Nirmatrelvir/ritonavir

Nirmatrelvir is an orally administered protease inhibitor that works against MPRO, a viral protease that is vital in viral replication. It accomplishes this by cleaving the two viral polyproteins¹. Nirmatrelvir has displayed antiviral activity against all known human-affecting coronaviruses². It is administered in combination with ritonavir as a part of Paxlovid, a potent inhibitor of the cytochrome P450 (CYP) 3A4 enzyme that also acts as a pharmacokinetic enhancing agent. Ritonavir has been previously used to boost the effectiveness of HIV protease inhibitors. The co-administration of ritonavir is necessary to elevate nirmatrelvir concentrations to the desired therapeutic range. The FDA granted Emergency Use Authorization (EUA) for ritonavir-boosted nirmatrelvir on December 22, 2021, for COVID-19 treatment³.

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Ritonavir structure

Effectiveness against Variants

There is currently no clinical trial data for the use of ritonavir-boosted nirmatrelvir in patients with COVID-19 caused by the Omicron variant. However, ritonavir-boosted nirmatrelvir is predicted to be effective against this variant and its subvariants⁴-⁷.

Recommendations

The COVID-19 Treatment Guidelines Panel recommends the use of nirmatrelvir 300 mg with ritonavir 100 mg (Paxlovid) orally twice daily for 5 days in nonhospitalized adults and pediatric patients aged ≥12 years and weighing ≥40 kg who have mild to moderate COVID-19 and are at high risk of disease progression. Treatment should be initiated as soon as possible and within 5 days of symptom onset. For information on medical conditions that confer high risk, see the Centers for Disease Control and Prevention webpage People With Certain Medical Conditions.

Ritonavir-boosted nirmatrelvir may be used in patients who are hospitalized for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19 (i.e., those who do not require supplemental oxygen), are at high risk of progressing to severe disease, and are within 5 days of symptom onset.

Ritonavir-boosted nirmatrelvir has not been studied in patients who were hospitalized for mild to moderate COVID-19. The FDA EUA allows ritonavir-boosted nirmatrelvir to be used in these patients if they are at high risk of progressing to severe COVID-19 and are within 5 days of symptom onset.

Drug-Drug Interactions

Ritonavir-boosted nirmatrelvir has significant drug-drug interactions, primarily due to the ritonavir component of the combination. Clinicians should carefully review the patient’s concurrent medications, including over-the-counter medications, herbal supplements, and recreational drugs, to evaluate potential drug-drug interactions. Many drug-drug interactions between ritonavir-boosted nirmatrelvir and concurrent medications can be safely managed.

Rationale

The EPIC-HR trial enrolled nonhospitalized adults with mild to moderate COVID-19 who were not vaccinated and who were at high risk of progressing to severe disease. The trial demonstrated that starting ritonavir-boosted nirmatrelvir within 5 days of symptom onset in these patients reduced the risk of hospitalization or death through.

The EPIC-SR study was a multinational randomized trial that compared ritonavir-boosted nirmatrelvir PO twice daily for 5 days to placebo in nonhospitalized patients aged ≥18 years with mild to moderate COVID-19 who were at low risk of clinical progression. These patients were either unvaccinated or vaccinated but at high risk of progressing to severe disease. The patients in the study were randomized within 5 days of symptom onset. This study, however, did not yield a statistically significant effect on the duration of symptoms or the risk of hospitalization or death compared to the placebo group. Nevertheless, there were few event rates in this study, implying the results should be interpreted with caution.

Regarding viral rebound and recurrence of symptoms, observational studies and the EPIC-HR trial have noted these phenomena in some patients after completing ritonavir-boosted nirmatrelvir treatment. However, the frequency, mechanism, and clinical implications of these events are still unclear. It's also important to note that viral rebound and symptom recurrence can also occur without nirmatrelvir treatment. Despite this, the recurrence of symptoms following the use of ritonavir-boosted nirmatrelvir has not been associated with progression to severe COVID-19. Therefore, these concerns should not deter clinicians from prescribing the treatment.

The EUA only authorizes a 5-day course of ritonavir-boosted nirmatrelvir, and there are insufficient data on the efficacy of administering a second course. Notably, research has raised concerns about potential resistance to nirmatrelvir due to viral mutations. Such resistance has been observed in in vitro studies, but the fitness of these mutations is yet to be determined. Thus, continued surveillance for the emergence of significant resistance to nirmatrelvir is critical.

Patients with severe immunodeficiency may experience prolonged periods of SARS-CoV-2 replication, potentially leading to rapid viral evolution. This raises theoretical concerns that using a single antiviral agent in these patients may produce antiviral-resistant viruses. Further studies are needed to assess this risk and to understand the potential role of combination antiviral therapy or a longer treatment duration in treating patients who are severely immunocompromised.

In terms of administration, nirmatrelvir must be taken with ritonavir to achieve sufficient therapeutic plasma concentrations. Patients are advised to complete the 5-day treatment course, as concerns exist that a shorter treatment course may be less effective or lead to resistance. If a patient requires hospitalization after starting treatment, the full 5-day course should be completed unless drug-drug interactions prohibit its use.

There are currently no data on combining ritonavir-boosted nirmatrelvir with other antiviral therapies to treat nonhospitalized patients with COVID-19. Consequently, clinical trials are necessary to determine whether combination therapy has a role in the treatment of COVID-19. As per the EUA, crushing nirmatrelvir and ritonavir tablets is not advised. However, some data suggest that the tablets can be split or crushed if necessary.

As for side effects, the most common adverse effects of ritonavir-boosted nirmatrelvir include dysgeusia, diarrhea, hypertension, and myalgia. Severe allergic reactions, including anaphylaxis, have also been reported. Renal impairment can reduce the clearance of nirmatrelvir, and in patients with suspected renal impairment, clinicians may consider checking the patient’s renal function to inform the dosing of ritonavir-boosted nirmatrelvir. The dose should be reduced to nirmatrelvir 150 mg with ritonavir 100 mg twice daily in patients with severe renal impairment (eGFR <30 mL/min). Patients with end-stage renal disease (ESRD) on hemodialysis should not receive ritonavir-boosted nirmatrelvir.

Patients with hepatic impairment are also at risk for increased nirmatrelvir exposure. In patients with mild hepatic impairment (Child-Pugh A), no dose adjustment is necessary. However, in patients with moderate (Child-Pugh B) or severe hepatic impairment (Child-Pugh C), ritonavir-boosted nirmatrelvir is not recommended.

Ritonavir is a potent inhibitor of CYP3A4 and can interact with many medications. Clinicians should review the patient's medication list for potential drug-drug interactions before starting ritonavir-boosted nirmatrelvir. The most significant concern is with medications that have a narrow therapeutic index and are metabolized by CYP3A4, such as certain statins, anticoagulants, antipsychotics, and others. If a significant drug-drug interaction is suspected, consultation with a pharmacist or an infectious disease specialist is advised.

Regarding use in pregnancy, there are no adequate and well-controlled studies in pregnant individuals. Therefore, ritonavir-boosted nirmatrelvir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Similarly, it is not known whether nirmatrelvir and ritonavir are excreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ritonavir-boosted nirmatrelvir and any potential adverse effects on the breastfed infant.

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