Iranian Journal of Medical Sciences

Document Type : Review Article

Authors

1 Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo University, No. 378 Dongqing Road, Yinzhou District, Ningbo

2 Department of Cardiology, Shantou University Medical College, Shantou University, Shantou, 515000, China

3 Department of Gastroenterology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China

4 School of Medicine, Ningbo University, Ningbo, 315211, Zhejiang, China

Abstract

Background: The RNA-dependent RNA polymerase (RdRp) inhibitors, molnupiravir and VV116, have the potential to maximize clinical benefits in the oral treatment of COVID-19. Subjects who consume these drugs may experience an increased incidence of adverse events. This study aimed to evaluate the safety profile of molnupiravir and VV116.
Methods: A comprehensive search of scientific and medical databases, such as PubMed Central/Medline, Embase, Web of Science, and Cochrane Library, was conducted to find relevant articles in English from January 2020 to June 2023. Any kind of adverse events reported in the study were pooled and analyzed in the drug group versus the control group. Estimates of risk effects were summarized through the random effects model using Review Manager version 5.2, and sensitivity analysis was performed by Stata 17.0 software.
Results: Fifteen studies involving 32,796 subjects were included. Eleven studies were placebo-controlled, and four were Paxlovid-controlled. Twelve studies reported adverse events for molnupiravir, and three studies described adverse events for VV116. The total odds ratio (OR) for adverse events in the RdRp inhibitor versus the placebo-controlled group was 1.01 (95% CI=0.84-1.22; I2=26%), P=0.88. The total OR for adverse events in the RdRp inhibitor versus the Paxlovid-controlled group was 0.32 (95% CI=0.16-0.65; I2=87%), P=0.002. Individual drug subgroup analysis in the placebo-controlled study showed that compared with the placebo group, a total OR for adverse events was 0.97 (95% CI, 0.85-1.10; I2=0%) in the molnupiravir group and 3.77 (95% CI=0.08-175.77; I2=85%) in the VV116 group.
Conclusion: The RdRp inhibitors molnupiravir and VV116 are safe for oral treatment of COVID-19. Further evidence is necessary that RdRp inhibitors have a higher safety profile than Paxlovid.

Keywords

What’s Known

Molnupiravir and VV116, novel RNA-dependent RNA polymerase inhibitors, have shown promise in COVID-19 clinical trials. Prior studies have reported various adverse events such as gastrointestinal symptoms, headaches, fatigue, and abnormal liver function tests, but a comprehensive and systematic assessment remains an area for further exploration.

What’s New

This is a comprehensive meta-analysis of the safety of the RNA-dependent RNA polymerase inhibitors, molnupiravir and VV116, for the oral treatment of COVID-19 based on available clinical trials. This study showed no increased adverse event risk compared to placebo and potentially lower risk than Paxlovid, another COVID-19 antiviral agent.

Introduction

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several variants of the virus have been identified, including alpha, beta, gamma, delta, and omicron. 1 Vaccination may be the best solution to control the epidemic, but new novel coronavirus variants present a challenge to this measure. Individuals with weakened immune systems may not attain complete protection from vaccination, and there is growing apprehension about the effectiveness of existing vaccines against emerging COVID-19 variants. 2 Consequently, it becomes crucial to prioritize the investigation and creation of alternative treatments, specifically emphasizing the development of orally administered drugs to combat COVID-19. The exploration of oral medications assumes a pivotal role in managing the pandemic, particularly in situations where vaccines may not provide optimal protection or face accessibility challenges. 3 , 4

RNA-dependent RNA polymerase (RdRp) is an essential enzyme in RNA viruses that participates in RNA synthesis by forming phosphodiester bonds. 5 RdRp has been acknowledged as a valuable target for antiviral drugs in RNA virus infections such as SARS-CoV-2. 6 Apart from the best-known RdRp inhibitors, such as remdesivir and favipiravir, the US Food and Drug Administration (FDA) has issued an emergency license for molnupiravir. 4 , 7 Molnupiravir is an orally active RdRp inhibitor. 4 It is a nucleoside analogue prodrug that is rapidly converted to nucleoside triphosphate (NTP) by an intracellular metabolic process. NTP inhibits viral polymerase by acting as an alternative substrate. 8 Molnupiravir has been evaluated in phase I, II, and III trials where it has shown promising efficacy and safety in patients with COVID-19. Bernal and others reported clinical benefit and adverse event rates comparable to the placebo group for molnupiravir in unvaccinated adults with COVID-19 in a phase III trial. 9

