RESUMO
BACKGROUND: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. METHODS: To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. RESULTS: Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. CONCLUSION: We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoterapia Adotiva , Leucoencefalopatia Multifocal Progressiva/terapia , LinfócitosAssuntos
Líquido Ascítico/virologia , Betacoronavirus/genética , Colecistectomia/métodos , Infecções por Coronavirus/virologia , Estado Terminal , DNA Viral/análise , Doenças da Vesícula Biliar/complicações , Pneumonia Viral/virologia , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Transmissão de Doença Infecciosa/prevenção & controle , Doenças da Vesícula Biliar/cirurgia , Humanos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , SARS-CoV-2RESUMO
BACKGROUND: Sub-Saharan Africa has a high prevalence of hepatitis B virus (HBV) infections. Health care workers (HCWs) are at high risk of contracting HBV infection through their occupation. Vaccination of HCWs against HBV is standard practice in many countries, but is often not implemented in resource-poor settings. We aimed with this cross-sectional study to determine HBV prevalence, HCW vaccination status, and the risk factors for HCWs contracting HBV infection in Tanzania. METHODS: We enrolled 600 HCWs from a tertiary Tanzanian hospital. Their demographics, medical histories, HBV vaccination details and risk factors for contracting blood-borne infections were collected using a standardized questionnaire. Serum samples were tested for HBV and hepatitis C virus (HCV) markers by ELISA techniques, PCR and an anti-HBs rapid test. HCWs were divided in two subgroups: those at risk of contracting HBV (rHCW 79.2%) via exposure to potentially infectious materials, and those considered not at risk of contracting HBV (nrHCW, 20.8%). RESULTS: The overall prevalence of chronic HBV infection (HBsAg+, anti-HBc+, anti-HBs-) was 7.0% (42/598). Chronic HBV infection was found in 7.4% of rHCW versus 5.6% of nrHCW (p-value = 0.484). HCWs susceptible to HBV (HBsAg-, anti-HBc-, anti-HBs-) comprised 31.3%. HBV immunity achieved either by healed HBV infection (HBsAg-, anti-HBc+, anti-HBs+) or by vaccination (HBsAg-, anti-HBc-, anti-HBs+) comprised 36.5% and 20.2%, respectively. 4.8% of participants had indeterminate results (HBsAg-, anti-HBc+, anti-HBc-IgM-, anti-HBs-). Only 77.1% of HCWs who received a full vaccination course had an anti-HBs titer >10 ml/U. An anti-HBs point-of-care test was 80.7% sensitive and 96.9% specific. There was a significantly higher risk for contracting HBV (anti-HBc+) among those HCW at occupational risk (rHCW) of older age (odds ratios (OR) in rHCW 3.297, p < 0.0001 vs. nrHCW 1.385, p = 0.606) and among those HCW being employed more than 11 years (OR 2.51, p < 0.0001***). HCV prevalence was low (HCV antibodies 1.2% and HCV-RNA 0.3%). CONCLUSIONS: Chronic HBV infection is common among Tanzanian HCWs. One third of HCWs were susceptible to HBV infection, highlighting the need for vaccination. Due to high prevalence of naturally acquired immunity against HBV pre-testing might be a useful tool to identify susceptible individuals.
