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Nirmatrelvir and ritonavir safe in pregnancy

12th December 2022

The combination of nirmatrelvir and ritonavir appear to be safe and well tolerated when used in pregnancy among mothers infected with COVID-19

The nirmatrelvir and ritonavir (Paxlovid) can be used safely in pregnant women infected with COVID-19 according to a case series study by researchers from Johns Hopkins University School of Medicine, Baltimore, US.

Pregnant women with COVID-19 leads to a consistent and substantial increase in severe maternal morbidity and mortality and neonatal complications. In fact, available data suggests that severe acute respiratory syndrome caused by COVID-19 during pregnancy, leads to placental inflammation and a reduced antiviral antibody response and which could impact upon the efficacy of treatment in pregnancy. The combination of nirmatrelvir and ritonavir has been authorised by the EMA for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19. However, the summary of product characteristics states that ‘there are no data from the use of paxlovid in pregnant women‘ and that ‘paxlovid is not recommended during pregnancy.’ Despite the lack of human data animal studies of nirmatrelvir and ritonavir reported no clinically relevant risks associated with administration during pregnancy and in males and females of reproductive age.

In the present study, the US researchers reported on a case series that included pregnant patients who were diagnosed with COVID-19 and who received nirmatrelvir and ritonavir. The team recorded the clinical characteristics and pregnancy outcomes through a manual review of medical records.

Nirmatrelvir and ritonavir and pregnancy outcomes

A total of 47 women with a median age of 34 years were included and who received the drugs during pregnancy, 57.4% during the third trimester and 34% during the second trimester. In addition, 85.1% of women had received some level of COVID-19 vaccination, with 44.7% having received the initial series and one booster. Co-morbidities included a mental health disorder (44.7%), obesity (25.5%) and diabetes (10.6%).

A total of 53.2% of mothers delivered after treatment with nirmatrelvir and ritonavir and of whom, 12 (48%) underwent a caesarean delivery, although three quarters of these were scheduled. Only two patients discontinued the drugs due to adverse effects.

Based on these findings, the authors concluded that pregnant patients treated with nirmatrelvir and ritonavir tolerated the treatment although there was an unexpectedly high rate of caesarean deliveries. They added that the lack of serious adverse effects affecting pregnant patients or offspring suggests that the drug combination is suitable for the treatment of infected, pregnant women.

Garneau WM et al. Analysis of Clinical Outcomes of Pregnant Patients Treated With Nirmatrelvir and Ritonavir for Acute SARS-CoV-2 Infection. JAMA Netw Open 2022

Oral nirmatrelvir and ritonavir decrease risk of COVID-19 progression by 89%

24th February 2022

Oral nirmatrelvir and ritonavir use in symptomatic COVID-19 patients with a high-risk of disease progression significantly reduced this risk

Giving oral nirmatrelvir and ritonavir to patients with COVID-19 within three days of symptom onset and a potentially high risk for disease progression has been shown to reduce that risk by 89% compared to placebo. This was the conclusion of a randomised trial by the manufacturer, Pfizer.

While the introduction of COVID-19 vaccines have led to a significant reduction in the level of hospitalisation of patients, many individuals with risk factors remain at an increased risk of more severe disease. In a 2021 meta-analysis, it was concluded that patients with hypertension, obesity, diabetes and cardiovascular disease had more COVID-19 severity and mortality respectively. Given the existence of these factors, it is necessary to have treatments which can halt the progression of an infection to more severe disease, shorten the recovery period and ultimately reduce the burden on healthcare systems.

Within the COVID-19 virus, the enzyme 3-chymotrypsin–like cysteine protease (Mpro) is vital for replication and oral nirmatrelvir is an anti-viral agent which targets this enzyme. Moreover, research has shown that nirmatrelvir is metabolised by CYP3A4 and that addition of a low dose of ritonavir, favourably enhanced nirmatrelvir pharmacokinetics.

For the present Phase II-III randomised trial, the authors evaluated the combination of oral nirmatrelvir 300mg and 100mg of ritonavir every 12 hours for 5 days, in non-hospitalised adults with mild-to-moderate COVID-19 but who also had risk factors for progression to severe disease. Enrolled patients were randomised 1:1 to the treatment combination or matching placebo. The primary objective of the trial was to compare the proportion of patients with COVID-19 hospitalised or who died over a 28 day period after randomisation, compared to placebo. This comparison was made at two time-points: after three and five days of treatment.

Oral nirmatrelvir and COVID-19 outcomes

A total of 2246 patients with a median age of 46 years (51.1% male) were randomised to active treatment (1120) or placebo. The most common coexisting conditions associated with a risk of progression to severe COVID-19 were a BMI of 25 or above (80.5%), current smoking (39.0%) and hypertension (32.9%). In addition, 61.0% of participants had two or more coexisting conditions.

In the final analysis, among 1379 patients treated with oral nirmatrelivir and ritonavir and placebo, within less than 3 days of symptom onset, 5 patients in the nirmatrelivir and ritonavir group and 44 in the placebo arm, were hospitalised for COVID-19 or died within 28 days. This corresponded to an 88.9% relative risk reduction in the primary objective. When patients were treated less than 5 days after the onset of symptoms, 0.77% of the oral nirmatrelvir and ritonavir group and 6.31% of the placebo group met the primary outcome, giving a relative risk reduction of 87.8%.

Data on the viral load in both groups showed that when treatment was started within 3 days of symptom onset, the load was 10-times lower in the oral nirmatrelvir and ritonavir group compared to placebo. In addition, the incidence of adverse effects was similar between the two groups.

The authors concluded that treatment with oral nirmatrelvir and ritonavir early in COVID-19 illness, reduced disease progression and viral load.

Hammond J et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 N Engl J Med 2022