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The role of the food industry in tackling Australia’s obesity epidemic

Whilst a number of factors contribute to Australia’s rapidly rising obesity rates, the role of fast food companies in addressing the epidemic remains controversial. This report discusses the contribution of fast food companies to high obesity rates, explores the notion of corporate social responsibility, and discusses a range of government policies that could be implemented to limit the contribution of fast food chains in promoting obesity.

Introduction

Obesity is a major concern in Australia, with 62.8% of the adult population termed overweight (35.3%) or obese (27.5%). [1] Multiple factors contribute to these rising statistics, and whilst fast food companies undeniably contribute to obesity, defining the exact role that they play and their responsibility remains controversial. Whilst difficult to numerically define, previous studies have offered various definitions of fast food, broadly defining it as food purchased from cafeterias, restaurants and ‘big brand’ companies (such as McDonalds) that are high-calorie and low in nutritional value. [2-4] Food produced in restaurants, for example, is at least 20% higher in fat-content than the home-cooked equivalent. [5] It has now been over a decade since the infamously termed ‘McLawsuit,’ in which a group of overweight children in America filed legal action against the McDonalds corporation for their obesity-related health problems, first bringing the issue of corporate responsibility to a head. [6] Increasingly, now, trends are towards increasing regulation of the fast food industry, with recent debate over a fat tax in Australia, [7] and New South Wales enforcing nutrition labelling of fast food products. [8] The obesity epidemic continues to contribute to the morbidity and health expenditure of many developed countries, with minimal resolution on the role that fast food companies should play in tackling it.

Obesity in Australia: The contribution of fast food companies

The complex array of factors contributing to obesity makes the issue of responsibility a difficult one. [9] Australia’s obesogenic environment comprises multiple factors, such as increasingly sedentary lifestyles, poor education regarding nutrition and the accessibility of fast food. [10] In this respect, fast food companies, government and the wider community are all stakeholders with differing degrees of responsibility.

Fast food companies are considered a key stakeholder in contributing to Australia’s obesogenic environment. This is attributed to factors such as their large portion sizes, and marketing ploys that intensively promote the accessibility of unhealthy snack foods and target vulnerable groups such as low-income earners and children. [11] These factors make it difficult for consumers to make informed choices and resist unhealthy options, ultimately contributing to overeating and excess body weight. [12] Establishing a causal link between fast food companies and obesity is difficult due to the complexity of the relationship. An analysis by Chou, Rashad and Grossman (2005) indicated that a ban on fast food advertising would reduce the number of overweight children by 10% in the 3-11 year age group, and by 12% amongst 12-18 year olds, suggesting a causal component to the relationship in this vulnerable population group. [13] Accessibility of fast food outlets is also a contributing factor, with Maddock and colleagues (2004) showing that there is a significant correlation between proximity to fast food restaurants and obesity. [14] Furthermore, ever-increasing portion sizes also provide evidence for the influence of fast food companies on obesity; with Young and Nestle (2002) noting that portion sizes have paralleled the increase in average body weight. [15] Whilst some claim that fast food companies simply respond to consumer desires, and that the average consumer is well aware of the obesity epidemic, it can be argued that they are still partly responsible by providing and promoting this supply.

Corporate Social Responsibility

Corporate Social Responsibility (CSR) is a form of self-regulation that corporations integrate into their business model. [16] It involves taking responsibility for the impact of the company’s decisions on society and the environment. [17] Guler and Crowther (2010) further describe CSR as honouring the triple bottom line of people, planet and profit rather than solely focusing on profit maximisation. [18]

Proponents of CSR claim that it maximises long-term profits by encouraging firms to operate sustainably, decreasing risks despite initial costs. [19] Wood (2010) argues that ‘strategic CSR’ rewards business for CSR activities via the positive responses of consumers, employees and shareholders. [20] Ethical business policy may lead to brand differentiation and customer loyalty, increasing purchase intention and willingness to pay. Similarly, employees may be attracted and motivated by strong CSR policies, potentially increasing recruitment, work ethic and employee loyalty. Successful CSR strategies can also improve a firm’s reputation, reduce external pressure from non-government organisations (NGOs) and attract shareholders. [21] For example, Becker-Olsen et al. (2006) argues that McDonald’s funding of programs such as Maths Online, Little Athletics and its Ronald McDonald House Charities acts as subconscious advertising to improve its reputation. [21-23]

However, as well as these incentives, firms also face challenges in establishing CSR policies. Some economists claim that CSR distracts from the role of business, which is to maximise profit. [24] The financial costs of introducing CSR policies may also be barriers for firms, particularly small businesses that lack the required resources. [20] Moreover, CSR does not necessarily equate to positive consumer perceptions, as the credibility of corporations is often doubted. [21] For example, partnerships between KFC and the McGraw foundation, McDonalds and WeightWatchers, and Nestle and Jenny Craig have been criticised as marketing ploys, termed ‘weightwashing’ by the Obesity Policy Coalition. [25]

In the context of Australia’s obesity epidemic, CSR policies in the food industry may have varied impacts. Fast food companies, at a time of increasing obesity rates, may see an opportunity in utilising health policy to establish consumer goodwill and brand value, creating a profit-driven incentive to engage in obesity prevention. Self-motivation in CSR policy construction could, however, be detrimental to health prevention, with, for example, fast food companies shifting blame from ‘foods’ to ‘sedentarism’ in their marketing, rather than altering the quality of their products. [20] Additionally, as a defensive response to avoid government regulation, the food industry has created an opening for itself in a health and sports promotion role, which, whilst contributing to preventative health programs in the short-term, may in time detract from the conventional governmental role in public health, devolving government of some responsibility without effectively satisfying community needs.

Despite its challenges, the potential benefits of CSR and the rise of privatisation and globalisation make self-regulation in the food industry an important, and perhaps inevitable, approach to consider in tackling obesity. [25]

Government Regulation

In light of steadily increasing obesity rates in many Western societies, a number of governments have implemented policies to reduce the impact of fast food companies in promoting overeating. [26,27] Outlined below are four categories of legislative change and their implications.

Restricting fast food advertising

Fast food advertising can send misleading messages to consumers, particularly those less informed. [28] Ethically, from a communitarian perspective, restricting advertising may denormalise fast food by making it less ubiquitous, helping change social attitudes, which is key to combating obesity. [29] Conversely, restrictions on advertising limit choice by making consumers less aware of their options, contradicting the principle of autonomy. Whilst it could be said that advertising of healthy foods continues to provide this autonomy, critics argue that fast food is not harmful in moderation and thus consumers should be able to make an informed decision of their purchases. Similarly, in alignment with narrative ethics, individuals have different approaches to eating, which may be compromised by eliminating the information delivered by fast food advertising. [30,31] It is important to note, however, that many of these concerns assume advertising delivers accurate information, which is often not the case. Critics also claim that restricting advertising is ineffective, as there are more important factors contributing to obesity. In addition, there are concerns about how the distinction between healthy and unhealthy foods would be made and the rights of companies to market their goods. [32]

Examples of restrictions on fast food advertising include banning fast food company sponsorship of sporting events and celebrity endorsement of unhealthy foods, as well as banning advertising that targets children, a population group particularly susceptible to marketing ploys. In regards to this, banning advertising to children in prime-time hours has already been successfully achieved in a number of countries. Quebec, for example, has had a 32-year ban on fast food advertising to children, leading to an estimated US$88 million reduction in fast food expenditure. [33] Australia has been moving towards restricting fast food advertising that targets children, with the Australian Food and Grocery Council resolving to not advertise fast foods in programs where at least 35% of the audience are children. [34] However, analyses of the difficulties of self-regulation in the food industry indicate that its effectiveness depends on the rate of engagement by individual companies and is not sufficient to adequately protect consumers. [35,36]

Cost measures

A ‘fat tax’ would involve taxing foods or beverages high in fat content (other ‘unhealthy’ components such as sugar and salt could also be taxed). It aims to discourage consumers from unhealthy products and offset their health costs with the tax revenue generated. [37] Subsidies for healthy food options are considered less practical with a greater cost-burden for taxpayers. Critics argue that a ‘fat tax’ would disproportionately affect low socio-economic consumers, unless healthy alternatives are made cheaper. [38] Some argue that obese individuals are also less responsive to increased prices than consumers of average BMI, reducing the effectiveness of a tax. [39] A ‘fat tax’ could even exacerbate health problems – a tax only on saturated fat, for example, may increase salt intake, which increases cardiovascular risk. [38] Denmark was the first country to introduce a tax on fat in 2011; however, it has since resolved to repeal the legislation, claiming that it increased consumer prices, increased corporate administration costs, and damaged Danish employment prospects without changing Danish eating habits, reducing the likelihood of this approach being trialled by other countries, including Australia. [40] It should be noted, however, that country-specific differences may have contributed to its lack of success.  These include the ability of the Danish population to travel to neighbouring countries to maintain their eating habits despite the government tax, which would not be feasible in Australia. Alternatively, the government could consider combining subsidies for healthy food options with a ‘fat tax,’ as this approach would be more acceptable to the public than a tax alone, and also yield a lower cost-burden for taxpayers than subsidies alone.