Assuntos
Pessoal de Saúde/estatística & dados numéricos , Hepatite B/epidemiologia , Centros de Atenção Terciária/estatística & dados numéricos , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/isolamento & purificação , Hepatite C/epidemiologia , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Sistemas Automatizados de Assistência Junto ao Leito , Tanzânia/epidemiologia , Vacinação/estatística & dados numéricos , Adulto JovemRESUMO
BACKGROUND: Interferon-induced depression represents a major complication in antiviral treatment of chronic hepatitis C virus (HCV) infection. AIM: To evaluate in a placebo-controlled study the efficacy of a selective serotonin reuptake inhibitor (SSRI) in HCV patients on antiviral therapy with interferon-associated depression. METHODS: 100 HCV outpatients were included in a randomised, double-blind, placebo-controlled study. During interferon therapy (peginterferon alpha-2b plus ribavirin), depression was monitored using the Hospital Anxiety and Depression Scale (HADS). Patients with clinically relevant interferon-induced depression (HADS >or=9) were randomly assigned to placebo or citalopram (SSRI, 20 mg/day). RESULTS: In 28 patients (28%), HADS scores increased to >8 during interferon therapy. They were treated with placebo (n = 14) or SSRI (n = 14). HADS scores declined significantly in SSRI patients within four weeks of therapy (p<0.001) but not in placebo patients. This difference between subgroups was statistically significant (p = 0.032). Unblinding became necessary in five placebo patients as a result of intolerable depression. Rescue medication (20 mg citalopram) led to a significant decrease in HADS scores (p = 0.008). All citalopram patients were able to complete interferon therapy as planned. As an interim analysis showed a significant superiority of SSRI over placebo, the study was terminated prematurely. Three patients, who became depressed afterwards, were treated in an unblinded fashion with citalopram. CONCLUSIONS: The findings demonstrate clearly that citalopram treatment is highly effective in HCV patients on interferon therapy, when initiated after the onset of clinically relevant depressive symptoms. This suggests that a general SSRI prophylaxis is not necessary in these patients.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Adulto , Antivirais/efeitos adversos , Transtorno Depressivo/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Escalas de Graduação Psiquiátrica , Psicometria , Proteínas Recombinantes , Resultado do TratamentoRESUMO
The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Organofosfonatos/administração & dosagem , Piridinas/administração & dosagem , Piridinas/sangue , Pironas/administração & dosagem , Pironas/sangue , Ritonavir/administração & dosagem , Adenina/administração & dosagem , Alcinos , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade , Benzoxazinas/administração & dosagem , Ciclopropanos , Interações Medicamentosas , Monitoramento de Medicamentos , Enfuvirtida , Proteína gp41 do Envelope de HIV/administração & dosagem , Humanos , Fragmentos de Peptídeos/administração & dosagem , Piridinas/farmacocinética , Pironas/farmacocinética , Estudos Retrospectivos , Ritonavir/sangue , Sulfonamidas , TenofovirRESUMO
Freezing human milk is recommended to inactivate cytomegalovirus (CMV). A case of a preterm infant exclusively receiving frozen breast milk from his CMV seropositive mother showed that storage of breast milk for two months at -20 degrees C did not prevent symptomatic postnatal CMV infection.
Assuntos
Criopreservação , Infecções por Citomegalovirus/transmissão , Recém-Nascido Prematuro , Leite Humano/virologia , Infecções por Citomegalovirus/prevenção & controle , Evolução Fatal , Seguimentos , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , MasculinoRESUMO
Products expressed from the second (P/V/C) gene are important in replication and abrogating innate immune responses during acute measles virus (MV) infection. Thirteen clone sets were derived from the P/V/C genes of measles virus (MV) RNA extracted from brains of a unique collection of seven cases of subacute sclerosing panencephalitis (SSPE) caused by persistent MV in the central nervous system (CNS). Whether these functions are fully maintained when MV replicates in the CNS has not been previously determined. Co-transcriptional editing of the P mRNAs by non-template insertion of guanine (G) nucleotides, which generates mRNAs encoding the viral V protein, occurs much less frequently (9%) in the SSPE derived samples than during the acute infection (30-50%). Thus it is likely that less V protein, which is involved in combatting the innate immune response, is produced. The P genes in MV from SSPE cases were not altered by biased hypermutation but exhibited a high degree of variation within each case. Most but not all SSPE derived phospho-(P) proteins were functional in mini genome replication/transcription assays. An eight amino acid truncation of the carboxyl-terminus made the P protein non-functional while the insertion of an additional glycine residue by insertion of G nucleotides at the editing site had no effect on protein function.
