Effect of Maraviroc and/or Favipiravir plus systemic steroids versus systemic steroids only on the viral load of adults with severe COVID-19:&nbsp; clinical trial

Elba Medina; Ana Laura Sanchez-Sandoval; Eira Valeria Barrón-Palma; Ana María Espinosa-García; Alma Maria de la Luz Villalobos-Osnaya; Mireya León-Hernández; María Luisa Hernández-Medel; Joselin Hernández-Ruiz; Mara Medeiros; Alberto Cedro-Tanda; Adolfo Pérez-García; Lucía Monserrat Pérez-Navarro

doi:10.12688/f1000research.143776.2

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Research Article

Revised

Effect of Maraviroc and/or Favipiravir plus systemic steroids versus systemic steroids only on the viral load of adults with severe COVID-19: clinical trial

[version 2; peer review: 1 approved]

Elba Medina^1,2, Ana Laura Sanchez-Sandoval³, Eira Valeria Barrón-Palma³, [...] Ana María Espinosa-García⁴, Alma Maria de la Luz Villalobos-Osnaya⁴, Mireya León-Hernández^4,5, María Luisa Hernández-Medel⁶, Joselin Hernández-Ruiz⁷, Mara Medeiros⁸, Alberto Cedro-Tanda⁹, Adolfo Pérez-García^4,5, Lucía Monserrat Pérez-Navarro^2,5

Elba Medina^1,2, Ana Laura Sanchez-Sandoval³, [...] Eira Valeria Barrón-Palma³, Ana María Espinosa-García⁴, Alma Maria de la Luz Villalobos-Osnaya⁴, Mireya León-Hernández^4,5, María Luisa Hernández-Medel⁶, Joselin Hernández-Ruiz⁷, Mara Medeiros⁸, Alberto Cedro-Tanda⁹, Adolfo Pérez-García^4,5, Lucía Monserrat Pérez-Navarro^2,5

PUBLISHED 11 Jun 2024

Author details Author details

¹ Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Universidad Nacional Autonoma de Mexico, Mexico City, 04510, Mexico
² Nephrology, Hospital General de Mexico Dr Eduardo Liceaga, Mexico City, 06720, Mexico
³ Genomic, Hospital General de Mexico Dr Eduardo Liceaga, Mexico City, 06720, Mexico
⁴ Pharmacology, Hospital General de Mexico Dr Eduardo Liceaga, Mexico City, 06720, Mexico
⁵ Research, Hospital General de Mexico Dr Eduardo Liceaga, Mexico City, 06720, Mexico
⁶ Infectology, Hospital General de Mexico Dr Eduardo Liceaga, Mexico City, 06720, Mexico
⁷ School of Medicine, University of Utah, Utah, 84112, USA
⁸ Research and Diagnostic Unit in Nephrology and Bone Mineral Metabolism, Hospital Infantil de Mexico Federico Gomez, Mexico City, 06720, Mexico
⁹ Genomic, National Institute of Genomic Medicine, Mexico City, 14610, Mexico

Elba Medina
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Ana Laura Sanchez-Sandoval
Roles: Investigation, Methodology, Validation, Visualization, Writing – Review & Editing

Eira Valeria Barrón-Palma
Roles: Methodology, Validation, Writing – Review & Editing

Ana María Espinosa-García
Roles: Formal Analysis, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Alma Maria de la Luz Villalobos-Osnaya
Roles: Conceptualization, Methodology

Mireya León-Hernández
Roles: Conceptualization, Data Curation, Methodology

María Luisa Hernández-Medel
Roles: Conceptualization, Methodology, Resources

Joselin Hernández-Ruiz
Roles: Conceptualization, Methodology, Project Administration, Resources, Writing – Review & Editing

Mara Medeiros
Roles: Methodology, Visualization, Writing – Review & Editing

Alberto Cedro-Tanda
Roles: Methodology, Validation

Adolfo Pérez-García
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Writing – Review & Editing

Lucía Monserrat Pérez-Navarro
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Coronavirus disease 2019 (COVID-19) has created the need to evaluate drugs such as favipiravir (FPV), an antiviral inhibitor of RNA-dependent RNA-polymerase (RdRp), and Maraviroc (MVC), an antiretroviral that antagonizes the chemokine receptor CCR5, which could affect the modulation of inflammation and viral replication in the treatment of COVID-19. We sought to evaluate the effect of MVC and/or FPV plus systemic steroid (SS) vs. SS alone on the viral load and progression to critical disease.

Methods

Sixteen patients with severe COVID-19 were evaluated in three treatment arms: 1) SS only (n=6), 2) SS plus one test drug MVC or FPV (n=5), and 3) SS plus both test drugs (MVC and FPV, n=5). The viral load was determined for N, E, and RdRp viral genes.

Results

A significant decrease in viral load was observed in the three treatment groups, with a larger effect size in the group that combined SS with both test drugs. The E, N, and RdRp genes with Cohen’s d were 120%, 123%, and 50%, respectively.

Conclusions

The largest effect on viral load reduction, as measured by effect size, was observed in the combination treatment group; however, no statistical significance was found, and it did not prevent progression to critical illness.

