At IDWeek 2023 in Boston, investigators presented data regarding the treatment of COVID-19 in outpatients. This article includes a summary of selected presentations on ritonavir-boosted nirmatrelvir (r/NMV) and molnupiravir for non-immunocompromised patients. See here for a summary of data from IDWeek on therapeutics in immunocompromised patients. Although not formally peer-reviewed, all presentations at IDWeek underwent expert assessment. Registered attendees can access IDWeek content online until March 31, 2024.
EPIC-SR: r/NMV for Standard-Risk Patients
While not yet published, the Phase 2/3 EPIC-SR study of r/NMV versus placebo for unvaccinated (without risk factors) or vaccinated (with at least one risk factor for severe disease) adult outpatients with symptomatic COVID-19 showed there was no difference in time to symptom improvement between the 654 r/NMV recipients and the 634 placebo recipients (Poster #532). When the secondary outcomes were examined among vaccinated participants with one or more risk factors for severe disease, 2.2% (7/317) of r/NMV recipients and 5.4% (17/314) of placebo recipients had a COVID-19–related medical visit, corresponding to a 59% relative risk reduction with treatment. The same was not shown for the secondary outcome of hospitalization or death, which occurred in 0.9% (3/317) and 2.2% (7/314) in study drug and placebo recipients who were vaccinated and had at least one risk factor, respectively, with a p-value for the comparison of 0.197. When the results of EPIC-SR vaccinated high-risk participants were pooled with the results of the previously published EPIC-HR participants, there was a significant reduction in risk of hospitalization or death of 83% in r/NMV recipients compared to placebo (12/1,294 vs. 71/1,303; p<0.0001). The poster also explored the impact of r/NMV among those seropositive for SARS-CoV-2, consistent with having immunity from past infection, and still showed protective efficacy against COVID-19–related hospitalization or all-cause death within 28 days: RRR of 87.8% (p=0.0179) in EPIC-HR seropositive people and 73.8% (p=0.01) when vaccinated high-risk EPIC-SR participants were pooled with EPIC-HR seropositive participants.
r/NMV and Post-COVID Conditions
Dalton et al. presented data on ritonavir-boosted nirmatrelvir use to assess the occurrence of post-COVID conditions (PCC) with and without treatment (Abstract #1937). Though they tried to match treated and untreated groups as much as possible, a lower proportion of the treated individuals had a documented prior COVID episode, and because we know that risk of PCC accumulates with every episode of COVID an individual has, this could favor the treatment arm. In a large database of 4.3 million people 12 years and older with symptomatic COVID-19 and risk factors for progressive disease, the overall finding was of a mildly lower occurrence of PCC among the treated group in adults over age 50 years (RR, 0.91; 95% CI, 0.91-0.92). However, there was no significant difference in PCC occurrence between treated and untreated patients in 18-49 year olds, and in 12-17 year olds, there was an overall higher risk of PCC among treated individuals (RR, 1.09; 95% CI, 1.04-1.15).
Calderon et al. looked at receipt of various therapeutics between patients who developed PCC/PASC and those who did not (Poster #392). Forty-seven percent of the PCC group required hospitalization compared to 39% for the group without PCC. There was no difference in r/NMV receipt between the groups. There was a trend towards more remdesivir receipt among patients who developed PCC (18% vs. 5%; p=0.053) and a significantly higher occurrence of dexamethasone receipt among the group who did not develop PCC (72% vs. 28%; p<0006).
Mpro Resistance Analysis
Baniecki et al. presented an analysis of resistance to this agent across the Phase 3 EPIC-HR and EPIC-SR trials (Poster #361). These were primarily Delta variant cases (91%). Three cases of emergence of the Mpro mutation E166V were observed in the r/NMV group, all of whom had suppressed viral load by day 14 post-treatment and none of whom had severe disease. One participant had viral rebound on day 10 but quickly resuppressed, so it was concluded that rebound was not due to r/NMV resistance.
More on Real-World Use of r/NMV
Bhargava et al. looked at a historical cohort of 371 patients who had received r/NMV for treatment of COVID-19 and examined risk factors for seeking medical care within the 4 weeks after treatment (Poster #511). Factors associated with having an emergency department visit or inpatient hospitalization after r/NMV included female sex (OR, 3.1; 95% CI, 1.4-15.3; p=0.01), myocardial infarction (OR 4.1, 95% CI 1.4-11.8; p=0.01) and diabetes with complications (OR, 6.9; 95% CI, 2.0-23.3; p=0.002). People with alcohol use, conversely, were less likely to seek medical care in the 4-week window (OR, 0.39; 95% CI, 0.2-0.9; p=0.04).
