Masquelier Bernard, Breilh Dominique, Neau Didier, Lawson-Ayayi Sylvie, Lavignolle Valérie, Ragnaud Jean-Marie, Dupon Michel, Morlat Philippe, Dabis F, Fleury H
Laboratoire de Virologie, Hôpital Pellegrin, Bordeaux, France.
Antimicrob Agents Chemother. 2002 Sep;46(9):2926-32. doi: 10.1128/AAC.46.9.2926-2932.2002.
The response to regimens including lopinavir-ritonavir (LPV/r) in patients who have received multiple protease (PR) inhibitors (PI) can be analyzed in terms of human immunodeficiency virus type 1 (HIV-1) genotypic and pharmacokinetic (pK) determinants. We studied these factors and the evolution of HIV-1 resistance in response to LPV/r in a prospective study of patients receiving LPV/r under a temporary authorization in Bordeaux, France. HIV-1 PR and reverse transcriptase sequences were determined at baseline LPV/r for all the patients and at month 3 (M3) and M6 in the absence of response to treatment. pK measurements were determined at M1 and M3. Virological failure (VF) was defined as a plasma viral load >or=400 copies/ml at M3. A multivariate analysis of the predictors of VF, including clinical and biological characteristics and the treatment history of the patients, was performed. The PR gene sequence at M0, including individual mutations or a previously defined LPV mutation score (D. J. Kempf, J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode, J. Virol. 75:7262-7269, 2001), and the individual exposure to LPV were also included covariates. Sixty-eight patients were enrolled. Thirty-four percent had a virological response at M3. An LPV mutation score of >5 mutations, the presence of the PR I54V mutation at baseline, a high number of previous PIs, prior therapy with ritonavir or indinavir, absence of coprescription of efavirenz, and a lower exposure to LPV or lower LPV trough concentrations were independently associated with VF on LPV/r. Additional PI resistance mutations, including primary mutation I50V, could be selected in patients failing on LPV/r. Genotypic and pK parameters should be used to optimize the virological response to LPV/r in PI-experienced patients and to avoid further viral evolution.
对于接受过多种蛋白酶（PR）抑制剂（PI）治疗的患者，含洛匹那韦 - 利托那韦（LPV/r）方案的疗效可依据1型人类免疫缺陷病毒（HIV - 1）基因型和药代动力学（pK）决定因素进行分析。在法国波尔多一项针对接受临时授权使用LPV/r治疗患者的前瞻性研究中，我们研究了这些因素以及HIV - 1耐药性随LPV/r治疗的演变情况。对所有患者在基线使用LPV/r时以及在治疗无反应的第3个月（M3）和第6个月（M6）测定HIV - 1 PR和逆转录酶序列。在第1个月（M1）和第3个月测定pK值。病毒学失败（VF）定义为M3时血浆病毒载量≥400拷贝/毫升。对VF的预测因素进行多变量分析，包括患者的临床和生物学特征以及治疗史。M0时的PR基因序列，包括单个突变或先前定义的LPV突变评分（D. J. Kempf、J. D. Isaacson、M. S. King、S. C. Brun、Y. Xu、K. Real、B. M. Bernstein、A. J. Japour、E. Sun和R. A. Rode，《病毒学杂志》75:7262 - 7269，2001），以及个体对LPV的暴露情况也作为协变量纳入分析。共纳入68例患者。34%的患者在M3时有病毒学反应。LPV突变评分＞5个突变、基线时存在PR I54V突变、既往使用过大量PI、既往使用过利托那韦或茚地那韦、未联合使用依非韦伦以及较低的LPV暴露量或较低的LPV谷浓度与LPV/r治疗的VF独立相关。在LPV/r治疗失败的患者中可选择其他PI耐药突变，包括原发突变I50V。基因型和pK参数应用于优化PI经验丰富患者对LPV/r的病毒学反应，并避免病毒进一步演变。
