Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden.
PLoS One. 2019 Dec 11;14(12):e0226276. doi: 10.1371/journal.pone.0226276. eCollection 2019.
Because tenofovir alafenamide (TAF) leads to significantly lower plasma tenofovir concentrations than tenofovir disoproxil fumarate (TDF) and is a stronger substrate for P-glycoprotein (P-gp) than TDF, TAF could lead to decreased central nervous system (CNS) tenofovir exposure than TDF. We aimed to determine if switching from TDF to TAF increases the risk of neuronal injury, by quantifying plasma levels of neurofilament light protein (NfL), a sensitive marker of neuronal injury in HIV CNS infection.
Plasma NfL concentration was measured at baseline, week 24, and week 84 in stored plasma samples from 416 participants (272 switching to elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF and 144 continuing E/C/F/TDF) enrolled in the randomized, active-controlled, multicenter, open-label, noninferiority Gilead GS-US-292-0109 trial.
While plasma NfL levels in both groups were within the normal range, we found a small but significant decrease in the E/C/F/TAF arm after 84 weeks from a geometric mean of 9.3 to 8.8 pg/mL (5.4% decline, 95% CI 2.0-8.4, p = 0.002). This change was significantly different (p = 0.001) from that of the E/C/F/TDF arm, in which plasma NfL concentration changed from 9.7 pg/mL at baseline to 10.2 pg/mL at week 84 (5.8% increase, 95% CI -0.8-12.9, p = 0.085). This increase is in line with what could be expected in normal ageing. Plasma NfL concentrations significantly correlated with age. No correlation was found between plasma NfL and serum creatinine.
We found no biomarker evidence of CNS injury when switching from TDF to TAF. It is unclear whether the small decrease in plasma NfL found after switch to TAF is of any clinical relevance, particularly with plasma NfL levels in both arms remaining within the limits found in HIV-negative controls. These results indicate that switching from TDF to TAF appears safe with regard to neuronal injury.
替诺福韦艾拉酚胺（TAF）导致的血浆替诺福韦浓度明显低于替诺福韦二吡呋酯（TDF），且作为 P-糖蛋白（P-gp）的底物强于 TDF，因此 TAF 可能导致中枢神经系统（CNS）内替诺福韦暴露减少。我们旨在通过定量测定 HIV 感染者 CNS 感染中神经元损伤的敏感标志物神经丝轻链蛋白（NfL），来确定从 TDF 转换为 TAF 是否会增加神经元损伤的风险。
在一项随机、活性对照、多中心、开放性、非劣效性吉利德 GS-US-292-0109 试验中，对 416 名参与者（272 名转换为埃替格韦（E）/考比司他（C）/恩曲他滨（F）/TAF，144 名继续使用 E/C/F/TDF）的储存血浆样本，在基线、第 24 周和第 84 周测量血浆 NfL 浓度。
虽然两组的血浆 NfL 水平均在正常范围内，但我们发现 84 周后 E/C/F/TAF 组的 NfL 水平略有但显著下降，从几何均数 9.3pg/mL 降至 8.8pg/mL（下降 5.4%，95%CI：2.0-8.4，p=0.002）。与 E/C/F/TDF 组相比，这种变化具有显著差异（p=0.001），后者的血浆 NfL 浓度从基线时的 9.7pg/mL 升高至第 84 周时的 10.2pg/mL（升高 5.8%，95%CI：-0.8-12.9，p=0.085）。这一升高与正常衰老时的预期相符。血浆 NfL 浓度与年龄显著相关。未发现血浆 NfL 与血清肌酐之间存在相关性。
当从 TDF 转换为 TAF 时，我们未发现中枢神经系统损伤的生物标志物证据。从 TAF 转换后发现的 NfL 血浆浓度的轻微下降是否具有任何临床意义尚不清楚，特别是两个治疗组的血浆 NfL 水平均保持在 HIV 阴性对照的范围内。这些结果表明，从 TDF 转换为 TAF 似乎不会导致神经元损伤。
