P1034 (VERSION 10) A COMPARATIVE TRIAL OF PROTEASE-CONTAINING AND PROTEASE-S

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 摘要 假设 直觉上，人们会怀疑每天一次的方案比每天两次的方案更好，但目前还没有这样的方案存在。 有每日一次给药的药物，如依法韦仑（Sustiva），但他们仍然需要添加药物，每天两次给药。 在选择洛匹那韦/利托那韦（Kaletra）作为蛋白酶抑制剂和依法韦仑（Sustiva）作为非核苷逆转录酶抑制剂（NNRTI）时，有意选择了一种对漏服剂量更宽容的方案。 这两种药物的半衰期都很长，使它们成为青少年人群中使用的理想药物。但在REACH队列中，那些被报告为不依从的青少年，最常见的原因是忘记服药，没有随身携带药物，日常生活发生变化，以及在服药期间睡觉。 Efavirenz（Sustiva）是一种600毫克胶囊。 洛匹那韦/利托那韦（Kaletra）剂量为3粒胶囊，每日两次。 这些方案最大限度地减少了青少年服用避孕药的负担。 使用依法韦仑（Sustiva <$）和洛匹那韦/利托那韦（Kaletra <$）的治疗药物监测（TDM）的依据是观察到药物血浆水平的个体间变异性。 在瑞士进行的一项研究（Marzolini et.例如，2001），226 efavirenz（Sustiva <$）血浆水平从130名HIV感染者获得，这些HIV感染者已经接受含有efavirenz（Sustiva <$）的方案至少3个月。 在药物摄入后14小时（平均）获得血液样本。 依非韦伦（Sustiva）血浆水平存在显著的患者间变异性。 50%的依法韦仑（Sustiva â）水平较低（<1000微克/升）的患者出现病毒学失败，而依法韦仑（Sustiva â）水平较高（>4000微克/升）的患者中，中枢神经系统毒性的发生率大约是1000-4000微克/升患者的三倍。 测量依法韦仑（Sustiva））和洛匹那韦/利托那韦（Kaletra）血浆水平，并相应调整剂量应导致更好的病毒学结果。 具体目标 主要目标 比较含PI（2种NRTI+洛匹那韦/利托那韦（Kaletra））和保留PI（2种NRTI+依法韦仑（Sustiva））HAART方案在青少年中的有效性。 确定洛匹那韦/利托那韦（Kaletra）或依法韦仑（Sustiva）的治疗药物监测（TDM）以及这两种药物中任一种的剂量调整是否可改善病毒学应答。 次要目的 通过MEMS帽、受试者自我报告、谷浓度和药丸计数测量依从性，并比较这些指标。 比较两个HAART治疗组的治疗依从性，并将依从性与病毒学结局相关联。 确定所有治疗组中心理困扰和CNS副作用症状的频率和严重程度。 确定研究药物的安全性特征和TDM策略。 确定每个研究组的至病毒学失败时间。 确定治疗失败受试者基线时HIV耐药突变的患病率。 确定病毒耐药性、药物剂量不足、心理困扰症状和CNS副作用以及对HAART治疗失败的依从性差对青少年的相对影响。 确定治疗前免疫状态在预测治疗反应中的预后意义。 确定HIV感染青少年免疫重建的独特方面。

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. ABSTRACT HYPOTHESIS Intuitively one would suspect that a once-daily regimen would be better than a twice-daily regimen, but currently no such regimen exists. There are once-daily dosing drugs such as efavirenz (Sustiva¿), but they still require the addition of drugs that are administered twice daily. In choosing lopinavir/ritonavir (Kaletra¿) as the protease inhibitor and efavirenz (Sustiva¿) as the non-nucleoside reverse transcriptase inhibitor (NNRTI), a regimen that would be more forgiving of missed doses was intentionally chosen. Both of these drugs have long half-lives that make them the ideal drugs to be used in the adolescent population. But within the REACH cohort, those adolescents who were reported non-adherent, the most frequent reasons cited were forgetting medication, not having their medication with them, experiencing a change in daily routine, and sleeping through their dose. Efavirenz (Sustiva¿) is available as one 600mg capsule. The lopinavir/ritonavir (Kaletra¿) dose is 3 capsules twice-daily. These regimens have minimized the burden of pill taking for adolescents. The rationale for using therapeutic drug monitoring (TDM) with efavirenz (Sustiva¿) and lopinavir/ritonavir (Kaletra¿) is based on the observation of inter-individual variability in drug plasma levels. In a study conducted in Switzerland (Marzolini et. al., 2001), 226 efavirenz (Sustiva¿) plasma levels were obtained from 130 HIV-infected individuals who had been on an efavirenz (Sustiva¿) containing regimen for at least 3 months. The blood samples were obtained 14 hours (on average) after drug intake. There was marked inter-patient variability in the efavirenz (Sustiva¿) plasma levels. Virologic failure was observed in 50% of patients with low efavirenz (Sustiva¿) levels (<1000 micrograms/l) and CNS toxicity was approximately three times more frequent in patients with high efavirenz (Sustiva¿) levels (>4000 micrograms/l) compared with patients with 1000-4000 micrograms/l. Measuring efavirenz (Sustiva¿) and lopinavir/ritonavir (Kaletra¿) plasma levels and adjusting the doses accordingly should lead to a better virological outcome. SPECIFIC AIMS Primary Objectives To compare the effectiveness of a PI-containing (2 NRTIs + lopinavir/ritonavir (Kaletra)) and a PI-sparing (2 NRTIs + efavirenz (Sustiva)) HAART regimen in adolescents. To determine if therapeutic drug monitoring (TDM) of either lopinavir/ritonavir (Kaletra) or efavirenz (Sustiva) with dose adjustment of either of these two drugs improves virologic response. Secondary Objectives To measure adherence by MEMS caps, subject self-report, trough concentrations and pill count, and to compare these measures. To compare adherence to therapy in the two HAART treatment arms and to correlate adherence with the virologic outcome. To determine the frequency and severity of symptoms of psychological distress and CNS side effects in all treatment arms. To determine the safety profiles of the study medications and the TDM strategy. To determine time to virologic failure for each of the study arms. To determine the prevalence of HIV resistance mutations at baseline among subjects who fail therapy. To determine the relative contribution of viral resistance, inadequate drug dosage, symptoms of psychological distress and CNS side effects, and poor adherence to the failure of HAART in adolescents. To determine the prognostic significance of pre-therapy immune status in predicting response to therapy. To define unique aspects of immune reconstitution in HIV-infected adolescents.