Explained: What is ‘Paxlovid rebound’, the return of Covid-19 infection after taking a highly recommended oral medication for it?


United States President Joe Biden tested positive for Covid-19 on Saturday (July 30), immediately after repeatedly testing negative earlier in the week. Biden’s doctor, Kevin O’Connor, said that after testing negative on Tuesday evening, Wednesday morning, Thursday morning, and Friday morning, the President tested positive on Saturday morning in an antigen test. He has no symptoms and is feeling “quite well”, though.

The return of the President’s infection is another case of what is being described as a “Paxlovid rebound” — the phenomenon of patients who have been administered the antiviral drug Paxlovid, experiencing a return of the infection days after testing negative. Before Biden, Dr Anthony Fauci, chief medical officer to the President, experienced a Paxlovid rebound as well.

More than a third of Americans who have tested positive for Covid-19 this summer have been given Paxlovid, and a large number of those patients have tested back positive immediately after testing negative.

While there is no data yet on the frequency of the recurrence of infection or its long-term effects on the patient, “Paxlovid rebound” is now acknowledged as a thing in the more than two-and-a-half-year battle against the coronavirus. In May, the US public health agency, Centres for Disease Control and Prevention (CDC), said that patients who had completed a course of Paxlovid medication could test positive again, and that these people should isolate themselves for five days.

What is causing the rebound of the infection?

The facts are these: both Biden and Fauci are old men — 79 and 81 respectively — and both are fully vaccinated. Biden was likely infected with the BA.5 sub variant of Omicron, Dr O’Connor had said last week. BA.5 is the dominant variant in the US at the moment. It is also the most transmissible variant of the coronavirus identified so far. BA.5 has shown a powerful ability to escape immune protection — both protection provided by vaccines, and by prior Covid-19 infection.

Many doctors and experts have been unenthusiastic about Paxlovid, especially in the case of vaccinated patients. While Paxlovid has been hyped as a “wonder drug” against Covid, its success has been spoken about mainly in the context of unvaccinated recipients of the medication. On April 22, the World Health Organisation (WHO) said Paxlovid was “strongly recommended” — but for patients with non-severe Covid-19 who are at highest risk of developing severe disease and hospitalisation, such as unvaccinated, older, or immunosuppressed patients.

A report in The Atlantic  on Saturday quoted Dr Reshma Ramachandran, a researcher at Yale, as saying she was feeling a sense of “resignation” about Paxlovid because despite the drug being one of the few Covid-19 treatments she could offer, she could not say with confidence that the pills would help someone who’d been immunised. The same report quoted Bob Wachter, the chair of medicine at UC San Francisco, as saying that assessing the value of Paxlovid for these patients was a “massively complicated three-dimensional chess game.”

The report noted that Biden had been started on Paxlovid immediately after his infection was confirmed, and that in June, Fauci had taken not one, but two courses of the medication.

OK, so what is Paxlovid, and how does it work?

Paxlovid is an antiviral drug developed by Pfizer, which consists of nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use. It was given emergency use authorisation (EUA) by the USFDA in December last year.

Paxlovid is administered as three tablets — two of nirmatrelvir and one of ritonavir — taken together orally twice daily for five days. That is, a total of 30 tablets. The USFDA authorised Paxlovid for use only up to five consecutive days. (After the cases of rebound in the US, there is some discussion now on whether five days are too few to effectively tackle the infection, but there is no firm medical opinion on this aspect as yet.)

Of the two components of Paxlovid, nirmatrelvir inhibits a viral enzyme called protease that is necessary for the virus to replicate itself inside the host cell. And the second component, ritonavir, slows down the breakdown of nirmatrelvir in order to help it remain in the body for longer at higher concentrations.

A drug like nirmatrelvir is considered to have an advantage over vaccines because it attacks a vulnerability in the virus that does not mutate like spike proteins — which vaccines target — do. As a result, the medication is seen to be effective against all variants. This was seen as especially important because the Omicron wave had shown that in a very large number of cases, vaccines were unable to prevent infection, even though they did prevent serious illness and deaths. (This pattern was seen in India as well.)

