The COVID-19 pandemic is still spreading around the world and affecting nearly 2.4 million people, with over 164,000 dead so far. With neither vaccine nor proven therapeutic drug being available so far, the need of the hour is for effective treatment. Now, a new study reports the potential usefulness of a combination of hydroxychloroquine and azithromycin as a treatment in mild cases of COVID-19 infection and urges the need for further evaluation and widespread use if its findings are confirmed.
Why do we need a COVID-19 cure?
COVID-19 began in December 2019, caused by a novel coronavirus called SARS-CoV-2, in Wuhan city, Hubei province, in China. It rapidly spread to over 185 countries and territories and was declared a pandemic on the 12th of March, 2020. The overall case fatality rate is about 2.3%, but in older people, this is 8% and 15% in those aged 70-79 years and 80-plus years, respectively. The fact that up to 80% of cases are asymptomatic or mildly symptomatic means that the actual fatality rate may be much less.
Novel Coronavirus SARS-CoV-2: This scanning electron microscope image shows SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab. SARS-CoV-2, also known as 2019-nCoV, is the virus that causes COVID-19. The virus shown was isolated from a patient in the U.S. Credit: NIAID-RML
However, the need remains to contain the spread of the virus, which can be done by limiting the duration of virus carriage. Repurposing older drugs for use against the virus is a highly regarded strategy because these drugs are already approved for use in humans. Their safety, tolerability side effects, and drug interactions are established. Among these drugs, antibiotics similar to azithromycin, and the immunomodulatory drug hydroxychloroquine, have gained widespread attention.
Over a third of physicians already prescribe or believe they should prescribe hydroxychloroquine or azithromycin for COVID-19 infections. This makes it urgent to find out if these are indeed effective.
Preclinical studies have shown that chloroquine phosphate and hydroxychloroquine sulfate inhibit viral activity in vitro. The current study authors report that another of their studies show a synergistic effect when both azithromycin and hydroxychloroquine are used on cells infected with the SARS-CoV-2, at levels similar to the probable concentrations in humans dosed with these drugs. Some studies have also shown that chloroquine reduces fever and leads to an improvement in the CT signs on imaging, as well as delaying the progression of symptoms. This has led some Chinese researchers to recommend a chloroquine-based treatment for COVID-19, of all severities.
The virus is shed for a median of 20 days in survivors (8-37 days), but until death in fatal cases. Treatment is thus required to shorten this period and produce clinical cure without a progression to severe symptoms.
The current study
A small pilot study on 20 cases showed a 100% resolution with hydroxychloroquine 600 mg per day. On day 6, the viral carriage was reduced, and nasopharyngeal swabs were negative in 70% of cases, in contrast to 12.5%. Another study failed to show any significant difference, but this study tested several other drugs as well.
The current study is an uncontrolled observational study in 80 COVID-19 patients with mild infection. All were treated with the two drugs, hydroxychloroquine, and azithromycin for three or more days. The researchers assessed the clinical outcome, the degree of transmissibility as measured by the PCR and viral culture, and the period of patient stay in the infectious disease unit.
What did the study show?
The median age of the 80 patients with confirmed COVID-19 was 52 years. 57% of them had one or more chronic medical conditions, which are considered a risk factor for severe COVID-19. Patients were hospitalized five days on average from the onset of symptoms. The most common symptoms were lower respiratory in 54%, and upper respiratory symptoms in 41%. Fever was present in only 15%. 92% of them were assessed as low-risk for progression. About 54% had CT findings suggestive of pneumonia.
Most patients started treatment either on the day of admission or the next day. Almost all of them were treated daily for a maximum of 10 days. One patient stopped treatment early due to the risk of drug interaction with another medication. Safety and tolerability were acceptable.
In 65 patients, that is, 81%, patients were discharged with a good clinical outcome. Oxygen therapy was required for 15% during their hospital stay. Intensive care admission was required for three patients, of whom two improved and returned to the ward. One patient died in the ward, and one was still in the ICU.
Did the hydroxychloroquine-azithromycin combo work?
The administration of hydroxychloroquine and azithromycin brought about an improvement in all but one patient (who was elderly, had severe symptoms, and had an irreversible disease). The improvement appeared to be better than that described in other hospitalized cohorts.
PCR and culture results show reduced transmissibility
The viral load in the nasopharynx reduced rapidly as per qPCR, with 83% and 93% of patients having a negative swab by day seven and day eight, respectively. The number of contagious patients was two by ten days, and zero by day 12, but had declined markedly by day 6.
In over 97% of patients, respiratory swabs proved negative on culture by day 5. Only two cultures were still positive after day 5, one by day 8 and none by day 9.
Most patients stayed in hospital for five days on average before being discharged.
What can be inferred about the drug combination?
The researchers emphasize the need to treat the condition effectively to avoid progressive worsening of the lung symptoms, typically around the 10th day, which may end in acute respiratory distress syndrome, of poor prognosis, especially in older people.
The researchers point to the rapid symptomatic improvement, with the parallel reduction in viral DNA load, both by PCR and by culture, as evidence for the potential of these drugs to produce a favorable outcome.
The safety of these drugs is not in question, at the recommended doses, but ECG monitoring is recommended since hydroxychloroquine has occasionally been reported to cause heart block in patients with underlying heart conditions. Careful monitoring of high-risk patients by ECG and watching for possible drug interactions should be sufficient to avoid this complication.
The researchers are planning a larger trial in their institution to validate their early findings. They summarize, “We have provided evidence of a beneficial effect of co-administration of hydroxychloroquine with azithromycin in the treatment of COVID-19 and its potential effectiveness in the early reduction of contagiousness. Given the urgent therapeutic need, and the negligible cost of both hydroxychloroquine and azithromycin, we believe that there is an urgent need to evaluate this strategy further.”
Gautret, P., Lagier, J.-C., Parolam P., Hoang, V. T. et al. (2020). Clinical and Microbiological Effect of a Combination Of Hydroxychloroquine And Azithromycin In 80 Covid-19 Patients With At Least A Six-Day Follow Up: A Pilot Observational Study. Travel Medicine and Infectious Disease (2020), doi: https://doi.org/10.1016/j.tmaid.2020.101663.