Nutrition labelling

Nutrition labelling aims to ensure consumers understand the nutritious value of foods. In Australia, all food labels must abide by the national Food Standards Code. [41] Options to simplify food labelling include traffic light food labelling, which codes foods red, yellow or green based on their fat, sugar and salt content. [42] Another option is health warnings on unhealthy foods to deter consumption. [43] Australia-wide, a new star rating system for packaged foods has been developed by a working group which included industry and public health experts; as of June 2013, this has been approved by state and federal governments. [44] The scale will rate foods from half-star to five stars based on nutritional value, despite concerns raised by the Australian Food and Grocery Council over the cost to manufacturers and how nutritional value would be determined. Sacks et al. (2009) argues, however, that there is insufficient evidence to suggest that food labelling would reduce obesity. [45] Critics also argue that more restrictive practices, such as health warnings, are excessive and impractical considering the ubiquity of high fat foods. [46]

Limit physical accessibility of fast food

Easy accessibility of unhealthy foods makes them difficult to resist. Making fast food less accessible again denormalises it, helping change social attitudes. This is supported by studies showing that obesity rates are higher in areas with an increased number of fast food outlets. [14] Zoning laws have been suggested as a policy tool to limit the accessibility of fast food, with findings suggesting success in reducing alcohol-related problems. [47] Other approaches to restrict access include removing fast food from high accessibility shelves in supermarkets, banning fast food vending machines and banning fast food from school canteens. Victoria, for example, has imposed strict canteen rules restricting the sale of fast food to twice a term. [48] However, critics argue that restricting the accessibility of fast food may undermine consumer autonomy and choice, impinge on the legal rights of companies to market their goods, and could also be a precedent for government intervention in other areas. [49]

Conclusion

Whilst it is difficult to define the extent of the role that fast food companies play, there is no doubt that they significantly contribute to Australia’s obesity epidemic through their large portion sizes, low quality food, extensive fast food advertising and high accessibility. Ultimately, combating obesity will require a multi-faceted approach that denormalises unhealthy foods – a process that requires both consumers and government to take a role in regulating the quality, marketing practices and accessibility of unhealthy products produced by the food industry.

Conflict of interest

None declared.

Correspondence

S Bobba: samantha.bobba@gmail.com

References

References

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[2] Driskell, J, Meckna, B, Scales, N. Differences exist in the eating habits of university men and women at fast-food restaurants. Nutri Res. 2006; 26(10):524-530.

[3] Pereira, M, Karashov, A, Ebbeling, C, Van Horn, L, Slattery, M, Jacobs, D, Ludwig, D. Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet. 2005; 365(9453):36-42.

[4] Duffy, B, Smith, K, Terhanian, G, Bremer, J. Comparing data from online and face-to-face surveys. Int J Market Res. 2005; 47(6):615-639.

[5] Seiders, K, Petty, RD. Obesity and the role of food marketing: a policy analysis of issues and remedies. JSTOR. 2004; 23(2):153-169.

[6] Mello, MM, Rimm, ER, Studdert, DM. The McLawsuit: The fast-food industry and legal accountability for obesity. Health Aff. 2003; 22(6):207-216.

[7] Lewis, S. Federal government backed study into fat tax on fast foods. News.com [Internet]. May 20 2013. [Cited 2013 Apr 15]; Available from: http://www.news.com.au/lifestyle/food/federal-government-backed-study-into-fat-tax-on-fast-foods/story-fneuz8wn-1226646283704

[8] Thompson, J. Forcing fast food chains to join the fight against obesity. ABC News [Internet]. November 8 2010. [Cited 20/4/2013]; Available from: http://www.abc.net.au/news/2010-11-08/forcing-fast-food-chains-to-join-the-fight-against/2328572

[9] Frewer, LJ, Risvik, E, Schifferstein, H. Food, people and society: A European perspective of consumers’ food choices. Heidelberg: Springer; 2001.

[10] Germov, J, Williams, L. A Sociology of food & nutrition: The social appetite. Melbourne: Oxford University Press; 2004.

[11] Bronwell, KD. Fast food and obesity in children.  Paediatrics 2004; 113(1):132.

[12] Young, LR, Nestle, M. Portion sizes and obesity: Responses of fast-food companies. .J Public Health Policy. 2007; 28(2):238-248.

[13] National Bureau of Economic Research. Fast-food restaurant advertising and its influence on childhood obesity. Cambridge: NBER, 2005. [Cited 2013 Apr 55/4/2013]. Available from: http://www.nber.org/papers/w11879

[14] Maddock, J. The relationship between obesity and the prevalence of fast food restaurants: state-level analysis. Am J Health Promot. 2004; 19(2):137-143.

[15] Young, LR, Nestle, M. The contribution of expanding portion sizes to the US obesity epidemic. Am J Public Health. 2002; 92(2):246-249.

[16] McBarnet, DJ, Voiculescu, A, Campbell, T. The new corporate accountability: corporate social responsibility and the law. Cambridge: Cambridge University Press; 2007.

[17] Maloni, MJ, Brown, ME. Corporate social responsibility in the supply chain: An application in the food industry. J Bus Ethics. 2007; 68(1):35-52.

[18] Guler, A, Crowther, D. A handbook of corporate governance and social responsibility. Fanham: Gower; 2010.

[19] Porter, ME, Kramer, MR. Strategy and society: the link between competitive advantage and corporate social responsibility. Harv Bus Rev. 2006; 84(12):78-92.

[20] Wood, DJ. Measuring corporate social performance: A review. Int J Manag Rev. 2010; 12(1):50-84.

[21] Becker-Olsen, KL, Cudmore, AB, Hill, RP. The impact of perceived corporate social responsibility on consumer behaviour. J Bus Research. 2006; 59(1):46-63.

[22] McDonalds. McDonalds Corporation: Worldwide social corporate responsibility. 2009. [Cited 2013 Apr 16]. Available from: http://www.aboutmcdonalds.com/etc/medialib/csr/docs.Par.32488.File.dat/mcd063_2010%20PDFreport_v9.pdf

[23] Royle, T. Realism or idealism? Corporate social responsibility and the employee stakeholder in the global fast-food industry. Business Ethics: A European Review. 2005; 14(1):42-55.

[24] Peattie, K. Corporate social responsibility and the food industry. AIFST. 2006; 20(2):46-48.

[25] Martin, J. Rich pickings, fat or thin. Sydney Morning Herald [Internet]. 2010. [Cited 2013 Apr 27]; Available from: http://www.smh.com.au/lifestyle/wellbeing/rich-pickings-fat-or-thin-20110115-19rvj.html

[26] Mitchell, C, Cowburn, G, Foster, C. Assessing the options for local government to use legal approaches to combat obesity in the UK: Putting theory into practice. Obes Rev. 2011; 12(8):660-667.

[27] Diller, PA, Graff, S. Regulating food retail for obesity prevention: How far can cities go? J Law, Med Ethics. 2011; 39(1):89-93.

[28] Carter, OB, Patterson, LJ, Donovan, RJ, Ewing, MT, Roberts, CM. Children’s understanding of the selling versus persuasive intent of junk food advertising: Implications for regulation. Soc Sci Med. 2011; 72(6):962-968.

[29] Veerman, JL, Van Beeck, EF, Barendregt, JJ, MacKenbach, JP. By how much would limiting TV food advertising reduce childhood obesity. Eur J Public Health. 2009; 19(4):365-369.

[30] Caraher, M, Landon, J, Dalmeny, K. Television advertising and children: lessons from policy development. Public Health Nutr. 2006; 9(5):596-605.

[31] McNeill, P, Torda, A, Little, JM, Hewson, L. Ethics Wheel. Sydney: University of New South Wales; 2004.

[32] Henderson, J, Coveney, J, Ward, P, & Taylor, A. Governing childhood obesity: Framing regulation of fast food advertising in the Australian print media. Soc Sci Med. 2009 69(9): 1402-1208.

[33] Dhar, T, & Baylis, K. Fast-food consumption and the ban on advertising targeting children: the Quebec experience. J Marketing Research. 2011 48(5).

