Saturday, 30 August 2014

A Second Look at the Ebola Secret Serum


After analysing the Ebola crisis in a previous post, I reasoned that a single drug would be unlikely to control the crisis due to its lack of supply, the lack of infrastructure to transport and distribute the drug in a controlled setting and the long periods of testing that have to be endured by potential drugs. In this post, I will analyse the ZMapp drug (the so called “secret serum”) in greater detail although I still maintain that the lack of supply and wide spread testing of the drug will limit its immediate use in Ebola stricken countries.

The Drug

The ZMapp drug consists of a “combination of monoclonal antibodies “(originating from a single immune cell which has been cloned to produce identical antibodies). This unites two previous cocktails of antibodies, MB-003 and ZMAb. According to a research article published in the journal Nature, this combination was shown to save the lives of all of the rhesus macaques monkeys tested in the trial. Yet more promisingly, the drug showed that late symptoms of “elevated liver enzymes, mucosal haemorrhages and … pertechia (red blood spots beneath the skin) could be reversed”. This is particularly useful as it allows symptoms to be seen which means that individuals could be reported for treatment by communities and non-healthcare professionals. This is important in the general dispersed living conditions of Western Africa where screening for the virus is not capable so detection in earlier stages is not an option.

MB-003 was described as “partially efficacious” by the research team, yet this was only administered therapeutically after the detection of disease “triggers” which delays the treatment and also limits its widespread use. Similarly ZMAb added to an adenovirus adjuvant therapy provides full protection in rhesus macaques yet only up to 72 hours after infection. The ZMapp drug however, uses a combination of these treatment drugs whilst adapting the murine based antibodies in the ZMAb drug so that they would last longer in humans by slowing breakdown in the body.

The Research

Initially, the research group tested on guinea pigs, comparing the efficacy of the adapted ZMAb drug, MB-003, the individual antibodies that comprise MB-003 and a control (Phosphate Buffered Saline). Survival and weight loss were tracked over the period of the trial which was 28 days. During this test, it was shown that c13C6 and h13F6 (individual antibodies) gave a survival rate of 17% (as shown above). These drugs tests were repeated in monkeys yet ZMAb wasn’t tested. Here c13C6 again showed the highest individual success rate with 1/3 of monkeys surviving the virus. Thus c13C6 was incorporated as a central antibody in the new ZMapp cocktail. However, this can be questioned as the success rate of MB-003 (which included c13C6) in guinea pigs was significantly less than in primates, the MB-003 drug saving 1 in 3 primates yet none of the guinea pigs. This implies that the success of c13C6 in guinea pigs may have been cancelled out and so this would imply that certain combinations including the antibody may limit the therapeutic effect. Furthermore, the wide variation in the success of MB-003 across guinea pigs and primates implies that the Ebola virus may be more susceptible to mutation and hence resistance in guinea pigs. This undermines the potential of such drugs in humans. On the other hand, the primate data is arguably more valid as humans are more genetically similar to primates and hence this data is more applicable. Therefore the success of c13C6 in primates when in combination with other antibodies, suggests that the virus that primates are susceptible to responds to the drug and hence a similar result may be expected in humans.

Another slight criticism I have of this selection is that it ignores the efficacy of h13F6 which showed equal success in guinea pigs. While I understand that the lack of apparent effectiveness in primates is more important, the interpretation of the data is subjective as if we were to select based on guinea pig data then in situations where survival was similar we may look to those cases of death and compare which gave the longest survival. Alternatively other researchers may argue that the least weight loss signifies a potential palliative effect. Thus based on “time to death” h13F6 had a time of 10.2 days in guinea pigs, whereas c13C6 had a time of 8.4 days. Yet based on weight loss, h13F6 fared worse with a loss of 21% in weight compared to only 9% with c13C6. Thus this research could be improved by a clearer definitive statement over which results they prioritise to explain the selection process of the drugs. Ideally however, two branches of trials should have been conducted to assess this discrepancy further with c13C6 as the starting antibody of one branch and h13F6 the starting point of another.

Hence, three new drugs were created, ZMapp1, ZMapp2 and Zmapp3. This is useful in trials such as these because it allows subtle variations to be made to an initial drug. This ensures that the maximum efficacy can be achieved which is more cost effective as it means that drugs companies don’t miss out on a slight variation of a drug that could have offered a larger advantage. This means that the most ‘efficient’ drug can be found. From the guinea pig data collected on these three variations, the researchers concluded that ZMapp1 gave the greatest effect saving 67% of the guinea pigs, followed by ZMapp2 which saved 50% and then ZMapp3 which had no statistical difference to the existing drug, ZMAb. Thus ZMapp1 and 2 were carried forward to be tested on monkeys. Arguably, the reasons for the distinct lack of effectiveness of ZMapp3 over the other two forms could have been identified which due to the cocktail variations must have arose due to conflicting effects between the drugs. More investigative research into this could have explained it further and hence allowed the researchers to consider whether the maximum effect was being achieved in the other two forms. Consequently, this would have enabled potential further production of varieties of the ZMapp1 form for example to achieve the most efficacious response.

Yet the researchers changed the cocktail of ZMapp1 by swapping on version of an antibody with another similar yet not identical version. This is important as it shows the inconsistency in the chemicals across the guinea pigs and primates and so this means that the results seen in the guinea pig data for ZMapp1 may not be representative of the drug seen in the primate trials. Although this is only a slight change, it deserves attention as it undermines the reliability of the data and therefore this means that the initial tests of ZMapp1 lose, in part, their validity. Furthermore, the apparent repeatability across both tests is questioned and so suggests that we cannot assess the repeatability.


