Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
PLoS One. 2011;6(10):e25753. doi: 10.1371/journal.pone.0025753. Epub 2011 Oct 7.
Genetic studies have demonstrated a strong association between single nucleotide polymorphisms (SNPs) at IL28B and response to treatment with peginterferon (PEG) and ribavirin (RBV) in HCV monoinfected persons. We sought to test these associations in a prospective PEG / weight based ribavirin (WBR) treatment trial (ACTG A5178) (National Institution of Health registration number NCT00078403) in persons with HCV-HIV coinfection, and to develop a prediction score.
We selected subjects enrolled in A5178 who completed at least the first 12 weeks of the trial and had DNA available, and genotyped three SNPs at IL28B (rs12979860, rs12980275, rs8099917). We used multivariate logistic regression analysis to evaluate the association between IL28B SNPs and HCV treatment outcomes and to develop the prediction score.
231 HCV/HIV coinfected subjects were included. We observed a strong association between IL28B genotype and response to therapy among those with genotypes 1 or 4 (odds ratio for complete early virologic responses (cEVR) and sustained virologic response (SVR) was 2.98 [1.7-5.3] and 3.4 [1.7-6.9], respectively, for each additional copy of the C allele of rs12979860). Differences in frequency of the responder allele explained some of the discrepancy in HCV treatment outcomes between blacks and whites. A simple pretreatment prediction score that incorporates the IL28B genotype and baseline HCV viral load has a 93% negative predictive value (NPV) for SVR.
IL28B SNPs have an additive allele dose effect in predicting HCV treatment outcomes in HCV/HIV coinfected persons and can be incorporated into a simple pretreatment prediction score that could minimize the risk of exposure to PEG/RBV therapy for persons with unfavorable scores.
基因研究表明，在 HCV 单一感染患者中，白细胞介素 28B（IL28B）的单核苷酸多态性（SNP）与聚乙二醇干扰素（PEG）和利巴韦林（RBV）治疗反应之间存在很强的关联。我们试图在 HCV-HIV 合并感染的患者中，对这些关联进行前瞻性 PEG/体重为基础的利巴韦林（WBR）治疗试验（ACTG A5178）（美国国立卫生研究院注册号 NCT00078403）进行检测，并开发一个预测评分。
我们选择了完成至少前 12 周试验且有 DNA 可用的 A5178 入组患者，并对 IL28B 的三个 SNP（rs12979860、rs12980275、rs8099917）进行了基因分型。我们使用多变量逻辑回归分析来评估 IL28B SNP 与 HCV 治疗结果之间的关系，并开发预测评分。
共纳入 231 例 HCV/HIV 合并感染患者。我们观察到，在基因型 1 或 4 的患者中，IL28B 基因型与治疗反应之间存在很强的关联（对于完全早期病毒学应答（cEVR）和持续病毒学应答（SVR），rs12979860 的 C 等位基因每增加一个拷贝，优势比分别为 2.98[1.7-5.3]和 3.4[1.7-6.9]）。应答等位基因的频率差异解释了黑人和白人 HCV 治疗结果之间的一些差异。一个简单的治疗前预测评分，纳入了 IL28B 基因型和基线 HCV 病毒载量，对 SVR 的阴性预测值（NPV）为 93%。
IL28B SNP 在预测 HCV/HIV 合并感染患者的 HCV 治疗结果方面具有累加等位基因剂量效应，可纳入一个简单的治疗前预测评分，该评分可最大限度地降低对 PEG/RBV 治疗的不利评分人群的暴露风险。