Assuntos
Vírus do Sarampo/genética , Fosfoproteínas/genética , Edição de RNA , Panencefalite Esclerosante Subaguda/virologia , Proteínas Virais/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Vírus do Sarampo/isolamento & purificação , Vírus do Sarampo/metabolismo , Mutação , Fosfoproteínas/metabolismo , Proteínas Virais/metabolismoRESUMO
Decrease of libido and erectile dysfunction are reported by male patients during antiviral therapy of chronic hepatitis C, but therapy-associated underlying factors for sexual dysfunction are not well defined. To assess putative contributions of interferon-induced sex hormone changes to sexual dysfunction, we prospectively investigated changes in free testosterone, total testosterone, dehydroepiandrosterone sulfate, prolactin, sex hormone-binding globulin, FSH and LH levels and psychometric self-assessment scores in 34 male patients treated with interferon alfa-2b (5 MIU three times weekly) (n=19)+ ribavirin (n=15) for 6-12 months. Depression was measured by the Hospital Anxiety and Depression Scale. Sexual dysfunction was evaluated by the Symptom Checklist 90 Item Revised and a five-point rating scale assessing sexual arousal disorder. Free and total testosterone decreased significantly during antiviral therapy in close correlation with libido/sexual function. Depression scores increased during therapy and were also significantly associated with sexual dysfunction. However, androgen levels displayed no significant correlation with depression. These results suggest that interferon-induced decrease in sexual function is associated - but not causally related -with both androgen reduction and increased depressive symptoms. These findings may affect care for male hepatitis C patients during interferon therapy.
Assuntos
Androgênios/sangue , Antivirais/efeitos adversos , Disfunção Erétil/etiologia , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Adulto , Análise de Variância , Antivirais/uso terapêutico , Sulfato de Desidroepiandrosterona/sangue , Depressão/complicações , Disfunção Erétil/metabolismo , Disfunção Erétil/psicologia , Hormônio Foliculoestimulante/sangue , Hepatite C Crônica/metabolismo , Hepatite C Crônica/psicologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Libido , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Prolactina/sangue , Estudos Prospectivos , Proteínas Recombinantes , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue , Fatores de TempoRESUMO
BACKGROUND: Natural infections bear the risk of triggering MS bouts, whereas epidemiologic studies have not delineated an increased risk for disease activity after influenza virus vaccination. OBJECTIVE: To examine influenza A virus-specific and myelin protein-reactive T-cell frequencies by interferon gamma (IFNgamma)-enzyme-linked immunospot and the response of these cells by IFNgamma-reverse transcription (RT) PCR after immunization and any incidental upper respiratory tract infection (URI) in 12 patients with MS (seven with a relapsing-remitting course; five with a secondary progressive course; Kurtzke Expanded Disability Status Scale [EDSS] score from 1.0 to 6.5, without immunosuppressive treatment) and 28 healthy volunteers. RESULTS: A cellular immune response against influenza A virus was mounted in both populations at 2 weeks after vaccination. Patients with MS showed a higher relative increase (p = 0.008) than controls with respect to the number of influenza-specific T cells. Mean antibody responses against influenza A virus were increased in both populations after 2 weeks (p < 0.01). Despite these virus-specific reactions, no increase in T-cell frequencies responsive to human myelin basic protein (MBP) or recombinant human myelin oligodendrocyte protein (MOG) was observed after immunization, arguing against a general immune stimulation by influenza vaccination. In contrast, MBP-specific T-cell responses became detectable in several individuals after febrile infection. CONCLUSION: These data support the clinical observations that influenza vaccination is effective and safe in patients with MS with respect to cellular immunoreactivity against two main CNS myelin proteins.
Assuntos
Encéfalo/imunologia , Vacinas contra Influenza/imunologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Vacinação , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To test the hypothesis that different preceding infections influence the neurophysiologic classification and clinical features of Guillain-Barré syndrome (GBS). METHODS: We tested pretreatment sera, 7 +/- 3 (mean +/- SD) days from onset, from 229 patients with GBS in a multicenter trial of plasma exchange and immunoglobulin, for serological markers of infection, adhesion molecules, and cytokine receptors, and compared these with neurophysiologic and clinical features. RESULTS: Recent infection by Campylobacter jejuni was found in 53 patients (23%), cytomegalovirus in 19 (8%), and Epstein-Barr virus in four (2%). Patients with C. jejuni infection were more likely than others to have neurophysiologic criteria of axonal neuropathy or inexcitable nerves, antiganglioside GM(1) antibodies, pure motor GBS, lower CSF protein, and worse outcome. Patients with cytomegalovirus infection were younger and more likely than others to have raised serum concentrations of molecules important in T lymphocyte activation and migration, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble leukocyte selectin, and soluble interleukin-2 receptor (sIL-2R). Concentrations of sICAM-1 and soluble tumor necrosis factor receptor were higher in patients with inexcitable nerves than those with demyelinating neurophysiology. Logistic regression analysis showed death or inability to walk unaided at 48 weeks were associated with diarrhea, inexcitable nerves, severe arm weakness, age over 50, raised sIL-2R concentration and absence of immunoglobulin (Ig) M antiganglioside GM(1) antibodies. CONCLUSIONS: Subtypes of GBS defined by preceding infections were only approximately associated with different patterns of clinical, neurophysiologic, and immunologic features. A single infectious agent caused more than one type of pathology in GBS, implying interaction with additional host factors. Most patients had no identified infection.
