RESUMEN
PURPOSE: To compare the antiviral activity and ocular distribution of first- and second-generation antisense oligonucleotides intended for the treatment of cytomegalovirus (CMV) retinitis. METHODS: The antiviral activity of ISIS 13312 and ISIS 2922 (Isis Pharmaceuticals, Inc., Carlsbad, CA) against 10 clinical CMV isolates was compared with a plaque-reduction assay. The ocular pharmacokinetics were compared after intravitreal injection in rabbits (36-90 microg) and monkeys (125-500 microg). Vitreous and/or retina were collected after single and multiple injections to characterize ocular distribution, clearance, and accumulation. Oligonucleotide concentrations were measured by capillary gel electrophoresis and immunohistochemical techniques. RESULTS: ISIS 13312 and ISIS 2922 demonstrated comparable antiviral activity that was consistent among the 10 clinical isolates examined (50% inhibitory concentration [IC(50)], <1 microM). Activity was independent of the resistance of CMV isolates to DNA polymerase inhibitors. After intravitreal injection, the kinetics of ISIS 2922 and ISIS 13312 were characterized by clearance from vitreous and distribution to the retina; however, ISIS 2922 was cleared more quickly from the retina than ISIS 13312. The half-life of ISIS 13312 in the monkey retina was approximately 2 months. Retinal concentrations of ISIS 13312 were dose dependent, with approximately a twofold increase in concentration after once-monthly doses compared with single-dose concentrations. Immunohistochemical analysis indicated that both oligonucleotides were efficiently distributed to numerous ocular tissues, including retina, ciliary body, and optic nerve. CONCLUSIONS: ISIS 13312 possesses antiviral activity and pharmacokinetic properties that favor its use as a therapeutic agent in treatment of CMV retinitis. The half-life of ISIS 13312 in retina is longer than that of ISIS 2922, potentially allowing for less frequent administration.
Asunto(s)
Antivirales/farmacología , Antivirales/farmacocinética , Citomegalovirus/efectos de los fármacos , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/farmacocinética , Retina/metabolismo , Replicación Viral/efectos de los fármacos , Animales , Secuencia de Bases , Disponibilidad Biológica , Cuerpo Ciliar/metabolismo , Citomegalovirus/crecimiento & desarrollo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Fibroblastos/virología , Semivida , Humanos , Macaca fascicularis , Datos de Secuencia Molecular , Oligonucleótidos Fosforotioatos , Conejos , Tionucleótidos/farmacocinética , Tionucleótidos/farmacología , Distribución Tisular , Ensayo de Placa Viral , Cuerpo Vítreo/metabolismoRESUMEN
BACKGROUND: CMV DNA screening may be a useful adjunct to serologic tests in distinguishing potentially infectious blood donations from those that are "CMV-safe." However, there is currently no consensus on the optimal assay method for accurate detection of CMV DNA in donors. STUDY DESIGN AND METHODS: A blinded multicenter evaluation of seven CMV PCR assays was performed by five laboratories by using coded sets of analytical controls and donor blood samples. RESULTS: Five assays displayed sufficient sensitivity for donor screening, as judged by consistent detection of a minimum of 25 CMV genome equivalents (geq) in analytical controls constructed to contain from 1 to 100 CMV geq in background DNA from 250,000 cells, while the other two assays displayed inadequate sensitivity. Three sensitive assays, two based on nested PCR directed at the UL93 and UL32 regions of the CMV genome and another test (Monitor Assay, Roche), did not detect CMV DNA in samples from any of 20 pedigreed CMV-seronegative, Western blot-negative (S-/WB-) donors. Two other assays based on nested PCR occasionally detected CMV DNA in S-WB- samples, and one sensitive nested PCR assay directed at UL123 detected CMV DNA in a large proportion (85%) of S-WB- samples. CONCLUSION: Seven CMV PCR assays currently used for research and/or diagnostic applications displayed marked variations in sensitivity, specificity, and reproducibility when applied to coded analytical and clinical control samples containing cellular DNA from the equivalent of 250,000 WBCs. These results will be useful in the selection of assays with performance characteristics appropriate to donor screening objectives. They may also help explain discrepant findings from previous studies that used PCR to determine CMV DNA prevalence in seronegative and seropositive blood donors.
