Real-world untreated risk of hospitalization and death in a nirmatrelvir/ritonavir treatment-eligible population with mild-to-moderate COVID-19 in the United States: a systematic literature review.

BACKGROUND: No study has systematically reviewed published estimates of real-world risk of hospitalization and death among untreated COVID-19 patients. We aimed to characterize the risk of hospitalization and death in real-world US clinical practice for untreated patients at high-risk for progression to severe COVID-19 and critically assess differences in patient populations. METHODS: We conducted a systematic literature review to identify US real-world evidence studies (December 21, 2021 – January 30, 2024) of patients aged 12 years and older diagnosed with mild-to-moderate COVID-19, at high risk for progression to severe COVID-19, and treated with nirmatrelvir/ritonavir (NMV/r) or untreated/best supportive care. Primary outcomes were reported risks of all-cause hospitalization, death, and hospitalization or death at 1 month. To account for heterogeneity across studies and confounding within studies, outcomes were estimated as: 1) observed risk, untreated risk as reported, 2) within-study adjusted risk, applying an adjusted treatment effect within studies to calculate risk in the untreated population, and 3) adjusted and standardized estimate, using the relative risk reduction for all-cause hospitalization or death from the study with highest validity. RESULTS: Of 1023 studies screened, we retained 23 for data extraction after applying inclusion and exclusion criteria (384,793 NMV/r patients from 22 studies; 1,062,757 no treatment from 14 studies). Studies were heterogenous, primarily retrospective, utilizing claims (e.g., TriNetX) and integrated health system data (e.g., Veterans Affairs). Most (n = 21, 91%) were US only; 20 (87%) were cohorts from December 2021 onward. Risk of all-cause hospitalization ranged from 0.9–7.7% (observed), 0.8–2.0% (within-study adjusted), and 2.3–6.9% (adjusted and standardized). Hospitalization or death ranged from 0.6–10.2% (observed), 0.4–5.6% (within-study adjusted), and 1.0–15.6% (adjusted and standardized). Death risk ranged from 0.1–3.1% (observed) and 0.0–0.9% (within-study adjusted). CONCLUSIONS: Estimating the risk of hospitalization and death for untreated high-risk COVID-19 patients from the literature is limited by inherent differences in study designs, patient populations, and reporting. Observed risk of hospitalization ranges from 1 to 8%, and the risk of death from 0 to 3%. Understanding the hospitalization risk among untreated patients provides context for the clinical and economic value of current antiviral treatments. This study was sponsored by Pfizer, Inc.