ZMapp NHP results coloured based on when they received the drug
Non-human primate (NHP) trials showed that 100% of the monkeys treated with ZMapp1 survived whereas 5 out of the 6 monkeys tested with ZMapp2 survived. Both of these drugs were better than the control monkey treated with Phosphate based saline and also the control monkey treated with a control antibody. Both of these controls died. Initially this would seem to suggest that ZMapp1 was the more effective than ZMapp2. However, the monkey that died in the ZMapp2 treated group may have had a natural susceptibility to the virus. Hence this would suggest that the death was due to heterogeneity as opposed to the inadequacy of the treatment. Adding to this, the clinical score for the NHP that died was higher than the others. This is a scoring method which determines the severity of the symptoms and hence could be used to predict the death of organisms. This suggests that this monkey was already vulnerable to the virus due to the large degree of difference between it and the other NHPs treated with ZMapp2. Furthermore, only 6 NHPs were tested in each group. Hence the natural level of this susceptibility couldn’t be identified. This means that the results do not take into account this level of susceptibility in the population which may mean that the NHPs treated with ZMapp1 were misrepresentative of the population, this means that it undermines the validity of this conclusion because the conclusion assumes that the development of symptoms were solely dependent on the drug as opposed to other factors. This means that it may not have been a fair test. The number of NHPs tested is also an issue because it means that the results are less reliable as the result as a whole is more likely to be influenced by chance or genetic misrepresentation as I have already discussed. In addition, the animal that died had elevated levels of “alanine aminotransferase, total bilirubin, blood urea nitrogen and creatinine, in addition to decreased levels of glucose, suggesting multiple organ failure”. When the data for these levels are plotted on a graph, this particular individual follows the path of the control groups closely which again infers that this animal was ‘resistant’ to the drug due to a lack in any meaningful change.


Despite these issues, ZMapp1 was considered the most efficacious drug and hence was carried through to the next stage of testing. ZMapp1 is now trademarked as ZMapp. In this final test stage, the drug was given to sets of NHPs at different times, e.g. one primate group received it on days 3, 6 and 9 whereas another group received it on days 4, 7 and 11 etc. Yet it was found that all animals survived the infection (shown to the left). Nevertheless, in two primates (named E4 and E6) who were treated last, their clinical score peaked close to the limit that would mandate euthanasia. This again suggests a level of natural resistance and hence supports my view that ZMapp2 should not have been discarded purely based on its survival rate. In addition, E4 incurred a severe rash on 40% of its body surface between days 5 and 8.


On the other hand, this genetic susceptibility is overcome even in E4 and E6 and although the NHP that begun treatment first shows the most positive result (due to a lower amount of viraemia and less advanced symptoms) by the end of the trial there is no discernible difference graphically in the clinical scores of the NHPs hence suggesting normalisation. This is significant as it could infer that the drug was able to reverse even advanced symptoms in later test groups. This can be seen in the results for the F group which was treated last. The peak in the clinical score for this group was one of the highest which can explained by their later treatment. On the other hand the length of time this level took to descend is a useful measure of responsiveness to a treatment (this can be seen in the partially resistant E4 and E6 which took a longer time to decline. This supports the correlation as I believe that these animals were resistant and so their longer decline could be linked to this. From this, one can conclude that perhaps time taken for decline represents responsiveness). Therefore the rapid decline of the F group (as shown in the graphs above) shows that the drug remains effective at later stages. This cannot fully be assigned to the drug though as this may be part of a natural decline yet we cannot test this as control groups died before this stage.

Will it be Useful?

Even so, the form of Ebola currently spreading in West African is a form called EBOV-G (the Guinean variety) whereas this trial uses EBOV-K as the virus to be treated. This poses a problem in the application of these results to the current crisis. However, the researchers explain that the “epitopes (targeted areas of the virus) targeted by ZMapp were not mutated between the two virus variants” and hence the antibodies should “retain their specificity”. Nevertheless the group admits that the susceptibility of survivors to re-infection is unknown yet I don’t believe that this is a substantial issue as the aim of this particular drug is to treat those infected with the virus and hence has an immediate benefit. Therefore, the susceptibility after treatment, although advantageous if reduced, is not a massive drawback if it is not.

My Verdict

Overall, these results are positive and the method used is reliable and valid. The only issue I have with the method is the limited aspect of the testing which is an issue as it means that genetic variability and natural resistance are not taken into account. Furthermore, it means that the results are vulnerable to chance which may mean that the result obtained is not reliable. This is an issue because, when considering that this drug could be used as a forefront method of treatment of Ebola it means that the small test group size may misrepresent a wider response to the drug and hence may cause health to be threatened due to adverse reaction for example which may not have been seen in prior tests. In addition I maintain my previous viewpoint despite the high potential of the drug. This is because the drug is not yet being considered for passionate use and instead wider trials in human volunteers will occur. This, the researchers estimate could take months (a significantly shortened timescale due to the urgency of the situation yet still long-enough to avoid depending on a drug based control system). To conclude, the drug in my view shows massive potential particularly over the current treatments and the control group yet is not yet to be considered vital for the fight against Ebola.

Sources

http://www.nature.com/nature/journal/vnfv/ncurrent/full/nature13777.html

 

Saturday, 23 August 2014

A Double Dose for Polio


Recent research, conducted in India, has suggested that the Polio virus, endemic in three countries (Nigeria, Pakistan and Afghanistan), can be more efficiently eradicated by using a combination based on the widely used Oral vaccine supplemented with the injected form. The research therefore recommends the introduction of at least one dose of the injected vaccine in addition to the regular vaccination schedule.

The Research


This research was “carried out by researches from the WHO, the US Centers for Disease Control and Prevention, Imperial College London, the Enterovirus Research Centre in India and Panacea Biotech Ltd”. This is important to recognise as it represents an international collaboration and so this suggests that the research is credible. This is because all parties involved would have to produce consistent results and respect the end result. Hence by involvement of national organisations and the WHO this means that all researchers would have had to follow protocols to ensure comparative ability to produce reliable results. Thus this suggests that these protocols were checked and affirmed and analysed to produce valid results.  Furthermore, the trial was randomised and so this ensures that genetic variability, for example in natural slight immunity is evenly distributed over the two groups. This also prevents scientists from being influenced by bias to include only the strongest individuals in the trial for example. Adding to this, 954 children were involved and so due to this large sample, the range of results is more likely to be representative of the entire population thus ensuring that the data is useful. This is because it ensures that similar results can be expected if the vaccine was extended further. It also involved three distinct age groups: 6-11 months, children aged 5 and children aged 10. Through use of three groups it ensured that differences in the development of immunity could be accounted for. Hence, this meant that in the future, these results could be used most effectively to target a specific age group and therefore achieve maximum efficiency. The distinction between the groups was also important as it ensured that the control group could be matched more closely to the group receiving treatment to ensure that any response produced by one group was not magnified or diminished because of other factors associated with age. This meant that the results would be repeatable and hence reliable.