Keywords

Steroids, Treatment, antiviral drugs, COVID-19, Favipiravir, Maraviroc, severe disease

Corresponding author: Lucía Monserrat Pérez-Navarro

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 Medina E et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Medina E, Sanchez-Sandoval AL, Barrón-Palma EV et al. Effect of Maraviroc and/or Favipiravir plus systemic steroids versus systemic steroids only on the viral load of adults with severe COVID-19: clinical trial [version 2; peer review: 1 approved]. F1000Research 2024, 13:180 (https://doi.org/10.12688/f1000research.143776.2) First published: 11 Mar 2024, 13:180 (https://doi.org/10.12688/f1000research.143776.1) Latest published: 11 Jun 2024, 13:180 (https://doi.org/10.12688/f1000research.143776.2)

Revised Amendments from Version 1

We have included many important references in the introduction section and discussion parts about new compounds/drugs, that are effective against the different variants of SARS-CoV2, as well as the last reports for COVID-19 disease treatment in general.

See the authors' detailed response to the review by Amgad M Rabie

Introduction

The abrupt emergence of COVID-19 took the world's healthcare services by surprise like no other global public health event in the last century. Medicine had neither vaccines nor treatments that could help contain the exponential spread of infections and the increasing deaths observed in the first stages of the pandemic.¹^,²

Consequently, one of the first responses of the medical communities around the world was to propose a myriad of clinical trials in search of an already known drug that could be repurposed to target one of the pathogenic mechanisms of the novel infection that was being understood in a parallel manner to the advance of the pandemic.³^–⁵

This elicited the emergence of multiple trials where the antiviral capacity of many previously existing drugs for different stages of the infection was evaluated with a wide variety of results such as remdesivir,⁶ ensitrelvir,⁷ nirmatrelvir,⁸ teriflunomide,⁹ and nucleoside/nucleotide analogs.¹⁰^–¹²

In hospitalized patients with coronavirus disease 2019 (COVID-19), five percent of patients with severe disease can progress to critical condition; therefore, the WHO designed a 10-point progression and severity score.¹³ Most patients who progress to severe disease have at least one risk factor, such as old age, type 2 diabetes mellitus (T2DM), obesity, hypertension (HTN),¹⁴ and high viral load with a cycle threshold (Ct) <25.¹⁵ High viral load at admission and within the first 12 days, as well as old age and comorbidities, are independently associated with the risk of intubation and mortality.¹⁵^,¹⁶ The severity of COVID-19 prompted both new therapeutic strategies; dexamethasone helped to reduce mortality¹⁷ and at the same time, in silico studies revealed an area of opportunity for Favipiravir (FPV), a prodrug developed in 2002 for the influenza virus as a ribonucleotide analog that inhibits the viral replication by inhibiting the viral enzyme RNA-dependent RNA-polymerase (RdRp).¹⁸^–²⁰ Moreover, its known adverse effects include thoracic pain, diarrhea, hyperuricemia, and liver damage.²¹^–²⁵ Another repositioned drug is Maraviroc (MVC), developed for human immunodeficiency virus (HIV), which antagonizes the chemokine receptor CCR5,²⁶ additionally modulates inflammation,²⁷^–²⁹ and could have a dual block of CCR5 and the NSP5 (3CLpro or M^pro) viral protease of the SARS-CoV-2 virus, which is responsible for the regulation of replication.²⁸^,³⁰ It could also inhibit S-protein-mediated cell fusion and syncytia-forming capacity.²⁹ The most frequent adverse effects were skin rash, infections, bronchitis, cough, and fever.³¹ Subsequently, the development of vaccines has reduced mortality,³² and the antivirals approved thus far are not fully effective, and their availability is limited.³³^,³⁴ Notwithstanding, new infections continue to occur in vulnerable people, so there is still a need for effective drugs. Therefore, this study aimed to assess the effect of MVC and/or FPV plus systemic steroids (SS) vs. SS only on the viral load and progression to critical disease in COVID-19 patients.

Methods

This was a randomized, unicentric, parallel, single-blinded study (only the patient was blinded to the allocation). The participants were severe, non-critical COVID-19 patients admitted between July 2021 and June 2022 who met the following inclusion criteria: Age 18-80 years, within the first 12 days of onset of symptoms, oxygen saturation ≤90%, positive test for SARS-CoV-2, and at least one risk factor for progression to critical: T2DM, Body mass index (BMI) ≥30, HTN, and age ≥65 years. The women agreed to use contraceptives for up to 90 days. Exclusion criteria were breastfeeding or pregnant women, encephalopathy, renal function ≤ 30 ml/min/1.73 m² estimated by CKD-EPI, acute coronary disease, any state of immunosuppression, and treatment with psychotropics. All the participants signed an informed consent form. We screened 237 patients, of which 19 met the inclusion criteria, 16 completed the assigned treatment, and were analyzed, as shown in Figure 1—CONSORT flow diagram.

Figure 1. CONSORT flow diagram.

Due to the low recruitment rate, the treatment group with only MVC plus SS or FPV plus SS was grouped into a single treatment group named only one antiviral. Three patient was not included in the analysis because one patient of the FPV group developed severe sinus bradycardic (35 bpm) on the second day of treatment, so it was suspended for the patient's safety; this patient was on concomitant treatment with an antitussive (dropropizine), which has been associated with bradycardia due to its alpha-blocker effect, and therefore was also suspended; three days after suspension, the patient recovered heart rate without additional further treatment or procedure, another patient also development severe sinus bradycardia (<40 bpm) on the third day parallel to the intubation process, demanding the use of vasopressors, and dobutamine, recovered heart rate the same day; the remaining patient escaped from the hospital, then only analyzed 16 patients.

SS, Systemic Steroid only; MVC+SS, Maraviroc, and Systemic Steroid; FPV+SS, Favipiravir, and Systemic Steroid; FPV+MVC+SS; Favipiravir plus Maraviroc and Systemic Steroid; bpm, beats per minute.