[34] Collier, K. Crackdown on junk food advertising during shows children watch. Sydney Mornng Herald [online newspaper]. November 02 2012. [Cited 2013 Apr 20]; Available from: http://www.news.com.au/lifestyle/parenting/crackdown-on-junk-food-advertising-during-shows-children-watch/story-fnet08ui-1226508730232

[35] Sharma, L, Teret, S, Brownell, K. The Food Industry and Self-Regulation: Standards to promote success and to avoid public health failures. Am J Pub Health. 2010; 100(2):240-246.

[36] King, L, Hebden, L, Grunseit, A, Kelly, B, Chapman, K, Venugopal, K. Industry self regulation of television food advertising: responsible or responsive? Int J Ped Obes. 2011; 6(2):390-398.

[37] Mytton, O, Gray, A, Rayner, M, Rutter, H. Could targeted food taxes improve health? J Epidemiol Community Health. 2007; 61(1):689-694

[38] Clark, JS, Dittrich, OL. Alternative fat taxes to control obesity. Int Adv Econ Res. 2007; 16(4):388-394.

[39] Tiffin, R, Arnoult, M. The public health impacts of a fat tax. Eur J Clin Nutr. 2011; 65(1):427-433.

[40] Denmark to scrap world’s first fat tax. ABC News [online newspaper]. November 11 2012. [Cited 2013 Apr 16]; Available from: http://www.abc.net.au/news/2012-11-11/denmark-to-scrap-world27s-first-fat-tax/4365176

[41] Martin, T, Dean, E, Hardy, B, Johnson, T, Jolly, F, Matthews, F, et al. A new era for food safety regulation in Australia. Food Control. 2003; 14(6):429-438.

[42] Magnusson, R. Obesity prevention and personal responsibility: the case of front-of-pack labelling in Australia. National Institute of Health; 2010. [Cited 2013 Apr 24]; Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091573/

[43] Cinar, AB, Murtomaa, H. A holistic food labelling strategy for preventing obesity and dental cavities. Obes Rev. 2009; 10(3):357-361.

[44] Winter, C. Government touts star rating system for food to fight obesity epidemic, ABC News [online newspaper]. June 27 2013. [Cited 2013 Apr 21]; Available from: http://www.abc.net.au/news/2013-06-13/food-labelling-system-to-encourage-healthy-eating-options/4752032

[45] Sacks, G, Rayner, M, Swinburn, B. Impact of front-of-pack ‘traffic-light’ nutrition labelling on consumer food purchases in the UK.Health Promot Int. 2009; 24(4):344-352.

[46] Dunbar, G. Task-based nutrition labelling. Appetite. 2010 55(3): 431-435.

[47] Mair, JS, Pierce, MW, Teret SP. The use of zoning to restrict fast food outlets: a potential strategy to combat obesity.  2005. [Cited 2013 Apr 22]; Available from: http://www.publichealthlaw.net/Zoning%20Fast%20Food%20Outlets.pdf

[48] Rout, M. Junk food bans at schools. Herald Sun [online newspaper]. October 16 2006. [Cited 2013 Apr 21]; Available from: http://www.heraldsun.com.au/news/victoria/junk-food-bans-at-schools/story-e6frf7kx-1111112365970

[49] Reynolds, C. Public health law and regulation. Annandale: Federation Press; 2004.

 

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Feature Articles Articles

Patient Specific Total Knee Arthroplasties: A technological solution to the ageing population

Australia is faced with an ageing population and is bracing for the significant health challenges of this changing demographic. Individuals born during the post-war population boom of the late 1940s are now progressing into the over 65 age bracket, which has led to the emergence of a number of unique health and economic challenges. While the majority of older adult Australians continue to live at home, caring for the ageing population will inevitably require additional healthcare resources.

Of today’s older Australians, nearly half of the individuals aged 65-75 will have five or more long term physical health conditions. [1] By 2050, it is expected that the number of individuals aged 65-84 will have doubled, and the number of people aged over 85 quadrupled. [2]

The full challenge of the ageing population will be faced by today’s generation of medical students. The future health system will not simply need to deliver more of the same services, but do so in a more efficient manner, making use of the most advanced technologies in a cost and time-efficient manner. The system will need to adapt to the complex needs of the elderly patient, optimising coordinated care between primary and tertiary health care facilities.

Currently, within the population of Australia some 15% (3.1 million) are affected by arthritis, with osteoarthritis being the leading cause. [1] Being a degenerative condition, the incidence of osteoarthritis increases with age, and accounts for the primary cause of approximately 97% of total knee arthroplasties (TKAs) performed in Australia. [3] The dramatic increase in the population aged over 65 represents an immense increase in the numbers of individuals at risk of osteoarthritic knee changes. Given the inevitable wave in those requiring joint arthroplasty, are we fully prepared for this expected number?

In 2011, a total of 40,470 TKAs were performed in Australia. [3] This represents an increase of 5.7% on the previous year and a further increase of 83.7% since 2003. [3] There is also a growing trend of patients requiring TKAs at an earlier age, further adding to the workload of surgeons and hospitals. [3] Given the growing demand and expected increase in the patient population, there is a clear impetus to evaluate novel surgical approaches used in total knee arthroplasties.

Patient specific total knee arthroplasties (PSTKA) are one possible solution to this growing demand. They provide an anatomically individualised approach to surgery based on pre-operative computer tomography (CT) or magnetic resonance imaging (MRI). Following imaging, a patient specific cutting block is manufactured from a digital 3D reconstruction of the patient’s joint. The cutting blocks are then used to guide intra-operative bone resection, followed by installation of a pre-sized prosthesis. [4]

After initial assessment, the surgeon will decide upon the use of CT or MRI, based on personal preference. The scans are sent electronically to a manufacturing company of choice, where they are converted into a digital 3D reconstruction of the patient’s anatomy using computer-aided design. At this stage, the surgeon will review the digital reconstruction and finalise coronal and rotational alignment parameters. The review process allows the surgeon to make changes prior to manufacture, specific to the patient’s functional requirements. Following this process, the custom designed disposable cutting blocks are then authorised for fabrication. Intra-operatively, the cutting blocks are attached to the distal femur and proximal tibia to accurately guide bone resection prior to the insertion of a customised prosthesis. [4] The primary advantage of the fabricated cutting blocks is their ability to accurately guide the quantity of bone resection, maintaining the desired coronal and rotational alignment for optimal prosthesis placement. [4]

Companies such as Medacta in Sydney, NSW, currently offer this service. From the time of the initial scans, the patient specific cutting blocks can be reviewed, and manufactured ready for use in as little as three weeks. Review prior to manufacture is a fully online process, allowing the surgeon to log in via any computer and make the necessary changes before authorising the cutting blocks for production. The time taken by the surgeon to review the specifications can range from 5-15 minutes, depending on the complexity of patient anatomy and individual skills. [5]

By finalising operative procedures prior to surgery, there is less demand for intra-operative decision making by the surgeon, further streamlining the process. [6] The individualised planning allows finalisation of prosthesis size, position and alignment prior to the first incision being made. [4] While this process may require additional out-of-operating commitments by the surgeon, overall it may lead to a reduction in the total theatre time per patient.

 

 

 

 

 

 

 

 

 

Manufacturers of this technology propose a number of positive outcomes. Advantages include reduced operative time when compared to conventional techniques, [4] pre-operative sizing of prosthesis, reduced bone resection [6] and optimal alignment of the tibia and femur post-surgery. [7-9] This method also does not require violation of the intramedullary canal as used in some conventional TKA methods. [4] Additional costing benefits may also be found in a reduction in the number of instrument trays required for surgery, leading to reduced setup time and sterilisation cost. Conventional methods require an average of 7.3 intra-operative instrument trays, compared to 2.5 used in PSTKA (p <0.001). [14]

A sensitive indicator of the success of TKA is prosthesis survival, measured in years post surgery. This idea is supported in research by Berend et al. (2004), who demonstrated that a tibial varus deformity greater than three degrees was associated with implant failure at rates 17 times greater than seen in patients with tibial deviation of less than three degrees post surgery. [10] In the literature, alignment of the tibia on the femur within three degrees in the coronal plane remains a consistent indicator of surgical outcome. [10-12]

A study conducted by Ng et al. (2012) examined the post-operative alignment outcome in 569 PSTKA, compared to 155 TKAs performed using intra- and extra-medullar alignment techniques. Of the patients undergoing PSTKA, only 9% had alignment outside of three degrees post-operatively, when compared to 22% using conventional methods (p=0.02). [11] While there is evidence in the literature that alignment outcome in PSTKA are comparable to those achieved with computer assisted surgery (CAS), utilisation of CAS in America remains low due to the cost of the technology, with only 3% percent of TKA being performed using CAS alignment systems. [12]

Of particular interest to both surgeons and hospitals is the proposed reduction in surgical time offered by PSTKA. Research conducted by Hamilton et al. (2013) compared intra-operative time of 52 patients undergoing PSTKA, and those undergoing conventional methods. [14] That study demonstrated no reduction in surgical time offered by those receiving PSTKA. Of interest, the study noted the fact that the surgeon who performed all 52 of the cases had vast experience using conventional methods prior to the study. This included performing over 1,500 conventional TKAs compared to 20 PSKTA. [14] With this significant limitation in mind, there is clear impetus for further evaluation into the possible time efficacy of PSTKA when performed by surgeons equally skilled in both techniques.

