INTRODUCTION
Remdesivir (formerly GS-5734) is a broad-spectrum antiviral medication. It was first developed by Gilead Sciences for the treatment of Ebola virus infection in West Africa (2014–2016).[1 2 3 4
On May 1, 2020, the U.S. Food and Drug Administration (FDA) has granted Emergency Use Authorization (EUA) for remdesivir to treat Covid-19 patients.[5 6 7
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazine[ZERO WIDTH SPACE]carboxamide) is a purine nucleoside analog. It has a broad-spectrum antiviral activity and it is demonstrated to inhibit, in vitro and in animal models, the replication of different RNA viruses, including flaviviruses,[8 9 10 11 favipiravir received the Drug Controller General of India approval in India for mild and moderate Covid-19 infections.[12
Favipiravir acts by competitive inhibition of viral RdRp. Within the tissue, the molecule undergoes phosphoribosylation to its active form favipiravir -favipiravir ribofuranosyl-5′-triphosphate (RTP). The active favipiravir -RTP inhibits RdRp and prevents replication of the viral genome. Also, it gets incorporated in the viral RNA strand, preventing further elongation and proliferation.[13 favipiravir for adults is 1800 mg orally twice daily on 1st day followed by 800 mg orally twice daily, up to a maximum of 14 days.[14
In the present article, a systematic review of mucocutaneous adverse effects of remdesivir and favipiravir which are the two antiviral drugs used widely during the pandemic of Covid-19 was performed.
MATERIALS AND METHODS
The study is performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The PRISMA flow charts regarding the article search for remdesivir and favipiravir are mentioned as Figures 1 and 2 .
Figure 1: PRISMA 2020 flow diagram for the present systematic review of remdesivir
Figure 2: PRISMA 2020 flow diagram for the systematic review of favipiravir
Eligibility criteria
All original articles, case series, and case reports pertaining to mucocutaneous adverse drug reactions caused by either remdesivir or favipiravir administered to Covid-19-infected patients were included in the present study. The exclusion criteria comprised animal studies, in-vitro studies, review articles, and all the articles which did not meet the above inclusion criteria.
Source of information
The articles were searched in the following databases: PubMed (http://pubmed.ncbi.nlm.nih.gov https://scholar.google.com
Search strategy
The search was conducted using the following keywords: (“remdesivir ”) AND (“cutaneous adverse drug reaction” OR “mucocutaneous adverse drug reaction” OR “drug reaction” OR “drug rash” OR “skin rash” OR “rash” OR “skin adverse reactions” OR “adverse effects skin” OR “urticarial” OR “maculopapular” OR “erythroderma” OR “steven Johnson syndrome” OR “toxic epidermal necrolysis” OR “erythema multiforme” OR “blister” OR “acute generalised exanthematous pustulosis” OR “drug hypersensitivity syndrome”).
The term “remdesivir ” was replaced by “favipiravir ” to search the articles regarding the cutaneous adverse drug reactions caused by favipiravir . The search was performed from July 30 until August 15, 2021. The period of search was any article published pertaining to the above search terms until August 15, 2021. The search was done in PubMed and Google Scholar.
Study selection
Initially, the search was conducted using the search terms in the databases. The titles and abstracts of the manuscripts were read. If the articles satisfy the eligibility criteria of the present study, the full text of the articles were read and included. All the available data regarding the mucocutaneous adverse effects of remdesivir or favipiravir mentioned in the eligible manuscripts were extracted and the data were compiled. The PRISMA 2020 flow diagrams pertaining to the systematic review of mucocutaneous adverse effects of remdesivir and favipiravir are mentioned in Figures 1 and 2 .
RESULTS
Based on the above search criteria, six articles were identified pertaining to the mucocutaneous adverse reactions of remdesivir , of which two were original articles and four were case reports, the details of which are presented in Tables 1 and 2 . In the randomized, double blind, placebo controlled trial performed by Wang et al .,[15 remdesivir arm and 2 patients (3%) developed cutaneous rash in the control arm. In the single-arm study performed by Grein et al. ,[16 remdesivir was administered.
Table 1: Interventional studies which reported the cutaneous rash caused by remdesivir
Table 2: Case reports of the cutaneous adverse effects implicated to remdesivir
The following were the case reports pertaining to the cutaneous adverse events caused by remdesivir : painful blisters of the left hand following extravasation of remdesivir infusion,[17 remdesivir infusion in two patients which resolved following withdrawal of remdesivir ,[18 remdesivir which resolved spontaneously following the withdrawal of remdesivir .[19
One case series and one case report pertaining to the mucocutaneous adverse effects of favipiravir were identified based on the search criteria and are presented in Table 3 . The case reported by Atak et al. [20 favipiravir . Punyaratabandhu and Chirachanakul[21 favipiravir , favipiravir cannot be solely implicated as the causative drug.
Table 3: Case reports pertaining to mucocutaneous adverse effects of favipiravir
DISCUSSION
In the studies performed by Wang et al. [15 et al .,[16 remdesivir was observed in 11 (7%) and 4 (8%) patients, respectively. The type of rash was not mentioned in both the studies mentioned earlier. The cutaneous adverse events published as case reports were painful blisters following extravasation of remdesivir ,[17 18 19
Charan et al .[22 remdesivir mentioned in the World Health Organization (WHO) database. The authors derived the data from Vigibase, which is a database maintained by the WHO. The adverse drug reactions due to remdesivir notified in Vigibase from January 1, 2015 to July 19, 2020 were included. It was observed that adverse events pertaining to skin and subcutaneous tissue were reported in 36 patients. The description of the cutaneous adverse effects is not mentioned in their study.
Kaur et al. [23 favipiravir . In this study, 194 adverse drug reactions were seen in 93 patients, of which 20 adverse events were skin-related. The following are the cutaneous adverse events due to favipiravir mentioned in the study: pruritus in five patients, rash in five patients (type of rash is not mentioned), erythema in four patients, maculopapular rash in two patients, hair color change in one patient, nail discoloration in one patient, purpura in one patient, and vasculitis in one patient. In the study conducted by Najar Nobari et al. ,[24 favipiravir has superior adverse effect profile with no or very few side effects being reported.
Intriguing findings of fluorescence involving the nail plate and hair on performing Wood’s lamp examination in patients who were administered favipiravir were reported by Aslan Kayıran et al. [25 favipiravir or due to ingredients such as titanium dioxide or ferric oxide present in the tablet. Similar reports of fluorescence of nail and hair were published by Gülseren and Yalıcı-Armagan[26 27
CONCLUSION
In the present systematic analysis, the mucocutaneous adverse events of the two widely used antiviral medications in Covid-19 were described. This article throws light on the aspects which are hardly reported or discussed in the literature.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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