Nirmatrelvir combined with ritonavir for preventing and treating COVID‐19

Is the combination nirmatrelvir plus ritonavir effective for treating or preventing COVID‐19?

Key messages

Nirmatrelvir/ritonavir (Paxlovid®) is evaluated for the treatment of coronavirus disease 2019 (COVID‐19).

Nirmatrelvir/ritonavir may lead to fewer deaths and improve patient condition, as assessed by need for hospitalization or death within 28 days. 

Data are only available for non‐vaccinated people at increased risk for disease progression receiving treatment within five days of symptom onset.

We found eight ongoing studies. We will update our search every month.

What is nirmatrelvir/ritonavir (Paxlovid®)?

The combination of nirmatrelvir with ritonavir (Paxlovid®) is a new medicine developed to treat infection with the SARS‐CoV‐2 virus and aims to avoid severe COVID‐19 in people without symptoms, or those with mild symptoms. Ritonavir increases the effectiveness of nirmatrelvir, however it can interact with many other drugs which can increase side effects.

What did we want to find out?

We wanted to know if nirmatrelvir/ritonavir reduces death, illness, and length of infection in people with COVID‐19, or if it is useful in prevention of the disease. We included studies comparing the medicine with placebo (dummy treatment), no treatment, usual care, or any other treatments for COVID‐19. We addressed equity and wanted to know whether there are certain groups of people for which nirmatrelvir/ritonavir works best or is less effective. We looked at elderly people, socially disadvantaged people with comorbidities, people from low‐income and lower‐middle‐income countries, and people from different ethnic and racial backgrounds.

We evaluated the effects of nirmatrelvir/ritonavir in people with COVID‐19 regarding:

– people dying; 

– whether people's COVID‐19 symptoms got better or worse; 

– quality of life; 

– unwanted effects of the drug; 

– virus elimination. 

For prevention, we sought the effect on preventing COVID‐19 and SARS‐CoV‐2 infection.

What did we do? 
We searched for randomized controlled trials that investigated nirmatrelvir/ritonavir to prevent or treat COVID‐19 in humans. People receiving nirmatrelvir/ritonavir as treatment had to have laboratory‐test confirmed COVID‐19 and be treated in hospital or as outpatients. People receiving nirmatrelvir/ritonavir to prevent an infection had to have a high risk of contacting the disease or had to have a high risk contact with a confirmed COVID‐19 patient.

We compared and summarized the results of the studies and rated our confidence in the evidence, based on common criteria as to how reliable the evidence is.

For all effects, we examined differences with respect to age groups, level of comorbidity, country according to the World Bank country classification by income level, and ethnicity.

What did we find? 

We found one study with 2246 participants that investigated nirmatrelvir/ritonavir compared to placebo for the treatment of COVID‐19 in outpatients. The included participants were not vaccinated, without previous confirmed SARS‐CoV‐2 infection, had a symptom onset of no more than five days before start of the treatment, and were at high risk for progression to severe disease due to a comorbidity or risk factor such as current smoking.

We also found eight ongoing studies that have not yet been completed.

Main results

Treating outpatients with COVID‐19

For the specific population of unvaccinated, high‐risk patients, nirmatrelvir/ritonavir may;

‐ lead to fewer deaths; and

‐ improve patients' condition assessed by need for hospitalization or death within 28 days;

‐ reduce serious unwanted events.

For the specific population of unvaccinated, high‐risk patients, nirmatrelvir/ritonavir probably:

‐ has little effect on any unwanted events;

‐ increases any treatment‐related unwanted events (mostly taste disturbance and diarrhoea);

‐ probably decreases discontinuation of study drug due to unwanted events.

Equity aspects

Most study participants were younger than 65 years, of white ethnicity and were from upper‐middle‐ or high‐income countries. There was no difference in effectiveness between younger and older participants. There was a positive effect in all ethnic groups, which was clearest for people of white ethnicity but numbers of participants in the other ethnic groups were low. No subgroups were reported for different levels of comorbidity and World Bank country classification by income level. 

No subgroups were reported for other outcomes.

What are the limitations of the evidence?

Our confidence in the evidence is low to moderate because we could only include one study and some events, such as deaths or serious adverse events were rare. The study did not report everything we were interested in, such as quality of life and symptom resolution and had a highly specific patient population of unvaccinated people at high risk of progression to severe COVID‐19.

How up to date is this evidence?

The evidence is up‐to‐date to 11 July 2022. 

According to this review's living approach, we will update our search monthly. We are making search results and new relevant studies publicly available.