Asunto(s)
Donantes de Sangre , Citomegalovirus/genética , ADN Viral/sangre , Reacción en Cadena de la Polimerasa/métodos , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Anticuerpos Antivirales/sangre , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/microbiología , Cartilla de ADN , Humanos , Tamizaje Masivo , Reacción en Cadena de la Polimerasa/normas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Método Simple CiegoRESUMEN
BACKGROUND: Identification of human cytomegalovirus (CMV) genome variation is important for understanding mutations associated with drug resistance. OBJECTIVES: To investigate the CMV resistance to foscarnet (PFA) and ganciclovir (GCV) in patients treated with antiviral drugs and to identify the DNA polymerase (UL54) and phosphotransferase (UL97) gene mutations inducing resistance. STUDY DESIGN: Antiviral susceptibility of CMV strains/isolates for PFA and GCV was compared by plaque reduction assay and in situ ELISA. UL54 and UL97 gene mutations were identified by sequencing. Growth phenotype of two CMV recombinants with mutations in UL54 was studied. RESULTS: Six of seven GCV resistant strains had alterations within the UL97. Five of them also had alterations in the UL54 (F412C, L802M or K513E), previously shown to induce GCV resistance. Seven isolates had no or reduced susceptibility to PFA, which had alterations in the UL54 (D588N, E756K, V781I or L802M). By in vitro mutagenesis, it was shown that a mutation at codon D588N of UL54 conferred 9-fold reduced susceptibility to PFA, while a mutation at codon V781I induced 4-fold reduced susceptibility to PFA and GCV. Both recombinants showed the same kinetics of protein expression (IE, E, and L antigen) and virus yields as the CMV Towne strain. CONCLUSIONS: The recombinants containing alterations within the UL54 (D588N and V781I) showed a reduced susceptibility to antiviral drugs but no change in the replication rate compared to the CMV Towne.
Asunto(s)
Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , ADN Polimerasa Dirigida por ADN/genética , Foscarnet/farmacología , Ganciclovir/farmacología , Genes Virales , Fosfotransferasas/genética , Codón , Citomegalovirus/genética , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Farmacorresistencia Viral Múltiple/genética , Variación Genética , Humanos , Pruebas de Sensibilidad Microbiana , Replicación ViralRESUMEN
The Viral Activation Transfusion Study compared leukocyte-reduced to unfiltered red blood cell transfusions in human immunodeficiency virus (HIV)- and cytomegalovirus (CMV)-coinfected patients. Relationships between serially measured plasma CMV load and clinical and laboratory outcomes over a median of 12 months were examined in 511 subjects. At baseline, subjects had a median of 15 CD4(+) cells/mm(3), 25% had CMV disease, and 21.5% were viremic. No relationship was found between changes in CMV viremia and changes in HIV RNA. Increased CMV viremia was associated with a concomitant fall in Karnofsky score. Highly active antiretroviral therapy (HAART) led to a decrease in CMV viremia after a 90-day delay. After adjustment for HIV load and CD4(+) cell count, CMV viremia remained associated with an increased risk of CMV disease (relative hazard, 5.78). In late-stage HIV-infected patients, CMV viremia was associated with lower functional status and increased risk of CMV disease. HAART suppressed CMV viremia only after a delay of several months.
Asunto(s)
Infecciones por Citomegalovirus/complicaciones , Citomegalovirus/aislamiento & purificación , Transfusión de Eritrocitos , Infecciones por VIH/complicaciones , Adulto , Fármacos Anti-VIH/uso terapéutico , Transfusión de Sangre Autóloga , Recuento de Linfocito CD4 , Citomegalovirus/genética , Infecciones por Citomegalovirus/virología , ADN Viral/análisis , Método Doble Ciego , Femenino , Infecciones por VIH/terapia , Infecciones por VIH/virología , Humanos , Estado de Ejecución de Karnofsky , Masculino , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , Viremia/tratamiento farmacológicoRESUMEN
The Viral Activation Transfusion Study (VATS) was a randomized trial that compared leukocyte-reduced transfusions with unfiltered red blood cell transfusions in HIV and cytomegalovirus (CMV) antibody-positive patients with anemia who were undergoing their first blood transfusion. The relations of the baseline qualitative and quantitative polymerase chain reaction (PCR) measures of plasma CMV viremia, HIV RNA, CD4(+) cell counts, and quality of life in these study subjects were examined. The 511 study subjects had a median CD4(+) cell count equal to 15 cells/mm3, and 110 (21.5%) had CMV viremia by qualitative assay. In multivariate models, frequency of positive qualitative CMV increased with decreasing CD4(+) cell counts (p =.04 trend), higher HIV RNA (p <.001), and a history of CMV disease (p <.001). Quantitative CMV PCR were performed on the 110 qualitative assay-positive study subjects. Median CMV viral load was 1780 copies/ml. In multivariate regression models, lower CD4(+) cell count (p =.03), and a history of CMV disease (p <.001) correlated with the level of CMV load. HIV RNA load and CMV load were not correlated. A lower Karnofsky score was associated with both the presence and quantity of CMV DNA.
