have nothing to declare.
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This study was conducted on data collected for clinical purposes. All data used in the study were previously anonymized, according to the requirements set by Italian Data Protection Code (leg. decree 196/2003) and by the General authorizations issued by the Data Protection Authority. Written informed consent for medical procedures/interventions performed for routine treatment purposes was collected for each patient included in the ARCA database or from other clinical centers involved in the study, in accordance with the ethics standards of the committee on human experimentation and the Helsinki Declaration (1983 revision).
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Alteri, C., Scutari, R., Bertoli, A. et al. Integrase strand transfer inhibitor-based regimen is related with a limited HIV-1 V3 loop evolution in clinical practice. Virus Genes 55, 290–297 (2019). https://doi.org/10.1007/s11262-019-01649-z
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DOI: https://doi.org/10.1007/s11262-019-01649-z