From Positive to Negative to Positive Again—The Mystery of Why COVID-19 Rebounds in Some Patients Who Take Paxlovid | Infectious Diseases | JAMA | JAMA Network
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June 8, 2022

From Positive to Negative to Positive Again—The Mystery of Why COVID-19 Rebounds in Some Patients Who Take Paxlovid

JAMA. 2022;327(24):2380-2382. doi:10.1001/jama.2022.9925

David Ho, MD, managed to avoid contracting COVID-19 for more than 2 years.

But SARS-CoV-2 finally got the best of the pioneering HIV researcher on an April trip to Paris for, of all things, a 2-day COVID-19 conference.

Europa Press/C.Luján.POOL/AP Images

The irony is not lost on Ho, director of the Aaron Diamond AIDS Research Center at Columbia University. He figures he most likely became infected at a preconference dinner for a small group of attendees. They dined inside a restaurant, and the waitstaff weren’t wearing masks, Ho explained in an interview.

Shortly after he returned home, Ho started coughing. His throat hurt, his head ached, his nose was runny, and he felt even more fatigued than a healthy person should after a quick trip across the pond and back. He immediately assumed that this was no cold, and a rapid antigen test followed by a polymerase chain reaction (PCR) test confirmed that he indeed had COVID-19.

About 12 hours after his symptoms arose, Ho swallowed his first dose of Pfizer’s antiviral nirmatrelvir/ritonavir, better known as Paxlovid. By day 4, his symptoms had resolved and he tested negative for COVID-19. After testing negative again on day 5, he ended his isolation from his family but continued to test daily.

After 6 consecutive negative rapid antigen tests, plus a negative PCR test, Ho awoke feeling under the weather. “I tested myself immediately, and I was completely surprised that I was positive again,” Ho recalled. “The initial shock was, ‘Wow, this is positive. I’ve never seen this.’”

A PCR test confirmed the positive rapid antigen test, and it was “back to jail” for Ho. “If you’re positive, you have to assume you’re infectious to others,” he explained.

In recent weeks, similar cases have been reported in the medical literature and on social media, prompting the Health Alert Network of the US Centers for Disease Control and Prevention (CDC) to issue a health advisory on May 24. COVID-19 rebound in people who’ve taken nirmatrelvir/ritonavir appears to be mild and short-lived, resolving, on average, in 3 days without additional anti-COVID-19 treatment, according to the advisory.

“I would say the anecdotes are pretty consistent and pretty pronounced,” H. Clifford Lane, MD, deputy director for clinical research and special projects at the National Institute of Allergy and Infectious Diseases, said in a recent interview. “Is there something here? If there is, what is it, and what do we do about it?”

No one is suggesting that people stop using the drug. In boldface type, the CDC’s health advisory says the agency continues to recommend nirmatrelvir/ritonavir for early treatment of mild to moderate COVID-19 among people at high risk of progression to severe disease, the population eligible for the drug under its Emergency Use Authorization (EUA), granted by the US Food and Drug Administration (FDA) in December 2021.

However, the unexpected rebound phenomenon raises questions about how best to use this antiviral. “There are more questions than answers,” Myron Cohen, MD, director of the University of North Carolina Institute for Global Health & Infectious Diseases in Chapel Hill and a leader of the National Institutes of Health’s COVID-19 Prevention Network, noted in an interview.

Choices

Under its EUA, nirmatrelvir/ritonavir can be prescribed for mild to moderate COVID-19 in nonhospitalized patients aged 12 years or older who are at high risk of progression to severe disease due to age, obesity, cancer, or chronic diseases such as type 1 or type 2 diabetes. (High-risk patients who have mild to moderate COVID-19 but are hospitalized for other reasons are also eligible.)

A 3-pill dose of Paxlovid consists of 2 nirmatrelvir pills and 1 ritonavir pill, which has no activity against SARS-CoV-2 on its own. Nirmatrelvir is a protease inhibitor that blocks SARS-CoV-2 from replicating, while ritonavir boosts nirmatrelvir by slowing its metabolism in the liver. Ritonavir, which has been used to boost HIV protease inhibitors, also can slow the metabolism of an assortment of other drugs, increasing blood concentrations too much. In many cases, though, drug-drug interactions can be managed by temporarily withholding, adjusting the dose of, or using an alternative to the concomitant medication and by increasing monitoring for potential adverse reactions, according to the National Institutes of Health’s COVID-19 Treatment Guidelines, advice echoed in Infectious Diseases Society of America guidelines published May 6.