Asunto(s)
Transfusión Sanguínea , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Adulto , Recuento de Linfocito CD4 , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/tratamiento farmacológico , ADN Viral/análisis , ADN Viral/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/terapia , VIH-1/genética , VIH-1/fisiología , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Calidad de Vida , ARN Viral/análisis , ARN Viral/genética , Análisis de Regresión , Factores de Tiempo , Carga ViralRESUMEN
To determine the risk factors and outcomes associated with rising cytomegalovirus (CMV) antigenemia levels during preemptive therapy among stem cell allograft recipients, 119 patients with CMV antigenemia were studied. Patients were prospectively monitored for CMV antigenemia weekly; those with positive findings on antigenemia tests were treated with intravenous ganciclovir (5 mg/kg twice daily for 1 week, followed by 5 mg/kg per day for 5-6 d/wk). While on therapy, 47 of 119 (39%) patients demonstrated increases that were 2 or more times greater than their baseline values, whereas 33 of 119 (28%) patients demonstrated increases that were 5 or more times greater. Rising antigenemia was confirmed by polymerase chain reaction for CMV DNA. Multivariate analysis identified corticosteroids as the primary risk factor for increasing antigenemia: for increases greater than or equal to twice the baseline, 1 to 2 mg/kg steroids was associated with an odds ratio (OR) of 4.0. For increases greater than or equal to 2 mg/kg steroids, the OR was 10.1. CMV isolates obtained at the time of rising antigenemia were susceptible to ganciclovir, indicating that resistance was not a major factor. Overall, rising antigenemia levels were not correlated with CMV disease. All 4 patients in whom CMV disease developed during therapy, however, had rising antigenemia levels. Among the 47 patients with antigenemia increases greater than or equal to twice the baseline, 15 were re-induced with antivirals, whereas 32 continued to receive maintenance therapy. All 4 patients in whom CMV disease developed during therapy received maintenance therapy, and 3 died with CMV disease. Thus, host factors such as the receipt of corticosteroids explain increasing viral load during the early phase of preemptive therapy. Continued induction dosing or re-induction may protect against early breakthrough CMV disease and CMV-related death among patients with rising antigenemia on preemptive therapy. (Blood. 2001;97:867-874)
Asunto(s)
Antígenos Virales/sangre , Infecciones por Citomegalovirus/sangre , ADN Viral/sangre , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Fosfoproteínas/sangre , Trasplante Homólogo/efectos adversos , Proteínas de la Matriz Viral/sangre , Viremia/sangre , Adolescente , Corticoesteroides/efectos adversos , Adulto , Anciano , Antivirales/uso terapéutico , Causas de Muerte , Niño , Preescolar , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/transmisión , Femenino , Foscarnet/uso terapéutico , Ganciclovir/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Factores de Riesgo , Análisis de Supervivencia , Donantes de Tejidos , Acondicionamiento Pretrasplante/efectos adversos , Resultado del Tratamiento , Carga Viral , Activación ViralRESUMEN
This article reviews the biology of cytomegalovirus (CMV), the approved antiviral therapies, and mechanisms of resistance to these drugs. The rates of resistance development in clinical trials are presented, as are the assays for testing susceptibility by phenotypic and genotypic methods. Factors that favor the development of clinical and in vitro antiviral resistance are discussed. Finally, approaches to altering antiviral therapy as resistance develops are outlined.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus/genética , Farmacorresistencia Viral , Citomegalovirus/efectos de los fármacos , Ganciclovir/farmacología , Ganciclovir/uso terapéutico , Humanos , MutaciónRESUMEN
A patient with AIDS and cytomegalovirus (CMV) retinitis received ganciclovir and foscarnet for 20 and 5 months, respectively, with evidence of periodic disease progression. After this therapy, a CMV isolate from the patient was resistant to ganciclovir, foscarnet, and cidofovir. Sequence analysis showed a known ganciclovir resistance mutation in the viral UL97 phosphotransferase (L595F) and a new mutation in conserved region V of the DNA polymerase gene (pol) sequence (codons 981-982 deleted). The pol mutation was transferred to a laboratory CMV strain (Towne) by homologous recombination and selection with either ganciclovir or foscarnet. Recombinant viruses containing this deletion showed a 6-8-fold increased ganciclovir resistance and a 3-5-fold increased resistance to both foscarnet and cidofovir, compared with the wild-type CMV. A single mutation in region V of CMV pol can, therefore, confer multiple drug resistance in a clinical isolate.
