Episode 3: Highlights in the Treatment of COVID-19

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Matteo Bassetti, MD, PhD: Hello. I am Matteo Bassetti. I am professor of infectious diseases at the University of Genoa and chief of the Infectious Disease Clinic in San Martino University Hospital in Genoa, Italy. Welcome to Medscape's InDiscussion series on COVID-19. Today we will discuss highlights in the treatment of COVID: antivirals, corticosteroids, immunomodulators, and monoclonal antibodies. I think the situation now is different compared to what it was 3 years ago. However, it's important to discuss the different options.

First, let me introduce my guest. Dr Tobias Welte, who is a professor and head of the Department of Respiratory Medicine and Infectious Diseases at Hannover Medical School. Welcome to InDiscussion, Tobias.

Tobias Welte, MD: Pleasure to be here with you today.

Bassetti: It is a pleasure for me. Tobias is a very important professor and was involved — and is still involved in the treatment of COVID — and he has a very great knowledge about COVID. Before we begin our discussion today, what was it that sparked your interest in COVID-19, and what keeps you engaged today?

Welte: Well, I'm the head of the Department of Infectious Diseases here in Hannover. When the coronavirus pandemic started in 2020, we here in Germany looked very excitedly — but in fear — to Italy and what happened in your region. I was chosen to organize the coronavirus measures here in the Federal Republic of Flöha Saxony in Germany. In between, I had been on the advisory board of English Public Health for Austria and for Greece. So, I got a lot of insights from other countries on how to deal with COVID.

Bassetti: This means that you are the perfect person to do this podcast today. As you know, the World Health Organization (WHO) says that the emergency of COVID has gone, and the media are talking about the fact that COVID is gone. But it's not true, particularly for immunosuppressed and immunocompromised patients.

What is your idea about the future and the presence of COVID, not only in the general population but particularly in immunocompromised patients?

Welte: In principle, I would say COVID has not gone. COVID is here. And it's not only here for special patient groups, although special patient groups are at high risk for a more severe course of the disease. Altogether, COVID is still in the population. I do not know how it is in Italy, but in Germany, we have no surveillance system in place at the moment, so we do not know what the daily incidence is and what's going on in the population. But what we see here in the hospital is mainly immunosuppressed patients, and this is mainly the group of transplant patients — kidney, worse than lung, then liver, then heart. Then also the patients with hematological disorders, so lymphoma and leukemia, mainly when the B-cell compartment is affected. And then it's the patients with autoimmune disease who are treated with B-cell-depleting treatments — anti-CD20, such as rituximab — who are still at risk.

Bassetti: What about the elderly population? Do you believe we can have a patient profile based on the comorbidities? Are you still seeing hospitalizations and death in this type of patient?

Welte: Yeah, the elderly patient is a bit tricky. First, I am not so amused by age being a defining factor. There are very, very fit 75-year-old people, and these are not at-risk patients. It's more the multimorbid patient.

Multimorbidity is the main cause for more severe courses of COVID. If you are a chronic respiratory patient, chronic heart failure patient, chronic kidney failure patient, a liver cirrhosis patient, that increases your risk. So, the focus should be more on multimorbidity and frailty than on age.

And, yes, these patients are admitted to the hospital, and these patients die. But the cause of death is a little different than it had been in the pre-Omicron era. In the pre-Omicron era, it was COVID pneumonia, and most of the patients died due to acute respiratory failure. Now, it's multimorbid patients with a more intensive systemic disease. No more pneumonia, but the alteration of the other organ systems leads to a decompensation of the pre-existing organ failure. But, yes, there's still remarkable mortality in this patient group.

Bassetti: Looking at the future, what do you expect looking at the next autumn, the next winter? Do you believe we have to expect new waves like we had in the past, or will the scenario of the future be different?

Welte: That's very hard to say. I would say this is a Nobel Prize question. What we are facing now is very good population immunity, and this is a consequence of either vaccination or infection. For Germany, for example, 98% of the population show SARS-CoV-2 antibodies. However, what we know is with time since the last vaccination, with time since the last infection, the immune response is going down. If you look at antibody levels, mainly in the elderly and the comorbid but also in the immunosuppressed, 6 months after vaccination, there are no or only low levels of detectable antibodies. What I expect is the population immunity will come down, and there will be — as there is for every seasonal virus — an increase in prevalence in the autumn and winter.

The best scenario would be that there are other kinds of immunity — for example, T-cell immunity, which lasts longer than B-cell immunity — then we would not see a dramatic wave in the wintertime. The worst scenario is that with population immunity very quickly dropping down, we will have a coronavirus wave in the wintertime, as we have seen in 2020 and 2021.

Bassetti: Do you think that it is important to talk with health authorities to prepare and to have a strategy for the future? Or do we have to consider COVID-19 similar to many other diseases or viruses that we have experienced in the past? Is it important to have a COVID-specific strategy or a general overall strategy for respiratory tract infections?

Welte: Yes, you need a strategy. COVID may be the same as it has been with influenza for decades. So, yes, to your second point, having a strategy for all more severe viral respiratory diseases is what I'm in favor of. However, there are COVID-specific issues that need to be solved. To make it clearer, we need a vaccination strategy for the at-risk patients, which means the elderly, the comorbid, and the immunosuppressed. However, my personal expectation is that vaccination adherence will come down, because there is an exhaustion in the population. We need to advertise, but I'm not sure we will reach the same vaccination rates as we have seen in 2021 and 2022. Given this, I think we need to have good treatment strategies and antiviral strategies for those who are at risk. And we have to advertise that the drugs that are available are used not only in the hospitals but also by general practitioners.