These children had already being vaccinated with the oral polio vaccine thus ensuring protection. However, the trial compared whether giving an additional dose of Salk IPV (the injected vaccine) would be more effective than an additional dose of the oral vaccine. Thus three groups were established: a group receiving the Salk IPV; a group receiving another dose of the oral vaccine to assess whether worthwhile gains in immunity were achieved by using the IPV over the oral vaccine; and a group receiving no additional vaccine to more easily quantify the efficacy of either vaccine (since without this third group the gain from the Salk IPV would only be relative to the oral vaccine and so the gains couldn’t be assessed i.e. if the Salk IPV addition meant that 5 more children remained immune after a period than in the oral vaccine then this may be small and not worthwhile yet if the oral vaccine meant that 1 more child remained immune as opposed to no vaccination, then the 5 child gain would be much more significant). After 4 weeks the children received a dose of the oral polio vaccine, containing dead or weakened forms of the virus. The amount of polio virus in their faeces was then monitored to quantify the immunity of the child. The lower the amount of poliovirus in the faeces, the greater the immunity and hence the lower the risk of transferring the virus.

Two types were studied, type 1 poliovirus and type 3 poliovirus. In the 6-11 month old group it was found that booster injections of the vaccine “significantly reduced the proportion of infants with type 3 poliovirus in their faeces compared to no vaccine, but did not significantly alter the proportion of infants with type 1 poliovirus in their faeces”.  In the 5 year old group a similar result was seen yet the immunity to type 1 poliovirus also increased with injections. Finally, in the 10 year old group a similar result was seen to the 5 year old group. However, with the 10 year olds, a booster of the oral vaccine had a similar effect. This was not the case in the younger groups. Hence this could suggest that immunity gradually decreases with time and so, because the 10 year old children responded in a similar way to the oral and injected vaccines, the increase in immunity may have simply been due to a lower general level of immunity anyway. In contrast the younger groups produced results which suggested an additional dose of injected vaccine was more effective than the oral dose. Thus, this infers that an additional layer of immunity was added due to immunity in a different area of the body. This is shown in the basic diagrams. Assuming 30 units is the maximum limit that can be achieved with an oral booster, in younger children that have recently being vaccinated both initial levels are at 30 (graph 1). An injection booster can therefore raise this further (graph 2). In a 10 year old where the immunity has decline to, for example, 10 units (graph 3), a booster using either method can have an effect as the oral vaccine is not limited (graph 4).
Graph 1
Graph 2
Graph 3
Graph 4

Cost vs. Effectiveness

This has been called a “historic” finding by the WHO yet although the injected method of vaccine may be useful, in the past it has been limited due to its higher cost and higher risk. For example, the benefit of the injected vaccine is that it increases the immunity within the bloodstream which is more useful as this supplies all areas with blood, hence immunising the blood massively restricts the capability of the virus to multiply and hence this increases general immunity. In contrast, the oral vaccine mainly immunises the digestive tract. This is essential yet is arguably not as important as immunising the blood as there is a greater risk that the virus could ‘bypass’ an immunised digestive system, yet with the blood, because it works everywhere and is a step beyond digestion, it is more encompassing of infection. However, the cost of needles, careful transportation methods to avoid damage to these needles, sterilisation costs and maintaining sterilisation through hygienic methods, is high. This means that in unstable countries that are economically unstable, reliance on other nations is not surprising, hence this means that the overall cost to more developed nations is higher. Alternatively, oral vaccines can be packages with plastic and sealed it can then be transported to health care centres in mass numbers without a fear of damage. Thus the cost is much lower. Furthermore, oral vaccines involve no contact with anything except for the vaccine. On the other hand, injected vaccines involve needles and so this can introduce infection which is a particularly significant issue in these underdeveloped countries where hygiene is not prioritised as much. Thus, the involvement of injected vaccines can place patients at risk of contracting other, more prevalent diseases.

Furthermore, in 1988, there were 350,000 cases of polio in more than 125 countries. This has fallen today by over 99% and is now only prevalent in three countries. Hence, mass development of prepared needles and new protocols on transportation and access may be considered ‘too much’ for such a limited disease. This is because, as the oral vaccine has dominated the battle against polio, injected vaccines have declined and hence the infrastructure to suddenly produce more injected based vaccines may involve high set-up costs. Thus if the relatively small scale of the disease may not justify this. Nevertheless, Professor Nicholas Grassly states “If you have limited access, you want the biggest return”. This may be the reason why Polio is still prevalent despite mass eradication schemes and international efforts: a lack of access to the most vulnerable areas followed by insufficient vaccine effectiveness when access is allowed. Therefore a more effective combination of the oral and injected vaccines might allow a more efficient eradication of the disease in limited access areas. Furthermore, it is unlikely that in the long-term these set-up costs will be significant. This is because, these immediate costs would be balanced by continuous savings on healthcare for victims of the polio virus. Adding to this, if injected vaccines hasten the decline of the disease, the overall amount of vaccine produced (oral and injected) will decline over time hence cutting the cost of producing the vaccine. Consequently, I don’t believe that the monetary argument is appropriate (to deny fragile countries access to medications, I believe, is ethically wrong) or significant.

Practical Problems

Therefore, the only other important consideration about whether this trial can be considered “historic” is whether it can practically be used. This is an issue as some countries use vaccination programmes as a political weapon. For example, in 2012, the Taliban banned the vaccine in the North and South Waziristan regions of Pakistan unless the US agreed to negotiate. This meant that the vaccine program risked opposing the government and hence causing an international conflict. Also access to countries to supply vaccines is limited. This is because, with a weak healthcare system, many vaccines are given to community doctors. Thus there can be no standards testing which means that vaccines may be viewed suspiciously by authorities.

Added to this are various misconceptions over vaccines which some attribute to religion. Admittedly, there are some fringe groups that do oppose vaccination however I don’t believe this can be considered valid for two main reasons. Firstly, these religious groups that are in opposition to vaccines can and are spread widely throughout the word. Thus, the fact that only three countries still suffer from Polio would infer (if we were to use the argument that religion can stop vaccination) that these countries have a greater proportion of these sceptical religions. This is not the case. This is clearly seen in religious statistics (50.4% of Nigeria’s citizens are Christian) yet can also be inferred when we consider that religious ideologies often diffuse from a point and the fact that Nigeria is so far away from Pakistan and Afghanistan weakens my confidence that they share a strong religious opposition to vaccines. Also, many established religions decide on modern issues by looking at various ethical arguments as well as religious arguments. As a result, I will consider two ethical schools of thought:

·         Consequentialism

    This would appear to support vaccination as vaccines minimise the pain of disease and hence maximise the duration of the pleasure of life. Furthermore, as more people are vaccinated, the risk to unvaccinated people decreases as they are less likely to come into contact with an infected person. This is called herd immunity and means that the extent of ‘pleasure’ created by vaccination is large. Alternatively, we cannot be certain that a vaccine would be of individual benefit (some may not come into contact with the disease anyway). Also the benefit of a vaccine may not show until much later, hence the pleasure is remote. Even so, I believe that the fact that vaccines minimise pain means that vaccines are acceptable on hedonic calculus (a measure of pleasure vs. pain).

