拉米夫定与阿德福韦酯初始联合与单药优化治疗慢性乙型肝炎96周临床疗效比较

A 96-week comparison of de novo combination therapy with lamivudine and adefovir dipivoxil to optimization monotherapy for chronic hepatitis B

目的观察拉米夫定（LAM）与阿德福韦酯（ADV）初始联合与单药优化治疗慢性乙型肝炎患者96周的临床疗效。方法选择2007-2009年安徽医科大学第一附属医院的155例慢性乙型肝炎患者，所有患者采用随机数字表法分为LAM治疗组（53例）、ADV治疗组（50例）和LAM＋ADV联合治疗组（52例），每24周检测患者肝肾功能、HBV血清学标志物和血清HBVDNA载量。单用LAM或ADV组中应答不佳或病毒学突破患者分别在24、48和72周加用ADV或LAM进行优化治疗。多组计量资料组间比较，正态分布且方差齐性采用单因素方差分析，非正态分布采用秩和检验；二分类Logistic回归分析影响产生早期病毒学应答的因素。结果治疗24周时，LAM组、ADV组以及LAM＋ADV组的完全病毒学应答率分别为66．0％（35／53）、34．0％（17／50）和90．4％（47／52），差异有统计学意义（X^2=35．282，P〈0．01）；治疗96周时，三组患者的完全病毒学应答率分别为96．2％（51／53）、86．0％（43／50）和100．0％（52／52），组间比较差异无统计学意义（X^2=19．115，P〉0．05）。治疗96周时，LAM组、ADV组以及LAM＋ADV组的ALT累计复常率分别为86．8％（46／53）、82．0％（41／50）和94．2％（49／52），比较差异无统计学意义（X^2=3．613，P〉0．05），但ALT水平在三组间的差异有统计学意义（X^2=11．195，P〈0．01）。治疗96周时，LAM组、ADV组以及联合治疗组的HBeAg血清学转换率分别达到31．3％（10／32）、20．7％（6／29）和38．7％（12／31），但差异无统计学意义（X2=2．313，P〉0．05）。LAM组无早期应答1例，发生病毒学突破11例；ADV组无早期应答19例，发生病毒学突破1例；联合组无1例发生早期无应答和病毒学突破。Logistic回归显示，24周完全病毒学应答与基线HBeAg、初始治疗方案和基线HBVDNA载量相关。分层评价发现，对于HBeAg阳性、HBVDNA〉6．28×10^6拷贝／mL和AⅡ≤5x正常值上限（ULN）的患者，LAM、ADV单药治疗和初始联合治疗24周时的完全病毒学应答率比较差异有统计学意义（X^2=7．726、10．921和6．100，P〈0．05或〈0．01）；对于基线HBVDNA〉6．28×10^6拷贝／mL的患者，ADV单药治疗24周，无1例产生完全病毒学应答。结论LAM＋ADV联合治疗具有更强的抗病毒活性和改善肝功能的能力，可提高病毒学应答率和降低耐药变异率，尤其对HBeAg阳性、HBV高载量和ALT≤5×ULN的患者更值得推荐使用。

Objective To compare the 96-week efficacy of de novo combination therapy with lamivudine （LAM） and adefovir dipivoxil （ADV） to that of optimization monotherapy for chronic hepatitis B （CHB）. Methods A total of 155 CHB patients were collected from the First Affiliated Hospital of Anhui Medical University during 2007 and 2009. All patients were randomly assigned to LAM monotherapy group （ n = 53 ）, ADV monotherapy group （ n = 50 ） or LAM with ADV combination group （ n = 52 ） according to randomized digital table. The liver and kidney functions, HBV serum markers, and HBV DNA loads were tested every 24 weeks. If patients in LAM or ADV group had poor response or virological breakthrough, they were given optimized therapy with AD~ or LAM at week 24, 48 or 72. One-way ANOVA （normal distribution and homoscedasticity） and non-parametric test （non-normal distribution ） were performed to compare measurement data among groups. The impact factors of early virological response were analyzed by binary Logistic regression method. Results At week 24, the complete virological responses in LAM group, ADV group, and LAM ＋ ADV group were 66.0% （35/53）, 34.0% （17/50） and 90.4% （47/52）, respectively （X^2 = 35. 282, P 〈 0.01 ） ; while, at week 96 the complete virological responses in three groups were 96.2% （51/53）, 86.0% （43/50） and 100.0% （52/52）, respectively （X^2 = 19.115, P 〉 0.05 ）. At week 96, the cumulative recover rates of ALT in LAM group, ADV group, and LAM ＋ ADV group were 86.8% （46/53）, 82.0% （41/50） and 94. 2% （49/52）, respectively （X^2 =3.613, P 〉0.05）; however, the ALT levels in three groups were statistically different （X^2 = 11. 195, P 〈0.01）. At week 96, the HBeAg seroconversion rates in LAM group, ADV group, and LAM ＋ ADV group were 31.3% （10/32） , 20.7% （6/29） and 38.7% （ 12/31 ）, respectively （X^2 = 2. 313, P 〉 0.05 ）. Early virological response was not found in 1 patient in LAM group and 19 patients in ADV group; virological breakthrough occurred in 11 patients in LAM group and 1 patient in ADV group. All patients in LAM ＋ ADV group had early virological responses and had no virological breakthrough. Logistic regression showed that complete virological response at week 24 was correlated with the baseline HBeAg, the initial treatment and HBV DNA load. Layered evaluation showed that there were significant differences in early complete virological responses among three groups for patients with positive HBeAg, HBV DNA 〉 6. 28 × 10^6 copies/mL and ALT ≤ 5× ULN （X^2 =7. 726, 10. 921 and 6. 100, P 〈 0.05 or 〈 0.01 ） ; for those with HBV DNA 〉 6.28× 10^6 copies/mL, complete virological response was not observed in ADV group treated for 24 weeks. Conclusion LAM combined with ADV has stronger antiviral activity, lower resistance rate and can improve liver function and virological response, especially for the patients with HBeAg-positive, high HBV DNA loads and ALT ≤ 5 × ULN.