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24th February 2022
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
14th July 2021
The oral macrolide antibiotic, azithromycin, has antibacterial, anti-inflammatory and anti-viral properties and in a study examining drugs that could be repositioned for the management of COVID-19, azithromycin was identified as a potential candidate. Moreover, an in vitro study has also identified a synergistic effect between azithromycin and hydroxychloroquine. While based on only 20 patients, one preliminary study of hydroxychloroquine in COVID-19, found that adding azithromycin to prevent bacterial super-infection resulted in significantly more efficient elimination of the virus. However, despite these theoretical advantages, large-scale studies of patients hospitalised with COVID-19 have not demonstrated any benefit from the drug. For example, in the RECOVERY trial, among patients hospitalised because of COVID-19, addition of azithromycin did not lead to improved patient outcomes compared to standard care.
Nevertheless, as most studies have occurred within a hospital setting, it remained unclear whether the use of azithromycin could prevent disease progression and hence avoid the need for hospitalisation. With this important remaining gap in the current evidence, a team from the Respiratory Medicine Unit and National Institute for Health Research, Oxford University, undertook a prospective, open-label, randomised trial, among patients with mild-to-moderate COVID-19, to determine if azithromycin was effective at reducing the need for hospital admission. Eligible participants were adults (18 years and over) assessed in an acute hospital, where symptom onset was within 14 days. All eligible patients were randomised to either azithromycin 500mg daily plus standard care or standard care alone. Disease severity was assessed using an ordinal scale from 0 to 8, with higher scores indicating more severe disease. Subsequent assessments were performed after 14 and 28 days and the primary outcome was the proportion of participants with hospital admission or death (from any cause) within 28 days of randomisation. Secondary outcomes included the proportion of patients with admitted to hospital with respiratory failure or requiring non-invasive mechanical ventilation with 28 days of randomisation.
A total of 295 participants were enrolled and randomised to either arm. Among the 147 allocated to azithromycin, the mean age was 45.5 years (48% female) and the majority (73%) did not have any co-morbidities. More than 60% of participants in both arms had low baseline severity scores (either 0 or 1) and there was no difference in peak severity scores between the groups (odds ratio, OR = 0.91, 95% CI 0.57–1.46, p = 0.69). A total of 15 (10%) and 17(12%) of those assigned to azithromycin and standard care respectively, were hospitalised or died. The primary outcome was not significantly different between the two groups (OR = 0.91, 95% CI 0.43–1.92, p = 0.80) and there was also no difference in the time to hospitalisation.
Based on their findings, the authors concluded that the use of azithromycin in those with mild-to-moderate COVID-19 managed in an ambulatory care setting had no impact on hospital admissions or other relevant disease outcomes such as respiratory failure or death. They suggested that azithromycin should not be used in the management of COVID-19.
Hinks TSC et al. Azithromycin versus standard care in patients with mild-to- moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet 2021