RESUMEN

The response of chronic hepatitis C to interferon (IFN) treatment is classified as complete response (CR), biochemical response (BR), or no response (NR). Several studies have found no difference in prevention of hepatocellular carcinoma by IFN therapy between patients with CR and those with BR. We investigated whether specific human leukocyte antigen (HLA) alleles were associated with response to IFN, especially BR, in 138 patients with chronic hepatitis C. Comparing patients with and without CR, male, a low viral titer, genotype 2a or 2b, HLA-B55, and HLA-DRB1-0803 were more common in the group with CR. Multivariate analysis showed that age (adjusted odds ratio [OR], 0.95 by every year [95% confidence interval [CI] 0.90 - 0.99], p = 0.028), genotype 2a or 2b (5.21 [95% CI 1.63 - 16.6], p = 0.005), and low viral titer (8.58 (2.66 - 27.7), p < 0.001) were associated with CR. Comparing patients with BR and NR, the pretreatment alanine aminotransferase (ALT) level was lower in the BR group (p < 0.001). Both HLA-B7 and HLA-DRB1-0101 were more common in this group (p = 0.002). As the alleles HLA-B7 and HLA-DRB1-0101 were in linkage disequilibrium, the HLA-B7-DRB1-0101 haplotype may be associated with BR. Multivariate analysis indicated that a low ALT level (0.98 by every 1 IU/L [95% CI 0.98 - 0.99], p = 0.001) and HLA-B7-DRB1-0101 haplotype (32.3 [95% CI 1.50 - 693.1], p = 0.026) contributed significantly to BR. This study suggested that host HLA expression, but not viral factors, can influence BR.

Asunto(s)

Alelos , Antígenos HLA/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Interferones/uso terapéutico , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Biomarcadores/sangre , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fibrosis/complicaciones , Fibrosis/tratamiento farmacológico , Genotipo , Antígenos HLA-A/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/patología , Prueba de Histocompatibilidad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/patología , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Interferón beta/administración & dosificación , Interferón beta/uso terapéutico , Interferones/administración & dosificación , Japón , Masculino , Persona de Mediana Edad , ARN Viral/sangre , ARN Viral/efectos de los fármacos , Proteínas Recombinantes , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

BACKGROUND/AIMS: The outcome of interferon (IFN) therapy of hepatitis C virus (HCV) infection can be classified as a complete viral response (CR), biochemical response (BR), or no response (NR). Why alanine aminotransferase (ALT) activity decreases in patients with BR despite viral persistence is unknown. METHODS: Of 158 patients infected with HCV genotype 1b, all 20 patients with BR and 20 of the 114 patients with NR, matched for viral load to the BR group, were studied. We sequenced nucleotides in the hypervariable region (HVR) of serum HCV RNA, and analyzed quasispecies of this region by the polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP). RESULTS: In HVR 1, SSCP patterns differed after therapy; the major clone before therapy disappeared with therapy in eight of the 20 BR patients, but in none of the 20 NR patients (P=0.0033; Fisher's exact test). PCR products of HVR 1 from six patients were cloned before and after therapy, and 40 clones from each patient were sequenced each time. Results of cloning and sequencing were generally consistent with those of SSCP. For the six patients, a major clone could be identified both before and after therapy. In two patients with BR, there were many changes in the amino acid sequence of the major clone after IFN; in one patient with NR, mutations were not found. CONCLUSION: Changes in the major viral clone with IFN treatment may be related to the decrease in ALT activity in some patients, in spite of the continued presence of HCV RNA.