In December, 2019, an outbreak of pneumonia with unknown cause occurred in Wuhan city, the
capital of Hubei province in China. On January 7th, the scientists succeeded to isolate a
novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). WHO
nominated it as coronavirus disease 2019 (COVID-19) in February, 2020.

COVID 19 which started from a zoonotic transmission related to crowded markets was confirmed
to have a high potential for transmission to close contacts on 20 January 2020 by the
National Health Commission of China and it was announced as a pandemic by the WHO on 11 March
2020.

SARS-CoV-2 infection have a wide clinical spectrum ranging between asymptomatic infection,
mild upper respiratory tract symptoms, and severe viral pneumonia (fever, malaise, dry cough,
shortness of breath, and respiratory distress) that may result in respiratory failure and
finally death.

There is currently no clinically proven specific antiviral agent available for SARS-CoV-2
infection. Supportive treatment, including oxygen therapy, conservation fluid management, and
broad-spectrum antibiotics to cover secondary bacterial infection, remains the most important
management strategy.

For direct antiviral treatment of SARS-CoV-2, the China International Exchange and Promotive
Association for Medical and Health Care (CPAM) recommended usage of lopinavir; ritonavir.
Their recommendation was based on weak evidence from retrospective cohort, historically
controlled studies, case reports, and case series reporting a clinical benefit of lopinavir;
ritonavir in the management of other coronavirus infection [i.e., SARS-CoV 1 and Middle East
respiratory syndrome coronavirus (MERS-CoV)] .

However, the first randomized clinical trial with lopinavir/ritonavir demonstrated no benefit
over standard care in 199 hospitalized adults with severe COVID-19. There is no evidence to
support the use of other antiretrovirals, including protease inhibitors; indeed, structural
analysis demonstrates no darunavir binding to COVID-19 protease.

A group of Korean physicians experienced in SARS-CoV-2 infected patients' treatment developed
recommendations for the treatment of COVID-19. According to them, antiviral medications
lopinavir 400 mg; ritonavir 100 mg or chloroquine is considered to be used in older patients
or patients with chronic health conditions and life threatening symptoms. If chloroquine is
unavailable, hydroxychloroquine is recommended. Both of them have reported ability of
inhibition of SARS-CoV-2 in vitro.

CPAM guidelines included them as they were associated with reduced progression of disease and
decreased duration of symptoms. In an open-label study of 36 patients with COVID-19, use of
hydroxychloroquine (200 mg three times per day for 10 days) was associated with a higher rate
of undetectable SARS-CoV-2 RNA on nasopharyngeal specimens at day 6 compared with no specific
treatment (70 versus 12.5 percent). In this study, the use of azithromycin in combination
with hydroxychloroquine appeared to have additional benefit, but there are methodologic
concerns about the control groups for the study, and the biologic basis for using
azithromycin in this setting is unclear. In the United States, the FDA issued an emergency
use authorization to allow the use of these agents in adolescents or adults hospitalized for
COVID-19.

One of the studies done on SARS-COV-1 strongly suggested that using ribavirin as therapy
should be reconsidered until further animal studies clarify the effects of ribavirin on
cytokine and chemokine profiles during an infection and until ribavirin can be demonstrated
to have a significant effect on reducing viral replication in vivo. Data from a molecular
docking experiment using the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) model identified
tight binding of sofosbuvir and ribavirin to the coronavirus RdRp, thereby suggesting
possible efficacy of sofosbuvir and ribavirin in treating the COVID-19 infection.

Chen et al. prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like
protease (3CL ) then performed virtual screening for purchasable drugs checking the actions,
targets and side effects of the 16 candidates. Among these, we first noticed velpatasvir and
ledipasvir, which are inhibitors of the NS5A protein of the hepatitis C virus (HCV). Both are
marketed as approved drugs in combination with sofosbuvir, which is a prodrug nucleotide
analogue inhibitor of RNA-dependent RNA polymerase (RdRp, or NS5B).

Interestingly, sofosbuvir has recently been proposed as an antiviral for the SARS-CoV-2 based
on the similarity between the replication mechanisms of the HCV and the coronaviruses.

Based on this data the investigators suggest that these dual-component HCV drugs, Epclusa
(velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir), may be attractive candidates to
repurpose because they may inhibit two coronaviral enzymes. A drug that can target two viral
proteins substantially reduces the ability of the virus to develop resistance. These
direct-acting antiviral drugs are also associated with very minimal side effects and are
conveniently orally administered.

Aim of the study is to assess the safety and efficacy of the addition of HCV treatment to the
standard regimen for the treatment of patients who are candidates to receive Hydroxy
Chloroquine according to MOHP protocol.