Assuntos
Anticorpos/imunologia , Infecções Bacterianas/imunologia , Moléculas de Adesão Celular/imunologia , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/imunologia , Receptores de Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Síndrome de Guillain-Barré/microbiologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Prognóstico , Análise de RegressãoRESUMO
Virus-specific helper T cell responses are thought to be an important host defense in HIV infection. The proliferative responses to HIV p24, p55, and gp120 were tested in a cohort of 27 HIV-infected subjects. Vigorous proliferative responses directed at the Gag protein with stimulation indices in excess of 6 were detected in 10 of the individuals tested but an Env-specific response was present in only 1 subject. Viral load and proliferative activity to Gag were inversely correlated in untreated individuals. Proliferation was also observed in some individuals treated in the chronic phase of infection, and responses were maintained over time in the absence of detectable viremia. Positive proliferative responses could also occasionally be detected in treated persons with CD4(+) cell counts below 200/microl. Thus, vigorous Gag-specific proliferative responses are present in a minority of HIV-infected individuals and can be detected in individuals receiving highly active antiretroviral therapy at advanced disease stages. Proliferative responses are maintained for an extended time period in the presence of antiviral therapy.
Assuntos
Proteína do Núcleo p24 do HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , Linfócitos T/fisiologia , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Carga Viral , ViremiaRESUMO
BACKGROUND: Nephropathia epidemica (NE) caused by the hantavirus serotype Puumala (PUUV) is endemic in large parts of Europe. The prognosis of this disease is usually good. However, a rapid serological diagnosis is important to differentiate NE from potentially more severe renal conditions. OBJECTIVE: To evaluate the diagnostic usefulness of a novel pan-reactive hantavirus enzyme immunoassay (EIA) and of a novel hantavirus immunoblot (IB). STUDY DESIGN: Three groups of serum samples were tested with both assays: 79 samples from 43 patients with acute NE, 27 samples from healthy adults, and 29 tricky samples from patients with autoantibodies, with acute Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infections, and from pregnant women. RESULTS: With the EIA, all but two of the early samples of the NE patients and all of the follow-up samples were positive for hantavirus IgG. All control samples were negative. The IgM EIA was positive in 42 of the 43 primary NE samples. Weak IgM EIA reactions were observed for some of the serum samples from patients with acute EBV and CMV infections. Optimal sensitivity and specificity values for the EIA were achieved when both the IgG and the IgM results were considered for the diagnosis of acute NE. All of the early NE samples reacted with the hantavirus nucleocapsid proteins in the IgG IB and all but one of these samples in the IgM IB. Cross reactions between the PUUV and the Hantaan antigens were very common. Several of the control samples did show borderline or positive bands, but these were mostly bands against only one hantavirus antigen in either the IgG or the IgM IB. The presence of at least three hantavirus bands (PUUV or HTNV) in the IgG and IgM assays was highly predictive of acute NE. CONCLUSION: Both assays were highly sensitive for the diagnosis of acute NE. However, the specificity of the IB IgM was only 76%. The specificity of both the IB and the EIA can be increased by modifications of the result interpretation.
