Effectiveness of COVID-19 Treatment With Nirmatrelvir–Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes

Bajema, Kristina L.; Berry, Kristin; Streja, Elani; Rajeevan, Nallakkandi; Li, Yuli; Mutalik, Pradeep; Yan, Lei; Cunningham, Francesca; Hynes, Denise M.; Rowneki, Mazhgan; Bohnert, Amy S. B.; Iwashyna, Theodore J.; Maciejewski, Matthew L.; Osborne, Thomas F.; Viglianti, Elizabeth M.; Aslan, Mihaela; Huang, Grant D.; Ioannou, George N.

doi:10.7326/m22-3565

Cited by 54 publications

(68 citation statements)

References 24 publications

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“…Additional demographic information included VHA facility and Veterans Integrated Service Network (VISN, the 18 regional systems of care) associated with the SARS-CoV-2 test and rurality of residence based on the Rural-Urban Commuting Areas system . We also determined smoking status, alcohol or substance use disorder, Charlson Comorbidity Index (CCI) score, COVID-19 vaccination status, and underlying medical conditions, including immunocompromised status, as previously described …”

Section: Methodsmentioning

confidence: 99%

“…17 We also determined smoking status, alcohol or substance use disorder, Charlson Comorbidity Index (CCI) score, COVID-19 vaccination status, and underlying medical conditions, including immunocompromised status, as previously described. 8,9…”

Section: Study Population and Baseline Characteristicsmentioning

confidence: 99%

“…2 Collectively, these pharmacotherapies have been demonstrated to aid clinical recovery and reduce the risk of hospitalization and death. [3][4][5][6][7][8] After slow early uptake, 8.9 million courses of nirmatrelvir-ritonavir and 1.3 million courses of molnupiravir had been administered across the US by April 2023. [9][10][11][12] Despite this, challenges that impede broader uptake among populations at increased risk remain, and information on use more than 1 year after authorization remains limited.…”

Section: Introductionmentioning

confidence: 99%

“…These include ritonavir-boosted nirmatrelvir, remdesivir, and molnupiravir, which received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) between December 2021 and January 2022 . Collectively, these pharmacotherapies have been demonstrated to aid clinical recovery and reduce the risk of hospitalization and death . After slow early uptake, 8.9 million courses of nirmatrelvir-ritonavir and 1.3 million courses of molnupiravir had been administered across the US by April 2023 .…”

Section: Introductionmentioning

confidence: 99%

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Anti–SARS-CoV-2 Pharmacotherapies Among Nonhospitalized US Veterans, January 2022 to January 2023

Yan,

Streja,

et al. 2023

JAMA Netw Open

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ImportanceSeveral pharmacotherapies have been authorized to treat nonhospitalized persons with symptomatic COVID-19. Longitudinal information on the use of these therapies is needed.ObjectiveTo analyze trends and factors associated with prescription of outpatient COVID-19 pharmacotherapies within the Veterans Health Administration (VHA).Design, Setting, and ParticipantsThis cohort study evaluated nonhospitalized veterans in VHA care who tested positive for SARS-CoV-2 from January 2022 through January 2023 using VHA and linked Community Care and Medicare databases.ExposuresDemographic characteristics, underlying medical conditions, COVID-19 vaccination, and regional and local systems of care, including Veterans Integrated Services Networks (VISNs).Main Outcomes and MeasuresMonthly receipt of any COVID-19 pharmacotherapy (nirmatrelvir-ritonavir, molnupiravir, sotrovimab, or bebtelovimab) was described. Multivariable logistic regression was used to identify factors independently associated with receipt of any vs no COVID-19 pharmacotherapy.ResultsAmong 285 710 veterans (median [IQR] age, 63.1 [49.9-73.7] years; 247 358 males [86.6%]; 28 444 Hispanic [10.0%]; 61 269 Black [21.4%] and 198 863 White [69.6%]) who tested positive for SARS-CoV-2 between January 2022 and January 2023, the proportion receiving any pharmacotherapy increased from 3285 of 102 343 veterans (3.2%) in January 2022 to 5180 of 21 688 veterans (23.9%) in August 2022. The proportion declined to 2194 of 10 551 veterans (20.8%) by January 2023. Across VISNs, the range in proportion of patients who tested positive who received nirmatrelvir-ritonavir or molnupiravir during January 2023 was 41 of 692 veterans (5.9%) to 106 of 494 veterans (21.4%) and 2.1% to 120 of 1074 veterans (11.1%), respectively. Veterans receiving any treatment were more likely to be older (adjusted odds ratio [aOR] for ages 65-74 vs 50-64 years, 1.18; 95% CI, 1.14-1.22; aOR for ages ≥75 vs 50-64 years, 1.19; 95% CI, 1.15-1.23) and have a higher Charlson Comorbidity Index score (aOR for CCI ≥6 vs 0, 1.52; 95% CI, 1.44-1.59). Compared with White veterans, Black veterans (aOR, 1.06; 95% CI, 1.02-1.09) were more likely to receive treatment, and compared with non-Hispanic veterans, Hispanic veterans (aOR 1.06; 95% CI, 1.01-1.11) were more likely to receive treatment.Conclusions And RelevanceThis study found that prescription of outpatient COVID-19 pharmacotherapies in the VHA peaked in August 2022 and declined thereafter. There were large regional differences in patterns of nirmatrelvir-ritonavir and molnupiravir use.