Asunto(s)
Antivirales/farmacología , Citomegalovirus/genética , ADN Polimerasa Dirigida por ADN/genética , Organofosfonatos , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/virología , Antivirales/uso terapéutico , Cidofovir , Citomegalovirus/efectos de los fármacos , Citomegalovirus/enzimología , Retinitis por Citomegalovirus/complicaciones , Retinitis por Citomegalovirus/tratamiento farmacológico , Retinitis por Citomegalovirus/virología , Citosina/análogos & derivados , Citosina/uso terapéutico , Farmacorresistencia Microbiana/genética , Resistencia a Múltiples Medicamentos/genética , Foscarnet/uso terapéutico , Ganciclovir/uso terapéutico , Eliminación de Gen , Humanos , Mutación , Compuestos Organofosforados/uso terapéutico , Fosfotransferasas/genética , TransfecciónAsunto(s)
Citomegalovirus/efectos de los fármacos , Ganciclovir/uso terapéutico , Simplexvirus/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Retinitis por Citomegalovirus/tratamiento farmacológico , Retinitis por Citomegalovirus/virología , Manejo de la Enfermedad , Farmacorresistencia Microbiana , Foscarnet/uso terapéutico , Infecciones por Herpesviridae/tratamiento farmacológico , Infecciones por Herpesviridae/virología , Humanos , Huésped Inmunocomprometido/efectos de los fármacos , Trasplante de Órganos/efectos adversosRESUMEN
Twelve laboratories collaborated in formulating and testing a standardized plaque reduction assay for cytomegalovirus (CMV) cell-associated clinical isolates. Four characterized and plaque-purified CMV strains, as well as six coded clinical isolates obtained after antiviral therapy, were distributed and tested. Good agreement was obtained for four of the clinical isolates, but a broad distribution of results was obtained for two isolates. Analysis of these results indicates the problems associated with clinical isolates, including the large genetic variability and the highly cell-associated phenotype. This collaborative effort, by addressing these problems, represents a significant step toward the development of a standardized assay.
Asunto(s)
Antivirales/farmacología , Infecciones por Citomegalovirus/virología , Citomegalovirus/efectos de los fármacos , Ensayo de Placa Viral/métodos , Ensayo de Placa Viral/normas , Células Cultivadas , Citomegalovirus/fisiología , Fibroblastos/virología , Foscarnet/farmacología , Ganciclovir/farmacología , Humanos , Laboratorios/normas , Pruebas de Sensibilidad Microbiana/métodos , Pruebas de Sensibilidad Microbiana/normas , Reproducibilidad de los ResultadosAsunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Organofosfonatos , Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/prevención & control , Enfermedades del Sistema Nervioso Central/virología , Coriorretinitis/virología , Cidofovir , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/prevención & control , Citosina/análogos & derivados , Citosina/uso terapéutico , Resistencia a Medicamentos , Foscarnet/uso terapéutico , Ganciclovir/uso terapéutico , Enfermedades Gastrointestinales/virología , Humanos , Compuestos Organofosforados/uso terapéutico , Neumonía/virología , Enfermedades Virales de Transmisión Sexual/prevención & controlRESUMEN
