Post-COVID-19 condition persists for at least 2 years

24th November 2022

Post-COVID-19 condition symptoms are still present in both hospitalised and non-hospitalised patients two years after their acute infection

Research by a Spanish team has revealed how symptoms of post-COVID-19 condition (i.e., long covid) persist in both hospitalised and non-hospitalised patients for at least 2 years following their acute infection with the virus.

It has become increasingly recognised that approximately 10% – 20% of people infected with COVID-19 continue to experience a variety of mid- and long-term effects after they recover from their initial illness. The World Health Organisation uses the term ‘post-COVID-19 condition’ and which refers to the constellation of long-term symptoms that some people experience after they have been infected with COVID-19. A wide range of symptoms have been reported affecting various systems in the body, some of which leading to both cognitive and sensory impairment. In fact, a 2021 scoping review identified more than 100 symptoms and whose prevalence varied significantly and were not explained by data collection approaches, study design or other methodological approaches. To date several reviews have examined post-COVID-19 condition symptoms but have only been able to report on the prevalence up to 1 year following an acute infection. In the present study, the Spanish team set out to explore and compare the presence of symptoms in both hospitalised and non-hospitalised patients after a follow-up period of two years.

Hospitalised and non-hospitalised patient data was collected and a random sample from both cohorts who were infected during the first wave of the pandemic and had not been subsequently re-infected were included. Demographic and clinical data were collected from medical records and invited participants agreed to have a scheduled telephone interview 2 years after their infection and which enquired about the presence of a range of symptoms.

Post-COVID-19 condition symptoms after 2 years

A total of 360 hospitalised patients with a mean age of 60.7 years (45% female) and 308 non-hospitalised patients (mean age = 56.7, 59.4% female) were included in the study. The hospitalised and non-hospitalised groups were assessed after a mean of 23.8 and 23.4 months respectively.

Overall, 59.7% of hospitalised and 67.5% of non-hospitalised patients reported having at least 1 post-COVID-19 condition symptom at their follow-up interview. Dyspnoea was more prevalent at the onset of illness among hospitalised compared to non-hospitalised patients (31.1% vs 11.7%, p < 0.001). In contrast, anosmia was more common among non-hospitalised individuals (21.4% vs 10.0%, p = .003).

Th most frequent condition in both cohorts was fatigue (44.7% vs 47.7%, hospitalised vs non-hospitalised), with a similar level of pain symptoms including headaches (35.8% vs 29.9%), memory loss (20% vs 15.9%) and dyspnoea at rest (3.9% both groups).

In multivariate regression analysis, among hospitalised patients, the number of pre-existing co-morbidities was significantly associated with fatigue (odds ratio, OR = 1.93, 95% CI 1.09 – 3.42, p = 0.02) and dyspnoea (OR = 1.91, 95% CI 1.04 – 3.48, p = 0.03). Among non-hospitalised patients, the number of pre-existing co-morbidities (OR = 3.75) and the number of symptoms at infection onset (OR = 3.84) were both associated with the presence of fatigue.

The authors concluded that their cross-sectional study suggested the presence of at least 1 post-COVID-19 symptom in a large proportion of infected patients and which appeared to be irrespective of disease severity.

Citation
Fernández-de-las-Peñas C et al. Post-COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients. JAMA New 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.

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

Molnupiravir treatment halves rate of hospitalisation in unvaccinated COVID-19 patients

20th December 2021

Molnupiravir treatment initiated within 5 days of symptom onset in unvaccinated individuals with COVID-19 halved the risk of hospitalisation

The use of oral molnupiravir treatment within 5 days of COVID-19 symptom onset, led to a 50% reduction in the risk of hospitalisation for any cause of death among unvaccinated patients. This was the main finding of a study by the MOVe-OUT group which was supported by the manufacturer of the drug, Merck Sharp and Dohme.

Molnupiravir is a small-molecule ribonucleoside pro-drug of N-hydroxycytidine (NHC) and which has been shown to inhibit the influenza virus and is phosphorylated in vivo and incorporated into viral RNA, rendering the virus non-infectious. Early trial data suggested that the drug was efficacious and safe in patients infected with COVID-19 which formed the basis for the current MOVe-OUT trial.

For the Phase II-III trial, non-hospitalised patients with mild or moderate, laboratory confirmed COVID-19, symptom onset of no more than 5 days and at least one risk factor for more severe disease, were enrolled in the study. Risk factors included age (> 60 years), active cancer, chronic kidney disease, COPD, obesity, diabetes or serious heart conditions such as heart failure and coronary artery disease. Patients were excluded where there was an anticipated need for hospitalisation (due to COVID-19) within the next 48 hours.

Those enrolled were randomised 1:1 to molnupiravir treatment (800 mg) twice daily for five days or identical placebo. The primary efficacy endpoint was the incidence of hospitalisation for any cause, which the researchers defined as > 24 hours of acute hospital care or death through to day 29. The researchers also included a primary safety outcome as the incidence of adverse events.

Findings

A total of 1433 participants with a median age of 42 (53.6% female) were assigned to molnupiravir treatment (716) or placebo. Overall, 99.4% of these individuals had at least one risk factor for severe COVID-19, most commonly obesity (73.7%), age > 60 (17.2%) and diabetes (15.9%) with disease severity classed as mild in more than half (55.2%) of all cases.

The percentage of patients meeting the primary endpoint was 7.3% (molnupiravir) and 14.1% (placebo), a treatment difference of 6.8% (95% CI -11.3 to – 2.4, p = 0.001). Patients receiving molnupiravir had a lower risk of hospitalisation or death through to day 29 (6.8% vs 9.7%). There was one death reported in the molnupiravir group and 9 in the placebo group, all of which were considered to be COVID-19-related.

In terms of safety, 30.4% vs 33% of participants in the molnupiravir treatment arm vs placebo, experienced > 1 adverse event including diarrhoea, nausea and dizziness.

Since the trial was undertaken among unvaccinated participants, the potential value of the drug in preventing breakthrough infections could not be evaluated. Nevertheless, authors concluded that molnupiravir treatment was effective for the treatment of COVID-19 and that it did not appear to have any major safety concerns.

Citation

Bernal AJ et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients N Engl J Med 2021