Tenofovir Disoproxil Fumarate/Emtricitabine and Baricitinib for Patients at High Risk of Severe Coronavirus Disease 2019: The PANCOVID Randomized Clinical Trial

Abstract

Background This study was designed to evaluate if patients with high risk for severe COVID-19 would benefit from treatment with TDF/FTC followed by baricitinib in case of hypoxemia and systemic inflammation. Methods PANCOVID is an open-label, double-randomized, phase 3 pragmatic clinical trial including adults with symptomatic COVID-19 with ≥ 2 comorbidities or older than 60 years conducted between 10 October 2020 and 23 September 2021. In the first randomization patients received TDF/FTC or not TDF/FTC. In the second randomization patients with room-air O2 saturation <95% and at least one increased inflammatory biomarker received baricitinib plus dexamethasone or dexamethasone alone. The primary endpoint was 28-day mortality. Main secondary endpoint was 28-day disease progression or critical care unit admission or mortality. The trial was stopped before reaching planned sample size due to the decrease in the number of cases and a mortality rate substantially lower than expected EudraCT registration number: 2020-001156-18. Results Of the 355 included participants 97% were hospitalized at baseline. Overall, 28-day mortality was 3.1%. The 28-day mortality relative risk (RR) for participants treated with TDF/FTC was 1.76 (95% CI 0.52-5.91; p= 0.379); it was 0.42 (95% CI 0.11-1.59; p= 0.201) for those treated with baricitinib. The 28-day RR for the main secondary combined endpoint for participants treated with TDF/FTC was 0.95 (95% CI 0.66-1.40; p = 0.774); it was 0.90 (95%CI 0.61-1.33; p = 0.687) for those treated with baricitinib. Conclusions Our results do not suggest a beneficial effect of TDF/FTC; nevertheless, they are compatible with the beneficial effect of baricitinib already established by other clinical trials.

Heterogeneity and Risk-of-Biases are No Longer the Issues to Conclude the Effectiveness of Baricitinib in Reducing COVID-19 Related Mortality: A Systematic Review and Meta-Analysis of Eight Randomised Controlled Trials

“…The corresponding author replied yes, they did the blinding strategy to assess the outcome of the work. The similar email was sent to PANCOVID/Montejano [22] but no reply received.…”

“…Furthermore, RECOVERY study contributed the greatest number of participants plus events and the weightage of the study was 90.7% with the remaining weightage of just 8.3% is shared by another 2 small studies in figure 1C. Besides, based on table 1, karampitsakos [21] and PANCOVID/Montejano [22] produced different outcomes where the former mentioned baricitinib statistically reduced mortality while the latter mentioned the opposite. Based on the MA of these 2 studies, baricitinib statistically did not reduce mortality (data not shown) in COVID-19 patients where the RR = 0.76 [95% CI: 0.55 to 1.05; p = 0.1; I 2 = 0%; p = 0.35].…”

Drug Repurposing and Observational Studies: The Case of Antivirals for the Treatment of COVID-19

“…There were 3 randomized trials of TDF–FTC, but none were phase 3 randomized trials for COVID-19 treatment in nonhospitalized patients. A trial in hospitalized patients, funded by Spain's Instituto de Salud Carlos III, found no clinical benefit of TDF–FTC ( 34 ), as expected for antivirals. A phase 2 trial in 60 persons with mild COVID-19, funded by Caen University Hospital in France, found reduced nasopharyngeal shedding of SARS-CoV-2 in the TDF–FTC group ( 35 ).…”

No association between use of tenofovir disoproxil fumarate, etravirine, or integrase-strand transfer inhibitors and acquisition or severe outcomes of SARS-CoV-2 infection in people with HIV in the Netherlands

“…Since the start of the COVID-19 pandemic, several studies have tried to determine factors associated with acquisition of and clinical outcome of SARS-CoV-2 infection in people with HIV (PWH). Recent observational studies have suggested a protective effect of tenofovir disoproxil fumarate (TDF) against acquisition of SARS-CoV-2 [1,2] and severe COVID-19 outcomes [1,3,4], whereas other studies found no benefit of TDF or tenofovir alafenamide (TAF) in PWH [5,6] or adults without HIV [7,8].…”

“…A study in Lesotho estimated that 94% of treatment-experienced persons with viral loads 80-999 copies/ml harbored drugresistant mutations [6]. Likewise, persistent low-level viremia (50-999 copies/ml over >6 months) has been linked to residual inflammation and subsequent virologic failure [7][8][9]. These findings, coupled with rising levels of HIV-1 drug resistance across Africa, have prompted calls to redefine VLS using lower cutpoints [10,11].…”