·         Kant’s ethics and deontology

   Kant believed that if you choose to perform an action then you accept that it should become a universal maxim, i.e. if you kill someone you accept that everyone can kill whoever they want. Vaccines therefore may be accepted by Kant as by accepting vaccination it is perfectly acceptable to state that everyone should be able to have a vaccination. On the other hand, deontology argues that the intention of an action is more important than its consequence. Thus, if the US government continued to supply vaccines to Pakistan in 2012 to undermine the Taliban, this may be considered unacceptable as its intention is to cause harm however slight. Nevertheless, if we take this situation from another perspective then it could still be seen as acceptable. This is because if not vaccinating people makes them vulnerable and dependent on the state and unable to make rational and free decisions, then Kant may argue that not vaccinating causes people to become a ‘means to an end’ without free choices. Thus we have a duty to prevent this – a duty to vaccinate.

Consequently, it is unlikely that religions would be opposed to vaccines due to the benefit that they offer.

Another area of difficulty with introducing injection based vaccines is that it would need an outside authority to supply and administer the vaccine. In contrast, in order for Polio to be eradication, countries must be self-sufficient and willing to focus on the disease to eradicate it. Hence this would require a localised effort which would be much harder to achieve with an injected vaccine as opposed to an oral vaccine. This is perhaps the most limiting factor in implementing the research as due to the Ebola crisis, Nigeria’s healthcare system is debilitated and so this means that vaccination programs would be considered to be a far lower priority. This therefore encourages long-term dependency on other countries and would distract from a community based vaccination scheme that would allow a vaccine to be ‘rolled out’ and made accessible to everyone.

My Verdict

However, to conclude, I am optimistic that this research will lead to a more effective battle against Polio and will continue to cause the decline of the disease which has stabilised now in Nigeria at 70-80 infections every year since 2009. I am confident about this as, recently, TechNet-21 (the Technical Network for Strengthening Immunization Services) launched a resource to allow immunisation professionals to compare immunisation equipment. Also, the resource will enforce equipment that has passed through the “Performance, Quality, and Safety (PQS) programme” advocated by the WHO. Thus this demonstrates the growing coordination and research into immunisation projects and so will establish a greater focus on Polio which is already encouragingly close to eradication.
Sources
 



Sunday, 10 August 2014

Ebola Strikes

As you may have heard, there has recently been a large outbreak of the Ebola virus in four West African countries (as of today, the 10th of August) with the virus threatening to spread further due to the high infectivity of the disease. However, without assessing the risk of the virus, which encompasses both the lethality of becoming infected and the probability that this will occur, the threat to the world (and hence whether it should be declared a global emergency) cannot be determined.

Details and Death Rates

This virus causes internal bleeding as well as bleeding outside the body by damaging liver and reticuloendothelial cells. Blood capillaries then leak fluids which causes a clotting response inside blood vessels which rapidly consumes platelets (clotting agents), thus preventing clotting elsewhere causing bleeding. Also the water loss caused by this leads to clinical shock which causes organ failure. This explains why the death rate of the Sudan Ebola virus is 60% for those who are infected. The virus, however, can also spread through bodily fluids such as sweat and so can be transferred by skin contact. This also means that infected needles can transfer the virus. The incubation stage of the disease lasts 2-21 days, after which, those who don’t show symptoms do not develop the disease.

This specific crisis has led to 1700 cases of the disease in Guinea, Liberia, Nigeria and Sierra Leone, with the BBC reporting that 930 people have died in Western Africa this year from the Ebola disease. In order to compare this figure reliably we must first analyse the total populations of these countries:

·         Guinea: 11,474,383

·         Liberia: 4,092,310

·         Nigeria: 177,155,754

·         Sierra Leone: 5,743,725

 
Hence the overall population of these countries is 198,466,172. As a result, the infected population represents 0.0009%. This would be normally considered small yet considering the infectivity of Ebola I estimate that the number of cases of Ebola will at least rise to 1891 (as shown on the graph for September). I estimate this due to a number of reasons. First, the Centre for Disease Control and Spread is now sending in 50 experts to help deal with the outbreak this is likely to cause a small decrease in the rate at which new infections are occurring. This means that the infected population may continue to rise. Furthermore, the virus has a short time to spread due to its high lethality. As a result, the infection rate in the past for Ebola outbreaks has been characterised by sharp declines and rises as shown in the table. Thus this may mean that when we see a sharp rise such in infections, as seen in the last month, we can suggest that a fast decline may ensue. The question this raises is “when will that be?” Consequently, due to this unpredictability, an estimated slow in the rate of infection is likely, as opposed to the exponential growth of the disease over the last few months. Even so, this may be a “false” plateau and the infection rate rises more rapidly again. Furthermore, as the infection rate rises, the probability of coming into contact with an infected person increases and so this means that the spread of the disease may become more rapid. Nevertheless, I believe that this could, at least in part, be offset by the global effort to isolate and track down contacts to prevent spread. This is because, as the disease becomes more prominent, more countries will become involved and so this increases the pressure to slow the spread.

A "Global Emergency"?

To assess whether the situation should be considered a global “emergency”, as has been proposed, more information is needed. This is because predicted figures lack meaning and cannot be a firm base to judge the severity of the situation. This is because, these estimates account for the current global effort, thus if complacency is established and healthcare levels are only maintained (not increased); the result would be that the exponential spreading of the disease may overcome this level of healthcare, hence changing the prediction. Instead the density of the infected population needs to be considered. Overall, the infected countries share a land area of 1,324,425 km2 giving an infected population density of 149.85 people per km2. This is important to calculate as it allows a comparison to be made to Britain, which has a population density of 263.48 people per km2. This appears to suggest that these infected countries have fewer people living within the same land space which is confirmed as Liberia’s urban population is 48.2% of the total population whereas Britain’s is 79.6%. Consequently, this means that the spread of the disease would be less than in developed countries as fewer people live together in a nucleated settlement. Hence this means that the risk of infection may be less. However, this uses the assumption that population density is the only factor affecting the spread of the disease yet other factors, such as knowledge and awareness of the disease may offset this. Also due to the hostility of some areas of these infected countries, it means that people may be more concentrated in certain areas, which would reduce the validity of the population density figure.

