Wednesday, October 15, 2014

Untested Treatments for the Current Ebola Outbreak

Using Untested Treatments

Given that we have no specific treatment for Ebola virus disease (EVD), and given that the doubling rate for incidence in West Africa is about 4 weeks, it is clear that urgent action is required. Much effort is rightly being put into health education and the community response, and the British Government’s input in supplying money has been exemplary.

This paper relates specifically to the medical response. It is very clear that we need to step outside of normal treatment development protocols and test any treatment that offers a reasonable, if at first theoretical, possibility of assisting recovery from the disease. Normal protocols for drug development are rightly detailed, precautionary and protracted, taking months or years before a treatment can be offered to patients. This approach is not appropriate to the current Ebola crisis. The medical profession must be enabled to step outside of the normal system of treatment assessment and deploy untested treatments, “off-license”, but in an orderly way so that the benefit or disbenefit of any treatment can be discovered. Specifically, doctors need to know that they are not at risk of being sued if a patient who has been given an untested treatment dies.

This approach can legitimately be used in the UK on a “Named Patient Basis”, and in the USA under the “Expanded Access Programme”.

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.

Prioritising health care staff
If medications are in short supply, they should be reserved for health care staff who may become infected with EVD.

There are three reasons for this:

First, the staff will be able to give informed consent to the treatment, understanding that it has not been fully tested.

Second, healthcare staff need to feel that they have an improved chance of recovery in case they become infected. Without this job-related bonus, there is a possibility that morale may fall to a point where they simply stop coming to work. If supplies permit, their family may also be offered vaccination, in order to help overcome the fear of contamination from the worker that some families show.

Third, the staff will be able to be followed up and monitored for side effects and for blood tests.

Treatments available

There are two broad categories of treatment: Vaccines (active and passive) directed at the virus itself, and those directed at the cytokine storm that is the cause of the high morbidity and mortality of Ebola.

Vaccines exist for Ebola which have been shown to be effective in animal studies. 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.

The use of ZMapp in these cases sets an important precedent for using untested treatments in this present crisis.

Treating the Cytokine Storm

Cytokine storm can be seen as an over-reaction on the part of the 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 that causes Ebola infection (and, incidentally, other viral infections such as SARS and high-morbidity influenza such as type H5N1) 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. 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.

3. ACE Inhibitors and Angiotensin II receptor blockers are medications in common use against hypertension. They have been shown to reduce the cytokine feedback loop especially in lung conditions.

4. TNF Blockers are medications routinely used in arthritis and other inflammatory conditions. They may 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 that 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 also low-cost. 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 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 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 forbid or delay their use because they have no official license to be used in this condition would be unethical and irrational.

A fully referenced version of this paper will be available shortly

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