DAY 5:
Compared to the placebo group, there was a significant drop in the viral RNA burden in the molnupiravir group from baseline. (WMD: -0.09; 95% CI; [-0.45,-0.26] p=0.60; I²=0%) (Fig 4C)
Overall: The pooled analysis of 200mg molnupiavir compared with placebo explicit no significance (WMD: -0.07; 95% CI; [-0.31,0.17] p=0.56; I²=0%) (Fig 4C)
Adverse events: Results on Adverse events are provided in supplementary document 2.0.
Discussion In this meta-analysis, we evaluate the safety and virology profile of molnupiravir at three dosages (800mg, 400mg, and 200mg) in Covid-19 positive patients. Our combined analysis of seven RCTs, comprising 2369 adult patients in total demonstrates that no particular dose of molnupiravir has a statistically significant effect on all three efficacy parameters (namely SARS-CoV-2 viral RNA error rate, time for clearance of SARS-CoV-2 RNA from nasopharyngeal sample, and mean change in SARS-CoV-2 RNA from nasopharyngeal sample from baseline). Moreover, compared with a placebo, molnupiravir was not associated with an increased risk of other adverse events. However, the drug manifests a decrease in the rate of deaths in patients receiving 400mg of molnupiravir.
To our knowledge, this is the first meta-analysis focusing on the Virology and safety profile of molnupiravir alone. Prior to our study, two network meta-analyses; one by Pitre T et.al [15], the other by Lai et.al. [16], and one meta-analysis by Wen W et.al [17] was conducted. However, all of these studies assessed the safety and efficacy of molnupuravir in addition to other antiviral agents and none of these studies accounted for the dosage of molnupuravir.
With regards to the efficacy of molnupiravir against SARS-CoV-2, our analysis demonstrates that when compared with the placebo, 800 mg molnupiravir had the highest SARS-COV2 RNA error rate on day 5, end of treatment (EOT). Furthermore, a significant reduction in mean change in SARS-Cov-2 from baseline in nasopharyngeal swabs was also observed on day 3 and day 5 with 800mg and overall efficacy with 400mg. Consistent with the mode of action of molnupiravir.  Fischer et al. concluded that the least squares mean viral load change from baseline was substantially higher for patients who received 400 or 800 mg of molnupiravir on day 5 when compared to the placebo group, with differences in the least squares means of 0.434 and 0.547 log10 copies/ml (P = 0.030 and 0.006, respectively). It was also noticed that when patients taking 800 mg of molnupiravir were compared to those taking a placebo, infectious virus isolation dropped significantly on Day 3 (1.9% vs. 16.7%; P=0.016). Moreover, no viruses were isolated from participants who received 400 or 800 mg of molnupiravir, compared with 11.1% (6/54) of those who got a placebo (p=0.03), infectious viral isolation decreased on Day 5 after molnupiravir treatment. [7]
After it enters the host cell, molnupiravir is converted into its active form (NHC-triphosphate) which is then used as a substrate for RNA replication by the pathogen’s RNA-dependent RNA polymerase (RdRp). NHC- triphosphate exists in two tautomeric forms and can thus act as Cytosine (C) or Uracil (U). [18] Normally, Adenine (A) binds with Uracil (U) and Guanine (G) pairs with Cytosine (C). However, with molnupiravir, the viral RdRp incorporates NHC-triphosphate with G and A respectively. One important property of NHC-triphosphate is that it does not halt the extension of the antisense viral RNA. When this negative (-) RNA strand with NHC-triphosphate is used as a positive (+) template for progeny RNA strands, it produces mutations in the offspring RNA. This leaves the virus unable to translate the mutated RNA into proteins which eventually is lethal for the virus and ceases its spread as explained above. This effect is more prominent with higher concentrations of the drug. [18] This signifies the result of our analysis which demonstrates favorable outcomes in the virology profile only for 800mg and 400mg of molnupiravir, however, no significant result was reported with a 200mg dose of molnupiravir.
These findings are following the original studies by Arribas et al., and Caraco et al.[6,14]
The time for clearance of SARS-COV-2 was insignificant at all doses of molnupiravir. However, while considering this finding the methodological differences between trials should be kept in mind. One of the trials by Arribas et al., included in our meta-analysis had a patient population that consisted of hospitalized patients in whom the symptoms began 10 days before their inclusion in the trial while the rest of the trials included participants from the outpatient department (OPD) in whom the onset of symptoms was 5 days before their inclusion in the trial. [3,4,6,7,8,14]. The trial with the hospitalized patient population had non-significant outcomes while the trials that consisted of patients from the OPD tended to have better prognoses. This goes to show that molnupiravir might only be effective against SARS-CoV-2 if administered during the early days of the disease. All three of the previous meta-analyses were conducted on patients from the OPD and their results also show that molnupiravir had a significant effect in reducing mortality and hospitalization rate among those in the intervention group. [15,16,17]
In the preceding reviews, only a few adverse events were analyzed. These include any AEs, serious AEs, and discontinuation of the drug due to adverse events. Consistent with the results of previous meta-analyses, our analysis also shows that when compared to a placebo, molnupiravir does not significantly increase the risk of development of these outcomes. Furthermore, we also weigh up the adverse effects of molnupiravir on various organ systems such as cardiac, respiratory, renal, GI, and CNS. This is another feature that is unique to our manuscript. According to our analysis, molnupiravir carries no such significant adverse effects in comparison to placebo. This is true for all three dosages which goes to show that even increasing the dose of molnupiravir does not significantly increase the risk of development of any of the aforementioned adverse outcomes. One significant and perhaps one of the most important findings from our analysis is the significantly lower incidence of death in patients who were treated with 400mg molnupiravir as compared to those administered placebo. These results provide a much clearer picture concerning the dangers and safety profile of molnupiravir and indicate that molnupiravir is safe to use in clinical practice as a form of antiviral therapy.
Several factors enhance the reliability of our results. Firstly, we only included RCTs in our analysis, which generally tend to have lesser confounders when compared to observational studies. Add to that, all of the trials included in our analysis were judged as having a low to moderate risk of bias. Moreover, we performed an exhaustive literature search, consisting of multiple databases which reduce the risk of publication bias. We observed low to moderate heterogeneity in all of our outcomes.
Despite our best efforts, this study has some limitations. Firstly, our analysis lacks sufficient power. Therefore, our findings should be considered rather exploratory than definitive. Secondly, we had to account for methodological heterogeneity among trials, as such, we had to use a random-effects model for our analysis. Furthermore, there was one significant difference between our trials. Some of the trials consisted of hospitalized patients while the rest consisted of patients from the outpatient department (OPD) who had mild to moderate Covid-19 infection. Due to lack of power and insufficient number of studies a sub-group analysis comparing the effects of molnupiravir in both populations could not be performed. All of the trials included in this study excluded pregnant and lactating patients which is why no pregnancy-related adverse events or teratogenic effects of the drug could be evaluated. Patients with SARS-CoV-2 vaccinations were also not available in any of the trials so a drug interaction between the vaccine and molnupiravir could not be studied.