Antiviral Combination Clinically Better Than Standard Therapy in Severe but Not in Non-Severe COVID-19

Abstract

Purpose

Definitive antiviral treatment is not available for COVID-19 infection, with the exception of remdesivir, which still evokes many doubts. Various monotherapy or combination therapies with antivirals or other agents have been tried. The present study aims to evaluate the therapeutic potential of hydroxychloroquine and lopinavir–ritonavir in combination with ribavirin in mild–severe COVID-19.

Patients and Methods

A single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of combination antiviral therapies. Enrolled patients in the severe category were randomized into three groups: (A) standard treatment, (B) hydroxychloroquine+ribavirin+standard treatment, or (C) lopinavir+ritonavir+ribavirin+standard treatment; while the non-severe category comprised two groups: (A) standard treatment or (B) hydroxychloroquine+ribavirin. Combination antivirals were given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report.

Results

In total, 111 patients were randomized: 24, 23, and 24 in severe categories A, B, and C, respectively, and 20 in each of the non-severe groups. Two patients receiving ribavirin experienced drug induced liver injury, and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups, respectively, showed symptomatic recovery, compared to 93.3% and 86.7% in A and B groups, respectively, in the non-severe category at 72 hours (P>0.05).

Conclusion

Though the results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19 due to very small sized trial, clinically hydroxychloroquine+ribavirin therapy is showing better recovery by 7.4% than standard therapy in the former category. However, results do indicate the benefit of standard therapy in the non-severe category by 6.6%. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population.

Keywords:

• coronavirus disease 2019
• interventional trial
• hydroxychloroquine
• lopinavir/ritonavir combination
• ribavirin

Acknowledgments

Thanks to Prof Manoj Gupta, Prof UB Mishra of the institute for providing logistics required for the trial; to Dr. Arkapal Bandyopadhyay, Dr Ramanuj Samanta, Dr Rohit Walia, Dr Itish Patnaik, Dr Gaurav Chikara, Dr Ravi Gupta, and Dr Bharat Bhusan Bhardwaj, for helping protocol preparation and handling drug complications in any of the study participants; and to Dr Deepjyoti Kalita and Dr Puneet Gupta for performing laboratory diagnosis of the study participants.

Data Sharing Statement

The authors intend to share individual deidentified participant data of all studied variables after contacting the corresponding author’s email address and these data will be available for 10 years.

Ethics Statement

All participants were informed about the purpose of the trial, consented, and the trial was conducted in accordance with the Declaration of Helsinki.

Author Contributions

All authors made substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.