“These stories raise important questions about how doctors should use the most effective Covid-19 treatment to date."
- Jason Mast, science reporter, STAT
“The person who takes medicine must recover twice, once from the disease and once from the medicine."
- William Osler, Canadian physician, father of modern medicine
In late April, the Center for Disease Control and Prevention (CDC) reported that in the past six months more than half of Americans had contracted COVID-19. I’m sorry to report that I’m among them. I caught SARS-CoV-2 (or did it catch me?) on a recent visit to New York City to celebrate my medical school class’s 50th reunion. Upon my return to Minnesota, I tested positive for COVID, and began treatment with Paxlovid. So the topic of this week’s Germ Gems post—the challenges of treatment with Paxlovid—is more personal than most.
Paxlovid: who, why, when, and where? Paxlovid is a combination of two oral protease inhibitors (nirmatrelvir plus ritinovir). In my November 19, 2021 Germ Gems post, “News Flash—Pfizer’s COVID-19 Pill, Paxlovid, Looks Like a Winner,” I suggested this antiviral drug would be a game changer. The Federal Drug Administration (FDA) granted Paxlovid Emergency Use Authorization (EUA) on December 22, 2021. On April 14, 2022, the New England Journal of Medicine published the results of a randomized, controlled trial (RCT) of Paxlovid. According to this report, the risk of progression from mild or moderate disease to severe or life-threatening disease was 89% lower in those who received Paxlovid versus those who were randomized to receive a placebo, and there was no evidence of safety concerns. Treatment with Paxlovid needs to commence within 5 days of symptom onset and the only contraindication is hypersensitivity to Paxlovid.
These findings catapulted Paxlovid into first position of all treatment options for outpatients who are at least 12 years-of-age and at risk of progression to severe COVID-19. No other available oral outpatient treatment of COVID-19 can compete with Paxlovid. Merck’s antiviral molnupiravir which also has FDA EAU has an efficacy rate of less than 50%. Another oral agent, fluvoxamine (Luvox) that has FDA approval as an antidepressant was shown to reduce hospitalization and death in a RCT in Brazil, but this drug lacks FDA approval for treatment of COVID-19.
Scientists have suggested that everybody is going to get COVID-19 and not just once, but again and again. For the immediate future, Paxlovid will be the preferred treatment option. Nonetheless, taking Paxlovid is not without its challenges. Here are the three I confronted in my Paxlovid journey. When (it’s not if) you get COVID-19, you may face them too.
Challenge No. 1: Access. As I mentioned in my May 18, 2022 Germ Gems post, “Navigating the COVID-19 Controlled Pandemic,” the federal government consolidated most of the information you need regarding COVID-19 in one user-friendly website (Covid.gov). There you’ll find a “Tool Kit” designed for the County that you live in. Therefore, if you develop any of the symptoms you ordinarily would associate with an upper respiratory tract infection (“a cold”), the first thing to do is get tested for COVID-19. On the Covid.gov website you’ll find locations where you can get tested. Or better yet, if you haven’t already done so, you should order via the website 8 free test kits that will be mailed to you so you can test yourself at home.
If you test positive for COVID-19, the next step is to contact your primary healthcare provider who can tell you whether you have any of the underlying conditions that increase your risk for progression to severe disease. (If you’re interested, you can find a list of these 30 medical problems at “Interim DOH Guidance for Use of Paxlovid, May 11, 2022.”) If you fulfill the eligibility criteria, your healthcare provider can prescribe Paxlovid at the pharmacy of your choice.
To facilitate initiating Paxlovid in a timely manner, on May 26, the White House launched the first federally-supported “Test-to-Treat” site in Rhode Island, with more to come in other states. On Covid.gov, you can find pharmacies in your County that provide the Test-to-Treat option. While I applaud this innovative approach to facilitating early treatment, I believe it is a mistake to bypass your primary care provider—your internist, pediatrician, family medicine doctor, or physician assistant. (Also, I believe more thought needs to be given to equity issues, such as, how to get timely treatment to people who don’t have access to the Internet or, for that matter, to a primary care provider.)
