Taylor Milton W, Tsukahara Takuma, McClintick Jeanette N, Edenberg Howard J, Kwo Paul
Department of Biology, Indiana University, Bloomington, IN 47401, USA.
J Transl Med. 2008 Nov 5;6:66. doi: 10.1186/1479-5876-6-66.
This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron) and ribavirin (administered by weight) in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys) and ribavirin were administered.
RNA was isolated from peripheral blood monocytes (PBMC) from twenty treatment-naïve patients just before treatment (day 1) and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1.
The expression of many genes differed significantly (p <or= 0.001 and changed at least 1.5-fold) at days 3 (290 probes) and 10 (255 probes), but the number dropped at days 6 (165) and 13 (142). Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1), TRAIL, IL1Ralpha and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1) was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR) was 35%. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment.
The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our data suggest that more than once a week dosing might be desirable early during treatment to maintain high levels of response as measured by gene expression.
本研究确定了丙型肝炎病毒（HCV）患者接受聚乙二醇化干扰素α2b（派罗欣）和利巴韦林（按体重给药）治疗的前10周内基因表达的动力学变化，并将其与最近完成的Virahep C研究12进行比较，后者使用的是聚乙二醇化干扰素α2a（佩乐能）和利巴韦林。
从20例初治患者治疗前（第1天）及治疗后第3、6、10、13、27、42和70天的外周血单核细胞（PBMC）中分离RNA。每次均使用Affymetrix微阵列检测基因表达，并与第1天的基因表达进行比较。
在第3天（290个探针）和第10天（255个探针），许多基因的表达有显著差异（p≤0.001，且变化至少1.5倍），但在第6天（165个）和第13天（142个）差异基因数量减少。在整个试验期内，大多数基因持续上调。第二组基因，包括CXCL10、CMKLR1（趋化因子受体1）、TRAIL、IL1Rα以及与补体和脂质代谢相关的基因，在治疗早期被短暂诱导。CDKN1C（细胞周期蛋白激酶抑制剂1）在早期被诱导，但在后期受到抑制。后期诱导的基因大多与血液化学和氧运输有关。到第10周时，11例患者对治疗有阳性反应，最终持续病毒学应答（SVR）为35%。基因诱导或减少的水平与先前报道的佩乐能/利巴韦林治疗情况非常相似。
尽管给药量存在一些差异，但派罗欣/利巴韦林的治疗反应与佩乐能/利巴韦林报道的情况相似。我们未在治疗反应者与无反应者之间检测到基因组水平的重大差异，这可能是由于样本量有限。基因诱导呈周期性发生，在干扰素给药后立即达到峰值，在两次给药之间下降。我们的数据表明，在治疗早期可能需要每周给药不止一次，以维持基因表达所衡量的高反应水平。
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