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所有hiv感染婴儿开始抗逆转录病毒治疗，无论其免疫或临床情况如何。在使用奈韦拉平（NVP）预防母婴艾滋病毒传播（PMTCT）后，考虑到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LPV/r为基础的治疗（通常推荐作为二线方案，但这里推荐作为一线方案）是否应该对所有感染艾滋病毒的儿童在年轻时开始治疗终身持续的具体建议。不确定、长期使用LPV/r为基础的治疗存在一些风险，包括其适口性差（提高幼儿和较大儿童的依从性挑战），与利福平联合治疗结核病的相互作用，缺乏任何合适的二线方案，以及在发育中儿童中使用其长期代谢毒性的不确定性。我们提出了一项非盲随机临床试验，以评估nvp暴露的hiv感染儿童最初接受LPV/r治疗的简化，蛋白酶抑制剂（PI）节约治疗策略。主要目的是测试在接受LPV/r为基础的治疗抑制的儿童中，当儿童转向以依非韦伦（EFV）为基础的治疗时，病毒抑制的持久性是否相同。以efv为基础的治疗是一种有吸引力的替代方案，因为它已经被推荐用于治疗0 - 3岁的儿童，广泛使用，每日一次儿科配方，毒性低，描述良好，并建议与利福平联合治疗。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岁感染艾滋病毒的儿童。纳入标准将包括作为PMTCT的一部分暴露于NVP，在生命的前36个月内开始LPV/r为基础的治疗，以及病毒载量< 50拷贝/ml。这些儿童将随机接受EFV替代LPV/r或继续以LPV/r为基础的方案。随机分组后，儿童将接受48周的常规病毒载量和其他临床测试。在实验组中，在基于efv的方案中出现突破性病毒血症的儿童将立即重新启动LPV/r方案。次要目的包括比较免疫保存、毒性、抗性突变的选择和两臂的粘附性。将调查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建立证据基础，以便扩大资源匮乏地区感染艾滋病毒儿童的治疗选择。

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.