Nirmatrelvir/ritonavir
Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19.[8][11][10][17] It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer.[8][10] Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect.[10][18] It is taken by mouth.[10]
Combination of
Paxlovid
In unvaccinated high-risk patients with COVID-19, nirmatrelvir/ritonavir can reduce the risk of hospitalization or death by 88% if taken within five days of symptom onset.[19] Patients who take nirmatrelvir/ritonavir also test negative for COVID-19 about two and a half days earlier than patients who do not take the drug.[20] Side effects of nirmatrelvir/ritonavir include changes in sense of taste (dysgeusia), diarrhea, high blood pressure (hypertension), and muscle pain (myalgia).[10]
In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization (EUA) by the United States Food and Drug Administration (FDA) to treat COVID‑19.[13][21] It was approved in the United Kingdom later that month,[22] and in the European Union and Canada in January 2022.[15][23][24] In May 2023, it was approved in the US to treat mild-to-moderate COVID‑19 in people over 12 years who are at high risk for progression to severe COVID‑19, including hospitalization or death.[14][17] The FDA considers the combination to be a first-in-class medication.[25]
Contraindications[edit]
The medication is contraindicated in those with hypersensitivity to either of the two main components, and in those with severely reduced kidney or liver function.[13] Co-administration with certain drugs may have serious, sometimes fatal, effects.[32]
Side effects[edit]
Nirmatrelvir/ritonavir has a high potential for potentially serious drug interactions due to strong CYP3A inhibition by ritonavir.[10][18] The US FDA label, the FDA fact sheet, and the FDA EUA contain a boxed warning about the CYP3A inhibition.[10][14]
Adverse events of the co-packaged medication, regardless of causality, observed in the phase II-III EPIC-HR study included: dysgeusia (6% vs. < 1% for placebo), diarrhea (3% vs. 2% for placebo), hypertension (1% vs. < 1% for placebo), and myalgia (1% vs. < 1% for placebo).[10][13][33] In clinical trials, 2% of people discontinued treatment due to side effects with nirmatrelvir/ritonavir while 4% in the placebo group did so.[10] Nirmatrelvir/ritonavir is under investigation, so its side effects have yet to be fully evaluated and may not be completely known.[18]
Other side effects of nirmatrelvir/ritonavir may include hypersensitivity reactions, liver toxicity, and development of HIV drug resistance in people with uncontrolled or undiagnosed HIV infection.[10][18] Hypersensitivity reactions (allergic reactions) may manifest as skin rash, hives, difficulty swallowing, difficulty breathing, angioedema, and/or anaphylaxis.[10][18] Liver toxicity may manifest as elevated transaminases and clinical hepatitis, including symptoms like appetite loss, jaundice (yellowing of the skin and whites of eyes), dark-colored urine, pale-colored stools, itchy skin, and abdominal pain.[10][18]
Interactions[edit]
Co-administration of nirmatrelvir/ritonavir with certain drugs is contra-indicated, including drugs dependent on CYP3A for removal, for which a raised concentration results in serious reactions, or those with potent CYP3A inducers, for which reduced blood concentration of the two main components may result in loss of effect against the virus and possible resistance, among others.[10] Co-administration also affects the concentration of several drugs, sometimes requiring changing the dose or careful monitoring.[13][33] Many of these drugs are widely prescribed to people at high risk from COVID‑19.[34] With the extension of the emergency authorization in August 2022, the FDA updated a checklist to help evaluate potential drug interactions and other patient factors before prescribing Paxlovid, including more than 120 drugs which are either contraindicated, should be avoided or held from use, or require dose adjustments or special monitoring.[35][13]
Nirmatrelvir/ritonavir is said to be safe in combination with over-the-counter pain- and fever-reducing medications such as paracetamol (acetaminophen) and ibuprofen.[36]
Research[edit]
Rebound[edit]
An additional analysis of the original EPIC-HR clinical trial data (Delta variant) showed that about 2% of both the treatment and placebo groups experienced a symptomatic rebound after the 5 day treatment, meaning they felt ill again and tested positive again (antigen test and PCR test) after testing negative.[37] The exact cause is not known, but there is speculation that it is due to reservoirs in tissues that are not reached by the medication, or reinfection. In May 2022, Pfizer suggested repeating the treatment, but the FDA said there was no evidence of benefit.[38][39]
In June 2022, a US case report of ten people with rebound COVID‑19 had found viral load during relapse was comparable to levels during an initial infection, and high enough to cause secondary transmission.[40] President Joe Biden, First Lady Jill Biden, Anthony Fauci,[38] Peter Hotez and Rochelle Walensky[41] are known to have experienced rebound.
