Treatment Options for Protease Inhibitor Exposed Children

描述（由申请人提供）：新的儿科治疗指南建议开始对所有艾滋病毒感染的婴儿进行抗逆转录病毒治疗，无论其免疫学或临床特征如何。由于担心使用奈韦拉平（NVP）预防母婴HIV传播（PMTCT）后对非核苷类逆转录酶抑制剂（NNRTI）的耐药性，建议开始使用洛匹那韦/利托那韦（LPV/r）治疗。指南没有提供关于基于LPV/r的治疗（通常推荐作为二线治疗方案，但在此推荐作为一线治疗方案）是否应该终身持续治疗所有在年轻时开始治疗的HIV感染儿童的具体建议。无限期、长期使用基于LPV/r的治疗存在若干风险，包括其适口性差（提高幼儿和年龄较大儿童的依从性挑战）、与用于结核病联合治疗的利福平相互作用、缺乏任何合适的二线治疗方案以及在用于发育中儿童时其长期代谢毒性的不确定性。我们提出了一个非盲随机临床试验，以评估一个简单的，蛋白酶抑制剂（PI）的保留治疗策略NVP暴露的HIV感染的儿童最初治疗LPV/r。主要目的是测试在LPV/r为基础的治疗中受到抑制的儿童中，当儿童转换为依法韦仑（EFV）为基础的治疗时，病毒抑制的持久性是否等同。基于EFV的治疗是一种有吸引力的替代方案，因为它已被推荐用于治疗>3岁的儿童，被广泛使用，与每日一次的儿科制剂一起使用是可口的，具有低的、充分描述的毒性特征，并且被推荐用于与利福平联合治疗。我们建议在南非约翰内斯堡的一个临床地点招募300名3至5岁的艾滋病毒感染儿童。入选标准将包括暴露于NVP作为PMTCT的一部分，在生命的前36个月内开始基于LPV/r的治疗，以及病毒载量< 50拷贝/ml。这些儿童将随机接受EFV替代LPV/r或继续接受基于LPV/r的方案。随机化后，将对儿童进行常规病毒载量和其他临床检查，持续48周。实验组中接受EFV为基础的治疗方案时出现突破性病毒血症的儿童将立即重新开始LPV/r治疗方案。次要目的包括比较两组的免疫保护、毒性、耐药突变的选择和依从性。将研究抗逆转录病毒药物浓度和依从性，作为这种简化方案效果的可能解释。这项研究的总体目标是为证据基础作出贡献，以便在资源匮乏的环境中扩大艾滋病毒感染儿童的治疗选择。 公共卫生相关性：我们提出了一项随机临床试验，以评估，在奈韦拉平暴露，艾滋病毒感染的儿童开始和抑制洛匹那韦/利托那韦为基础的抗逆转录病毒治疗，是否切换到依法韦仑为基础的治疗在3至5岁的病毒学抑制的维持与继续洛匹那韦/利托那韦为基础的治疗。

DESCRIPTION (provided by applicant): New pediatric treatment guidelines recommend starting all HIV-infected infants on antiretroviral treatment regardless of their immunologic or clinical profile. Treatment initiation with Lopinavir/ritonavir (LPV/r) is recommended because of concerns about resistance to non-nucleoside reverse transcriptase-inhibitors (NNRTI) following use of nevirapine (NVP) in prevention of mother-to-child HIV transmission (PMTCT). Guidelines offer no specific advice about whether LPV/r-based therapy (usually recommended as a second- line regimen but here recommended as first-line) should be continued life-long for all HIV-infected children starting therapy at a young age. There are several risks associated with indefinite, long-term use of LPV/r- based therapy, including its poor palatability (raising adherence challenges in toddlers and older children), interactions with rifampicin used for co-treatment for tuberculosis, the lack of any suitable second-line regimens, and uncertainty about its long-term metabolic toxicities when used in developing children. We propose an unblinded randomized clinical trial to evaluate a simplification, protease-inhibitor (PI)-sparing treatment strategy among NVP-exposed HIV-infected children treated initially with LPV/r. The primary objective is to test, among children suppressed on LPV/r-based therapy, whether the durability of viral suppression is equivalent when children are switched to efavirenz (EFV)-based therapy. EFV-based therapy is an attractive alternative as it is already recommended for treatment of children >3 years, is widely used, palatable with once daily pediatric formulations, a low, well-described toxicity profile, and is recommended for co-treatment with rifampicin. We propose to recruit 300 HIV-infected children aged 3 to 5 years at a clinical site in Johannesburg, South Africa. Inclusion criteria will include exposure to NVP as part of PMTCT, initiation of LPV/r-based therapy in the first 36 months of life and a viral load < 50 copies/ml. These children will be randomized to either substitute EFV for LPV/r or to continue on their LPV/r-based regimen. Children will be followed with regular viral load and other clinical tests for 48 weeks after randomization. Children in the experimental arm who have breakthrough viremia on the EFV-based regimen will promptly reinitiate the LPV/r regimen. Secondary aims include comparison of immune preservation, toxicities, selection of resistance mutations, and adherence across the two arms. Antiretroviral drug concentrations and adherence will be investigated as possible explanations for the effects of this simplification regimen. The overall goal of the study is to contribute to the evidence base to allow expansion of treatment options for HIV-infected children in low resource settings. PUBLIC HEALTH RELEVANCE: We propose a randomized clinical trial to evaluate, among nevirapine-exposed, HIV-infected children initiated and suppressed on lopinavir/ritonavir-based antiretroviral therapy, whether switching to efavirenz-based therapy at the age of 3 to 5 years leads to comparable maintenance of virologic suppression as continuation of lopinavir/ritonavir-based therapy.