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Artikel: Longitudinal Trends in HIV-1 Subtypes and Drug Resistance in Children from Argentina over a 15-Year Period (2006-2021).

López, Natalia J / Arazi-Caillaud, Solange / Bologna, Rosa M / Mangano, Andrea M / Aulicino, Paula C

Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion

2024 Band 76, Heft 1, Seite(n) 29–36

Abstract: Background: Human immunodeficiency virus (HIV) drug resistance is a major cause of treatment failure in children and adolescents infected with the virus.: Objectives: The objectives of the study are to investigate HIV drug resistance (HIVDR) in ... ...

Abstract	Background: Human immunodeficiency virus (HIV) drug resistance is a major cause of treatment failure in children and adolescents infected with the virus. Objectives: The objectives of the study are to investigate HIV drug resistance (HIVDR) in patients who attended a referral care center in Argentina over a 15-year period and to compare mutational patterns between HIV-1 polsequences characterized as B or BF recombinants. Methods: Individual resistance-associated mutations (RAMs) (to protease and reverse transcriptase inhibitors) were identified according to IAS-USA guidelines in 374 HIV-1-infected children and adolescents. HIV-1 subtype was characterized by phylogenetic and recombination analysis using MEGA5.1 and Simplot. Poisson linear regression was used to model the dynamics of the RAMs over time. Results: The prevalence of RAMs to protease inhibitors (R2 = 0.52, p = 0.0012) and nucleoside reverse transcriptase inhibitors (R2 = 0.30, p = 0.0225) decreased over time. HIVDR to non-nucleoside reverse transcriptase inhibitors remained moderate to high, ranging between 33% and 76%. BF recombinants showed a higher frequency of thymidine analog mutation 1 RAMs profile and I54V mutation. Conclusion: In Argentina, HIVDR observed in children and adolescents has decreased over the past 15 years, regardless of the viral subtype. (REV INVEST CLIN. 2024;76(1):29-36).
Mesh-Begriff(e)	Adolescent ; Child ; Humans ; Argentina/epidemiology ; HIV-1/genetics ; Phylogeny ; Reverse Transcriptase Inhibitors/pharmacology ; Reverse Transcriptase Inhibitors/therapeutic use ; HIV Infections/drug therapy ; HIV Infections/epidemiology
Chemische Substanzen	Reverse Transcriptase Inhibitors
Sprache	Englisch
Erscheinungsdatum	2024-03-04
Erscheinungsland	Mexico
Dokumenttyp	Journal Article
ZDB-ID	138348-6
ISSN	0034-8376
ISSN	0034-8376
DOI	10.24875/RIC.23000210
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: HIV-1 pretreatment drug resistance in vertically infected children is associated with poor virological response to protease inhibitor (PI)-based first-line antiretroviral therapy (ART): results from a cohort study in Argentina.

Rozenszajn, Mijael / Arazi-Caillaud, Solange / Taicz, Moira / Bologna, Rosa / Mangano, Andrea / Aulicino, Paula C

The Journal of antimicrobial chemotherapy

2022 Band 77, Heft 7, Seite(n) 1969–1973

Abstract: Background: Increasing evidence from adult cohorts suggests an important role of HIV-1 pretreatment drug resistance (PDR) in ART failure, in spite of treatment being fully active according to baseline genotyping tests. Whether this is also true for ... ...