While the antiviral remdesivir (Veklury) also has been shown to be highly effective in decreasing the risk of hospitalization of people with mild to moderate COVID-19, patients must go to an infusion center on 3 consecutive days for treatment. Nirmatrelvir/ritonavir pills, on the other hand, can be picked up at the drugstore and taken at home.

Similarly, the antiviral molnupiravir (Lagevrio), which received an EUA in December 2021 for treating mild to moderate COVID-19 in high-risk adults aged 18 years or older, is taken as a pill for 5 days, starting within 5 days of symptom onset.

However, when compared with a placebo in the clinical trials supporting their EUAs, molnupiravir, a collaboration between Merck and Ridgeback Biotherapeutics, was not as effective as nirmatrelvir/ritonavir in keeping patients out of the hospital. Molnupiravir is authorized for use only by patients for whom alternative FDA-authorized COVID-19 treatments aren’t accessible or clinically appropriate. Also, while nirmatrelvir/ritonavir is authorized for use in children as young as 12 years old, molnupiravir isn’t authorized for use in children younger than 18 years because it may affect bone and cartilage growth. Molnupiravir, which stops SARS-CoV-2 from replicating but via a different pathway than nirmatrelvir/ritonavir, is not recommended for pregnant individuals because animal studies suggest it could cause fetal harm.

The US government has purchased 3.1 million courses of molnupiravir and 20 million courses of nirmatrelvir/ritonavir, to be delivered this year. The Office of the Assistant Secretary for Preparedness and Response, part of the US Department of Health and Human Services, maintains a web-based site locator for drugstores and other facilities that have received an order of nirmatrelvir/ritonavir or molnupiravir in the previous 2 months or reported their availability within the previous 2 weeks. In addition, a constantly updated website enables people to search specifically for SARS-CoV-2 treatments in their community.

Although nirmatrelvir/ritonavir protects against severe COVID-19 in symptomatic people who’ve tested positive for SARS-CoV-2 infection, it doesn’t prevent individuals from becoming positive and symptomatic, according to an April 29 Pfizer press release about the findings of a randomized, placebo-controlled clinical trial among adults who had been exposed to SARS-CoV-2 through a household contact.

A Different World

Rebound isn’t even mentioned in the article that in April reported results from the EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial, which was the basis of Paxlovid’s EUA. Omicron isn’t mentioned either because trial participants, none of whom were vaccinated, contracted COVID-19 before Omicron burst onto the scene.

A clinical trial among unvaccinated people that predates Omicron, which now accounts for 100% of circulating SARS-CoV-2 in the US, “holds little clinical relevance” today, Emory University School of Medicine and Grady Health System infectious disease specialist Carlos del Rio, MD, said in an interview. Even unvaccinated people today are different from unvaccinated people pre-Omicron because they’re more likely to have had at least 1 previous COVID-19 infection, Cohen pointed out.

A study posted online May 26 but not peer-reviewed is one of the first to explore real-world effectiveness of nirmatrelvir/ritonavir and molnupiravir in vaccinated as well as unvaccinated patients infected with Omicron, according to its authors.

Conducted in Hong Kong, the retrospective cohort study focused on nearly 1.1 million nonhospitalized patients territory wide with confirmed SARS-CoV-2 infection during the Omicron BA.2.2 wave between February 26 and May 3, 2022. Among them, 5257 took molnupiravir and 5663 took nirmatrelvir/ritonavir.

Both antivirals were associated with lower all-cause mortality risk—a 39% reduction for molnupiravir, 75% for nirmatrelvir/ritonavir—compared with no antiviral use. Both also were associated with a lower risk of in-hospital disease progression—36% for molnupiravir and 53% for nirmatrelvir/ritonavir—compared with no antiviral use. Nirmatrelvir/ritonavir was associated with a 31% lower risk of hospitalization, while the hospitalization risk in patients who took molnupiravir was comparable with that of patients who didn’t take an antiviral.

