STUDIES OF THE NATURAL HISTORY AND TREATMENT OF CHRONIC HEPATITIS B

乙肝病毒感染是全球肝病的主要原因，占美国慢性肝病和肝硬变的5%至10%。现在已有安全有效的疫苗可用于预防乙肝。然而，这种疾病一旦发生，其治疗方法并不令人满意。阿尔法干扰素是第一种被证明对这种疾病有效的抗病毒药物，并于1993年在美国获得了这一适应症的许可。获得许可的基础部分是在美国国立卫生研究院肝病科进行的研究。然而，α干扰素只对三分之一的典型慢性乙肝患者有效，它在这种疾病的非典型形式中的作用尚不清楚。肝病科目前的活动重点是开发更好的治疗方法，以防止长期后果。自1996年以来，拉米夫定(3-硫胞苷)治疗HBeAg阳性和抗-HBe阳性慢性乙型肝炎的长期研究一直在进行中。几乎所有慢性乙肝患者对每天100毫克剂量的拉米夫定都有血清生化、病毒学和组织学反应。然而，在最初HBeAg阳性的患者中，75%的患者出现了病毒耐药性的突破，但在最初抗HBe阳性(而HBeAg阴性)的患者中，只有10%的患者出现了突破。治疗3到5年后的肝脏活检显示，所有保持病毒学应答的患者都有显著改善，但对病毒具有抵抗力的患者没有改善或恶化。一些反应持续的患者已经清除了所有感染标志物(HBeAg、HBs Ag和HBVDNA)。其他人仍为乙肝表面抗原阳性，但肝脏活检正常。的确，一些活检显示先前的纤维化已经消退。一个中心问题是如何管理对拉米夫定产生耐药性的患者。出现疾病进展的耐药患者将接受阿尔法干扰素治疗，试图诱导长期缓解。对这种方法没有反应的患者或尽管有耐药性但有轻微疾病的患者将被登记参加未来单独或与拉米夫定联合使用的新抗病毒药物(阿德福韦)的试验。对对抗病毒治疗有长期反应的患者将进行评估，以确定病毒是否只是被抑制，仍然处于低水平，或者是被根除，甚至在肝脏中也检测不到。对肝炎抗原的免疫应答将在长期应答者和无应答者之间进行比较，试图剖析乙肝痊愈的免疫学和病毒学决定因素。

Infection with hepatitis B virus is a major cause of liver disease worldwide and accounts for 5-10 per cent of chronic liver disease and cirrhosis in the United States. Safe and effective vaccines are now available for prevention of hepatitis B. However, therapies for the disease once it has occurred are unsatisfactory. Alpha interferon was the first antiviral agent shown to be effective in this disease and was licensed for this indication in the United States in 1993. The basis for licensure were, in part, studies conducted in the Liver Diseases Section of NIH. However, alpha interferon is effective in only one-third of patients with typical chronic hepatitis B and its role in atypical forms of this disease remain unclear. Current activities in the Liver Diseases Section are focused on developing better therapies to prevent long-term consequences. A longterm study of lamivudine (3-thiacytidine) for both HBeAg positive and anti-HBe positive chronic hepatitis B has been underway since 1996. Virtually all patients with chronic hepatitis B have had a serum biochemical, virological and histological response to lamivudine in a dose of 100 mg once daily. However, breakthrough with viral resistance has occurred in 75% of patients who were initially HBeAg positive but in only 10% of those initially anti-HBe positive (and HBeAg negative). Liver biopsies taken after 3 to 5 years of therapy show marked improvements in all patients who maintained a virological response, but no improvement or worsening in those with viral resistance. Some patients with a maintained response have cleared all markers of infection (HBeAg, HBsAg and HBV DNA). Others remain HBsAg positive but have normal liver biopsies. Indeed, some biopsies show resolution of previous fibrosis. A central issue is how to manage patients who develop lamivudine resistance. Patients with resistance demonstrating progression of disease will be treated with alpha interferon in an attempt to induce a longterm remission. Patients who fail to respond to this approach or who have mild disease despite resistance will be enrolled in future trials of new antivirals (adefovir) alone or in combination with lamivudine. Patients who have had a long term response to antiviral therapy will be evaluated for whether the virus is merely suppressed and is still present in low level or is eradication and no longer detectable even in liver. Immune responses to hepatitis antigens will be compared between long term responders and non responders to attempt to dissect out the immunology and virologic determinants of recovery from hepatitis B.