Cytomegalovirus (CMV) viremia, as measured by a hybrid capture assay, was used to measure the effectiveness of "immune reconstitution" in human immunodeficiency virus (HIV)-infected subjects treated with highly active antiretroviral therapy (HAART). Of the 28 enrolled patients (mean age, 38 years), 86% were male and 68% were antiretrovirally naive. Of the 23 patients who returned for follow-up, baseline median characteristics were 4.1 log10 CMV DNA copies/106 white blood cells (WBCs), 5.1 log10 HIV RNA copies/mL, and 35 CD4 cells/mm3. After initiation of HAART, median log10 CMV DNA copies/106 WBCs at means of 33, 87, and 385 days were 4.0, 3.3, and 2.5, respectively. Median log10 HIV RNA levels declined from 5.1 to 1.7 at 385 days with a commensurate rise in median CD4 T cells to 166/mm3. Immune reconstitution secondary to HAART results in a significant and progressive decline in CMV viremia in the absence of specific anti-CMV therapy.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus/fisiología , Replicación Viral/efectos de los fármacos , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adulto , Recuento de Linfocito CD4 , Citomegalovirus/efectos de los fármacos , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/inmunología , ADN Viral/sangre , Quimioterapia Combinada , Femenino , Humanos , Leucocitos/virología , Masculino , ARN Viral/sangre , Carga ViralRESUMEN
Treatment of cytomegalovirus (CMV) retinitis with oral ganciclovir results in relatively low plasma concentrations of drug, which theoretically could cause more frequent viral resistance compared with intravenous (iv) ganciclovir. By use of a plaque-reduction assay to quantify phenotypic sensitivity to ganciclovir, virus isolates were studied from patients with CMV retinitis participating in four clinical trials of oral ganciclovir. Before treatment, 69% of patients were culture-positive but just 1.1% of patients yielded a resistant CMV, defined as a median inhibitory concentration (IC50) >6 microM. On treatment, the first resistant isolate was recovered at 50 days. Overall, 3.1% of patients receiving iv ganciclovir and 6. 5% of those taking oral ganciclovir shed resistant CMV (median ganciclovir exposures of 75 and 165 days, respectively). Since IC50s for clinical isolates increased proportionately with treatment duration, it is likely that viral resistance would be more frequent with longer treatment.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/virología , Retinitis por Citomegalovirus/virología , Citomegalovirus/efectos de los fármacos , Ganciclovir/farmacología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Administración Oral , Antivirales/farmacología , Antivirales/uso terapéutico , Retinitis por Citomegalovirus/complicaciones , Retinitis por Citomegalovirus/tratamiento farmacológico , Farmacorresistencia Microbiana , Ganciclovir/administración & dosificación , Ganciclovir/uso terapéutico , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Factores de TiempoRESUMEN
Blood culture isolates from patients receiving first- (peripheral retinitis) or second-line (relapsing retinitis) therapy with intravenous cidofovir were obtained from three clinical trials for in vitro antiviral susceptibility analyses. Isolates from 6 patients obtained after 14.3 weeks (mean) of first-line cidofovir therapy showed complete susceptibility to cidofovir, ganciclovir, and foscarnet. Isolates from 20 patients were obtained after 17.3 weeks (mean) of second-line cidofovir therapy. Ten showed complete susceptibility to all inhibitors, 3 showed low-level ganciclovir resistance (<6-fold) but were sensitive to cidofovir and foscarnet, and 7 showed moderately reduced susceptibility (<8-fold) to cidofovir and high-level resistance (8- to 23-fold) to ganciclovir in vitro. Four of these 7 isolates showed reduced susceptibility (4-fold) to foscarnet. Notably, there was no difference in time to retinitis progression in patients that were on cidofovir therapy when sensitive isolates were compared with those showing reduced susceptibility to cidofovir in vitro.
