6. Future Outlook
Reviewing the safety of potential COVID-19 treatments (table 1) is
complex due to the fast-moving pace of research in this field. For
example, chloroquine and hydroxychloroquine with or without an
accompanying macrolide antibiotic, have consistently been at the
forefront of COVID-19 research efforts since the outbreak began.
However, the astonishing developments over a week or so have led to
retraction of a highly publicised paper, and results from a
post-exposure prophylaxis trial and a treatment trial (RECOVERY), both
of which have shown no beneficial effect of hydroxychloroquine (Boulware
et al., 2020; Horby & Landray, 2020; Mehra, Ruschitzka, & Patel,
2020). This highlights that the rapid rate of discoveries surrounding
COVID-19 therapies generates the need to update this perspective
frequently, in order to ensure that the safety of any newly repositioned
therapies, novel developmental compounds, or new therapeutic
combinations are investigated. For example, the potential use of heparin
in novel forms, including nebulised therapy (clinical trial identifier
NCT04397510), as an antiviral agent is currently the subject of several
investigational trials. In addition, the potential utility of
nitazoxanide is currently the subject of several clinical trials
(Clinical Trials.gov, 2020a; Pepperrell, Pilkington, Owen, Wang, &
Hill, 2020; Rajoli et al., 2020).
It is clearly essential that the harm:benefit ratio of any
pharmaceuticals being considered for use in the treatment of COVID-19
are thoroughly considered. This ratio changes dependent upon the disease
stage and is correlated to potential mortality. For example, a higher
risk may be accepted for patients in the later stage of severe disease
than the same therapeutic agent administered in mild disease. This
difference in harm-benefit analysis becomes even more striking when
considering the use of such agents to prevent infection. As is the case
for many highly contagious viruses, prevention by prophylaxis would be
incredibly valuable. Some of the agents described in this review,
including chloroquine and ritonavir have been suggested as potential
prophylactic agents, but to date, data on efficacy have been
disappointing (Rathi, Ish, Kalantri, & Kalantri, 2020; Spinelli,
Ceccarelli, Di Franco, & Conti, 2020). Clearly, treatment duration for
prophylaxis is expected to be longer than for treatment of COVID-19, and
this may further alter the harm-benefit ratio, reinforcing the need for
safety considerations at the outset of any clinical trials.
Similarly, the evaluation of therapy risk also applies to long-term
recovery. As the current pandemic progresses, it is becoming apparent
that being discharged from hospital does not necessarily mean that
patients are free from COVID-19 symptoms. Large numbers of patients who
have survived severe SARS-CoV-2 infection may have incurred long-term
health problems, including some permanent loss of lung and kidney
function (Foundation, 2020; Su et al., 2020; Summers, 2020).
Consequently, it is probable that long-term therapies will be required
for many patients to maintain, or ideally restore, normal physiological
organ function. It is vital that therapies which will be used to treat
patients during their long-term recovery are also undergoing evaluation
for their safety, particularly as many of these agents may need to be
administered over much longer periods of time than initial COVID-19
treatments.
The identification and characterisation of biomarkers of disease and
safety will be invaluable in the further development and deployment of
therapies for COVID-19. Disease biomarkers, for example of lung injury
or the hyperinflammatory reponse, may allow the stratification of
therapy in order to select the agent best suited to the stage of
disease. Moreover, biomarkers should be considered to monitor patient
safety in cases of known AEs. For example, the manufacturer’s guidelines
for remdesivir recommend daily liver function tests due to the risk of
transaminase elevations (Gilead, 2020). These tests are essential,
particularly with regards to COVID-19 where increased ALT levels are
reported to be common amongst hospitalised patients (Bangash et al.,
2020; L. Zhang et al., 2009). Looking to the future, improvements in the
specificity, predictivity and reliability of drug-induced organ damage,
through academic-industry partnerships such as the Biomarker
Qualification Program in the Critical Path Institute in the US, and the
European Innovative Medicines Initiative consortium Transbioline, will
help improve clinical assessment of COVID-19 drug safety issues.
Continued enhancements in the speed, predictivity, and human translation
of safety assessment for toxicity of anti-viral compounds is clearly
warranted, and this may include animal models of SARS-CoV-2 as well asin vitro models, in order to assess efficacy alongside safety.
Such a full understanding for individual therapies will indicate the
combinations that can have the potential to provide the best synergy for
benefit, while forewarning of the potential for increased risk/harm
through pharmacokinetic or toxicodynamic interaction.
Although outside the scope of this review, a vaccine for COVID-19
remains the greatest hope to end the pandemic and protect the
population. As of 6th June 2020, according to WHO
there are 10 vaccines in clinical trial stages and 123 in preclinical
stages of evaluation (World Health Organisation, 2020b). Currently,
potential vaccines are only just beginning to be tested for efficacy in
humans in early phase studies, and therefore safety data will begin to
emerge as larger numbers of individuals are administered the vaccine.
Safety data regarding preliminary vaccinations against SARS and MERS are
limited, but the available information may be useful during the
development of COVID-19 vaccines due to the similarities between the
coronavirus strains (Padron-Regalado, 2020). One safety concern relevant
to coronaviruses is the potential for the induction of
antibody-dependent enhancement (ADE), a phenomenon which was observed in
cats vaccinated against feline infectious peritonitis coronavirus, and
has also been seen in patients vaccinated against Zika virus and Dengue
virus (Khandia et al., 2018; Padron-Regalado, 2020; Vennema et al.,
1990). ADE can occur when non-neutralising antibodies bind to virus
particles and increase their uptake into host cells, instead of
rendering them non-infectious (Padron-Regalado, 2020; Tirado & Yoon,
2003). This caused concern in initial SARS vaccine development, but can
reportedly be avoided by using truncated versions of the viral S
glycoproteins (He et al., 2004). Acknowledging safety concerns such as
this, as well as the ways they can be attenuated, may be paramount in
the timely development of a vaccine against COVID-19.
In conclusion, although expanding extremely rapidly, the field of
therapies to treat COVID-19 remains in its infancy. Safety will continue
to play a major role in therapeutic success, as apparent with recent
reports of increased cardiac toxicity associated with the use of
chloroquine/hydroxychloroquine in the treatment of COVID-19, despite its
long history of use as an antimalarial. Above all, this review has
exemplified the need to view safety concerns in the context of the
individual and specific phase of disease in order to formulate a
comprehensive harm-benefit balance. Importantly, an awareness of
potential safety concerns will support the development of the next stage
of therapy targeting prophylaxis and recovery post-COVID infection. It
is imperative that safety scientists look to rise to the challenge of
COVID-19 by utilising their expertise in mechanistic understanding,
biomarker development and toxicokinetic modelling in order to support
the development of COVID-19 therapies that can be used effectively and
safely.