Hill Andrew, Hughes Sophie L, Gotham Dzintars, Pozniak Anton L
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Faculty of Medicine, Imperial College London, UK.
J Virus Erad. 2018 Apr 1;4(2):72-79. doi: 10.1016/S2055-6640(20)30248-X.
Higher plasma tenofovir concentrations are associated with higher risks of renal and bone adverse events. The pharmacokinetic boosters ritonavir (RTV) and cobicistat (COBI) significantly increase plasma area under the curve (AUC) concentrations of tenofovir disoproxil fumarate (TDF), by 25-37%. When combined with RTV or COBI, the dose of tenofovir alafenamide (TAF) is lowered from 25 mg to 10 mg daily, but the TDF dose is maintained at 300 mg daily.
To assess the differences in safety and efficacy between tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) in regimens with and without the pharmacokinetic boosters RTV and COBI.
A PubMed/Embase search inclusive of dates up to 17 July 2017 identified 11 randomised head-to-head trials (8111 patients) of TDF versus TAF. The Mantel-Haenszel method was used to calculate pooled risk differences and 95% confidence intervals using random-effects models. A pre-defined sub-group analysis compared TAF with TDF, either when boosted with RTV or COBI, or when unboosted.
Nine clinical trials compared TAF and TDF for treatment of HIV-1 and two were for hepatitis B treatment. The eleven clinical trials documented 4574 patients with boosting RTV or COBI in both arms, covering 7198 patient-years of follow-up. Some 3537 patients received unboosted regimens, totalling 3595 patient-years of follow-up. Boosted TDF-treated patients showed borderline lower HIV RNA suppression <50 copies/mL (=0.05), more bone fractures (=0.04), larger decreases in bone mineral density (<0.001), and more discontinuations for bone (=0.03) or renal (=0.002) adverse events. By contrast, there were no significant differences in HIV RNA suppression rates or clinical safety endpoints between unboosted TAF and unboosted TDF.
TDF boosted with RTV or COBI was associated with higher risks of bone and renal adverse events, and lower HIV RNA suppression rates, compared with TAF. By contrast, when ritonavir and cobicistat were not used, there were no efficacy differences between TAF and TDF, and marginal differences in safety. The health economic value of TAF versus low-cost generic TDF may be limited when these drugs are used without cobicistat or ritonavir.
较高的血浆替诺福韦浓度与肾脏和骨骼不良事件的较高风险相关。药代动力学增强剂利托那韦（RTV）和考比司他（COBI）可使富马酸替诺福韦二吡呋酯（TDF）的血浆曲线下面积（AUC）浓度显著增加25%-37%。与RTV或COBI联用时，替诺福韦艾拉酚胺（TAF）的剂量从每日25毫克降至10毫克，但TDF的剂量维持在每日300毫克。
评估在有和没有药代动力学增强剂RTV和COBI的治疗方案中，替诺福韦艾拉酚胺（TAF）和富马酸替诺福韦二吡呋酯（TDF）在安全性和疗效上的差异。
通过检索截至2017年7月17日的PubMed/Embase数据库，确定了11项TDF与TAF的随机对照试验（8111例患者）。采用Mantel-Haenszel方法，使用随机效应模型计算合并风险差异和95%置信区间。一项预先定义的亚组分析比较了TAF与TDF在接受RTV或COBI增强或未增强时的情况。
9项临床试验比较了TAF和TDF用于治疗HIV-1，2项用于治疗乙型肝炎。这11项临床试验记录了双臂均接受RTV或COBI增强治疗的4574例患者，随访时间共计7198患者年。约3537例患者接受了未增强方案，随访时间共计3595患者年。接受增强TDF治疗的患者在HIV RNA抑制水平<50拷贝/mL方面略低（P=0.05），骨折发生率更高（P=0.04），骨矿物质密度下降幅度更大（P<0.001），因骨骼（P=0.03）或肾脏（P=0.002）不良事件停药的情况更多。相比之下，未增强的TAF和未增强的TDF在HIV RNA抑制率或临床安全性终点方面没有显著差异。
与TAF相比，用RTV或COBI增强的TDF与更高的骨骼和肾脏不良事件风险以及更低的HIV RNA抑制率相关。相比之下，当不使用利托那韦和考比司他时，TAF和TDF在疗效上没有差异，在安全性上有微小差异。当这些药物在不使用考比司他或利托那韦的情况下使用时，TAF相对于低成本通用TDF的健康经济价值可能有限。
