Today’s post is from guest blogger Helen Fry, who is a student at the University of Leicester.
MicrobiologyBytes welcomes guest bloggers who would like to contribute occasional posts which conform to the style and content of this site. If you would like to be a guest blogger here, please email your post with a completed copyright release form to me at: alan.cann@gmail.com
A quick glance at the British National Formulary and it’s easy to see just how many antibiotics are licensed for use in the UK. What is more difficult to see is how many antiviral agents are available, and this is because there are much fewer. The only viral diseases with treatments listed in BNF 57 are HSV, VZV, HIV, RSV, viral hepatitis and influenza. Viruses are the most abundant ‘lifeforms’ on the planet and there is a huge diversity of viruses that cause disease in humans. Viral disease, although often milder than bacterial or eukaryotic disease, accounts for a major burden on the health service and is a considerable cause of morbidity and mortality. Some viral diseases cause very severe infections and are a heavy global issue, such as HIV and viral diarrhoea (a major cause of infant and childhood mortality in countries without safe drinking water). So if viruses are so abundant and are such a global health pest, why are there so few antiviral agents?
There are several reasons why this is the case. First there is the difficulty of researching viral disease. Most pathogenic bacteria can be cultured and investigated fairly easily, with some notable exceptions such as TB and Chlamydia trachomatis. Culturing and investigating viruses is a lot harder, as it requires cell culture methods, where the appropriate line of eukaryotic cells is grown up and infected with the virus. This means that the virus cannot be studied directly, as with a growing population of bacteria, and because they are so small they can only be visualised via electron microscopy (The impact of cell culture sensitivity on rapid viral diagnosis: a historical perspective). There are non-culture based detection methods, but these only confirm the presence of the virus, they do not allow it to be studied. Viruses do not release any compounds on their own, any proteins made are produced in the host cell, whereas bacteria release toxins and chemotactic agents, quorum sensing molecules and siderophores, to name a few. This makes them easier to study. The fact that viruses are harder to study means that less is generally known about them, and it is a lot harder to identify potential targets for antivirals. On the other hand, viruses have much smaller genomes (on the whole, with some obvious exceptions), meaning that the genomes can be sequenced easily (Role of Cell Culture for Virus Detection in the Age of Technology).
Once a virus has been fully characterised, despite the difficulties, it is still problematic to make useful antiviral agents, and even the ones licensed in the UK are often quite toxic. This is for several reasons. Since the most important part of the virus life cycle takes part inside host cells antivirals often have to penetrate the cell in order to be effective. This means that the drug has to be highly specific for virally infected cells or risk being toxic to healthy cells. The viruses use host cell machinery to replicate themselves, meaning that a drug targeted against this part of the cycle risks affecting genome replication in healthy cells unless a virus specific target can be identified. Bacteria are prokaryotes, which mean that their cells are highly different to ours and it is often a simple matter of identifying a difference between our cells and theirs, and finding a molecule that interacts with it, such as the beta-lactams and cell wall synthesis. Antivirals have similar issues to antiprotozoals, in that finding a compound active against the microbe is not that hard, the difficulty lies in finding one that does not interact with host processes and is therefore non-toxic.
Finally, however, it all comes down to money. Drug development is now a process that is left exclusively to pharmaceutical companies due to its prohibitive costs, and since they are primarily a business rather than a service, all activity undertaken by them will inevitably be profit driven, rather than need driven. Bringing a drug to market now costs several million US$ and taken over 10 years from target identification to phase IV clinical trials. It is therefore a huge investment, and the drug companies want to be as such as possible that their drug will make it to market and will make as much money as possible before the patent runs out. Since patents last for 20 years, a drug may only have 5 years to make back the money it took to develop before cheaper generics can be made. This has caused companies to focus on drugs that are least likely to fail trials due to toxicity and that will make the most money in a short amount of time. Therefore the focus has been on lifestyle drugs that people will take every day for years on end, such as statins and antihypertensives, that have a low risk of toxicity and are well established in doctors’ prescribing pads. HIV therapy has benefited from this, as HIV+ people will need to take their medication every day for the rest of their lives. This, along with the fact that HIV is a rapidly fatal disease without medication meaning that drug companies can charge almost what they like for them, has meant that the number of effective, less toxic antiretrovirals is increasing and is already fairly big in comparison to other viral illnesses. Drug companies will risk producing drugs that are more likely to be toxic if they can charge a large amount for them once approved. This is usually the case for life-threatening illnesses, explaining why chemotherapy for cancer costs so much (in the tens of thousands for a single cycle in some cases), but is quite good these days, at least for the common cancers.
The incentive of money can be seen with the influenza drugs. Not many people have the need for influenza antivirals, since there is a pretty good vaccine produced each year for those at risk, and those not in high risk groups do not tend to suffer from severe enough disease to warrant treatment with anything other than blankets and Lemsip. So why are there two good drugs sitting on the market when they are not needed? The answer lies with the government who, fearing an approaching flu pandemic (we are due for one) decided to stockpile the anti-influenza drugs before they were widely used and resistance developed.
The biggest burden of viral disease, as with most infectious diseases, lies in developing countries. They are the worst hit by the HIV pandemic, suffer outbreaks of haemorrhagic fevers, are plagued by water borne viral diarrhoeal diseases and various other viral nasties. However, since they for the most part do not have the capital to fund a national health service and the people cannot afford medications themselves, these countries and their endemic diseases have been largely ignored by the drug companies due to the lack of profit potential. This means that the countries worst affected by HIV are the ones who do not have access to effective antiretroviral therapy, and that children die in the thousands because of viral diarrhoea. Some drug companies are starting to research third world diseases, but progress is slow and funding is not the best. Since we in the west need medications we cannot boycott the companies, and allowing patents to be extended would only put more strain on the already overwrought NHS. However, there needs to be a shift in attitudes towards making the companies more responsible for the drugs they develop.
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