Abstract
This paper relates specifically to the pharmaceutical
response to the outbreak of Ebola Virus Disease (EVD) in West Africa. It
advocates the use of drugs (some listed in the Appendix) that already have an
established place in other fields of medicine, and that have been shown in
animal studies to be effective in reducing the life-threatening “cytokine
storm” associated with some infections, but that have not been through the
normal process of human trials in EVD. These medications should be re-purposed
for use in EVD, and their efficacy tested in simple field trials.
Education (“sensitisation”) about the way that EVD is
transmitted is absolutely vital in prevention of spread, and re-hydration and
correction of metabolic abnormalities rightly remain the mainstay of therapy in
EVD. We must make sure that enough materials, skills and personnel are
available to maintain these general supportive measures, but at the same time,
we must look for medicines that can increase the recovery rate.
Treatment approaches
Rapid development of vaccines is a hopeful avenue of
progress[i],
but the limitation with vaccines is the lag between gathering evidence that
they are effective, and producing sufficient doses to meet the need of the
whole population. However, they certainly will have a role in protecting the
very courageous medical and nursing staff.
“Convalescent Serum” - transfusions of serum from patients
who have recovered from the infection is being tested[ii]. This
approach has the clear advantage that the supply is provided by grateful
recovered patients, and will therefore be more commensurate with the demand. It
is promising, and is under development[iii],
although preparation of safe, pure serum will be challenging and costly. If we
can increase the recovery rate, more serum will become available.
Established anti-viral agents such as Brincidofovir are
also being tested.
The World Health Organisation confirmed on 12th
August in Geneva that the use of untested drugs on Ebola patients would be
ethical[iv].
“On 11
August 2014, WHO convened an Ethics Panel to consider and assess the ethical
implications of the potential use of unregistered interventions. The panel
reached consensus that in the particular circumstances of this outbreak, and
provided certain conditions are met, it is ethical to offer unproven
interventions for which the safety and efficacy have not yet been demonstrated
in humans as potential treatment or prevention… In addition, existing
drugs approved for other conditions, which show good evidence of activity
against Ebola in laboratory models, may be evaluated and ‘re-purposed’ for use,
if efficacy is demonstrated.[v]
Note
that the only way of demonstrating efficacy is by trials in the field. However,
the meeting decided to
concentrate efforts on a small number of potential treatments, notably
convalescent serum and vaccines, and there was no resolution to further explore
the use of re-purposed drugs.
Meeting in Geneva on 4-5th
September 2013[vi], WHO
participants concluded “the highest therapeutic priority should be given to
human convalescent serum, whole blood, and blood products. It was proposed that
survivors of EVD should be followed up carefully, not only to determine the
long-term effects of EVD, but also to identify potential donors of blood for
therapeutic use. The next priority would be the promising vaccine candidates
and potential therapeutics”. Perhaps regrettably, the use of re-purposed
medicines was not prioritised at this meeting.
The reason given for this decision is that the
challenges of field testing of any medical intervention are daunting. “For
any study to be planned and then conducted, there is a need for a number of key
players to be fully behind and aligned: manufacturers/developers, regulators
both in the affected countries and other regions, WHO, MSF and other NGOs who
are providing help locally[vii]”.
This decision suggests that organisational difficulties
are inadvertently inhibiting chances of improvement in the medical treatment of
a serious epidemic. Such difficulties can be overcome, given political will. If
manufacturers, national health services and NGOs can agree, trials of
re-purposed medicines, could go ahead. We should therefore consider how this
roll-out could be designed.
Trials of re-purposed medicines
In a situation where patients are dying because there are
not enough nurses to attend to them, a full research effort which stands a
chance of being published in a peer-reviewed journal would be inappropriate and
incongruous, since, unlike practical medicine and nursing in a developing world
setting, research requires a full complement of staff and very high standards
of control of the patient’s situation. However, the demands of perfection must
not be allowed to stand in the way of medical progress.
To insist on classically perfect study conditions is to
insist that very little research will be carried out during the present
epidemic – or indeed, any epidemic of this magnitude. This would be irrational.
It is highly likely that in coming years, medicine will encounter an epidemic
with a comparable mortality rate to EBV, but with air-borne transmission, which
would make it a far greater challenge. In this event, we will need all the help
we can get, and it would be deeply regrettable if medicine is lacking
inexpensive and effective ways of treating a disastrous epidemic simply because
it is deemed that re-purposed medicines are not worth testing in the present
outbreak. The West African Ebola epidemic presents us with an opportunity to
learn about controlling the cytokine storm. We may find that it is impossible
to do so with re-purposed drugs. Equally, we may discover that they are helpful
additions to existing supportive treatments.
Study design
The present proposal is that we should carry out a number
of very simple tests for re-purposed drugs as follows:
1.
A research team approaches a field treatment centre and
explains that if the staff wish to collaborate, they will be supplied with
medications, some of which will be Preparation A and some Preparation B. One of
them is a dummy, one is a drug that is used in other fields of medicine, that
has demonstrated efficacy against fever in animals, but has not yet been tried
out on humans. It is explained that there is no guarantee that the preparations
will work to help patients with EBV, but that there is a chance that a new
therapy for Ebola may be discovered by their work.
2.
If the treatment centre staff agree, a trial is commenced. The
initial dose given will be a fraction of the smallest dose used for the
medicine’s official indication, the dose to be decided by consideration of the
drug’s known side effects.
3.
One or two research workers will join the treatment centre
team to supervise delivery of medications, and to collect the data.
4.