Bassetti: We've still had the same variant for more than a year and a half. Do you expect new subvariants of Omicron, or do you expect new variants that are more pathogenetic? Or do we have to look at the future with variants that are more contagious but not more pathogenetic?

Welte: To be honest, I had expected that when the incidence rates increased again, we would see new variants. However, if you look at China, after the stop of the zero-COVID strategy, there had been about 200 million infections. I had, in fact, expected that we would see new variants. Very surprisingly, we did not see new variants. If there had been new variants, we would have seen them in the neighboring countries, and this is not the case. This means Omicron is a very dominating variant and very stable. And due to the high transmissibility, it will be very hard to substitute Omicron. So, at the moment, my feeling is the dominant variant for the autumn/wintertime this year will still be Omicron. It's not very pathogenic but very transmissible; nevertheless, we will see severe cases in high-risk groups.

Bassetti: You already mentioned antivirals. We know that we have antivirals, but looking at the past, we didn't use the right drug at the right time for the right patient, unfortunately. What have we learned from the past, and what can we do better for the future not only in terms of antivirals but also in terms of the other drugs? I know that you are an expert on corticosteroids. Is there still a role for corticosteroids outside of the hospital, or is the role only inside of the hospital? What is the role of the different antivirals?

Welte: What we learned is — and we had known this from the flu, for example — if you use an antiviral in respiratory infections, you have to start early. And for COVID-19, this means you have a time window of starting within the day of infection and ending after 5 to 7 days. The earlier treatment is initiated, the more effective it is. What we have seen in Germany, but I know it is a problem in other countries, too, is a structural healthcare problem because the site of diagnosis is not the site of treatment. General practitioners normally are more cautious in prescribing antivirals, so we need better, intersectoral care in the future involving the general practitioner area. For the other question, corticosteroids have shown to be effective in patients who are more severely ill, and they are mainly effective in patients suffering from COVID pneumonia. It's not very surprising that it has been shown in a recently published paper that in all kinds of community-acquired pneumonia, corticosteroids reduce morbidity and mortality.

However, with Omicron, there's very often no pneumonia, and I'm not sure whether corticosteroids are effective or have more benefits than harm in patients who do not suffer from pneumonia. This means outside the hospital, there's no place for corticosteroids. In patients who are not oxygen dependent, there's no benefit. Corticosteroids are focused on the more severely ill patients, and my personal opinion is they only work if there is severe hyperinflammation and pulmonary consolidation.

Bassetti: Going back to antivirals, could you please tell me and our listeners about the different options for the treatment of COVID-19? Could you please try to position the use of these three drugs in COVID-19 cases?

Welte: Yeah, it's more difficult than it had been months ago because molnupiravir, which is one of the orally available compounds, has not been approved by the European Medical Agency (EMA). There is a rebuttal procedure and a new hearing in June at the EMA site. However, at the moment, it's not reimbursed in most of the European countries. The reason for this is that the randomized control trials, which had taken place in the pre-Omicron era, did not show a convincing efficiency for molnupiravir. Personally, I'm convinced it's effective. It has very low side effects, and it's a drug we need for patients who need treatment. However, at the moment, it's not available.

Paxlovid is a very effective anti-coronaviral. It's designed to fight coronavirus; however, it has some side effects mainly in patients who are on a lot of other drugs — for example, immunosuppressants, antihypertensives, oral anticoagulants, or statins — because there is a competition in metabolism with Paxlovid and other drugs. So, there are a number of patients with a high usage of daily medication who cannot use Paxlovid due to side effects from these drug interactions. However, it's effective.

The third drug available is remdesivir. This is an IV drug; there's no oral form yet, but it should become available around the end of next year. The application of IVs outside the hospital is only feasible in very specialized settings.

Bassetti: Do you think that we need better structures for early treatment? And maybe include a very quick note about the role of monoclonal antibodies.

Welte: Monoclonal antibodies is a difficult topic because with different variants and even with Omicron dominating, Omicron is sometimes changing. And some of these monoclonal antibodies are not effective for new variants.

So, you need a variant-guided antimicrobial treatment, and it's hard to see where we are at the moment. We still use monoclonal antibodies but only in selected patients. We need a better collaboration among the outside hospital, the outpatient sector, and infectious disease specialists for special indications.

Bassetti: I would like to close this episode by asking you what advice you would share with a clinician who is treating COVID?

Welte: If it is a high-risk patient, and you see signs and symptoms of infection, you should treat these patients as early as possible after a COVID test. Even though the antigen tests are not the best ones, I would focus on this because it's quick, if the antigen test is possible. It's harder to oversee and not treat an at-risk patient, as you will then see him later in the hospital and the ICU.

Bassetti: Today, we have talked with Dr Tobias Welte about highlights in the treatment of COVID patients. We discussed antivirals, corticosteroids, and monoclonal antibodies. We also discussed the future of COVID and how to treat and manage this very important disease in the future. Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on COVID-19. This is Dr Matteo Bassetti for InDiscussion.

Resources

Coronavirus Disease 2019 (COVID-19) Treatment & Management

Anti-CD20 Monoclonal Antibody TL011

Rituximab (Rx)

Coronavirus Disease 2019 (COVID-19)

SARS-CoV-2 Variants

Not Just Antibodies: B Cells and T Cells Mediate Immunity to COVID-19

Antivirals, Including Antibody Products

Hydrocortisone in Severe Community-acquired Pneumonia

Molnupiravir (Investigational)

Nirmatrelvir/ritonavir (Rx)

Remdesivir (Rx)

Anti-SARS-CoV-2 Monoclonal Antibodies

Considerations for SARS-CoV-2 Antigen Testing for Healthcare Providers Testing Individuals in the Community

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