RESUMEN
BACKGROUND: Although both tipranavir and darunavir are important options for the management of patients with multidrug resistant HIV, there are at present no studies comparing the effectiveness and safety of these 2 antiretroviral drugs in this population of patients. OBJECTIVE: To compare the effectiveness and safety of ritonavir (TPV/r)- and darunavir/ritonavir (DRV/ r)-based therapies in treatment-experienced patients (n = 38 and 47, respectively). METHODS: Multicenter, retrospective cohort study. RESULTS: The median baseline viral load and CD4 count were 4.7 copies/mL (interquartile range [IQR] 4.3, 5.2) and 168 cells/mm( 3) (IQR 80, 252) for TPV/r patients and 4.7 copies/mL (IQR 3.7, 5.1) and 171 cells/mm(3) (IQR 92, 290) for DRV/r patients. The median number of years on antiretroviral therapy (ART) prior to starting DRV/r or TPV/r were 12.7 (10.2-15.5) and 10.5 (8.4-12.6), respectively (P < .01). Current raltegravir (RAL) use (odds ratio [OR] 5.53, 95% CI 1.08-28.34) was significantly associated with virologic suppression at week 24 in multivariable logistic regression models, whereas the use of TPV/r was not significantly associated with virologic suppression compared to DRV/r (OR 0.93, 95% CI 0.27-3.18, P = .91). CONCLUSION: No significant difference was observed between DRV/r and TPV/r in terms of virologic suppression.
Asunto(s)
Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacología , Piridinas/farmacología , Pironas/farmacología , Ritonavir/farmacología , Sulfonamidas/farmacología , Adulto , Recuento de Linfocito CD4 , Darunavir , Resistencia a Múltiples Medicamentos , Femenino , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/inmunología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Ontario , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/inmunología , Pironas/administración & dosificación , Pironas/efectos adversos , Pironas/inmunología , Estudios Retrospectivos , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , Ritonavir/inmunología , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/inmunología , Análisis de Supervivencia , Carga Viral/efectos de los fármacosRESUMEN
A HIV-infected patient treated since eight years with all antiretroviral classes save boosted protease inhibitors, at the time of changing therapy due to an emerging genotyping resistance to non-nucleoside reverse transcriptase inhibitors, experienced repeated episodes of hypersensitivity reactions to all available boosted protease inhibitors. After documenting a combined ritonavir and lopinavir hypersensitivity by means of a specific in vitro cellular antigen stimulation test (CAST), antiretroviral therapy was safely continued with unboosted atazanavir. According to our knowledge, we report the first case of application of the in vitro CAST assay to antiretroviral intolerance, and the subsequent, specific regimen selection in a HIV-infected subject who showed multiple allergy to all boosted protease inhibitors. Further, controlled investigation is strongly needed to implement in vitro allergometric testing in patients with HIV infection and related diseases, who are prone to show unpredictable drug intolerance reactions. In fact, HIV-infected patients may suffer from frequent allergic drug reactions which may be difficult to be systematically recognized (due to the frequent, multiple concurrent pharmacotherapy), while eventual drug rechallenges are expected to be potentially dangerous.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Inhibidores de Proteasas/efectos adversos , Pirimidinonas/efectos adversos , Ritonavir/efectos adversos , Adulto , Fármacos Anti-VIH/inmunología , Hipersensibilidad a las Drogas/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Inmunoensayo/métodos , Lopinavir , Masculino , Inhibidores de Proteasas/inmunología , Pirimidinonas/inmunología , Ritonavir/inmunologíaRESUMEN
Drug-resistant HIV-1 is a cause of growing clinical and public-health concern. In many patients, combination antiretroviral therapy fails to achieve complete viral suppression (virological failure). Continuing viral replication during therapy leads to the accumulation of drug-resistance mutations, resulting in increased viral load and a greater risk of disease progression. Patients with drug-resistant HIV-1 infection have three therapeutic options: a change to a salvage regimen with the aim of fully suppressing viral replication; interruption of therapy; or continuation of a partially effective regimen. The first strategy is preferred for most patients failing their first or perhaps their second regimen. However, the best approach remains unclear for patients who have failed multiple treatment regimens and who have limited options for complete viral suppression. The management of such patients requires a careful understanding of the pathogenesis of drug-resistant HIV-1, the clinical consequences of virological failure, the potential benefits and limitations of diagnostic assays, and the likelihood that agents in development will be effective.