Recently, the WHO’s director general, Margaret Chan (shown right) stated that “Ebola is a public health emergency of international concern” despite it being confined to a small area of Africa. This was because she claimed that countries affected don’t have the “capacity to manage the outbreak…on their own” and hence the collective security from illnesses is threatened. Yet, this assumes that the virus will spread if countries cannot manage the outbreak which can be challenged by stating that the virus, if spread to the USA for example, could be contained immediately and isolated. Hence, this means that the spread of the virus would be unlikely to jeopardise the health of developed regions. This, however, isn’t an excuse for inaction, the virus has already infected two American medical workers who have had to be flown back to the US for treatment. This treatment, as well as the cost of isolating, tracking then isolating and tracking, is expensive and so it is not practical nor ethical to ignore the virus and allow it to continue to spread and infect other countries causing many more to die. Therefore, as undeveloped countries such as the African nations affected do not have the resources to recognise the illness and prevent it from spreading by use of quarantining, this could be considered a global emergency. Furthermore, as these countries lack a developed health structure it also means that infected people cannot be identified and cared for efficiently as an underdeveloped structure may lead to work duplication as records and treatments are ordered twice. Whereas in other situations, people may not get access to treatment at all. Hence this means that it would be more economic for developed regions to take control and hence benefit from economies of scale. Also less people will realise the symptoms and even those who do may not be able to. This is because the dependency ration in Nigeria is over 80% with the majority of this due to children. Thus will this pressure to support families, taking time off already scarce work I would be viewed as a massive cost to these families.

Rescuing Responses

The response that the world should take is a complex issue so I will start by identifying the basic major control methods. Border control is particularly significant. A potential sufferer of the Ebola disease would have to show symptoms to be recognised and so this is a major risk to undermining the border control system. This argument assumes that border control cannot detect the disease without symptoms and do not check ‘normal’ people coming into the country. Being no expert on border control, I cannot assert that this is true, however careful planning could help to make it a reality if it isn’t already.

Another clear method of control is contact investigation. This involves tracking people with the disease and their contacts for 21 days. If they contract Ebola then health services isolate them and track their contacts for 21 days and the process is repeated. This forms core barriers to the disease spreading and, due to the incubation period of disease, can allow the infection to be caught up with if enough people are working in contact investigation. However, this is not currently the case due to infrastructural limits in terms of hospitals in the affected areas. This means that isolation is difficult and the administrative process of following contacts can be difficult and may lead to work duplication where the same contact is tracked or if a person is not tracked for the sufficient time and then gets Ebola. Nevertheless, these are key principles to tackle outbreaks and should be focused on and increased dramatically, this is the first action I would suggest.

Secondly, there is the issue of treating people with the disease and supporting measures to stop the spread, i.e. finding a cure or vaccine. A vaccine has not yet been developed and cannot be considered a realistic approach to stopping this particular outbreak. This is because in the long-term, a vaccine may have the benefit of containing a disease through herd immunity by reducing the contact of vulnerable people with the disease, yet in the short-term vaccines have to be tested for efficacy and safety and then have to enter an additional stage of distribution which can also be time consuming and not immediately impactful. Thus during this process, the virus may have spread which would add onto the time taken to control the disease. This is made worse by the fact that scientists have no distinct evidence of the natural host of Ebola, even though bats are strongly suspected. This is because the virus kills people and monkeys so fast that, evolutionary, these organisms cannot be hosts because otherwise the virus would have died out.

Any cure of the disease would likely have to tackle the genetic structure of the virus yet this is made difficult by the fact that there are many different families of the virus, such as Ebola Zaire and Ebola Sudan, which are genetically distinct. If these viruses would have shared more genes then it could be suggested that they would have inherited these shared genes from a common ancestor and so they represent a more basic function. Yet genes that are not common may have been inherited more recently and so the part they code for will tend to vary more as it has not been “fixed” by evolution. This means that it is more difficult to identify which gene we should target.

On the other hand, in recent news a “secret serum” has been created and used experimentally to treat one infected medical worker from the USA. This uses antibodies which lock onto the virus and prevent it from spreading. These antibodies are being produced from GM tobacco plants which means that treatment is also time consuming which means that it is a defensive measure against the disease as opposed to an offensive measure (i.e. it cannot realistically be offered to everyone with the disease to end the outbreak). This drug is also in its experimental stages and has passed the animal testing stage yet has not been clinically tested. Hence this means that the efficacy and safety has not been tested reliably. This also means that the drug risks being influence by the results of only a few people which cannot account for genetic variability and potential success on a large scale so the results have not been analysed to see whether they are repeatable and hence produce a dependable treatment. This danger of not enough testing is particularly the case with new drugs as the seemingly positive effects may have been in fact due to other factors that interact and so and success could be a coincidence. Alternatively, both the administering of the drug and recovery could be because that this has been used in a hospital setting so the drug is more likely to be given. Hence recovery may instead be influence by increase hygiene or rest. It’s a classic case of cause vs correlation. Finally, there are ethical issues over who should have access to the drug with one person questioning whether the people with the largest families should get the drug, or whether economic contribution is more important. It is an issue over deciding who should live and who should die which traditional ethical theories struggle to account for, as even the utilitarian argument (which would seem to argue that those who have the largest benefit in the long-run should live) may struggle to quantify benefit.

