A Randomized, Double-Blind, Multicenter Clinical Study Comparing the Efficacy and Safety of a Drug Combination of Lopinavir/Ritonavir-Azithromycin, Lopinavir/Ritonavir-Doxycycline, and Azithromycin-Hydroxychloroquine for Patients Diagnosed with Mild to Moderate COVID-19 Infections

Abstract

Background: At the present time, COVID-19 vaccines are at the testing stage, and an effective treatment for COVID-19 incorporating appropriate safety measures remains the most significant obstacle to be overcome. A strategic countermeasure is, therefore, urgently required.

Aim: This study aims to evaluate the efficacy and safety of a combination of lopinavir/ritonavir-azithromycin, lopinavir/ritonavir-doxycycline, and azithromycin-hydroxychloroquine used to treat patients with mild to moderate COVID-19 infections. Setting and Design. This study was conducted at four different clinical study sites in Indonesia. The subjects gave informed consent for their participation and were confirmed as being COVID-19-positive by means of an RT-PCR test. The present study constituted a randomized, double-blind, and multicenter clinical study of patients diagnosed with mild to moderate COVID-19 infection.

Materials and methods: Six treatment groups participated in this study: a Control group administered with a 500 mg dose of azithromycin; Group A which received a 200/50 mg dose of lopinavir/ritonavir and 500 mg of azithromycin; Group B treated with a 200/50 mg dose of lopinavir/ritonavir and 200 mg of doxycycline; Group C administered with 200 mg of hydroxychloroquine and 500 mg of azithromycin; Group D which received a 400/100 mg dose of lopinavir/ritonavir and 500 mg of azithromycin; and Group E treated with a 400/100 mg dose of lopinavir/ritonavir and 200 mg of doxycycline.

Results: 754 subjects participated in this study: 694 patients (92.4%) who presented mild symptoms and 57 patients (7.6%) classified as suffering from a moderate case of COVID-19. On the third day after treatment, 91.7%-99.2% of the subjects in Groups A-E were confirmed negative by a PCR swab test compared to 26.9% in the Control group. Observation of all groups which experienced a significant decrease in virus load between day 1 and day 7 was undertaken. Other markers, such as CRP and IL-6, were significantly lower in all treatment groups (p < 0.05 and p < 0.0001) than in the Control group. Furthermore, IL-10 and TNF-α levels were significantly elevated in all treatment groups (p < 0.0001). The administration of azithromycin to the Control group increased CRP and IL-6 levels, while reduced IL-10 and TNF-α on day 7 (p < 0.0001) compared with day 1. Decreases in ALT and AST levels were observed in all groups (p < 0.0001). There was an increase in creatinine in the serum level of the Control, C, D, and E groups (p < 0.05), whereas the BUN level was elevated in all groups (p < 0.0001).

Conclusions: The study findings suggest that the administration of lopinavir/ritonavir-doxycycline, lopinavir/ritonavir-azithromycin, and azithromycin-hydroxychloroquine as a dual drug combination produced a significantly rapid PCR conversion rate to negative in three-day treatment of mild to moderate COVID-19 cases. Further studies should involve observation of older patients with severe clinical symptoms in order to collate significant amounts of demographic data.

Figure 1

Patients' clinical study disposition algorithm for comparing the efficacy of lopinavir/ritonavir and azithromycin, lopinavir/ritonavir and doxycycline, and hydroxychloroquine and azithromycin drug combinations in improving clinical outcomes of COVID-19 patients hospitalized with mild and moderate symptoms. Control group: 1 × 500 mg azithromycin per day; Group A: 2 × 200/50 mg lopinavir/ritonavir + 1 × 500 mg azithromycin per day; Group B: 2 × 200/50 mg lopinavir/ritonavir + 2 × 100 mg doxycycline per day; Group C: 2 × 100 mg hydroxychloroquine + 1 × 500 mg azithromycin per day; Group D: 2 × 400/100 mg lopinavir/ritonavir + 1 × 500 mg azithromycin per day; Group E: 2 × 400/100 mg lopinavir/ritonavir + 2 × 100 mg doxycycline per day.

Figure 2

The RT-PCR analysis results of all subjects in the Control and treatment groups of A–E on day 3 (a) and day 7 (b) during the study period (^∗∗∗p < 0.0001 compared with the Control). Control group: 1 × 500 mg azithromycin per day; Group A: 2 × 200/50 mg lopinavir/ritonavir + 1 × 500 mg azithromycin per day; Group B: 2 × 200/50 mg lopinavir/ritonavir + 2 × 100 mg doxycycline per day; Group C: 2 × 100 mg hydroxychloroquine + 1 × 500 mg azithromycin per day; Group D: 2 × 400/100 mg lopinavir/ritonavir + 1 × 500 mg azithromycin per day; Group E: 2 × 400/100 mg lopinavir/ritonavir + 2 × 100 mg doxycycline per day.