RESUMEN
Human immunodeficiency virus type 1 (HIV-1) strains resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) may easily be selected for in vitro and in vivo under a suboptimal therapy regimen. Although cross-resistance is extensive within this class of compounds, newer NNRTIs were reported to retain activity against laboratory strains containing defined resistance-associated mutations. We have characterized HIV-1 resistance to loviride and the extent of cross-resistance to nevirapine, delavirdine, efavirenz, HBY-097, and tivirapine in a set of 24 clinical samples from patients treated with long-term loviride monotherapy by using a recombinant virus assay. Genotypic changes associated with resistance were analyzed by population sequencing. Overall, phenotypic resistance to loviride ranged from 0.04 to 3.47 log10-fold. Resistance was observed in samples from patients who had discontinued loviride for up to 27 months. Cross-resistance to the other compounds was extensive; however, fold resistance to efavirenz was significantly lower than fold resistance to nevirapine. No genotypic changes were detected in three samples; these were sensitive to all of the NNRTIs tested. The most common genotypic change was the K103N substitution. The range of phenotypic resistance in samples containing the K103N substitution could not be predicted from a genotypic analysis of known NNRTI resistance-associated mutations. The Y181C substitution was detected in one isolate which was resistant to loviride and delavirdine but sensitive to efavirenz, HBY-097, and tivirapine. Our data indicate that the available newer NNRTIs which retain activity against some HIV-1 strains selected by other compounds of this class in vitro may have compromised clinical efficacy in some patients pretreated with NNRTI.
Asunto(s)
Acetamidas/farmacología , Acetofenonas/farmacología , Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Acetamidas/uso terapéutico , Acetofenonas/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Microbiana , Resistencia a Múltiples Medicamentos , Genotipo , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Fenotipo , Estudios RetrospectivosRESUMEN
BACKGROUND: Itraconazole is a broad-spectrum antifungal agent that has been used to treat dermatomycosis and onychomycosis using continuous therapy. More recently the drug has been used as pulse dosing. OBJECTIVE: Our purpose was to review the studies in which itraconazole pulse therapy (PT) has been administered in the management of dermatomycoses. RESULTS: For tinea pedis and manuum, the recommended dosage is itraconazole 200 mg twice daily for 1 week (n = 220). A clinical response and mycologic cure rate of 90% +/- 4% and 76% +/- 6%, respectively, has been obtained. For tinea corporis/cruris, itraconazole 200 mg/day for 1 week (n = 354) resulted in a clinical response and mycologic cure rate of 90% +/- 4% and 77% +/- 6%, respectively. When three pulses of itraconazole are used to treat toenail onychomycosis (n = 1389), the clinical cure rate, clinical response, and mycologic cure rate at follow-up 12 months after the start of therapy were 58% +/- 10%, 82% +/- 3%, and 77% +/- 5%, respectively. With two pulses for onychomycosis of the fingernails, the clinical cure rate, clinical response, and mycologic cure rate at follow-up, 9 months after the start of therapy, were 78% +/- 10%, 89% +/- 6%, and 87% +/- 8%, respectively. CONCLUSION: Itraconazole PT is effective and safe in the treatment of tinea pedis/manuum, tinea corporis/cruris, and onychomycosis.
Asunto(s)
Antifúngicos/uso terapéutico , Dermatomicosis/tratamiento farmacológico , Itraconazol/uso terapéutico , Onicomicosis/tratamiento farmacológico , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Esquema de Medicación , Monitoreo de Drogas , Estudios de Seguimiento , Dermatosis del Pie/tratamiento farmacológico , Dermatosis de la Mano/tratamiento farmacológico , Humanos , Itraconazol/administración & dosificación , Itraconazol/efectos adversos , Inducción de Remisión , Seguridad , Tiña/tratamiento farmacológico , Tiña del Pie/tratamiento farmacológicoRESUMEN
OBJECTIVE: To compare two antiretroviral regiments, loviride plus lamivudine (3TC) plus zidovudine (ZDV) (triple combination) and loviride plus ZDV (double combination) in terms of pharmacokinetic interactions, tolerability, safety, and immunological and virological efficacy. STUDY DESIGN: An open, case-controlled, pharmacokinetic and 24-week continuous treatment pilot study. PATIENTS: Twenty p24 antigen-positive patients, 10 per treatment group, were matched according to p24 antigenaemia less or more than 100 pg, CD4 count less or more than 150 x 10-(6)/l, and gender. Eight out of 10 cases and seven out of 10 controls had received previous antiretroviral therapy. RESULTS: No clinically relevant pharmacokinetic interactions were observed. Both treatment combinations were well tolerated. Median absolute and percentage CD4 count increases above baseline were more pronounced in the triple combination arm than in the double combination arm. Median p24-antigen and plasma viraemia level decreases below baseline were more pronounced in the triple combination arm. The M(184)I/V mutation was detected in all plasma samples of triple combination patients examined at week 12. Mutations conferring resistance to loviride and ZDV were found in a significant subset of patients in both treatment arms. CONCLUSIONS: Both combination regimens have an excellent safety/tolerability profile, but a higher level of in vivo efficacy is achieved by the triple combination, despite genotypic changes conferring resistance to one or all of these agents. The conclusions drawn are limited by small population size and the heterogenous pretreatment history. However, they support the validity of and strongly encourage a rationally designed multidrug combination approach to HIV therapy.
