High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/58943 |
Resumo: | Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A. |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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7160 |
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High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing PatientsHIV-2antiretroviral activityintegrase inhibitors (INIs)spiro-β-lactam BSS-730Ainstantaneous inhibitory potential (IIP)drug resistanceIntegrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.This work was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal, Aga Khan Development Network (AKDN)–Portugal Collaborative Research Network in Portuguese-speaking countries in Africa (project 332821690). CQC is supported by FCT through projects UIDB/00313/2020 and UIDP/QUI/00313/2020, co-funded by COMPETE2020-UE. iMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Portugal, is supported by FCT through projects UIDB/04138/2020 and UIDP/04138/2020. Inês Bártolo is supported by FCT through Norma Transitória–DL57/2016/CP1376/CT0012. Ana Rita Diniz (SFRH/BD/89140/2012), Francisco Martin (SFRH/BD/87488/2012), Inês Moranguinho (SFRH/BD/131062/2017), and Américo Alves (SFRH/BD/128910/2017) were supported by Ph.D. grants from FCT, Portugal.MDPIRepositório da Universidade de LisboaBártolo, InêsMoranguinho, InêsGonçalves, PalomaAna Rita DinizBorrego, PedroMartin, FranciscoFigueiredo, InêsGomes, PerpetuaGonçalves, Maria FátimaAlves, AméricoAlves, NunoCaixas, UmbelinaVaz-Pinto, InêsBarahona, IsabelMelo, Teresa M. V. D. Pinho ETaveira, Nuno2023-08-21T14:34:05Z2022-11-182023-02-03T12:06:33Z2022-11-18T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/58943engBártolo I, Moranguinho I, Gonçalves P, Diniz AR, Borrego P, Martin F, et al. High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients. International Journal of Molecular Sciences [Internet]. 2022 Nov 18;23(22):14300. Available from: http://dx.doi.org/10.3390/ijms232214300cv-prod-309186610.3390/ijms232214300info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:03:32Zoai:repositorio.ul.pt:10451/58943Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:06:41.047576Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients |
title |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients |
spellingShingle |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients Bártolo, Inês HIV-2 antiretroviral activity integrase inhibitors (INIs) spiro-β-lactam BSS-730A instantaneous inhibitory potential (IIP) drug resistance |
title_short |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients |
title_full |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients |
title_fullStr |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients |
title_full_unstemmed |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients |
title_sort |
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients |
author |
Bártolo, Inês |
author_facet |
Bártolo, Inês Moranguinho, Inês Gonçalves, Paloma Ana Rita Diniz Borrego, Pedro Martin, Francisco Figueiredo, Inês Gomes, Perpetua Gonçalves, Maria Fátima Alves, Américo Alves, Nuno Caixas, Umbelina Vaz-Pinto, Inês Barahona, Isabel Melo, Teresa M. V. D. Pinho E Taveira, Nuno |
author_role |
author |
author2 |
Moranguinho, Inês Gonçalves, Paloma Ana Rita Diniz Borrego, Pedro Martin, Francisco Figueiredo, Inês Gomes, Perpetua Gonçalves, Maria Fátima Alves, Américo Alves, Nuno Caixas, Umbelina Vaz-Pinto, Inês Barahona, Isabel Melo, Teresa M. V. D. Pinho E Taveira, Nuno |
author2_role |
author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Bártolo, Inês Moranguinho, Inês Gonçalves, Paloma Ana Rita Diniz Borrego, Pedro Martin, Francisco Figueiredo, Inês Gomes, Perpetua Gonçalves, Maria Fátima Alves, Américo Alves, Nuno Caixas, Umbelina Vaz-Pinto, Inês Barahona, Isabel Melo, Teresa M. V. D. Pinho E Taveira, Nuno |
dc.subject.por.fl_str_mv |
HIV-2 antiretroviral activity integrase inhibitors (INIs) spiro-β-lactam BSS-730A instantaneous inhibitory potential (IIP) drug resistance |
topic |
HIV-2 antiretroviral activity integrase inhibitors (INIs) spiro-β-lactam BSS-730A instantaneous inhibitory potential (IIP) drug resistance |
description |
Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-11-18 2022-11-18T00:00:00Z 2023-08-21T14:34:05Z 2023-02-03T12:06:33Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/58943 |
url |
http://hdl.handle.net/10451/58943 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Bártolo I, Moranguinho I, Gonçalves P, Diniz AR, Borrego P, Martin F, et al. High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients. International Journal of Molecular Sciences [Internet]. 2022 Nov 18;23(22):14300. Available from: http://dx.doi.org/10.3390/ijms232214300 cv-prod-3091866 10.3390/ijms232214300 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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