Question 2. should antiviral agents be administered?
Several antiviral agents have demonstrated in vitro activity against SARS-CoV-2 or other coronaviruses, but currently there are no approved antiviral agents for coronavirus-related diseases, and there are still no favourable efficacy results from RCT available at the present time. Lopinavir is a protease inhibitor used for the treatment of HIV patients, administered in combination with ritonavir to improve its serum half-life. On the basis of its activity against SARS-CoV-1 and/or Middle East respiratory syndrome (MERS)-CoV observed in in vitro and animal studies [[19], [20], [21]], lopinavir/ritonavir (LPV/RTV) was compared to supportive care alone for the treatment of COVID-19 patients in an open-label RCT in China [22]. The primary time-to-event endpoint was clinical improvement from randomization (defined as a composite of discharge from the hospital or improvement of two points on a seven-category ordinal scale, ranging from no need of hospitalization to death). Overall, 199 patients were enrolled (99 and 100 in the LPV/RTV and supportive care arms, respectively). No differences were observed in the intent-to-treat population with regard to clinical improvement (hazard ratio 1.24 with standard of care as reference, 95% confidence interval (CI) 0.90 to 1.72). In addition, no associations were observed with regard to 28-day mortality, although a smaller number of deaths were registered in the LPV/RTV arm (19.2% vs. 25.0% in investigational and comparator arms, respectively; percentage difference −5.8%, 95% CI −17.3 to 5.7). Although some important considerations preclude a definite judgement on the possible efficacy of LPV/RTV (e.g. some major limitations are the open-label nature of the trial and the fact that LPV/RTV was initiated late with respect to the onset of symptoms; see question 7), especially in the case of early therapy initiation, the results of this RCT provide evidence currently discouraging the use of LPV/RTV (or of other protease inhibitors such as darunavir) in COVID-19 patients (also considering the potential side effects; Table 3 ), unless favourable results from other ongoing RCT in specific subgroups of patients are available (Table 2). Furthermore, harmful drug interactions of antivirals with other drugs (such as hydroxychloroquine) cannot be excluded a priori because there are currently no large clinical data about the use of these combinations.
Table 3 Known adverse events of marketed anti-infective and anti-inflammatory drugs mostly provided as off-label treatments in the first phase of the COVID-19 pandemic
Drug Adverse events
Lopinavir/ritonavir • Hypercholesterolaemia and increased serum triglycerides (3–39%)
• Increased γ-glutamyl transferase (10–29%)
• Diarrhoea (7–28%; greater with once-daily dosing)
• Increased serum ALT (grade 3/4: 1–11%)
• Nausea (5–16%)
• Upper respiratory tract infection (14%)
• Abdominal pain (1–11%)
• Vomiting (2–7%)
• Fatigue (8%)
• Increased serum amylase and/or lipase (3–8%)
• Headache (2–6%)
• Skin rash (≤5%)
• Neutropenia (grade 3/4: 1–5%)
• Anxiety (4%)
• Insomnia (≤4%)
Chloroquine/hydroxychloroquine • Retinopathy (4% of treated patients)a
• Other adverse effects with unknown frequency included Stevens-Johnson syndrome, abdominal pain, diarrhoea, nausea, vomiting, agranulocytosis, leukopenia, thrombocytopenia, abnormal hepatic function tests, acute hepatic ailure, myopathy, bronchospasm
• Risk of prolonged QT interval, further increased when administered with fluoroquinolones or azithromycin
Tocilizumab • Increased serum ALT (≤36%) and AST (≤22%)
• Increased LDL cholesterol (9–10%)
• Injection site reaction (4–10%)
• Neutropenia (grade 3: 2–7% of all adult patients)
• Headache (1–7%)
• Hypertension (1–6%)
• Dizziness (3%)
• Hypothyroidism (<2%)
• Abdominal pain (2%)
• Oral mucosa or gastric ulcers (2%)
• Infections due to Pneumocystis, Mycobacterium tuberculosis and varicella zoster have been reported after tocilizumab, but their prevalence has not been clearly established
Anakinra • Injection site reactionb (24–71%)
• Antibody development (up to 50% of the patients but no correlation of antibody development and adverse effects)
• Headache and vomiting (12–14%)
• Arthralgia (10–12%)
• Fever (10–12%)
• Haematologic disorder including eosinophilia, leukopenia and change in platelet count (2–9%)
• Nausea and diarrhoea (7–8%)
• Serious infectionc (2–3%)
Off-label drugs mostly provided in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; LDL, low-density lipoprotein.
a Serum concentration dependent adverse effect; early changes are generally reversible but may progress despite discontinuation if advanced.
b Injection site reactions were considered serious in 2–3% of cases.
c Serious infections included cellulitis, pneumonia, and bone and joint infections.
Remdesivir is an investigational nucleotide analogue undergoing clinical development for Ebola and showing in vitro activity against coronaviruses (SARS-CoV-2, SARS-CoV-1 and MERS-CoV) and favourable effects in animal MERS models [[23], [24], [25], [26]]. Following these promising preclinical findings, RCT in COVID-19 patients have been initiated (Table 2). However, pending their results, and considering the investigational nature of the drug, access to remdesivir outside RCT is currently provided only within strictly regulated and limited compassionate-use/expanded-access frameworks.
Oseltamivir and zanamivir are neuraminidase inhibitors used for treating influenza which are also being tested in RCT for treating COVID-19 patients (Table 2). However, no apparent activity of oseltamivir and zanamivir has previously been observed against SARS-CoV-1 in vitro [27], and the fact that up to 76% of the first critically ill patients with COVID-19 received oseltamivir may also be related to the suspicion of infection (or coinfection) with influenza [28]. Overall, this information is currently insufficient for supporting the use of these agents in COVID-19 patients unless in the presence of suspected/proven concomitant influenza.
Other antiviral agents currently being investigated in RCT for the treatment of COVID-19 patients are favipiravir, an RNA-dependent RNA polymerase inhibitor with anti-influenza activity, and umifenovir, and anti-influenza membrane fusion inhibitor [29]. Even though these two agents attracted important media attention in the last few months, and even though there were some favourable preliminary results, especially for favipiravir, released as preprints, we advocate caution in using these agents outside investigational studies until completion of the standard peer-review processes of the first released trials. For example, in a recent RCT comparing 120 COVID-19 patients treated with favipiravir versus 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir, but it is of note that the all-cause mortality was 0 in the entire study population, making it uncertain whether, if confirmed, these favourable results may be extrapolated to relevant survival endpoints in critically ill COVID-19 patients [30]. Finally, antiviral activity against SARS-CoV-2 in vitro has been recently reported for ivermectin, but clinical data are still lacking [31].

Question 2 statement
At the present time, evidence from the first published RCT does not support off-label treatment with LPV/RTV in COVID-19 patients. This result should also discourage the use of other protease inhibitors (e.g. darunavir), at least until results of dedicated RCT are available. Although promising in preclinical studies, remdesivir should be currently provided for treating COVID-19 patients only within RCT (preferentially) or compassionate-use/expanded-access programmes, owing to its investigational nature. Pending high-level supporting evidence, favipiravir and umifenovir should not be provided outside RCT, at least in those countries where they are not approved for other indications. Oseltamivir or zanamivir should be provided only in the presence of suspected/proven concomitant influenza.