[This is an updated version of this post]
21 October 2014
21 October 2014
Using Untested Treatments
Given that the doubling
rate for incidence of Ebola in West Africa in October 2014 is about 4 weeks, it
is clear that urgent action is required. This short paper relates specifically
to the medical response. The World Health Organisation confirmed on 12th
August in Geneva that using untested drugs on Ebola patients would be ethical[i].
Ideally, experimental
treatments should be assessed in Randomised Controlled Trials (RCTs), but in
the situation on the ground in Africa, this may not be possible. In this case,
simple audits of treatments may be used instead. Any treatment centre will know
the recovery rate that it is experiencing. If an agent is introduced, whether
in comparison with placebo or not, if the recovery rate rises, we would have an
indication that the agent may be effective, and deserves more precise
assessment.
There are two broad
categories of treatment: Vaccines (active and passive) and drugs directed at
the virus itself, and those directed at the cytokine storm that is the cause of
the high morbidity and mortality of Ebola.
Medications directed at the virus
Vaccines exist for Ebola which have been shown to be
effective in animal studies[ii].
Some take 6 months to produce immunity, but others produce antibodies within 28
days. Health care staff (and if possible, their families) should be offered
vaccination on a voluntary basis as and when they become available.
ZMapp is a monoclonal antibody that provides passive
immunity by attacking the Ebola virus. It has been effective in rhesus macaque
monkey trials, but has not been in human trials. It is produced by a
genetically modified tobacco plant, and supplies ran out in August 2014, after
7 patients had been treated. Of those seven, 5 recovered, 2 died. This compares
favourably with 2 recoveries and 5 deaths that would be expected from the
untreated population, although of course the number of cases treated is far too
small to be of any statistical significance. Icon Genetics are working on
producing more, but production is slow and quantities will be limited.
TKM-Ebola
This targets the RNA of
the Ebola virus. Studies are limited[iii]
to a small animal test and one human patient who recovered. A trial is planned,
but generating large amounts of TKM will be difficult.
Brincidofovir
An antiviral that
prevents viral replication. Effective in vitro against Ebolavirus. The
manufacturer, Chimerix, has enough for trials.
All of the above pharmaceuticals
are limited by the amount that is already available, or can be prepared in a
short time. These limitations are
significant in terms of the sheer numbers of people affected. They may have a
role to play in the treatment of health care staff who are at risk of infection
(in the case of limited vaccines), and those who fall ill, but they are
unlikely to play a large part in controlling the present epidemic.
Convalescent Serum
Transfusions of serum
from patients who have recovered from the infection may be beneficial[iv]. The
limitation is that the patient should have recovered for 28 days, and should
not have any serum-transmissible diseases like HIV and Hepatitis. It does
require skilled work to prepare and administer the serum.
This approach has the
clear advantage that the supply is provided by grateful recovered patients, and
will therefore be commensurate with the demand. It is promising, and is under
development.
Medications directed at the Cytokine Storm
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.
Several approaches have
been put forward for reducing cytokine storm:
1.
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[v].
It was tested in 2003, but its present availability is uncertain, and its cost
is likely to be high.
2.
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[vi].
Terblanche has reviewed the properties of simvastatin[vii].
3.
ACE Inhibitors and Angiotensin II receptor blockers are
medications in common use against hypertension. The Renin-angiotensin system is
involved in the cytokine storm[viii].
ACE is involved in pulmonary inflammation[ix],[x].
They have been shown to reduce the cytokine feedback loop[xi].
4.
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. They may possibly have a role to
play, but are relatively costly.
5.
Naltrexone, an established opioid receptor
antagonist, may inhibit cytokine storm. There is evidence from animal studies[xii],[xiii],[xiv],[xv]
that shows it may be clinically effective. It is inexpensive.
6.
Antioxidants such as Ascorbic acid may have a role
to play in reducing the adverse effects of cytokine storm.
Note
that the latter five groups of medicines are already in use, and therefore have
been tested for human acceptability. They are relatively inexpensive. Their
side effects are known. It is true that we do not know what happens when they
are used in patients infected with the Ebola virus, but the only way to find
out in good time is to test them. They may have adverse effects in the given
situation, they may have no benefit, but equally, one or more of them, alone or
in combination, may prove helpful, and the exercise will be worthwhile – 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
effectiveness must be monitored, but to test their effectiveness in the Ebola
situation that we are currently in would be ethical and rational.
[v] 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
[vi] 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
Research. 2009;37:601-10.
[vii] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751082/
[viii] Genctoy, G; B Altun et al. (February 2005). "TNF
alpha-308 genotype and renin-angiotensin system in hemodialysis patients: an
effect on inflammatory cytokine levels?". Artif Organs 29 (2): 174–178.
[ix] Marshall, RP; P Gohlke et al. (January 2004).
"Angiotensin II and the fibroproliferative response to acute lung
injury". Am J Physiol Lung Cell Mol Physiol (Royal Free and University
College London Medical School) 286 (1): 156–164. PMID 12754187.
[x] Moldobaeva, A; EM Wagner (December 2003). "Angiotensin-converting
enzyme activity in ovine bronchial vasculature". J Appl Physiol
(Department of Medicine, Johns Hopkins University) 95 (6): 2278–2284.
[xi] Ruiz-Ortega
M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angiotensin II
regulates the synthesis of proinflammatory cytokines and chemokines in the
kidney. Kidney Int. 2002;62(S82):S12-S22.
[xii] Peng
X, Mosser DM, Adler M, et al. Morphine enhances interleukin-12 and the
production of other pro-inflammatory cytokines in mouse peritoneal macrophages,
Journal of Leukocyte Biology. 2000;68:723-728.
[xiii] Hola
N V, Zaji Cova A, Krulova M, Blahoutova V, Wilczek H. Augmented production of
proinflammatory cytokines and accelerated allotransplantation reactions in
heroin-treated mice. Clinical & Experimental Immunology 2003;132:40-45.
[xiv] Lin
S L, Lee Y M, Chang H Y, Cheng Y W and Yen M H. Effects of naltrexone on
lipopolysaccharide-induced sepsis in rats. J Biomed Sci. 2005;12:431-40.
[xv] Greeneltch
KM, Haudenschild CC, Keegan AD, Shi Y. The opioid antagonist naltrexone blocks
acute endotoxic shock by inhibiting tumor necrosis factor-alpha production.
Brain Behav Immun. 2004;18:476-84.
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