The Seventh Update of the WHO’s Living Guideline on COVID-19 Therapeutics

The World Health Organization (WHO) has released the seventh update of their living guideline on medications for the treatment of COVID-19 infection. These updates were published in BMJ.

The new update included 3 additional recommendations about the use of specific Janus kinase (JAK) inhibitors and monoclonal antibodies. These recommendations were formulated on the basis of findings from 7 randomized clinical trials (RCT) that assessed medications for the treatment of COVID-19 infection. Of these RCTs, 3 assessed baricitinib (n=2659), 2 assessed ruxolitinib (n=475), 1 assessed tofacitinib (n=289), and 1 assessed sotrovimab (n=1057).

First Update (strong recommendation):

As an alternative to interleukin-6 (IL-6) receptor blockers, the guideline authors strongly recommended combination treatment with baricitinib and corticosteroids for patients with severe or critical COVID-19 infection. Results of the 3 RCTs that assessed baricitinib showed that this medication was associated with decreased mortality risk (odds ratio [OR], 0.62; 95% CI, 0.44-0.85) and a decreased length of hospitalization, with no evidence indicating an increased risk for severe adverse events. However, these RCTs may not have been robust enough to assess the risk for fungal infections due to short follow-up duration.

Baricitinib is administered either orally, via nasogastric tube, or dispersed in water. The recommended dose is 4 mg for adults with estimated glomerular filtration rates greater than or equal to 60 mL/min/1.73 m2 for 14 days or until hospital discharge.

None of the RCTs that assessed baricitinib included children or women who were pregnant and/or lactating. Although the guideline authors did not have reason to suspect that these populations would respond differently, they noted that the decision to administer baricitinib should be made after an informed discussion with the patient.

Second Update (conditional or weak recommendation):

The second recommendation was against the use of ruxolitinib or tofacitinib for the treatment of patients with severe or critical COVID-19 infection. This recommendation was made on the basis of low certainty evidence that these JAK inhibitors decrease the risk of mortality, as well as the duration of mechanical ventilation among patients who require supplemental oxygen. In addition, there is some evidence that treatment with these JAK inhibitors may increase the risk for severe adverse events.

The authors stated that treatment with ruxolitinib or tofacitinib should be considered only if alternative treatments options, such as baricitinib, tocilizumab, or sarilumab are unavailable. In addition, the authors noted that the effects of ruxolitinib and tofacitinib on children and women who are pregnant and/or lactating are unknown.

Third Update (conditional or weak recommendation):

In regard to the third recommendation, the authors suggested the use of monoclonal antibody treatment with sotrovimab only among patients with nonsevere COVID-19 infection at increased risk for hospitalization, such as those who are unvaccinated, older adults, and those who are immunocompromised or have chronic diseases. Despite moderate certainty evidence that sotrovimab significantly decreases the risk for hospitalization (OR, 0.19; 95% CI, 0.06-0.51), with insignificant or no effect on mortality (OR, 0.11; 95% CI, 0.01-2.60), only a minority of patients are likely to benefit due to the risks associated with this therapy.

Sotrovimab should be administered at a dose of 500 mg in a single intravenous infusion over 30 minutes, and patients who receive the infusion should be monitored for 1 hour after administration. In addition, patients should receive the infusion immediately after testing positive for SARS-CoV-2 infection, up to 10 days after the initial onset of symptoms.

There was no evidence to support the use of monoclonal antibodies for patients with severe or critical COVID-19 infection.

Similar to the first recommendation, no children or women who were pregnant and/or lactating were included in the RCT that served as the basis for this recommendation. However, results of this RCT showed no evidence that responses to this medication would differ among either of these populations. Of note, children are significantly less likely to be at increased for hospitalization, thus the authors suggested this treatment only be considered among children who are immunocompromised.

Another monoclonal antibody previously recommended by the guideline authors is casirivimab-imdevimab. Sotrovimab and casirivimab-imdevimab should not be administered as combination treatment. The choice of monoclonal antibody treatment should be assessed using the most recent data on the effects of these medications. There are currently no ongoing head-to-head trials comparing the effects of sotrovimab with casirivimab-imdevimab, and all previous trials were conducted prior to the emergence of the Omicron variant.

These living recommendations will likely be updated about the efficacy of these monoclonal antibodies on the Omicron variant once sufficient data have been published. Although preclinical evidence suggests that casirivimab-imdevimab lacks neutralization activity against Omicron in vitro, Pseudovirus assays have indicated that sotrovimab retains neutralization activity at increased doses.

Conclusions and Future Directions

There are two major lines of research about which the guidelines authors are focused on for ongoing or future studies:

  • Accurate guidelines for establishing the predicted risk for hospitalization among patients with nonsevere COVID-19 infection.
  • Efficacy and safety of treatments for patients with severe or critical seronegative COVID-19 infection, those with infection caused by emerging SARS-CoV-2 variants, and among pediatric and pregnant populations.

This living guideline will continue to be updated by the WHO as new data emerges.

Reference

Agarwal A, Rochwerg B, Lamontagne F, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. doi:10.1136/bmj.m3379

This article originally appeared on Infectious Disease Advisor