In this issue of the American Journal of Therapeutics, Cha-Silva et al publish the article Effectiveness of Nirmatrelvir–Ritonavir for the Prevention of Coronavirus Disease 2019 (COVID-19)–Related Hospitalization and Mortality: A Systematic Literature Review. This is an important addition to the literature as it successfully reviews several studies examining the effectiveness of nirmatrelvir/ritonavir (NMV/r).

The article begins with an introduction that highlights the tremendous experience the authors have had using this medication, with over 12.7 million treatment courses prescribed since it became available at the end of 2021. The article also points out that NMV/r is recommended as the preferred outpatient COVID-19 treatment for individuals at high risk of progression to severe disease.1

Before moving on to the results of their systematic literature review (SLR), they mention the pivotal randomized double-blind placebo-controlled multinational trial Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients, which resulted in an 86% reduction in the combined end point of COVID-19–related hospitalization or death from any cause when patients were treated within 5 days of the symptom onset.2 They also comment on the Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients that looked at vaccinated adults and reported a 62% decrease in COVD-19–related medical visits relative to placebo.3

While this is an important background, the authors rightfully point out that many have questions about the effectiveness of treatment with NMV/r in patients with preexisting immunity that is vaccination-induced or due to surviving a prior infection when infected with the current circulating variants.

This SLR was conducted in accordance with the Cochrane Handbook for Systematic Review of Interventions and Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines and identified published articles, as well as reviewing the gray literature from conference proceedings. They ultimately included 18 studies, with a total of 343,197 receiving NMV/r treatment, that reported on NMV/r effectiveness for prevention of hospitalization or mortality. The majority of these studies looked at a composite outcome of prevention of hospitalization or mortality.

All the included studies are retrospective, and only 7 of the 18 studies reported administering NMV/r ≤5 days after symptom onset. Most of the studies included vaccination status and the number of vaccine doses received by patients. Most of the studies mentioned the predominant COVID-19 variant, and of contemporary relevance, most of these studies looked at periods with omicron as the dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant. This context makes this analysis very appropriate as the authors can get retrospective real-world efficacy data on the use of NMV/r in patients with preexisting immunity with infection with omicron.

The analysis revealed an NMV/r effectiveness of 21%–89% for the prevention of all-cause hospitalization and 24%–60% for COVID-related hospitalization. Their analysis revealed that this impact was regardless of vaccination status. Two studies reported NMV/r effectiveness of 66% and 85% against all-cause mortality. When looking at the prevention of the composite outcome of hospitalization or mortality, the studies reported that the effectiveness of prevention of the composite end point of hospitalization or mortality was 54%–92%.

Often overlooked but included in this analysis was the impact of NMV/r on longer-term outcomes. There was a reported reduction in hospitalization, mortality, and the composite end point of hospitalization or mortality. Unfortunately, there was no mention of any results looking at post-acute sequelae in this investigation. The impact of NMV/r on long COVID-19 is a matter of great interest to clinicians and patients.

Despite the fact that NMV/r is recommended as the preferred outpatient COVID-19 treatment for individuals at high risk of progression to severe disease during the first 5 days while symptoms are still mild, this effective therapeutic is underutilized.4 This SLR summarizes the effectiveness of NMV/r in contemporary patients with preexisting immunity with infection due to omicron. This investigation supports the current treatment guidelines and hopefully will lead to higher utilization of this effective therapeutic.

2. Hammond J, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. 2022;386:1397–1408. 3. Pfizer Reports Additional Data on PAXLOVID™ Supporting Upcoming New Drug Application Submission to U.S. FDA. Pfizer Inc; 2022. Available at: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-reports-additional-data-paxlovidtm-supporting. Accessed March 9, 2024. 4. Wilcock AD, et al. Clinical risk and outpatient therapy utilization for COVID-19 in the medicare population. JAMA Health Forum 2024;5:e235044.