key: cord-0980153-mp8kwd93
authors: Hassaniazad, Mehdi; Farshidi, Hossein; Gharibzadeh, Abdollah; Bazram, Ali; Khalili, Elham; Noormandi, Afsaneh; Fathalipour, Mohammad
title: Efficacy and safety of favipiravir plus interferon‐beta versus lopinavir/ritonavir plus interferon‐beta in moderately ill patients with COVID‐19: A randomized clinical trial
date: 2022-03-24
journal: J Med Virol
DOI: 10.1002/jmv.27724
sha: 97eada8e875e5cd2c567d8f9f5bc6e67dd6293e1
doc_id: 980153
cord_uid: mp8kwd93

Favipiravir (FVP), lopinavir/ritonavir (LPV/RTV), and interferon‐beta (INF‐beta) are considered as potential treatments for COVID‐19. We examined the efficacy and safety of FVP and INF‐beta compared to LPV/RTV and INF‐beta combinations for the treatment of SARS‐CoV‐2. It was a single‐center randomized clinical trial. Eligible patients were randomized to receive FVP plus INF‐beta versus LPV/RTV plus INF‐beta. The primary endpoint was the viral clearance after seven days of randomization. ICU admission, length of stay (LOS) in hospital, in‐hospital mortality, and the incidence of adverse events were also measured. This trial was registered on the Iranian Registry of Clinical Trials (IRCT20200506047323N3). Patients were randomly allocated to the FVP (n = 33) and LPV/RTV (n = 33) groups. The viral clearance on Day seven was not significantly different between the FVP (31.1%) and the LPV/RTV groups (16.1%). The rate of ICU admission and likewise the in‐hospital mortality in the FVP group (12.5% and 6.3%, respectively) were similar to the LPV/RTV groups (19.4% and 19.4%, respectively). The median LOS in the hospital was also not different (6.8 days [interquartile range; IQR = 5.0–11.0] in the FVP and (8.0 days [IQR = 5.5–12.5]) in LPV/RTV groups (p = 0.140). Adverse events were observed in 25.0% of FVP and 32.3% of LPV/RTV groups. The combination therapy with FVP did not exert a higher efficacy compared to the combination regimen of LPV/RTV. However, both treatment regimens demonstrated a mild profile of adverse events.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the new coronavirus, has spread through the world and caused the recent pandemic of Coronavirus disease 2019 . The clinical symptoms of COVID-19 vary, including fever, cough, breathing difficulties, fatigue, and dyspnea. 1 While the majority of patients with COVID-19 developed asymptomatic, self-limiting, or mild disease, the other patients progress to multiorgan failure, severe pneumonia, or even death. 2 Favipiravir (FVP) is a broad-spectrum, oral RNA-dependent RNA polymerase inhibitor approved for the treatment of influenza. 4 It was also revealed the antiviral effects of FVP in the in vitro model of . Several clinical studies have demonstrated the beneficial effects of FVP in the treatment of COVID-19, and WHO also entered favipiravir as a candidate trial therapy. 5 Lopinavir/ritonavir (LPV/RTV) as a combined protease inhibitor has been approved by the US Food and Drug Administration (FDA) for the treatment of acquired immunodeficiency syndrome (AIDS).

Moreover, it has also exerted antiviral function against Middle East respiratory syndrome coronavirus (MERS-CoV) and previous SARS-CoV. 6 Nevertheless, the impacts of this combination for the patients with COVID-19 are unknown. 7 INFs have been used in clinical trials against SARS-CoV-1 and improved clinical outcomes. 8 The study was also undertaken in accordance with the guidelines of the Declaration of Helsinki and the principles of the International Conference on Harmonization Good Clinical Practice.

All patients with age 18-80 years and confirmed diagnosis of SARS-CoV-2 based on the positive real-time polymerase chain reaction (RT-PCR) test in requirement of hospital admission due to an oxygen saturation (SpO 2 ) of ≤93% or/and respiratory rate (RR) of 30 were eligible to enroll in the study. The time from onset of symptoms to randomization was not to be more than 7 days.

