Bagnis Corinne Isnard, Stellbrink Hans-Jürgen
Nephrology Department, Pitie Salpetriere Hospital and UPMC-CNAM-EHESS Research Chair for "Patient Education", Pierre et Marie Curie University, Paris, France,
Infect Dis Ther. 2015 Jan 8;4(1):15-50. doi: 10.1007/s40121-014-0056-4.
Despite antiretroviral (ARV) therapy reducing renal disease in human immunodeficiency virus overall, there is concern that certain ARVs, particularly tenofovir disoproxil fumarate (TDF) with or without a boosted protease inhibitor (PI), may reduce renal function over time. It is not known whether effects seen with PI-based regimens are independent, result from interactions with TDF coadministration, or are artefactual owing to inhibition of renal tubular creatinine transport by ritonavir or cobicistat pharmacoenhancement. The aim of this review was to conduct a systematic review of studies, weighted toward high-quality evidence, examining changes in renal function over time with PI-based regimens.
PubMed, Embase, and Medline databases and conference abstracts were searched using pre-defined terms for English language articles, published up to and including August 12, 2013, describing changes in renal function over time with PI-based regimens. All available randomized controlled trials (RCTs) were selected; however, to reduce bias, only observational studies recruiting from more than one center and analyzing data from more than 1,000 patients were included. Evidence was qualitatively evaluated according to levels established by the Oxford Centre for Evidence-Based Medicine (OCEBM).
A total of 2,322 articles were retrieved by the initial search. Of these, 37 were selected for full review, comprising 24 RCTs (OCEBM Level 1 evidence: 4 reports of fully double-blinded or blinded with respect to the PI component). The remaining 20 RCTs and 13 observational studies qualified as OCEBM Level 2 evidence. Level 1 evidence showed initial but non-progressive increases in serum creatinine and corresponding decreases in estimated glomerular filtration rate (eGFR), suggesting an effect on renal tubular transport of creatinine. Level 2 evidence suggested that atazanavir and lopinavir especially in combination with TDF were associated with non-progressive reductions in eGFR over time, with a decreased risk for the development of chronic kidney disease (CKD) on cessation and without the development of advanced CKD or end-stage renal disease (ESRD); whether these reductions were independent or associated with interactions with coadministered TDF could not be established with certainty. Data on darunavir were insufficient to draw any conclusions. The principal limitation of the reviewed studies was the lack of standardization of creatinine measurements in virtually all studies and the lack of corroborative data on changes in proteinuria or other indices of renal function.
In this review, there was little evidence for progressive changes in eGFR, or the development of advanced CKD, or ESRD with lopinavir or atazanavir. Further long-term studies, employing a wide range of validated renal function assessments, are required to fully evaluate potential association of PIs with CKD.
尽管抗逆转录病毒（ARV）疗法总体上可减轻人类免疫缺陷病毒患者的肾脏疾病，但人们担心某些抗逆转录病毒药物，特别是富马酸替诺福韦二吡呋酯（TDF），无论是否联用增效蛋白酶抑制剂（PI），随着时间推移可能会降低肾功能。基于PI的治疗方案所产生的影响是独立的，是与TDF联用的相互作用导致的，还是由于利托那韦或考比司他的增效作用抑制肾小管肌酐转运而造成的假象，目前尚不清楚。本综述的目的是对各项研究进行系统综述，重点关注高质量证据，研究基于PI的治疗方案随时间推移对肾功能的影响。
使用预定义术语检索了PubMed、Embase和Medline数据库以及会议摘要，以查找截至2013年8月12日（含该日）发表的描述基于PI的治疗方案随时间推移对肾功能影响的英文文章。所有可用的随机对照试验（RCT）均被选中；然而，为减少偏倚，仅纳入了从多个中心招募且分析了1000多名患者数据的观察性研究。根据牛津循证医学中心（OCEBM）制定的标准对证据进行定性评估。
初步检索共获得2322篇文章。其中37篇被选中进行全面审查，包括24项RCT（OCEBM 1级证据：4篇关于PI成分完全双盲或盲法的报告）。其余20项RCT和13项观察性研究符合OCEBM 2级证据标准。1级证据显示血清肌酐最初有升高但无进行性升高，估计肾小球滤过率（eGFR）相应降低，提示对肌酐的肾小管转运有影响。2级证据表明，阿扎那韦和洛匹那韦，特别是与TDF联用时，随着时间推移与eGFR的非进行性降低有关，停药后慢性肾脏病（CKD）发生风险降低，且未发展为晚期CKD或终末期肾病（ESRD）；这些降低是独立的还是与联用TDF的相互作用有关尚不能确定。关于达芦那韦的数据不足以得出任何结论。所审查研究的主要局限性在于几乎所有研究中肌酐测量缺乏标准化，且缺乏蛋白尿或其他肾功能指标变化的确证数据。
在本综述中，几乎没有证据表明洛匹那韦或阿扎那韦会导致eGFR进行性变化、晚期CKD或ESRD的发生。需要进一步开展长期研究，并采用多种经过验证的肾功能评估方法，以全面评估PI与CKD之间的潜在关联。