In further research assessing the time efficacy of PSTKA, Nunley et al. (2012) reported a positive trend in reducing tourniquet time from 61.0 ± 15.0 minutes in the conventional group, compared to 56.2 ± 15.1 minutes in the PSTKA group (p=0.09).  Alternately, another recent study demonstrated a significant reduction in total operating theatre time from 137.2 ± 33.6 in the conventional group, compared to 125.1± 22.7 in the PSTKA group (p=0.028). [6] While some of these results are not statistically significant, they highlight the need for continued evaluation of PSTKA compared to alternative methods of TKA. Evaluation of the current research reveals an optimistic view of PSTKA in its ability to reduce intra-operative time. [15] With any new approach to surgery, practice is needed to hone the skills essential for efficiency.

Possible drawbacks highlighted in current literature include the additional workload of pre-operative imaging. Specifically, the cost of pre-operative CT or MRI remains a consideration. While the scans do not require interpretation by a radiologist, saving both time and money, the cost of a MRI ranges from A$500 to A$1000 depending on the institution. Additionally, in the use of CT imaging there is dosing of ionizing radiation, which must be considered. [4]

In addition to patient outcomes, the cost involved in adopting a new approach to surgery must always be considered. Currently, PSTKA is not cost-effective on a case-by-case basis, when compared to conventional TKA. PSKTA is, however, more cost effective when compared to computer-assisted TKA surgery. [13]  Interestingly, the authors noted a reduction of 28 minutes per case of operating room time in PSTKAs, and this was not factored into the costing analysis. At an institutional level, perhaps an increased case turnover in the operating room will prove cost effective when compared to alternative techniques. [13]

At this point in time, further research needs to be conducted into the durability and longevity of PSTKA. While this requires extended follow-up and evaluation of records, survival rates of implants may become particularly important in light of the growing trend toward a younger patient population. [3] Currently, TKAs are being performed at an earlier age due to increasing levels of obesity, active lifestyles and increasing life expectancy. [3] With this younger population group comes the need to provide patients with prostheses that will last, reducing the need for subsequent revision. Importantly, with aseptic loosening of prosthesis being shown as the most common cause of premature failure, perhaps a customised approach to initial surgery may demonstrate improved longevity at follow-up. [9]

As in any new area of research, there is a particular need for larger trials with extended follow-up. The purpose of this article is not to condone the widespread use of PSTKA, but rather to illustrate the importance of technology and the continued search for improvement. As doctors, it is essential to always question current methods of practice and seek to refine technique, finding improvements where possible. PSTKA makes use of some of the most advanced imaging and engineering techniques currently available, and provides an innovative approach to knee surgery. There is no doubt PSTKA offers an exciting alternative to conventional surgical methods, meshing surgical expertise with advanced engineering technologies. In the future, could the 3D printing of patient specific prostheses take this technology to the next level?

Acknowledgements

Associate Professor Nigel Hope (MBBS, PhD, FRACS, FAOrthA) for continued encouragement and sparking an interest in Orthopaedic research.

Medacta for providing images.

Conflict of interest

None declared.

Correspondence

D Kerr: davidkerr56@gmail.com

References

[1] Australian Institute of Health and Welfare 2010. Australia’s health 2010. Australia’s health series no. 12. P1-523. Canberra: AIHW.

[2] Australian Government. Australia to 2050: future challenges. Canberra: 2010 Feb p1-22.

[3] Ryan P, Miller S, Cashman K, Lui YL, Tyman S. Hip and Knee Arthroplasty Annual Report. Australian Orthopaedic Association Joint replacement registry 2012, p120-124.

[4] Nam D, Mc Arthur BA, Cross MB Mayman DJ, Haas SB. Patient-specific instrumentation in total knee arthroplasty: a review. J Knee Surg. 2012 Jul;25(3):213-9.

[5] Spencer BA, Mont MA, McGrath MS, Boyd B, Mitrick MF. Initial experience with custom-fit total knee replacement: intra-operative events and long-leg coronal alignment. Int Orthop. 2009 Dec;33(6):1571-5.

[6] Nunley RM, Ellison BS, Ruh EL, Williams BM, Foreman K, Ford AD, Barrack RL. Are patient-specific cutting blocks cost-effective for total knee arthroplasty? Clin Orthop Relat Res. 2012 Mar;470(3):889-94.

[7] D. White K. L. Chelule B. B. Seedhom .Accuracy of MRI vs CT imaging with particular reference to patient specific templates for total knee replacement surgery. Int J Med Robotics Comput Assist Surg 2008; 4: 224–231.

[8] Harrysson OL, Hosni YA, Nayfeh JF. Custom-designed orthopedic implants evaluated using finite element analysis of patient-specific computed tomography data: femoral-component case study. BMC Musculoskelet Disord. 2007 Sep 13;8:91.

[9] Boonen B, Schotanus MG, Kort NP. Preliminary experience with the patient-specific templating total knee arthroplasty. Acta Orthop. 2012 Aug;83(4):387-93.

[10] Berend ME, Ritter MA, Meding JB,Faris PM, Keating EM, Redelman R, Faris GW, Davis KE. Tibial component failure mechanisms in total knee arthroplasty. Clin Orthop Relat Res 2004;428(428):26-34.

[11] Ng VY, DeClaire JH, Berend KR, Gulick BC, Lombardi AV Jr. Improved accuracy of alignment with patient-specific positioning guides compared with manual instrumentation in TKA. Clin Orthop Relat Res. 2012 Jan;470(1):99-107.

[12] Canale ST, Beaty JH. Campbell’s operative orthopaedics. Vol One. Elventh ed. Philadelphia, PA: Elsevier Inc; 2008.

]13] Watters TS, Mather RC III, Browne JA, Berend KR, Lombardi AV Jr, Bolognesi MP. Analysis of procedure related cost and proposed benefits of using patient –specific approach in total knee arthroplasty. J Surg Orthop Adv 2011;20(2).

[14] Hamilton WG, Parks NL, Saxena A. Patient-Specific Instrumentation Does Not Shorten Surgical Time: A Prospective, Randomized Trial. J Arthroplasty. 2013 Aug;(13)00480-4.

[15] Mont MA, McElroy MJ, Johnson AJ, Pivec R; Single-Use Multicenter Trial Group Writing Group. Single-use instruments, cutting blocks, and trials increase efficiency in the operating room during total knee arthroplasty: a prospective comparison of navigated and non-navigated cases.J Arthroplasty. 2013 Aug;28(7):1135-40.

Categories
Feature Articles Articles

Chocolate, Cheese and Dr Chan: Interning at the World Health Organization Headquarters, Geneva

Introduction

In early 2013, Ban Ki-Moon, Margaret Chan and Kofi Annan had something in common: they may be completely unaware of it, but I saw them speaking in Geneva, and not merely because I lurked around Palais de Nations. Rather, wielding my very own blue United Nations (UN) ID card as an intern at the World Health Organization headquarters (WHO), I became a de facto insider to events on the international stage.

Between January and March, I undertook an 11 week internship with the WHO Emergency and Essential Surgical Care (EESC) Program in the Clinical Procedures Unit, Department Health Systems Policies and Workforce. The WHO is the directing and coordinating authority for health within the UN. It is responsible for providing leadership on global health issues, setting the research agenda, setting and articulating norms, standards and evidence-based policy options, providing technical support to countries, and monitoring and assessing health trends. [1] At some point during your studies, you will encounter material developed and disseminated by the WHO. You may have cited WHO policies in your assignments, looked up country statistics from the Global Health Observatory before your elective, or at least seen the ubiquitous Five Moments for Hand Hygiene posters, which emerged from WHO guidelines. [2] In other words, if you haven’t heard of the WHO or don’t recognize the logo, then I suggest taking a break from textbooks and click around the many fascinating corners of their website. Perhaps watch Contagion for a highly stylized (but filmed partially on location) view of an aspect of their work. [3]

The WHO and Surgery

The WHO established the EESC Program in 2005, in response to growing recognition of the unaddressed burden of mortality and morbidity caused by treatable surgical conditions. [4] This reflects the lack of prioritization of surgical care systems in national health plans and the ongoing public health misconception that surgical care is not cost-effective and impacts only upon a minority of the population. [5] These misconceptions apply as much to those in the field of public health, as well as to surgeons on the ground and in the literature, let alone those at other agencies. This was reflected by the question I all too commonly faced when explaining my internship: “The WHO is involved in surgery?”

