RESUMEN
Historically, the leading cause of death among persons with haemophilia and other congenital coagulation disorders was uncontrolled bleeding. Mortality was associated with severe deficiency of coagulation factors VIII or IX and especially with high-titre antifactor neutralizing antibodies (inhibitors). The catastrophic contamination of plasma donor pools with human immunodeficiency virus (HIV) resulted in acquired immunodeficiency syndrome replacing haemorrhage as the leading cause of death among persons with haemophilia. Rather little has been written, however, about mortality among those not infected with HIV. The objective of this study was to identify conditions associated with all-cause mortality among HIV-uninfected patients who were followed for a mean of 8.8 years in the Multicentre Hemophilia Cohort Study. Among the 364 children (mean age 8 years), there were four deaths; two related to cancer, one to trauma, and the fourth to haemorrhage, end-stage liver disease and sepsis. Among the 387 HIV-uninfected adults (mean age 35 years) there were 29 deaths, with haemorrhage the leading cause of death, followed by hepatic, stroke and cancer deaths. Prognostic factors for all-cause mortality among the adults included haemophilia Type A with neutralizing antibodies [age-adjusted relative rate (RR) 3.1, 95% confidence interval (CI) 1.4-6.9] and serologic evidence of both hepatitis B and C virus (RR 4.1, 95% CI 0.97-17.6). Although hepatitis C viral load was slightly lower in patients with hepatitis B virus surface antigenaemia, it was unrelated to vital status. We conclude that causes of death and prognostic factors for current HIV-uninfected haemophilia patients are similar to those noted before the HIV epidemic. Better understanding, prevention and control of neutralizing antibodies and hepatitis infections may substantially improve longevity for people with haemophilia.
Asunto(s)
Trastornos de la Coagulación Sanguínea/mortalidad , Seronegatividad para VIH , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/virología , Inhibidores de Factor de Coagulación Sanguínea/metabolismo , Causas de Muerte , Niño , Factor VIII/inmunología , Femenino , Hemofilia A/sangre , Hemofilia A/mortalidad , Hemofilia A/virología , Hemofilia B/sangre , Hemofilia B/mortalidad , Hemofilia B/virología , Hemorragia/mortalidad , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Humanos , Hepatopatías/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/mortalidad , Enfermedades de von Willebrand/sangre , Enfermedades de von Willebrand/mortalidad , Enfermedades de von Willebrand/virologíaRESUMEN
Our aim was to evaluate the severity of liver disease resulting from chronic hepatitis C in haemophilia or von Willebrand disease and the efficacy of 6 months treatment with interferon alpha and ribavirin. Fifty-five liver biopsies were performed in 43 patients without any bleeding complications, as seen with ultrasound immediately after the biopsy and 48 h thereafter. Histological changes were mild, with low scores for both inflammation and fibrosis, in spite of long exposure to blood products (mean 27 years). Two patients had compensated cirrhosis. Thirty-five out of 39 included patients completed study treatment. Hepatitis C virus (HCV)-RNA was negative in 77% (30/39) of patients at the end of treatment, and 36% (14/39) achieved a complete sustained response at follow-up 6 months after treatment. Treatment failure was more frequent in patients with virus genotype 1 compared with non-1 (P = 0.0003). The response rate correlated well with that of non-haemophilic patients. In summary: (1) liver biopsy was safe with our regimen; (2) liver disease in our patients was usually mild and had a slow progress; (3) only HCV genotype 1 predicted treatment failure; (4) our treatment results agreed with those from non-haemophilic patients.
Asunto(s)
Antivirales/uso terapéutico , Hemofilia A/virología , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Ribavirina/uso terapéutico , Enfermedades de von Willebrand/virología , Adolescente , Adulto , Anciano , Biopsia , Quimioterapia Combinada , Femenino , Fibrosis , Estudios de Seguimiento , Genotipo , Hemofilia A/tratamiento farmacológico , Hemofilia A/patología , Hepatitis C/patología , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Hígado/virología , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Resultado del Tratamiento , Ultrasonografía , Enfermedades de von Willebrand/tratamiento farmacológico , Enfermedades de von Willebrand/patologíaRESUMEN
In the seventh national voluntary cross-sectional survey (in 1999) of Finnish patients with haemophilia A or B, type 3 von Willebrand disease or factor XIII deficiency, a plasma sample was received from 193 patients (67%). The samples were tested for hepatitis B and C, human immunodeficiency virus (HIV) and human T-cell leukaemia virus (HTLV) antibodies. Fifty-one percent of the patients were hepatitis C antibody positive and 34% hepatitis B core antibody positive. None of the patients had antibodies against HIV or HTLV. Eighteen percent of the patients had an elevated alanine aminotransferase activity. Abnormal alanine aminotransferase was significantly associated with hepatitis C seropositivity. No new seroconversions were detected among the haemophiliacs or patients with type 3 von Willebrand disease when compared with the last two surveys in 1993 and 1996, and there was no seroconversion in sole users of solvent/detergent-treated factor products. Currently, 32% of the patients use prophylactic factor treatment as their principal mode of therapy, particularly the younger patients with severe forms of the bleeding diseases.