VV116 (GS-621763) is a next-generation RdRp inhibitor. Unlike intravenously administered remdesivir, VV116 is an oral GS-441524 derivative (the active metabolite of remdesivir). 10 , 11 VV116 has shown effectiveness against SARS-CoV-2 infection in preclinical studies. 12 , 13 With no serious adverse events reported in clinical studies, VV116 demonstrated a satisfactory safety and tolerability profile. 14 , 15 Recent trials have reported a lower incidence of adverse events in the VV116 group than in the nirmatrelvir-ritonavir (Paxlovid) group (67.4% vs. 77.3%). 16 Nevertheless, comprehensive and timely updated assessments remain an area for further exploration.

Given that the clinical administration of the RdRp inhibitors, molnupiravir and VV116, increased during the COVID-19 pandemic, a meta-analysis of the safety of these drugs is important. This study pools the currently available data from clinical trials of molnupiravir and VV116 in COVID-19 to assess their adverse events.

Materials and Methods

This meta-analysis was written to comply with the PRISMA statement. 17

Inclusion and Exclusion Criteria

The inclusion criteria were based on the PICO framework as follows:

Population: Adult patients with confirmed or suspected COVID-19 infection who received oral treatment with RdRp inhibitors (molnupiravir or VV116) or control (placebo or Paxlovid) from January 2020 to June 2023.

Intervention: Oral administration of RdRp inhibitors (molnupiravir or VV116) at any dose, frequency, or duration.

Comparison: Oral administration of control (placebo or Paxlovid) at any dose, frequency, or duration.

Outcomes: Adverse events of any type, severity, or duration reported by the studies, such as gastrointestinal symptoms, headache, fatigue, and liver function test abnormalities.

The exclusion criteria were as follows: (1) unrelated research directions; (2) no relevant data; (3) review papers; (4) repeated articles; (5) studies on animal models, case reports, comments, and letters to the editor; (6) included articles must be in the English language.