Challenge No. 2: drug-drug interactions. Even though there were no safety concerns in the patients who received Paxlovid in the RCT that led to its EUA by the FDA, in the “real world” where patients are taking a wide variety of medicines, there is potential for developing what is called a “drug-drug interaction.” For Paxlovid there is a long list of such recognized interactions.
Assessing whether you are at risk of experiencing such a drug-drug interaction is one reason why you need to consult your primary care provider. (In my case, I have an outstanding internist, who not only provided a Paxlovid prescription but also advised me to stop taking my statin while I was on it.) If you receive your Paxlovid in a Test-to-Treat site, a medical professional should provide this service. (If it happens to be a pharmacist, you should know they are generally highly knowledgeable about drug-drug interactions, as well as the side effects of medicines.)
To help inform primary care providers about these drug-drug interactions, several organizations, such as, the Infectious Diseases Society of America (IDSA), provide guidelines on-line. (If you’re curious to know what they are, visit the IDSA’s guideline, “Management of Drug Interactions with Nirmatrelavir/Ritinovir [Paxlovid]: Resource for Clinicians.”)
Challenge No. 3: Paxlovid Rebound. I initiated Paxlovid within the first two days of developing symptoms (dry cough, runny nose, and feverishness), so I was confident I’d nip my COVID-19 in the bud. Sure enough, within four days my symptoms almost completely cleared, and my rapid in-home antigen test was negative. But then out of the clear blue, one day after completing five days of Paxlovid, my symptoms (runny nose and dry cough) recurred. And my rapid in-home antigen test was again positive.
At about the same time that my illness recurred I was reading a slew of articles about a new entity called “COVID-19 Rebound.” Initially, I was skeptical that this “rebound” entity even existed. And my skepticism was reinforced by the CDC’s statement that “A brief return of symptoms may be part of the natural history of SARS-CoV-2 infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status.”
Nonetheless, this “rebound” sounded exactly like what I was experiencing. (See the CDC’s May 24 Health Advisory, “COVID-19 Rebound After Paxlovid Treatment”). My anecdotal experience suggested the entity is real, and I was reassured to read there are no reports of severe disease. The CDC recommended a wait-and-see approach with no additional Paxlovid. Within an additional five days my symptoms cleared, and I was again rapid antigen-negative.
Future challenges with Paxlovid treatment. To date, resistance of SARS-CoV-2 to Paxlovid has not been reported. But as is suggested by science reporter Jason Mast in a May 27 article in STAT News, “Coronavirus hasn’t developed resistance to Paxlovid. How long can that last?,” this is likely to happen. And development of resistance will be fostered by increasingly widescale use of Paxlovid.
Antiviral resistance isn’t new. In the early years of HIV treatment, for example, rampant antiviral resistance of this RNA virus occurred that led to the strategy of using multiple drugs that acted at different targets within the virus, including inhibitors of viral protease (the same enzyme in SARS-CoV-2 that is targeted by Paxlovid). Thus, while we should applaud Pfizer for developing the potent viral protease inhibitor, Paxlovid, pharmaceutical companies should be incentivized to discover additional drugs that act at sites within SARS-CoV-2 other than its protease. (Merck’s antiviral drug, molnupiravir, induces mutations in the virus’s RNA, and down the line, testing a drug combination with Paxlovid may be considered.)
Paxlovid treatment: the big picture. Preliminary evidence suggests that Paxlovid treatment doesn’t prevent infection. It therefore remains essential that all eyes aren’t taken off the mainstay of COVID-19 prevention—vaccination. It is important to remember that none of the COVID-19 vaccines are 100% effective, but by and large, full vaccination (including two booster shots) is still effective in preventing severe disease. Also, it’s important to remember that although SARS-CoV-2 can and does cause life-threatening disease, a very large, and perhaps growing majority of COVID-19 infections now resemble the common cold. If you’ve recovered from such an infection, before going to bed tonight, please thank your immune system for its service whether it acted on its own or by priming with a vaccine.
very good, informative!!! Should be read by many