In reality, surgical conditions contribute to an estimated 11% of the global burden of disease. It is a field that cuts across a number of public health priorities. [6] For example, progress on many of the Millennium Development Goals demands the prioritization of surgical care systems, most obviously in connection with maternal and newborn care. [7] Timely access to surgical interventions, including resuscitation, pain management and caesarean section, are vital to reducing maternal mortality. [8] Even in its most basic forms, surgical procedures can play a role in both preventative and curative therapies, from male circumcision in relation to HIV control to the aseptic suturing of wounds. However, surgery also has a very real impact on poverty by addressing the underlying causes of disability which often contribute to unemployment and debt.  These include the management of congenital and injury incurred disabilities and preventable blindness. [9] Surgery can be a complex intervention because it relies upon numerous elements of the health system to be functioning completely. There is little point in having access to basic infrastructural amenities like electricity, running water and oxygen, when at the moment of an emergency it is unavailable. Similarly, having equipment and supplies alone are insufficient when there is a shortage of a skilled workforce to wield them.

The WHO EESC is dedicated to supporting life-saving surgical care systems in the areas of greatest need, through collaborations between the WHO, Ministries of Health and other agencies. The WHO Global Initiative for Emergency and Essential Surgical Care (GIEESC) is an online network linking academics, policy makers, health care providers and advocates across 100 countries. Together, they developed the WHO Integrated Management for Emergency and Essential Surgical Care (IMEESC) toolkit to equip health and government workforces with WHO recommendations, skills and resources, focusing on emergency, trauma, obstetrics and anaesthesia, in order to improve the quality of, and access to, surgical services. [4]

In terms of my role, let me begin with the caveat that, as an intern, one can be called upon to conduct a wide variety of tasks within the huge scope of the WHO. My experiences differed greatly from those of colleagues and are not necessarily reflective of what one may encounter in other departments, or even in the same program at different times of year. I applied through the online internship application, but amongst my colleagues, this was in fact a rarity. [10] By far the majority of interns had applied directly or through their university to the specific areas of the WHO that aligned with their interests.

I undertook both administrative and research tasks, working very closely with my supervisor, Dr. Meena Cherian. There is a paucity of evidence capturing the surgical capacity, including infrastructure, equipment, health workforce and surgical procedures provided, across facilities in low- and middle-income countries. Through the GIEESC network, the WHO Situation Analysis Tool captures the capacity of first-referral health facilities to provide emergency and essential surgical care. [4] One of my key roles was in data collation and analysis. In terms of tangible outcomes, in the span of my internship I was able to contribute to two research papers for submission. In terms of my education, however, it was the administrative roles that demonstrated many of the key lessons about working in international organizations, and for which I am most grateful. Although menial tasks like photocopying and editing PowerPoint presentations can seem futile, carrying those documents into meetings allows one to witness the behind-the-scenes exchanges that drive many international organizations. This deepened my understanding of the WHO’s functions, strengths and limitations. In my experience, exacerbated by funding limitations and the rise of game-changing new players from the non-government sector, such as the Bill and Melinda Gates Foundation, attracting and justifying resource allocation to marginalized areas like surgery becomes a full-time job in itself. Opportunities for collaboration with such NGOs can result in successful innovation and programming, as with the polio eradication campaign. However, although inter-sector and inter-department collaboration is seemingly an obvious win-win, the undercurrents of turf wars and politicization of health issues can make such collaborations seem like a delicate diplomatic performance. Effective WHO engagement with external stakeholders cannot come at the cost of its intergovernmental nature or independence from those with vested interests. [1] Such are the limitations imposed on international organizations by the international community and the complex relationships between member states.

Ultimately, learning to collaborate with colleagues across cultural, economic, resource and contextual barriers under the tutelage of my supervisor has implications for any future endeavor in our increasingly globalized workplaces.  Learning to navigate such competing social and political interests is as applicable to clinical practice as it is to public health. Furthermore, the Experts for Interns program initiated by the WHO Intern Board provides bi-weekly lunchtime seminars specifically designed to broaden the scope of the intern experience by facilitating discussion with experts in various fields. [11] These were particularly valuable as an opportunity to ask direct questions, challenge preconceived notions and reexamine the historical development of public health, global health and the role and scope of the WHO.

Personal Highlights and Challenges

Geneva is an international city, home not only to WHO HQ and the United Nations in Europe, but also to a number of other UN Agencies and international non-governmental organisations, including Médecins Sans Frontières and the International Committee of the Red Cross. This means that, at any given time, there are a huge number of international and cultural events occurring. During my stay alone, there was the WHO Executive Board Meeting, the Geneva Human Rights Film Festival, a number of conferences, the UN Human Rights Council and some truly high profile speakers. Hans Rosling, the rock star of epidemiology and a founder of GapMinder, has put together a great TED Talk, but seeing him speak in person was one of my most lively, educative and stimulating experiences. [12,13] It is a memory I will treasure and return to for motivation, particularly when rote learning another fact for an  exam seems impossible. For many of us who aspire towards a career in global health, seeing these famous faces and learning firsthand about their work and career pathways is more than just inspiring, it can become a raison d’être.

From a slightly more cavalier perspective, Switzerland is centrally located in Europe, and Geneva as an international city is a great base from which to travel. It is easy to find sale flights to major European destinations, and the train to Paris takes only three hours. As an unpaid intern, your weekends are your own and most supervisors are generous about allowing travel grace. The opportunity to explore a new city every weekend is alluring, and with options like the demi-tariff, the half-priced fares on Swiss trains, it’s certainly a possibility. The Geneva and Lac Leman region features charming villages and cities with the sort of breathtaking mountain views that makes everything look like a postcard, not least if it’s covered in a blanket of pristine white snow. This is the other key attraction of Geneva in winter: if you’re into snow sports, you will be based within an easy day trip to some of the best pistes in the world. Indeed, the Swiss penchant for such trips seems to be why Sundays find Geneva a ghost town of sorts. Aside from the odd museum, absolutely nothing is open on Sundays, to the point where if you make my mistake of arriving on Sunday, it may be difficult to even find food.

Even if you can find food on a Sunday, affording it and anything else in Geneva is not easy. The cost of living is high, and, despite the high turnover of ex-pat staff, finding a place to stay is extremely difficult. As Australians we have it luckier than most, by being able to make use of OS-HELP loans while studying overseas. There is an ongoing discussion about paid internships within the UN, and there are varying practices amongst agencies. Some, notably the International Labor Organization, pay interns, while the WHO and others do not. This has become an advocacy issue amongst interns, as it severely limits access to the educative and career-oriented experiences internships provide for those from middle- and low-income nations. However, it seems unlikely that this will change in the near future. Nonetheless, with careful saving, planning and some basic austerity measures, finances should not deter you from this experience.

Another potential challenge is that Geneva is in francophone Switzerland; it is geographically surrounded on most sides by France. Many WHO staff and interns live, or at least shop, across the French border, where I discovered amazing supermarkets with entire aisles devoted to Swiss and French cheeses and chocolate. As a hopeless Francophile, this was a delicious highlight. I took classes and developed my French while safely working in a predominantly anglophone environment. If you have never studied French, then learning basics pre-arrival would be recommended, though it is possible to get around Geneva without, as the locals are very generous in this regard. However, there were often times when my linguistic limitations perpetuated anglophone dominance, forcing colleagues to transition into my language of choice. Such language barriers can also contribute to cultural misunderstandings.  For example, early on I committed the fauxpas of being too casual in the more hierarchical workplace, where professional titles were used even in personal conversations. Coming from the more egalitarian Australian context, this can come as something of a culture shock, though it varies considerably between different offices and departments.

As a result of my experiences, I am now both more cynical and more hopeful about the future of global health. The bureaucratic limitations of the WHO are also where its authority lies. Sifting through convoluted Executive Board meetings, it is easy to become skeptical about the relevance of this 65-year old organization. However, this belies the power of health mandates supported by member state consensus, whether in regards to the Tobacco Free Initiative or the Millennium Development Goals. Such change and reform, though slow, is broad reaching and invigorating.