Abstract	Background: Increasing evidence from adult cohorts suggests an important role of HIV-1 pretreatment drug resistance (PDR) in ART failure, in spite of treatment being fully active according to baseline genotyping tests. Whether this is also true for children is unknown. Methods: Virological and immunological parameters were longitudinally assessed in a group of 39 HIV-1 vertically infected children starting first-line lopinavir/ritonavir-based ART at a median of 5.0 months (IQR = 3.0-9.0). Evolution of viral load (VL) over time was compared between children with and without baseline PDR, as defined by the WHO mutation list. Results: Resistance-associated mutations (RAMs) in the HIV-1 pol gene were present in nine HIV-1-infected children (23%) before initiation of first-line ART (PDR group). Of them, six carried RAMs associated with NNRTIs (NNRTI-PDR subgroup). At 4-8 weeks after ART initiation, the proportion of children achieving ≥1 log VL reduction was 87% for the no-PDR group versus 33% and 16.7% for the PDR group and the NNRTI-PDR subgroup, respectively. During follow-up, children with no PDR reached virological suppression almost four times faster than children with PDR or NNRTI-PDR [no-PDR = 631 days and PDR = 2134 days (P = 0.1249) and NNRTI-PDR = 2134 days (P = 0.0447)]. CD4 T cells remained similar between the study groups over time. Conclusions: HIV-1 baseline genotyping at diagnosis in vertically infected children is important for improved personalized medicine. While the mechanism is unclear, cases with PDR (particularly to NNRTIs) require closer monitoring of their first-line ART regimens in order to avoid early virological failures and prevent further accumulation of resistance.
Mesh-Begriff(e)	Anti-HIV Agents/pharmacology ; Anti-HIV Agents/therapeutic use ; Anti-Retroviral Agents/therapeutic use ; Argentina ; Cohort Studies ; Drug Resistance ; Drug Resistance, Viral/genetics ; HIV Infections/drug therapy ; HIV Seropositivity/drug therapy ; HIV-1/genetics ; Humans ; Protease Inhibitors/therapeutic use ; Viral Load
Chemische Substanzen	Anti-HIV Agents ; Anti-Retroviral Agents ; Protease Inhibitors
Sprache	Englisch
Erscheinungsdatum	2022-05-05
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkac138
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: HIV-1 subtype F integrase polymorphisms external to the catalytic core domain contribute to severe loss of replication capacity in context of the integrase inhibitor resistance mutation Q148H.

Aulicino, Paula C / Momin, Zoha / Rozenszajn, Mijael / Monzon, Arturo / Arazi-Caillaud, Solange / Bologna, Rosa / Mangano, Andrea / Kimata, Jason T

The Journal of antimicrobial chemotherapy

2022 Band 77, Heft 10, Seite(n) 2793–2802

Abstract: Background: In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug ... ...

Abstract	Background: In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration. Methods: Integrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+ G140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200 bp fragment spanning amino acids 85-150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay. Results: At least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105-106 pg/mL) for WT and NL4-3-Q148H; by contrast, it was low (102-104 pg/mL) for both F1(BF)-Q148H + G140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (P = 0.05), 9-fold for URTR23-Q148H (P = 0.01) and 16000-fold for ARMA159-Q148H (P = 0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants. Conclusions: The functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.
Mesh-Begriff(e)	Amino Acids/therapeutic use ; Catalytic Domain ; Drug Resistance, Viral/genetics ; HIV Infections/drug therapy ; HIV Integrase/metabolism ; HIV Integrase Inhibitors/pharmacology ; HIV Integrase Inhibitors/therapeutic use ; HIV-1/genetics ; Humans ; Mutation ; Pyrrolidinones/pharmacology ; Raltegravir Potassium/pharmacology ; Raltegravir Potassium/therapeutic use
Chemische Substanzen	Amino Acids ; HIV Integrase Inhibitors ; Pyrrolidinones ; Raltegravir Potassium (43Y000U234) ; HIV Integrase (EC 2.7.7.-)
Sprache	Englisch
Erscheinungsdatum	2022-07-20
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkac238
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Variable antiviral activity of islatravir against M184I/V mutant HIV-1 selected during antiretroviral therapy.

Aulicino, Paula C / Sharma, Suman / Truong, Khanghy / Kukunoor, Vindhya / Ghei, Karm / Arazi-Caillaud, Solange / Taicz, Moira / Bologna, Rosa / Mangano, Andrea / Kimata, Jason T

The Journal of antimicrobial chemotherapy

2023 Band 79, Heft 2, Seite(n) 370–374

Abstract: Background: Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the ...

