Real-World Assessment of Renal and Bone Safety among Patients with HIV Infection Exposed to Tenofovir Disoproxil Fumarate-Containing Single-Tablet Regimens

ObjectivesTenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens have been associated with an increased incidence of renal and bone adverse outcomes. Here, we estimated the real-world incidence of renal and bone adverse outcomes among patients with HIV infection receiving different TDF-containing single-tablet regimens (STRs).MethodsThis cohort study used US health insurance data spanning the years 2008–2014. We identified HIV-infected patients aged ≥18 years (all HIV patients) and those with ≥6 months of continuous enrollment prior to initiating efavirenz/emtricitabine/TDF (EFV/FTC/TDF), rilpivirine/FTC/TDF (RPV/FTC/TDF) or elvitegravir/cobicistat/FTC/TDF (EVG/COBI/FTC/TDF). Renal adverse outcomes were identified using renal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Bone adverse outcomes were identified using ICD-9-CM diagnosis codes for fracture. Incidence rates (IRs) and associated 95% confidence intervals (CIs) were estimated assuming a Poisson distribution, and outcomes between STRs were compared using IR ratios (IRRs) and IR differences (IRDs).ResultsWe identified 9876 and 10,383 eligible patients for the renal and fracture analyses, respectively. Observed IRs for renal adverse outcomes were 9.7, 10.5, 13.6, and 18.0 per 1000 person-years among those receiving EFV/FTC/TDF, RPV/FTC/TDF, or EVG/COBI/FTC/TDF, or all HIV patients, respectively. Corresponding values for IRs of fracture were 3.4, 3.6, 7.2, and 4.4 per 1000 person-years, respectively. Renal adverse outcomes with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRD −3.96; 95% CI: −7.31, −1.06). No IRR differences were identified for the renal analysis. Fractures with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRR 0.47; 95% CI: 0.27, 0.81 and IRD −3.85; 95% CI: −5.02, −2.78).ConclusionsIn this large real-world database, observed IRs for renal adverse outcomes with TDF-containing STRs were lower or similar to those for all HIV patients, with the lowest IRs observed among patients receiving EFV/FTC/TDF. Compared with all HIV patients, the observed IR for fracture was higher with EVG/COBI/FTC/TDF, comparable with RPV/FTC/TDF, and lower with EFV/FTC/TDF.

研究目的：含富马酸替诺福韦二吡呋酯（Tenofovir disoproxil fumarate, TDF）的抗逆转录病毒治疗方案与肾脏及骨骼不良结局的发生率升高相关。本研究旨在评估接受不同含TDF单片复方制剂（single-tablet regimens, STRs）的HIV感染患者中，肾脏与骨骼不良结局的真实世界发生率。

研究方法：本队列研究使用2008-2014年的美国健康保险数据。我们纳入了年龄≥18岁的HIV感染者（所有HIV患者），且这些患者在启动依非韦伦/恩曲他滨/富马酸替诺福韦二吡呋酯（EFV/FTC/TDF）、利匹韦林/恩曲他滨/富马酸替诺福韦二吡呋酯（RPV/FTC/TDF）或埃替格韦/考比司他/恩曲他滨/富马酸替诺福韦二吡呋酯（EVG/COBI/FTC/TDF）治疗前，具有至少6个月的连续参保记录。肾脏不良结局通过国际疾病分类第九版临床修订版（International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM）诊断编码识别，骨骼不良结局通过骨折相关ICD-9-CM诊断编码识别。假设服从泊松分布以估计发病率（incidence rates, IRs）及对应的95%置信区间（95% confidence intervals, CIs），并通过发病率比（IR ratios, IRRs）与发病率差（IR differences, IRDs）比较不同STRs组间的结局差异。

研究结果：本研究分别纳入9876例和10383例合格患者用于肾脏与骨折分析。接受EFV/FTC/TDF、RPV/FTC/TDF、EVG/COBI/FTC/TDF治疗的患者及所有HIV患者的肾脏不良结局观察发病率分别为每1000人年9.7、10.5、13.6和18.0例。对应的骨折发病率分别为每1000人年3.4、3.6、7.2和4.4例。EFV/FTC/TDF组的肾脏不良结局发生率显著低于EVG/COBI/FTC/TDF组（IRD -3.96；95%CI：-7.31, -1.06）。肾脏分析未发现组间发病率比存在差异。EFV/FTC/TDF组的骨折发生率显著低于EVG/COBI/FTC/TDF组（IRR 0.47；95%CI：0.27, 0.81；IRD -3.85；95%CI：-5.02, -2.78）。

研究结论：在这项大型真实世界数据库研究中，含TDF的STRs的肾脏不良结局观察发生率低于或与所有HIV患者的整体水平相当，其中EFV/FTC/TDF组的发生率最低。与所有HIV患者相比，EVG/COBI/FTC/TDF组的骨折发病率更高，RPV/FTC/TDF组与整体水平相当，而EFV/FTC/TDF组的骨折发病率更低。