**11. Darunavir**

Darunavir, an anti-HIV drug, is recommended for COVID-19 treatment in Italy. It is used in a combined regimen along with cytochrome P-450 inhibitors such as ritonavir or cobicistat and confirmed their replication inhibitory effect against SARS-CoV-2. A clinical trial assessed the effectiveness of darunavir combination with other antivirals and hydroxychloroquine for COVID-19 patients. A combination of darunavir and cobicistat is also being tested [93]. PREZCOBIX®, a fixed-dose combination of darunavir and cobicistat, is also used to treat COVID-19. COVID-19 infection was recently discovered in HIV-positive individuals who were already taking darunavir, raising questions about the effectiveness of this HIV protease inhibitor. The darunavir might not be effective in preventing SARS-CoV-2 infection at the dosage of 800 mg [94]. Darunavir is a second generation of HIV-1 protease inhibitors used to prevent SARS-CoV-2 infection in vitro [17] by inhibiting viral replication at 300 μM, and this inhibition efficiency was 280-fold compared with the untreated groups. Darunavir boosted with ritonavir or cobicistat is used in HIV/AIDS treatment. The efficacy of darunavir or ritonavir is enhanced by cytochrome p450 (CYP3A) inhibition [95]. Cell experiments with darunavir showed that the drug inhibited viral replication of COVID-19 in vitro. The lopinavir/ritonavir used in the treatment of HIV/AIDS has more efficacy and tolerability than darunavir, its use in COVID-19 is limited.

### **11.1 Oseltamivir**

Oseltamivir (Tamiflu) is an antiviral agent that is used for patients with influenza A and B. It is a protease inhibitor, which specifically inhibits the neuraminidase enzyme in the influenza virus. This enzyme has a key role in the binding of the influenza virus to the cell membrane and spread throughout the body. Therefore, Oseltamivir, by targeting neuraminidase, prevents the spread of the influenza virus and its progression inside the body [96]. This drug was used in the treatment of COVID-19 infection, which showed an appropriate effect on patients [41]. Oseltamivir has been applied in concomitant regimens with other drugs such as Hydroxychloroquine or Favipiravirs [97]. In addition to treating influenza A and B patients, this drug may also be used in severe cases. For the treatment of flu patients, Tamiflu is prescribed in a 75 mg dosage twice a day and once a day as prophylaxis. The main side effects of this drug can be nausea and headache [98]. Neuraminidase inhibitors seem beneficial for COVID-19 patients and can reduce their ventilator requirements [99]. The precise mechanism of action of Oseltamivir against COVID-19 infection is still unclear. Oseltamivir is a synthetic derivative prodrug of ethyl ester [100]. It acts as a neuraminidase inhibitor against the influenza virus and is also effective for various avian influenza virus strains [101]. An in vitro oseltamivir study on H5N1 influenza showed that the IC50 was 0.1–4.9 nM [102]. In vivo study involving H5N1 infection required a longer course and higher dosage of Oseltamivir. The COVID-19 originated in China during flu season, and hence earlier, many patients received oseltamivir treatment until the causative agent SARSCoV-2 was discovered. Some current clinical trials have used oseltamivir in combination with other major therapeutic drugs [31, 41].

### **11.2 Sofosbuvir**

Sofosbuvir is an antiviral drug and RdRp inhibitor that exerts its effect by suppressing RdRp enzyme activity. A combination of Sofosbuvir with Ledipasvir is used for treating patients with genotype 1 of HCV67. Because of the similarity in the transcription and replication mechanism of the SARS-CoV-2 with HCV in host cells, physicians speculate that this drug may help treat COVID-19 patients [103]. This drug disrupts the activity of RdRp by acting like free nucleotides that are essential for viral mRNA synthesis [104]. Sofosbuvir is a potential option for COVID-19 treatment [105], and extensive clinical studies should be performed to verify the effectiveness of this drug.
