慢性病毒性肝炎的治疗进展

Yasuyuki  Arakawa  日本东京Nihon医科大学内科学三系  教授

　　对慢性肝炎的患者进行治疗的目标是：1）清除病毒；2）抑制病毒复制；3）减慢肝炎的进展，防止发展成肝硬化； 4）阻止它发展成为肝细胞癌。因此，对于一名肝炎患者所采取的治疗措施必须是建立在准确掌握疾病的背景材料上，而这些材料是通过掌握血液生化及病毒学的实验室检查结果和活检标本的组织病理学结果得到的。治疗上最重要的目标就是防止肝炎发展成为肝硬化和肝癌。治疗慢性肝炎的两个主要方面是：1）通常使用的肝炎的支持治疗，和2）清除病毒以减慢疾病的进展，防止发展成为肝硬化和肝细胞癌。基于肝纤维化程度上的肝细胞癌的发生率是：低纤维化的患者为0.5％；中等程度的纤维化（F2）为1.5％；F3为3.0％；F4（肝硬化）的患者为7－8％。既然慢性肝炎和肝硬化的患者是发展成为肝细胞癌的高危组，所以治疗的目标是阻止慢性肝炎发展为肝硬化。

　　尽管肝炎病毒不能被支持治疗所根除（例如熊去氧胆酸，Glycyrrhzin, Stronger Neo-Minophagen C, 水解肝素，中药），但任何一种药物或药物的联合使用都可以减轻肝细胞坏死和炎症的程度，或把血转氨酶的水平降低到正常水平高限的两倍以下，能够改善疾病的预后。

　　日本医疗保险所推荐的四周干扰素治疗方案已被证明不能改善乙型慢性肝炎的临床病程，现又提出六周干扰素治疗方案其疗效将通过进一步的临床试验来验证。在日本拉米夫定的临床试验（一种逆转录酶的抑制剂）是去年在慢性乙型肝炎的患者上开始进行的。尽管长期联合使用拉米夫定和干扰素在一些患者上显示出有益的结果（抗病毒的效果和提高肝功能），

　　但这种治疗在另外一些患者上导致了肝炎的恶化和乙肝病毒变异株YMDD的出现，改变了乙肝病毒表型。拉米夫定的疗效包括它与干扰素等其它药物的联合使用，以及化疗适宜的时间必须等待进一步的深入的临床试验。 已经报道干扰素的疗效取决于许多因素包括HCV RNA的数量及基因型，肝炎病毒的变异率，还有患者的因素包括肝脏组织学改变的时间。那些感染了基因型为2a或2b的肝炎病毒的患者其病毒滴度较低，相对较适宜采用干扰素治疗。这些患者中的80％其病毒能被干扰素根除。相反，干扰素对于那些基因型为1b的患者几乎没有作用，尤其是那些HCV RNA水平较高的患者，尽管采取了许多措施如改变剂量和干扰素给药的方法，但单独使用干扰素仍没有作用。新近，美国和欧洲报道联合使用a-干扰素和Ribavirin，对于干扰素抵抗的患者有明显疗效。日本即将得到Ribavirin这个药物，我们将会在干扰素抵抗的患者上验证药物的疗效。不论一个患者感染的是乙型还是丙型肝炎病毒，在感染的早期给予适宜的抗病毒药物是非常重要的。通过联合使用干扰素和其它药物如核酸类似物或新型干扰素，将会提高慢性病毒性肝炎的疗效。

Progress on treatment of chronic viral hepatitis

Yasuyuki Arakawa, M.D.  

Professor&Chairman,　Third Department of Internal Medicine

Nihon University School of Medicine,　Tokyo, Japan

     The goals of the treatment of patients with chronic hepatitis are: 1) eradication of the virus; 2) suppression of replication of the virus; 3) slowing the progression of hepatitis and preventing the development of liver cirrhosis; and 4) prevention of its development to hepatocellular carcinoma. The treatment strategy for a patient with hepatitis, therefore, must be developed on the basis of accurate understanding of the background factors of the disease by careful examination of the laboratory results of virology and blood biochemistry, and the results of histopathological examination of biopsied specimens . The most important goal is to prevent its progression to liver cirrhosis and hepatocellular carcinoma. The two major treatment modalities of chronic hepatitis are: 1) generally used supportive treatment of hepatitis, and 2) therapy for eradication of the virus to slow the progression of the disease and to prevent the development of liver cirrhosis and hepatocellular carcinoma.  The incidence of hepatocellular carcinoma based on the degree of fibrosis in the liver is: patients with low degree of fibrosis, 0.5%; those with moderate degree of fibrosis (F2), 1.5%; those with F3, 3.0%, and those with F4 (liver cirrhosis), 7-8%. Since patients with chronic hepatitis and those with liver cirrhosis are high-risk groups for the development of hepatocellular carcinoma, treatments should be targeted to preventing the progression of chronic hepatitis to liver cirrhosis.

  Although the hepatitis virus cannot be eradicated by supportive treatments (e.g., UDCA, Glycyrrhzin, Stronger Neo-Minophagen C, Proheparum, traditional Chinese medicine, etc.), any drug or combination of drugs that reduces the degree of necrosis and inflammation of liver cells, or that lowers the blood transaminase level to lower than twice the upper limit of the normal range, can improve the prognosis of the disease.

  Four-week interferon (IFN) therapy, which was recommended by the Japanese Medical Insurance , was found to not improve the clinical course of chronic hepatitis B. Recently, six-month IFN therapy has been approved and its effectiveness will be known after extensive clinical trials. Clinical trials of Lamivudine, a synthetic reverse transcriptase inhibitor, were started for the treatment of patients with chronic hepatitis B last year in Japan. Although long-term treatment with the combined use of this drug and IFN showed beneficial effects in some patients (antiviral effect and improvement of liver function tests), this treatment led to exacerbation of the hepatitis and the appearance of YMDD variant hepatitis virus in several patients. The effectiveness of Lamivudine, including its combined use with other drugs such as IFN, and the appropriate length of chemotherapy treatment must await continued, extensive clinical trials.

  It has been reported that the effectiveness of IFN depends on various factors including the amount of HCV RNA ,genotype, and the mutation rate of the hepatitis virus, and various factors in patients including the stage of histological change of the liver. Patients who are infected with hepatitis virus of genotype 2a or 2b, with a low viral titer, are relatively easily treated with IFN. In 80% of patients who carry this genotype, the virus can be eradicated by treatment with IFN.  In contrast, IFN shows nearly no effect in patients who carry genotype 1b and particularly when the HCV RNA level is high. Although various attempts have been made by changing the dose and method of administration of IFN, IFN alone has not shown any effect. Recently, it has been reported in the United States and Europe that the combined use of IFN-a (Intron A) and the anti-virus agent, Ribavirin, had a significant effect on patients who carry IFN-resistant viruses. This drug will become available in Japan soon and we would like to test the effectiveness of these drugs on our IFN-resistant patients.

  Regardless of whether a patient is infected with hepatitis B or C, it is important to treat patients at the early stage of infection with the appropriate antiviral agents.  Treatment of chronic viral hepatitis will be improved by the combined use of IFN and other drugs such as nucleotide analogues.or development of a new type of IFN.

 2001-11-9