My Verdict

To conclude, I believe that the issue is not a global “emergency” as of today, but instead should be considered a grave concern that all countries have a duty to acknowledge. This is because I believe that an emergency implies that the situation represents a direct threat to a majority of countries which I believe it does not. In regards to the response then, I think that core control methods should be fully enforced and attention should not be massively diverted to “wonder drugs” such as the “secret serum”. I think this because the success of these drugs is fragile and if we rely too much on single drugs, then if these drugs cannot fully protect people or only work in a small proportion of people then the opportunity cost is grave. On the other hand, contact investigation and border control methods are tried and tested. Secondly, these basic methods use a systematic approach where the limits are known. For example, it is clear where you should stop checking contacts as this is the point when no more contacts are infected. The development of drugs however is less definite as although they are both objective, drug development has many more failures and it is difficult to test, compare and improve drugs. This means that when to stop looking for new treatments and to focus on a specific treatment is difficult to determine. Thirdly, imagine a long line of infected people. Using contact investigation with one worker may take a week. With two workers, this time is halved, with three workers, the time is split into three. On the other hand, with drug development, if you employ one worker to develop a drug and then another to develop another drug to see which is better, then one worker’s efforts will be eventually wasted. Thus, whilst both methods have diminishing returns (i.e. the more workers you have the less the next worker can add to the team), drug development suffers much greater. Hence, I believe that the WHO should focus on these basic methods yet still allow labs to develop drugs when they cannot contribute to preventing disease spread.

Sources

 

 

Monday, 21 July 2014

Assisted Suicide - Right or Wrong?


Recently in British news, and across the world, the argument over whether terminally ill patients are allowed to request assisted suicide, that is the administering of drugs to end their own life. This has been supported by Lord Falconer’s bill which proposes that doctors should be allowed to prescribe a dose of medicine that will end a terminally ill person’s life (a person who is judged by two clinicians to have less than six months to live). The debate occurs in government tomorrow and more than 130 peers have put their name down to speak. I apologise for the length of this post but the arguments are complex and depend on many things. Skip to the section you want to read.

Schools of Thought

This raises the question: how should we decide on matters of life such as this? I will briefly here consider two schools of ethical thought, although there are many others, skip this and the next paragraph if you wish to hear the main issues involved in the debate. Utilitarianism is the belief that we should do whatever brings the widest good and the smallest harm. This considers the intensity of pain and how long the pain lasts. This pain is not only direct pain but also includes a loss of dignity (described as “purity”). The number of people influenced by an action is then considered and the richness of a life is considered i.e. whether an individual life would lead to other pleasures. Finally, universalism considers the certainty that a cure will be found in time. When we consider this school of thought we can address the issue of assisted suicide (effectively active euthanasia) in a systematic way. First the pain. The pain may be great and may last for significant amount of time as a terminally ill person may not be able to control their body and may suffer as a result, this suffering may then be prolonged as their death may be gradual and may be characterised by the gradual shut down of organs. Thus, in contrast, assisted suicide would lead to “pain” in the fact that the body is directly dying yet wouldn’t offer physical pain that could be monitored by the patient, this “pain” is also quicker. Furthermore, dignity may be dramatically reduced if a terminally ill person is kept alive against their wishes, this is because they may not be able to perform basic tasks. Alternatively, assisted suicide could also reduce dignity because it is viewed by some to be “admitting defeat” therefore by committing suicide of any kind it is a rejection of your identity as a human and so may undermine dignity. Furthermore, the extent of introducing active euthanasia for the terminally ill would be undoubtedly great and whether this is beneficial is based on opinions I will discuss later. Finally the richness of life, this is difficult as it is very subjective and does depend on the type of illness and the influence it has over life. For example, an athlete who develops MND will lose control of his body and so this may be viewed as a great loss so the richness of his life, because he gained pleasure from training, would be greatly reduced. In comparison, Stephen Hawking is a scientist and so developing motor neuron disease didn’t affect his ability to ‘write’ books and continue his career so his pleasure was preserved.

Another school of thought is virtue ethics which was developed by Aristotle who believed that the effect on the individual character is more important than the action itself. Thus we should aim for eudaimonia (a type of life that results from perfect balance). This is a form of happiness that is based on patience, temperance and courage which are developed so that we can be happy and so is not in the interest of others. Thus this school of thought doesn’t consider the “extent” as utilitarianism does, but instead looks at the extent as merely a collection of individuals. This school of thought would argue that people suffering from terminal illnesses cannot be ‘happy’ (although this is clearly controversial) and that people should strive to preserve the values of a eudaimonian life. This may mean for example taking courage to end your life, or to have the patience to deal will illness and not resort to assisted suicide. This depends on interpretation.

In Support of Assisted Suicide

Now we come to the main issues and we will first consider the arguments for assisted suicide for the terminally ill. Some people argue that it is a human right to die and that because illness takes away the autonomy of the individual then death is the only autonomous decision left. This argument is particularly supported in that clinical guidelines advise clinicians to act in the interests of the patient and to appreciate each patient’s individual needs. This means that if a patient says they want to die, then this should be respected as opposed to being ignored and forcing the patient into schemes which clearly oppose what the patient wants. For example, a patient suffering from a terminal illness may state they want to die, in response a doctor, under current legalisation, couldn’t offer euthanasia and instead may deal with the problem by increasing support to the patient through nurses and hospices. This, although helping to alleviate the complaints of the patient is acting in precise opposition to what they originally wanted. This creates the image that the healthcare profession is disrespecting to patients and so this may humiliate and frustrate patients. In addition, supporters of the bill may argue that allowing the terminally ill to ask for assisted suicide is the most loving and compassionate response. This was presented by Lord Falconer who stated that his bill would lead to “less suffering not more deaths”.

This would also be viewed as more considerate as Stephen Hawking described current laws preventing the disabled asking for assisted suiced as “discrimination against the disabled to deny them the right to kill themselves that able bodied people have”. This is a particularly strong argument as it suggests that death is an individual choice and thus is a private matter that the individual takes responsibility for. Therefore this implies that only the sufferer can decide and so acting on behalf of the disabled to preserve their life when they do not want it, may be wrong because it undermines their equality and humanity. Furthermore, this argument draws on the inconsistency within society that people are legally able to commit suicide yet those who cannot move for example, do not have access to this law. Thus this discredits arguments against the bill which state that assisted suicide could lead to people being pressured into assisted suicide. This is because, arguably, people are already being restricted in their choice to be able to commit suicide. However, we cannot call this “discrimination” as discrimination is acting on prejudice and so because prejudice isn’t being used (indeed, it is attempting to act in the best interest of the terminally ill) then it is not discrimination. Instead, it is an issue of consent and practicality.

Finally, some believe that assisted suicide should be allowed as the end (the relief of suffering) is more important than the means (helping someone to die). Therefore this is based on situation ethics which argues that certain actions are only justified in certain circumstances which are based on personal judgement. Therefore the benefit and damage of the respective end and means depends on a variety of influences. Hence, because situation ethics is very personal then it is very subjective and so cannot be analysed fully.

