HIV-1蛋白酶抑制剂利托那韦安全性、药代动力学及疗效的短期研究。欧洲-澳大利亚利托那韦协作研究组

A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group.

作者信息

Danner S A, Carr A, Leonard J M, Lehman L M, Gudiol F, Gonzales J, Raventos A, Rubio R, Bouza E, Pintado V

机构信息

Academic Medical Center, Amsterdam, The Netherlands.

出版信息

N Engl J Med. 1995 Dec 7;333(23):1528-33. doi: 10.1056/NEJM199512073332303.

DOI:10.1056/NEJM199512073332303

PMID:7477167

Abstract

BACKGROUND

Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability.

METHODS

We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens.

RESULTS

During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment.

CONCLUSIONS

In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established.

摘要

背景

逆转录酶抑制剂对1型人类免疫缺陷病毒（HIV-1）的临床疗效仅为中等。利托那韦是一种HIV-1蛋白酶抑制剂，具有强大的体外抗HIV特性和良好的口服生物利用度。

方法

我们在一项双盲、随机、安慰剂对照的1期和2期研究中评估了利托那韦对84例每立方毫米CD4+淋巴细胞计数为50个或更多的HIV阳性患者的抗病毒活性和安全性。患者被随机分配到四种利托那韦治疗方案之一，或接受四周安慰剂治疗，然后（通过随机分配）接受其中一种利托那韦方案治疗。

结果

在最初4周内，四个剂量组的CD4+淋巴细胞计数增加和每毫升血浆中HIV-1 RNA拷贝数对数减少情况相似，但在三个低剂量组中，到16周时又回到了基线水平。32周后，在最高剂量组（每12小时服用600毫克利托那韦）的7例患者中，CD4+淋巴细胞计数自基线的中位数增加为每立方毫米230个细胞，血浆中HIV-1 RNA浓度的平均降低（通过分支DNA测定法测量）为0.81对数（95%置信区间，0.40至1.22）。在两个高剂量组的17例患者亚组中，还使用基于聚合酶链反应的测定法测量了RNA，治疗8周后病毒RNA平均最大降低1.94对数（9 %置信区间，1.37至2.51）。不良事件包括恶心、口周感觉异常、肝转氨酶水平升高和甘油三酯水平升高。10例退出研究被判定与利托那韦治疗有关。