RESUMEN
Subtype-dependent selection of HIV-1 reverse transcriptase resistance mutation K65R was previously observed in cell culture and small clinical investigations. We compared K65R prevalence across subtypes A, B, C, F, G, and CRF02_AG separately in a cohort of 3,076 patients on combination therapy including tenofovir. K65R selection was significantly higher in HIV-1 subtype C. This could not be explained by clinical and demographic factors in multivariate analysis, suggesting subtype sequence-specific K65R pathways.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Transcriptasa Inversa del VIH/genética , Organofosfonatos/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adenina/uso terapéutico , Adulto , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , Variación Genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , ADN Polimerasa Dirigida por ARN/genética , Inhibidores de la Transcriptasa Inversa/farmacología , TenofovirRESUMEN
OBJECTIVES: The use of tenofovir is highly associated with the emergence of mutation K65R, which confers broad resistance to nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs), especially when tenofovir is combined with other NRTIs also selecting for K65R. Although recent HIV-1 treatment guidelines discouraging these combinations resulted in reduced K65R selection with tenofovir, updated information on the impact of currently recommended regimens on the population selection rate of K65R is presently lacking. METHODS: In this study, we evaluated changes over time in the selection rate of resistance mutation K65R in a large population of 2736 HIV-1-infected patients failing combination antiretroviral treatment between 2002 and 2010. RESULTS: The K65R resistance mutation was detected in 144 patients, a prevalence of 5.3%. A large majority of observed K65R cases were explained by the use of tenofovir, reflecting its wide use in clinical practice. However, changing patterns over time in NRTIs accompanying tenofovir resulted in a persistent decreasing probability of K65R selection by tenofovir-based therapy. The currently recommended NRTI combination tenofovir/emtricitabine was associated with a low probability of K65R emergence. For any given dual NRTI combination including tenofovir, higher selection rates of K65R were consistently observed with a non-nucleoside reverse transcriptase inhibitor than with a protease inhibitor as the third agent. DISCUSSION: Our finding of a stable time trend of K65R despite elevated use of tenofovir illustrates increased potency of current HIV-1 therapy including tenofovir.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/administración & dosificación , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Mutación Missense , Organofosfonatos/administración & dosificación , Selección Genética , Adenina/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Humanos , Tenofovir , Factores de Tiempo , Insuficiencia del TratamientoRESUMEN
The increased complexity of HIV-1 genetic heterogeneity raises the issue for reliable classification and analysis of these sequences. Until now, bootscanning analysis has been the main method used for the analysis of potential HIV-1 intersubtype recombinants. We show evidence that in some cases of complex recombinants, where three or more segments with discordant phylogenetic signal may exist in protease (PR) and partial reverse transcriptase (RT) region, Bayesian scanning provides a clearer picture than bootscanning plots about the boundaries of potential recombination. Thus, a recently developed Bayesian scanning tool can facilitate the analysis and classification of HIV-1 mosaic sequences.
Asunto(s)
Teorema de Bayes , VIH-1/genética , Recombinación Genética , Análisis de Secuencia/métodos , África Central , Variación Genética , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , Filogenia , Programas InformáticosRESUMEN
Few molecular epidemiological data on HIV-1 in Angola are available. In this study, we analysed 37 pol sequences from patients originated from Luanda and Cabinda in Angola. It was our objective to investigate the circulation of different HIV-1 subtypes in this country. We found a high HIV-1 genetic diversity. The predominant subtypes were C and F, while subtypes A, D, G and H were also detected. Three sequences were untypable and may possibly belong to new subtypes or recombinants of unknown subtypes. Moreover, 13 recombinant sequences were found, most of them with very complex patterns including untypable fragments.