Divisione Clinicizzata di Malattie Infettive, Dipartimento di Scienze Biomediche e Cliniche "Luigi Sacco", Universita' degli Studi di Milano, Milano, Italy.
Clin Microbiol Infect. 2013 Oct;19(10):936-42. doi: 10.1111/1469-0691.12100. Epub 2013 Jan 4.
Raltegravir (RAL) is the only licensed human immunodeficiency virus (HIV) integrase inhibitor. The factors associated with the virological response to RAL-containing regimens and the prevalence of integrase mutations associated with RAL failure deserve further investigation. From the Antiretroviral Resistance Cohort Analysis database, we selected triple-class-experienced subjects failing their current treatment with complete treatment history available. Selection criteria included HIV-RNA, CD4 count and HIV genotype within 3 months of RAL initiation. Factors associated with 24-week response were analysed; genotypic sensitivity scores (GSS) and weighted-GSS were evaluated. Virological response was achieved in 74.3% of 105 subjects. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00-6.87). was found to be a associated with response. Weighted-GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96-4.33) When stratifying for different cut-offs (<1 as reference, 1-1.49, ≥1.5), a borderline significant increase in the probability of response appeared for GSS ≥1.5 (p 0.053, OR 4.00; 95% CI 0.98-16.25). GSS ≥1 showed the highest sensitivity, 82.6%. Receiver operating characteristic curves depicted the widest area under the curve (0.663, p 0.054) of GSS ≥1. Unresponsiveness to RAL-containing regimens among triple-class-experienced subjects was low. The activity of the background regimen was strongly associated with response. Although few integrase genotypes were available at failure, half of these were without integrase resistance mutations. The substantial rate of RAL failure in the absence of known RAL-resistance mutations may be associated with adherence issues and this issue warrants further analysis in longer observations.
拉替拉韦（RAL）是唯一获得许可的人类免疫缺陷病毒（HIV）整合酶抑制剂。与 RAL 包含的方案的病毒学反应相关的因素以及与 RAL 失败相关的整合酶突变的流行情况值得进一步研究。从抗逆转录病毒耐药性队列分析数据库中，我们选择了当前治疗失败的三药经验丰富的受试者，并且可获得完整的治疗史。选择标准包括 HIV-RNA、CD4 计数和 HIV 基因型在 RAL 开始后 3 个月内。分析了与 24 周反应相关的因素；评估了基因型敏感性评分（GSS）和加权-GSS。在 105 名受试者中，有 74.3%达到了病毒学反应。在有整合酶基因型的 24 名受试者中，有 12 名检测到与 RAL 失败相关的突变，流行的突变是 Q148H+G140S。发现 GSS 的每个额外单位（p 0.05，OR 2.62；95%CI 1.00-6.87）与反应相关。加权-GSS 具有边缘统计学意义（p 0.063，OR 2.04；95%CI 0.96-4.33）。当按不同的截止值（<1 作为参考，1-1.49，≥1.5）分层时，GSS≥1.5 的反应概率呈边缘显著增加（p 0.053，OR 4.00；95%CI 0.98-16.25）。GSS≥1 显示出最高的敏感性，为 82.6%。受试者工作特征曲线描绘了 GSS≥1 的曲线下面积最宽（0.663，p 0.054）。在三药经验丰富的受试者中，对 RAL 包含的方案无反应的比例较低。背景方案的活性与反应强烈相关。尽管在失败时可获得的整合酶基因型很少，但其中一半没有整合酶耐药突变。在没有已知的 RAL 耐药突变的情况下，RAL 失败的发生率很高，这可能与依从性问题有关，这一问题需要在更长时间的观察中进一步分析。