Asunto(s)
Fármacos Anti-VIH/inmunología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Terapia Antirretroviral Altamente Activa/métodos , Farmacorresistencia Viral/genética , Farmacorresistencia Viral/inmunología , Quimioterapia Combinada , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/inmunología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/inmunología , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Ritonavir/inmunología , Ritonavir/uso terapéutico , Resultado del Tratamiento , Carga Viral/estadística & datos numéricos , Replicación Viral/efectos de los fármacos , Replicación Viral/inmunologíaRESUMEN
BACKGROUND: Hypertriglyceridemia (HTG) is frequently observed during highly active antiretroviral therapy (HAART) including protease inhibitor. Apolipoprotein (apo) CIII could be involved in this HTG by inhibition of triglyceride (TG) hydrolysis, which leads to the occurrence of small dense low density lipoprotein (sdLDL), a recognized cardiovascular risk factor. OBJECTIVE: To characterize the influence of lopinavir/ritonavir-containing regimen on lipoprotein profile. DESIGN AND METHODS: 24 antiretroviral-experienced HIV infected adults (including 14 patients in therapeutic interruption of at least 2 months) and 14 HIV uninfected healthy controls were enrolled. Serum lipid parameters (total cholesterol (TC), HDL-C, LDL-C, TG, apoA1, apoB, apoCIII), lipoprotein composition and LDL size were determined before initiation of lopinavir/ritonavir-containing regimen, and at 1 and 3 months thereafter. RESULTS: At baseline an atherogenic lipid profile was evidenced, characterized by a moderate HTG associated to a smaller mean LDL size (25.16 vs 25.93 nm, P<0.001), an enrichment in TG of LDL (11.4 vs 6.0%, P<0.01) and a high prevalence of sdLDL (75 vs 7%, P<0.01) when compared to controls. After 1 month of lopinavir/ritonavir-containing regimen, a significant reduction of LDL size (24.81 vs 25.16 nm, P<0.05) and a significant increase in cholesterol total (5.53 vs 4.49 mmol/l, P<0.001), in TG (4.20 vs 2.01 mmol/l, P<0.001), in apoA1 (1.28 vs 1.11 g/l, P<0.001), in apoB (1.08 vs 0.94 g/l, P<0.01), in apoCIII (0.16 vs 0.10 g/l, P<0.001), in TG percentage in LDL (14.4 vs 11.4, P<0.05) and in TG percentage in HDL (10.2 vs 8.3, P<0.05) were observed. CONCLUSIONS: Advanced stage of HIV infection is associated with an atherogenic lipid profile including a high prevalence of sdLDL. Lopinavir/ritonavir-containing regimen accentuates the reduction of LDL size. Since fibrates decrease TG and increase LDL size, they appear as a logical option to manage HAART-induced HTG.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Inhibidores de la Proteasa del VIH/uso terapéutico , Lipoproteínas LDL/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Pirimidinonas/uso terapéutico , Ritonavir/uso terapéutico , Adulto , Terapia Antirretroviral Altamente Activa , Apolipoproteína A-I/metabolismo , Apolipoproteína C-III , Apolipoproteínas B/metabolismo , Apolipoproteínas C/metabolismo , Biomarcadores/sangre , HDL-Colesterol/metabolismo , Femenino , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/inmunología , Humanos , Lipoproteínas VLDL/metabolismo , Lopinavir , Masculino , Fosfolípidos/metabolismo , Pirimidinonas/inmunología , Ritonavir/inmunología , Estadística como Asunto , Factores de Tiempo , Resultado del Tratamiento , Triglicéridos/metabolismo , Carga ViralRESUMEN
BACKGROUND: P-glycoprotein causing multidrug resistance (MDR) and limiting the efficacy of antineoplastic drugs and protease inhibitors (PIs) is expressed in human CD4+ T lymphocytes, one of the main targets of HIV, in a range of pharmacological barriers and at varying degrees in non-Hodgkin's lymphoma and Kaposi's sarcoma. METHODS: The differential effect of PIs on P-glycoprotein function was studied by measuring drug efflux inhibition, MDR-reversing ability and MAb UIC2 epitope modulation in MDR variants of the human T lymphoblastoid CEM cell line. RESULTS: The treatment of MDR cells with PIs induces different UIC2 epitope modulations indicating a differential recognition and binding of these antiviral drugs by MDR1 P-glycoprotein. In fact, ritonavir, saquinavir and indinavir act differently to the P-glycoprotein blocker in CEM-VBL10 cells. The MDR level of these cells was markedly affected by ritonavir and saquinavir in the order, while the PI indinavir does not seem to compete with the P-glycoprotein drug transport function. In CEM-VBL100 cells, expressing a very high number of P-glycoprotein molecules, only ritonavir acts as an efficient drug efflux inhibitor and MDR-reversing agent. CONCLUSION: The HIV-1 PIs ritonavir and saquinavir even at different levels act as genuine P-glycoprotein substrates by inhibiting dye substrate efflux, modulating UIC2 epitope and reversing drug resistance. Conversely, at least in the in vitro system used in the present study, the PI indinavir does not significantly alter P-glycoprotein drug transport activities and function.