Treatment groups and allocation

Patients were recruited from the emergency room, infectology, or pneumology services. They were randomly assigned to one of four parallel groups in a 1:1:1:1 ratio; patients were allocated according to a chart of aleatory numbers stratified by sex; using your hospital record number, randomization was by a computer-generated random number list prepared by an investigator with no clinical involvement in the trial. After the researcher obtained the patient’s consent, the research nurse telephoned a contact independent of the recruitment process for allocation consignment. The nurses and investigators were trained in good clinical practice. Treatments were defined as follows: only (SS), MVC+SS, FPV+SS, and MVC+FPV+SS. Due to the low recruitment rate and adverse events of FPV, the clinical trial was closed, and the treatment groups with only MVC plus SS or FPV plus SS were gathered as a single group called treatment with only one antiviral for statistical analysis, as shown in Figure 1.

Outcomes

Primary outcomes: Decrease the viral load, and progression to critical disease.

Sample size calculation

Sample size calculation was performed using the statistical package GPower 3.1.9^®, applying an F-family test for between-factors repeated measures ANOVA considering three treatment groups, three viral load measurements, and an effect size of 0.5, (odds ratio: 6) by Magleby et al.,¹⁶ and 0.8 power, obtaining a total of 24 patients: six per group, plus an additional 20% for losses, thus summing eight per group.

Treatment and clinical follow-up

Dosing: MVC (300 mg Selzentry, GSK) was administered orally at 300 mg twice a day for ten days.³⁵ FPV (200 mg Avigan, Fujifilm Pharma) was administered orally, 1600 mg twice daily on the first day, and 600 mg twice daily on days 2-7.³⁶ SS: All patients received intravenous steroids: dexamethasone (6 mg daily) or its steroid equivalent,¹⁷ enoxaparin, or fractioned heparin. Patients who missed two dose administrations for any reason were excluded from the protocol. The patients’ participation could also end before term due to a complication or life-threatening adverse event, and clinical assessment was performed daily for seven days, and on day 28.

Results

Viral load analysis and identification of SARS-CoV-2 variants

RNA was extracted from nasopharyngeal exudates using QIAamp^® and the QIAGEN kit. Viral genes E, N, and RdRp were identified by qRT-PCR using the GeneFinder™ COVID-19 Plus RealAmp kit (OSANG Healthcare, South Korea), according to the manufacturer’s protocol. The results were analyzed using QuantStudio^TM Design & Analysis version 1.5.1 (Thermo Fisher Scientific, USA). The Ct was determined in duplicate to identify the concordance between measurements, and the reported values are the means of measurements. The viral load was calculated from calibration curves and reported as the number of copies per microliter of RNA extracted per sample. Briefly, primer pairs were designed to amplify each of the three viral genes detected with the kit (E, N, and RdRp) using one of the positive samples with a Ct value of <25 for all three genes. The PCR amplification products were purified and quantified, and 1:10 dilutions with known copy numbers were generated for subsequent analysis by qRT-PCR. The Ct values obtained were plotted against log (number of copies/μl) to calculate a linear fitting equation (R²>0.97) for each viral gene. Finally, the Ct values for each gene in the samples were used to calculate the number of copies/μl of RNA, using the fitting equations of the calibration curve for each gene sequence. Libraries were prepared using the Illumina COVIDSeq test protocol, following the manufacturer’s instructions. First-strand synthesis was performed using the RNA samples. The synthesized cDNA was amplified using ARTIC primers v4 for multiplex PCR, generating 98 amplicons across the SARS-CoV-2 genome. The PCR-amplified product was tagged and adapted using IDT for Illumina Nextera UD Indices Set A, B, C, and D (384 indices) (Illumina, San Diego, CA, USA). Sequencing was performed on the NextSeq 2000 platform (Illumina, San Diego, CA, USA).

Adverse events

All adverse events, related or unrelated to the study drugs, were analyzed by the Pharmacovigilance Service of the Hospital and duly notified to the competing authorities.

Statistical analysis

Given that the patients were discharged before ten days, we analyzed the data up to day seven; chi-square and Kruskal-Wallis tests were used to compare clinical and laboratory characteristics in the three treatment groups. The effect of the three treatments on viral load was measured using effect size (Cohen’s d). T-tests for related samples were performed to compare the clinical and laboratory characteristics within the groups. SPSS version 26 (IBM, Chicago, IL, USA) was used for all the statistical analyses. The significance level was set at p < 0.05 for all statistical tests.

Ethics

This clinical trial was approved by the Committee of Bioethics, Research, and Biosafety of Hospital General de Mexico “Dr. Eduardo Liceaga” (registration number DI/20/407/04/38) and by the Federal Commission for Protection Against Sanitary Risk (COFEPRIS). The procedures followed were in accordance with the ethical standards of the responsible institutional committee on human experimentation, World Medical Association, and Helsinki Declaration.

Results

General characteristics of all patients

We included 16 patients with severe COVID-19 (9 women, seven men) with a mean age of 53±14 years. The clinical characteristics, viral loads, and adverse events of each treatment group are summarized in Table 1.

Table 1. Demographic characteristics and clinical by treatment group.