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Section: Methodsmentioning

confidence: 99%

Section: Study Population and Baseline Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti–SARS-CoV-2 Pharmacotherapies Among Nonhospitalized US Veterans, January 2022 to January 2023

Yan,

Streja,

et al. 2023

JAMA Netw Open

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“…Anecdotal reports suggest that nirmatrelvir may improve Long COVID symptoms 12–14 . However, whether treatment with nirmatrelvir during acute infection reduces post‐COVID conditions is uncertain, with two studies finding conflicting results in the same population 15,16 . Use of EHR‐based diagnosis of post‐COVID conditions, as in those studies, relies on patient reporting and clinician documentation of medical diagnoses so may not capture the possible treatment effect on Long COVID symptoms.…”

Section: Introductionmentioning

confidence: 99%

Association of nirmatrelvir for acute SARS‐CoV‐2 infection with subsequent Long COVID symptoms in an observational cohort study

Durstenfeld,

Peluso,

Lin

et al. 2024

Journal of Medical Virology

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Oral nirmatrelvir/ritonavir is approved as treatment for acute COVID‐19, but the effect of treatment during acute infection on risk of Long COVID is unknown. We hypothesized that nirmatrelvir treatment during acute SARS‐CoV‐2 infection reduces risk of developing Long COVID and rebound after treatment is associated with Long COVID. We conducted an observational cohort study within the Covid Citizen Science (CCS) study, an online cohort study with over 100 000 participants. We included vaccinated, nonhospitalized, nonpregnant individuals who reported their first SARS‐CoV‐2 positive test March–August 2022. Oral nirmatrelvir/ritonavir treatment was ascertained during acute SARS‐CoV‐2 infection. Patient‐reported Long COVID symptoms, symptom rebound and test‐positivity rebound were asked on subsequent surveys at least 3 months after SARS‐CoV‐2 infection. A total of 4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the Long COVID survey (n = 1611). Among 1611 participants, median age was 55 years and 66% were female. At 5.4 ± 1.3 months after infection, nirmatrelvir treatment was not associated with subsequent Long COVID symptoms (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 0.80–1.64; p = 0.45). Among 666 treated who answered rebound questions, rebound symptoms or test positivity were not associated with Long COVID symptoms (OR: 1.34; 95% CI: 0.74–2.41; p = 0.33). Within this cohort of vaccinated, nonhospitalized individuals, oral nirmatrelvir treatment during acute SARS‐CoV‐2 infection and rebound after nirmatrelvir treatment were not associated with Long COVID symptoms more than 90 days after infection.

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Clinical Risk and Outpatient Therapy Utilization for COVID-19 in the Medicare Population

Wilcock,

Kissler,

Mehrotra

et al. 2024

JAMA Health Forum

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ImportanceMultiple therapies are available for outpatient treatment of COVID-19 that are highly effective at preventing hospitalization and mortality. Although racial and socioeconomic disparities in use of these therapies have been documented, limited evidence exists on what factors explain differences in use and the potential public health relevance of these differences.ObjectiveTo assess COVID-19 outpatient treatment utilization in the Medicare population and simulate the potential outcome of allocating treatment according to patient risk for severe COVID-19.Design, Setting, and ParticipantsThis cross-sectional study included patients enrolled in Medicare in 2022 across the US, identified with 100% Medicare fee-for-service claims.Main Outcomes and MeasuresThe primary outcome was any COVID-19 outpatient therapy utilization. Secondary outcomes included COVID-19 testing, ambulatory visits, and hospitalization. Differences in outcomes were estimated based on patient demographics, treatment contraindications, and a composite risk score for mortality after COVID-19 based on demographics and comorbidities. A simulation of reallocating COVID-19 treatment, particularly with nirmatrelvir, to those at high risk of severe disease was performed, and the potential COVID-19 hospitalizations and mortality outcomes were assessed.ResultsIn 2022, 6.0% of 20 026 910 beneficiaries received outpatient COVID-19 treatment, 40.5% of which had no associated COVID-19 diagnosis within 10 days. Patients with higher risk for severe disease received less outpatient treatment, such as 6.4% of those aged 65 to 69 years compared with 4.9% of those 90 years and older (adjusted odds ratio [aOR], 0.64 [95% CI, 0.62-0.65]) and 6.4% of White patients compared with 3.0% of Black patients (aOR, 0.56 [95% CI, 0.54-0.58]). In the highest COVID-19 severity risk quintile, 2.6% were hospitalized for COVID-19 and 4.9% received outpatient treatment, compared with 0.2% and 7.5% in the lowest quintile. These patterns were similar among patients with a documented COVID-19 diagnosis, those with no claims for vaccination, and patients who are insured with Medicare Advantage. Differences were not explained by variable COVID-19 testing, ambulatory visits, or treatment contraindications. Reallocation of 2022 outpatient COVID-19 treatment, particularly with nirmatrelvir, based on risk for severe COVID-19 would have averted 16 503 COVID-19 deaths (16.3%) in the sample.ConclusionIn this cross-sectional study, outpatient COVID-19 treatment was disproportionately accessed by beneficiaries at lower risk for severe infection, undermining its potential public health benefit. Undertreatment was not driven by lack of clinical access or treatment contraindications.

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Effectiveness of COVID-19 Treatment With Nirmatrelvir–Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes

Cited by 54 publications

References 24 publications

Anti–SARS-CoV-2 Pharmacotherapies Among Nonhospitalized US Veterans, January 2022 to January 2023

Anti–SARS-CoV-2 Pharmacotherapies Among Nonhospitalized US Veterans, January 2022 to January 2023

Association of nirmatrelvir for acute SARS‐CoV‐2 infection with subsequent Long COVID symptoms in an observational cohort study

Clinical Risk and Outpatient Therapy Utilization for COVID-19 in the Medicare Population

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