Against Assisted Suicide

In regards to the views against the bill and assisted suicide the main argument is that it could lead to pressure from family for a person to commit suicide so that the choice doesn’t represent the individual’s personal wishes. This leads to the possibility of coercion and so this undermines the value of the individual and instead makes life disposable and discredits the value of life which is the basis of society (e.g. doctors always help to preserve life, fire fighters do not see the burn marks on a person and think “I’ll leave him to die in the fire” because of them). This view has been mainly presented by Tanni Grey-Thompson who stated that 61% of people in Washington State choose assisted suicide because of family pressure. Thus laws should protect public safety. There are many issues with this argument. Firstly, this figure is likely to be unreliable as for the figure to be true, people committing assisted suicide, quite obviously, would have to be living. Therefore the fact that many living people are saying that they are being forced into death without even identification by a consultant seems quite unlikely. Furthermore, another way of viewing the statistic, although more controversial and robotic, is that because people are choosing death because their family wants them to (and then reporting this, seemingly uncaringly to the media) indicates a lack of self-value: the “I may as well” argument. This is a much more risky argument as I don’t know whether the 61% of people were crying out for help or simply regarding it as a factor in their decision. Adding to this, however, there may be pressure from the NHS and assisted suicide risks clinic as viewing patients as potential costs. This is much easier to argue against as doctors are unlikely to suddenly abandon their duty of care and begin viewing patients as merely costs. Furthermore, as the patient has become more empowered in recent years with the formation of regulation and stricter guidelines, doctors may become even more cautious when dealing with active euthanasia as they would be worried about complaints. Hence, the seemingly reckless attitude implied by this argument is very unrealistic. Furthermore, as many people have said, there will be regulations and controls in place to prevent this pressure and so this will mean that any exaggerated pressure from doctors would be even further reduced as two doctors would be needed to verify it. Some here may argue that so is the case with abortion and yet we have widespread abortion anyway. To this statement I would say that in the issue of assisted suicide we would be dealing with clear and tangible lives, as opposed to the life of a foetus which is disputed. In this case no-one can dispute that a person is living and so the regulation would be tighter than abortion.

Another argument is that assisted suicide promotes a risk to the development of palliative (pain-relieving) care as less people use palliative care and so development slows. This again can be easily contradicted by splitting the argument into a list of points (P1-4) and a conclusion:

P1: More people choose euthanasia

P2: Less people depend on palliative care

P3: Less people needing care slows the rate of research

P4: Less research means less palliative care

Conclusion: Introducing euthanasia means less palliative care.

First let me address P2. This is not a sound point as due to a growing population the number of people requiring palliative care may grow. This is further amplified when only those who have a reasonable chance of death in 6 months would be able to claim assisted suicide and even then many still would not. Furthermore, many people choosing euthanasia may have previously depended on palliative care e.g. a person due to die in 12 months may go to a hospice for 6 months and then choose assisted suicide. This would mean that the same if not more people will depend on palliative care in the future. Points 3 and 4 are also not sound as palliative care is a growing area of medicine and a number of hospices are already established – they are unlikely to suddenly close. Adding to this in 2014 “there are 230 nurses specially trained in 82 districts. They are supplemented by clinical officers and even doctors to deliver Palliative care at the 131 facilities that are accredited. We also have 12 stand-alone health centre providing Palliative services” according to Ms Kiwanuka, minister of finance in Uganda. This is compared to the 120 specially trained nurses in 2011 in Uganda. Also, points 3 and 4 confuse the rate of improvement with improvement itself. Although, the rate of improvement may slow, improvement will undoubtedly continue as although research may be scarcer, offering patients the choice will lead to palliative care becoming more willing to offer leading support and care to patients to encourage them to continue living. It will become a ‘competition’.

Finally, some people who are against the bill state that doctors may simply estimate wrongly, an example of which is seen in Stephen Hawking. This, however, is rare and could be tackled by a system which allows patients to make the decision and then doctors affirming it. For example, a patient suffering from a terminal illness may state to a doctor that they would like to die, the doctor could then review the patient and if it is found that they could die in 6 months then assisted suicide could take place so that the patient is not influence by the diagnosis and instead makes the choice based on how they are feeling. In contrast a patient who enjoys life may never mention assisted suicide and so the doctor would not tell them how long they have left. This clearly is dishonest and undermines the right of the individual to information and so this method would have to be modified further.

My Verdict

Overall the issues are complex and depends on whether you believes that we all need rules and certain actions are always wrong or whether it depends and must be resolved by looking to the individual. In discussing the issues above, I believe that people should have the choice to die and assisted suicide should be allowed for the terminally ill but this is my opinion. Regardless of your viewpoint however it is clear that if assisted suicide is allowed, it would make doctors’ jobs a whole lot harder and would intensify the debate even more. If you want to give your opinion, I have created a survey in the top right.

Sources

Friday, 18 July 2014

Can we end AIDS?


According to the latest BBC news, if spending on AIDS increased then there is a possibility that the disease could be ended by 2030. Yet the meaning of this statement is unclear. For example “end” could mean that the disease will be eradicated globally or it could mean that the disease would just be restricted to certain areas so that it would cease being an epidemic and instead become an endemic viral disease. There is further obscurity in the latter definition as the success of “ending” the disease in some areas would depend on the size of the area, the population of the people living in these areas, the lack of development in areas still suffering from AIDS. An example of this would be if AIDS was eliminated in Britain yet the whole continent of Africa still suffered from AIDS and didn’t even have access to palliative care let alone a potential cure if Britain developed it. In this case the declaration of “ending” AIDS in Britain would be still less important when we account for global progress and the suffering of individuals. It is for this reason why I shall consider the former interpretation that we can eradicate AIDS altogether in order to set a clear target to be able to compare our current progress to that needed.

Can it be done?

The figures are initially encouraging as in 2013, there were 38% fewer cases than in 2001 representing a decrease of 1.3 million cases worldwide. This trend, if it continued at a current rate of decreasing by 1.3 million every 12 years would lead us to believe that AIDS could be eradicated in 19.38 years which arrives at an estimate of eradication at the year 2032. However this is likely to be far too optimistic. This is because the rate of decline is not likely to remain constant and instead is likely to plateau. This is because the recent fall in AIDS related cases has primarily been in Western Africa. Therefore as these areas become more developed and AIDS cases fall to a minimum other areas of the world may not improve and so this may mean that, as the rate of the fall is due to development, when development has been reached, the rate of the fall will be less. The graph to the right also appears to suggest that although in some cases HIV is declining in proportion, it is only doing so at a very slow rate and that the actual number of infections is increasing, even if this increase is slowing down. Also we must consider the possible 15 year delay when infected people are unaware they have AIDS. This means that any increase in spending to make people more aware of the dangers of unprotected sex will not be seen until 2029 at a maximum. Thus the effect of increased spending is unlikely to influence the decline of AIDS in order to meet the 2030 “target”. 

