Shindo M, Hamada K, Koya S, Arai K, Sokawa Y, Okuno T
Department of Internal Medicine, Akashi Municipal Hospital, Japan.
Hepatology. 1996 Nov;24(5):1018-23. doi: 10.1053/jhep.1996.v24.pm0008903369.
We examined changes in the hypervariable region 1 of the hepatitis C virus (HCV) RNA that occurred with interferon therapy in 33 patients with chronic hepatitis C to assess the clinical significance of this region. The 33 patients had HCV genotype 1b and were classified into three groups based on serum aminotransferase levels during and after therapy with alpha interferon; long-term responders (n = 9), short-term responders (n = 11), and nonresponders (n = 13). Changes in the genetic heterogeneity of the hypervariable region 1 were determined by using nonisotopic polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). HCV RNA levels were evaluated by reverse transcriptase PCR and branched DNA probe assays. Changes in sequences were determined by cloning and sequencing analysis. Before therapy, the long-term responders had significantly lower degrees of heterogeneity and lower viral levels than nonresponders. There were no significant differences between short-term and nonresponders. With interferon therapy, viral levels and degree of heterogeneity decreased to a greater extent among long-term and short-term responders than among nonresponders. Sequencing analysis showed that the three groups had similar clone numbers initially, but long-term responders had rather homogeneous viral populations, whereas short-term and nonresponders had heterogeneous populations, but that there were no nucleotide sequences or amino acid alignments that were specific for any group before, during, and 6 months after therapy. Approximately half of short-term and nonresponders received a second course of interferon 7 to 10 months after the initial therapy; all showed an identical response to the second course of therapy regardless of interim changes in the heterogeneity of hypervariable region 1. These findings suggest that (1) patients who were nonresponders or short-term responders had mixed viral populations that had differing sensitivities to interferon, (2) the changes in the hypervariable region 1 (HVR 1) did not affect responsiveness to interferon, and (3) the lower heterogeneity in the HVR 1 was associated with a long-term response to interferon only when the viral levels were low.
我们检测了33例慢性丙型肝炎患者在接受干扰素治疗过程中丙型肝炎病毒（HCV）RNA高变区1的变化，以评估该区域的临床意义。这33例患者为HCV 1b基因型，根据α干扰素治疗期间及治疗后的血清转氨酶水平分为三组：长期应答者（n = 9）、短期应答者（n = 11）和无应答者（n = 13）。采用非同位素聚合酶链反应-单链构象多态性（PCR-SSCP）方法测定高变区1的基因异质性变化。通过逆转录PCR和分支DNA探针分析评估HCV RNA水平。通过克隆和测序分析确定序列变化。治疗前，长期应答者的异质性程度和病毒水平显著低于无应答者。短期应答者与无应答者之间无显著差异。接受干扰素治疗后，长期和短期应答者的病毒水平和异质性程度下降幅度大于无应答者。测序分析表明，三组最初的克隆数相似，但长期应答者的病毒群体较为均一，而短期应答者和无应答者的群体则具有异质性，且在治疗前、治疗期间及治疗后6个月，没有任何核苷酸序列或氨基酸比对是任何一组所特有的。约一半的短期应答者和无应答者在初始治疗7至10个月后接受了第二疗程的干扰素治疗；无论高变区1异质性的中期变化如何，所有患者对第二疗程治疗的反应均相同。这些发现表明：（1）无应答者或短期应答者的病毒群体混合，对干扰素的敏感性不同；（2）高变区1（HVR 1）的变化不影响对干扰素的反应性；（3）仅当病毒水平较低时，HVR 1中较低的异质性才与对干扰素的长期反应相关。