		Antiviral combination (MVC + FPV + SS) n=5	Single antiviral (MVC+SS or FPV+SS) n=5	Non-Antiviral treatment SS only n=6	p<0.05*
Age	mean±sd	58±8	52±14	48±18	0.49^a
Female	n (%)	3 (60)	3 (60)	3 (50)	0.93^b
Days between the start of symptoms and hospital admission	mean±sd	7±2	7±3	7±3	0.97^a
Number of risk factors for Critical disease
One	n (%)	0 (0)	2 (40)	5 (80)	0.19
Two	n (%)	4 (80)	1 (20)	0 (0)
Three	n (%)	1 (20)	1 (20)	1 (20)
Four	n (%)	0 (0)	1 (20)	0 (0)
CRP mg/L	mean±sd	47±51	91±40	141±101	0.23^a
D Dimer mg/L	mean±sd	954±486	4237±8242	1196±944	0.28^a
LDH U/L	mean±sd	286±48	332±106	324±113	0.72^a
Creatinine mg/dl	mean±sd	0.77±0.21	0.79±0.32	0.79±0.14	0.98^a
Primary Outcome
No progress to Critical disease	n (%)	4 (80)	4 (80)	5 (83.4)	0.22
Secondary Outcomes
Decrease ≥ 2 points on the WHO score (Improvement on day 7)	n (%)	1 (20)	2 (40)	1 (16.6)	0.68^b
Death (28 days)	n (%)	0 (0)	1 (33.3)^d	1 (33.3)^e	0.22^b
Range of days of hospital stay	Min-max	7 to 53	7 to 11 days	6 to 54 days	0.69^a
Adverse Events	n (%)	2 (40)	2 (40)	2 (40)	0.22^b
Adverse Events	n (%) per patient	1(20) Uncontrolled glycemia, atrial fibrillation, deep venous thrombosis SDRA, sacral ulcer 1(20) asymptomatic sinus bradycardia.^f	1(20)^d SDRA pulmonary septic shock AKI stage 3 KDIGO upper gastrointestinal bleeding, dead 1(20) symptomatic sinus bradycardia.	1(16.6)^e Urinary sepsis SDRA, dead 1(16.6) Uncontrolled glycemia Empyema, Mild hyponatremia Abdominal pain.
CRP mg/L (Day 7)	mean±sd	31±41	3.5±1.49^c*	38±43^c*	0.80^a
D Dimer mg/L (Day 7)	mean±sd	9136±18749	821±415	592±338	0.31^a
LDH U/L (Day 7)	mean±sd	199±6	324±113	275±178	0.83^a
Creatinine mg/dl (Day 7)	mean±sd	1.17±0.61	1.4±1.7	0.67±0.14	0.52^a
Follow-up (28 days)	n (%)	2 (40)	3 (60)	4 (83.3)	0.33^b
Follow-up (28 days)	n (%) Per patient	1 (20) Hospitalized and extubation. oxygen requirement, weakness, neuropathy, recovery from AKI Poor blood glucose control 1 (20) oxygen requirement wet cough, hyporexia, fatigue, depression, uncontrolled HTN.	1 (20) Dyspnea, chest pain myalgia 1 (20) Hair loss, Blurred vision resumed his normal activities. 1 (20) Oxygen requirement hoarseness.	1 (16.6) Dyspnea, headache, dysgeusia, anxiety, hair loss, insomnia 1 (16.6) Tachycardia, headache, dizziness, dysphagia 1 (16.6) Back pain, headache, oxygen requirement 1 (16.6) Hospitalized, poor blood glucose control, empyema, oxygen requirement.

a Kruskal-Wallis (compared to three treatments on day 0, and day 7).

b Chi-square test.

c T test for related samples.

d This patient had four risk factors for critical disease, received treatment with MVC, required invasive mechanical ventilation, and died at 10 days.

e The patient was not vaccinated, he does not accept invasive mechanical ventilation and died at 9 days.

f Started day seven and recovered normal heart rate on day 12.

* p < 0.05 with statistical significance.

Four of 16 patients reached a decrease of ≥ 2 points in the WHO score on day seven; 50 percent of which were in the single antiviral group; however, no statistically significant difference was found.

Viral load

The largest viral load reduction was observed in the MVC and FPV+MVC groups (days three, and seven compared with day 0) (Figure 2). The delta variant was identified in 10 of 16 patients, and the remaining six patients were infected with the Omicron variant.

Figure 2. Viral load in the three treatment groups.

Percentage of change on day 3 vs day 0 in nasopharyngeal exudate in the three treatment groups. The most considerable percentage of reduction in the number of copies per microliter of RNA was observed in the MVC and FPV+MVC groups. Percentage of change on day 7 vs day 0 in nasopharyngeal exudate in the three treatment groups. The decrease in viral load measured in the percentage of the gene copies per microliter of RNA of nasopharyngeal exudate on day seven was larger in the MVC and FPV+MVC groups.

Adverse events

Three patients had bradycardia, two had FPV, and one had FPV+MVC. According to the Pharmacovigilance Service, these are related to FPV. All patients recovered; however, two patients were excluded from the study because of severe bradycardia and were not included in the analysis. Figure 1—CONSORT flow diagram.

Combined antiviral group

General characteristics

This group included five patients (three women and two men). Of the five patients, one received two doses of vaccination, and in the remaining four patients, none received at least one dose. The mean patient age was 58±8 years.

Viral load

The viral load was analyzed in five patients. This group had a larger effect size in reducing the viral load at day seven compared with the other treatment groups; genes E, N, and RdRp with Cohen’s d of 120%, 123%, and 50%, respectively (Table 2). One of the five patients maintained a persistently high viral load, and this patient survived. The Omicron variant was found in four out of five patients; the remaining patient had the delta variant.

Table 2. The effect size of each treatment on viral load was compared from day 0 versus day 7.

