Pharmacokinetics of Single-Dose Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen.

IF 2.9 3区 医学 Q3 IMMUNOLOGY
Rulan Griesel, Clifford G Banda, Ying Zhao, Zaayid Omar, Lubbe Wiesner, Graeme Meintjes, Phumla Sinxadi, Gary Maartens
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引用次数: 0

Abstract

Background: Dolutegravir exposure is reduced after switching from efavirenz, which could select for dolutegravir resistance if switching occurs during virologic failure.

Methods: We measured serial dolutegravir trough concentrations after switching from efavirenz in a clinical trial, which randomized some participants to a supplemental dolutegravir dose or placebo for the first 14 days. Changes in dolutegravir trough concentrations between days 3, 7, 14, and 28 were evaluated. The primary outcome was the geometric mean ratio of dolutegravir trough concentrations on day 7 versus day 28.

Results: Twenty-four participants received double-dose dolutegravir (50 mg twice daily) and 11 standard dose for the first 14 days. Baseline characteristics were 77% female, median age 36 years, CD4 cell count 254 cells/mm3, and HIV-1 RNA 4.0 log10 copies/mL. The geometric mean ratio (90% CI) of dolutegravir trough concentrations on day 7 versus day 28 was 0.637 (0.485 to 0.837) in the standard-dose group and 1.654 (1.404 to 1.948) in the double-dose group. There was a prolonged induction effect at day 28 in participants with efavirenz slow metaboliser genotypes. One participant in the double-dose group had a dolutegravir trough concentration below the protein-binding adjusted concentration needed to inhibit 90% of HIV-1 (PA-IC90) at day 3.

Conclusions: No participants on standard-dose dolutegravir had dolutegravir trough concentrations below the PA-IC90. Slow efavirenz metaboliser genotypes had higher baseline efavirenz concentrations and more pronounced and longer period of induction postswitch. These findings suggest that a 14-day lead-in supplemental dolutegravir dose may not be necessary when switching from a failing efavirenz-based first-line regimen.

从失败的依非韦伦治疗方案转用多拉韦后,单剂量与双剂量多拉韦的药代动力学对比。
背景: 从依非韦伦换药后,多鲁曲韦的暴露量减少,如果在病毒学失败时换药,可能会产生多鲁曲韦耐药:从依非韦伦换药后,多鲁曲韦的暴露量减少,如果在病毒学失败时换药,可能会产生多鲁曲韦耐药:在一项临床试验中,我们测量了从依非韦伦转为多鲁曲韦后的连续多鲁曲韦谷浓度。该试验评估了第3、7、14和28天之间多鲁曲韦谷浓度的变化。主要结果是第7天与第28天多鲁曲韦谷浓度的几何平均比(GMR):24名参与者接受了双剂量多鲁曲韦(50 毫克,每天两次)治疗,11 名参与者在前 14 天接受了标准剂量治疗。基线特征如下77%为女性,中位年龄为 36 岁,CD4 细胞计数为 254 cells/mm3,HIV-1 RNA 为 4.0 log10 copies/mL。第 7 天与第 28 天多鲁曲韦谷浓度的 GMR(90% CI)分别为标准剂量组为 0.637(0.485 至 0.837),双剂量组为 1.654(1.404 至 1.948)。在第 28 天,依非韦伦慢代谢基因型参与者的诱导效果有所延长。双剂量组中有一名参试者在第3天时,多鲁特韦谷浓度低于抑制90% HIV-1所需的蛋白结合调整浓度(PA-IC90):没有服用标准剂量多拉韦的参与者的多拉韦谷浓度低于抑制 90% HIV-1 所需的蛋白结合调整浓度(PA-IC90)。慢速依非韦伦代谢基因型的基线依非韦伦浓度更高,转换后的诱导期更明显、更长。这些研究结果表明,从失败的依非韦伦一线治疗方案转换到其他治疗方案时,可能不需要14天的前导补充剂量。
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来源期刊
CiteScore
5.80
自引率
5.60%
发文量
490
审稿时长
3-6 weeks
期刊介绍: JAIDS: Journal of Acquired Immune Deficiency Syndromes​ seeks to end the HIV epidemic by presenting important new science across all disciplines that advance our understanding of the biology, treatment and prevention of HIV infection worldwide. JAIDS: Journal of Acquired Immune Deficiency Syndromes is the trusted, interdisciplinary resource for HIV- and AIDS-related information with a strong focus on basic and translational science, clinical science, and epidemiology and prevention. Co-edited by the foremost leaders in clinical virology, molecular biology, and epidemiology, JAIDS publishes vital information on the advances in diagnosis and treatment of HIV infections, as well as the latest research in the development of therapeutics and vaccine approaches. This ground-breaking journal brings together rigorously peer-reviewed articles, reviews of current research, results of clinical trials, and epidemiologic reports from around the world.
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