In high-risk patients, this oral drug combination reduced hospitalization or death by almost 90%.

The oral antiviral nirmatrelvir inhibits a SARS-CoV-2 protease that is crucial for viral replication. It is given along with ritonavir, an HIV drug that boosts nirmatrelvir levels to a therapeutic range by inhibiting CYP3A4. Now, results of a manufacturer-sponsored trial that led the FDA to authorize nirmatrelvir/ritonavir (Paxlovid) have been published.

In this phase 2/3 clinical trial, 2246 nonhospitalized adults with COVID-19 and ≤5 days of symptoms were randomized to receive nirmatrelvir/ritonavir or placebo for 5 days. Participants had at least one risk factor for progression to severe COVID-19 and were not yet vaccinated for COVID-19. Among those treated within 5 days of symptom onset, hospitalization or death occurred in 0.77% (nirmatrelvir/ritonavir) and 6.31% (placebo) — a relative risk reduction of 88%. The most frequently reported adverse events were dysgeusia (5.6% [nirmatrelvir/ritonavir] vs. 0.3% [placebo]) and diarrhea (3.1% vs. 1.6%).

COMMENT

Within the past few months, multiple drugs have been authorized by the FDA to treat high-risk, nonhospitalized patients with mild to moderate COVID-19, including those with breakthrough infection after receiving the COVID-19 vaccine. Among these drugs, nirmatrelvir/ritonavir is the first choice according to the NIH COVID-19 treatment guidelines. The combination’s advantages include oral administration and activity against variants of concern, including the BA.1 and BA.2 lineages of Omicron. Its major limitation is interaction with medications metabolized by CYP3A4. This consequence can be managed in many — but not all — patients by temporarily stopping or reducing the dose of the interacting drug. Does nirmatrelvir/ritonavir also benefit patients who do not have a risk factor for progression to severe COVID-19 or who have received the vaccine? An ongoing study is examining this question.