Activity Transcript

Richard A. Elion, MD: Hello there. I'm Dr Richard Elion, Clinical Professor of Medicine at George Washington University School of Medicine, talking about COVID oral therapeutics, how to implement current antivirals into practice. You see here the Medscape Education disclaimer. There's been previous webinars prior to this one to help broaden your education and understanding of the topics. The first one was about testing and treating. The second one was about updates on treatment for non-hospitalized patients. And today's webinar's going to focus on oral therapies, implementing current antivirals in practice, some of the different dynamics that one thinks about, and also a view towards long COVID.

We can get right into just for the material. So if an unvaccinated patient or even perhaps a vaccinated patient presents with minor symptoms, are you likely to treat based on presentation or on patient demographics? Let's go over 3 different cases. The first is an immunocompromised patient. A male 68 years old, presents with mild symptoms of an URI and SARS-CoV-2 positive antigen test of 1-day duration. Has a history of multiple myeloma, had a bone marrow transfusion 8 years ago, off all medicines, was told he was cured. He's got hypertension, and he's got an elevated BMI -- He's obese. His labs are within normal, O₂ sat[uration] greater than 97%.

Second case, a male, 40 years old. LR has wheezing and a cold and is sneezing a great deal producing purulent mucus. He says he gets asthma when he has a cold but not otherwise. He's on inhalers in the past, both steroids and bronchodilators to use when he's symptomatic. His labs are within normal limits.

Third case, FS presents with a mild cold. Female, 65 years old. She presents with a mild cold with a slight cough and a runny nose. She doesn't feel sick at all, wouldn't have gotten tested if she wasn't going to a friend's home for dinner; she's a responsible friend. History of pre-diabetes, elevated blood sugars but not in the diabetic range. Elevated BMI of 32. Hypertension that's well treated on amlodipine 10 milligrams daily. She has a history of a pituitary adenoma that's been successfully treated. Her labs are within normal limits except for elevated lipids.

How would you think about each of these 3 patients differently, or would you think of them differently? We know that when we look at the timeline of SARS's testing that the original time we first start to see the antigen positive is somewhere, and you can see here, after the onset of symptoms and just at the beginning in that first period of time. It then goes on that PCR becomes positive later. Excuse me, PCR is becoming positive earlier. But we're not detecting that. So the antigen is really your first marker, and it's occurring in the first week.

There are some interesting aspects about how we look at the patients who come in based on their history of prior vaccination or not. There's obviously been a big debate in the United States about vaccination, non-vaccinated, recent ruling suggesting that the military no longer needs to be vaccinated. I thought it would be useful to review some of those data. The first is that patients had a 2-fold lower rate of infection following a prior COVID infection compared with vaccinated individuals. There was an additional 4-fold reduction for acute care hospitalization or fatalities for those with prior infection compared to those vaccinated. In other words, having a natural exposure is synergistic with vaccination. It doesn't imply that it should be used in place of, but it certainly adds a greater level of protection. To take this one step further, vaccinated individuals without prior COVID infection were 3-fold more likely to contract COVID-19 than unvaccinated people with prior infection, so that having prior infection confers a greater degree of protection then merely vaccination.

Finally, the duration of this protection from infection is shorter with vaccination compared to natural infection, and this is greatly improved by subsequent vaccination. And the point of this slide is to help us understand the synergies between natural exposure, the development of natural immunity from COVID-19 itself, and also the benefits and the synergies of vaccination. We've come to a world these days where we talk so much about the vaxxers and the anti-vaxxers. And in fact, each of them has something to learn from each other. And I think as healthcare practitioners, and especially when we talk to our patients, we want to present to them the data so they can make the best possible decision.

The decision that our individuals face here is relationship to which of these treatments are going to be the best. You see here that we've got it grouped by no illness, exposed, and mild to moderate symptoms. So for the no illness, baseline health status, infection, COVID vaccinations, we could have thought for some of those people to use monoclonal antibodies for PrEP. For those who are exposed, the question is, is someone who exposed be someone we would ever give antivirals to? And the answer to that is no. We save the use of antivirals for people who have a positive test. And then the question becomes, we have mild to moderate symptoms. Well, what if they have no symptoms? And so we see here the choices of therapies. The first 2 choices for oral are either Paxlovid (nirmatrelvir and ritonavir -- I still have trouble saying that). Or molnupiravir is the alternative. Or the question about monoclonal antibodies, and we'll talk about those shortly, or remdesivir. And then we get into all of the other issues around hospital admission and ICU admission.