Abstract	Background: Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. Methods: HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. Results: In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. Conclusions: Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic.
Mesh-Begriff(e)	Humans ; Anti-HIV Agents/pharmacology ; Anti-HIV Agents/therapeutic use ; HIV-1/genetics ; HIV Infections/drug therapy ; Lamivudine/therapeutic use ; Mutation ; HIV Reverse Transcriptase/genetics ; Drug Resistance, Viral/genetics ; Reverse Transcriptase Inhibitors/pharmacology ; Reverse Transcriptase Inhibitors/therapeutic use ; Deoxyadenosines
Chemische Substanzen	Anti-HIV Agents ; islatravir (QPQ082R25D) ; Lamivudine (2T8Q726O95) ; HIV Reverse Transcriptase (EC 2.7.7.49) ; Reverse Transcriptase Inhibitors ; Deoxyadenosines
Sprache	Englisch
Erscheinungsdatum	2023-12-28
Erscheinungsland	England
Dokumenttyp	Journal Article
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkad390
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Impact of genotypic diversity on selection of subtype-specific drug resistance profiles during raltegravir-based therapy in individuals infected with B and BF recombinant HIV-1 strains.

Sánchez, Daniela / Arazi Caillaud, Solange / Zapiola, Ines / Fernandez Giuliano, Silvina / Bologna, Rosa / Mangano, Andrea / Aulicino, Paula C

The Journal of antimicrobial chemotherapy

2020 Band 75, Heft 6, Seite(n) 1567–1574

Abstract: Background: Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate.: Materials and ...

Abstract	Background: Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate. Materials and methods: HIV-1 drug resistance genotyping was performed in 30 HIV-1-infected individuals undergoing virological failure to raltegravir. Drug resistance mutations (DRMs) and HIV-1 subtype were characterized using Stanford HIVdb and phylogenetic analyses. Results: Of the 30 integrase (IN) sequences, 14 were characterized as subtype F (47%), 8 as subtype B (27%), 7 as BF recombinants (23%) and 1 as a putative CRF05_DF (3%). In 25 cases (83%), protease and reverse transcriptase (PR-RT) sequences from the same individuals confirmed the presence of different BF recombinants. Stanford HIVdb genotyping was concordant with phylogenetic inference in 70% of IN and 60% of PR-RT sequences. INI DRMs differed between B and F IN subtypes, with Q148K/R/H, G140S and E138K/A being more prevalent in subtype B (63% versus 0%, P = 0.0021; 50% versus 0%, P = 0.0096; and 50% versus 0%, P = 0.0096, respectively). These differences were independent of the time on raltegravir therapy or viral load at the time of genotyping. INI DRMs in subtype F IN genomes predicted a lower level of resistance to raltegravir and no cross-resistance to second-generation INIs. Conclusions: Alternative resistance pathways to raltegravir develop in subtypes B and F IN genomes, with implications for clinical practice. Evaluating the role of HIV-1 subtype in development and persistence of mutations that confer resistance to INIs will be important to improve algorithms for resistance testing and optimize the use of INIs.
Mesh-Begriff(e)	Drug Resistance, Viral/genetics ; Genotype ; HIV Infections/drug therapy ; HIV Integrase/genetics ; HIV-1/genetics ; Humans ; Mutation ; Phylogeny ; Raltegravir Potassium/therapeutic use
Chemische Substanzen	Raltegravir Potassium (43Y000U234) ; HIV Integrase (EC 2.7.7.-)
Sprache	Englisch
Erscheinungsdatum	2020-03-03
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkaa042
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Impact of the time to achieve viral control on the dynamics of circulating HIV-1 reservoir in vertically infected children with long-term sustained virological suppression: A longitudinal study.

