Are nucleotide inhibitors, already used for treating hepatitis C virus infection, a potential option for the treatment of COVID-19 compared with standard of care? A literature review

Table 1 Current ongoing treatment for coronavirus disease 2019

	Rationale of use	Notes
Steroids	Prevent and treat acute lung injury and respiratory distress due to host inflammatory response secondary to SARS-CoV-2 infection	May determine Hyper-glicemia, arterial hypertension
Anticoagulation therapy	Prevent and/or treat the over-activation of the coagulation cascade, responsible for ischaemic events and disseminated intravascular coagulation	May determines Hemorrhagic risk
Antiviral agents	Protease inhibitors (lopinavir), nucleotide analogue (remdesivir)	May determine Drug/drug interactions, allergic reactions, acquired resistance
Chloroquine/hydroxychloroquine	Increasing in endosomal pH, avoiding the fusion between the virus and the host cell, but also the interference with the ACE2 cell receptor targeted by the virus. immunomodulatory activity	May determine common side effects (nausea, vomiting, diarrhea, abdominal pain, extrapyramidal disorders), and arrhythmogenic cardiotoxicity (thus monitor QT interval)
Oxygen therapy	Treatment of hypoxia basically administered through a nasal cannula, face mask or noninvasive CPAP. If an adequate arterial O2 level is not reached (SatO2 < 93%), invasive mechanical ventilation via intubation is necessary. Advanced technique such as prone positioning should be considered as well as extracorporeal membrane oxygenation
Antinflammatory molecules – multiple monoclonal antibodies/immunostimulants (anti IL-17, interferon and mesenchymal stromal cells)	Able to reduce inflammation and stimulate regeneration of tissues as well, the amplification of anti-2019nCoV specific T lymphocytes, the employment of anti-Th1-mediated inflammatory cascade such as canakinumab (anti IL-1B) and roflumilast (inhibitor of enzyme phosphodiesterase-4 already used to control neutrophilic inflammation in patients with COPD)
Sartanics (angiotensin receptor 1 blockers)	Could be considered for their ability to inhibit the link between the spike S protein of the virus and ACE2	According to other studies could predispose to COVID targeting ACE receptors on pulmonary tissue
Some broad spectrum antiviral agents (dsRNA-activated caspase oligomerizer)	Cause selective apoptosis of host cells containing virus, this skill could be exploited in fighting COVID-19
Bradykinin receptors B1 and B2 antagonists	COVID related bradykinin-dependent local lung angioedema
Plasma	Passive immunotherapy

COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin receptor 2; RNA: Ribonucleic acid.

Table 2 Primary and secondary outcomes of studies included in simmons’ meta-analysis

			Intervention arm (92 patients)	Control arm (84 patients)
Outcomes	Primary	Clinical recovery in 14 d	86 (93%)	57 (68%)
		All cause mortality	5 (5%)	17 (20%)
	Secondary	Duration of hospitalization	6 (IQR: 5-7)	8 (IQR: 6-11)
		ICU admission/imv needed	9 (10%)	24 (29%)

ICU: Intensive care unit.

Table 3 Therapeutic schedule of clinical trials considered in meta-analysis

	Disease stage	Treatment arm	Control arm	Duration
Eslami	Severe	35 patients: SOC (lopinavir/ritonavir + hydroxychloroquine) + Sof/dac started 24-48 h later (after PCR and TC confirmation of COVID-19)	27 patients: SOC (lopinavir/ritonavir + hydroxychloroquine) + ribavirin	14 d
Kasgari	Moderate	24 patients: Sof/dac + ribavirin	24 patients: Lopinavir/ritonavir + hydroxychloroquine ± Ribavirin	6 d?
Sadeghi	severe	33 patients: Sof/dac + lopinavir/ritonavir	33 patients: Lopinavir/ritonavir	14 d

SOC: Standard of care; COVID-19: Coronavirus disease 2019.