Different from recombinant and mRNA vaccines that manipulate the body’s immune response to a virus and its genetics, antiviral drugs attempt to boost the immune defense to inhibit viral development. They block receptors so viruses cannot bind to and enter healthy cells and they lower the amount of active virus in the body. Antivirals may be broad-spectrum and treat a variety of viruses while others target a specific viral protein to disable the virus and remain nontoxic to the host cells. Thus, most antivirals are considered relatively harmless to the host, and thus can be used aggressively (large dosages) to treat infections (e.g., acyclovir). Among the antiviral drugs being used since the COVID-19 pandemic, some have proven to be effective in certain forms and variants and have been given FDA emergency or full-use authorization. Other drugs, FDA-approved for uses other than antiviral therapy have been promoted as having antiviral qualities based on anecdotal evidence. Hydroxychloroquine (Plaquenil), a biologic used for malaria and lupus, combined with azithromycin (Zithromax), and Ivermectin, an FDA-approved drug to treat certain forms of parasitic worms, are 2 of the drugs questionable or wholly ineffective in the treatment of coronaviruses and having even shown adverse effects.
Paxlovid (nirmatrelvir/ritonavir) is a protease inhibitor, similar to those used against HIV. SARS-CoV-2 uses its cellular enzymes (protease) to replicate its RNA-containing “polyproteins” (see Life
Cycle, Blog #35). By blocking the enzyme’s activity, the drug prevents the production of new, functional viral particles. Paxlovid is quickly broken down in the body, so it needs a booster in the form of a second drug called ritonavir (also a protease inhibitor) to keep it active for a longer period in the host. Notwithstanding potential drug-drug interactions, these drugs have shown significant promise with a 90% reduction in hospitalization rates.
Molnupiravir (Merck/Ridgeback Biotherapeutics) is known as a nucleoside analog that mimics one of the RNA proteins that make up SARS-CoV-2. Once inside cells, the virus uses a polymerase enzyme to attach to its RNA and assemble them into new copies of viral RNA. The virus needs a template for the construction of new viral RNA and molnupiravir interrupts this template and causes the virus to continuously mutate until it virtually destroys itself with defective genetic material. Due to some side effects from the drug, it is used only in high-risk patients with advanced disease.
Remdesivir is antiviral drug thought to interfere with the mechanism that coronavirus uses to make copies of itself (see Fig. 7.1 and Life Cycle). A preliminary report published in The New England Journal of Medicine showed that the drug shortened recovery time for people with COVID-19 from an average of 15 days to about 11 days. The drug also seems to show increased benefits when used in combination therapies (e.g., with Baricitinib and monoclonal antibodies). It is recommended for use in hospitalized patients who require supplemental oxygen.
Other developing antiviral drugs for COVID-19 will continue to be developed as adjunctive therapies to vaccines and any other evolving immunotherapeutic measures to COVID-19. No doubt by the time you are reading this, beyond all of the drugs and treatment modalities listed below and mentioned in this section, there will be an array of new therapeutic measures being implemented for patient treatments and hopefully, for prevention.
Interferons: antiviral cytokines under investigation;
Lopinavir/Ritonavir and other HIV protease inhibitors;
Nitazoxanide: antiparasitic drug under investigation;
Lopinavir/Ritonavir and other HIV protease inhibitors;
Fluvoxamine: an antidepressant pill as an anti-inflammatory;
Budesonide: an inhaled steroid used to prevent asthma symptoms.
Discussion Questions:
Paxlovid combined with nirmatrelvir/ritonavir has proven to be a highly effective antiviral therapy for SARS-CoV-2 infection. What is the clinical logic of the drug combination?
Recombinant and mRNA vaccines manipulate the body’s immune response to a virus and its genetics. What are the differences in antiviral drugs’ mechanism and their advantages?
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