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Oral nirmatrelivir and ritonavir reduce risk of COVID-19 progression by 89%

Oral nirmatrelivir combined with ritonavir given for five days, reduced disease progression in high risk patients infected with COVID-19

Use of oral nirmatrelivir and ritonavir within five days of symptom onset in patients with mild-to-moderate COVID-19 and a potentially high risk for disease progression, has been shown to reduce that risk by 89% compared to placebo. This was the conclusion of a randomised trial by the manufacturer, Pfizer.

Although the introduction of COVID-19 vaccines has been a major step in the war against the virus, leading to a significant reduction in the number of hospitalised patients, many individuals with risk factors remain at an increased risk of more severe disease if infected. In fact, a 2021 meta-analysis, concluded that patients with hypertension, obesity, diabetes and cardiovascular disease, had more COVID-19 severity and mortality respectively. With such factors present in a number of patients, the introduction of an oral therapy which, when given to such patients once infected, halted progression of the infection, ultimately reducing the burden on healthcare systems, would represent an important development.

Within the COVID-19 virus, the enzyme 3-chymotrypsin–like cysteine protease (Mpro) it vital for replication and oral nirmatrelivir is an anti-viral agent which targets this enzyme. Moreover, research has shown that nirmatrelivir is metabolised in the body by the enzyme, CYP3A4 and that addition of a low dose of ritonavir, favourably enhanced nirmatrelivir pharmacokinetics.

For the present phase 2 – 3 randomised trial, the authors evaluated the combination of oral nirmatrelivir 300 mg and ritonavir 100 mg, given every 12 hours for 5 days, in non-hospitalised adults with mild-to-moderate COVID-19 but who also had risk factors for progression to severe disease. Enrolled patients were randomised 1:1 to the treatment combination or matching placebo. The primary objective of the trial was to compare the proportion of patients with COVID-19 hospitalised or who died over a 28 day period after randomisation, compared to placebo. This comparison was made at two time-points: after three and five days of treatment.

Oral nirmatrelivir and COVID-19 outcomes

A total of 2246 patients with a median age of 46 years (51.1% male) were randomised to active treatment (1120) or placebo. The most common coexisting conditions associated with a risk of progression to severe COVID-19 were a BMI of 25 or above (80.5%), current smoking (39.0%) and hypertension (32.9%). In addition, 61.0% of participants had two or more coexisting conditions.

In the final analysis, among 1379 patients treated with oral nirmatrelivir and ritonavir and placebo, within less than 3 days of symptom onset, 5 patients in the nirmatrelivir and ritonavir group and 44 in the placebo arm, were hospitalised for COVID-19 or died within 28 days. This corresponded to an 88.9% relative risk reduction in the primary objective. When patients were treated less than 5 days after the onset of symptoms, 0.77% of the oral nirmatrelivir and ritonavir group and 6.31% of the placebo group met the primary outcome, giving a relative risk reduction of 87.8%.

Data on the viral load in both groups showed that when treatment was started within 3 days of symptom onset, the load was 10 times lower in the oral nirmatrelivir and ritonavir group compared to placebo. In addition, the incidence of adverse effects was similar between the two groups.

The authors concluded that treatment with oral nirmatrelivir and ritonavir early in COVID-19 illness, reduced disease progression and viral load.

Hammond J et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 New Eng J Med 2022

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