PACTG P1030

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 洛比那韦是一种有效的蛋白酶抑制剂，即使在低剂量的利托那韦(RTV)促进药代动力学时也很敏感，从而在整个剂量区间内提供治疗性LPV浓度。由于血浆中蛋白水解酶抑制剂的浓度与抗病毒效果密切相关，这潜在地为病毒耐药性的出现提供了药理学障碍(1，2)。 洛匹那韦/利托那韦在成人和6个月大的儿童(3、4、5岁)的临床试验中显示出显著的抗病毒活性和耐受性。在感染抗逆转录病毒的成人中，LPV400毫克/RTV 100 mg BID的组合产生的平均LPV谷浓度(C槽)比野生型HIV的EC50高50倍以上(6)。相比之下，对于目前可用的蛋白酶抑制剂(PI)，在人血清存在的情况下，C/EC50比率为&lt；4。 在21名HIV感染者中，研究了LPV400 mg与RTV 100 mg Bid合用的药代动力学，无饮食限制。在研究的第三周到第四周，LPV的平均(+/-SD)药代动力学参数包括：平均12小时AUC为82.8+/-44.4克/毫升，峰值血药浓度为9.6+/-4.4克/毫升，低谷血药浓度为5.5+/-4.0克/毫升，中低谷浓度为4.23克/毫升(雅培实验室，2001年3月，Kaletra Package Insert)。 可以说，一旦婴儿被垂直感染，对长期临床结果最关键的时期是出生后的头几个月。在感染早期积极治疗可能会导致更好的预后。这可以在病毒和细胞动力学的背景下进行评估。Luzuriaga等人记录了在研究的最小一组婴儿(2周至3个月大)中，与较大婴儿(3-24个月大)相比，使用含有奈韦拉平但不含PI的方案(8)，病毒清除较慢。在相同年龄组(PACTG 345)中研究的含PI方案没有发现与年龄相关的病毒清除差异(9)。这仍然是一个悬而未决的问题，这些差异对婴儿的最终临床病程有潜在的影响，特别是6个月以下的婴儿，这是本研究的目标人群。 预计相当大比例的参与婴儿将达到并保持无法检测到的血浆病毒状态(&lt；400或&lt；50拷贝/毫升)。鉴于这将是一组在婴儿期很早就被发现并积极治疗的婴儿(在“初次感染”期间)，人们对以转录和有效复制的形式监测残留的病毒活动非常感兴趣。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lopinavir is a potent protease inhibitor that is sensitive to pharmacokinetic enhancement by ritonavir (RTV) even at low RTV doses, thus providing therapeutic LPV concentrations over the entire dose interval. As plasma trough concentrations of protease inhibitors have been shown to correlate closely with antiviral effect, this potentially provides a pharmacologic impediment to the emergence of viral resistance (1, 2). Lopinavir/ritonavir has shown significant antiviral activity and tolerability in clinical trials in adults and children >6 months of age (3, 4, 5). In antiretroviral-nanve HIV-infected adults, the combination of LPV 400 mg/RTV 100 mg BID produces a mean LPV trough concentration (Ctrough) which is more than 50 times higher than the EC50 of wild-type HIV (6). In comparison, the Ctrough/EC50 ratio in the presence of human serum for currently available protease inhibitors (PIs) is <4. The pharmacokinetics of LPV 400 mg co-administered with RTV 100 mg BID was studied in 21 HIV-infected adults, without meal restrictions. At study weeks three through four, the mean (+/- SD) pharmacokinetic parameters for LPV included an average 12-hour AUC of 82.8 +/- 44.4 g/ml, a peak plasma concentration of 9.6 +/- 4.4 g/ml, and a trough plasma concentration of 5.5 +/- 4.0 g/ml. The median trough concentration was 4.23 g/ml (Kaletra package insert, Abbott Laboratories, March 2001). It can be argued that once an infant has been vertically infected, the most critical period regarding long-term clinical outcome is the first months of life. Aggressive therapy early in infection may result in a better prognosis. This can be evaluated within the context of viral and cellular dynamics. Luzuriaga et al documented slower viral clearance among the youngest group of infants studied (2 weeks to 3 months of age) compared with older infants (3-24 months of age) with a regimen containing nevirapine but no PI (8). PI-containing regimens studied across the same age groups (PACTG 345) did not reveal age-related differences in viral clearance (9). This remains an open question, and these differences have a potential impact on ultimate clinical course among infants, especially infants under 6 months of age, which is the target population for this study. It is anticipated that a sizeable proportion of participating infants will achieve and maintain non-detectable plasma virus status (<400 or <50 copies/ml). Given that this will be a group of infants identified and aggressively treated very early in infancy (during "primary infection"), there is considerable interest in monitoring residual, viral activity in the form of transcription and competent replication.