Finally, the most significant and meaningful experiences I shared during my internship were not with the famous faces of global health, but with my peers. Across the various organizations based in Geneva, there are a huge number of interns from all over the world. Making connections with these kindred spirits, who shared my interests and a similar desire for an international career, was such a privilege. Even when our areas of interest did not intersect, it was amazing to learn from the expertise of fellow interns and students. For example, a fascinating experience was encountering a student at CERN (Conseil Européen pour la Recherche Nucléaire, better known to us non-physicists as the home of the Large Hadron Collider) with whom I was able to have a sticky beak at the labs and lifestyles of modern physics’ greatest thinkers. Just as he is progressing towards becoming a don of theoretical physics, at some point in the next few decades many of the friends I’ve made through this internship are going to become the next generation of global health leaders. More importantly, creating such networks across continents and across specializations has been instrumental in shaping my sense of self and perspective, and has left an indelible mark in the form of new education, career and lifestyle aspirations.

Where to from here for you

There is an online intern application through the WHO website. Although I completed this as my elective term, I also encountered a number of students from Australia for whom this was a summer opportunity to experience the organization, or as part of their research. I would strongly urge any student with interests in public health, global health, policy or research to consider applying for this opportunity, and to do so by contacting the departments of your interests directly.

In terms of surgery and global health, please visit the EESC program website at www.who.int/surgery for further information, and to become a GIEESC member.

Acknowledgements

The author wishes to acknowledge the generosity of the WHO Clinical Procedures Unit, particularly Dr. Meena Cherian of the WHO Emergency and Essential Surgical Care Program, who hosted her internship, and the financial support of the Australian government OS-HELP loan program.

Conflict of interest

None declared.

Correspondence

L Hashimoto-Govindasamy: laksmisg@gmail.com

References

[1] World Health Organization. About the WHO. [Internet]. 2013 [cited 2013 March 26]. Available from: http://www.who.int/about/en/

[2] World Health Organization. Clean care is safer care: five moments in hand hygiene. [Internet]. 2013 [cited 2013 March 26]. Available from: http://www.who.int/gpsc/tools/Five_moments/en/

[3] International Movie Database. Contagion. [Internet]. 2013 [cited 2013 March 26]. Available from: http://www.imdb.com/title/tt1598778/

[4] World Health Organization. Emergency and essential surgical care. [Internet]. 2013 [cited 2013 March 26]/ Available from: http://www.who.int/surgery/en/

[5] Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, Gawande AA. An estimation of the global volume of surgery: a modeling strategy based on available data. Lancet. 2008;372:139–44.

[6] Debas HT, Gosselin R, McCord C, Thind A. Surgery. In: Jamison D, editor. Disease Control Priorities in Developing Countries. 2nd ed. New York. Oxford University Press; 2006.

[7] United Nations. Millennium Development Goals. [Internet]. 2013 [cited 2013 March 26]. Available from: http://www.un.org/millenniumgoals/

[8] Kushner A, Cherian M, Noel L, Spiegel DA, Groth S, Etienne C. Addressing the Millennium Development Goals from a surgical perspective: essential surgery and anesthesia in 8 low- and middle-income countries. Arch Surg. 2010;145(2):154-160.

[9] PLOS Medicine Editors. A crucial role for surgery in reaching the UN Millennium Development Goals. PLOS Med. 2008;5(8):e182.doi:10.1371/journal.pmed.0050182

[10] World Health Organization. WHO employment: WHO internships. [Internet]. 2013 [cited 2013 March 26]. Available from: http://www.who.int/employment/internship/interns/en/index1.html

[11] WHO Interns. Experts for interns (E-4-I). [Internet]. 2013 [cited 2013 March 26]. Available from: http://whointerns.weebly.com/experts-for-interns.html

[12] TED: Ideas worth spreading. Hans Rosling: Stats that reshape your worldview. [Internet]. 2006 [cited 2013 March 26]. Available from: http://www.ted.com/talks/hans_rosling_shows_the_best_stats_you_ve_ever_seen.html

[13] Gapminder. Gapminder: for a fact-based worldview. [Internet]. 2013 [cited 2013 March 26]. Available from: http://www.gapminder.org/

Categories
Articles Review Articles

Factors that influence Australian medical graduates to become General Practitioners

Aim: To determine the factors that influence Australian medical graduates to become general practitioners. Method: A literature review was conducted. Medline, PubMed and Cochrane Library were searched using the terms; “Australia”, “medical”, “graduates”, “interns”, “students”, “choice”, “specialty”, “general”, “practice”, “factors” and “influencing”. Results: The factors were grouped into intrinsic (age, gender, personality and skill set,) and extrinsic influences (lifestyle, income, stress, location and role models), with extrinsic influences regarded as the most influential. Most importantly, 72% of the Australian medical graduates viewed work culture as important, while 56% prioritised flexibility of working arrangements and hours of work. Conclusion: There are a variety of both intrinsic and extrinsic factors influencing medical graduates to choose General Practice over others. This can be seen as an opportunity for Australian workforce planners and policy makers to target the extrinsic factors with the aim of balancing the medical workforce to combat the shortage of rural general practitioners.

Introduction

In the field of medicine, a specialty is simply a specific study of medical science. [1] Dermatology, Obstetrics and Gynaecology, Cardiology, Neurosurgery and General Practice are just a few of the vast array of medical specialties that medical graduates must decide between before embarking on a long, strenuous but nevertheless, highly rewarding journey. Students endure four to six years of medical school, only to begin a new journey as junior doctors. Internship is followed by residency, and the pathway after this depends upon the choice of specialty. [2] Medical students and junior doctors are faced with the tough challenge of selecting a specialty. This review seeks to precisely identify the factors influencing medical graduates to undertake General Practice.

This narrative review aims to explore the intricate complexities that invade the mind of medical graduates faced with the dilemma of choosing a specialty; in particular, what influences them to choose General Practice. The aims of this literature review are to highlight the spectrum of factors that play a role in medical students and interns choosing to undertake General Practice, and present medical colleges, recruitment agencies, workforce planners and national organisations with a platform upon which they can correct the imbalances in the medical workforce.

Methodology

This literature review covered recent literature that has focused on the factors influencing choice of medical specialisation (in particular General Practice) in Australia. Medical and social science databases were searched for publications from 1990-2013. Medline, PubMed and Cochrane Library were searched using these terms; “Australia”, “medical”, “graduates”, “interns”, “students”, “choice”, “specialty”, “general”, “practice”, “factors” and “influencing”. 7670 papers were identified through the database searches. These were then reviewed to only include studies conducted in Australia and concerning Australian medical graduates, which narrowed it down to 25 papers. 9 of these papers were excluded because they were not completely relevant to the topic. In addition, the bibliographies of articles were searched for further relevant publications. Studies referred to in this review vary widely and include both qualitative and quantitative studies.

Results

The primary influential factors involved in the selection of a particular specialisation can be separated into intrinsic and extrinsic factors.

Intrinsic Factors

Intrinsic factors include age, personality and gender. Individuals have little or no control over such factors. [8]

Age is an intrinsic factor that plays a role in the selection of a particular specialty. The majority of medical students in Australian universities are under the age of 24. [9] Despite this, there has been an increase in the number of ‘mature age’ students over the past two decades. One Australian study, that compared the career choices of medical graduates, found that older students were more likely to specialise in a primary care field such as General Practice. [3]

An individuals’ personal set of skills and the satisfaction they receive from using these skills are intrinsic factors which play a large role in influencing medical graduates to undertake General Practice. In 2005, Harris et al examined the factors influencing the choice of specialty of 4259 Australian medical graduates. [3] The study showed that 79% of graduates considered their own skills and aptitude to be of importance when selecting General Practice. Personal satisfaction was also linked to choosing General Practice as a specialty. Laurence and Elliot supported this in their 2007 study which concluded that personal satisfaction arises from procedural skills, activities involved and patient contact. [4] All of the 54 Pre-Registration Junior Medical Officers (PMJOs) interviewed in South Australia, agreed with this however, this was only a small sample size.

Gender has been shown by studies to be a vital influencing factor for Australian medical graduates when choosing General Practice as a speciality. Whilst the responsibilities of raising children have evolved over the past few decades, Prideaux et al found that Australian female medical graduates are more likely to become specialists in General Practice due to child bearing responsibilities and family commitments. [10] It has been noted the Australian literature that female doctors tend to work shorter hours and have a preference for working shorter hours due to family commitments. [11] Despite this, there has been a rise in male doctors choosing to work fewer hours due to family reasons. [10] This reflects the fact that both partners now commonly work.

