聚乙二醇干扰素α联合利巴韦林治疗人类免疫缺陷病毒合并丙型肝炎病毒感染者最佳时机的探讨

Discussion on optimal duration of pegylated interferon a combined with ribavirin for chronic hepatitis C in HIV-infected patients

目的探讨聚乙二醇干扰素α（Peg—INFα）联合利巴韦林（RBV）治疗人类免疫缺陷病毒（HIV）合并丙型肝炎病毒（HCV）感染者的最佳时机。方法为前瞻性多中心研究，A组：158例，HIV合并HCV感染者；B组：对照组，60例，单一HCV感染者，均接受Peg—INFα联合RBV标准治疗。A组根据CD4^＋T淋巴细胞计数分为3个亚组：A1组，79例，CD4^＋T淋巴细胞〉350个／μl，先抗HCV治疗再进行联合抗病毒治疗（cART）；A2组，45例，CD4^＋T淋巴细胞200～350个／μl，先给予cART，耐受后开始抗HCV治疗;A3组，34例，CD4^＋T淋巴细胞〈200个／μl，先给予cART，待CD4^＋T淋巴细胞〉200个／μl开始抗HCV治疗。比较各组及亚组问抗HCV的疗效。对于服从正态分布、方差齐性资料两组之间采用t检验，计数资料采用χ^2检验（或Fisher确切概率法），非正态数据采用Mann-Whitney U检验。多组均数比较采用单向方差分析，随后进行SNK检验。多组疗效比较采用多个独立样本非参数检验。结果各组及亚组年龄、基线HCVRNA水平，差异无统计学意义（P值均〉0．05）。两组意向性分析：A组完全早期病毒学应答率（cEVR）率75．3％（119／158），治疗结束时病毒学应答（eTVR）率68．4％（108／158），持续病毒学应答（SVR）率48．7％（77／158）；B组cEVR率93．3％（56／60），eTVR率90．0％（54／60），SVR率71．7％（43／60），A组各疗效指标明显低于B组，差异有统计学意义（P值均〈0．05）。经过符合方案分析，A组cEVR率仍低于B组（P〈0．05），但eTVR率及SVR率与B组比较，差异无统计学意义（P值均〉0．05）。A组各亚组间疗效比较，意向性分析：A1亚组cEVR率78．5％（62／79），eTVR率68．4％（54／79），SVR率41．8％（33／79）；A2亚组cEVR率75．6％（34／45）。eTVR率80．0％（36／45），SVR率64．4％（29／45）；A3亚组cEVR率67．6％（23／34），eTVR率52．9％（18／34），SVR率44．1％（15／34）。A2亚组的eTVR率、SVR率分别明显高于A3、A1亚组，差异有统计学意义垆值均〈0．05）。经过符合方案分析，各亚组疗效的差异无统计学意义（P值均〉0．05）。结论HIV合并HCV感染使用Peg—INFα-2a联合RBV可获得良好抗HCV疗效，患者CD4^＋T淋巴细胞计数为200个／μl时，是开始抗HCV治疗的最佳时机。

Objective To investigate the optimal duration ofpegylated-alpha interferon （Peg-INFα） combined with ribavirin （RBV） in treating chronic hepatitis C infection in human immunodeficiency virus （HIV）-infected patients. Methods A multicenter prospective study was conducted. The study subjects were divided into two groups; HIV/HCV co-infections （Group A, n = 158） and control with HCV-monoinfections （Group B,n = 60）. All recruited patients received standard Peg-INFer plus RBV therapy. Group A was divided into 3 subgroups according to CD4^＋ cell counts： A1 subgroup, 79 cases, CD4^＋ counts 〉 350 cells/μl, who received anti-HCV before combination antiretroviral therapy（cART）; A2 subgroup, 45 cases, CD4^＋ counts between 200 and 350 cells/μl, who did not start anti-HCV until they could tolerate cART well; A3 subgroup, 34 cases, CD4^＋ counts 〈 200 cells/pl, cART was administered first, and anti-HCV therapy was started when CD4^＋ counts 〉 200 cells/μl. The anti-HCV efficacy of two groups and 3 subgroups were compared. Statistical analysis for normal distribution and homogeneity of variance data was calculated by t-test and the counting data was analyzed by χ^2 test. The Mann-Whitney Utest was used for non-normal data. A one-way analysis of variance （ANOVA） was used for the comparison of multiple groups, followed by SNK method. Multiple independent samples were used for non-parametric tests. Results There was no significant difference in age and baseline HCV RNA levels between groups and subgroups （P 〉 0.05）. By an intent-to-treat （ITT） analysis, in Group A, the ratio of complete early virological response （cEVR） rate was 75.3% （119/158）, the ratio of end of treatment virological response （eTVR） rate was 68.4% （108/158）, and the ratio of sustained virological response （SVR） rate was 48.7% （77/158）; in Group B, the ratio of cEVR rate was 93.3% （56/60）, the ratio of eTVR rate was 90.0% （54/60）, and the ratio of SVR rate was 71.7% （43/60）; The therapeutic index of Group A were lower than those of Group B （P≤ 0.05）. By per-protocol （PP） analysis, the ratio of cEVR rate in Group A [75.2% （88/112）] was still lower than that in Group B [93.3% （56/60）], but no significant differences were found in the ratio of eTVR rate and SVR rate between 2 groups （P 〉 0.05）. Comparing the efficacy of subgroups （A1, A2 and A3） by ITT analysis, the ratios of cEVR rate were respectively 78.5% （62/79）, 75.6% （34/45） and 67.6% （23/34）; the ratios of eTVR rate were respectively 68.4%（54/79）, 80.0%（36/45）and 52.9%（18/34）; and the ratios of SVR rate were respectively 41.8%（33/79）, 64.4%（29/45）and 44.1%（15/34）. The ratio of eTVR in subgroup A2 was obviously higher than that in subgroup A3 and the ratio of SVR in subgroup A2 was statistically higher than that of subgroup AI（P ≤ 0.05）. However, by PP analysis, no significant differences of the therapeutic indexes were found among the respective subgroups （P 〉 0.05）. Conclusion HIV-HCV co-infected patients would have better anti-HCV efficacy with Peg-INFct-2a plus RBV than HCV- monoinfected patients. The best time for initiating anti-HCV therapy in HIV-HCV co-infected patients is when CD4^＋ counts 200 ceils/μl.