As of June 2022, Pfizer studied the phenomenon in a new trial it called EPIC-SR (standard risk) while the omicron variant was circulating.[40] Both EPIC-HR and EPIC-SR were randomized controlled trials which provide information about COVID‑19 rebound.[14] Data from these two trials showed that rebound in SARS-CoV-2 (RNA or virus) shedding or COVID‑19 symptoms occurred in a subset of participants and happened in both the participants receiving nirmatrelvir/ritonavir and the placebo.[14] As of 2023, the FDA found there was no clear association between nirmatrelvir/ritonavir treatment and COVID‑19 rebound based on the data available to them.[14]
Resistance[edit]
As of July 2022, no nirmatrelvir/ritonavir drug resistant SARS-CoV-2 had been observed in clinical context.[42] The engineering of a nirmatrelvir-resistant chimera of vesicular stomatitis virus (VSV) under laboratory conditions was published without formal peer review in July 2022.[43] As of November 2022, multiple pathways that could lead to resistance to nirmatrelvir/ritonavir had been demonstrated in vitro.[44]
History[edit]
Nirmatrelvir belongs to a family of 3C-like protease inhibitors developed in the late 2010s against feline coronavirus, while ritonavir is an antiretroviral drug developed in the 1980s and used since the 1990s to inhibit the enzyme that metabolizes other protease inhibitors.
The primary data supporting the US Food and Drug Administration (FDA) emergency use authorization for nirmatrelvir/ritonavir were from the EPIC-HR trial, a randomized, double-blind, placebo-controlled clinical trial studying nirmatrelvir/ritonavir for the treatment of non-hospitalized symptomatic adults with a laboratory-confirmed diagnosis of SARS-CoV-2 infection.[10][12][45] Participants were 18 years of age and older with a pre-specified risk factor for progression to severe disease, or were 60 years and older regardless of pre-specified chronic medical conditions.[12] No participants had received a COVID‑19 vaccine or been previously infected with COVID‑19.[12] The main outcome measured in the trial was the proportion of people who were hospitalized due to COVID‑19 or died due to any cause during 28 days of follow-up.[12] EPIC-HR started in July 2021, and completed in December 2021.[46] Nirmatrelvir/ritonavir significantly reduced the proportion of people with COVID‑19-related hospitalization or death from any cause by 88% compared to placebo among participants treated within five days of symptom onset and who did not receive COVID‑19 therapeutic monoclonal antibody treatment.[12] On 14 December 2021, Pfizer also announced that a Phase II/III study of nirmatrelvir/ritonavir showed a reduced risk of hospitalization or death.[47]
In August 2021, Pfizer began a phase II/III trial of nirmatrelvir/ritonavir for COVID‑19 in standard-risk individuals with COVID‑19 known as EPIC-SR.[48][49] Interim results of this trial were announced in December 2021, and final results were released in June 2022.[48] Pfizer discontinued enrollment in the study, with the reason given being the very low rate of hospitalization and death in this population.[50] EPIC-SR was another clinical trial that enrolled vaccinated participants with at least one risk factor for progression to severe COVID‑19.[14] Although not statistically significant, among these vaccinated participants, there was a reduction in the risk of COVID‑19 related hospitalization or death from any cause.[14]
In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID‑19.[13] On 31 December, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) approved the use of nirmatrelvir combined with ritonavir for adults with mild to moderate infection and at high risk of their illness worsening.[51][22]
In April 2022, it was announced that the PANORAMIC trial would start testing the effectiveness of nirmatrelvir/ritonavir for treating COVID‑19 infections.[52]
Nirmatrelvir/ritonavir has been evaluated in the treatment of COVID‑19 in standard-risk individuals in the EPIC-SR trial.[48][50] This study did not achieve its primary goal of reducing time to sustained alleviation of COVID‑19 symptoms (treatment: 13 days (95% CI 12–15 days); placebo: 13 days (95% CI 11–14 days)).[48][50] It also did not find a statistically significant reduction in the risk of hospitalization or death (treatment: 5/576 [0.9%]; placebo: 10/569 [1.8%]; p > 0.05).[48][50] Likewise, findings were not statistically significant for reducing hospitalization rates in a subgroup of vaccinated adults with at least one risk factor for severe COVID‑19 (treatment: 3/361 [0.8%]; placebo: 7/360 [1.9%]; 57% reduction – RR 0.43, 95% CI 0.11–1.64).[48][50] However, the trial did find a statistically significant 62% decrease in COVID‑19-related medical visits, similar to the 67% reduction from the EPIC-HR study of high-risk individuals.[48][50] Enrollment in EPIC-SR was discontinued due to the low rate of hospitalization and death in this population.[48][50]
In May 2023, nirmatrelvir/ritonavir received FDA approval for the treatment of mild-to-moderate COVID‑19 in adults who are at high risk for progression to severe COVID‑19, including hospitalization or death.[14] In November 2023, the FDA revised the EUA for nirmatrelvir/ritonavir to authorize EUA- or NDA-labeled nirmatrelvir/ritonavir for the treatment of mild-to-moderate COVID‑19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb), who are at high risk for progression to severe COVID‑19, including hospitalization.[17]