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.