Neither drug was associated with as high a level of protection among the Hong Kong patients infected with Omicron as was seen in its clinical trial among unvaccinated patients infected by the Delta variant. (In its trial, molnupiravir reduced hospitalization risk by 30% compared with placebo, while nirmatrelvir/ritonavir reduced it by 88%.)

In the Hong Kong study, nirmatrelvir/ritonavir use was associated with greater and more consistent protection than molnupiravir use, and the protective effects of nirmatrelvir/ritonavir were similar regardless of vaccination status and age. However, the apparent superiority of nirmatrelvir/ritonavir to molnupiravir in the study could have been due in part to a higher proportion of patients older than 65 years and a lower proportion of fully vaccinated patients among those who received the latter drug, the authors noted.

Pfizer is currently enrolling an estimated 1980 adults in a trial comparing Paxlovid with placebo, similar to EPIC-HR. But in the newer trial, participants have only a standard risk, not a high risk, of progressing from mild or moderate COVID-19 to severe disease. Another major difference between EPIC-HR and EPIC-SR (standard risk) is that all the participants are likely to have been infected with Omicron, not Delta, given the timing of the trial. Anyone who received any COVID-19 vaccine within 12 months of screening is ineligible to enroll in EPIC-SR, which means participants could have received their primary vaccine doses but not boosters.

Is It the Drug, or Is It the Disease?

The CDC’s May 24 health advisory noted 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.”

The FDA is aware of cases in which patients treated with Paxlovid tested positive at least once after testing negative, John Farley, MD, MPH, director of the Office of Infectious Diseases at the FDA’s Center for Drug Evaluation and Research, noted in an early May update for health care professionals. An additional analysis of the EPIC-HR clinical trial data showed that about 1% to 2% of participants in both the treatment and placebo groups tested positive after testing negative, Farley wrote, “so it is unclear at this point that this is related to drug treatment.”

In an email, Pfizer spokeswoman Jerica Pitts echoed the CDC and FDA. “We believe the return of elevated detected nasal viral RNA [is] uncommon and not uniquely associated with treatment,” she wrote.

Ho, coauthor of a study posted May 23 about 10 people—he is the second case described in the report—who rebounded after taking nirmatrelvir/ritonavir, disagrees. When asked whether he thought the rebound could be part of the natural course of SARS-CoV-2 infection, he replied “absolutely not.”

As evidence, he and his coauthors pointed to the experience of the National Basketball Association (NBA), which tests personnel daily. From December 14, 2021, to March 1, 2022, a period during which Omicron was dominant, rebounds occurred only on the basketball court—not among the nearly 1000 NBA personnel who were diagnosed with COVID-19 but not treated with nirmatrelvir/ritonavir, according to Ho and his coauthors. Their study had not undergone peer review.

However, Johns Hopkins breast cancer specialist Tatiana Prowell, MD, recently tweeted that she’s heard from physicians who’ve had patients with COVID-19 rebound or test positive on rapid antigen tests for up to 3 weeks, even though they never took nirmatrelvir/ritonavir or any other treatment. Perhaps, she speculated, Omicron and its subvariants take longer to peak or to clear than earlier SARS-CoV-2 variants. (Prowell had recently tweeted about how a household member’s symptoms disappeared and rapid antigen test results turned negative after completion of a course of nirmatrelvir/ritonavir. A week later, though, the symptoms returned, as did positive rapid antigen test results.)

Still, “[y]ou just didn’t hear about many rebounds pre-Paxlovid,” Robert Wachter, MD, who tweeted in May about wife Katie Hafner’s rebound after taking Paxlovid, said in an interview. “You have to say that there’s something about Paxlovid and Omicron that predisposes you to this phenomenon.”

The fact that few EPIC-HR participants experienced a rebound “gives me less confidence in all of the findings,” said Wachter, chair of the University of California, San Francisco, Department of Medicine. If he tested positive—despite his wife’s COVID-19 bout, he hasn’t—Wachter said he’d be “much more on the borderline” trying to decide whether to take Paxlovid than he would have been before he started hearing about rebounds.

“Even if rebounds turn out to be mild and self-limited, they have consequences for people in terms of their ability to go back to work or to school,” Wachter pointed out.

