COVID-19 Treatments – Safety and Efficacy

There have been a number of emergency therapeutic interventions used for the treatment of both severe and non-severe COVID-19; none though that are formally accepted as a pharmacological treatment.  These include ivermectin, avifavir, doxycycline, monoclonal antibodies, proxalutamide, lopinavir/ritonavir (LPV/r) and convalescent plasma (CP) among others.  The safety and efficacy of these treatments remain challenging to address as large scale studies have yet to be conducted or are currently in progress.  This network meta-analysis compares the safety and efficacy of interventions listed above in COVID-19 patients.  The time period for the analysis was from the beginning of the pandemic until July 31, 2021.  The authors included randomized placebo-controlled trials (RPCTs) which compared 49 medications and placebo in the treatment of severe and non-severe COVID-19 patients.  Approximately 61 articles related to 73 RPCTs (16 in severe patients and 57 in non-severe patients) were included in the meta-analysis.  There were 20,680 patients in the analysis with a mean sample size of 160.  Significant findings are presented below:

For increase in virological cure, proxalutamide (OR 9.16, 95% CI 3.15–18.30), ivermectin (OR 6.33, 95% CI 1.22–32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12–24.99) were associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43–17.65). For decrease in all-cause mortality, proxalutamide (OR 0.13, 95% CI 0.09–0.19), imatinib (OR 0.49, 95% CI 0.25–0.96), and baricitinib (OR 0.58, 95% CI 0.42–0.82) were associated with non-severe COVID-19 patients; immunoglobulin gamma (OR 0.27, 95% CI 0.08–0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, sotrovimab (OR 0.21, 95% CI 0.13–0.34) was associated with non-severe COVID-19 patients.

According to the results, treatment with monoclonal antibodies (low dose bamlanivimab, baricitinib, imatinib, and strovimab) is suggested to be a better choice for either category of patients.  Large-scale RPCTs need to be done to more accurately identify the safety and efficacy of potential treatments.

Furthermore, this study examines the case-fatality rate in COVID-19 patients from a Peruvian primary care center treated with hydroxychloroquine/azithromycin.  Approximately 1,265 patients were studied; mean age was 44.5.  Time to onset of symptoms was 5.9 days and 41% had at least one comorbidity.  The treatment began as soon as the physician determined that the patient exhibited symptoms that met the COVID-19 patient clinical criteria The most common comorbidities were obesity (17.3%), hypertension (8.3%), chronic respiratory disease (7.2%), and diabetes (6.1%).  Factors associated with higher mortality were:   age (OR = 1.06; 95% CI 1.01–1.11, p = 0.021), SpO2 (OR = 0.87; 95% CI 0.79–0.96, p = 0.005) and number of days until start of treatment (OR = 1.16; 95% CI 1.06–1.27, p = 0.002).  The overall case-fatality rate was 0.6%.  There were no deaths among patients treated with hydroxychloroquine/azithromycin if treatment was given within 72 hours of onset of symptoms.  The percentage of case-fatality increased with the number of days passed until the start of treatment  reaching 0.89% (95% CI: 0.1–6.12%) among those who received treatment from day 10–12 of illness.

Breakthrough Infections vs. Reinfections

This preprint study from Israel compares reinfection rates to breakthrough infections.  The retrospective observational study compared three groups: 1) individuals who received two doses of Pfizer/BioNTech vaccine, 2) individuals previously infected with COVID-19 but not vaccinated, and 3) those previously infected and had a single dose of the vaccine.  The population consisted of those 16 or older who were vaccinated by February 28, 2021 or who had both an infection by the time period and received one dose of the vaccine by May 25, 2021 as Israeli guidelines allowed previously infected individuals to receive one dose of the vaccine.  Data related to vaccine dates, results of PCR tests, infection-related hospitalizations, and infection-related mortality were used.  Sociodemographic characteristics such as age, sex, SES, and a coded geographical statistical area were also included.  Logistic regression models were used for the analysis.  The study population consisted of 673,676 individuals that were fully vaccinated, 62,883 that were unvaccinated but previously infected, and 42,099 that were previously infected and had a single-dose.  During the study follow-up period, there were 257 cases of infection of which 238 occurred in the vaccinated group and 19 in the previously infected group.  The authors found a statistically significant increased risk for breakthrough infection vs reinfection (OR: 13.1; 95% CI, 8.1 to 21.1).  Aside from age (>=60), there was no evidence that other factors may have affected the risk of infection during follow-up.  For symptomatic follow-up, the authors found an increased risk for symptomatic breakthrough infection vs symptomatic reinfection  (OR: 27 95% CI, 12.7 to 57.5).  There were nine hospitalizations (8 in vaccinated group and 1 in previously infected group).  An additional comparison was made with those previously infected and those previously infected and had one dose of the vaccine.  The authors found that there was a decreased risk for reinfection  (OR: 0.5; 95% CI, 0.3 to 0.92) for those who were previously infected and had one dose of the vaccine.  This is the first large-scale to compare breakthrough infections to reinfections but there are study limitations to note.  The Delta variant was the predominant variant during the outcome period so the findings from this study may not be applicable to other variants.  Also, the findings may not be applicable with other vaccines as the study was done with the Pfizer/BioNTech vaccine.  Lastly, there is no information regarding how long natural immunity lasts so a more robust study design such as a prospective cohort study may provide long-term findings.