Exclusion criteria included cirrhosis, chronic hepatitis, cholestatic liver diseases, chronic renal failure, peptic ulcers, known history of allergy to studied medicines, pregnancy, and lactation. Patients with severe infection (need for invasive or noninvasive ventilator support or shock requiring vasopressor support) were excluded. An informed and written informed consent was obtained from all participants.

Eligible patients were randomized in a 1:1 ratio to FVP and LPV/RTV groups. A stratified block randomization was used with a block size of six to create the randomization sequence. Sealed envelopes were used to protect the randomization sequence. A special code was allocated to every patient to conceal their identity, and patients were assigned to the groups based on their unique code.

Patients in the FVP group received 1600 mg favipiravir (Zhejiang Hisun) twice a day for the first day and 600 mg twice a day for the following 4 days. Patients in the LPV/RTV group received 200/50 mg lopinavir/ritonavir (Heterd Company) twice a day for 7 days. Five doses of 44 mcg interferon beta-1a (CinnaGen) every other day were also administrated to the patients in both groups. Another routine and supportive care were the same in both groups.

The primary outcome was the viral clearance of SARS-CoV-2 in the nasopharyngeal samples assessed by RT-PCR after 7 days of randomization. The improvement in SpO 2 (after 5 min discontinuation of supplemental oxygen), body temperature (temperature), and RR were assessed during the intervention and after 7 days of randomization.

Secondary outcomes were as follows: admission in intensive care unit (ICU), length of stay (LOS) in hospital, and in-hospital mortality. Improvement in clinical symptoms, including fever, chill, headache, sore throat, diarrhea, cough, fatigue, sputum, nausea or vomiting, myalgia, anorexia, taste and smell changes. The incidence of serious adverse drug events was recorded within 7 days of randomization.

The study sample size was calculated upon the assumption that the clinical improvement by Day 6 would be 80% in the treatment group and 35% in the control group, according to the previous studies. Considering a power of 80% and a significance level of 0.05, this study needed 26 participants in each arm. Accounting for a probable 20% dropout rate, 32 patients were required in each group.

Continuous variables were presented as mean and standard deviation, and categorical variables were expressed as frequency and percentages of patients in each category. Fisher's exact test was used to compare viral clearance, ICU admission, mortality, and adverse drug reactions between the two groups. The daily values of SpO 2 , temperature, and RR were compared between the studied groups using the generalized estimation equation (GEE) analysis considering the time, treatment regimen, and their interaction in this model. Moreover, LOS in hospital, temperature, and RR at the end of intervention were compared by the Mann-Whitney U-test.

The efficacy outcomes were assessed in the per-protocol population who had received complete treatment regimens. The safety outcome was studied in the per-protocol population as well as the intent-to-treat population who had received at least one dose of the medications. The SPSS version 18.0 (SPSS Inc.) was used for statistical analysis, and p < 0.05 was considered statistically significant.

A total of 91 patients with laboratory-confirmed SARS-CoV-2 infection were recruited, and after assessment of eligibility criteria, 66 patients were randomly allocated to the FVP (n = 33) and LPV/RTV (n = 33) groups. One patient in the FVP group and two patients in the LPV/RTV group were excluded from the study after randomization due to withdrawal of consent, and the remaining 63 patients completed the treatment regimen and were used for analysis as the per-protocol population (Figure 1 ).

The mean age was 53.75 years (SD, 13.48), and 36 (57.1%) patients were men in the per-protocol population (n = 63). A total of 37 patients (58.7) had a body temperature of ≥37.5°C at baseline. Demographic criteria were not statistically different between FVP and LPV/RTV groups (Table 1) . Baseline laboratory findings ( Table 2 ) and clinical characteristics (Supporting Information file) were generally similar between the studied groups. A more significant improvement was seen in the FAV group regarding some clinical characteristics including, cough, fatigue, and smell change after 7 days of randomization.

The viral clearance on Day 7 in the FVP group (31.1%) was higher compared to the LPV/RTV group (16.1%); however, the difference was not statistically significant. Table 3 .

Overall, more adverse reactions were reported in the LPV/RTV group compared to the FAV group. Gastrointestinal reactions and leukopenia were the most prevalent side effects. However, there was no significant difference between FVP and LPV/RTV groups. Recorded adverse drug reactions in the studied groups are summarized in Table 4 . Note: Values were expressed as mean ± SD, median (IQR), or n (%).