Besides Paxlovid, a second oral Covid-19 drug, molnupiravir, manufactured by Merck and Ridgeback, too received FDA authorisation in December last year. But it showed a somewhat lower efficacy in clinical trials.

The WHO issued a strong endorsement of the drug in April this year based on new data from two randomised controlled trials involving 3,078 patients. The data show that the risk of hospitalisation was reduced by 85% following this treatment, the WHO said in a statement at the time. In a high-risk group (over 10% risk of hospitalisation), that meant 84 fewer hospitalisations per 1,000 patients.

The USFDA’s EUA for Paxlovid was based on clinical data that showed a reduced risk of hospitalisation or death by 89 per cent within three days of the onset of symptoms, and 88 per cent within five days of the onset of symptoms, compared to the placebo group.

The European Medicines Agency (EMA) issued advice that Paxlovid can be used to treat adults with Covid-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe disease.

Is Paxlovid widely available and prescribed?

In the US, yes. Literally tens of thousands of Paxlovid prescriptions are written daily. US government data  show more than 5.6 million courses of the medication were ordered, and more than 3 million courses were administered between mid-December 2021 and July 24, 2022. The Biden administration has been aiming to expand access to oral antiviral treatments like Paxlovid.

On November 16 last year, Pfizer had announced it had signed a voluntary licence agreement for Paxlovid that would facilitate the production and distribution of the drug by granting sub-licences to qualified generic medicine manufacturers.

Pfizer’s licensing agreement with the United Nations-backed public health organisation Medicines Patent Pool (MPP) was intended to enable the supply of the medicines to 95 low- and middle-income countries including India, comprising approximately 53% of the world’s population.

It was announced at the time that Pfizer would not receive royalties on sales in low-income countries, and that royalties would be waived on sales in all countries covered by the agreement for as long as Covid-19 remained classified as a Public Health Emergency of International Concern by WHO.

Subsequently, on March 17 this year, the MPP announced that it had signed agreements with 35 companies to manufacture the generic version of nirmatrelvir, which in combination with a low dose of ritonavir can be supplied in 95 low- and middle-income countries. Six companies will produce the drug substance, nine will produce the drug product, and the rest will do both, the MPP said in a release.

The companies are located, besides India, in Bangladesh, Brazil, China, Dominican Republic, Jordan, Israel, Mexico, Pakistan, Serbia, Republic of Korea, and Vietnam.

The MPP, founded by the Geneva-based Unitaid, works to increase access to, and facilitate the development of, life-saving medicines for low- and middle-income countries. MPP partners with civil society, governments, international organisations, industry, patient groups, and other stakeholders to prioritise and license needed medicines and pool intellectual property to encourage generic manufacture and the development of new formulations.

So is the drug used to treat Covid-19 in India?

Despite being approved in India, physicians are not prescribing Paxlovid widely. Most cases of Covid-19 in India have been mild, and there has been no push from the government for the use of the medication so far.

Nineteen of the 35 companies with which the MPP has signed sub-licensing agreements are Indian, and they include drugmakers such as Bengaluru-based Biocon Ltd; Mumbai-based Glenmark Pharmaceuticals, Sun Pharmaceuticals, and Cipla; Ahmedabad headquartered Torrent Pharmaceuticals and Cadila Pharmaceuticals; Hetero Drugs and Laurus Labs of Hyderabad; and Emcure Pharmaceuticals of Pune.

In its April 22 statement, WHO said it was “extremely concerned” that low- and middle-income countries could be pushed to the “end of the queue” while accessing Paxlovid treatment — in the same way these countries had suffered when it came to the supply of Covid-19 vaccines. It said that Pfizer’s licensing agreement with the MPP limited the number of countries that can benefit from generic production of the medicine.





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