Asunto(s)
Anticuerpos Antivirales/análisis , Deficiencia del Factor XIII/virología , Hemofilia A/virología , Enfermedades de von Willebrand/virología , Anticuerpos Antivirales/inmunología , Biomarcadores , Anticuerpos Antideltaretrovirus/análisis , Anticuerpos Antideltaretrovirus/inmunología , Deficiencia del Factor XIII/epidemiología , Finlandia/epidemiología , Anticuerpos Anti-VIH/análisis , Anticuerpos Anti-VIH/inmunología , Hemofilia A/epidemiología , Hemofilia A/etiología , Anticuerpos contra la Hepatitis B/análisis , Anticuerpos contra la Hepatitis B/inmunología , Anticuerpos contra la Hepatitis C/análisis , Anticuerpos contra la Hepatitis C/inmunología , Humanos , Enfermedades de von Willebrand/epidemiologíaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) infected hemophiliacs respond at low rate to interferon (IFN) monotherapy. AIMS: To assess efficacy of IFN and RBV in HIV negative hemophiliacs with chronic hepatitis C and identify early predictive factors of response. METHODS: Twenty naive patients were treated with interferon and RBV for twelve months. Response was assessed by both serial ALT and HCV RNA levels. RESULTS: Normalization of ALT with clearance of HCV RNA occurred in seven (35%) patients. Age and age at infection were the only features associated with a higher likelihood of response. In all responders the viral load had decreased by at least one log within two months of starting treatment. CONCLUSIONS: Combination of interferon and ribavirin is well tolerated by hemophiliacs who achieve similar sustained response rates to non-hemophiliacs. Quantitative assessment of viral load at two months of treatment is a useful method to identify non-responders at an early stage.
Asunto(s)
Trastornos de la Coagulación Sanguínea/virología , Seronegatividad para VIH/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Alanina Transaminasa/sangre , Antivirales/administración & dosificación , Antivirales/efectos adversos , Trastornos de la Coagulación Sanguínea/congénito , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Niño , Enfermedad Crónica , Quimioterapia Combinada , Deficiencia del Factor VII/tratamiento farmacológico , Deficiencia del Factor VII/virología , Femenino , Anticuerpos Anti-VIH/sangre , Hemoglobinas/metabolismo , Hemofilia A/tratamiento farmacológico , Hemofilia A/virología , Hemofilia B/tratamiento farmacológico , Hemofilia B/virología , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/etiología , Humanos , Interferones/administración & dosificación , Interferones/efectos adversos , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Pronóstico , ARN Viral/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribavirina/administración & dosificación , Ribavirina/efectos adversos , Sensibilidad y Especificidad , Resultado del Tratamiento , Enfermedades de von Willebrand/tratamiento farmacológico , Enfermedades de von Willebrand/virologíaRESUMEN
The majority of patients receiving plasma-derived clotting factor concentrates between 1970s and the mid-1980s are now hepatitis C positive. The progression of hepatitis C is extremely variable and there is frequently a poor correlation among liver biochemistry, viral load and the stage of liver disease. Liver biopsy remains the only definitive way of staging fibrosis and grading necroinflammatory activity. Concerns have been expressed about the safety of the procedure; however, with modern regimes for the correction of coagulopathy in patients with inherited bleeding disorders, normal haemostasis may be maintained during the peribiopsy period. We performed 21 liver biopsies between 1984 and 1997 on patients with factor VIII (FVIII) or IX (FIX) deficiency and von Willebrand's Disease (VWD). Four had concomitant human immunodeficiency virus (HIV) infection, five were thrombocytopenic and one had a prolonged prothrombin time (PT). Haemostasis was achieved using an intermittent bolus of factor concentrate or continuous infusion regimens. One patient with VWD received Desmopressin (DDAVP). There were no bleeding episodes associated with biopsy. We suggest that liver biopsy is a safe procedure in patients with inherited bleeding disorders when the coagulopathy is fully corrected. It is the only definitive method of staging the extent of fibrosis associated with hepatitis C infection, and it is this that defines prognosis.
