Chen Beatrice A, Panther Lori, Marzinke Mark A, Hendrix Craig W, Hoesley Craig J, van der Straten Ariane, Husnik Marla J, Soto-Torres Lydia, Nel Annalene, Johnson Sherri, Richardson-Harman Nicola, Rabe Lorna K, Dezzutti Charlene S
*Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA; †Magee-Womens Research Institute, Pittsburgh, PA; ‡Department of Medicine and Infectious Disease, Fenway Institute, Boston, MA; §Department of Pathology and Medicine, Johns Hopkins University, Baltimore, MD; ‖Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; ¶Women's Global Health Imperative (WGHI) RTI International, San Francisco, CA; #Center for AIDS Prevention Studies, University of California San Francisco, Department of Medicine, San Francisco, CA; **Statistical Center for HIV/AIDS Research & Prevention/Fred Hutchinson Cancer Research Center, Seattle, WA; ††NIAID/DAIDS, Bethesda, MD; ‡‡International Partnership for Microbicides, Silver Spring, MD; §§FHI 360, Durham, NC; and ‖‖Alpha StatConsult, Damascus, MD.
J Acquir Immune Defic Syndr. 2015 Nov 1;70(3):242-9. doi: 10.1097/QAI.0000000000000702.
Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery.
MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics.
There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels.
In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.
依从性的差异限制了每日口服及阴道内使用含替诺福韦暴露前预防药物的有效性。每月一次的阴道抗逆转录病毒环是提高依从性和药物递送的一种方法。
MTN - 013/IPM 026是一项在美国48名HIV阴性女性中开展的多中心、双盲、随机、安慰剂对照试验，评估了含达匹韦林（DPV，25毫克）和马拉维罗（MVC，100毫克）的阴道环、仅含DPV的阴道环、仅含MVC的阴道环以及安慰剂，持续使用28天。通过不良事件评估安全性。对血浆、宫颈阴道液（CVF）和宫颈组织中的药物浓度进行定量。对宫颈活检外植体进行体外HIV攻击以评估药效学。
与安慰剂相比，各治疗组之间泌尿生殖系统相关不良事件无差异。与单药环相对稳定的浓度相比，联合环中DPV和MVC的浓度最初上升更高，随后下降更快。两种环的CVF中DPV浓度比宫颈组织和血浆中的浓度分别高1和5个对数10。仅在CVF中持续检测到MVC。取环后，CVF中的DPV和MVC浓度以及DPV组织浓度迅速下降。宫颈组织显示HIV复制与DPV水平之间存在显著的负线性关系。
在这项首次关于联合杀微生物剂阴道环的研究中，所有4种环均安全且耐受性良好。组织中DPV浓度比血浆浓度高1000倍，单药环具有更稳定的药代动力学。DPV而非MVC在宫颈组织中显示出对HIV - 1感染的浓度依赖性抑制。由于仅在CVF中持续检测到MVC浓度而血浆中未检测到，因此需要改进MVC环的药物释放。