Asunto(s)
Antivirales/farmacología , Antivirales/uso terapéutico , Retinitis por Citomegalovirus/tratamiento farmacológico , Citomegalovirus/efectos de los fármacos , Citosina/análogos & derivados , Organofosfonatos , Compuestos Organofosforados/uso terapéutico , Cidofovir , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Retinitis por Citomegalovirus/virología , Citosina/uso terapéutico , Farmacorresistencia Microbiana , Foscarnet/farmacología , Ganciclovir/farmacología , Genotipo , Humanos , Pruebas de Sensibilidad Microbiana , RecurrenciaRESUMEN
Three human immunodeficiency virus-infected subjects with progressive cytomegalovirus (CMV) retinitis despite prolonged antiviral therapy had buffy coat CMV isolates that were resistant to both ganciclovir and foscarnet. Genetic analysis of the resistant isolates showed that each contained a well-known ganciclovir resistance mutation in the viral UL97 phosphotransferase sequence, as well as a mutation (Ala to Val at codon 809, V809) in conserved region III of the DNA polymerase (Pol) sequence. A segment of the Pol sequence from one of the clinical isolates was transferred to CMV laboratory strain AD169 by homologous recombination. The recombinant virus containing V809 showed 6.3-fold increased foscarnet resistance and 2.6-fold increased ganciclovir resistance. Occurrence of the V809 mutation in 3 unrelated cases suggests that it is a clinically significant viral genetic marker for foscarnet resistance and decreased susceptibility to ganciclovir.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/virología , Antivirales/farmacología , Retinitis por Citomegalovirus/virología , Citomegalovirus/enzimología , ADN Polimerasa Dirigida por ADN/genética , Foscarnet/farmacología , Mutación Puntual , Inhibidores de la Transcriptasa Inversa/farmacología , Proteínas Virales , Infecciones Oportunistas Relacionadas con el SIDA/fisiopatología , Adulto , Alanina/genética , Citomegalovirus/efectos de los fármacos , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Retinitis por Citomegalovirus/fisiopatología , Farmacorresistencia Microbiana/genética , Ganciclovir/farmacología , Humanos , Masculino , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Valina/genéticaRESUMEN
OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Organofosfonatos , Fármacos Anti-VIH/uso terapéutico , Cidofovir , Citosina/análogos & derivados , Citosina/uso terapéutico , Foscarnet/uso terapéutico , Ganciclovir/uso terapéutico , Humanos , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/virología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/virología , Compuestos Organofosforados/uso terapéutico , Retinitis/tratamiento farmacológico , Retinitis/virologíaRESUMEN
The proposed switching of oral acyclovir from prescription to over-the-counter (OTC) status for the 5-day episodic treatment of genital herpes was considered by a consensus panel. It was concluded that self-diagnosis/misdiagnosis, misuse, and adverse drug effects were potential problems with the OTC use of acyclovir. While acyclovir reduces asymptomatic shedding of herpes simplex virus type 2, the reduction in transmission of virus potentially resulting from increased acyclovir use was felt to be of unknown extent but likely to be of benefit overall. The availability of acyclovir would likely be improved. There were differences in opinion as to whether widespread availability of acyclovir (prescription or OTC) may speed the development of viral resistance. However, all panel members felt that granting OTC status may set an undesirable precedent for the switch from prescription to OTC use of other systemically administered antiinfective agents. The effect of this precedent, in terms of accelerating development of multidrug-resistant bacteria, was a major concern of all panel members. The consensus was that the switch of acyclovir to OTC status could not be supported.
Asunto(s)
Aciclovir , Antivirales , Prescripciones de Medicamentos , Política de Salud , Herpes Genital/tratamiento farmacológico , Aciclovir/efectos adversos , Aciclovir/toxicidad , Administración Oral , Antivirales/efectos adversos , Antivirales/toxicidad , Conferencias de Consenso como Asunto , Seguridad de Productos para el Consumidor , Consejo , Farmacorresistencia Microbiana , Educación en Salud , Herpes Genital/diagnóstico , Herpes Genital/epidemiología , Herpes Genital/transmisión , Humanos , Tamizaje Masivo , Enfermedades de Transmisión Sexual , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Adefovir dipivoxil is a novel nucleotide analogue with several promising in vitro anti-human immunodeficiency virus (HIV) characteristics. To evaluate the safety and efficacy of adefovir dipivoxil monotherapy, a randomized, double-blind, placebo-controlled study was initiated involving 72 subjects with moderately advanced HIV disease. Subjects were randomly assigned in a 2:1 ratio to receive adefovir dipivoxil or placebo as a once-daily oral dose for 6 weeks, followed by 6 weeks of open-label adefovir dipivoxil. Two dose levels were studied (125 mg and 250 mg). Adefovir dipivoxil was determined to be safe and well-tolerated when administered for 12 weeks. At week 6, changes in absolute CD4 T cell levels and HIV-1 RNA levels were significantly greater with adefovir dipivoxil than with placebo. These effects were sustained through 12 weeks of treatment. As determined by standard RNA sequencing techniques, only 1 of the 24 subjects who received adefovir dipivoxil (125 mg/day) developed any genotypic change from baseline.