Assuntos
Anticorpos Antivirais/sangue , Vírus Hantaan/imunologia , Infecções por Hantavirus/diagnóstico , Immunoblotting/métodos , Técnicas Imunoenzimáticas/métodos , Doença Aguda , Reações Cruzadas , Feminino , Seguimentos , Infecções por Hantavirus/sangue , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Nucleocapsídeo/imunologia , Gravidez , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Despite the availability of several different markers for Epstein--Barr virus (EBV) serology, the EBV status of some patients cannot be resolved from a single serum sample with routine testing. To avoid the requirement of follow-up samples, supplementary tests have to be used in these cases. OBJECTIVE: To evaluate the usefulness of avidity and immunoblot assays as supplementary tests for the diagnosis of acute EBV infections. STUDY DESIGN: Three groups of samples for which a definite diagnosis on the EBV status could not be obtained with the routine serological tests were further examined by an EBV IgG avidity assay, by an immunoblot based on a lysate of EBV infected cells, and by a second immunoblot based on recombinant EBV antigens. The three groups consisted of 38 samples with negative/borderline EB nuclear antigen 1 (EBNA-1) antibodies, negative/borderline EBV IgM and positive EBV IgG; 10 samples with indeterminate EBNA-1 and/or EBV IgM assays because of control antigen reactions; and 4 samples with positive EBV IgM results that were not plausible. RESULTS: The avidity assay differentiated between acute and past infections for all samples. In contrast, some cases remained unresolved with both the recombinant and the lysate immunoblot. Two samples were incorrectly classified with the lysate immunoblot. Interpretation of the lysate immunoblot banding patterns was complicated when anticellular antibodies were present. CONCLUSION: Avidity testing appears to be the confirmatory method of choice to differentiate between acute and past EBV infections.
Assuntos
Anticorpos Antivirais/sangue , Afinidade de Anticorpos/imunologia , Western Blotting/métodos , Infecções por Herpesviridae/diagnóstico , Herpesvirus Humano 4/imunologia , Imunoglobulina G/sangue , Infecções Tumorais por Vírus/diagnóstico , Doença Aguda , Antígenos Virais/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Humanos , Imunoglobulina M/sangue , Proteínas Recombinantes/imunologiaRESUMO
BACKGROUND: In a retrospective study of HIV patients under antiretroviral therapy, we investigated the influence of the MDR1 genotype (C3435T) on plasma levels of lopinavir (LPV) and efavirenz (EFV). METHODS: The MDR1 genotype was analysed from 67 patients who were treated with LPV (n = 32; mean treatment period 53 weeks) and/or EFV (n = 43, mean treatment period 105 weeks) between 1999 and 2003. Plasma levels of LPV (trough levels) and EFV (12-h-levels) were determined every three months. Data were analysed by the Kruskal-Wallis test. RESULTS: There were no significant differences in the LPV and EFV plasma levels with respect to the MDR1 3435 genotype. CONCLUSIONS: We did not find evidence for an influence of the MDR1 3435 genotype on plasma levels of LPV and EFV.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Fármacos Anti-HIV/sangue , Infecções por HIV/tratamento farmacológico , Oxazinas/sangue , Pirimidinonas/sangue , Adulto , Idoso , Alcinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas , Ciclopropanos , Feminino , Genótipo , Infecções por HIV/sangue , HIV-1 , Humanos , Lopinavir , Masculino , Pessoa de Meia-Idade , Oxazinas/uso terapêutico , Polimorfismo Genético , Pirimidinonas/uso terapêutico , Estudos RetrospectivosRESUMO
OBJECTIVE: Efavirenz (EFV) plasma levels have been discussed as a predictor of treatment failure in HIV infected patients. The aim of this prospective, open-labeled, case-control study was to evaluate pretreated patients in regards to efavirenz plasma levels and efficacy of therapy. METHODS: Blood samples were obtained monthly from 33 patients receiving efavirenz in combination with other antiretroviral agents for at least 3 months. EFV plasma concentrations and potease inhibitor (PI) plasma levels were measured by high-performance liquid chromatography (HPLC). EFV plasma levels were correlated with efficacy. In patients with virologic failure genotypic resistance testing was performed. RESULTS: Mean efavirenz plasma levels (n = 240) of 33 patients were 3.119 +/- 2.497 ng/ml. There were no significant differences between median efavirenz plasma levels of 24 patients (72%) with a HIV-RNA < 20 copies/ml (2.168 ng/ml), 3 patients with HIV-RNA of 20 500 copies/ml (3.362 ng/ml), and 6 patients with a virologic failure (>500 copies/ml) (2.190 ng/ml) respectively. Efavirenz plasma levels below 1.000 ng/ml were found in 4/27 effective treated patients, and in 4/6 patients with virologic failure. In all patients with virologic failure multiple NRTI, NNRTI and PI mutations were found in genotypic resistance testing. CONCLUSION: An individual EFV plasma level below 1.000 ng/ml in one single measurement seems to be predictive of viral failure and the developement of genotypic resistance. Therapeutic drug monitoring of EFV might be helpful, especially in heavily pretreated patients, to reach long term sufficently effectiveness of therapy.
Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Oxazinas/sangue , Oxazinas/uso terapêutico , Alcinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas , Ciclopropanos , Farmacorresistência Viral , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Oxazinas/administração & dosagem , Oxazinas/farmacocinética , Prognóstico , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/uso terapêutico , Falha de TratamentoRESUMO
Therapeutic drug monitoring is essential in HIV-patients undergoing highly active antiretroviral therapy (HAART). Saquinavir (SQV) is used alone or in combination with ritonavir (RTV) or nelfinavir (NLF), respectively, in the context of the HAART drug regimen. The achievable SQV concentration range in clinical practice remains to be elucidated. A non-randomized prospecitve clinical trial 19 patients (group I) receiving SQV (1x600 mg/d Invirase or Fortovase), 29 patients (group II) receiving SQV (2x600 mg/d Fortovase) plus RTV (2x400 mg/d Norvir), and 21 patients (group III) receiving SQV (2x600 mg/d Fortovase) plus NLF (2x750 mg/d Viracept) was conducted to determine SQV plasma concentrations. SQV levels were determined as trough levels during routine outpatient visits. Analysis was performed by HPLC with UV detection. The lowest SQV plasma levels were found in group I (95% CI 89-177 ng/ml). Significantly higher SQV levels were found in group III (combination with NLF) ranging from 242 to 398 ng/ml (95% CI) and in group II (combination with RTV) ranging from 1354 to 1747 ng/ml (95% CI). The IC 50% of 54 ng/ml was not reached in at least one sample during the study (mean duration of study 16+/-10 months) in 14/19 patients of group I, 9/29 patients in group II and 13/21 patients in group III, respectively. A positive correlation between patient compliance, defined by SQV levels in the 95% CI of the used combination, and the HIV RNA plasma level was found. The presented data confirm that therapy with SQV alone may not be effective, since trough levels are near the lower limit of antiretroviral efficacy. Although the combination of SQV with NLF results in higher SQV plasma concentrations in a bid regimen, in more than 60% of the patients SQV concentrations below IC 50 level were detected during the twelve-months study period. The combination of SQV with RTV yields the highest SQV-trough levels. SQV concentrations below the IC 50 were seen in only 31% of patients with the SQV/RTV combination. In conclusion, therapeutic drug monitoring allows an efficient surveillance of patients compliance. In addition, therapeutic drug monitoring represents a valuable tool for management of HAART in patients receiving a complex comedication or suffering from advanced liver disease.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Nelfinavir/uso terapêutico , Ritonavir/uso terapêutico , Saquinavir/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Humanos , Masculino , Nelfinavir/administração & dosagem , Nelfinavir/sangue , Estudos Prospectivos , RNA Viral/sangue , Ritonavir/administração & dosagem , Ritonavir/sangue , Saquinavir/administração & dosagem , Saquinavir/sangue , Carga ViralRESUMO
INTRODUCTION: Epidemics of meningoencephalitis due to echovirus 9 were commonly occurred when a children population become susceptible for the first time in front the virus. OBJECTIVE: To present the intrathecal synthesis pattern of immunoglobulins of the epidemic that affected Cuba in 1999 and to probe the usefulness of reibergram and antibody index in the diagnostic and characterization of the outbreak. PATIENTS AND METHODS: 23 pediatric patients suffering from viral meningoencephalitis due to echovirus 9 were studied in the income moment. Serum and cerebrospinal fluid IgA, IgM, IgG, albumin and glucose were quantified. Cerebrospinal fluid total protein content and lactate were quantified. Titles of antibodies against echo 9 and Coxsackie A9 and differential cell count were performed. RESULTS: A mean of 555 cells/10 6 L mainly lymphocytes were obtained. Glucose in cerebrospinal fluid was over 50%, serum glucose and lactate levels below 2.1 mmol/L. In the reibergram an absence of intrathecal synthesis was predominant (15/23), IgM synthesis (6/23) and IgM+IgA (2/23). Blood cerebrospinal fluid dysfunction was observed in 15 patients. The mean antibody index was 1,8 for echo 9 and 0,9 for Coxsackie A9. CONCLUSIONS: The intrathecal synthesis pattern of immunoglobulins was different from other enterovirus and from echovirus 9 in non epidemic situations before this epidemic, probably with alteration of viral genome.
