RESUMEN
OBJECTIVE: To study the evolution of multi-drug-resistant HIV-1 in treatment-experienced patients receiving foscarnet (PFA) as part of salvage therapy and to investigate the virological consequences of emerging mutations. METHODS: Genotypic and phenotypic resistance tests were performed on plasma viruses from seven patients at baseline and during treatment with PFA. The phenotypic effects of mutations suspected to be associated with PFA resistance were evaluated by site-directed mutagenesis of wild-type or thymidine analogue mutations (TAM)-carrying pNL4-3. Reversion of single mutations was performed in a patient-derived recombinant clone. RESULTS: Baseline multi-drug-resistant isolates exhibited hypersusceptibility to PFA. In two patients who received > 12 months of PFA treatment, a novel mutation pattern including K70G, V75T, K219R and L228R emerged. These viruses had 3-6-fold resistance to PFA, a 2-20-fold decrease in resistance to zidovudine compared to baseline, and 14-39-fold resistance to lamivudine, in the absence of M184V. In wild-type clones mutations K70G and V75T induced moderate PFA resistance. In the case of TAMs, combinations of > or = 3 mutations (K70G+K219R+L228R+/-V75T) induced PFA resistance and decreased zidovudine resistance 3-13-fold. These mutants exhibited high-level lamivudine resistance (>20-fold) without mutation M184V. Reversion of K70G --> R and K219R --> E in a patient-derived clone confirmed the contribution of individual mutations and the negative association between PFA resistance and zidovudine resistance. CONCLUSIONS: In the context of multiple TAMs, hypersusceptibility to PFA was observed and a novel pattern of resistance, including alternative amino acid substitutions at TAM loci, emerged. This mutational pattern was associated with decreases in zidovudine resistance and surprisingly high-level lamivudine resistance.
Asunto(s)
Fármacos Anti-VIH/farmacología , Foscarnet/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Lamivudine/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Zidovudina/farmacología , Sustitución de Aminoácidos , Farmacorresistencia Viral Múltiple/genética , Evolución Molecular , Foscarnet/farmacología , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Humanos , Pruebas de Sensibilidad Microbiana , Mutación Puntual , Inhibidores de la Transcriptasa Inversa/farmacología , Especificidad de la Especie , Timidina/análogos & derivados , Timidina/genética , Factores de TiempoRESUMEN
Climate changes in the Arctic are predicted to alter distributions of marine species. However, such changes are difficult to quantify because information on present species distribution and the genetic variation within species is lacking or poorly examined. Blue mussels, Mytilus spp., are ecosystem engineers in the coastal zone globally. To improve knowledge of distribution and genetic structure of the Mytilus edulis complex in the Arctic, we analyzed 81 SNPs in 534 Mytilus spp. individuals sampled at 13 sites to provide baseline data for distribution and genetic variation of Mytilus mussels in the European Arctic. Mytilus edulis was the most abundant species found with a clear genetic split between populations in Greenland and the Eastern Atlantic. Surprisingly, analyses revealed the presence of Mytilus trossulus in high Arctic NW Greenland (77°N) and Mytilus galloprovincialis or their hybrids in SW Greenland, Svalbard, and the Pechora Sea. Furthermore, a high degree of hybridization and introgression between species was observed. Our study highlights the importance of distinguishing between congener species, which can display local adaptation and suggests that information on dispersal routes and barriers is essential for accurate predictions of regional susceptibility to range expansions or invasions of boreal species in the Arctic.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Foscarnet/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Terapia Recuperativa/métodos , Recuento de Linfocito CD4 , Farmacorresistencia Viral Múltiple , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Mutación , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Carga ViralRESUMEN
We present a case with important pharmacogenetic and pharmacokinetic aspects of antiretroviral therapy in a patient with high efavirenz concentrations, severe CNS side-effects and low lopinavir concentrations. Despite therapeutic drug monitoring and subsequent efavirenz dosage reductions, side-effects did not resolve completely and lopinavir concentrations remained relatively low.
Asunto(s)
Fármacos Anti-VIH/sangre , Hidrocarburo de Aril Hidroxilasas/genética , Enfermedades del Sistema Nervioso Central/inducido químicamente , Infecciones por VIH/sangre , Infecciones por VIH/enzimología , VIH , Oxazinas/sangre , Oxidorreductasas N-Desmetilantes/genética , Adulto , Alquinos , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/metabolismo , Benzoxazinas , Enfermedades del Sistema Nervioso Central/sangre , Enfermedades del Sistema Nervioso Central/enzimología , Enfermedades del Sistema Nervioso Central/genética , Ciclopropanos , Citocromo P-450 CYP2B6 , Monitoreo de Drogas , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Humanos , Lopinavir , Masculino , Oxazinas/efectos adversos , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Oxidorreductasas N-Desmetilantes/metabolismo , Pirimidinonas/efectos adversos , Pirimidinonas/sangre , Pirimidinonas/uso terapéuticoRESUMEN
A 55-y-old male developed severe metabolic acidosis and renal failure during tenofovir therapy. Increased tenofovir exposure due to low body weight and chronic stable renal insufficiency could have enhanced the risk of nephrotoxicity, and creatinine clearance should be estimated before initiation of tenofovir.