Effect of Tenofovir Disoproxil Fumarate and Emtricitabine on nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: A pilot, randomized, open-label phase 2 trial

Abstract

Background: 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.

Methods: 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.

Findings: From November, 20th 2020 to March, 19th 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], p = 0.13) at day 4 and 2.9 (95% CI [0.1 to 5.2], p = 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.

Interpretation: 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.

Funding: No external funding.

Conflict of interest statement

J.-JP reports personal fees and grant support from Gilead Sciences, Merck Sharp & Dohme and ViiV Healthcare outside the submitted work. L.H. reports personal fees and non-financial support from Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme and ViiV Healthcare outside the submitted work. Other authors declare no competing interests.

© 2021 The Author(s).

Figures

Fig. 1

Flow diagram of participant selection and allocation.

Fig. 2. Variation of Ct RT-PCR for SARS-CoV-2 in fresh nasopharyngeal samples by study visit according to allocated groups. The length of the box represents the interquartile range (IQR, the distance between the 25th and 75th percentiles). The horizontal line and the larger circle within the box are the median and the arithmetic mean, respectively. The upper and lower whiskers mark the more extreme observations within 1.5(IQR) above the 75th percentiles and within 1.5(IQR) below the 25th percentiles, respectively. The smaller circles are the raw data.

Fig. 3

Kaplan-Meier curves of symptomatic patients according to allocated groups