Extrinsic Factors

Extrinsic factors include stress, work hours, family commitments, lifestyle and mentors. They are variables that may be controlled. [8]

Lifestyle plays the greatest role in influencing medical graduates to choose particular specialties over others. Laurence and Elliot found that 100% of the 54 South Australian PMJOs interviewed regarded lifestyle as a vital factor in choosing General Practice as a specialty. [4] This included hours worked, stress, career potential and potential for travel (55%). Most participants described their ideal job as having shorter working hours and less time on call. Most PMJOs also wanted a certain amount of control over hours and hence chose anaesthesia and GP practice. Wanting a life outside of medicine (85%) for example, spending more time with family and friends was also important. [4] Similarly, Harris et al also rated extrinsic factors as the most influential factors of choosing a medical specialty in Australia. [3] Seventy two percent of the Australian medical graduates viewed work culture as important, while 56% prioritised flexibility of working arrangements and hours of work. In contrast, Thomas concluded that only 28% of Australian medical graduates saw work life balance and lifestyle as important to selecting General Practice as their specialty. [7] However, this study had a small sample size and focused on only one speciality (General Practice).

Location is of importance when choosing a medical specialty. Stagg et al found that key influences on choosing a rural pathway specialty were mentors and undergraduate rural exposure. [6] In contrast, Ward et al, in a longitudinal study that followed 229 UWA medical graduates, showed that a rural background is the most important predicator of rural general practice. [5] Clearly, there factors that influence an individual to undergo a rural generalist pathway are multifactorial and more research is needed in this area.

The studies used in this literature review all stressed the importance of role models in influencing Australian medical graduates to choose particular specialties. Laurence and Elliot studied when, what and how SA pre-registration junior medical officers made their career choice. [4] Fifty four percent of the 54 graduates perceived the role of mentors, supervisors and consultants to be of importance in selecting General Practice as a specialty. Their interaction with ‘mentors’ was through observing and asking questions. Role models were seen to demonstrate specific characteristics admired by the students. [12]

Discussion

The results confirm that choosing General Practice as a specialty is a complex decision strongly influenced by personal qualities (intrinsic factors), individual experiences and opportunities (extrinsic factors), and domestic circumstances. Whilst parenting dynamics have changed over the last century, there is still a trend for females to choose General Practice over other specialties due to flexibility and option of part time employment, which may be helpful when choosing to start a family. [13]

The most important extrinsic factors include lifestyle, work experience since graduation, flexible hours, influence of mentors and hours of work. [3] In Australia, it was concluded that factors relating to lifestyle and job satisfaction were the most important influencing factor. [4] This is consistent with the belief that recent graduates regard lifestyle factors as more important than income. [14] The younger generation of graduates also prioritise potential for travel. These graduates are influenced by their experience of General Practice and confirm that work experience is helpful for developing knowledge within medical. [3]

The results also suggested that trainees in different specialties prioritised certain influencing factors over others. Surgical trainees viewed mentors and role models as more important than trainees in other specialties. Additionally, General Practice trainees were more likely to prioritise flexibility, whilst this factor was of less importance to trainees in Adult Medicine. [15] Compounding this notion is the fact that surgical and emergency trainees found it extremely important to do procedural work compared to trainees in other programs. [3]

Clearly, there is not one single factor that influences an individual to undertake a particular career path, rather a vast array of factors. A medical graduate’s choice of career is dependent upon a wide range of intrinsic and extrinsic factors. [3] Whilst there is not much chance of altering intrinsic factors, the nature of extrinsic factors allows for an interventionist approach.  [16]

The main goal of medical workforce agencies and groups is to ensure a balance of doctors across a vast array of specialties to provide equal, effective and holistic medical care to the community. For 80% of doctors, the decision about choice of specialty has to be made by the end of the third postgraduate year (PGY3). [3] As such, training programs, teaching facilities and recruitment agencies involved in medical workforce planning should aim to educate medical students and graduates up until PGY3 and allow them to make an informed decision. Given the importance of extrinsic factors, there should be a review of the work culture typical of specialties that are under-represented. [13] Training providers can therefore implement strategies that attempt to increase entry to less well-represented specialties. [4]

This literature review has a number of limitations. Firstly, this review was limited to articles concerning the Australian medical workforce. This review excluded international medical graduates, which may have given greater insight into the factors influencing the specialty choice of graduates. A comparison study could be done in the future, comparing the mindset of Australian medical graduates to overseas graduates. Secondly, whilst certain conclusions can be made concerning the factors which influence choice of General Practice as a specialisation, this review did not focus on the factors that influence doctors to change specialties or even the percentage of medical students that graduate without having made a decision about their future career. Research on the factors influencing General Practice specialty choice could be improved by including a larger number of schools and students, studying trends over several years, and using validated measures and outcomes.

Conclusion

The main factors which were identified as influencing medical graduates to choose General Practice included both intrinsic and extrinsic factors. Additionally, a career choice that is made when an individual is young may not represent how they will feel as they progress through life and their priorities will often change. While there remains a continuous need for valuable research in the area of factors affecting medical specialisation, it appears that we need to use this information to prevent imbalances and skews in medical workforce planning. There is a great opportunity for governments, health authorities and the medical profession to influence extrinsic determinants of choice of specialty. [13]

Acknowledgements

I was given the opportunity to conduct this research through the GPSN First Wave Scholarship and Tropical Medical Training (TMT). I am thankful to Dr. Aileen Traves who provided me with support, encouragement and feedback throughout the course of this review.

Conflict of interest

None declared.

Correspondence

K Singh: karan.singh@my.jcu.edu.au

References

[1] Ellsbury, K. E., & Stritter, F. T.. A study of medical students’ specialty-choice pathways: trying on possible selves. Acad Med. 1997; 72, 534-541.

[2] Zurn, P., Dal Poz, M. R., Stilwell, B., & Adams, O. Imbalance in the health workforce. Hum Resour Health. 2004; 2(1), 13.

[3] Harris, M. G., Gavel, P. H., & Young, J. R. Factors influencing the choice of specialty of Australian medical graduates. Med Educ. 2005; 183(6), 295.

[4] Laurence, C. and Elliott, T. When, what and how South Australian pre-registration junior medical officers’ career choices are made. Medical Educ. 2007; 41: 467–475. doi: 10.1111/j.1365-2929.2007.02728.x

[5] Ward, A. M., Kamien, M. and Lopez, D. G. Medical career choice and practice location: early factors predicting course completion, career choice and practice location. Medical Educ. 2004; 38: 239–248. doi: 10.1046/j.1365-2923.2004.01762.x

[6] Stagg, P., Greenhill, J., & Worley, P. A new model to understand the career choice and practice location decisions of medical graduates. Rural Remote Health. 2009; 9(4):1245.

[7] Thomas, T. Factors affecting career choice in psychiatry: a survey of RANZCP trainees. Australas Psychiatry. 2008; 16(3), 179-182.

[8] Belfer, B. Stress and the medical practitioner. Stress Medicine. 1989; 5(2), 109-113.

[9] Joyce C, McNeil J & Stoelwinder J, ‘More doctors, but not enough: Australian medical workforce supply 2001–2012’, Med J Australia 2006; 185(3):182

[10] Prideaux D, Saunders N, Schofield K, Wing, L, Gordon J, Hays R, Worley P, Martin A, Paget N, ‘Country report: Australia’, Med Educ. 2001;35:495-504.

[11] Firth-Cozens J. and Lema VC. ‘Specialty choice, stress  and  personality:  Their relationships over time’, Hosp Med. 1999; 60(10):751-55

[12] Dunbabin, J., & Levitt, L. (2003). Rural origin and rural medical exposure: their impact on the rural and remote medical workforce in Australia. Rural Remote Health, 3(1), 212.

[13] Australian Medical Workforce Advisory Committee. Career decision making by doctors in their postgraduate years — a literature review. Sydney: AMWAC, 2002. (AMWAC Report 2002.1.)

[14] Joyce, C. M., & McNeil, J. J. Fewer medical graduates are choosing general practice: a comparison of four cohorts, 1980-1995. Med J Australia. 2006;185(2):102.

[15] Mowbray, R. Research in choice of medical  speciality: A review of the literature 1977-87. Aust NZ J Med. 1989;19(4):389-399.

[16] Joyce, C. M., Stoelwinder, J. U., McNeil, J. J., & Piterman, L. Riding the wave: current and emerging trends in graduates from Australian university medical schools. Med J Australia. 2007;186(6): 309.

Categories
Review Articles Articles

Sugammadex – the solution to our relaxant problems?

Sugammadex is the first of a class of selective relaxant binding agents. It acts by binding with high affinity to steroidal non-depolarising neuromuscular blockade drugs terminating neuromuscular blockade (NMB) through 1:1 encapsulation. Reversal of NMB has traditionally been performed by acetylcholinesterase inhibitors however these drugs have their drawbacks and are therefore not ideal.  This review examines the indications and advantages of sugammadex as well as the potential risks and shortcomings associated with its use.  Sugammadex is a relatively new drug that has been shown to be efficacious with an improved side effect profile as compared to its alternatives however several factors associated with its use have yet to be determined. These shortcomings have relevance on a therapeutic level as well as on a health economics level.

