1.2 Ribavirin
SARS-CoV-2, a single-stranded RNA beta coronavirus, reproduces itself by utilizing enzymes such as 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase. The potential therapy against SARS-CoV-2 may target to its virus structure. For instance, a study reported that nucleoside analogs are effective against HIV and respiratory viruses by targeting the viral RNA polymerase (Li & De Clercq, 2020). Owing to the similarity of structure between SARS-CoV-2 and HIV or respiratory virus, nucleoside analogues may have a therapeutic role by blocking RNA synthesis in SARS-CoV-2. Ribavirin, a guanine analog, showed activity against other coronaviruses, showing itself as a suitable candidate for COVID-19 treatment. A clinical study on SARS revealed that 126 SARS-CoV patients on ribavirin treatment, presented with hemolysis and anemia in up to 76% and 49% of the cases, respectively (Booth et al., 2003; Tan et al., 2004). And in vivostudy demonstrated that the serum concentrations of ribavirin, inhibited viral replication effectively, surpassed the safe human concentration (Tan et al., 2004). In vitro data suggests that ribavirin monotherapy confers rapid resistance for SARS and MERS, whereas the combination therapy with Lopinavir/ritonavir or chloroquine analogs showed potential activity (”[Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia],” 2020; Falzarano et al., 2013).
The therapeutic regimen of ribavirin is 500 mg twice/thrice in a day combined with Lopinavir/ritonavir or IFN-α, based on the Treatment Plan Revised Edition 5 from China (” Treatment Plan Edition 5 revision edition,” 2020). Although this information may be updated as new evidence becomes available, previous experience in SARS and MERS can provide an appropriate direction for enhancing the efficacy of ribavirin. An in vitro study demonstrated antiviral activity against the WIV04 strain of SARS-CoV (M. Wang et al., 2020). There is no sufficient data on clinical trials for ribavirin, thus its efficacy may be speculated from the experience against MERS and SARS.
The most commonest adverse effect of ribavirin is hemolytic anemia, which occurred in up to 61% of the patients in a study assessing its adverse effects in the treatment of SARS (Knowles, Phillips, Dresser, & Matukas, 2003). Hemolytic anemia occurs within 3-5 days after high loading doses (> 1-2 g) against coronavirus infection (C. H. Chang, Chen, Lai, & Chan, 2002; Chu et al., 2004). Ribavirin is eliminated primarily through renal excretion; it is important to effect strict dose reductions that vary based on the indication, for patients with renal insufficiency. Ribavirin has teratogenic potential and is contraindicated in pregnancy and male partners of pregnancy (Altınbas, Holmes, & Altınbas, 2020).
The evidence from the treatment of ribavirin against other coronaviruses suggests limited efficacy and potential toxicity, which indicates that its therapy in patients with COVID-19 should be considered as combination therapy for enhancing the clinical efficacy.