Nirmatrelvir-ritonavir cuts disease progression, viral load in unvaccinated COVID-19 outpatients

In the phase II/III EPIC-HR* trial, the novel oral antiviral nirmatrelvir-ritonavir reduced the risk of progression of COVID-19 to severe disease, as well as viral load, in symptomatic, high-risk, unvaccinated nonhospitalized adults confirmed to have SARS-CoV-2 infection.

Despite their reported efficacy, monoclonal antibodies (mAbs) against COVID-19 require IV or SC administration in a healthcare setting, and may be less effective against emerging SARS-CoV-2 variants. [N Engl J Med 2021;385:1382-1392; N Engl J Med 2021;385:1941-1950; N Engl J Med 2021;385:e81; BMJ 2021;372:n158; Nat Rev Microbiol 2021;19:409-424]

“[As such, we need] safe and effective oral COVID-19 treatments that can prevent the progression of infection to more severe disease, hospitalization, and death; shorten time to clinical recovery; and reduce transmission rate … [to] help reduce current strains on healthcare systems,” said the researchers.

“[Our study showed that] nirmatrelvir-ritonavir resulted in a risk of progression to severe COVID-19 that was 89 percent lower than the risk with placebo,” they continued.

This was seen in the planned interim analysis of patients who received treatment within 3 days following symptom onset (n=774/1,361 patients in the full analysis set). By day 28, the incidence of COVID-19-related hospitalization or death was markedly lower with nirmatrelvir-ritonavir vs placebo (0.77 percent vs 7.01 percent; p<0.001). [N Engl J Med 2022;doi:10.1056/NEJMoa2118542]

A similar trend favouring nirmatrelvir-ritonavir over placebo was seen in the final analysis of patients who began treatment within 3 days after symptom onset and did not receive mAbs (n=1,379/2,246; 0.72 percent vs 6.45 percent; p<0.001), corresponding to an 89-percent relative reduction in the risk of the primary outcome.

Fewer nirmatrelvir-ritonavir vs placebo recipients were hospitalized for COVID-19 or died from any cause through day 28 in the analysis of participants who began treatment within 5 days after symptom onset (0.77 percent vs 6.31 percent) and when including those who received/were expected to receive mAb therapy (n=139; 0.81 percent vs 6.10 percent).

After adjusting for covariates**, viral load dropped at day 5 with nirmatrelvir-ritonavir, both when treatment was initiated within 3 and 5 days after symptom onset (by an adjusted mean of an additional 0.868 and 0.695 log₁₀ copies/mL, respectively; p<0.001 for both).

 

Safety

Most adverse events (AEs) tied to nirmatrelvir-ritonavir were grade 1/2 and resolved (or were resolving) at the time of the analysis. AEs deemed drug/placebo-related were more common with nirmatrelvir-ritonavir vs placebo (8 percent vs 4 percent), largely owing to dysgeusia (4.5 percent vs 0.2 percent) and diarrhoea (1.3 percent vs 0.2 percent).

Nonetheless, patients on nirmatrelvir-ritonavir had fewer grade 3/4 AEs (4 percent vs 8 percent), serious AEs (2 percent vs 7 percent), and AEs leading to drug discontinuation (2 percent vs 4 percent) than those on placebo.

The 13 deaths in the placebo arm were all COVID-19-related.

 

Considerations

EPIC-HR randomized 2,246 participants (median age 46 years, 51 percent male) 1:1 to receive nirmatrelvir 300 mg + ritonavir 100 mg or placebo Q12H for 5 days. Although the study was limited to unvaccinated individuals, another trial including vaccinated individuals – EPIC-SR (Standard-Risk), is underway.

The investigators raised the issue of drug interactions, as the concurrent use of nirmatrelvir-ritonavir and certain drugs run the risk of serious AEs. “[These should] be managed through dose reduction of the concomitant medication, use of an alternative concomitant medication, increased monitoring for AEs or concomitant medication levels, temporary discontinuation of concomitant medications, or avoidance of co-administration.”

Moreover, as the trial was performed during the latter half of 2021 (ie, when most infections were attributed to the Delta variant), “we do not yet know how nirmatrelvir-ritonavir will perform as new variants, such as Omicron, emerge,” noted Professors Eric Rubin from the Harvard School of Public Health, Boston, Massachusetts, US, and Lindsey Baden from the Harvard Medical School, Boston, Massachusetts, US, in a separate editorial. [N Engl J Med 2022;doi:10.1056/NEJMe2202160]

However, in vitro studies suggest that nirmatrelvir activity is preserved across all tested viral strains. [N Engl J Med 2022;386:995-998] “[While we have yet to see a] resistance to the new agent … it is likely that resistance to a single agent such as nirmatrelvir will become an issue,” they said.

“Given that likelihood, how can we best use this effective drug?” asked Rubin and Baden. “[EPIC-HR thus] provides some guidance – the absolute benefit will accrue primarily to patients at highest risk for disease progression, particularly those with multiple and serious co-existing conditions and those unable to mount sufficient immune responses.”

“[U]ntil we have a better idea of the potential for the emergence of resistance, we need to be good stewards of this medication. By limiting its use to those most likely to benefit, we can potentially prolong its useful life,” they added.