But the real subject for today's conversation is about these patients who fit into asymptomatic vs any symptoms, and what is the rational selection for the use of antivirals or not. So there are major risk factors for deciding about for severe COVID, and part of what we're talking about with antivirals is preventing the complications of infection. We know that when you look at the impact of antivirals on the duration of viremia, in fact, the time till first symptom appearance and when you start seeing declines in the disappearance of virus, it is not that different if you start on antivirals or if you [are] just exposed. Where it's different is really thinking about the risk of development of illness. And you can see here that folks who are over 65 [years], have underlying comorbidities such as past history of cancer, obesity, chronic liver disease, hypertension, diabetes type 1 or type 2, CKD, all of which affected some of the cases that we talked about in the earlier section, these are all rationales for pushing one to think about treatment. In essence, the use of antivirals in this setting is really to prevent functional impairment to prevent disease but not necessarily to shorten the duration of symptoms.

There are varying clinical spectrum of COVID-19. Mild is the ones where people have just colds and normal x-rays; moderate, where there's more lower respiratory disease by perhaps wheezing or perhaps chest x-rays showing increased interstitial markings, reflected in declines in SpO₂ saturations 94% or in that region, or lung infiltrates. And then you get into severe and critical, which we're not going to talk about because this wouldn't be where we'd be looking at outpatient management. The severity of illness, for the most part, 80% is mild. 14% are severe, 5% are critical. I would argue that this is different now. We know that in folks who've been vaccinated, and to some degree in the population that's been exposed from natural immunity, we see much, much lower risks of severe disease. We know with vaccination alone, the risks are markedly, markedly reduced. So it's not at all this kind of a significant picture.

So the first approach is to understand, A, is the patient positive. Two, to then evaluate the patient in terms of severity. The use of pulse oximetry I think is... It's listed as key here. I think in clinical practice, more often than not, it's optional. Is there any shortness of breath? Is there increased respiratory rate? If there's not, I don't think you always have to get an oxygen saturation. Most patients these days are monitored without oxygen saturation. To determine the presence of high-risk conditions, the comorbidities we described, and then if that's the case, to decide on what would be the appropriate therapy. When we talk about this appropriate therapy, we see that in general there's certain things that need to be considered because of the fact that Paxlovid has a CYP3A inhibitor, ritonavir, in it.

So the first decision tree is: is the patient hospitalized, requiring O₂? If that's the case, we send them into the hospital, and they have different set of guidelines that they're looking at. And then perhaps we're using Paxlovid or remdesivir, and then we'll talk about the use of other agents. If however, the symptoms are in the last 5 to 7 days, and really within the last 1 to 5 days, not later than 5 days, then the consideration of antivirals is appropriate. Paxlovid is certainly one of the therapies that I think is the most commonly used. It has to be done within 5 days of symptom onset, and it has to be modified based on renal impairment. There are 2 different ways that Paxlovid is provided. The first is if the eGFR is greater than 60 [mL/min], then you use the 300 milligrams of nirmatrelvir taken with a hundred milligrams of ritonavir twice a day for 5 days.

If on the other hand, the GFR is less than 60 [mL/min] but greater than 30 [mL/min], then the dose of the nirmatrelvir is reduced from 300 [milligrams], which you would've used for those over a GFR of 60 [mL/min], to 150 [milligrams], which you use for those between 30 [mL/min] and 60 [mL/min], taken again with a hundred milligrams of ritonavir for 5 days. And then any other drug-drug interactions have to be done on a case-by-case basis because anything that's cleared by the CYP3A system would have a drug-drug interaction. There are other agents that could be considered here as well besides the use of Paxlovid. Remdesivir and molnupiravir are also relevant to talk about here as well. Molnupiravir is if the patient is 18 [years] or older, and it'd be 800 milligrams by mouth Q12 hours for 5 days, again, beginning within 5 days of symptom onset. Remdesivir is also considered an option for this setting, but because it's IV, it's not used that often.