Cha-Silva et al., presented by the manufacturer of r/NMV, looked at 66 studies that included a total of 421,588 patients that received r/NMV (Poster #516). Of these, 14 reported on relative risk reduction of hospitalization or death, and eight of the 14 were from the Omicron era. When the composite outcome of hospitalization or death was examined, there was a range of effectiveness, with many of the confidence intervals crossing zero (i.e., not significant), but with a trend favoring r/NMV over the comparator. (Comparators included no treatment, best supportive care, mAbs and comparator antiviral.) However, when the lone outcome of hospitalization was examined, r/NMV was seen to have more favorable efficacy in every study, and none of the confidence intervals crossed zero. A similar effectiveness was seen for all-cause mortality (risk reduction ranging 39%-85%) when r/NMV was compared to no r/NMV; however, when r/NMV was compared to molnupiravir, the confidence intervals for the effectiveness crossed zero.
Scott et al. presented a retrospective analysis of real-world uptake of r/NMV in the Omicron era among high-risk people who were subsequently hospitalized for COVID-19 (Poster #522). Among 42,939 high-risk patients who were hospitalized for COVID-19, only 5.8% had received an outpatient therapeutic prior to their hospitalization. Among the 7,209 who died within 1 month, 4.5% had received a therapeutic prior to hospitalization. Treatment was about the same between the younger group (18-64 years) and the older group (>65 years) — 5.6% and 5.8%, respectively. This suggests an overall low uptake of COVID therapeutics among those who are hospitalized with COVID and those who die within a month of having COVID-19.
Butt et al. compared the real-world effectiveness of 5 days of molnupiravir versus 5 days of r/NMV among 9,586 patients with COVID-19 and risk factors for severe disease (Poster #514). The vast majority were male (87%), an average of 67 years of age, obese or overweight, and had a variety of other comorbidities, and 64% were vaccinated with the primary series and booster. The analysis was restricted to those who received the antiviral within 3 days of diagnosis. The incidence of hospitalization or death within 30 days was not different between the two therapeutics with a single exception: Among the unvaccinated, r/NMV was favored over molnupiravir, with an absolute risk difference of -2.3 (95% CI, -3.8 to -0.79). These were not randomized head-to-head comparisons, so bias and confounding are likely.
A retrospective study by Lee et al. looked at the efficacy and safety of r/NMV (received within 5 days of symptom onset) for adolescents (ages 12-18 years) with COVID-19 (Poster #523). The study looked at a primary endpoint of COVID-19-related medical visits, including hospitalization, occurring within 30 days of completing r/NMV. The two groups had important differences, namely a higher percentage of patients in the treated group who had asthma or immunosuppressing conditions. About 34% of both treated and untreated groups were obese. There were overall low rates of return to seek medical care — 2/92 (2.2%) in the treated group and 1/14 (7.1%) in the nontreated group; p=0.35. Both treated patients who returned for medical attention in the month after treatment died for reasons deemed unrelated to COVID-19 or its treatment. Safety was acceptable, with only 2/92 (2.2%) treated patients experiencing adverse events related to study drug (nausea and chest/right upper quadrant abdominal pain) and none in the control group.
Lastly, Paraskevis et al. presented another retrospective cohort study of the effectiveness (impact on hospitalization within 10 days or death within 35 days) of r/NMV or molnupiravir in a cohort of high-risk outpatients with COVID-19 (Poster #547). This study separately examined the effectiveness of each therapeutic and found in a multivariable logistic regression (adjusted for age, previous infection and vaccination) that molnupiravir recipients had a 0.40 OR for hospitalization (95% CI, 0.32-0.48; p<0.001) compared to nonrecipients. r/NMV recipients had a 0.31 (0.27-0.36; p<0.001) OR for hospitalization compared to nonrecipients. Both therapeutics were also seen to be associated with reduced risk of death (OR for death in molnupiravir recipients of 0.31 (0.22-0.43; p<0.001) and in r/NMV recipients of 0.28 (0.22-0.36; p<0.001). Though this was also not a head-to-head comparison and provided no data on safety, it did provide reassuring effectiveness data on molnupiravir for those who cannot take r/NMV due to drug-drug interactions or comorbidities.
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