Nevertheless, AIDS related deaths have fallen by a fifth in the last past three years and so this shows the rate of development of healthcare as AIDS was first recorded in 1980 and so the proportion of the last three years is 8.8% of the time we have known about AIDS. Thus if deaths have fell by a fifth in this time, this would seem to suggest that medicine has accelerated in regards to treating AIDS. Even so this assumption may not be accurate. For example if deaths decreased by half in the previous from 2008-2011 then this would suggest that medical development is slowing and although deaths are still being reduced, this occurs at a much lower rate. Furthermore, this doesn’t give us any information about the cases of infection or what proportion of people with AIDS survive. In 2011 there were “6280 new diagnoses of HIV in the UK. At the end of 2011 around 96,000 people were living with HIV”. Clearly if none of these 96,000 people died then it would appear a massive success (which it would be) and would seem to suggest that we can deal with AIDS, yet this ignores the fact that these 96,000 people still have AIDS and still may endure a low quality of life. Thus ending AIDS wouldn’t be much closer. Also the UK is more developed than Africa say and so may represent the next stage of development for Africa. Thus, if the UK still suffers from AIDS, then it is unlikely that we will see the complete abolition of AIDS globally if even the developed regions suffer. This is specifically shown in the pie chart in which high income countries still have a portion of the total number of AIDS sufferers, even if this portion is low. Hence, although death rates could show the level of medical treatment and care, it cannot indicate how close we are to eradicating a disease.

However, I must also consider the “trickledown effect” as it can be called, in that improving healthcare (and hence reducing the death rate) also allows development of knowledge. Hence if knowledge develops then we can more easily analyse and develop methods of destroying HIV. In addition, more knowledge of the disease can lead to more effective preventative campaigns which may reduce the infection rate and so this would mean that a reduced death rate could be an indicator that the number of cases of AIDS will decrease. In addition, in the book “Hippocratic oaths”, Raymond Tallis states that increases in life expectancy have not solely been gained through healthcare but also education and nutrition. This may be similar in the battle against AIDS because as poorer regions develop, education is likely to increase and so this will also cause a reducing in the infection rate. Despite these issues, though, the article still states that “there have been more achievements in the past five years than in the preceding 23 years” which suggests that this rate of achievement will continue to increase.

What should be done?

If we are to meet this target then, what should the areas of interest be? Fewer than 40% of HIV sufferers receive antiretroviral therapy, a treatment that is often lifesaving. If we focus on the wider circulation of this treatment then we should focus on getting these countries more independent and not reliant on foreign aid. This is because, whilst foreign aid can allow undeveloped areas to access high quality care, it doesn’t give these countries the flexibility that they need. For example, they may not be easily able to increase production. Also, because AIDS is less of an issue in developed regions then these countries may not produce these drugs on a large enough scale. In addition, drugs companies may exploit the reliance of undeveloped countries on their drugs by charging higher prices.

Another area of importance will be ensuring that a “final push” is made as AIDS becomes less common. This is particularly significant with disease as if complacency is allowed to grow then fewer people will acknowledge the issue which could lead to many people being put at risk without knowing. A similar case has been seen in vaccination which produces a cyclical pattern as people get vaccinated so herd immunity increases causing people to perceive the risk as lower as it is less likely to spread. This lowers the vaccination rate and so can cause mass infection which causes vaccinations to again rise. A similar, although not identical, pattern could be seen if complacency towards AIDS is developed

Drug resistant HIV strains could further complicate the issue as they may slow drug development. Methods of resistance could therefore mean that any cure is limited in the long-term as it is probable that HIV strains may mutate and hence render any treatment less effective than originally planned. This means that medical development will be sure to slow if the virus changes even as slightly as to cause a slight change in the success rate of treatment. However, this is already being tackled as in July 2006, a single-pill, once-a-day AIDS treatment (Atripla) was approved by the FDA which avoided the “cocktail” of drugs that is often used to manage the disease. By avoiding many drugs, this means that regular treatment can be given and so this will ensure that the AIDS virus cannot easily mutate as it will be regularly ‘attacked’ as opposed to previously where it could be given time to mutate and develop resistance to a drug which reduced the success of treatment hence leading to more prevalent HIV strains which increased the rate at which resistance to the other drugs could be achieved.

My Verdict

Ultimately, we could compare this attempt to eradicate AIDS to the eradication of smallpox which, so far is “the only infectious disease of humans, to be eradicated by deliberate intervention”. Hence any attempt to eradicate AIDS will require community effort and global interaction such as the AIDS meeting which recently took place in Australia in 2014. The method used to eradicate small pox was a mixture of focused surveillance to identify the smallpox virus, followed by “ring vaccination” which involved a series of quick vaccinations to increase herd immunity. However this is unlikely to be used in the war against AIDS as infections cannot easily be seen. Furthermore, when two sexual partners suddenly develop AIDS then it can be suggested that one must have breach monogamy. This is unpredictable and so it is difficult to prevent the spread of AIDS if people do not take personal responsibility, compared to small pox when it could easily be predicted when someone may develop symptoms (i.e. relatives may be more at risk). Hence, I don’t believe that the target to defeat AIDS by 2030 is realistic in the present day, but I do believe that we can beat AIDS if we introduce a more coherent and direct plan combining international collaboration in medical research with education programmes to allow “ring” approaches to be made.

Sources

http://www.rosehillnazarene.org/herald/hiv.bmp
http://www.nhs.uk/Livewell/STIs/Pages/HIV.aspx
http://www.wecanendaids.org/
http://www.infoplease.com/ipa/A0106323.html
http://en.wikipedia.org/wiki/Eradication_of_infectious_diseases
http://www.historyofvaccines.org/content/articles/disease-eradication
http://www.newscientist.com/data/images/ns/cms/dn9244/dn9244-1_700.jpg
Raymond Tallis - Hippocratic Oaths