Asunto(s)
Hemofilia A/patología , Hemofilia A/virología , Hepatitis C/patología , Hígado/patología , Adulto , Biopsia , Femenino , Fibrosis , Hemofilia B/patología , Hemofilia B/virología , Humanos , Irlanda , Tiempo de Internación , Masculino , Persona de Mediana Edad , Morbilidad , Enfermedades de von Willebrand/patología , Enfermedades de von Willebrand/virologíaRESUMEN
Two adult patients with life-long severe haemorrhagic disorders commenced on interferon-alpha2b therapy for chronic hepatitis C infection. Both developed Bell's palsy several weeks after commencing therapy, They were started on steroids and, in addition, the first patient discontinued interferon-alpha2b therapy while the second patient elected to continue with therapy. In both cases facial paralysis improved over the ensuing weeks. Bell's palsy is often idiopathic but has been reported. in association with herpesviruses. It is not a recognised complication of chronic hepatitis B or C infection, or interferon-alpha2b therapy. However, the interferons are associated with numerous adverse reactions including various neuropsychiatric manifestations and neurological syndromes. There are several reports of nerve palsies, including optic tract neuropathy, occurring during interferon therapy, and immune-based mechanisms are thought to play a role in the aetiopathogenesis. No reports of Bell's palsy in association with interferon therapy were identified in our literature search, although one possible case has been reported to the Committee of Safety in Medicine. Although Bell's palsy in our patients may have occurred by chance, a neuropathic effect of interferon-alpha2b on the facial nerve cannot be excluded and we urge physicians using interferons to be aware of this potential side-effect.
Asunto(s)
Parálisis de Bell/etiología , Trastornos Hemorrágicos/complicaciones , Hepatitis C Crónica/complicaciones , Interferón-alfa/efectos adversos , Adulto , Parálisis de Bell/inducido químicamente , Enfermedad Crónica , Diabetes Mellitus Tipo 2/complicaciones , Parálisis Facial/etiología , Enfermedades de las Válvulas Cardíacas/complicaciones , Hemofilia A/complicaciones , Hemofilia A/virología , Trastornos Hemorrágicos/virología , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Cirrosis Hepática/complicaciones , Masculino , Proteínas Recombinantes , Trombocitopenia/complicaciones , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/virologíaRESUMEN
Recently, several clusters of hepatitis A have been observed among hemophiliacs linked to factor VIII concentrates treated for virus inactivation solely with the solvent/detergent (S/D) method, a procedure that does not affect nonenveloped viruses such as the hepatitis A virus (HAV). A new outbreak of hepatitis A in six hemophiliacs treated with the same lot of a factor VIII preparation occurred recently in Germany. The objective of the study was to clarify whether these diseases were caused by the administration of the S/D-treated plasma product, rather than a community-acquired infection. Polymerase chain reactions designed to detect HAV nucleic acid have been carried out in the implicated factor VIII lots, in the corresponding plasma pools, and in serum samples of four out of six infected individuals. The nucleic acid sequences were determined in samples that resulted in positive amplification products. HAV sequences were found in one of the two plasma pools used for manufacture of the incriminated product, in the incriminated lot itself, and in all recipient sera tested so far, although the latter were collected up to 7 weeks after the onset of jaundice. The sequences obtained were completely identical, revealing a unique HAV strain of genotype IA. This study provides conclusive evidence that hepatitis A can be transmitted by factor VIII concentrates treated solely by the S/D procedure for virus inactivation. This inactivation method is not effective against nonenveloped viruses. Since a number of hepatitis A transmission episodes have been described with such preparations during the past 10 years, their continued use seems to be questionable unless additional virus removal or inactivation steps are introduced to prevent the transmission of nonenveloped viruses. Molecular approaches again proved to be reliable tools for elucidating the chain of virus transmission.
Asunto(s)
Brotes de Enfermedades , Factor VIII/efectos adversos , Hemofilia A/complicaciones , Hepatitis A/epidemiología , Hepatitis A/etiología , Adulto , Patógenos Transmitidos por la Sangre/aislamiento & purificación , Análisis por Conglomerados , Genotipo , Alemania , Hemofilia A/virología , Hepatitis A/complicaciones , Hepatitis A/virología , Hepatovirus/genética , Hepatovirus/aislamiento & purificación , Humanos , Persona de Mediana Edad , Filogenia , ARN Viral/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Proteínas Virales/genética , Proteínas Estructurales Virales/genética , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/virologíaRESUMEN
Eighty-two patients with bleeding, disorders registered with our centre were screened for infection with hepatitis G virus (HGV). 80 patients were positive for hepatitis C (HCV) antibodies, 66 of whom (83%) were HCV PCR positive. 11 patients (13%) were HGV RNA-positive, a similar prevalence rate to that of other studies of patients with bleeding disorders who received factor concentrates prior to the introduction of viral inactivation procedures. There was no significant difference in histological activity index (HAI) between the 10 HGV RNA-positive and the 31 HGV RNA-negative patients who underwent liver biopsy for assessment of HCV infection (median HAI scores 5.5, range 2-10 and four, range 0-10 respectively, P = 0.07). One patient in each group had established cirrhosis. In patients who underwent HCV quantitation there was no significant difference in HCV viral titre between HGV RNA-positive and negative patients (median HCV titre in HGV RNA-positive patients 2.10 x 10(5) DNA copies/ml (n = 8) range 4.17 x 10(2) to 4.17 x 10(6), median HCV titre in HGV RNA-negative patients 3.33 x 10(5) (n = 31) range 1.00 x 10(3) to 6.67 x 10(6), P = 0.68). In this study there was no evidence that individuals co-infected with HGV and HCV have more severe liver disease than those infected with HCV alone.