So the practical considerations, let me just review this one more time. We see that for ritonavir-boosted nirmatrelvir, greater than 12 [years of age] and greater than 40 kilograms, time from onset less than 5 days, PO administration. I already viewed the GFR. Therapy lasts for 5 days. Remdesivir, given IV, doesn't have the renal issue. You see the dosing, 200 milligrams on day 1, a loading dose, and then 100 milligrams in 2 to 3 days, done for 3 days. But IV, so not used that often. Molnupiravir if a patient's greater than 18 [years of age], again less than 5 days, 800 milligrams BID. And then finally, antibody treatment, bebtelovimab, greater than... never can't pronounce those very well. This is for greater than 12 [years of age] and greater than 40 [kilograms]. Time from onset has to be less than 7 days, and you can see the dosing. However, this has now been in somewhat use of decline because of changes in the variants, which I'll address shortly.

Special considerations, we talked about vaccination status or not. Perhaps if one was vaccinated, you should look at it one way, but arguably, if one had previous COVID and this is a second infection, you might have a little bit more equipoise. On the other hand, I think ultimately it's about the functional status of the patient. Do they have any comorbidities? They have moderate compromise, pediatric populations, pregnancy or recent pregnancy, any history of inflammatory disorders in the past? One of the concerns about post-long COVID is this issue about post-acute multi-systemic inflammatory syndrome. So this would be a reason why you'd want to treat earlier. Or if they have actual long COVID, that would also, I think, urge you to treat more aggressively.

In terms of the impact of these agents on the variants and what these agents have been over time, the only one that's really shifted out has been the antibody treatment. With omicron being the predominant variant these days rather than the delta or others that were present earlier, this is now considered for the most part inactive. And so as of November 30th, 2022, the FDA announced that this would no longer be authorized for emergency use and is not recommended. So these days, really, when you're looking at outpatient, if you're looking at oral, you're looking at Paxlovid or ritonavir-boosted nirmatrelvir or molnupiravir, which are the 2 oral agents. For the most part, people tend to use more nirmatrelvir because of rates of success, but those studies were done in unvaccinated patients, and we don't have true studies really comparing them very closely in vaccinated settings, or remdesivir, again, which is IV.

We can talk about the need for these therapies. However, these therapies are not being given equally to the population. As compared with white patients who are treated with Paxlovid, black patients received them over a third less often. Asian patients received them approximately 20% less often, and Hispanic patients received them 30% less often. I doubt that this is necessarily a proxy for one's ethnicity as it may be for socioeconomic status, but the bottom line is every patient deserves equal right to these therapies and equal right to the best healthcare they can provide. And currently, we're not really hitting that bar, which mirrors our approach in other areas of the United States’ therapeutics. So for all of you out there, think about that when you're seeing patients. Become an advocate in your community, both for other providers and for your patients. Help other providers understand the risks of the various populations, who's been underserved in that setting, who's not accessing those therapies, and how you want to go about helping that situation.

One of the biggest questions with Paxlovid is rebound, and the same for molnupiravir. In studies of ritonavir-based therapies, ritonavir-based nirmatrelvir, the rates of rebound have gone as high as 2% to 14%, and I've seen other studies that have listed as high as 20%. The rates generally increase as more time increases post-treatment, but many investigators have speculated the viral replication is occurring out to 7 days. So a treatment period that only lasts for 5 days is going to undershoot, perhaps, the necessary therapeutic window, and perhaps longer periods of time would be indicated. There are current studies looking at longer periods of time -- 7, 8 days of treatment. But for the most part now 5 days are what's offered, and 5 days have been associated with at least 80% successes in treatment. And the question about rebound is a slightly different story. I don't think that we think of rebound as a reason to withhold treatment, but it's something that has to be explained to the patient when they're deciding what to do.

There is a problem with any infection with COVID, and that is that not everybody gets better, and that the issue about post-COVID is a definite challenge. We know that post-COVID can last weeks, months, or longer. Close to 20% have symptoms lasting greater than 3 months, and there's no adequate test that can really identify that. In order to help understand that, again, we talked about 7% of patients are experiencing long COVID, more common in younger adults, more common in women, and more common in Hispanic and Latinx vs non-Hispanic, white, black or Asian patients. The risk factors include type 2 diabetes, circulating viremia, why COVID is continues to replicate and persist, patients with past Epstein Barr virus, and certain auto antibodies, suggesting perhaps an altered immune response is responsible for the perseveration of either viral replication or inflammation that leads to some of the symptoms associated with COVID.

It can affect a variety of body systems and physiologic functions because it's a systemic disorder. It's an inflammatory systemic disorder, so it can impact any of the areas you see. When we talk about some of these definitions, you can look here, and you can see it can affect kidney -- proteinuria, hematuria. It can affect GI -- diarrhea. It can affect pulmonary -- chronic cough. It can affect the heart -- cardiac arrhythmias. Neurologic -- headaches, dysfunction, change in memory, perhaps even changes in personality. Dermatologic issues. It's a systemic inflammatory disorder, so it can affect various parts of the body.