Moragas, Matías / Distefano, Maximiliano / Mecikovsky, Debora / Arazi Caillaud, Solange / Cernadas, Carolina / Bologna, Rosa / Aulicino, Paula / Mangano, Andrea

PloS one

2018 Band 13, Heft 10, Seite(n) e0205579

Abstract: Objective: Determine the decay rate of HIV-1 DNA reservoir in vertically infected children during sustained viral suppression (VS) and how it is affected by the age at VS.: Methods: This study included 37 HIV-1 vertically infected children on ... ...

Abstract	Objective: Determine the decay rate of HIV-1 DNA reservoir in vertically infected children during sustained viral suppression (VS) and how it is affected by the age at VS. Methods: This study included 37 HIV-1 vertically infected children on suppressive antiretroviral therapy for at least 4 years. Children were grouped according to the age of antiretroviral therapy initiation (≤0.5 or >0.5 yrs) and to the age at VS (≤1.5, between >1.5 and 4, and >4 years). Decay of cell-associated HIV-1 DNA (CA-HIV-DNA) level and 2-long terminal repeats (2-LTR) circles frequency were analyzed over 4 years of viral suppression using piecewise linear mixed-effects model with two splines and logistic regression, respectively. Results: CA-HIV-DNA in peripheral blood mononuclear cells had a significant decay during the first two years of VS [-0.26 (95% CI: -0.43, -0.09) log10 copies per one million cells (cpm)/year], and subsequently reached a plateau [-0.06 (95% CI: -0.15, 0.55) log10 cpm/year]. The initial decay was higher in children who achieved VS by 1.5 years of age compared to those who achieved VS between >1.5 and 4 years and those after 4 years of age: -0.51 (95% CI:-0.94, -0.07), -0.35 (95% CI:-0.83, 0.14), and -0.21 (95% CI:-0.39, -0.02) log10cpm PBMC/year, respectively. The 2-LTR circles frequency decayed significantly, from 82.9% at pre-VS to 37.5% and 28.1% at 2 and 4 years of VS, respectively (P = .0009). Conclusions: These data highlight that achieving VS during the first 18 months of life limit the establishment of HIV-1 reservoirs, reinforcing the clinical benefit of very early effective therapy in children.
Mesh-Begriff(e)	Anti-HIV Agents/therapeutic use ; Child ; Child, Preschool ; Cohort Studies ; DNA, Viral/blood ; Female ; HIV Infections/blood ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV-1/genetics ; Humans ; Infant ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/virology ; Longitudinal Studies ; Male ; Sustained Virologic Response ; Time-to-Treatment ; Viremia/blood ; Viremia/drug therapy ; Viremia/immunology
Chemische Substanzen	Anti-HIV Agents ; DNA, Viral
Sprache	Englisch
Erscheinungsdatum	2018-10-23
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0205579
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Longitudinal Trends in HIV-1 Subtypes and Drug Resistance in Children from Argentina over a 15-Year Period (2006-2021).

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Artikel ; Online: HIV-1 pretreatment drug resistance in vertically infected children is associated with poor virological response to protease inhibitor (PI)-based first-line antiretroviral therapy (ART): results from a cohort study in Argentina.

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Artikel ; Online: HIV-1 subtype F integrase polymorphisms external to the catalytic core domain contribute to severe loss of replication capacity in context of the integrase inhibitor resistance mutation Q148H.

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Artikel ; Online: Variable antiviral activity of islatravir against M184I/V mutant HIV-1 selected during antiretroviral therapy.

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Artikel ; Online: Impact of genotypic diversity on selection of subtype-specific drug resistance profiles during raltegravir-based therapy in individuals infected with B and BF recombinant HIV-1 strains.

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Artikel ; Online: Impact of the time to achieve viral control on the dynamics of circulating HIV-1 reservoir in vertically infected children with long-term sustained virological suppression: A longitudinal study.

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