Early COVID-19 Treatments Elicited No Real Benefits in Patients

April 27, 2021 - A JAMA Network Open study found that COVID-19 treatments hydroxychloroquine and lopinavir-ritonavir failed to show any significant benefit in hospitalized patients.

The study analyzed metrics such as  decreasing COVID-19-associated hospitalization, time to hospitalization, or time to viral clearance. 

Researchers also found no notable difference between the COVID-19 treatments and placebos. For example, individual symptom resolution did not differ between hydroxychloroquine and the placebo or lopinavir-ritonavir and the placebo. 

The randomized TOGETHER clinical trial was conducted in Brazil and enrolled 1,476 adults diagnosed with respiratory symptoms from SARS-CoV-2 infection between June and September 2020.

Patients were randomly assigned to groups either receiving 800 milligrams of hydroxychloroquine, then 400 milligrams for nine days, or 800 milligrams of lopinavir-ritonavir and 200 milligrams every 12 hours. 

The primary outcomes of the trial were COVID-19-associated hospitalization and death assessed at 90 days after randomization. Secondary outcomes included all-cause hospitalization, viral clearance, symptom resolution, and adverse events. 

In an additional analysis of clinical outcomes for the entire trial cohort and subgroups, no important clinical benefits of hydroxychloroquine or lopinavir-ritonavir were found. 

Additionally, there were some treatment-emergent adverse events. 

Of the patients in the hydroxychloroquine group, 22.2 percent experienced treatment-emergent adverse events, with 5.3 percent experiencing a serious event and 0.5 percent discontinuing the treatment after the event.

In the lopinavir-ritonavir group, 39.7 percent of patients reported treatment-emergent adverse events, of which 8.6 percent were serious. None led to discontinuation.

Researchers also found that, in the placebo group, 20.9 percent of patients had treatment-emergent adverse events, of which 5.5 percent were serious and zero led to discontinuation.

Based on these results, the independent data safety monitoring board made the decision to stop enrollment in the hydroxychloroquine and lopinavir-ritonavir groups.

 The trial outcomes also suggested that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic.

“Our study discontinued the treatment groups because of a low number of events occurring among participants in each group. We conducted a sample size reestimation based on the actual event rate occurring in our trial and detected that greater than 10,000 participants would be required to detect a statistically significant difference between groups, assuming the event rate remained constant,” researchers stated. 

There have been over 109 million COVID-19 cases globally, leading to an unprecedented global research effort to find effective treatments.

At the beginning of June, a clinical trial found that high doses of hydroxychloroquine did not prevent illness compatible with COVID-19 when initiated within four days after a high-risk or moderate-risk exposure.

The results published in NEJM found that new illness compatible with COVID-19 did not differ substantially between participants receiving hydroxychloroquine (11.8 percent) and those receiving placebo (14.3 percent).

The difference between those receiving hydroxychloroquine and those receiving placebo was -2.4 percentage points. New COVID-19 also developed in 107 of 821 participants, or 13 percent during the 14 days of follow-up. 

The World Health Organization (WHO) halted its hydroxychloroquine study in June 2020 and FDA reversed its emergency use authorization for hydroxychloroquine one month later, after various analyses and trial results showed the drug was not effective as a COVID-19 treatment. 

Gilead’s Ebola drug, remdesivir, is currently the only FDA-approved COVID-19 treatment to be used in adults and pediatric patients 12 years of age or older infected with the virus. 

The drug is widely available in hospitals and other healthcare settings across the country. 

“Discovery of effective and affordable treatments for preventing disease progression and subsequent hospitalization in outpatient settings are critical to minimizing limited hospital resources, particularly for resource-limited settings,” researchers said in the study.

“Repurposing existing treatments is an appealing approach, if effective, as they may already be available with known safety profiles,” they continued.