In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors

Condra, Jon H.; Schleif, William A.; Blahy, O M; Gabryelski, Lori J.; Graham, Donald J.; Quintero, J. C.; Rhodes, Audrey; Robbins, H L; Roth, E. Jill; Shivaprakash, Malathi; Titus, David C.; Yang, Tao; Tepplert, Hedy; Squires, Kathleen; Deutsch, Paul; Emini, Emilio A.

doi:10.1038/374569a0

Cited by 948 publications

(679 citation statements)

References 21 publications

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“…Los beneficios de la terapia antiviral pueden verse comprometidos cuando aparecen ciertos factores, como defectos de la inmunidad del huésped, alta capacidad del virus para desarrollar resistencia a los fármacos (13,(17)(18)(19)(20)(21), y pobre cumplimiento del tratamiento. A esto se suma el alto costo y el bajo acceso a los medicamentos en los países en vía de desarrollo, así como la alta toxicidad de los mismos (22,23).…”

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Patrones de prescripción de antirretrovirales en 997 pacientes colombianos

Machado

Alzate

2008

biomedica

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Introducción. El tratamiento antirretroviral de la infección por virus de inmunodeficiencia humana ha mejorado la supervivencia y la calidad de vida de los pacientes desde el advenimiento de la terapia combinada en 1996. Objetivos. Conocer el manejo farmacológico de la infección por VIH/sida. Materiales y métodos. Estudio descriptivo observacional con selección de pacientes con infección por VIH/sida, de ambos sexos, de todas las edades, en tratamiento, al menos, durante tres meses (julio a septiembre de 2006) localizados en diferentes ciudades colombianas y afiliados al Sistema General de Seguridad Social en Salud. Se diseñó una base de datos con registros sobre el consumo de medicamentos antirretrovirales, recolectados por la empresa que dispensa dichos fármacos a los pacientes de las entidades promotoras de salud. Resultados. Se estudiaron 997 pacientes con edad promedio de 37,7±13,2 años, 82,6% de hombres. Todos los pacientes recibían terapia con tres o más antirretrovirales; el orden de prescripción de medicamentos fue: inhibidores de nucleósidos de transcriptasa inversa (96,4%), inhibidores de transcriptasa inversa no nucleósidos (54,9%), inhibidores de proteasa (39,8%) y otros (0,4%), todos a dosis adecuadas. Las combinaciones más empleadas fueron: lamivudina-zidovudina-efavirenz (35%), lamivudina-zidovudina con lopinavir/ritonavir (8,4%), abacavir con lamivudina-zidovudina (5,5%), lamivudina-zidovudina con nevirapina (5,2 %) y otras 65 asociaciones diferentes (45,9%). Conclusiones. Todos los antirretrovirales se están utilizando a las dosis establecidas internacionalmente y predominan patrones de prescripción racionales para iniciar la terapia. Sin embargo, el encontrar 69 asociaciones diferentes de antirretrovirales lleva a considerar que no hay adecuados criterios para la implementación de los esquemas después del inicio del tratamiento, guiados según los datos científicos y quienes los prescriben adoptan múltiples opciones por fuera de lo recomendado a nivel mundial.Palabras clave: síndrome de inmunodeficiencia adquirida/terapia, terapia antirretroviral altamente activa, prescripción de medicamentos, Colombia. Patterns of antiretroviral drug prescripcion in 997 Colombian patientsIntroduction. Antiretroviral therapy for treatment of human immunodeficiency virus type 1 (HIV-1) infection has improved steadily since the advent of combination therapy in 1996. Objective. The pharmacological therapies of the infection by HIV/AIDS were documented in order to determine if effective treatment regimes were prescribed. Materials and methods. Pharmacological therapies of the human immunodeficiency virus infection were compared in 997 patients affiliated with the health security system, of both sexes and all ages. All had been in treatment for more than three months (July-September 2006) and were distributed in 15 Colombian cities. The data were retrieved from medication consumption files which were maintained by the institutions that had distributed medications to the selected patients. Results. The average age of...

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Patrones de prescripción de antirretrovirales en 997 pacientes colombianos

Machado

Alzate

2008

biomedica

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“…Mutations at 45 amino acid positions have been associated with resistance to one or more of the six presently used protease inhibitors (PIs) (8,17,18,31). Mutations at nine amino acid positions have been commonly designated primary or major resistance mutations (D30N, V32I, M46I/L, G48V, I50V, I54L/M/V, V82A/F/S/T, I84A/V, N88S, and L90M) (11,31).…”

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Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Grossman

Paxinos

Averbuch

et al. 2004

Antimicrob Agents Chemother

109

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Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C-and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P ‫؍‬ 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC 50 ) change in susceptibility to nelfinavir only. Other mutations increased IC 50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ؎ 22% to 22% ؎ 15% (P ‫؍‬ 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

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“…The L63P protease mutation is common in viruses that have never exposed to PIs (Kozal et al 1996) and may be more prevalent in viruses from patients in whom a protease inhibitorcontaining regimen has failed. Multi-PI resistance arises from accumulation of 4 or more of primary mutations M46I/L, V82A/F/T/S, I84V, L90M and secondary mutations L10F/I/R/V, I54V/M/L (Condra et al 1995).…”

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confidence: 99%