Search Strategy

An extensive literature search was conducted in PubMed Central/Medline, Web of Science, Embase, and Cochrane Library. We also searched the clinical trials database ClinicalTrials. gov to explore further records. The following keywords were used in the search: molnupiravir (Lagevrio, EIDD-2801, MK-4482), GS-621763 (GS-441524 derivative, JT001, VV116), and COVID-19 (SARS-CoV-2, SARS2, SARS Coronavirus 2, Coronavirus Disease 2019, 2019-nCoV, 2019 Novel Coronavirus). The search strategy in PubMed Central/Medline was as follows: (molnupiravir[mh] OR molnupiravir OR Lagevrio or EIDD-2801 or MK-4482 OR GS-621763[mh] OR GS-621763 OR GS621763 OR GS 621763 OR “GS-441524 prodrug” OR JT001 OR JT-001 OR VV116 OR VV-116 OR “GS-441524 derivatives” OR “GS-441524 derivative”) AND (COVID-19[mh] OR COVID-19 OR “COVID 19” OR “SARS-CoV-2” OR SARS2 OR “SARS Coronavirus 2” OR “Coronavirus Disease 2019” OR “2019-nCoV” OR “2019 Novel Coronavirus” OR “Severe Acute Respiratory Syndrome Coronavirus 2”). The rest of the detailed search strategy was as follows: Embase (‘molnupiravir’ OR ‘lageviro’ OR ‘eidd-2801’ OR ‘mk-4482’ OR ‘gs-621763’ OR ‘gs621763’ OR ‘gs 621763’ OR ‘gs-441524 prodrug’ OR ‘jt001’ OR ‘jt-001’ OR ‘vv116’ OR ‘vv-116’ OR ‘GS-441524 derivatives’ OR ‘GS-441524 derivative’) AND (‘covid-19’ OR ‘covid 19’ OR ‘sars-cov-2’ OR ‘sars2’ OR ‘sars coronavirus 2’ OR ‘2019-ncov’ OR ‘2019 novel coronavirus’ OR ‘severe acute respiratory syndrome coronavirus 2’ OR ‘coronavirus disease 2019’); Web of science ALL=(molnupiravir OR Lagevrio or EIDD-2801 or MK-4482 OR GS-621763 OR GS621763 OR GS 621763 OR “GS-441524 prodrug” OR JT001 OR JT-001 OR VV116 OR VV-116 OR “GS-441524 derivatives” OR “GS-441524 derivative”) AND ALL=(COVID-19 OR “COVID 19” OR “SARS-CoV-2” OR SARS2 OR “SARS Coronavirus 2” OR “Coronavirus Disease 2019” OR “2019-nCoV” OR “2019 Novel Coronavirus” OR “Severe Acute Respiratory Syndrome Coronavirus 2”); Cochrance Library (molnupiravir OR Lagevrio or EIDD-2801 or MK-4482 OR GS-621763 OR GS621763 OR GS 621763 OR “GS-441524 prodrug” OR JT001 OR JT-001 OR VV116 OR VV-116 OR “GS-441524 derivatives” OR “GS-441524 derivative”) AND (COVID-19 OR “COVID 19” OR “SARS-CoV-2” OR SARS2 OR “SARS Coronavirus 2” OR “Coronavirus Disease 2019” OR “2019-nCoV” OR “2019 Novel Coronavirus” OR “Severe Acute Respiratory Syndrome Coronavirus 2”) in Title Abstract Keyword; ClinicalTrials.gov (molnupiravir OR Lagevrio or EIDD-2801 or MK-4482 OR GS-621763 OR GS621763 OR GS 621763 OR “GS-441524 prodrug” OR JT001 OR JT-001 OR VV116 OR VV-116 OR “GS-441524 derivatives” OR “GS-441524 derivative” OR COVID-19).

Data Extraction

Two reviewers (ZZ and JZ) extracted information including (1) study characteristics (name and country of first author, year of publication, intervention, and control, total number of subjects); (2) interventions and control (sample size); and (3) safety outcomes.

Risk of Bias within Individual Studies

The risk of publication bias was determined based on each study for different analysis purposes using funnel plots and Begg and Peters tests. In addition, the Cochrane risk of bias tool (ROB) determined the risk of bias for each included study for quality assessment. The leave-one-out method is used to confirm the robustness of the findings.

Statistical Analysis

A meta-analysis of adverse events for the drugs versus the control was conducted using Review Manager version 5.2 (Cochrane Collaboration, London, UK) and Stata 17.0 software (Stata Corporation, Texas, USA). The pooled effects of studies were calculated using the random effects model with the Mantel-Haenszel method. The odds ratio (OR) and 95% confidence interval (CI) were used to measure the effect. I2 and P values were used to quantify the heterogeneity of the effects among the included studies. Publication bias was addressed through funnel plot analysis and statistical tests (Begg and Peters), with significance considered at P<0.1. Additionally, a leave-one-out analysis systematically excluded each study, allowing for a re-examination of the data to assess the stability and consistency of pooled effects. Levels of evidence and review findings were assessed following Cochrane Collaboration and Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) guidelines. 18

Results

Characteristics of Studies

As of 4 June 2023, a total of 1,740 references were searched; 1,108 duplicate references were excluded and then screened according to inclusion and exclusion criteria. Finally, a total of 15 studies were included. Figure 1 illustrates the overall program of the study and details the number of studies excluded. In addition, the main information on the included randomized controlled trials is shown in table 1.

Figure 1. The PRISMA flowchart presenting the process of research screening.