The endpoint will be death or discharge from hospital. If
possible, changes to the patient’s condition and possible side effects will be
noted.
5.
If a statistically significant advantage emerges from the
data, the code may be broken, and if improvement is associated with the active
drug, the trial will be repeated at a higher dose.
6.
If there is no difference between the placebo and the active
drug, the trial will again be repeated at a higher dose.
If any significant differences emerge between outcomes for
placebo and trial drug in these pilots, more elaborate and extensive trials
will be run.
Results from the various treatment centres will be
collated and reviewed.
Appendix: Medications that can
be re-purposed to treat EVD
Cytokine storm is an exaggerated reaction on the part of
the cellular immune system. A positive feedback loop forms between cytokines
released at the site of infection, which attract more defence cells, which
produce more cytokines. It is this vicious circle that causes Ebola infection
to have such high mortality.
OX40 is a protein secreted by T-cells that keeps them from
dying, and therefore perpetuates the feedback loop. OX40 IG is a
synthetic immunoglobulin that neutralises this protein. It has been shown to be
effective in mice[viii]. It was
tested in 2003, but it seems that it was bought by a venture capital group that
decided not to develop it.
Some of the drugs mentioned below act on cytokine storm,
but others have other modes of action.
The following are some examples of drugs that can be
re-purposed:
1.
Simvastatin and Gemfibrozil, both lipid-lowering
drugs in common use, have been shown to have an effect in reducing the cytokine
response. In the case of Simvastatin, an effect has been shown in humans,
albeit not in acute infection. Simvastatin also has an effect on the replication of some
viruses. It decreases OX40[ix].
Terblanche has produced an excellent review of the immunomodulatory and antiviral effects of statins[x].
Terblanche has produced an excellent review of the immunomodulatory and antiviral effects of statins[x].
2.
ACE Inhibitors and Angiotensin II receptor blockers are
medications in common use against hypertension. The Renin-Angiotensin System
(RAS) is involved in the cytokine storm[xi].
ACE is involved in pulmonary inflammation[xii],[xiii].
They have been shown to reduce the cytokine feedback loop[xiv].
Examples of ACE inhibitors are ramipril, perindopril and Lysinopril.
Angiotensin II blockers: losartan, candesartan, valsartan. Care must be
exercised in using these in Ebola, as their hypotensive effect may aggravate
any hypotension present due to dehydration.
3.
TNF Blockers are medications routinely used in
arthritis and other inflammatory conditions, and work by inhibiting Tumour
Necrosis Factor (TNF) which is implicated in cytokine storm. Some are
monoclonal antibodies (infliximab, adalimumab, certolizumab), and some are more
simple compounds such as bupropion, in common use in smoking cessation.
4.
Naltrexone, a long established opioid
receptor antagonist, may inhibit cytokine storm. There is evidence from animal
studies[xv],[xvi],[xvii],[xviii]
that shows it may be clinically effective. It is inexpensive.
5.
Selective
estrogen receptor modulators (SERMs) such as clomiphene, commonly used in treatment of
infertility and breast cancer, have been shown to inhibit the Zaire strain of
Ebola Virus in vitro and in vivo, in mouse studies[xix].
6.
Ion
channel blockers such
as Amiodarone commonly used in treating hypertension, have been shown to
have an effect on the entry of filoviruses into cells[xx].
Note that these medicines are
already in use, and therefore have been tested for human acceptability,
although not specifically in patients with fever. Their side effects and
contra-indications are known. They are relatively inexpensive, and can easily
be made available in quantities sufficient for initial trials.
It is self-evidently true that
we do not know what happens when these drugs are used in patients infected with
the Ebola virus, but the only way to find out in good time is to test them in
the field. They may have adverse effects in the given situation, they may have
no benefit whatsoever, but equally, one or more of them, alone or in
combination, may prove helpful, and the exercise will then have been at least
worthwhile, and even, possibly, game-changing.
In conclusion, there are
several modalities of treatment for Ebola that must be tried in the present
outbreak. Their deployment will be “off-licence” and their efficacy must be
monitored, but to subject them to trial in the Ebola situation that we are
currently engaged with is ethical and perfectly rational. It is hoped that the
small initial pilot studies outlined in this paper will be rolled out as soon
as possible.
Dr Richard Lawson MB BS,
MRCPsych
Churchill,
North Somerset, UK
Sunday, 07 December 2014
[vii] Enrica Alteri MD, Head of Human Medicines
Evaluation Division, European Medicines Agency, personal communication
[viii] Humphreys
I R, Walzl G, Edwards L, Rae A, Hill S, Hussell T. A Critical Role for OX40 in
T Cell-mediated Immunopathology during Lung Viral Infection. The Journal of
Experimental Medicine 2003;198:1237-1242
[ix] Liu
B, Yu G, Yang Z, Sun L, Song R, Liu F, et al. Simvastatin Reduces OX40 and OX40
Ligand Expression in Human Peripheral Blood Mononuclear Cells and in Patients
with Atherosclerotic Cerebral Infarction. The Journal of International Medical
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[xiii] Moldobaeva, A; EM Wagner (December 2003).
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[xiv] Ruiz-Ortega
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regulates the synthesis of proinflammatory cytokines and chemokines in the
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[xv] Peng
X, Mosser DM, Adler M, et al. Morphine enhances interleukin-12 and the
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[xvi] Hola
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[xvii] Lin
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[xviii] Greeneltch
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[xix]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955358/
[xx]
http://jac.oxfordjournals.org/content/69/8/2123
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