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1.
New Microbiol ; 39(3): 192-196, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27704143

RESUMO

This study assessed the 48-week efficacy of an antiretroviral therapy including maraviroc following the assessment of co-receptor tropism by use of Geno2Pheno algorithm or the Trofile phenotypic assay in failing treatment-experienced HIV-1 patients. This was a multicenter, randomized, open-label, non-inferiority trial. Treatment-experienced subjects with HIV-RNA ≥500 copies/mL were randomized (1:1) to undergo co-receptor tropism testing by the Geno- 2Pheno algorithm (with a false positive rate >10%) or the Trofile assay before starting a new antiretroviral treatment which included maraviroc. The primary endpoint was the 48 week proportion of patients with treatment success (TS). Intention-to-treat analyses are also reported. One hundred and fifty-five experienced patients were analysed: 77 patients in the Trofile arm and 78 in the Genotype arm. The 48-week proportion of TS was 87% in the Trofile arm and 89% in the Genotype arm (difference: 1.5%, 95%CI: -8.9% to 11.8%) suggesting non-inferiority. In the Trofile arm, 10 patients had treatment failure: 5 viral rebound, 5 discontinuations. In the Genotype arm, 9 patients had treatment failure: 7 viral rebound, 2 lost to follow-up. CD4+ significantly increased from baseline to week 48 in both arms. 48-week treatment success was similar for maraviroc-including therapy prescribed following the Trofile phenotypic assay or Geno2Pheno algorithm.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Cicloexanos/uso terapêutico , Genótipo , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Triazóis/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Cicloexanos/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Maraviroc , Pessoa de Meia-Idade , Falha de Tratamento , Triazóis/administração & dosagem , Tropismo Viral
2.
J Antimicrob Chemother ; 70(5): 1391-5, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25608585

RESUMO

OBJECTIVES: Although founder viruses in primary HIV-1 infections (PHIs) typically use the CCR5 coreceptor (R5-tropic), 3%-19% of subjects also harbour CXCR4-using viruses (X4-tropic), making tropism determination before CCR5 antagonist usage mandatory. Genotypic methods can be used to accurately determine HIV-1 tropism in chronically infected patients. METHODS: We compared the results of genotypic methods [geno2pheno, PSSMx4r5 including a novel nucleotide-input version (ntPSSM) and distant segments (ds)Kernel] to predict coreceptor usage in a cohort of 67 PHIs. Specimens with discrepant results were phenotypically tested after cloning the V3 gene region into proviral backbones. Recombinant viruses were used to infect U87 indicator cell lines bearing CD4 and either CCR5 or CXCR4. RESULTS: Geno2pheno10%, PSSMx4r5 and (ds)Kernel gave identical predictions in 85% of cases. Geno2pheno10% predicted the presence of CXCR4 viruses in 18% of patients. Two patients were predicted to carry X4-tropic viruses by all algorithms and X4-tropic viruses were detected in at least one of the recombinant AD8 or NL4-3 backbone-based assays. Ten samples resulted in discordant predictions with at least one algorithm. Full concordance between tropism prediction by using population sequencing and phenotypic assays was observed only with ntPSSM. Geno2pheno prediction and the phenotypic assay gave the same results in a minority of 'discordant' patients. CONCLUSIONS: Compared with both PSSMx4r5 versions, (ds)Kernel and our phenotypic assay, geno2pheno10% overestimated the frequency of X4-tropic viruses (18% versus 3%). ntPSSM was able to detect one additional X4 virus compared with (ds)Kernel that was confirmed with the phenotypic assay.


Assuntos
Técnicas de Genotipagem/métodos , Infecções por HIV/virologia , HIV-1/fisiologia , Receptores de HIV/análise , Tropismo Viral , Cultura de Vírus/métodos , Genótipo , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Fenótipo
4.
AIDS Res Hum Retroviruses ; 30(12): 1243-50, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25275490

RESUMO

Maraviroc (MVC) is licensed in clinical practice for patients with R5 virus and virological failure; however, in anecdotal reports, dual/mixed viruses were also inhibited. We retrospectively evaluated the evolution of HIV-1 coreceptor tropism in plasma and peripheral blood mononuclear cells (PBMCs) of an infected adolescent with a CCR5/CXCR4 Trofile profile who experienced an important but temporary immunological and virological response during a 16-month period of MVC-based therapy. Coreceptor usage of biological viral clones isolated from PBMCs was investigated in U87.CD4 cells expressing wild-type or chimeric CCR5 and CXCR4. Plasma and PBMC-derived viral clones were sequenced to predict coreceptor tropism using the geno2pheno algorithm from the V3 envelope sequence and pol gene-resistant mutations. From start to 8.5 months of MVC treatment only R5X4 viral clones were observed, whereas at 16 months the phenotype enlarged to also include R5 and X4 clones. Chimeric receptor usage suggested the preferential usage of the CXCR4 coreceptor by the R5X4 biological clones. According to phenotypic data, R5 viruses were susceptible, whereas R5X4 and X4 viruses were resistant to RANTES and MVC in vitro. Clones at 16 months, but not at baseline, showed an amino acidic resistance pattern in protease and reverse transcription genes, which, however, did not drive their tropisms. The geno2pheno algorithm predicted at baseline R5 viruses in plasma, and from 5.5 months throughout follow-up only CXCR4-using viruses. An extended methodological approach is needed to unravel the complexity of the phenotype and variation of viruses resident in the different compartments of an infected individual. The accurate evaluation of the proportion of residual R5 viruses may guide therapeutic intervention in highly experienced patients with limited therapeutic options.


Assuntos
Fármacos Anti-HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Adolescente , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Quimiocina CCL5/fisiologia , Cicloexanos/uso terapêutico , Darunavir , Farmacorresistência Viral Múltipla , Proteína gp120 do Envelope de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/fisiologia , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Maraviroc , Oxazinas , Fragmentos de Peptídeos/genética , Filogenia , Piperazinas , Piridonas , Receptores CCR5/fisiologia , Receptores CXCR4/fisiologia , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Triazóis/uso terapêutico , Carga Viral/efeitos dos fármacos , Tropismo Viral/efeitos dos fármacos
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