Nirmatrelvir/Ritonavir Added to Ninth Update of WHO’s Living Guideline on COVID-19 Therapeutics

The World Health Organization (WHO) has released their ninth update to the living guideline on drugs for COVID-19 infection, including new recommendations in regard to the use of nirmatrelvir/ritonavir and remdesivir among patients with nonsevere COVID-19 infection at increased risk for hospitalization. The full report was published in BMJ.

In this living guideline, the WHO’s guideline development group (GDP) updated previous recommendations and provided an overview of new treatments for patients with nonsevere COVID-19 infection.

New Recommendations

Nirmatrelvir/ritonavir (strong recommendation):

Based on results of 2 randomized controlled trials (RCT; N=3100), the GDP made a strong recommendation for the use of nirmatrelvir/ritonavir for adult patients with nonsevere COVID-19 infection at increased risk for hospitalization, as well as a conditional recommendation against its use for those at decreased risk for hospitalization. The GDP does not recommend this treatment for children or for women who are pregnant or breastfeeding. The administration of nirmatrelvir/ritonavir should occur immediately following COVID-19 onset. Owing to a lack of data, the GDP did not provide guidance on the use of nirmatrelvir/ritonavir for adult patients with severe disease.

Results of the 2 RCTs that assessed treatment with nirmatrelvir/ritonavir within 5 days of COVID-19 onset showed the following:

• A decreased risk for hospitalization (odds ratio [OR], 0.15; 95% CI, 0.06-0.38; moderate certainty evidence).
• No clinically meaningful difference in mortality risk compared with placebo (OR, 0.04; 95% CI, 0.00-0.67; low certainty evidence).
• Compared with placebo, there was little to no risk for adverse effects requiring subsequent medication discontinuation (OR, 0.48; 95% CI, 0.29-0.80; absolute difference [AR], 0; high certainty evidence).
• The occurrence of diarrhea and altered taste was more likely compared with placebo.

According to the GDP, “the strong recommendation for nirmatrelvir/ritonavir reflects what [is considered] a superior choice over other treatment options for [high-risk patients] with nonsevere [COVID-19] infection; it may prevent more hospitalization than the alternatives, has fewer harms than molnupiravir, and is easier to administered than intravenous options such as remdesivir and monoclonal antibodies.”

Updated Recommendation

Remdesivir (weak/conditional recommendation):

Although previous guidance recommended against the use of remdesivir regardless of COVID-19 disease severity, the WHO’s GDP now recommends remdesivir for patients with nonsevere COVID-19 at increased risk for hospitalization.

This recommendation for remdesivir was made on the basis of the following results from a meta-analysis that included 5 RCTs (N=2731):

• A decreased risk for hospitalization (OR, 0.25; 95% CI, 0.06-0.88; moderate certainty evidence).
• No clinically meaningful difference in mortality risk compared with placebo (OR, 0.68; 95% CI, 0.39-1.21; low certainty evidence).
• A decreased risk for mechanical ventilation (OR, 0.42; 95% CI, 0.08-1.96; very low certainty evidence).
• A decrease in the number of days to symptom resolution (mean difference, -1.8 days per 1000 patients; 95% CI, -5.7 to 3.5; very low certainty evidence).
• Compared with placebo, there was little to no risk for adverse effects requiring subsequent medication discontinuation (AR, 9 more per 1000 patients; 95% CI, -3 to 21; moderate certainty evidence).

The GDP noted “concerns regarding whether [remdesivir] would retain efficacy against emerging variants of concern, such as Omicron BA-1 or BA-2,” adding that “surveillance is needed for SARS-CoV-2 strains with reduced susceptibility to remdesivir, and further research examining the role of combination therapy in [patients who are] severely immunocompromised.”

There are several other COVID-19 therapeutics currently under consideration by the WHO for inclusion in future iterations of this living guideline, including fluvoxamine, colchicine, and therapeutic anticoagulation. There also is a review of sotrovimab underway as new evidence has emerged on its efficacy against the Omicron BA-1 and BA-2 variants.

Reference

Agarwal A, Rochwerg B, Lamontagne F, et al. Update to living WHO guideline on drugs for covid-19. BMJ. 2022;377:o1005.doi.10.1136/bmj.o1005