Author, year, country Intervention Control Subjects (n) Intervention group Control group
Adverse events (n) Total (n) Adverse events (n) Total (n)
Bernal, 2022, Russia 9 Molnupiravir Placebo 1433 216 716 231 717
Fischer, 2022, USA 19 Molnupiravir Placebo 202 42 140 18 62
Johnson, 2023, USA 20 Molnupiravir Placebo 1411 216 710 231 701
Khoo, 2021, UK 21 Molnupiravir Placebo 18 9 12 5 6
Khoo, 2023, UK 22 Molnupiravir Placebo 180 73 90 68 90
Sinha, 2022, India 23 Molnupiravir Placebo 1218 29 608 16 610
Zou, 2022, China 24 Molnupiravir Placebo 108 3 77 0 31
Butler, 2023, UK 25 Molnupiravir Placebo 25708 50 12774 45 12934
Arribas, 2022, Spain 26 Molnupiravir Placebo 293 121 218 46 75
Bruno,2022, Italy 27 Molnupiravir Paxlovid 719 55 554 65 165
Bruno, 2022, Italy 28 Molnupiravir Paxlovid 168 12 147 4 21
Tiseo, 2023, Italy 29 Molnupiravir Paxlovid 562 23 109 116 236
Qian, 2022, China 14 VV116 Placebo 86 31 67 10 19
Shen, 2022, China 15 VV116 Placebo 136 9 60 0 76
Cao, 2023, China 16 VV116 Paxlovid 771 259 384 299 387
Table 1.Basic information about the included studies

Safety Outcomes

A total of 32,796 subjects were involved in the 15 included studies. 9 , 14 - 16 , 19 - 29 11 studies were placebo-controlled 9 , 14 , 15 , 19 - 26 and four were Paxlovid-controlled. 16 , 27 - 29 Twelve studies reported adverse events with molnupiravir, 9 , 19 - 29 and three studies described adverse events with VV116. 14 - 16

A separate pooled analysis of the adverse events of RdRp inhibitors in two different control groups was performed. The overall OR of adverse events for the RdRp inhibitor versus placebo-controlled group was 1.01 (95% CI=0.84-1.22; I2=26%), P=0.88 (figure 2A). No significant difference was observed in the incidence of adverse events between the drug and placebo groups, and leave-one-out analysis further confirmed the reliability of this result (table 2). In the RdRp inhibitor versus the Paxlovid-controlled group, the total number of adverse events was 349 and 484, respectively. The overall OR for adverse events among COVID-19 patients in the RdRp inhibitors vs. Paxlovid group was 0.32 (95% CI=0.16-0.65; I2=87%), P=0.002 (figure 2B). None of the included studies resulted in significant differences due to their larger effect sizes (table 3). Funnel plots and quality assessment tools (ROB) determined the risk of bias for each included study (figure 3), and Begg and Peters tests suggested the absence of a significant small sample effect (publication bias) (RdRp inhibitors versus placebo group: Begg, P=0.16, Peters, P=0.94; RdRp inhibitors versus Paxlovid group: Begg, P>0.999, Peters, P=0.40) (table 4). Additionally, our analysis showed that adverse events occurred more frequently in the Paxlovid group (60.0%). Although the small-sample effect was not significant, the quality of evidence for the safety evaluation outcome of RdRp inhibitors versus Paxlovid was rated as low, given the unclear/high risk of bias in some of the studies and the small number of studies included. The low evidence grading suggests that further studies are likely to have an important impact on our confidence in the effect estimates and are likely to change the estimates (table 5).

Figure 2. Adverse event rates in the RNA-dependent RNA polymerase (RdRp) inhibitor group are compared with those in the placebo group (A) or the Paxlovid group (B).

