Repurposing Hepatitis C Direct-Acting Antivirals Against COVID-19

To the Editor:

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intervening early in the disease course by antivirals delays progression and improves clinical outcomes.¹ The pandemic has led to the rapid repurposing of many clinically approved drugs for other diseases.

Direct-acting antivirals (DAAs) changed the entire landscape of hepatitis C (HCV) treatment.² There has been considerable interest with DAAs such as sofosbuvir, daclatasvir, and velpatasvir as new kids in COVID-19 therapeutics. DAAs interfere with replication by targeting specific nonstructural proteins of the HCV. Various nonstructural proteins such as 1–14 in SARS-CoV-2 participate in viral RNA replication and virion assembly and likewise, the nonstructural proteins of HCV. Multifunctional NS5A protein is a significant regulator of viral replication, assembly, and modulating host interferon-mediated antiviral response in the HCV life cycle. The various binding motifs in HCV NS5A involved in cell events, similarly, were found distributed, and functions were exerted by several nonstructural proteins of SARS-CoV-2 such as nsp3 with the zinc motif and nsp4,5 with lipid-binding activity.³ Daclatasvir, by binding to N terminus of nonstructural (NS5A) protein, inhibits viral replication and assembly, whereas NS5B is an RNA-dependent RNA polymerase (RdRp) critical for RNA synthesis in HCV replication. Besides, the existence of similarities between HCV NS5B and SARS-CoV-2 RNA polymerase nsp12 in the nucleotide uptake channel makes it susceptible to the antiviral drug sofosbuvir, an NS5B inhibitor.⁴ The cellular enzymes such as nucleoside diphosphate kinases (NDK-A and B), cathepsin A, and carboxylesterase 1 are required for activation of prodrug sofosbuvir expressed in both liver and respiratory tract cells. In addition, the intracellular concentrations and high stability of biologically active triphosphate metabolites of sofosbuvir may inhibit SARS-CoV-2 RdRp effectively. Recent in silco and in vitro studies have shown effective blocking of SARS-CoV-2 RdRp by sofosbuvir and velpatasvir.^5,6 A recent in vitro (albeit non–peer reviewed) study has shown the inhibition of SARS-CoV-2 virus particles by daclatasvir in Vero cells, hepatoma cell line, and type II pneumocytes. Besides, daclatasvir blocked the production of inflammatory cytokines IL-6 and TNF- α by targeting early events during SARS-CoV-2 replication, whereas sofosbuvir inhibited SARS-CoV-2 replication in more potently hepatoma cell lines than in respiratory cell lines.⁷

Anahita Sadeghi et al conducted a randomized, open-label multicentre trial with adult patients hospitalized with severe COVID-19.⁸ After adjustment for baseline characteristics, multivariate analysis using logistic regression indicated that the clinical recovery was significantly better with sofosbuvir/daclatasvir treatment. In addition, the meta-analysis with three smaller studies (n = 176, sofosbuvir/daclatasvir arm: 92, control arm: 84) showed significantly higher survival (5.4% versus 20.2%, P = 0.013) and twice faster time to clinical recovery (sub hazard ratio (Sub HR) = 2.0 [95% confidence interval {CI}: 1.33–3.08], p≤0.001) with the sofosbuvir/daclatasvir group (8, 9, 10, Table 1). The analysis also suggests a 70% lower risk of death (relative risk = 0.31, 95% CI: 0.12 to 0.78) with sofosbuvir/daclatasvir treatment than the control arm. Based on preliminary encouraging results, randomized studies with larger sample size is already underway. The widespread availability of affordable generic DAAs and ease of administration make an ideal candidate in COVID-19 therapeutics early in the therapeutic window.

Table 1.

Summary of the Studies with Sofosbuvir and Daclatasvir for COVID-19.

Author	Inclusion criteria	Treatment vs. control arm	Age (years, IQR)	Time to clinical recovery	Recovered	ICU admission	Mortality
Eslami G et al.9	Adults with positive SARS-CoV-2 PCR and/or CT chest with spo2<94%/RR>24/decreased level of consciousness N-62 Severe disease	Sofosbuvir–daclatasvir (35) vs. ribavirin (27) for 14 days Both arms received lopinavir/ritonavir & hydroxychloroquine	62 (47–69)v s. 60 (43–73)	6 days vs.11 days (P-<0.01)	94% vs.67% (P-0.01)	17% vs.48% (P-0.01)	5.7% vs.33% (P-0.01) RR (95%CI) 0.17 (0.04–0.73) vs. 5.8 (1.4–25) (P-0.02)
Abbaspour Kasgari H et al.10	Adults with positive SARS-CoV-2 PCR and/or CT chest with spo2>94%/RR < 24/symptom onset ≤8 days prior to admission N-48 Moderate disease	Sofosbuvir–daclatasvir and ribavirin (24) vs. hydroxychloroquine and lopinavir/ritonavir with or without ribavirin (24)	45 (38–69)v s. 60 (47.5–68.5)	6 days vs. 6 days	100% vs. 88% (P-0.23)	0 vs. 17% (P-0.10)	0 vs. 13% (P-0.23)
Sadeghi A et al.8	Adults with positive SARS-CoV-2 PCR with fever (≥37.8 °C) plus at least one of: respiratory rate >24/min, spo2 <94% or Pa02/Fi02 ratio <300 mghg N-66 Severe disease	Sofosbuvir–daclatasvir for 14 days (33)+ lopinavir/ritonavir vs. lopinavir/ritonavir (33)	58 vs. 62	6 days vs. 11 days (P-0.04)	Clinical improvement within 14 days 88% vs 67% (P = 0.076)	9% vs. 21% (P-0.30)	9% vs.15% (P-0.70)

CT, computed tomography scan; ICU, Intensive care unit; IQR, interquartile range; PCR, polymerase chain reaction; RR, relative risk; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; vs., versus.

CRediT authorship contribution statement

Pramod Kumar: Conceptualization, Writing - original draft. Anand Kulkarni: Writing - review & editing. Mithun Sharma: Writing - review & editing. Padaki N. Rao: Supervision.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

None.