There are a variety of symptom inventories that can be done to assess this. You can look at functional tests, and you can download all of these to test and try this to look at one's functional assessment, to look at one's functional capabilities. And there are also things that can be filled out for neurologic, psychiatric conditions, respiratory conditions to help get a qualitative function to all of this, not just assessing what one did but also what the patient's experience is.

The potential causes of long COVID, I think, are still being understood. You can see here that on pulmonary you can have alveolar damage, cardiovascular, myocarditis, changes in oxygen perfusion resulting in MIs, neurologic -- neurotoxicity, probably directly related to impact on myelin and of the nerves themselves. It's a host of injuries that occur, really reflecting a broader post-viral, post-inflammatory syndrome. We've seen this in other infectious diseases in the past, and so the treatment and the approach to this is still in evolution. When we look at databases that look at the results of this, you can see that looking at a 2-year [retrospective cohort] with over a million patients that most of the common psychiatric disorders returned to baseline, but persistent cognitive deficits including psychotic disorders and dementia were still appearing at a 2-year period. And children were not at increased risk of mood or anxiety, but had similar presentations as adults.

This long COVID, we talked about. Again, these slides will be available to you. They can really affect so many different symptoms of the body that it becomes very difficult to really say for someone who had any amount of this prior to their COVID infection, what's new or what could be an exacerbation due to this inflammatory disorder. We know that when we look at people who were vaccinated, get infected, and then get into long COVID compared to those who were infected and got long COVID and then got the vaccine, that low-level evidence suggests that vaccination prior to infection could reduce the risk of long COVID. Two doses of vaccine more effective than one. And I think that the booster with the omicron variants will be even more impactful. And the impact of vaccination on those who had already developed long COVID were not as clear in that benefit.

Early antivirals, can they prevent it? I think that we're still waiting on those data. We know that receiving COVID vaccinations decreased the use. It's not a hundred percent clear that the use of antivirals will impact that. If it's related to viral load, it should. If it's related to just exposure, and it's an inflammatory disorder, it might depend on the duration of the viral stimulation that is made on the immune system. And so the jury's not finally in on that yet. There are a variety of treatment modalities that can be tried. I'll leave these for you to look at. The bottom line is we don't yet know what's going to work the best. These are some of the treatments that are under investigation. You can see a variety of targets for these treatments in general, these are all treatments that are intended to impact the inflammatory and autoimmune part of this, and whether we can affect that as the primary issue or whether we have to do supportive care for the physiology to improve physiologic function will be the subject of upcoming research studies.

In terms of dealing with this, I think all we can do is help patients to understand their risks and help the household contacts understand that those people who might have long COVID are not actively infectious anymore. For those people who've recently had COVID, you might want to delay the next vaccine dose, you don't have to get it right away, by 3 months from when your symptoms started or if you had no symptoms when you first received a positive test. There's a variety of things that we can do for helping patients to understand, and I think that part of both the issue about both antivirals as well as the risk of long COVID is something that we have to go over and explain to patients and help them understand so they can best make their risk [assessment].

We've come to a point in both science and therapeutics with COVID where we must be very careful to make sure that we as providers are advocates and educators for our patients; advocates, meaning advocate for them to make informed decisions, not necessarily advocate for them to do a particular therapy. With vaccinations as well as antivirals, I think we point out to our patient the benefits and the risks. I think for all of us, we believe that the benefits and risks are very strong for vaccination. And for the use of antivirals, there's certain situations where certain patients would be well served to do that.

Finally, in conclusion, COVID is in a very different stage now than it was two and a half years ago. I think back on February 2020. We're in a very different stage thanks to vaccinations, but it has not disappeared. We've seen that the benefits from vaccination, as significant as they are, there are significant benefits to having had COVID. However, the idea of getting auto-infected to provide that immunologic benefit is not a viable strategy because of the risk of disease. We know that the earlier treatment that we can treat for COVID to help reduce viremia and reduce the risk of long COVID is critically important, and that's part of the reason that we're advocating for what we hope will be a benefit of long-term therapies. And for providers, I hope that we can all find a way to help our patients understand these benefits and these risks so they can make a better-informed decision.

Thank you all for taking the time to be with me today. Thank you all very much. Have a great day.

This transcript has not been copyedited.