Nirmatrelvir reduces the risk of developing post-COVID-19 syndrome

SARS-CoV-2 infections can have a wide range of long-term health consequences. How can such long-term consequences be avoided? Research teams worldwide are working on therapeutic approaches.

Paxlovid® convinces in reducing the long-term consequences of COVID-19 disease

Long-lasting health impairments after infection with SARS-CoV-2 are known as long COVID and post-COVID 19 condition (PCC). According to the guideline recommendation of the British National Institute for Health and Care Excellence (NICE) published at the end of 2020, long COVID and post-COVID 19 condition are defined as follows:

Long-COVID: "Health complaints that persist beyond the acute phase of illness for 4 weeks or are new".
Post-COVID 19 condition: Health complaints "present and not otherwise explained" at >12 weeks after acute SARS-CoV-2 infection.

The term long COVID thus includes both the symptoms that persist 4 to 12 weeks after symptom onset (after an acute COVID-19 episode) and post-COVID-19 condition (PCC).¹ According to a large-scale study from the United Kingdom, the incidence of PCC is 7.8% to 17%.³

More than a year ago - on 28 January 2022 - Paxlovid® (nirmatrelvir + ritonavir) became the first antiviral drug to receive conditional approval for the treatment of COVID-19 disease.⁴ The results of a cohort study involving a total of 281,793 patients suggest that the active ingredient nirmatrelvir contained in Paxlovid® may be associated with a reduction in the risk of developing post-COVID condition.²

Nirmatrelvir therapy in non-hospitalised patients with at least one risk factor for a severe course of COVID-19

In the present cohort study, data collection was done by searching the US Department of Veterans Affairs (VA) health databases. Inclusion criteria were:

Positive SARS-CoV-2 test result.
At least one risk factor for progression to severe COVID-19 disease.
No hospitalisation before admission.
Survival of the first 30 days after SARS-CoV-2 diagnosis

The patients were divided into two groups. The control group included 246,076 people who had not received COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection. The nirmatrelvir group included those who had been treated with oral nirmatrelvir within 5 days of the positive SARS-CoV-2 test result. There were 35,717 people in this treatment group.²

Baseline characteristics balanced except for one point

If we take a look at the baseline characteristics, they make a balanced impression - except for the gender distribution. 15% of the people in the therapy group and 15% in the control group were smokers. The proportion of unvaccinated persons was 17% in both the therapy and control groups. Type 2 diabetes was present in 36% of the people in the therapy group and 36% in the control group. The presence of cardiovascular disease (29% of people in the treatment group and 30% of people in the control group) and hyperlipidaemia (40% of people in the treatment group and 40% of people in the control group) was also evenly distributed.²

Broad risk reduction with nirmatrelvir

The research group observed a reduction in PCC risk in the nirmatrelvir therapy group in unvaccinated, vaccinated and boosted individuals, as well as in individuals with primary SARS-CoV-2 infection and reinfection. Patients in the nirmatrelvir therapy group also had a reduced risk compared to the control group:

For the occurrence of post-COVID condition (RR, 0.74; 95% CI, 0.72-0.77; ARR, 4.51%; 95% CI, 4.01-4. 99).
For 10 of the 13 known post-acute PCC sequelae.
For post-acute death (HR, 0.53; 95% CI, 0.46-0.61); ARR, 0.65%; 95% CI, 0.54-0.77).
For post-acute hospitalisation (HR, 0.76; 95% CI, 0.73-0.80; ARR, 1.72%; 95% CI, 1.42-2.01).²

The 13 PCC components

The 13 consequences of PCC known to date include:

Cardiovascular system: Cardiac arrhythmias and ischaemic heart disease.
Coagulation system and haematological disorders: pulmonary embolism and deep vein thrombosis.
Neurological system: Neurocognitive impairment and dysautonomia; fatigue and malaise
Acute kidney disease.
Muscle pain.
Shortness of breath.²

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Illustration: Distribution of the study populations²

Important limitations of the study

The President and Chief Executive Officer of NYC Health + Hospitals, the largest community health system in the United States, has pointed out important limitations of this study. For example, one key criticism is the gender distribution: the study population was predominantly male at almost 89%. Another criticism was that the relationship between severe symptomatology in the acute episode and post-COVID condition was not clarified.

Mitchell H. Katz, MD, cited the research of Tsampasian V. et al. to support his statement.^5,6 In their meta-analysis, Tsampasian's research group had examined the factors associated with an increased risk of post-COVID syndrome. They found that those patients who had to be hospitalised due to their acute COVID-19 infection had a significantly higher risk of developing post-COVID condition (odds ratio, 2.48; 95% CI, 1.97-3.13). It is therefore quite conceivable that a certain part of the effect of nirmatrelvir with regard to post-COVID condition could be based on the prevention of severe sequelae during the initial infection.

Another observation was that COVID-19 vaccination was associated with a lower risk of PCC. It is known that immunisation against SARS-CoV-2 is associated with a reduction in the severity of an acute COVID-19 episode. The results of the study by Xie Y. et al. could thus also be based on this fact.⁵

References:

https://www.rki.de/SharedDocs/FAQ/NCOV2019/FAQ_Liste_Gesundheitliche_Langzeitfolgen.html; Stand: 28.04.2023
Xie Y. et al. (2023). Association of Treatment With Nirmatrelvir and the Risk of Post-COVID-19 Condition. JAMA Intern Med. 2023 Mar 23:e230743.
Thompson E.J. et al. (2022). Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat Commun. 2022;13(1):3528.
In German only: https://www.bfarm.de/DE/Arzneimittel/Arzneimittelinformationen/covid-19-arzneimittel.html#:~:text=Paxlovid®%20ist%20das%20erste,über%20den%20Großhandel%20bestellt%20werden.
Katz MH. (2023). While Waiting for a Randomized Clinical Trial of Nirmatrelvir for Prevention of Post-COVID-19 Condition. JAMA Intern Med. 2023 Mar 23.
Tsampasian V. et al. (2023). Risk factors associated with post−COVID-19 condition: a systematic review and meta-analysis. JAMA Intern Med. Published online March 23, 2023.