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Modulación Antigénica/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Inhibidores de la Proteasa del VIH/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/inmunología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Modulación Antigénica/inmunología , Antineoplásicos/farmacocinética , Compuestos de Boro/farmacocinética , Linfocitos T CD4-Positivos/clasificación , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Línea Celular , Doxorrubicina/farmacocinética , Resistencia a Múltiples Medicamentos/inmunología , Sinergismo Farmacológico , Quimioterapia Combinada , Glutatión Transferasa/efectos de los fármacos , Glutatión Transferasa/metabolismo , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/inmunología , Humanos , Indinavir/inmunología , Indinavir/farmacología , Conformación Proteica/efectos de los fármacos , Ritonavir/inmunología , Ritonavir/farmacología , Saquinavir/inmunología , Saquinavir/farmacología , Vinblastina/farmacocinéticaRESUMEN
The HIV protease inhibitor ritonavir (Norvir; ABT-578), currently used in combination with nucleoside analogs and other protease inhibitors in anti-HIV therapy, has previously been quantified by an HPLC procedure. Here, we report the first convenient one-step competitive ELISA for measuring plasma and intracellular ritonavir in HIV patients. Anti-ritonavir antibody was raised in rabbits using ritonavir-KLH conjugate as immunogen, and the enzymatic tracer was prepared by coupling the drug to acetylcholine esterase. Samples for analysis were first extracted with methanol. Bound/free separation was achieved in a microtiter plate previously coated with anti rabbit IgG monoclonal antibody. Fifty percent inhibition was observed at 1 ng/ml ritonavir and the method accurately and specifically detected as little as 3-4 ng/ml of plasma ritonavir as well as intracellular drug in the peripheral blood mononuclear cells of patients undergoing ritonavir therapy. Within-run and day to day coefficients of variation were below 10% and the drugs currently used in HIV therapy did not interfere with the test. The ELISA was applied to the measurement of plasma ritonavir and to the determination of the extracellular/intracellular drug level ratios in HIV patients receiving long-term multidrug therapy.
Asunto(s)
Ensayo de Inmunoadsorción Enzimática/métodos , Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH/sangre , Ritonavir/sangre , Animales , Anticuerpos/sangre , Línea Celular , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/inmunología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Líquido Intracelular , Conejos , Reproducibilidad de los Resultados , Ritonavir/inmunología , Ritonavir/uso terapéutico , Sensibilidad y EspecificidadRESUMEN
From March to July 1996, 61 patients with CD4<50/mm(3)began a therapy with protease inhibitors. Increase and maintenance of CD4>100/mm(3) was observed in 39/61 patients with a protective effect for occurrence of AIDS or death. This immunological response was correlated with the duration of the virological response. However, 38% of patients with long-term immunological response never had a undetectable viral load.
Asunto(s)
Recuento de Linfocito CD4 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/inmunología , Inhibidores de la Proteasa del VIH/uso terapéutico , Indinavir/inmunología , Indinavir/uso terapéutico , Ritonavir/inmunología , Ritonavir/uso terapéutico , Saquinavir/inmunología , Saquinavir/uso terapéutico , Progresión de la Enfermedad , Estudios de Seguimiento , Infecciones por VIH/sangre , Infecciones por VIH/mortalidad , Infecciones por VIH/virología , Humanos , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
UNLABELLED: This research comprised a pilot open prospective clinical study comparing T-cell subset reconstitution in antiretroviral-naive patients, after 12 months of HAART when treatment was initiated in early stages (ES; n = 18) of infection versus advanced stages (AS; n = 20). CONTROL GROUP: 10 healthy HIV-negative individuals. Immunophenotypic markers were evaluated before and after 6-and 12-months' therapy. Functional assays were performed in one subset. RESULTS: Viral load (VL) was < 200 copies/ml in all patients. Median percentages of CD4+ pretherapy were 33% and 6%, respectively, in the ES and AS groups, increment after 12 months of therapy was +15% and +13% respectively. Only the ES group achieved normal values. Declines of CD8+ percentage were significantly higher in the ES (-18%) than in the AS group (-2%). CD4+ memory and naive cells in the ES group were similar to those of controls before treatment and did not change after therapy. In contrast, CD4+ memory and naive cells in the AS group did not reach normal levels despite treatment. In the ES group, there was a significant increment in CD8+ naive cells (+8%) and a decrement in CD8+CD38+ cells (-17%), both populations reached values close to normal, whereas these subsets remained far from normal in the AS group. Improvement of lymphoproliferative response after therapy was observed in both groups. One patient in the ES group showed positive LPR against p24 after treatment. After 12 months' highly active antiretroviral therapy, only those who began such therapy in ES disease reached values within the range of healthy controls. To achieve a more complete immunologic reconstitution, early initiation of potent antiretroviral therapy should be recommended.