No one yet knows how common rebound is among people who’ve taken Paxlovid. “You need some very objective evaluation of it,” Lane said.

Ho dismisses Pfizer’s contention that rebound is uncommon. He and his coauthors noted that 5 of the 10 relapses described in their report occurred within 2 families—2 in his family and 3 in another—suggesting it isn’t rare.

That’s concerning, Ho said, because it appears that people who experience a relapse can infect others. Among the 10 cases in the report he coauthored, viral load during the relapse was comparable to levels during the initial infection. During their relapse, 1 symptomatic and 1 presymptomatic patient transmitted SARS-CoV-2 to family members, Ho and his coauthors wrote.

Trying to Figure It Out

Ho likely is one of very few people who’ve relapsed after taking nirmatrelvir/ritonavir and then sequenced their own virus both the first and second time around. (At least 1 other leading virologist, Peter Hotez, MD, PhD, of the Baylor College of Medicine, has revealed that he also experienced a post-Paxlovid relapse.)

Both of Ho’s sequences were identical, ruling out a couple of possible explanations for his relapse, he said. It couldn’t have been due to a stroke of bad luck—a second SARS-CoV-2 infection just as he was getting over his first one. And it couldn’t have resulted from the virus becoming resistant to nirmatrelvir. If either were the case, the virus pair wouldn’t have been identical.

Scientists have proposed a few other possible explanations for rebounds after nirmatrelvir/ritonavir treatment. “Question number 1 in my mind is the timing. I think maybe we’re giving it too early,” del Rio said. Perhaps, Wachter speculated, “If you get started right away, maybe you suppress the virus [and] the immune system doesn’t rev up in the way it normally would.” He and others have also suggested that 5 days might not be a long enough treatment course. “All these theories are total handwaving,” Wachter acknowledged.

To answer the outstanding questions about relapses, “I’m not sure we need a clinical trial in the classical definition,” del Rio said. “We need post-approval data.” It’s being collected, he said, but the findings probably won’t be available for months. For now, there is no evidence that additional treatment with nirmatrelvir/ritonavir is needed when a rebound is suspected after a 5-day course, according to both the CDC’s advisory and FDA official Farley’s recent update.

Despite all the questions about the rebound phenomenon, “the biggest challenge we’re having with the drug is it’s not being used as frequently as it should,” del Rio said. “Primary care physicians are freaked out about the drug-drug interactions.” The people in whom COVID-19 is most likely to progress to a serious or even deadly infection are also the ones most likely to be taking multiple medications, he noted.

One thing is for sure, testing is more important than ever, given the availability of effective treatments for COVID-19, Cohen said. “I see a sea change in the management of respiratory infections.”

Nobody says, “Oh, I think I have a cold” anymore, he explained. “If we’re going to treat people with COVID, we need to know if they have COVID.”

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Article Information

Published Online: June 8, 2022. doi:10.1001/jama.2022.9925

Conflict of Interest Disclosures: None reported.

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    3 Comments for this article
    EXPAND ALL
    Relapses after Paxlovid are Infectious
    Daniele Focosi, MD, PhD | North Western Tuscany Blood Bank, Pisa University Hospital, Pisa Italy
    The standard duration of Paxlovid treatment is 5 days. There are preprint case reports and case series of infectious relapses (1, 2), so patients should remain under isolation until the quick antigen assay is back negative.

    References

    1. Aaron F. Carlin, Alex E. Clark, Antoine Chaillon et al. Virologic and Immunologic Characterization of COVID-19 Recrudescence after Nirmatrelvir/Ritonavir Treatment, 18 May 2022, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1662783/v1]

    2. Julie Boucau, Rockib Uddin, Caitlin Marino, James Regan, James P. Flynn, Manish C. Choudhary, Geoffrey Chen, Ashley M. Stuckwisch, Josh Mathews, May Y. Liew, Arshdeep Singh, Zahra Reynolds, Surabhi L. Iyer, Grace C. Chamberlin, Tammy D. Vyas, Jatin M. Vyas, Sarah E. Turbett, Jonathan Z. Li, Jacob E. Lemieux, Amy K. Barczak, Mark J. Siedner. Virologic characterization of symptom rebound following nirmatrelvir-ritonavir treatment for COVID-19 medRxiv 2022.05.24.22275326; doi: https://doi.org/10.1101/2022.05.24.22275326

