The COVID-19 Textbook

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CHAPTER 15 • Treatment of COVID-19 in Adults

and remdesivir and molnupiravir (targeting RNA-dependent polymerase) have maintained activity against newer variants, likely because their target proteins evolve less rapidly than spike. The Omi cron subvariants in circulation in early 2023 are predicted to be resistant to previously authorized prophylactic or therapeutic anti-SARS-CoV-2 monoclonal antibodies targeting the spike protein, but the small-molecule antivirals are expected to still be active against these subvariants. Ritonavir-Boosted Nirmatrelvir Nirmatrelvir is an inhibitor of the SARS-CoV-2 main protease enzyme. Nirmatrelvir is coadmin istered with ritonavir, a potent inhibitor of CYP3A metabolism, to achieve adequate drug levels of nirmatrelvir. Nirmatrelvir/ritonavir was authorized by the U.S. FDA based on the results of the EPIC-HR trial that randomized high-risk unvaccinated outpatients who were within 5 days of symptom onset to receive the drug or placebo for 5 days. Hospitalization or death (the primary outcome) occurred in 0.8% (8 participants out of 1,039; 0 deaths) in the treatment arm and 6.3% (66 participants out of 1,046; 12 deaths) in the placebo arm. 16 The treatment group also had a faster drop in upper respiratory SARS-CoV-2 levels. One important limitation of nirmatrelvir/ritonavir is the potential for drug-drug interactions with medications that are metabolized by CYP3A. There are several medications that should not be taken with nirmatrelvir/ritonavir, whereas other medications may require dose adjustments or may be held during the short treatment course. There are several resources for identifying drug-drug interactions, including a website maintained by the University of Liverpool (https://www.covid19-­ druginteractions.org). Some people who receive nirmatrelvir/ritonavir experience a rebound in symptoms after complet ing the treatment course, occasionally accompanied by an increase in upper respiratory SARS-CoV-2 levels. Rebound symptoms are typically mild and resolve without additional therapy. Nirmatrelvir resistance has not been detected in people who have rebound. Of note, rebound of symptoms and in creases in SARS-CoV-2 levels have also been reported in people who have not received nirmatrelvir/ ritonavir or any other antiviral therapy, suggesting it may be part of the natural history of SARS CoV-2 infection. Whether rebound is more common in people who receive nirmatrelvir/ritonavir is uncertain and an important research question and knowledge gap. Longer courses of nirmatrelvir/ ritonavir are being evaluated to determine whether extending the treatment duration reduces the likelihood of rebound. Remdesivir for Mild-to-Moderate COVID-19 Remdesivir is an antiviral medication that inhibits the viral RNA polymerase. It is a prodrug of a nucleoside analog. Addition of the active molecule to the growing RNA strand by the SARS-CoV-2 RNA polymerase causes premature chain termination. Remdesivir was initially developed for the treatment of hepatitis C virus and was found to be a broadly active antiviral. It was evaluated for hospitalized individuals in the beginning of the COVID-19 pandemic and became the first FDA-approved medication for the treatment of COVID-19. 19 Remdesivir is the only antiviral tested so far that has shown benefit for hospitalized patients with severe COVID-19. Subsequently, it was evaluated in a randomized trial in nonhospitalized patients who were unvaccinated, at high risk for severe COVID-19, and within 7 days of symptom onset; in this population, remdesivir reduced hospitalizations by 87% compared to placebo. 17 Molnupiravir Molnupiravir is an oral ribonucleotide prodrug that is converted into β -d-N4-hydroxycytidine (NHC). NHC, in turn, incorporates into viral RNA and inhibits SARS-CoV-2 replication by induc ing RNA mutagenesis—a mechanism sometimes termed “error catastrophe.” In the MOVe-OUT randomized clinical trial, conducted in high-risk unvaccinated nonhospitalized adults with mild or moderate COVID-19 and within 5 days of symptom onset, the molnupiravir group had a 30% lower rate of hospitalizations and deaths than the placebo group. Molnupiravir was authorized by the FDA for high-risk individuals but only as an alternative if other more efficacious therapies cannot be used or accessed. 15 There is a concern for increased risk of mutagenesis with molnupiravir based on preclinical studies, and it is not recommended during pregnancy or for children. Moreover, some

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