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Patients with nonsevere COVID-19 may avoid progression to hospitalization or death through treatment with nirmatrelvir-ritonavir or molnupiravir, according to a systematic review and meta-analysis.
In trials conducted mostly in unvaccinated patients who had been infected with the Delta variant, treatment with nirmatrelvir-ritonavir was associated with 11.7 fewer deaths per 1000, compared with standard care or placebo.
“Although we recognize that the data were tested in patients with a different variant, we expect that there is likely still relevance for other variants,” study author Tyler Pitre, MD, told Medscape Medical News. “We present the most updated summary of the evidence, which suggests benefit for some of these medications. We hope that this will be useful.
“Most surprising was the lack of efficacy of remdesivir,” he noted. “Remdesivir is currently recommended for nonsevere disease, but there was no mortality benefit in our analysis, and there was also low-certainty evidence for other important endpoints, such as hospitalizations and reducing the risk of invasive mechanical ventilation.”
The study was published online July 25 in CMAJ.
Benefits “Probable”
Pitre and colleagues extracted data from randomized trials that compared antiviral therapies with placebo or standard care from the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database through April 25, 2022. Forty-one trials involving 18,568 patients with nonsevere COVID-19 were included in the analysis. Participants’ ages ranged between 36 and 65 years, and about half of participants were men.
The researchers assumed a baseline risk of 13.3 deaths per 1000 on the basis of median risk in the placebo group and standard-care group. Molnupiravir and nirmatrelvir-ritonavir each reduced risk of death (by 10.9 fewer deaths per 1000 and 11.7 fewer per 1000, respectively) with moderate certainty, compared with placebo or standard care.
By contrast, remdesivir had no effect on mortality risk, nor did sofosbuvir-daclatasvir or emtricitabine-tenofovir (moderate certainty).
Hospitalization risk was reduced with nirmatrelvir-ritonavir (46.2 fewer admissions per 1000, high certainty), compared with standard care or placebo. Molnupiravir probably reduced the risk (16.3 fewer admissions per 1000, moderate certainty), and remdesivir may have reduced the risk (39.1 fewer admissions, low certainty).
Furthermore, nirmatrelvir-ritonavir probably reduced hospitalization risk, compared with molnupiravir (27.8 fewer admissions per 1000, moderate certainty).
The analysis also showed that molnupiravir probably reduced the need for mechanical ventilation (13 fewer events per 1000, moderate certainty), compared with placebo or standard care, whereas remdesivir may have reduced risk of the need for mechanical ventilation (11.8 fewer events per 1000, low certainty).
Rates of adverse events were largely similar for nirmatrelvir-ritonavir and molnupiravir.
A subgroup analysis of two remdesivir trials did not find that age or sex had an effect on mortality risk. Only one molnupiravir trial reported subgroup data. In that trial, there was no evidence of an effect on hospital admissions disease by severity, age, or sex.
The analysis will be updated as results from large trials become available, said Pitre.
Current Impact “Unknown”
“Adaptive platform trials and large observational studies offer the best opportunities to generate timely evidence on the effectiveness of COVID-19 therapeutics,” write Corinne Hohl, MD, MHSc, associate professor of emergency medicine at University of British Columbia, Vancouver, and Andrew McRae, MD, PhD, assistant professor of emergency medicine at University of Calgary, Alberta, in an accompanying editorial. “These studies can be completed in Canada but need to be supported by Canadian research funders, health care institutions, data custodians, health care providers, and patients.”
Commenting on the report for Medscape, Robert M. Grossberg, MD, medical director, Center for Positive Living/ID Clinic at Montefiore Health System and associate professor of infectious diseases at Albert Einstein College of Medicine, New York City, said, “This analysis adds support to our current understanding of the landscape of COVID-19 antivirals.”
However, he added, “As the authors point out, the studies…were done in unvaccinated participants and before the emergence of Omicron. We would expect that vaccinated individuals are less likely to progress to serious illness or hospitalization. We also know that these outcomes are less likely with Omicron than earlier variants. We might expect, then, that the impact of these drugs in the current space would be far less, as most patients will do well without any antiviral treatment.”
Nevertheless, other endpoints, such as the duration of illness or duration of viral shedding, might affect transmission and should be considered, Grossberg said. “Ideally, these drugs would be best evaluated in a head-to-head fashion. That might provide a more robust picture of which drug is superior.
“The overall benefit for any of these drugs in vaccinated patients with the current variant is unknown,” Grossberg concluded.
The study was conducted without outside funding. Pitre and Grossberg reported no relevant financial relationships. Hohl has received grants from the COVID-19 Immunity Task Force, the Canadian Institutes for Health Research, Genome BC, the Michael Smith Health Research Foundation, and the Canadian Association of Emergency Physicians. McRae has received grants from the Canadian Institutes of Health Research and Roche Diagnostics Canada and honoraria from Western University and Servier Pharmaceuticals.
CMAJ. Published online July 25, 2022. Full text
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