Primary outcome	Antiviral combination MVC + FPV + SS n=5				Single antiviral (MVC+SS or FPV+SS) n=5				Non-Antiviral treatment SS only n=6
Primary outcome	Day 0 (mean±ds)	Day 7 (mean±ds)	Cohen’s d (%)	95% CI	Day 0 (mean±ds)	Day 7 (mean±ds)	Cohen’s d (%)	95%CI	Day 0 (mean±ds)	Day 7 (mean±ds)	Cohen’s d (%)	95%CI
Gene E copies/μl of RNA^a	1738.6±1625	353.1±468	120	-0.18 to -2.49	158107.9±298903	6781.8±13456	72	-0.56 to -1.99	123811.8± 269967	1589.7±3143	64	-0.52 to 1.8
Gene N copies/μl of RNA^a	174.2±173	20.2±35.7	123	-0.12 to -2.58	89877.2±143987	486.5±962	87	-0.42 to -2.18	61942.2±137659	227.5±542	63	-0.53 to -1.79
Gene RdRp copies/μl of RNA^a	3882.4±3702	1974.4±3867	50	-0.75 to -1.76	112028.8±175143	5806.9±11341	86	-0.44 to-2.15	3882.4±3702	197.4±3867	97	-0.22 to -2.17

a Sample nasopharyngeal exudate.

Single antiviral group

General characteristics

Five patients were included (three women and two men), with a mean age of 52±14 years. Four of the five patients received two doses of the vaccine, and one received only one dose.

Viral load

We did not identify a statistically significant difference in the viral load. The delta variant was found in four of five patients, and the other had the Omicron variant. One out of five patients maintained a persistently high viral load (≤ 25 Ct) and died.

Non-antiviral treatment

General characteristics

Six patients were included in this group (3 women and 3 men). The patients’ age was 48±18 years. Three of the six patients were vaccinated, two of the three had two doses, the other had one dose, and the other three patients were not vaccinated vs. final.

Viral load

We analyzed the viral load in six patients and found no statistical significance. The delta variant was found in five of six patients, and the remaining patient had the Omicron variant.

Discussion

In this study respect to the effect of three treatments on the viral load, and to avoid progress to critical disease in patients with severe COVID-19 found a reduction, and a quicker decrease in viral load in the combined treatment group (FPV+MVC) notwithstanding this did not prevent the progression to critical disease which could be attributed to the small size of the sample, notwithstanding several factors may affect the results; regarding Favipiravir, three significant factors that may affect the results: heterogeneity in doses, and duration of treatment (loading dose from 1600 to 4800 mg, maintenance dose of 1200 to 2000 mg, 2, 3, 4 doses for the next 4-13 days), older age, baseline disease severity.²¹^,²²^,³⁷^–³⁹ In one study, FPV slightly improved clinical and radiological manifestations or decreased viral load²² but in another study, it failed to improve viral elimination.³⁸ Siripongboonsitti et al 2023 found in patients with mild to moderate COVID-19, the use of favipiravir prevented severe COVID-19 when personalized, early treatment was performed, and dose adjustment was made based on ethnicity and body weight.³⁹

Currently, some antiviral drugs are approved by the FDA for emergency use,³³^,³⁴ whose main objective is to avoid hospital admission and death in unvaccinated, with mild to moderate disease, and without a requirement of oxygen, within the first seven days of the onset of symptoms. Recent studies evaluating Molnupiravir, Nirmatrelvir-Ritonavir, and Sotrovimab have shown positive results in preventing hospitalization when administered within the first 5-7 days of the onset of symptoms.⁴⁰^,⁴¹ In contrast, our study focused primarily on patients with severe clinical symptoms, in which the objective was to prevent their evolution to be critical.

Analysis of the epidemic waves of COVID-19 suggests that the SARS-CoV-2 virus evolved into less lethal variants, and the start of vaccination modified the severity of the infection; the oxygen requirement decreased from 80% to 17%, as well as a decrease in admission to the ICU, average days of hospital stay, and mortality.⁴² Therefore, conditions changed dramatically for the benefit of our population since 42% of the subjects in this study were recruited between the third and fourth COVID-19 waves when Delta and Omicron were the predominant variants. The Omicron variant has been described to have a 44% reduction in hospital admissions and a 69% lower risk of death than confirmed cases of the delta variant.⁴³ Delta and Omicron variants have shorter incubation periods, whereas higher infectious viral loads were detected in patients infected with Delta than in patients infected with Omicron.⁴⁴^,⁴⁵

The clearance time of viral load is slower in non-vaccinated individuals.⁴⁶ After one dose of vaccine, the number of Ct increased by 4.5 Ct, and with a booster, it increased by 2.4 Ct⁴⁷; therefore, the start of vaccination could be a factor that influenced our results; nevertheless, the combined treatment reached the effect faster in Ct, and a larger effect size in reducing viral load at seven days; some antivirals found a significant reduction in viral load,³³^,³⁴ remdesivir no provoke reduction, only positive clinical outcome.⁴⁸

The most prevalent risk factors in the population were T2DM or HTN (63%), followed by obesity and age >65 years, which differs from other studies in which 79% had a BMI ≥ 30, followed by age >60 years, and T2DM.³⁴

Regarding adverse events, we did not find hyperuricemia frequently reported in treatment with FPV;⁴⁹ three of our patients developed bradycardia; and there are two case reports that associate the development of bradycardia with FPV as a possible rare adverse event.⁵⁰^,⁵¹

The limitations were that pharmacokinetics could not be performed, and the study could not be double-blinded. Finally, the sample size was small, which limited statistical analysis. The public health emergency mainly generated this, adding to the lack of finances, shortage of human resources, and obstacles of the regulatory system.

Regarding MVC in COVID-19, there are few registered clinical trials on ClinicalTrials.gov, including this, and none have evaluated its combination with favipiravir.

