Key differences for ritonavir PK-enhanced antiviral treatment in patients with COVID-19 versus treatment for people living with HIV are the short-term duration of treatment and broader target population, which is more likely to receive prescriptions from general practitioners or pharmacists. Individuals with mild to moderate COVID-19 who are considered to be at high risk for progression to severe disease, as defined by the Centers for Disease Control and Prevention, are eligible for treatment with nirmatrelvir/ritonavir [
12,
64]. Approximately one in five individuals globally falls into this category [
65], with older age and certain underlying conditions (e.g., cardiovascular disease, obesity, and diabetes) being associated with an increased risk of severe outcomes from COVID-19 [
64,
66‐
69]. Individuals with multiple comorbidities are also associated with severe illness [
64]. These individuals may be more likely to be on medications for their conditions, potentially putting them at risk for DDIs if they receive nirmatrelvir/ritonavir. Drug–drug interactions with nirmatrelvir/ritonavir are expected to primarily be due to ritonavir [
70]. Proactive management of concomitant medications requires considering the contribution of ritonavir’s mechanisms of action to DDIs and adherence to labeled contraindications. Boxed warnings on the regulatory labels for both ritonavir and nirmatrelvir/ritonavir note the potential for serious or significant interactions [
1,
12], and health bodies such as the WHO recommend that clinicians review all medications an individual is taking and nirmatrelvir/ritonavir should be avoided in those with possible dangerous DDIs [
50]. For example, ritonavir is contraindicated with potent CYP3A inducers and drugs highly dependent on CYP3A for clearance, and dose reductions may be necessary when used with other protease inhibitors (i.e., atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir) [
1,
12]. The nirmatrelvir/ritonavir prescribing label notes that individuals receiving a ritonavir- or cobicistat-containing HIV regimen could continue their treatment as indicated, but should be monitored for increased nirmatrelvir/ritonavir or protease inhibitor AEs [
12]. Additionally, therapeutic concentration monitoring is recommended in patients receiving immunosuppressive drugs, such as tacrolimus; concomitant treatment should be avoided if monitoring is not possible, [
1,
12] because coadministration is associated with a risk for decreased clearance that can lead to adverse outcomes [
71‐
78]. However, strategies to manage these interactions have been described for both long-term and short-term treatments [
75,
77,
79‐
82]. Because many commonly prescribed medications among individuals who received or could receive nirmatrelvir/ritonavir for COVID-19 are not likely to cause a DDI with ritonavir [
83‐
85], most patients will not require complex co-medication management, especially for a short course of treatment for COVID-19.
Several real-world studies emphasize the importance of vigilance on the part of practitioners prescribing nirmatrelvir/ritonavir concurrently with other treatments; however, the overall rates and severity of DDIs among different populations imply a generous margin of safety. Among claims analyses and pharmacovigilance reports, 13–75% of individuals with COVID-19 who received nirmatrelvir/ritonavir were expected to be at risk for or experienced DDIs [
60,
85‐
88]. The highest rate of DDIs was reported in a retrospective analysis of 60 patients (
n = 55 with ≥ 2 risk factors for progression to severe disease) who received nirmatrelvir/ritonavir from clinical pharmacists, with 101 DDIs among 45 patients (75%), with 36 patients (60%) having ≥ 1 significant interaction [
86]. In the available literature, it is notable that problematic DDIs generally arise in a limited subset of nirmatrelvir/ritonavir recipients. In a survey of the French pharmacovigilance database that included 12,179 individuals who received nirmatrelvir/ritonavir in 2022, only 30 (13%) reports of DDIs were identified from 228 selected reports. The most frequently reported DDIs were with immunosuppressants (tacrolimus and ciclosporin) and anticoagulants; only 20 reports (9%) were considered serious [
60]. Methemoglobinemia related to a dapsone hydroxylamine and ritonavir DDI as well as bradycardia associated with anti-hypersensitive drugs were reported. A retrospective analysis of claims data from German statutory health insurance from 2018–2019 reported that approximately 44% of individuals were at risk for potential DDIs with nirmatrelvir/ritonavir, with 31–32% receiving contraindicated medications and 12–13% receiving medications that would require monitoring or dose adjustments [
87]. A cross-sectional study using US electronic health records from the National COVID Cohort Collaborative Enclave reported that only about 16% of individuals taking nirmatrelvir/ritonavir were at risk for a potential moderate-to-severe DDI [
89]. An analysis of pharmacy databases and electronic health records among individuals who tested positive for SARS-CoV-2 at the Chelsea and Westminster Hospital in London revealed that 11% received drugs with interactions that would have precluded coadministration [
88]. Several of the real-world studies above report that 60% of interactions may be addressed through mitigation strategies, with only about one-third of nirmatrelvir/ritonavir recipients estimated to be at risk for potential exposure to contraindicated medications or major DDIs [
60,
85,
86]. In fact, among the top 100 drugs most likely to be prescribed to US adults who are eligible for nirmatrelvir/ritonavir treatment due to high risk of progression to severe COVID-19, the vast majority (70%) are not expected to cause DDIs with nirmatrelvir/ritonavir [
83].