Asunto(s)
Acetamidas/uso terapéutico , Acetofenonas/uso terapéutico , Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Zalcitabina/análogos & derivados , Zidovudina/uso terapéutico , Acetamidas/efectos adversos , Acetamidas/farmacocinética , Acetofenonas/efectos adversos , Acetofenonas/farmacocinética , Adulto , Antivirales/efectos adversos , Antivirales/farmacocinética , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Estudios Cruzados , Análisis Mutacional de ADN , Farmacorresistencia Microbiana/genética , Quimioterapia Combinada , Femenino , Proteína p24 del Núcleo del VIH/sangre , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , Humanos , Lamivudine , Persona de Mediana Edad , Proyectos Piloto , ARN Viral/sangre , ARN Viral/genética , Zalcitabina/efectos adversos , Zalcitabina/farmacocinética , Zalcitabina/uso terapéutico , Zidovudina/efectos adversos , Zidovudina/farmacocinéticaAsunto(s)
Acetamidas/uso terapéutico , Acetofenonas/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Acetamidas/efectos adversos , Acetofenonas/efectos adversos , Biomarcadores/sangre , Recuento de Linfocito CD4 , Método Doble Ciego , Femenino , Estudios de Seguimiento , Infecciones por VIH/sangre , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Concentración 50 Inhibidora , Subgrupos Linfocitarios , Masculino , Neopterin/sangre , Receptores de Interleucina-2/sangre , Negativa del Paciente al TratamientoRESUMEN
It was our objective to investigate the effect of asymptomatic infection with HIV on the expression of lymphocyte activation markers after stimulation with mitogens. Whole blood cultures were made of HIV+ and HIV- subjects (29 asymptomatic HIV-1-infected subjects and 33 apparently healthy normal volunteers). At various times after stimulation with concanavalin A (Con A), anti-CD3 and pokeweed mitogen (PWM), the expression of activation markers (CD25 and HLA-DR) and the blastogenesis were quantified by flow cytometry. The flow cytometric quantification of the expression of activation markers and blastogenesis in whole blood cultures provided an easy and safe alternative to thymidine incorporation to assess lymphocyte responses in HIV+ subjects. Activation showed a tendency to be lower in the HIV+ subjects with all three stimulants. This difference with HIV- subjects was statistically significant only for stimulation with PWM after 4 days. Further investigations should be undertaken to show whether this functional impairment is related to disease progression and whether it can be influenced by effective therapy.
Asunto(s)
Infecciones por VIH/inmunología , Activación de Linfocitos/efectos de los fármacos , Mitógenos de Phytolacca americana/farmacología , Adulto , Antígenos de Diferenciación/análisis , Biomarcadores/análisis , Relación Dosis-Respuesta Inmunológica , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Despite major efforts by academic and pharmaceutical research teams, no definitive prevention or cure of AIDS has been achieved. Nevertheless, this research has yielded important information on how HIV replicates and causes disease. Moreover, several inhibitors, targeted at different steps in the life cycle of HIV, have been discovered, some of which have been licensed or are being studied in the clinic. One of the major obstacles towards more effective drugs or a vaccine, is the extraordinary variability in HIV strains which occur in different parts of the world over time, and in patients. The driving force behind these numerous variants is the combination of an error-prone reverse transcriptase, a viral enzyme transcribing the viral RNA genome into DNA on the one hand and the human immune system on the other hand. This puts a constant selection pressure on the HIV population leading to the emergence of escape mutants. It therefore poses an additional challenge on the discovery and development of HIV inhibitors. A research strategy should therefore encompass the following steps: (i) the identification of new lead compounds targeted at known or unknown steps in the HIV replicative cycle, (ii) the characterization and validation of their molecular targets with emphasis on the potential for lead optimization and the likelihood of resistance development, (iii) the study of combination strategies, and (iv) clinical evaluation and validation of the aforementioned concepts.