Omitted study OR [95%CI] I2 P value
None 1.01 [0.84, 1.22] 26% 0.88
Arribas, 2022 1.05 [0.86, 1.29] 30% 0.64
Bernal, 2022 1.08 [0.84, 1.38] 31% 0.56
Butler, 2023 1.01 [0.81, 1.25] 30% 0.95
Fischer, 2022 1.02 [0.83, 1.26] 33% 0.84
Johnson, 2023 1.08 [0.85, 1.37] 29% 0.53
Khoo, 2021 1.02 [0.84, 1.25] 33% 0.81
Khoo, 2023 1.00 [0.82, 1.21] 28% 0.97
Qian, 2022 1.03 [0.85, 1.26] 32% 0.76
Shen, 2022 0.96 [0.84, 1.10] 0% 0.57
Sinha, 2022 0.94 [0.82, 1.08] 1% 0.38
Zou, 2022 1.01 [0.84, 1.23] 31% 0.89
Table 2.Leave one out analysis in the RNA-dependent RNA polymerase (RdRp) inhibitor versus placebo group
Omitted study OR [95%CI] I2 P value
None 0.32 [0.16, 0.65] 87% 0.002
Bruno, 2022 0.31 [0.14, 0.71] 92% 0.005
Bruno,2022 0.42 [0.23, 0.77] 69% 0.005
Cao, 2023 0.22 [0.15, 0.34] 32% <0.001
Tiseo, 2023 0.34 [0.12, 0.92] 91% 0.03
Table 3.Leave one out analysis in the RNA-dependent RNA polymerase (RdRp) inhibitor versus Paxlovid group

Figure 3. Publication bias and quality assessments performed for the included studies. Funnel plots assess study publication bias in the RNA-dependent RNA polymerase (RdRp) inhibitor versus placebo group (A) or Paxlovid group (B). The quality assessment tool (ROB) determines the risk of bias for each included study (C).

RdRp inhibitors versus placebo group RdRp inhibitors versus Paxlovid group
Begg test Peters test Begg test Peters test
z P value z P value z P value z P value
1.40 0.16 -0.07 0.94 -0.34 >0.999 -0.84 0.40
Table 4.Meta bias based on Begg and Peters test
Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No. of participants(studies) Quality of the evidence (GRADE)
Assumed risk Corresponding risk
[Control] [Experimental]
RdRp inhibitors vs. Placebo Study population OR 1.01 (0.84 to 1.22) 30793 (11 RCTs) ⊕⊕⊕⊕ high
44 per 1000 52 per 1000 (4 to 811)
Medium risk population
31 per 1000 33 per 1000 (15 to 46)
RdRp inhibitors vs. Paxlovid Study population OR 0.32 (0.16 to 0.65) 2003 (4 RCTs) ⊕⊕⊝⊝ low
292 per 1000 598 per 1000 (190 to 772)
Medium risk population
19 per 1000 229 per 1000 (190 to 492)
Table 5.Summary of the evidence and quality of the findings (GRADE)

A subgroup analysis of individual drugs in placebo-controlled studies was conducted. Compared to the placebo group, the total OR of adverse events was 0.97 (95% CI=0.85-1.10; I2=0%) in the molnupiravir group and 3.77 (95% CI=0.08-175.77; I2=85%) in the VV116 group. There is no significant difference in adverse event occurrence between the medication group and the placebo group (figure 4).

Figure 4. Forest plot presenting a subgroup analysis for the incidence of adverse events for individual RdRp inhibitor drugs versus placebo.

Discussion

This meta-analysis found that RdRp inhibitors were not associated with an increased risk of adverse events compared to placebo in COVID-19 patients. The analysis produced a total odds ratio (OR) for adverse events of 1.01 (95% CI, 0.84-1.22) in the drug and placebo groups, indicating no significant difference in adverse event incidence between these two groups. However, another antiviral drug, Paxlovid, appeared to have a higher incidence of adverse events than RdRp inhibitors. These findings suggest that RdRp inhibitors are well tolerated for the treatment of COVID-19 and may have an advantage over Paxlovid in terms of safety.

