Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir
Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir
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利托那韦加沙奎那韦治疗的晚期 HIV 感染患者的毒性、疗效、血浆药物浓度和蛋白酶突变
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发表时间：
1997
期刊：
影响因子：
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通讯作者：
B. Hirschel
中科院分区：
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作者：
Patrizio Lorenzi;S. Yerly;Karmine Abderrakim;M. Fathi;O. Rutschmann;J. von Overbeck;D. Leduc;L. Perrin;B. Hirschel
目的：评价利托那韦联合沙奎那韦治疗晚期HIV感染的安全性、有效性及血药浓度。设计：多中心初步研究。患者：18例蛋白酶解酶初治患者，逆转录酶抑制剂不耐受或禁忌，中位CD 4细胞计数为12 × 106/l（范围：1-50 × 106/l），中位HIV病毒血症为5.25 log 10拷贝/ml（范围：4.00-6.13 log 10拷贝/ml）。方法：患者接受利托那韦和沙奎那韦600 mg，每日两次。在基线和第5、9和13周测量病毒血症。缓解定义为第5周病毒血症下降超过1 log 10。在至少3周的联合治疗后测定血浆药物水平：在早晨摄入两种药物之前和之后1、2和4 h采集样品。在基线和治疗期间对蛋白酶基因进行测序。结果：在第5周可评价的16例患者中，11例为应答者，在这些患者中，6例在第13周仍为应答者（2例未检测到病毒血症）。研究中止是由于副作用（n = 4）、患者选择（n = 3）、方案违背（n = 1）和死亡（n = 1）。应答者的药物水平高于无应答者（沙奎那韦P < 0.01，利托那韦P = 0.04）。在两个无应答者中，在5-13周后观察到在位置10、20、48、82、84和90处发生多个新突变。结论：利托那韦联合沙奎那韦治疗晚期HIV感染的疗效不可预测。少数患者的反应是HIV病毒血症消失。在其他患者中，通过良好的依从性和相对较高的血浆药物水平，并不能总是防止蛋白酶突变的快速累积出现，从而对治疗产生耐药性。
Objective:To assess the safety, efficacy and plasma drug levels of the combination of ritonavir plus saquinavir for the treatment of advanced HIV infection. Design:Multicentre pilot study. Patients:Eighteen protease inhibitor-naive patients, with intolerance or contraindication to reverse transcriptase inhibitors, a median CD4 cell count of 12 × 106/l (range, 1–50 × 106/l), and a median HIV viraemia of 5.25 log10copies/ml (range, 4.00–6.13 log10 copies/ml). Methods:Patients received 600 mg twice daily of both ritonavir and saquinavir. Viraemia was measured at baseline and at weeks 5, 9 and 13. Response was defined as a drop of viraemia of more than 1 log10 at week 5. Plasma drug levels were determined after at least 3 weeks of combined treatment: samples were collected before and 1, 2, and 4 h after the morning ingestion of both drugs. The protease gene was sequenced at baseline and under treatment. Results:Among the 16 patients evaluable at week 5, 11 were responders, and among these patients, six remained responders at week 13 (two with undetectable viraemia). Study discontinuations were due to side-effects (n = 4), patient choice (n = 3), protocol violation (n = 1) and death (n = 1). Responders had higher drug levels than non-responders (P < 0.01 for saquinavir, P = 0.04 for ritonavir). In two non-responders, development of multiple new mutations at positions 10, 20, 48, 82, 84 and 90 was observed after 5–13 weeks. Conclusion:The response to ritonavir plus saquinavir in advanced HIV infection is unpredictable. A minority of patients respond with disappearance of HIV viraemia. In other patients, rapid cumulative emergence of protease mutations conferring resistance to treatment cannot always be prevented by good compliance and relatively high plasma drug levels.