The development of drugs, whether approved or not, requires time and funding to determine the therapeutic target, the drug’s toxicity, and how to use it properly.⁵²^,⁵³ It has been challenging to draw any consistently valid conclusions about the efficacy of drugs in the treatment of COVID-19 disease⁵⁴^,⁵⁵; so far the cure has not been achieved with the use of a single particular drug.⁵²^,⁵⁶ Therefore, it is very important to continue studying potential new therapeutic targets such as: drug repurposing strategies, pan-coronavirus drug targets, in vitro assays, mouse models against SARS-CoV-2 and next Strains.⁵⁷^,⁵⁸

Pre-registered data analysis

For pre-registered analysis in clinical trials, we planned the analysis of data to be between the four treatment groups. However, because of the low recruitment rate and small sample size, it was necessary for statistical analysis to join the group of favipiravir plus systemic steroids with the group of Maraviroc plus systemic steroids in one antiviral treatment group.

Data and software availability

Figshare: Medina, Elba; Sanchez, Laura; Barron, Valeria; Espinosa, Ana Maria; Villalobos, Alma; Leon, Mireya; et al. (2024). Repository COMVIVIR.xlsx. figshare. Dataset. https://doi.org/10.6084/m9.figshare.25017992.v3.⁵⁹

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgments

CONAHCYT, CVU 785859. GlaxoSmithKline donated Maraviroc, and CCINSHAE (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta especialidad) donated Favipiravir. Hospital General de México “Dr. Eduardo Liceaga”.