RdRp inhibitors are a class of antiviral drugs that target the RdRp enzyme, which is essential for the replication of RNA viruses, such as SARS-CoV-2. 8 Molnupiravir is a mutagenic nucleotide analogue that induces lethal mutations in the viral genome. 5 VV116 (GS-621763) is a 1’-CN-substituted adenine C-nucleoside analog that inhibits the RdRp activity by competing with natural nucleotides. 10 Both drugs have shown promising efficacy against COVID-19 in preclinical and clinical studies. 6 , 10 , 16 Notably, most adverse events related to molnupiravir and VV116 in the included studies were mild, with few reports of serious adverse events. Common adverse events associated with RdRP inhibitors encompassed rash, nausea, diarrhea, and headache. Consistent with our findings, previous meta-analyses conducted by Wen and others 30 and Amani and others 31 also reported no significant differences in the occurrence of adverse events between the molnupiravir group and the control group. Amani and others 31 also performed a subgroup analysis based on intervention type and dose and found no significant difference in adverse events between the molnupiravir and placebo groups. Although clinical trials for VV116 are limited, these findings collectively emphasize the favorable safety profile of RdRp inhibitors.

A pooled analysis of four studies that compared adverse events between RdRp inhibitors and Paxlovid in COVID-19 patients was also conducted in our study. Paxlovid is a combination protease inhibitor that blocks the cleavage of viral polyproteins and thus prevents the maturation of SARS-CoV-2. 7 Paxlovid has been shown to reduce the risk of hospitalization and death in high-risk COVID-19 patients. 32 However, Paxlovid was found to be associated with a higher incidence of adverse events than RdRp inhibitors in our study, with an OR of 0.32 (95% CI, 0.16-0.65). This suggests that RdRp inhibitors may have a better safety profile than Paxlovid. The most common adverse events reported with Paxlovid were nausea, vomiting, diarrhea, and abdominal pain. These adverse events were also mostly mild and transient, but some serious adverse events were reported, such as liver injury and allergic reactions. 33 - 35 Currently, to our knowledge, no pooled analyses comparing the incidence of adverse events between the RdRp inhibitors, either molnupiravir or VV116 and Paxlovid, have been reported. More evidence is needed to confirm our findings and to explore the potential mechanisms underlying the difference in safety between these two classes of antiviral drugs.

The present study highlights the risk of adverse events that may be imposed by RdRp inhibitors. This meta-analysis has several strengths. First, the most recent and relevant studies on the safety of RdRp inhibitors in COVID-19 patients were included here. Second, a comprehensive search of multiple databases and preprint servers was performed to identify eligible studies. Third, the risk of bias for each included study was assessed using a standardized tool; and sensitivity analyses were performed to test the robustness of the obtained results. Nevertheless, caution is warranted in interpreting our primary findings. First, the restricted number of studies examining the safety of the comparison group with Paxlovid, coupled with a small sample size, raises concerns about a potential bias and results in overestimation. Notably, although small sample effects did not show significance, a mild to moderate asymmetry can be observed within the funnel plots, which may be attributed to the low sensitivity and specificity of these evaluation methods and may be confounded by other factors since the Cochrane Risk of Bias tool found that the risk of bias was unclear or high in some studies. Therefore, we could not completely exclude the possibility of publication bias, especially for the safety of the VV116 with only three studies. Second, we could not perform subgroup analyses based on other variables, such as severity of disease, duration of treatment, dose of drug, age, sex, comorbidities, and concomitant medications, due to insufficient data and heterogeneity among studies. These variables may have influenced the occurrence and severity of adverse events in different groups of patients. Third, we could not assess the long-term safety of RdRp inhibitors or Paxlovid, as most studies had a short follow-up period (less than 30 days). Long-term follow-up studies are needed to monitor the potential delayed or chronic adverse effects of these drugs. Fourth, the impact of adverse events on the quality of life or the cost-effectiveness of RdRp inhibitors or Paxlovid could not be evaluated, as these outcomes were not reported in the included studies. These outcomes are important to consider when choosing the optimal antiviral treatment for COVID-19 patients.

Conclusion

This study shows that the RdRp inhibitors molnupiravir and VV116 are safe for oral treatment of COVID-19 with no significant difference in the incidence of adverse events compared to the placebo. More evidence is needed to support the conclusion that RdRp inhibitors have a higher safety profile than Paxlovid.

Acknowledgement

We never used artificial intelligence (AI)-assisted technologies (such as Large Language Models [LLMs], chatbots, or image creators) in the production of submitted work. This study was supported by the General scientific research project of Zhejiang Provincial Department of Education [Grant Number Y202043693], the Natural Science Foundation of Ningbo [Grant Number 2021J296], and the Natural Science Foundation of Zhejiang Province [Grant Number LQQ20H160001].