Asunto(s)
Hemofilia A/virología , Hepatitis Viral Humana/complicaciones , Enfermedades de von Willebrand/virología , Adulto , Anciano , Enfermedad Crónica , Femenino , Flaviviridae , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Humanos , Persona de Mediana EdadRESUMEN
The distribution and kinetics of hepatitis C virus (HCV) genotypes and the prevalence of mixed infections were studied in a group of 45 French patients with haemophilia A or B or von Willebrand's disease, 21 of them being anti-human immunodeficiency virus (HIV) positive; genotyping was carried out by three methods based on the core, 5' untranslated region (5'UTR), and the detection of type-specific NS4 antibodies. Genotyping of the 5'UTR revealed genotypes 1a (n = 10), 1b (n = 13), 2a (n = 3), 2b (n = 4), 2NC (n = 3), 3a (n = 10), and two mixed infections (1a + 1b and 3a + 2). Five of 33 patients showed a change from one HCV genotype to another. The core genotyping assay showed 8 of 45 mixed infections: 6/8 1a + 1b and 2/8 3a + 2. Sequencing of core polymerase chain reaction (PCR) products showed that mixed infection 1a + 1b could be explained by nonspecific annealing of the 1b primer to type 1a sequence. By designing new primers whose sequence was more specific to HCV types 1a and 1b, we could confirm 1a + 1b mixed infection in only one of six cases. Serotyping assay showed for 17 of 21 anti-HIV negative patients a concordance with the 5'UTR genotype; however, only 6 of 19 anti-HIV positive patients showed detectable serological reactivity. In summary, we have observed a similar HCV genotype distribution between our haemophilic group and the French anti-HCV positive patients. The study demonstrates the difficulties of assessing with the presently available genotyping and serotyping assays the real prevalence of mixed infections in multiply transfused patients.
Asunto(s)
Antígenos Virales , Hemofilia A/virología , Hemofilia B/virología , Hepacivirus/genética , Hepatitis C/genética , Proteínas del Núcleo Viral/genética , Enfermedades de von Willebrand/virología , ADN Complementario/genética , ADN Viral/análisis , Ensayo de Inmunoadsorción Enzimática , Genes Virales , Infecciones por VIH/complicaciones , Seropositividad para VIH/complicaciones , Seropositividad para VIH/epidemiología , Hemofilia A/complicaciones , Hemofilia A/epidemiología , Hemofilia B/complicaciones , Hemofilia B/epidemiología , Hepacivirus/inmunología , Hepatitis C/complicaciones , Hepatitis C/epidemiología , Anticuerpos contra la Hepatitis C/análisis , Humanos , Epidemiología Molecular , Reacción en Cadena de la Polimerasa , Prevalencia , ARN/genética , Análisis de Secuencia de ADN , Serotipificación , Proteínas no Estructurales Virales/inmunología , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/epidemiologíaRESUMEN
The prevalence of antibodies to parvovirus B19 (B19) was measured in the sera of 566 hemophiliacs and 524 individuals of the general population by immunofluorescence assays, using antigen expressed by the baculovirus system. In the general population, anti-B19 IgG seroprevalence was found to continuously decline from 64 percent at birth to 0 percent in the age of 9-11 months and thereupon to increase to 61 percent in the age of 12 years. In younger adults and older people, IgG seroprevalence only slowly increased with age, reaching 77 percent in people aged 60 and above. In contrast, in hemophilic children treated exclusively with virally inactivated clotting factor concentrates, neither decrease nor increase of B19 IgG antibody was detectable and the overall seroprevalence was 92 percent. In the group of hemophiliacs older than 12 years and treated before 1984 with non-inactivated clotting factor concentrates, 98 percent showed antibody to B19. Anti-B19 IgM seroprevalence was significantly higher in hemophilic than in non-hemophilic individuals older than 12 years. Since it seems to be unlikely that the high seroprevalence in hemophiliacs is acquired by immunization with inactivated viral antigen, the results suggest that infection with B19 is transmitted by clotting factor concentrates, even if subjected to virucidal methods.