Comparison between groups was performed using the t-test, the Mann-Whitney U-test, or the Fisher's exact test.

Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood nitrogen urea; CRP, C-reactive protein; FVP, favipiravir; INR, international normalized ratio; LDH, lactate dehydrogenase; LPV/RTV, lopinavir/ritonavir; PT, prothrombin time; WBC, white blood cell.

The viral clearance after 7 days of hospitalization was not significantly different between the two groups, which could be due to inappropriate duration and dose of treatment with FVP. The dose of FVP in critically ill patients is controversial and recent data showing lower serum levels of FVP in these patients than in less severely ill ones. Hassanipour et al. 15 also showed that the viral titer on the 14th of treatment in the FVP group was significantly lower than the group receiving LPV/RTV. However, they showed that the differences were not statically significant on the seventh and 10th days of treatment. 15 Cai et al. 1 demonstrated that the viral clearance was significantly faster in the FVP group than in the LPV/RTV group.

Our study showed that SpO 2 temperature and RR had no significant differences between the groups during and at the end of the intervention.

Hassanipour et al. 15 showed that the need for supplemental oxygen therapy was less in the FVP group than in other treatment groups.

Shrestha et al. 13 also showed that noninvasive mechanical ventilation and requiring oxygen therapy was less in the patients receiving FVP.

Our analysis revealed the need for ICU admission LOS in the hospital was not statically different between the two groups. Khamis et al. 8 also showed the need for admission in ICU was not statically significant between the FVP and hydroxychloroquine groups. Additionally, Lou et al. 10 showed only one patient in the baloxavir marboxil group, and two patients in the FAV group needed ICU admission within 7 days of starting treatment. 10 Based on our results, there have been no differences in inhospital mortality on Days 7 and 14 between the two groups.

Dabbous et al. 17 reported no death in the FVP group. In contrast, one death occurred in the hydroxychloroquine group. 17 Hassanipour et al. 15 also showed a decrease in all-cause mortality in the FVP group compared to the control group.

The present study showed that adverse drug reactions had no differences between the two groups. However, serum creatinine was statically significant lower in the FVP group compared to the LPV/RTV Data were collected within 7 days of randomization.

Comparison between groups was performed using Fisher's exact test.

group. Other side effects had no differences between the two groups. In contrast, Cai et al. 1 found that more adverse events occurred in the LPV/ RTV arm than those in the FVP arm. Khamis et al. 8 showed that patients treated with FVP significantly had no side effects. 8 Erdem et al. 12 showed that adverse events occurred in 13% of patients treated with FVP. The most common adverse events include elevation of uric acid, total bilirubin, and liver enzymes, as well as gastrointestinal reactions. This trial includes five patients, and all of them experienced mild to moderate liver enzyme elevation. Nausea occurred in three patients, and neutropenia in one patient. All adverse events were self-limited. There was no association between serious side effects and underlying disease. 12 Pilkington et al. 18 found that intervention with FVP had no serious adverse events. However, hyperuricemia is a concern, and studies showed that an increase in the biochemical parameter is dose-dependent. Other complications,

including QTc prolongation and teratogenic potential, have not been sufficient studies. 18 Considering the importance of this pandemic and treating patients with COVID-19, more studies are recommended on the role of FVP and its side effects in the management of patients with COVID-19.

This study has several limitations. First, there is no high-effective clinically proven drug for COVID-19 to serve as a control group.

Second, observation time was limited because of the urgency of this pandemic. Third, the relationship between clinical prognosis and the viral titer was not well clarified. 

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The authors appreciably thank the trial patients and their families, whose help and participation made this study possible. This study was financially supported by Hormozgan University of Medical Sciences (Grant no: 990233).

The authors declare no conflicts of interest.

The authors confirm that the data supporting the findings of this study are available within the article and its Supporting Information file. Other data requests will be considered by the management group upon written request to the corresponding authors.

http://orcid.org/0000-0001-8354-9426Mohammad Fathalipour http://orcid.org/0000-0002-4568-7024