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.

Authors' conclusions: 

There is low-certainty evidence that nirmatrelvir/ritonavir reduces the risk of all-cause mortality and hospital admission or death based on one trial investigating unvaccinated COVID-19 participants without previous infection that were at high risk and with symptom onset of no more than five days. There is low- to moderate-certainty evidence that nirmatrelvir/ritonavir is safe in people without prior or concomitant therapies including medications highly dependent on CYP3A4.

Regarding equity aspects, except for ethnicity, no differences in effect size and direction were identified.

No evidence is available on nirmatrelvir/ritonavir to treat hospitalized people with COVID-19 and to prevent a SARS-CoV-2 infection.

We will continually update our search and make search results available on OSF. 

Read the full abstract...
Background: 

Oral nirmatrelvir/ritonavir (Paxlovid®) aims to avoid severe COVID-19 in asymptomatic people or those with mild symptoms, thereby decreasing hospitalization and death. Due to its novelty, there are currently few published study results. It remains to be evaluated for which indications and patient populations the drug is suitable. 

Objectives: 

To assess the efficacy and safety of nirmatrelvir/ritonavir (Paxlovid®) plus standard of care compared to standard of care with or without placebo, or any other intervention for treating COVID-19 and for preventing SARS-CoV-2 infection.

To explore equity aspects in subgroup analyses.

To keep up to date with the evolving evidence base using a living systematic review (LSR) approach and make new relevant studies available to readers in-between publication of review updates.

Search strategy: 

We searched the Cochrane COVID-19 Study Register, Scopus, and WHO COVID-19 Global literature on coronavirus disease database, identifying completed and ongoing studies without language restrictions and incorporating studies up to 11 July 2022. 

This is a LSR. We conduct monthly update searches that are being made publicly available on the open science framework (OSF) platform.

Selection criteria: 

Studies were eligible if they were randomized controlled trials (RCTs) comparing nirmatrelvir/ritonavir plus standard of care with standard of care with or without placebo, or any other intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection.

We screened all studies for research integrity. Studies were ineligible if they had been retracted, or if they were not prospectively registered including appropriate ethics approval.

Data collection and analysis: 

We followed standard Cochrane methodology and used the Cochrane risk of bias 2 tool. We rated the certainty of evidence using the GRADE approach for the following outcomes: 1. to treat outpatients with mild COVID-19; 2. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, quality of life, (serious) adverse events, and viral clearance; 3. to prevent SARS-CoV-2 infection in post-exposure prophylaxis (PEP); and 4. pre-exposure prophylaxis (PrEP) scenarios: SARS-CoV-2 infection, development of COVID-19 symptoms, mortality, admission to hospital, quality of life, and (serious) adverse events.

We explored inequity by subgroup analysis for elderly people, socially-disadvantaged people with comorbidities, populations from LICs and LMICs, and people from different ethnic and racial backgrounds.

Main results: 

As of 11 July 2022, we included one RCT with 2246 participants in outpatient settings with mild symptomatic COVID-19 comparing nirmatrelvir/ritonavir plus standard of care with standard of care plus placebo. Trial participants were unvaccinated, without previous confirmed SARS-CoV-2 infection, had a symptom onset of no more than five days before randomization, and were at high risk for progression to severe disease. Prohibited prior or concomitant therapies included medications highly dependent on CYP3A4 for clearance and CYP3A4 inducers. 

We identified eight ongoing studies.

Nirmatrelvir/ritonavir for treating COVID-19 in outpatient settings with asymptomatic or mild disease

For the specific population of unvaccinated, high-risk patients nirmatrelvir/ritonavir plus standard of care compared to standard of care plus placebo may reduce all-cause mortality at 28 days (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.00 to 0.68; 1 study, 2224 participants; estimated absolute effect: 11 deaths per 1000 people receiving placebo compared to 0 deaths per 1000 people receiving nirmatrelvir/ritonavir; low-certainty evidence, and admission to hospital or death within 28 days (RR 0.13, 95% CI 0.07 to 0.27; 1 study, 2224 participants; estimated absolute effect: 61 admissions or deaths per 1000 people receiving placebo compared to eight admissions or deaths per 1000 people receiving nirmatrelvir/ritonavir; low-certainty evidence).

Nirmatrelvir/ritonavir plus standard of care may reduce serious adverse events during the study period compared to standard of care plus placebo (RR 0.24, 95% CI 0.15 to 0.41; 1 study, 2224 participants; low-certainty evidence). Nirmatrelvir/ritonavir plus standard of care probably has little or no effect on treatment-emergent adverse events (RR 0.95, 95% CI 0.82 to 1.10; 1 study, 2224 participants; moderate-certainty evidence), and probably increases treatment-related adverse events such as dysgeusia and diarrhoea during the study period compared to standard of care plus placebo (RR 2.06, 95% CI 1.44 to 2.95; 1 study, 2224 participants; moderate-certainty evidence). Nirmatrelvir/ritonavir plus standard of care probably decreases discontinuation of study drug due to adverse events compared to standard of care plus placebo (RR 0.49, 95% CI 0.30 to 0.80; 1 study, 2224 participants; moderate-certainty evidence).

No study results were identified for improvement of clinical status, quality of life, and viral clearance. 

Subgroup analyses for equity

Most study participants were younger than 65 years (87.1% of the : modified intention to treat (mITT1) population with 2085 participants), of white ethnicity (71.5%), and were from UMICs or HICs (92.1% of study centres). Data on comorbidities were insufficient. 

The outcome ‘admission to hospital or death’ was investigated for equity: age (< 65 years versus ≥ 65 years) and ethnicity (Asian versus Black versus White versus others). There was no difference between subgroups of age. The effects favoured treatment with nirmatrelvir/ritonavir for the White ethnic group. Estimated effects in the other ethnic groups included the line of no effect (RR = 1). No subgroups were reported for comorbidity status and World Bank country classification by income level. No subgroups were reported for other outcomes.

Nirmatrelvir/ritonavir for treating COVID-19 in inpatient settings with moderate to severe disease

No studies available.

Nirmatrelvir/ritonavir for preventing SARS-CoV-2 infection (PrEP and PEP)

No studies available.