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What are the most effective pharmacologic therapies currently recommended for treating patients with moderate to severe COVID-19 — and what therapies may soon be emerging?
The range of pharmacologic therapies used in the management of patients with COVID-19 is ever-evolving, as new evidence from randomized controlled trials (RCTs) becomes available. The World Health Organization (WHO) recently published the 7th update (8th version) of their living guideline on current treatment recommendations and supporting evidence for patients with COVID-19 at various stages of severity.1 Based on RCT results, the updated guideline includes a strong recommendation for: (1) the Janus kinase (JAK) inhibitor baricitinib (as an alternative to interleukin-6 [IL-6] receptor blockers) combined with corticosteroids for patients with severe or critical COVID-19; and (2) a conditional recommendation against using ruxolitinib and tofacitinib in severe or critical COVID-19.1
To gauge clinician perspectives on pharmacologic therapies for treating patients with moderate to severe COVID-19, Pulmonology Advisor checked in with 3 experts: Sarina Sahetya, MD, MHS, assistant professor in the division of pulmonary and critical care medicine at Johns Hopkins School of Medicine in Baltimore, Maryland; Matthew Exline, MD, director of critical care at Ohio State Wexner Medical Center University Hospital and professor of internal medicine at The OSU College of Medicine in Columbus; and Minjoung Go, MD, clinical assistant professor of medicine at Stanford University School of Medicine in Palo Alto, California.
Drug Choice Depends on Disease Severity
Dr Sahetya: Just to make sure we are on the same page as we talk about moderate and severe COVID-19, moderate COVID-19 means that someone has evidence of lower respiratory illness such as pneumonia, but their oxygen levels are still in the normal range.2 Patients with moderate COVID-19 may be hospitalized but are more likely to be treated out of the hospital unless they have other comorbid conditions that put them at higher risk for decompensating.
Severe COVID-19 means someone has evidence of lower respiratory infection and has oxygen levels less than 94% or other signs of respiratory failure such as rapid breathing. Patients with severe COVID-19 should almost certainly be hospitalized to receive oxygen therapy and closer monitoring.2
The indications for different COVID-19 drugs are often stratified based on whether a patient has low oxygen levels. We don’t always see patients with moderate COVID-19 in the hospital unless they also have other issues that may put them at higher risk for a poor outcome. The main drugs that these patients can get while hospitalized are monoclonal antibodies and, based on a very recent clinical trial, remdesivir.
Monoclonal antibodies and antiviral agents like remdesivir are most effective early in the infection when viral levels are still high and the patient’s immune system hasn’t completely responded yet. Unfortunately, many people don’t come to the hospital until they are many days into their illness as they try to tough it out at home, which makes these therapies a little less effective than if given early in the disease process.
Dr Go: Effective treatment options may depend on the duration of symptoms at the time of hospital admission, medical comorbidities, and speed of the disease progression. IV remdesivir effectively decreases the recovery time among hospitalized patients based on the Adaptive COVID-19 Treatment Trial (ACTT), and it is probably most effective among patients who presented at the early phase of the COVID-19 infection.3
Targeting Inflammatory Response
Dr Exine: There are basically 2 strategies in treating COVID-19. The first is to provide treatments that target the virus itself: either antiviral medications or antibodies against the SARS-CoV-2 virus. The second set of treatments target the body’s inflammatory response to the virus. In general, once a patient has moderate to severe COVID-19 and is hospitalized, the antiviral treatments have little to no effect and most of the treatments that have been shown to be beneficial at this point are the anti-inflammatory treatments. This includes corticosteroids (usually dexamethasone) and other medications that block the body’s immune response.
Dr Go: Dexamethasone is effective for patients with moderate oxygen requirement (above 3-4L) regardless of the duration of symptoms. Patients with a rapid increase in oxygen requirements (high flow or noninvasive ventilation) benefit from baricitinib or tocilizumab. These treatments align with the National Institutes of Health (NIH) COVID-19 treatment guidelines.4
Dr Sahetya: For severe COVID-19, there are a few drugs that can be given, but in my opinion the most effective have been steroids and tocilizumab. These drugs are used to treat the inflammatory response to the virus.
I remember when the clinical trial showing that steroids were beneficial came out and it felt like a game-changer. It was a cheap, safe, effective therapy that we could give to pretty much everyone who had low oxygen levels. However, there were still clearly patients who had ongoing inflammation despite steroids and needed something more.
Tocilizumab, an IL-6 inhibitor, could be given to patients whose inflammatory response was ramping up to really help stop it in its tracks. Some other medications, like baricitinib, are also aimed at decreasing the inflammatory response and have been shown to improve outcomes in clinical trials, but it’s hard to know where to fit them in at this point.
Aligning Clinical Practice With WHO and NIH Recommendations
Dr Sahetya: I think the WHO living guideline1 has done a tremendous job providing updated recommendations for clinicians, especially considering the mountain of publications they have to keep up with.
Dr Exine: The WHO guideline1 is consistent with my clinical practice. For hospitalized patients the treatments have not changed much during the Omicron surge. However, there are new monoclonal antibodies and antiviral medications such as ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir which may be beneficial when given to patients early in their infection to prevent hospitalization.4
Dr Sahetya: My clinical practice aligns very closely with the WHO recommendations [with] 1 exception. The WHO has a weak/conditional recommendation against remdesivir.1 This is different than the NIH COVID-19 guidelines which have a moderate recommendation for remdesivir.4 I use remdesivir in most patients with moderate-severe disease, and I think the clinical evidence supports that decision, especially if it is early in the disease course.