Bibliography

1. Muralidar S, Ambi SV, Sekaran S, et al.: The emergence of COVID-19 as a global pandemic: Understanding the epidemiology, immune response and potential therapeutic targets of SARS-CoV-2. Biochimie. 2020; 179: 85–100. PubMed Abstract | Publisher Full Text | Free Full Text
2. Zumla A, Hui DS, Azhar EI, et al.: Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet. 2020; 395(10224): e35–e36. PubMed Abstract | Publisher Full Text | Free Full Text
3. Chan JF, Yuan S, Chu H, et al.: COVID-19 drug discovery and treatment options. Nat Rev Microbiol. 2024. PubMed Abstract | Publisher Full Text
4. Jeon S, Ko M, Lee J, et al.: Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs. Antimicro Agents Chemother. 2020; 64(7): e00819–e00820. PubMed Abstract | Publisher Full Text | Free Full Text
5. Jang WD, Jeon S, Kim S, et al.: Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay. Proc Natl Acad Sci USA. 2021; 118(30): e2024302118. PubMed Abstract | Publisher Full Text | Free Full Text
6. Jittamala P, Schilling WHK, Watson JA, et al.: Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV). J Infect Dis. 2023; 228(10): 1318–1325. PubMed Abstract | Publisher Full Text | Free Full Text
7. Lin M, Zeng X, Duan Y, et al.: Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants. Commun Biol. 2023; 6(1): 694. PubMed Abstract | Publisher Full Text | Free Full Text
8. Kuroda T, Nobori H, Fukao K, et al.: Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. J Antimicrob Chemother. 2023; 78(4): 946–952. PubMed Abstract | Publisher Full Text | Free Full Text
9. Rabie AM: Teriflunomide: A possible effective drug for the comprehensive treatment of COVID-19. Curr Res Pharmacol Drug Discov. 2021; 2: 100055. PubMed Abstract | Publisher Full Text | Free Full Text
10. Rabie AM: Potent Inhibitory Activities of the Adenosine Analogue Cordycepin on SARS-CoV-2 Replication. ACS Omega. 2022; 7(3): 2960–2969. PubMed Abstract | Publisher Full Text | Free Full Text
11. Rabie AM, Abdalla M: Forodesine and Riboprine Exhibit Strong Anti-SARS-CoV-2 Repurposing Potential: In Silico and In Vitro Studies. ACS Bio Med Chem Au. 2022; 2(6): 565–585. PubMed Abstract | Publisher Full Text | Free Full Text
12. Rabie AM: Efficacious Preclinical Repurposing of the Nucleoside Analogue Didanosine against COVID-19 Polymerase and Exonuclease. ACS Omega. 2022; 7(25): 21385–21396. PubMed Abstract | Publisher Full Text | Free Full Text
13. WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection: A minimal common outcome measure set for COVID-19 clinical research.Lancet Infect Dis.2020;20(8): e192–e197. Publisher Full Text
14. Kompaniyets L, Pennington AF, Goodman AB, et al.: Underlying Medical Conditions and Severe Illness Among 540,667 Adults Hospitalized With COVID-19, March 2020-March 2021. Prev Chronic Dis. 2021; 18: E66. Publisher Full Text
15. Liu Y, Yan LM, Wan L, et al.: Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020; 20(6): 656–657. Publisher Full Text
16. Magleby R, Westblade LF, Trzebucki A, et al.: Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load on Risk of Intubation and Mortality Among Hospitalized Patients With Coronavirus Disease 2019. Clin Infect Dis. 2021; 73(11): e4197–e4205. PubMed Abstract | Publisher Full Text | Free Full Text
17. Group RCHorby P, Lim WS, et al.: Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021; 384(8): 693–704. Publisher Full Text
18. Janissen R, Woodman A, Shengjuler D, et al.: Induced intra- and intermolecular template switching as a therapeutic mechanism against RNA viruses. Mol Cell. 2021; 81(21): 4467–4480.e7. PubMed Abstract | Publisher Full Text | Free Full Text
19. Shiraki K, Daikoku T: Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020; 209: 107512. PubMed Abstract | Publisher Full Text | Free Full Text
20. Furuta Y, Gowen BB, Takahashi K, et al.: Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013; 100(2): 446–454. PubMed Abstract | Publisher Full Text | Free Full Text
21. Ivashchenko AA, Dmitriev KA, Vostokova NV, et al.: AVIFAVIR for Treatment of Patients With Moderate Coronavirus Disease 2019 (COVID-19): Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis. 2021; 73(3): 531–534. PubMed Abstract | Publisher Full Text | Free Full Text
22. Chen C, Zhang Y, Huang J, et al.: Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial. Front Pharmacol. 2021; 12: 683296. Publisher Full Text
23. Sanders JM, Monogue ML, Jodlowski TZ, et al.: Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020; 323(18): 1824–1836. PubMed Abstract | Publisher Full Text
24. Doi Y, Ishihara T, Banno S, et al.: Favipiravir for symptomatic COVID-19: A nationwide observational cohort study. J Infect Chemother. 2023; 29(2): 150–156. PubMed Abstract | Publisher Full Text | Free Full Text
25. Kow CS, Ramachandram DS, Hasan SS: Favipiravir and hyperuricemia in patients with COVID-19-suggestions for future studies. Lancet Reg Health Southeast Asia. 2023; 16: 100267. PubMed Abstract | Publisher Full Text | Free Full Text
26. Dorr P, Westby M, Dobbs S, et al.: Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005; 49(11): 4721–4732. PubMed Abstract | Publisher Full Text | Free Full Text
27. Fantuzzi L, Tagliamonte M, Gauzzi MC, et al.: Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders. Cell Mol Life Sci. 2019; 76(24): 4869–4886. PubMed Abstract | Publisher Full Text | Free Full Text
28. Risner KH, Tieu KV, Wang Y, et al.: Maraviroc inhibits SARS-CoV-2 multiplication and s-protein mediated cell fusion in cell culture. bioRxiv. 2020.
29. Patterson BK, Seethamraju H, Dhody K, et al.: Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19. medRxiv. 2020.
30. Shamsi A, Mohammad T, Anwar S, et al.: Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy. Biosci Rep. 2020; 40(6). PubMed Abstract | Publisher Full Text | Free Full Text
31. Soriano V, Poveda E: Pharmacokinetics, interactions and mechanism of action of maraviroc. Enferm Infecc Microbiol Clin. 2008; 26(Suppl 11): 12–16. PubMed Abstract | Publisher Full Text
32. Polack FP, Thomas SJ, Kitchin N, et al.: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020; 383(27): 2603–2615. PubMed Abstract | Publisher Full Text | Free Full Text
33. Hammond J, Leister-Tebbe H, Gardner A, et al.: Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022; 386(15): 1397–1408. PubMed Abstract | Publisher Full Text | Free Full Text
34. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al.: Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022; 386(6): 509–520. PubMed Abstract | Publisher Full Text | Free Full Text
35. Mehta P, McAuley DF, Brown M, et al.: COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229): 1033–1034. PubMed Abstract | Publisher Full Text | Free Full Text
36. Cai Q, Yang M, Liu D, et al.: Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing). 2020; 6(10): 1192–1198. PubMed Abstract | Publisher Full Text
37. Konstantinova ID, LA V, Fateev IV, et al.: Favipiravir and Its Structural Analogs: Antiviral Activity and Synthesis Methods. Acta Naturae. 2022; 14(2): 16–38. PubMed Abstract | Publisher Full Text | Free Full Text
38. Doi Y, Hibino M, Hase R, et al.: A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19. Antimicrob Agents Chemother. 2020; 64(12). Publisher Full Text
39. Siripongboonsitti T, Muadchimkaew M, Tawinprai K, et al.: Favipiravir treatment in non-severe COVID-19: promising results from multicenter propensity score-matched study (FAVICOV). Sci Rep. 2023; 13(1): 14884. PubMed Abstract | Publisher Full Text | Free Full Text
40. Kauer V, Totschnig D, Waldenberger F, et al.: Efficacy of Sotrovimab (SOT), Molnupiravir (MOL), and Nirmatrelvir/Ritponavir (N/R) and Tolerability of Molnupiravir in Outpatients at High Risk for Severe COVID-19. Viruses. 2023; 15(5) PubMed Abstract | Publisher Full Text | Free Full Text
41. Cegolon L, Pol R, Simonetti O, et al.: Nirmatrelvir/Ritonavir, or Sotrovimab for High-Risk COVID-19 Patients Infected by the Omicron Variant: Hospitalization, Mortality, and Time until Negative Swab Test in Real Life. Pharmaceuticals (Basel). 2023; 16(5). PubMed Abstract | Publisher Full Text | Free Full Text
42. Maslo C, Friedland R, Toubkin M, et al.: Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave Compared With Previous Waves. JAMA. 2022; 327(6): 583–584. PubMed Abstract | Publisher Full Text | Free Full Text
43. Nyberg T, Ferguson NM, Nash SG, et al.: Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study. Lancet. 2022; 399(10332): 1303–1312. PubMed Abstract | Publisher Full Text | Free Full Text
44. Puhach O, Meyer B, Eckerle I: SARS-CoV-2 viral load and shedding kinetics. Nat Rev Microbiol. 2023; 21(3): 147–161. PubMed Abstract | Publisher Full Text
45. Covantes-Rosales CE, Barajas-Carrillo VW, Girón-Pérez DA, et al.: Comparative Analysis of Age, Sex, and Viral Load in Outpatients during the Four Waves of SARS-CoV-2 in A Mexican Medium-Sized City. Int J Environ Res Public Health. 2022; 19(9): 5719. PubMed Abstract | Publisher Full Text | Free Full Text
46. Kissler SM, Fauver JR, Mack C, et al.: Viral Dynamics of SARS-CoV-2 Variants in Vaccinated and Unvaccinated Persons. N Engl J Med 2021; 385(26): 2489–2491. PubMed Abstract | Publisher Full Text | Free Full Text
47. Levine-Tiefenbrun M, Yelin I, Katz R, et al.: Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine. Nat Med. 2021; 27(5): 790–792. PubMed Abstract | Publisher Full Text
48. Gottlieb RL, Vaca CE, Paredes R, et al.: Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022; 386(4): 305–315. PubMed Abstract | Publisher Full Text | Free Full Text
49. Pilkington V, Pepperrell T, Hill A: A review of the safety of favipiravir - a potential treatment in the COVID-19 pandemic? J Virus Erad. 2020; 6(2): 45–51. PubMed Abstract | Publisher Full Text | Free Full Text
50. Habib MB, Elshafei M, Rahhal A, et al.: Severe sinus bradycardia associated with favipiravir in a COVID-19 patient. Clin Case Rep. 2021; 9(8): e04566. PubMed Abstract | Publisher Full Text | Free Full Text
51. Szigeti J: Sinusbradycardia mint lehetséges favipiravir-mellékhatás. Orvosi Hetilap. 2022; 163(7): 267–270. PubMed Abstract | Publisher Full Text
52. Martinez MA: Efficacy of repurposed antiviral drugs: Lessons from COVID-19. Drug Discov Today. 2022; 27(7): 1954–1960. PubMed Abstract | Publisher Full Text | Free Full Text
53. Martinez M: Clinical Trials of Repurposed Antivirals for SARS-CoV-2. Antimicrob Agents Chemother. 2020; 64(9): e01101–e01120. Publisher Full Text
54. Bartoli A, Gabrielli F, Alicandro T, et al.: COVID-19 treatment options: a difficult journey between failed attempts and experimental drugs. Intern Emerg Med. 2021; 16(2): 281–308. PubMed Abstract | Publisher Full Text | Free Full Text
55. Esmail LC, Kapp P, Assi R, et al.: Sharing of Individual Patient-Level Data by Trialists of Randomized Clinical Trials of Pharmacological Treatments for COVID-19. JAMA. 2023; 329: 1695–1697. PubMed Abstract | Publisher Full Text | Free Full Text
56. Edwards A: What Are the Odds of Finding a COVID-19 Drug from a Lab Repurposing Screen? J Chem Inf Model. 2020; 60(12): 5727–5729. PubMed Abstract | Publisher Full Text
57. Cianfarini C, Hassler L, Wysocki J, et al.: Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant. Cells. 2024; 13(3). PubMed Abstract | Publisher Full Text | Free Full Text
58. Li G, Hilgenfeld R, Whitley R, et al.: Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discov. 2023; 22(6): 449–475. PubMed Abstract | Publisher Full Text | Free Full Text
59. Medina E, Sanchez L, Barron V, et al.: Repository COMVIVIR.xlsx. figshare. [Dataset]. 2024. Publisher Full Text

