Nirmatrelvir-ritonavir benefits persist against COVID

Management of most adults with COVID-19, particularly those with mild-to-moderate disease, is increasingly occurring in the outpatient setting due to the availability of effective treatment options. 

However, many high-risk patients hospitalized for COVID-19 still do not receive outpatient treatment for COVID-19 prior to admission, putting them at greater risk for severe disease, said Dr Florin Draica, senior medical director, Headquarters Team Lead Paxlovid, Pfizer US, at IDWeek 2023.

“In our study, for example, 40,463 (94.2 percent) high-risk patients did not receive outpatient treatment for COVID-19 within a month prior to their hospitalization. Of this number, 6,886 (17 percent) died within a month,” he said. “The most common high-risk conditions at admission were hypertension (88.2 percent), advanced age (≥65; 86 percent), and heart conditions (78.4 percent).” [IDWeek 2023, abstract 522]

The burden of COVID-19 hospitalization and death remains significant, particularly in patients with high-risk underlying conditions. “If only these patients received outpatient therapeutics, many lives could have been saved and hospitalizations may have been avoided,” said Draica.

First oral antiviral pill for COVID

Nirmatrelvir-ritonavir is US FDA-approved for treating mild-to-moderate COVID-19 in adults who are at high risk of developing severe disease. In the EPIC-HR study, treatment with nirmatrelvir-ritonavir within 5 days of symptom onset reduced the risk of hospitalization or death by 89 percent compared with placebo in symptomatic, unvaccinated, nonhospitalized patients at risk of progression to severe COVID-19. [N Engl J Med 2022;386:1397-1408]

Nirmatrelvir-ritonavir is also authorized for emergency use to treat mild-to-moderate COVID-19 in certain eligible paediatric patients.

Benefits regardless of age, vaccination status

A recent review of real-world studies presented at IDWeek 2023 showed that nirmatrelvir-ritonavir effectively protects against hospitalization and death during the Omicron era regardless of age, vaccination status, and underlying high-risk conditions. [Abstract 516]

Of 66 studies comprising 421,588 patients treated with nirmatrelvir-ritonavir, 14 reported effectiveness for at least one outcome and were included in the systematic literature review. Of the number, 8 studies reported predominance of Omicron, 6 of its sublineage BA.1/BA.2 and BA.4/BA.5). One study evaluated nirmatrelvir-ritonavir efficacy within 5 days of COVID-19 symptom onset.

Eight studies reported a risk reduction of 21–89 percent in all-cause hospitalization with nirmatrelvir-ritonavir, said Ms Ashley Cha-Silva, director, Pfizer, Connecticut, US. “Looking at COVID-19 related hospitalization (3 studies), all favoured the oral antiviral, with an efficacy of 24–60 percent regardless of age, vaccination, or high-risk conditions.”

All-cause mortality was also lower with nirmatrelvir-ritonavir treatment vs no treatment, with an efficacy of 39–85 percent (5 studies). Looking at the composite endpoint of hospitalization and death (7 studies), the efficacy was from 1–92 percent.

“This suggests the real-world effectiveness of nirmatrelvir-ritonavir against hospitalization and death,” said Cha-Silva.

PCC incidence lower in older adults

Treatment with nirmatrelvir-ritonavir also reduced the incidence of post-COVID conditions (PCCs) or long COVID in nonhospitalized older adults at risk for severe COVID-19 in a case-control study. [IDWeek 2023, abstract 1937]

Among adults ≥50 years, those who did vs did not receive nirmatrelvir-ritonavir within 5 days of the index date had a lower risk of PCCs (≥1 condition: relative risk [RR], 0.91; ≥2 conditions: RR, 0.86). [IDWeek 2023, abstract 1937]

“PCCs were defined as new-onset conditions that occurred >60 days after the index date and prior to December 31, 2022,” said study author Dr Alexandra Dalton from the Centers for Disease Control and Prevention in Raleigh, North Carolina, US. PCC occurrence was assessed for adolescents (12–17 years), young adults (181–49 years), and older adults (≥50 years).

Among young adults and adolescents, associations were observed only for certain conditions. Dalton said they are unsure about the reason for this, but it may have to do with the prescribing behaviour around nirmatrelvir-ritonavir, which she said could be their next area of interest.

COVID-19 rebound

Regardless of treatment, COVID-19 rebound has been reported, said Dr Mary Lyn Baniecki, Head of Infectious Disease for Translational Medicine, Pfizer, Cambridge, Massachusetts, US. “So, we did an integrated analysis of EPIC High-Risk and Standard Risk clinical trials. Virology data were conducted to evaluate resistance to nirmatrelvir-ritonavir and if it is associated with viral RNA load rebound (VLR) or progression to severe COVID-19.”

In vitro resistance substitution emerged in a few patients but was not associated with severe COVID. Of the 3 patients with E166V mutation, one experienced VLR on Day 10, but was effectively controlled on Day 14 and did not progress to severe COVID-19. [IDWeek 2023, abstract 361]

None of the treatment-emergent substitutions (TES) was associated with progression to severe disease. “VLR is not a result of treatment resistance to nirmatrelvir-ritonavir driven by TES or any M^pro substitution,” concluded Baniecki.