Dr Go: WHO does not recommend remdesivir regardless of the illness severity, whereas NIH recommends it for hospitalized patients, especially with an early course of the disease (symptom onset less than 10 days).1,4
Scientific evidence suggests the benefit of intravenous (IV) remdesivir. I agree that it is an effective treatment for the appropriate patient population. ACTT-1 demonstrated a decrease in recovery time among hospitalized patients.3 A recent study showed that a 3-day course of early treatment decreases the risk of disease progression among non-hospitalized patients with high risk for COVID-19 progression.5
I can see why WHO does not recommend IV remdesivir, as the WHO recommendation focuses on mortality benefit. The WHO needs to consider additional factors — such as cost, delivery methods, resources variability, disparity, and practicality — as their recommendations are targeting the global community.
Although remdesivir has not demonstrated mortality benefit, its reduction in recovery time provides significant tangential benefits to patients and the healthcare system, including a decrease in hospitalization duration.
Emerging Therapies Under Investigation
Dr Sahetya: Researchers continue to try to identify therapies that could benefit hospitalized patients. Most of the current medications fall into either the antiviral category which could be given early in the disease, or an anti-inflammatory therapy which could be given later as people get sicker.
Other therapies being investigated are drugs targeting the hypercoagulability and vascular inflammation that lead to thrombotic events seen more frequently in COVID-19 patients.
Another pathway being researched is the renin-angiotensin-aldosterone system. The NIH has a large platform trial investigating multiple drugs in all these pathways to hopefully keep identifying new and more effective targets for treatment.6
Dr Exine: Many additional anti-inflammatory agents are currently being investigated across the country and the world. It is crucial that as many patients as possible take part in clinical trials to see if there are additional medications that may be helpful in the treatment of COVID-19. As we discussed above, for patients that are in the hospital, there are only a handful of medications that have been proven to reduce mortality. There is a need to determine if there are other therapies that may be beneficial either to treat COVID-19 or to prevent long-term complications of COVID-19.
Dr Go: Immune modulators (infliximab, abatacept, and cenicriviroc) and monoclonal antibodies are being investigated for hospitalized patients with moderate to severe disease. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) is an excellent resource for current trials for this subset of patients.6
Where More Research Is Currently Needed
Dr Go: A better understanding of the short-term and long-term sequelae of COVID-19 infection is needed. I hope the RECOVER trial (Researching COVID to Enhance Recovery) can provide more insights into this area.7
Dr Sahetya: Although many clinical trials are ongoing to identify new therapies, I actually think the most pressing needs for the next wave aren’t just new drugs. The 3 areas I think about are:
1. Comparative effectiveness of already available drug. We have a reasonable amount of therapies that have been identified from current clinical trials. Now we need to figure out which populations they work best for and how to prioritize them. I would love to see trials comparing tocilizumab vs baricitinib, or remdesivir vs monoclonal antibodies. As we add more drugs to our arsenal against COVID-19, we need to know how to use them for the right people at the right time.
2. Pandemic preparedness. With each surge from a new variant, hospitals were completely overwhelmed with the influx of sick patients and the efflux of burned-out health care workers. We need to take the time in between surges to better prepare our work force and health care systems for the next inevitable wave. This means competitively hiring and training more health care workers — not just nurses, but also radiology technicians, phlebotomists, respiratory therapists, physical therapists, environmental services — all the people who help the hospital run. It also means establishing ways for hospitals to triage and transfer patients at a state and regional level to share the burden.
3. Vaccines. We still need vaccines approved for children under 5 years old. This has to be prioritized moving forward to avoid leaving vulnerable children and their parents behind. We also need more research on vaccines for different variants, how to effectively get them to the rest of the world, and how to reach the vaccine hesitant.
Dr Exine: Many patients hospitalized with COVID-19, especially those admitted to the intensive care unit (ICU), may develop severe scarring of the lungs. This mimics diseases such as pulmonary fibrosis. Many patients are left requiring long-term oxygen therapy or prolonged mechanical ventilation. In rare cases, lung transplant is necessary. Treatments aimed at preventing this fibrosis are necessary to prevent some of the most severe long-term complications of COVID-19.
The Most Effective Therapy: Vaccines
Dr Sahetya: The most effective therapy I have seen are vaccines. It’s been a very long time since I had to take care of a fully vaccinated patient in the ICU who wasn’t immunosuppressed in some way.
Dr Exine: Every article on COVID-19 should end with the statement that the vast majority of patients needing therapy for moderate to severe COVID-19 are unvaccinated. Use of the vaccine to prevent severe disease is the best treatment we have in our arsenal.
Dr Go: One of the most critical treatment and prevention methods is vaccination against COVID-19. As clinicians, we need to continue to encourage patients to be vaccinated against COVID-19.
References
1. 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
2. National Institutes of Health. Clinical spectrum of SARS-CoV-2 infection. COVID-19 Treatment Guidelines. Updated October 19, 2021. Accessed March 4, 2022.
3. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764
4. National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Updated March 2, 2022. Accessed March 4, 2022.
5. Gottlieb RL, Vaca CE, Paredes R, et al; GS-US-540-9012 (PINETREE) Investigators. Early remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med. 2022;386(4):305-315. doi:10.1056/NEJMoa2116846
6. National Institutes of Health. NIH-funded ACTIV/ACTIV-associated clinical trials. Updated March 2, 2022. Accessed March 4, 2022.7. National Institutes of Health. NIH builds large nationwide study population of tens of thousands to support research on long-term effects of COVID-19. September 15, 2022. Accessed March 4, 2022