Authors’ Contribution

Z.Z: Conceptualization; Data interpretation; Formal analysis; Writing, original draft preparation; Software; Resources. Y.S: Conceptualization; Writing-review & editing; Supervision; Funding acquisition; Project administration. J.Z: Investigation; Methodology; Supervision; Writing-review & editing. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of Interest:

None declared.

References

  1. Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19).. StatPearls: Treasure Island (FL); 2022.
  2. Christie A, Mbaeyi SA, Walensky RP. CDC Interim Recommendations for Fully Vaccinated People: An Important First Step. JAMA. 2021; 325:1501-2. DOI | PubMed
  3. Delang L, Neyts J. Medical treatment options for COVID-19. Eur Heart J Acute Cardiovasc Care. 2020; 9:209-14. Publisher Full Text | DOI | PubMed
  4. Imran M, Kumar Arora M, Asdaq SMB, Khan SA, Alaqel SI, Alshammari MK, et al. Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19. Molecules. 2021; 26Publisher Full Text | DOI | PubMed
  5. Hashemian SMR, Pourhanifeh MH, Hamblin MR, Shahrzad MK, Mirzaei H. RdRp inhibitors and COVID-19: Is molnupiravir a good option?. Biomed Pharmacother. 2022; 146:112517. Publisher Full Text | DOI | PubMed
  6. Zhao J, Guo S, Yi D, Li Q, Ma L, Zhang Y, et al. A cell-based assay to discover inhibitors of SARS-CoV-2 RNA dependent RNA polymerase. Antiviral Res. 2021; 190:105078. Publisher Full Text | DOI | PubMed
  7. Saravolatz LD, Depcinski S, Sharma M. Molnupiravir and Nirmatrelvir-Ritonavir: Oral Coronavirus Disease 2019 Antiviral Drugs. Clin Infect Dis. 2023; 76:165-71. Publisher Full Text | DOI | PubMed
  8. Kabinger F, Stiller C, Schmitzova J, Dienemann C, Kokic G, Hillen HS, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021; 28:740-6. Publisher Full Text | DOI | PubMed
  9. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022; 386:509-20. Publisher Full Text | DOI | PubMed
  10. Wang Z, Yang L, Song XQ. Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase. Front Immunol. 2022; 13:1015355. Publisher Full Text | DOI | PubMed
  11. Xie Y, Yin W, Zhang Y, Shang W, Wang Z, Luan X, et al. Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2. Cell Res. 2021; 31:1212-4. Publisher Full Text | DOI | PubMed
  12. Cox RM, Wolf JD, Lieber CM, Sourimant J, Lin MJ, Babusis D, et al. Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets. Nat Commun. 2021; 12:6415. Publisher Full Text | DOI | PubMed
  13. Schafer A, Martinez DR, Won JJ, Meganck RM, Moreira FR, Brown AJ, et al. Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice. Sci Transl Med. 2022; 14:3410. Publisher Full Text | DOI | PubMed
  14. Qian HJ, Wang Y, Zhang MQ, Xie YC, Wu QQ, Liang LY, et al. Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects. Acta Pharmacol Sin. 2022; 43:3130-8. Publisher Full Text | DOI | PubMed
  15. Shen Y, Ai J, Lin N, Zhang H, Li Y, Wang H, et al. An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants. Emerg Microbes Infect. 2022; 11:1518-23. Publisher Full Text | DOI | PubMed
  16. Cao Z, Gao W, Bao H, Feng H, Mei S, Chen P, et al. VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19. N Engl J Med. 2023; 388:406-17. Publisher Full Text | DOI | PubMed
  17. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372:n71. Publisher Full Text | DOI | PubMed
  18. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336:924-6. Publisher Full Text | DOI | PubMed
  19. Fischer WA, Eron JJ, Holman W, Cohen MS, Fang L, Szewczyk LJ, et al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med. 2022; 14:eabl7430. Publisher Full Text | DOI | PubMed