Asunto(s)
Antivirales/farmacología , VIH/efectos de los fármacos , Automatización , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , VIH/fisiología , Infecciones por VIH/tratamiento farmacológico , Humanos , Replicación Viral/efectos de los fármacosRESUMEN
The drug sensitivities of human immunodeficiency virus type 1 (HIV-1) isolates from a group of four untreated and seven TIBO R82913-treated patients were determined in a reverse transcriptase (RT) assay. Five of the treated patients harbored HIV-1 isolates with R82913 sensitivity comparable to that of the isolates of untreated patients, ranging from almost 2-fold higher sensitivity to 13-fold lower sensitivity than that of recombinant p66 RT. From one of the seven treated patients, an HIV-1 strain with a 20-fold reduced sensitivity to R82913 could be isolated; and from another patient, a strain with 100-fold reduced sensitivity (resistance) was isolated. The drug-resistant strain in this patient emerged after 3 weeks of treatment and was due to the Y188L mutation in its RT. On passaging the virus in cord blood lymphocytes, but not in CEM cells, the resistant virus was lost in favor of a different HIV-1 strain harboring the wild-type Y188 with a sensitivity to R82913 comparable to that of wild-type p66 RT. In several HIV-1 isolates (from treated and untreated patients), some HIV-2- and CIVgab-specific amino acids were found. One of these substitutions, that is, I/V179D (from an untreated patient), conferred a sevenfold reduced RT sensitivity to R82913.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Benzodiazepinas/uso terapéutico , VIH-1/efectos de los fármacos , Imidazoles/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/microbiología , Secuencia de Aminoácidos , Secuencia de Bases , Células Cultivadas , Cartilla de ADN , Farmacorresistencia Microbiana , Variación Genética , Transcriptasa Inversa del VIH , VIH-1/clasificación , VIH-1/aislamiento & purificación , Humanos , Datos de Secuencia Molecular , ADN Polimerasa Dirigida por ARN/genética , Inhibidores de la Transcriptasa Inversa , Alineación de SecuenciaRESUMEN
In vitro evaluation of a large chemical library of pharmacologically acceptable prototype compounds in a high-capacity, cellular-based screening system has led to the discovery of another family of human immunodeficiency virus type 1 (HIV-1) inhibitors. Through optimization of a lead compound, several alpha-anilinophenylacetamide (alpha-APA) derivatives have been identified that inhibit the replication of several HIV-1 strains (IIIB/LAI, RF, NDK, MN, HE) in a variety of host cell types at concentrations that are 10,000- to 100,000-fold lower than their cytotoxic concentrations. The IC50 of the alpha-APA derivative R 89439 for HIV-1 cytopathicity in MT-4 cells was 13 nM. The median 90% inhibitory concentration (IC90) in a variety of host cells was 50-100 nM. Although these alpha-APA derivatives are active against a tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione-(TIBO)-resistant HIV-1 strain, they do not inhibit replication of HIV-2 (strains ROD and EHO) or simian immunodeficiency virus (strains Mac251, mndGB1, and agm3). An HIV-1 strain containing the Tyr181-->Cys mutation in the reverse transcriptase region displayed reduced sensitivity. alpha-APA derivative R 89439 inhibited virion and recombinant reverse transcriptase of HIV-1 but did not inhibit that of HIV-2. Reverse transcriptase inhibition depended upon the template/primer used. The relatively uncomplicated synthesis of R 89439, its potent anti-HIV-1 activity, and its favorable pharmacokinetic profile make R 89439 a good candidate for clinical studies.
Asunto(s)
Acetamidas/farmacología , Acetofenonas/farmacología , Compuestos de Anilina/farmacología , Antivirales , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa , Acetamidas/farmacocinética , Acetofenonas/farmacocinética , Compuestos de Anilina/farmacocinética , Proteína p24 del Núcleo del VIH/metabolismo , Transcriptasa Inversa del VIH , VIH-2/efectos de los fármacos , Humanos , Masculino , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
R 82913, a tetrahydroimidazobenzodiazepinthione (TIBO) derivative with potent activity against human immunodeficiency virus 1 (HIV-1) in vitro, was given to 22 patients with AIDS or AIDS-related complex in a dose-escalating pilot study. Doses of 10 to 300 mg administered daily by intravenous infusion were well tolerated for up to 50 weeks, with no haematological or biochemical evidence of toxicity. Mean OKT4 cell count rose slightly during the second month of treatment when higher steady-state plasma concentrations of the drug were achieved. Median p24 antigen concentration fell by 41% during the first month of therapy. When the rise in p24 antigen before therapy was compared to the fall during treatment, end-point analysis showed a significant difference (p less than 0.03). The combination of potent antiretroviral activity in vitro and the observed effect on HIV p24 antigen and absence of toxicity in vivo indicate that R 82913 and related TIBO derivatives merit further study in the treatment of retroviral infections.