Yao Guang-bi, Wang Bao-en, Cui Zhen-yu, Yao Ji-lu, Zeng Min-de
Shanghai Jing An Qu Central Hospital, Shanghai 200040, China.
Zhonghua Nei Ke Za Zhi. 2003 Jun;42(6):382-7.
To evaluate the long-term efficacy and safety of 3-year lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV).
This multi-center, randomized, double-blind, placebo-controlled trial began in 1996. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily (n = 322) or placebo (n = 107) in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were offered open label lamivudine 100 mg/d for a total of 156 weeks.
After 12 weeks of lamivudine treatment, serum HBV DNA levels decreased rapidly; at week 12 the negativity of HBV DNA (< 1.6 pg/ml) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. After 1 year of lamivudine treatment, in 72.7% of the patients serum HBV DNA was undetectable (< 1.6 pg/ml). At the end of 3 years, serum HBV DNA continued to be substantially suppressed; the median level was below detectable level in non-YMDD variant patients and was increased to 10 pg/ml in YMDD variant patients. At the end of 1, 2 and 3 years, the HBeAg loss rates were 9.5%, 16.8% and 20.0% respectively; and the HBeAg/anti-HBe sero-conversion rates were 8.3%, 11.5% and 17.3% respectively. The rates of HBeAg loss and seroconversion correlated with baseline ALT levels, in patients with baseline ALT > 2ULN and ALT > 5ULN, the loss of HBeAg was 42.2% and 66.7%, sero-conversion rates were 34.4% and 61.1% respectively (P < 0.01) at the end of year 3. ALT levels at year 3 remained normal in 58.8%, and below baseline in 79.1% of the patients whose ALT were abnormal before treatment. YMDD mutations developed in 12.1%, 49.7% and 70.5% of the patients respectively at year 1, 2 and 3. HBV DNA levels were increased slightly or moderately and accompanied with elevation of ALT. HBeAg loss and sero-conversion could be achieved in YMDD variant patients to 20.0% and 15.1% at the end of year 3, but lower than that in non-variant patients (P < 0.01). The adverse drug reactions or events were generally mild to moderate, 2 patients were reported to have serious events related to the study medication. ALT flares (ALT > 5ULN) occurred in 17 patients, 10 with YMDD variants and 7 with non-variants, but all resolved. No deaths were reported in the 3 year treatment period.
Sustained HBV replication and clinical improvement could be obtained by 3-year long-term Lamivudine therapy with good tolerance.
评估拉米夫定3年治疗慢性乙型肝炎的长期疗效和安全性，以及乙肝病毒（HBV）YMDD变异出现的影响。
这项多中心、随机、双盲、安慰剂对照试验始于1996年。共有429例血清HBsAg、HBeAg和HBV DNA阳性患者按3:1比例随机分为两组，前12周分别接受每日100mg拉米夫定（n = 322）或安慰剂（n = 107）治疗。此后，所有患者接受开放标签的每日100mg拉米夫定治疗，共156周。
拉米夫定治疗12周后，血清HBV DNA水平迅速下降；第12周时HBV DNA阴性（<1.6 pg/ml）率为92.2%，而安慰剂组仅为14.1%（P<0.01）。拉米夫定治疗1年后，72.7%的患者血清HBV DNA检测不到（<1.6 pg/ml）。3年结束时，血清HBV DNA继续受到显著抑制；非YMDD变异患者的中位数水平低于检测下限，而YMDD变异患者则升至10 pg/ml。1年、2年和3年结束时，HBeAg消失率分别为9.5%、16.8%和20.0%；HBeAg/抗-HBe血清转换率分别为8.3%、11.5%和17.3%。HBeAg消失率和血清转换率与基线ALT水平相关，在基线ALT>2ULN和ALT>5ULN的患者中，第3年末HBeAg消失率分别为42.2%和66.7%，血清转换率分别为34.4%和61.1%（P<0.01）。治疗前ALT异常的患者中，58.8%在第3年ALT水平保持正常，79.1%低于基线水平。第1年、2年和3年分别有12.1%、49.7%和70.5%的患者发生YMDD变异。HBV DNA水平轻度或中度升高，并伴有ALT升高。第3年末，YMDD变异患者的HBeAg消失率和血清转换率分别可达20.0%和15.1%，但低于非变异患者（P<0.01）。药物不良反应或事件一般为轻至中度，有2例报告发生与研究用药相关的严重事件。17例患者发生ALT flare（ALT>5ULN），其中10例为YMDD变异，7例为非变异，但均缓解。3年治疗期内无死亡报告。
拉米夫定3年长期治疗可实现持续的HBV复制抑制和临床改善，耐受性良好。