  20. Johnson MG, Strizki JM, Brown ML, Wan H, Shamsuddin HH, Ramgopal M, et al. Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial. Infection. 2023; 51:1273-84. Publisher Full Text | DOI | PubMed
  21. Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R, et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicrob Chemother. 2021; 76:3286-95. Publisher Full Text | DOI | PubMed
  22. Khoo SH, FitzGerald R, Saunders G, Middleton C, Ahmad S, Edwards CJ, et al. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Infect Dis. 2023; 23:183-95. Publisher Full Text | DOI | PubMed
  23. Sinha S, N K, Suram VK, Chary SS, Naik S, Singh VB, et al. Efficacy and Safety of Molnupiravir in Mild COVID-19 Patients in India. Cureus. 2022; 14:e31508. Publisher Full Text | DOI | PubMed
  24. Zou R, Peng L, Shu D, Zhao L, Lan J, Tan G, et al. Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial. Front Pharmacol. 2022; 13:939573. Publisher Full Text | DOI | PubMed
  25. Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, Hayward G, Richards DB, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2023; 401:281-93. Publisher Full Text | DOI | PubMed
  26. Arribas JR, Bhagani S, Lobo SM, Khaertynova I, Mateu L, Fishchuk R, et al. Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19. NEJM Evid. 2022; 1:EVIDoa2100044. DOI | PubMed
  27. Bruno G, Giotta M, Perelli S, De Vita G, Bartolomeo N, Buccoliero GB. Early Access to Oral Antivirals in High-Risk Outpatients: Good Weapons to Fight COVID-19. Viruses. 2022; 14Publisher Full Text | DOI | PubMed
  28. Bruno G, Perelli S, Giotta M, Bartolomeo N, De Vita G, Buccoliero GB. Efficacy and safety of oral antivirals in individuals aged 80 years or older with mild-to-moderate COVID-19: preliminary report from an Italian Prescriber Center. Infez Med. 2022; 30:547-54. Publisher Full Text | DOI | PubMed
  29. Tiseo G, Barbieri C, Galfo V, Occhineri S, Matucci T, Almerigogna F, et al. Efficacy and Safety of Nirmatrelvir/Ritonavir, Molnupiravir, and Remdesivir in a Real-World Cohort of Outpatients with COVID-19 at High Risk of Progression: The PISA Outpatient Clinic Experience. Infect Dis Ther. 2023; 12:257-71. Publisher Full Text | DOI | PubMed
  30. Wen W, Chen C, Tang J, Wang C, Zhou M, Cheng Y, et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19:a meta-analysis. Ann Med. 2022; 54:516-23. Publisher Full Text | DOI | PubMed
  31. Amani B, Zareei S, Amani B. Rapid review and meta-analysis of adverse events associated with molnupiravir in patients with COVID-19. Br J Clin Pharmacol. 2022; 88:4403-11. Publisher Full Text | DOI | PubMed
  32. Faust JS, Kumar A, Shah J, Khadke S, Dani SS, Ganatra S, et al. Oral Nirmatrelvir and Ritonavir for Coronavirus Disease 2019 in Vaccinated, Nonhospitalized Adults Aged 18-50 Years. Clin Infect Dis. 2023; 77:1257-64. DOI | PubMed
  33. Amani B, Amani B. Efficacy and safety of nirmatrelvir/ritonavir (Paxlovid) for COVID-19: A rapid review and meta-analysis. J Med Virol. 2023; 95:e28441. Publisher Full Text | DOI | PubMed
  34. Cheema HA, Jafar U, Sohail A, Shahid A, Sahra S, Ehsan M, et al. Nirmatrelvir-ritonavir for the treatment of COVID-19 patients: A systematic review and meta-analysis. J Med Virol. 2023; 95:e28471. DOI | PubMed
  35. Zheng Q, Ma P, Wang M, Cheng Y, Zhou M, Ye L, et al. Efficacy and safety of Paxlovid for COVID-19:a meta-analysis. J Infect. 2023; 86:66-117. Publisher Full Text | DOI | PubMed