    id="gtx-trans" style="position: absolute; left: -8px; top: 260px;">
     
    CONFLICT OF INTEREST: None Reported
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    The Rebound Phenomenon is Not Unique to Paxlovid-Treated COVID-19
    John Leung, M.B.,B.S. | St. Paul's Hospital, Hong Kong
    The analysis and comments on Dr. David Ho's self-reported experience of a rebound of COVID-19 after treatment with nirmatrelvir and ritonavir is both informative and fascinating. The phenomenon of rebound is well-known in infectious disease. It was a common problem in the olden days when pulmonary tuberculosis was rampant. Even now, some patients suffering from various forms of respiratory infection may report an unexpected down-turn while they are well on the road to recovery. In the case of influenza we would readily blame it on new mutations as the influenza virus is notorious for such capability. Dr. Ho's meticulous sequencing of the virus genome on both the initial and subsequent virus specimens seemed to have dispelled such a mechanism and we would need to make further studies. I sincerely hope to see such works reported in JAMA in the not too distant future. In addition, as someone who has been practicing medicine for the past 64 years in Hong Kong, I am most appreciative of the citation of the recent report on our massive omicron virus outbreak in this review.

    CONFLICT OF INTEREST: None Reported
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    Potential Contributors to Apparent Rebound
    Kimthu Pham, MD, MPH | Hawai'i Department of Health, Maui District Health Office
    Prior experience gleaned from dealing with other infectious diseases might be applicable to addressing treatment failures of COVID.

    Consider the case of drug-resistant P. falciparum malaria some 30 or 40 years ago. At that time, we (Pang and colleagues) put forth various principles to elucidate why some treated patients were cured while others  failed treatment within a given study, or comparing different geographical regions, or for the same region over time (say a decade). There could be various reasons behind changing patterns of failures: P. falciparum strains were becoming more drug resistant, drug levels were lower, immunity
    was waning. Three basic criteria were standardized and investigated: (1) the definition of clinical failure, (2) isolation and characterization of the microorganism, and (3) drug levels attained in vivo.

    First, clinical criteria were standardized starting with inclusion and exclusion criteria. Like malaria, most relevant to COVID “early” treatment will be how to exclude patients so advanced/severe that no first line drugs could be expected to help. At least as important were very strict definitions of patterns of relapse depending on timing and parasitemia over the course of one month under conditions that preclude the possibility of re-infection (specifically R1, R2, and R3 patterns).

    Second, we drew isolates to test parasites’ in vitro drug sensitivity to a variety of drugs (and their active metabolites), including those with which the patients had been treated. These results were compared to those who had been treated successfully (isolates drawn on admission and used as needed to constitute the control group) as well as pre- vs post-treatment comparisons from patients who failed. Genetic testing was rudimentary back then but later began to be used to look for target mutations that were believed to represent drug resistance.

    Third, we drew drug levels at the time of failure in patients and compared them to corresponding levels for comparable patients who were cured. Alternatively, in some instances samples were collected from all patients at certain points of treatment, stored, and then assayed if treatment failure occurred. This step was critical in determining if sub-therapeutic drug levels contributed to treatment failure, whether due to poor adherence, drug intolerance (e.g., vomiting of doses), malabsorption, individual differences in rates of drug metabolism, etc.

    Through these steps we gained a better understanding of the interplay between drug sensitivity and development of resistance. When treatment failure occurred despite high drug levels and highly sensitive strains then individual immunity had to be considered. Though this field was as yet still poorly understood, we often asked for the number of malaria episodes in the previous 4 years as a surrogate marker. Today, we have the benefit of full genomic sequencing to alert us to mutations. Even so, we still must consider the other factors that may contribute to treatment failure. The above approach was very important as we saw clinical deterioration following first line therapeutic failures and had to turn to back-up therapies or quickly develop new ones. Finally, the above highlighted the importance of resistance emergence, usually from sub-therapeutic doses following poor patient adherence to prescribed regimens.

    Lorrin Pang, MD, MPH
    Director, Maui District Health Office

    Kim-Thu Pham, MD, MPH
    Medical Consultant, CDC Foundation

    CONFLICT OF INTEREST: None Reported
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