Update: Nirmatrelvir combined with ritonavir for preventing and treating COVID‐19

30 Nov 2023

Is the combination of 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 for unvaccinated outpatients at increased risk for disease progression receiving treatment within five days of symptom onset.

We are very uncertain about the effectiveness of nirmatrelvir/ritonavir in inpatients.

We excluded two studies due to concerns with research integrity. We found 13 ongoing studies.

What is nirmatrelvir/ritonavir?

The combination of nirmatrelvir with ritonavir 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 but it can interact with many other medicines, 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 other illnesses (comorbidities), people from low‐income and low‐ to 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 COVID‐19 symptoms got better or worse;

– quality of life;

– unwanted effects of the medicine;

– 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 (clinical studies where people are randomly put into one of two or more treatment groups) that investigated nirmatrelvir/ritonavir to prevent or treat COVID‐19. People receiving nirmatrelvir/ritonavir as treatment had to have laboratory‐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 contracting the disease or had to have had a high‐risk contact with a person with confirmed COVID‐19.

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

We examined differences with respect to age, level of comorbidity, country according to the World Bank country classification by income level, and ethnicity.

What did we find?

We found two studies with 2510 participants that investigated nirmatrelvir/ritonavir compared to placebo or standard of care for the treatment of COVID‐19 in people without previous confirmed SARS‐CoV‐2 infection and at increased risk for progression to severe disease due to a comorbidity or risk factor such as current smoking. Included outpatients were enrolled during the Delta wave, unvaccinated, and had a symptom onset of up to five days before starting treatment. Included inpatients were enrolled during the Omicron wave, mostly unvaccinated, and mildly to moderately affected.

We found 13 ongoing studies that have not yet been completed, and three studies are currently awaiting classification.

Main results

Treating outpatients with COVID‐19

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

– lead to fewer deaths;

– improve patients' condition assessed by need for admission to hospital 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);

– decreases discontinuation of study medicine due to unwanted events.

Equity aspects

Most study participants were younger than 65 years and of white ethnicity. There was no difference in effectiveness between younger and older participants and participants from different ethnic groups. No subgroups were reported for different levels of comorbidity and World Bank country classification by income level.

Treating inpatients with COVID‐19

We are uncertain whether, for the specific population of mildly to moderately affected, high‐risk patients, nirmatrelvir/ritonavir:

– leads to fewer deaths; and

– increases virus elimination

Equity aspects

Most study participants were older than 65 years. There was no difference in effectiveness between younger and older participants. No subgroups were reported for different levels of comorbidity, ethnicity, 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 for outpatients and very low for inpatients. The studies did not report everything we were interested in, such as quality of life and symptom resolution, and had a highly specific population of people at high risk of progression to severe COVID‐19.

How up to date is this evidence?

The evidence is up to date to 15 May 2023.

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