Assuntos
Anticorpos Antivirais/líquido cefalorraquidiano , Echovirus 9/imunologia , Infecções por Echovirus/imunologia , Imunoglobulinas/líquido cefalorraquidiano , Meningoencefalite/imunologia , Meningoencefalite/virologia , Criança , Pré-Escolar , Cuba/epidemiologia , Surtos de Doenças , Infecções por Echovirus/líquido cefalorraquidiano , Infecções por Echovirus/epidemiologia , Humanos , Meningoencefalite/líquido cefalorraquidiano , Meningoencefalite/epidemiologiaRESUMO
The diagnosis of acute Epstein-Barr virus (EBV) infection is based frequently on the combination of positive viral capsid antigen (VCA) IgM antibodies and negative EB viral nuclear antigen 1 (EBNA-1) IgG antibodies. However, both VCA IgM and EBNA-1 IgG can provide false positive and false negative results. Therefore, situations in which the EBV serology remains unclear are not uncommon. Determination of EBV IgG avidity can clarify the EBV status in these patients. So far, mainly immunofluorescence assays have been used for this purpose. These tests are laborious, their evaluation is subjective, and automation is difficult. Therefore, two commercially available microtiter plate enzyme immunoassays (EIA) were compared for their usefulness for semi-automated EBV IgG avidity determination. One assay is based on a mixture of EBV antigens, the other assay uses a synthetic peptide of the VCA-complex. Patient sera of confirmed acute and past EBV infections were tested for avidity by both assays. The results with the antigen mixture assay proved to be highly sensitive (100%) and specific (100%). Avidity index calculations on the basis of one-point-quantification titers gave better results than calculations using OD values. Determination of EBV IgG avidity by the peptide assay was complicated by the fact that it was less sensitive than the antigen mixture assay for IgG detection in acute EBV infections. On the other hand, about 30% of the samples had to be retested with the peptide assay in a higher dilution because the IgG units in initial testing fell outside the range covered by the standard curve. Using OD values of the peptide EIA, the sensitivity was 99% but the specificity of detection of acute EBV infections was only 86%. Thus, while the peptide EBV avidity assay is unsuitable as a confirmatory assay, avidity testing with the antigen mixture assay is a useful tool to resolve equivocal EBV serologies. Avidity assays on the basis of EIA can be automated which should lead to wider use of this methodology.
Assuntos
Anticorpos Antivirais/imunologia , Afinidade de Anticorpos , Herpesvirus Humano 4/imunologia , Imunoglobulina G/imunologia , Mononucleose Infecciosa/diagnóstico , Anticorpos Antivirais/sangue , Humanos , Técnicas Imunoenzimáticas , Imunoglobulina G/sangue , Mononucleose Infecciosa/sangue , Mononucleose Infecciosa/imunologia , Kit de Reagentes para DiagnósticoRESUMO
Conventional phenotypic analysis of resistance of the human immunodeficiency virus (HIV) to antiviral therapy is time-consuming and requires culture of infectious virus. Although phenotypic analyses may be desirable, rapid generation of test results and decentralized availability of the test system will be important to achieve utility in the clinical practice. This study describes the design of an alternative phenotypic resistance test using replication incompetent viral vectors. Chimeric HIV vectors containing a marker gene were generated. The env and most of the regulatory and accessory genes of HIV were removed. In addition, the 3'U3 region was deleted to obtain a self-inactivating construct. Cotransfection of the plasmid with a plasmid that provided the vesicular stomatitis virus glycoprotein resulted in the production of replication-incompetent virus vectors. Infection of susceptible cells with the vectors led to marker gene expression. Vector production in the presence of protease (PR) inhibitors, or infection in the presence of reverse transcriptase (RT) or integrase (IN) inhibitors reduced marker gene expression in a dose-dependent manner. Marker gene activity was preserved at higher drug levels if vectors contained RT and PR genes from resistant virus isolates. Sensitivity to nucleoside and non-nucleoside RT inhibitors, protease and integrase inhibitors could be determined in 10 working days. The phenotypic drug resistance test using replication-incompetent HIV vectors significantly speeds up drug resistance measurements and allows testing at reduced biosafety levels. This will make clinical use of phenotypic assessment of antiviral resistance more feasible.