Comments on this article Comments (1)

Version 2

VERSION 2 PUBLISHED 11 Jun 2024

Revised

Reader Comment 18 Mar 2025

Alvaro Diaz-Badillo, Department of Health & Behavioral Sciences, Texas A&M San Antonio, SAN ANTONIO, USA

18 Mar 2025

Reader Comment

Medina et al. present a commendable effort to evaluate the efficacy of Maraviroc (MVC) and Favipiravir (FPV) combined with systemic steroids (SS) versus SS alone in reducing viral load in ... Continue reading Medina et al. present a commendable effort to evaluate the efficacy of Maraviroc (MVC) and Favipiravir (FPV) combined with systemic steroids (SS) versus SS alone in reducing viral load in severe COVID-19 patients. The study’s strength lies in its randomized, single-blinded design and detailed viral load analysis across E, N, and RdRp genes, revealing a notable effect size in the combined MVC+FPV+SS group (Cohen’s d: 120%, 123%, 50%). However, the small sample size (n=16) limits statistical power, and the lack of significant differences in preventing critical progression highlights this constraint. The inclusion of Delta and Omicron variants adds relevance, though variant-specific effects could be further explored. Adverse events like bradycardia linked to FPV underscore the need for careful monitoring. While the findings suggest a potential benefit of combination therapy on viral clearance, the authors rightly note that larger, double-blinded trials are essential to confirm these preliminary results. This study contributes valuable data to the ongoing search for effective COVID-19 treatments, particularly in severe cases.
Medina et al. present a commendable effort to evaluate the efficacy of Maraviroc (MVC) and Favipiravir (FPV) combined with systemic steroids (SS) versus SS alone in reducing viral load in severe COVID-19 patients. The study’s strength lies in its randomized, single-blinded design and detailed viral load analysis across E, N, and RdRp genes, revealing a notable effect size in the combined MVC+FPV+SS group (Cohen’s d: 120%, 123%, 50%). However, the small sample size (n=16) limits statistical power, and the lack of significant differences in preventing critical progression highlights this constraint. The inclusion of Delta and Omicron variants adds relevance, though variant-specific effects could be further explored. Adverse events like bradycardia linked to FPV underscore the need for careful monitoring. While the findings suggest a potential benefit of combination therapy on viral clearance, the authors rightly note that larger, double-blinded trials are essential to confirm these preliminary results. This study contributes valuable data to the ongoing search for effective COVID-19 treatments, particularly in severe cases.
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