Parienti Jean-Jacques, Prazuck Thierry, Peyro-Saint-Paul Laure, Fournier Anna, Valentin Cécile, Brucato Sylvie, Verdon Renaud, Sève Aymeric, Colin Mathilda, Lesne Fabien, Guinard Jérome, Ar Gouilh Meriadeg, Dina Julia, Vabret Astrid, Hocqueloux Laurent
Department of Clinical Research and Innovation, Caen University Hospital, Caen, France.
Department of Infectious Diseases, Caen University Hospital, Caen, France.
EClinicalMedicine. 2021 Aug;38:100993. doi: 10.1016/j.eclinm.2021.100993. Epub 2021 Jun 27.
Tenofovir and emtricitabine interfere with the SARS CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). Several cohorts reported that people treated by tenofovir disoproxil fumarate and emtricitabine are less likely to develop SARS CoV-2 infection and related severe COVID-19.
We conducted a pilot randomized, open-label, controlled, phase 2 trial at two hospitals in France. Eligible patients were consecutive outpatients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and an interval from symptom onset to enrolment of 7 days or less. Patients were randomly assigned in a 1:1 ratio to receive oral tenofovir disoproxil fumarate and emtricitabine (2 pills on day 1 followed by 1 pill per day on days 2-7) or the standard of care. The primary and secondary endpoints were SARS-CoV-2 viral clearance from baseline assessed by cycle threshold (Ct) RT-PCR on nasopharyngeal swab collected at day 4 and day 7, respectively. A higher Ct corresponds to a lower SARS CoV-2 viral burden. Other endpoints were the time to recovery and the number of adverse events. This trial is registered with ClinicalTrials.gov, NCT04685512.
From November, 20 2020 to March, 19 2021, 60 patients were enrolled and randomly assigned to a treatment group (30 to tenofovir disoproxil fumarate and emtricitabine and 30 to standard of care). The median number of days from symptom onset to inclusion was 4 days (IQR 3-5) in both groups. Amongst patients who received tenofovir disoproxil fumarate, the difference from standard of care in the increase in Ct RT-PCR from baseline was 2.3 (95% confidence interval [-0.6 to 5.2], = 0.13) at day 4 and 2.9 (95% CI [0.1 to 5.2], = 0.044) at day 7. At day 7, 6/30 in the tenofovir disoproxil fumarate and emtricitabine group and 3/30 in the standard of care group reported no COVID-related symptoms. Adverse events included 11 cases of gastrointestinal side effects (grade ≤ 2), three of which leaded to drug discontinuation. Three patients had COVID-19 related hospitalisation, no participant died.
In this pilot study of outpatients adult with recent non-severe COVID-19, tenofovir disoproxil fumarate plus emtricitabine appeared to accelerate the natural clearance of nasopharyngeal SARS-CoV-2 viral burden. These findings support the conduct of larger trials of tenofovir-based therapies for the prevention and early treatment of COVID-19.
No external funding.
替诺福韦和恩曲他滨可干扰严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的核糖核酸（RNA）依赖性RNA聚合酶（RdRp）。几个队列研究报告称，接受富马酸替诺福韦二吡呋酯和恩曲他滨治疗的人感染SARS-CoV-2以及发生相关重症冠状病毒病2019（COVID-19）的可能性较低。
我们在法国的两家医院进行了一项2期试验，该试验为随机、开放标签、对照的试点试验。符合条件的患者为连续的门诊患者（年龄≥18岁），经逆转录聚合酶链反应（RT-PCR）确诊感染SARS-CoV-2，且症状出现至入组的间隔时间为7天或更短。患者按1:1的比例随机分配，接受口服富马酸替诺福韦二吡呋酯和恩曲他滨（第1天服用2片，随后第2 - 7天每天服用1片）或标准治疗。主要终点和次要终点分别为通过第4天和第7天采集的鼻咽拭子的循环阈值（Ct）RT-PCR评估的从基线开始的SARS-CoV-2病毒清除情况。Ct值越高，SARS-CoV-2病毒载量越低。其他终点为恢复时间和不良事件数量。本试验已在ClinicalTrials.gov注册，注册号为NCT04685512。
从2020年11月20日至2021年3月19日，共纳入60例患者并随机分配至治疗组（30例接受富马酸替诺福韦二吡呋酯和恩曲他滨治疗，30例接受标准治疗）。两组患者从症状出现到纳入研究的天数中位数均为4天（四分位间距3 - 5天）。在接受富马酸替诺福韦二吡呋酯治疗的患者中，第4天从基线开始的Ct RT-PCR升高与标准治疗的差异为2.3（95%置信区间[-0.6至5.2]，P = 0.13），第7天为2.9（95%置信区间[0.1至5.2]，P = 0.044）。在第7天，富马酸替诺福韦二吡呋酯和恩曲他滨组30例中有6例、标准治疗组30例中有3例报告无COVID-19相关症状。不良事件包括11例胃肠道副作用（≤2级），其中3例导致停药。3例患者因COVID-19住院，无参与者死亡。
在这项针对近期非重症COVID-19成年门诊患者的试点研究中，富马酸替诺福韦二吡呋酯加恩曲他滨似乎可加速鼻咽部SARS-CoV-2病毒载量的自然清除。这些发现支持开展更大规模的基于替诺福韦的疗法用于COVID-19预防和早期治疗的试验。
无外部资金。
