TREATMENT OF CHRONIC HEPATITIS B VIRUS INFECTION

我们一直在探索一类药物的潜在抗病毒效果 氟嘧啶核苷类似物。最初，我们探索了这种药物 FIAC用于抑制艾滋病患者巨细胞病毒感染。抗病毒活性 在耐受剂量下看不到，研究转向药物的代谢 衍生品，FIAU。研究表明，高剂量的不耐受性很好 较低剂量的耐受性和深刻的抑制力 乙肝病毒(乙肝病毒)。最初的研究涉及艾滋病毒阳性。 合并慢性乙肝病毒感染的患者。深沉而均匀 永久性地减少了循环中的HBVDNA和抗原 口服氟尿嘧啶，每日剂量为0.1、-0.5或1 mg/kg，连续14天。我们 然后转向对正常患者进行更广泛的剂量调整研究 慢性乙肝病毒感染。研究比较了0.05，0.1， 每天0.25 mg/kg和0.5 mg/kg，共28天。我们注意到深深地抑制了 即使在最低剂量和没有任何 很大的副作用。治疗9个月后，24名患者中有9名 2例HBVDNA丢失，其中2例HBeAg丢失。基于这些发现 其他HIV阴性的慢性乙肝患者参加了一项随机的 比较每天0.1毫克/公斤和0.25毫克/公斤6个月的研究，以确定长期 术语安全性和有效性。审判于1993年6月26日终止，原因是 在研究中出现了危及生命的毒性。过去的一年 这项工作需要对研究患者进行长期随访，并进行多项 对细胞和生化基础的多方面探索 毒性。

We have been exploring the potential antiviral efficacy of a class of fluoropyrimidine nucleoside analogues. Initially we explored the drug FIAC for inhibition of CMV infection in AIDS patients. Antiviral activity was not seen at tolerated doses and studies turned to the drug's metabolic derivative, FIAU. Studies showed intolerance at high doses but excellent tolerance and profound inhibitory activity at lower doses against hepatitis B virus (HBV). The initial studies involved HIV positive patients with co-existing chronic HBV infection. profound and even permanent reductions in circulating HBV DNA and antigens were achieved with oral FIAU at daily doses of 0.1, -.5, or 1 mg/kg for 14 days. We then turned to a broader dose modification study in normal patients with chronic HBV infection. Studies compared antiviral efficacy at .05, 0.1, 0.25 and 0.5 mg/kg per day for 28 days. We noted profound inhibition of HBV infection even at the lowest doses and in the absence of any substantial side effects. By 9 months after treatment 9 of 24 patients had lost HBV DNA; 2 of which lost HBeAg. Based on these findings additional HIV-negative chronic HBV patients were enrolled in a randomized study comparing 0.1 and 0.25 mg/kg per day for 6 months to determine long term safety and efficacy. The trial was terminated 6/26/93 because of the emergence of life-threatening toxicity in the study. The past year of work entailed long term follow up of the study patients and a multi- faceted exploration of the cellular and biochemical bases for the toxicity.