Gilead Sciences, Inc., Foster City, CA.
J Acquir Immune Defic Syndr. 2021 Mar 1;86(3):369-377. doi: 10.1097/QAI.0000000000002562.
Barriers to lifelong HIV-1 suppression by antiretrovirals include poor adherence and drug resistance; regimens with higher tolerance to missed doses (forgiveness) would be beneficial to patients. To model short-term nonadherence, in vitro experiments monitoring viral breakthrough (VB) and resistance development were conducted.
HIV breakthrough experiments simulated drug exposures at full adherence or suboptimal adherence to bictegravir+emtricitabine+tenofovir alafenamide (BIC+FTC+TAF) or dolutegravir + lamivudine (DTG+3TC). MT-2 cells were infected with wild-type or low frequency M184V HIV-1, exposed to drug combinations, monitored for VB, and rebound virus was deep sequenced. Drug concentrations were determined using human plasma-free adjusted clinical trough concentrations (Cmin), at simulated Cmin after missing 1 to 3 consecutive doses (Cmin - 1 or Cmin - 2, and Cmin - 3) based on drug or active metabolite half-lives.
Cultures infected with wild-type or low frequency M184V HIV-1 showed no VB with BIC+FTC+TAF at drug concentrations corresponding to Cmin, Cmin - 1, or Cmin - 2 but breakthrough did occur in 26 of 36 cultures at Cmin - 3, where the M184V variant emerged in one culture. Experiments using DTG + 3TC prevented most breakthrough at Cmin concentrations (9/60 had breakthrough) but showed more breakthroughs as drug concentrations decreased (up to 36/36) and variants associated with resistance to both drugs emerged in some cases.
These in vitro VB results suggest that the high potency, long half-lives, and antiviral synergy provided by the BIC/FTC/TAF triple therapy regimen may protect from viral rebound and resistance development after short-term lapses in drug adherence.
抗逆转录病毒药物抑制艾滋病毒-1（HIV-1）的终身复制存在障碍，包括治疗依从性差和耐药性；具有更高容忍度的方案（宽容性）对于患者更有益。为了模拟短期不依从，进行了监测病毒突破（VB）和耐药发展的体外实验。
HIV 突破实验模拟了在完全依从或非最佳依从情况下接受比替拉韦双夫定+恩曲他滨+丙酚替诺福韦（BIC+FTC+TAF）或多替拉韦+拉米夫定（DTG+3TC）的药物暴露。将 MT-2 细胞用野生型或低频率 M184V HIV-1 感染，暴露于药物组合中，监测 VB，并对反弹病毒进行深度测序。使用不含人血浆的调整后的临床谷浓度（Cmin）确定药物浓度，根据药物或活性代谢物半衰期，在错过 1 至 3 个连续剂量后的模拟 Cmin（Cmin-1 或 Cmin-2 和 Cmin-3）。
感染野生型或低频率 M184V HIV-1 的培养物在药物浓度相当于 Cmin、Cmin-1 或 Cmin-2 时未出现 VB，但在 Cmin-3 时，36 个培养物中有 26 个出现突破，其中一个培养物出现了 M184V 变异。使用 DTG+3TC 的实验在 Cmin 浓度时阻止了大多数突破（9/60 有突破），但随着药物浓度降低，突破增加（高达 36/36），并且在某些情况下出现了与两种药物耐药相关的变异。
这些体外 VB 结果表明，BIC/FTC/TAF 三联疗法的高效力、长半衰期和抗病毒协同作用可能在短期药物依从性丧失后防止病毒反弹和耐药性发展。
