What is the real-world efficacy of oral antivirals against the SARS-CoV-2 Omicron variant?

By Dr. Chinta SidharthanOct 12 2022Reviewed by Aimee Molineux

In a recent article published in The Lancet, the authors commented on a recent observational study by Wong et al. (2022), which explored the real-world effectiveness of oral antivirals against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant.

The original study

A recent study investigated the efficacy of oral antivirals among coronavirus disease 2019 (COVID-19) patients in Hong Kong, who had been administered either nirmatrelvir plus ritonavir or molnupiravir oral antiviral therapy in the initial stages of COVID-19, within five days of the onset of symptoms.

The study aimed to examine the real-world effectiveness of these antivirals against the recent SARS-CoV-2 Omicron variant since previous studies were all clinical trials conducted largely during the dominance of the SARS-CoV-2 Delta variant. The observational study found that both antiviral therapies significantly reduced the risk of severe COVID-19 and mortality. Additionally, nirmatrelvir plus ritonavir also decreased the risk of hospitalization.

The researchers found that molnupiravir users were older (60 years or older) than the COVID-19 patients on nirmatrelvir plus ritonavir treatment. Nirmatrelvir plus ritonavir therapy is known to have many drug-drug interactions with prescription medications such as amiodarone, enzalutamide, rifampicin, carbamazepine, phenobarbital, St John’s Wort (Hypericum perforatum), phenytoin, and many more. Molnupiravir also had an earlier release date than nirmatrelvir plus ritonavir. The researchers thought that this, combined with the drug reactivity, might explain the reduced use of nirmatrelvir plus ritonavir among the elderly.

The commentary

The authors of the present article reviewed two early randomized, placebo-controlled clinical trials MOVe-OUT and EPIC-HR, which included unvaccinated participants below 60 years and 65 years, respectively, who were at risk of severe COVID-19. The two trials administered the oral antivirals within five days of the onset of mild COVID-19 symptoms, and the major risk factor in both studies was found to be obesity or being overweight.

Although the clinical trials reported a significant reduction in the risk of hospitalization or death, given the current widespread use of these oral antivirals, the authors highlighted the need for updated real-world data on the efficacy of these antivirals under a wide range of conditions and against other variants,

Commenting on the study by Wong et al., the authors stated that despite the inherent limitations of the observational study, it highlighted the relevant real-world findings of the effectiveness of the two oral antiviral therapies in preventing all-cause mortality within a community-dwelling population like Hong Kong. They mentioned that the study had a potential self-reporting bias since mildly symptomatic patients might not seek medical aid. Furthermore, the case-controlled section of the study did not report a significant effect of molnupiravir on mortality, and the insufficient number of deaths in the study made it difficult to evaluate the efficacy of nirmatrelvir plus ritonavir in reducing mortality.

The authors compared the observational study by Wong et al. to another large-scale, real-world retrospective study from Israel which reported that administration of nirmatrelvir plus ritonavir within five days of the onset of SARS-CoV-2 infection symptoms significantly decreased COVID-19 severity and risk of mortality.

Moreover, the study from Israel tested the efficacy of the oral antivirals during the surge of SARS-CoV-2 Omicron subvariant BA.2.2. It also reported that among vaccinated individuals experiencing breakthrough SARS-CoV-2 infections, treatment with nirmatrelvir plus ritonavir resulted in comparatively lower rates of hospitalizations than those described elsewhere.

Conclusions

To summarize, the authors of this commentary reviewed the findings from two major clinical trials and two large-scale, real-world studies on the efficacy of oral antivirals molnupiravir and nirmatrelvir plus ritonavir in reducing the risk of mortality, hospitalization, and progression of severe COVID-19.

The authors concluded that while the studies reported a significant decrease in all-cause mortality and the risk of hospitalization with the early initiation of oral antiviral therapy, more prospective studies are required to understand antiviral use for breakthrough COVID-19. The development of new oral antivirals also necessitates combination trials to compare their efficacy against those of existing oral therapies.

Continuous monitoring and analysis of the efficacy and safety of COVID-19 antivirals are imperative to ensure the protection and health of at-risk populations.