Introduction

NMB has been an important development in anaesthetic practice improving operative scenarios through patient paralysis. Muscle relaxation facilitates endotracheal intubation, ensures patient immobility and improves conditions for laparoscopic abdominal surgery. [1] Broadly speaking, the two classes of agents used are the depolarising NMB agents, of which there is only one in use, and the non-depolarising NMB agents. One of the significant problems with the non-depolarising NMB agents is their propensity to cause post operative residual blockade. This side effect of the drug has both patient safety implications and economic implications. The perfect solution to post operative residual blockade is absolute reversal of a non-depolarising NMB agent. This is routinely performed by cholinesterase inhibitors. These drugs however are less than perfect, as will be discussed and come with their own side effects. [11] A relatively new drug that has appeared on the marked is sugammadex, a selective reversal agent that is considered far superior. Given the recent arrival of sugammadex to the market, its use is yet to be perfected and its risks are yet to be fully understood. Furthermore it is a very costly drug raising questions regarding cost effectiveness. This review article will look at the extent to which sugammadex is the solution to the problems associated with muscle relaxant in anaesthesia.

Method

The study was performed through review of existing literature on sugammadex and its use.  Searches were performed using Ovid MEDLINE and the Cochrane Database of Systematic Reviews using the following terms: sugammadex, rocuronium, pancuronium, neostigmine, vecuronium, neuromuscular block, neuromuscular blockade, post operative residual block, post operative residual curarisation, post operative residual paralysis and economic assessment. Titles and abstracts were read and assessed for relevance to the paper. Bibliographies of the identified articles were hand searched to find additional relevant studies. Searches were limited to: humans and the years 2000 to current.

Results

The Ovid MEDLINE search identified 1832 articles. Of these, 15 articles were identified as pertinent to this review. The Cochrane Database of Systematic Reviews identified one systematic review. A remaining six articles were identified from bibliographies. Therefore, a total of 21 articles were included in the final analysis.

Discussion

Neuromuscular Blockade

Neuromuscular blocking agents are used on certain patients undergoing anaesthesia in addition to an anaesthetic agent and an analgesic agent. The drugs have significant risks. They pose the hazard of post-operative residual blockade which will be discussed. They are also the most common cause of anaphylaxis during anaesthesia accounting for between 60% and 70% of cases. The most commonly offending agents are rocuronium and suxamethonium. [5]

Neuromuscular blocking agents aim to totally paralyse the surgical patient by creating a blockade at the neuromuscular junction. This is not a therapeutic intervention but is rather used to facilitate endotracheal intubation, to eliminate spontaneous ventilation and to provide abdominal muscle relaxation for laparoscopic surgery. [4]

There are two classes of neuromuscular blocking drugs; depolarising agents and non-depolarising agents. Depolarising agents work by binding to nicotinic receptors causing depolarisation. They are not metabolised by acetylcholinesterase unlike acetylcholine thus prolonged activation of the receptor is produced causing paralysis. The only clinically approved depolarising agent is suxamethonium, a very short acting non-reversible drug. [22]

The other class is the non-depolarising agents. These are competitive antagonists that bind to post-synaptic nicotinic receptors preventing access and depolarisation by acetylcholine. [22] There are numerous agents under this class, notably pancuronium, rocuronium, vecuronium and mivacurium. These drugs are categorised by their length of action; pancuronium is long acting, rocuronium and vecuronium are intermediate acting and mivacurium is short acting. They are used in different scenarios depending upon procedural requirements.

Rocuronium

Rocuronium is a commonly given non-depolarising neuromuscular blocking agent and is the primary target agent of sugammadex. It has a quick onset of action of 1-2 minutes and if given in high doses can mimic the rapid onset of suxamethonium. This is useful when considering rapid sequence induction for Caesarean section. If given in such high doses however its duration of action is lengthened behaving in a manner similar to pancuronium increasing the risk of postoperative residual blockade. It has a good side effect profile and has a 30 to 50% quicker recovery rate than pancuronium. [2,4] The problem with non-depolarising NMBDs is the risk of postoperative residual curarisation or residual NMB and the significant but small risk of anaphylaxis.

Post-operative residual neuromuscular blockade

Post-operative residual NMB presents a very real risk to surgical patients.  It is a potentially reversible condition and should be avoided where possible.  It has the potential to impair the integrity of an airway and can contribute to patient death. [6] Classic signs include airway obstruction, inadequate ventilation and hypoxia. Evidence suggests the incidence of adverse respiratory events is from 1.3 to 6.9% with one study suggesting the figure as high as 88% during the post anaesthetic care period. [7,8]  The reason for such great variability in figures is in part due to the different definitions and methods of detection.  In addition to patient risk, there is also evidence to suggest residual NMB has economic consequences contributing to operating theatre congestion and a bottleneck in patient flow. [9]

Postoperative residual blockade can be minimised through two strategies: 1) pharmacological reversal of NMBD effects and 2) optimisation of NMBD dosing through careful monitoring and titration of the relaxant. [11]

Neuromuscular Blockade Monitoring

Neuromuscular monitoring is routinely practiced, most commonly with train of four (TOF) ratios1. Classically a TOF of <0.7 was the criteria for residual NMB.  This, however, has been discredited by Murphy et al. (2009) with evidence suggesting a TOF <0.9 is required to ensure a recovery. [7] Despite increasing stringency of neuromuscular monitoring the methods are not sufficiently objective or accurate.  Naguib et al. [10] found in their meta-analysis the difference in residual NMB between TOF monitored and non-monitored patients with intermediate acting NMB agents was not statistically significant (P=0.314); however, incidence was increased with long acting NMB agents as compared with intermediate NMB agents. [10] Further methods of NMB monitoring include tidal volume, vital capacity, sustained tetanus, head lift and hand grips however all are considered inferior to TOF. [2]

Neuromuscular Blockade Reversal Agents

The other strategy for the prevention of residual paralysis is the use of pharmacological measures. Kovac et al. (2009) postulated that

“An ideal NMB reversal agent would; (1) have rapid onset; (2) be 100% effective and predictable; (3) reverse any degree of NMB; (4) be effective in the presence of potent anaesthetics; and (5) have minimal or no side effects.” [1]

Neostigmine

The common class of drug for NMB reversal agents are cholinesterase inhibitors, the most commonly used being neostigmine. [1,2] Cholinesterase inhibitors prevent the breakdown of acetylcholine in the neuromuscular junction, increasing neuromuscular transmission. [12] Neostigmine does not have a rapid onset, with the mean time to muscle recovery being 50.4 minutes. [16] The drug cannot reverse deep NMB with TOF<0.1. [13] The drug also has a ceiling dose and can only reverse drugs of certain potencies and of certain doses. [2] Duration of action is limited and consequently residual paralysis may still be evident or paralysis may reappear post administration. [3] The drug also has significant parasympathetic side effects due to excessive stimulation of muscarinic receptors. Side effects include bradycardia, arrhythmias, nausea, vomiting, increased GIT motility, bronchospasm and excessive secretions. To prevent these side effects, anticholinergic drugs are co-administered, notably glycopyrrolate or atropine, which have their own side effects, notably tachycardia, altered cardiac conduction, dysrhythmias and urinary retention. [1,12] In addition to the side effects, anticholinesterase drugs have further limitations including their lack of predictability and unreliability. [13]

As discussed, there are significant issues with residual NMB that are clinically underappreciated. The standard reversal agents that are routinely used are not without their drawbacks; their onset is slow, their side effect profile is significant and their efficacy is insufficient in particularly deep NMB. Furthermore, monitoring methods for residual blockade are inaccurate and technically difficult.

Sugammadex

Due to the limitations of the current class of NMB agents, sugammadex has become of interest. It is a modified cyclodextrin that has a high affinity with steroidal NMB agents (rocuronium>vecuronium>>pancuronium). [1,12] Cyclodextrins are oligosaccharides arranged in a circular shape surrounding a central cavity that can be used to bind molecules within the cavity, eliminating the target’s pharmacological action. In the case of sugammadex, cyclodextrins are modified to have a rocuronium inclusion complex. It will bind to all non-depolarising NMB agents, although with a decreased affinity. [23]

One of the major benefits of sugammadex is that unlike the anticholinesterase inhibitors, it does not interfere with the receptor systems but rather acts on the NMB agent itself, meaning there are little to no muscarinic side effects. The drug binds to the respective NMB agent rendering it unavailable at the neuromuscular junction. [12] A high dose can be given if required without a high risk of cardiovascular effects, as with neostigmine. Furthermore it does not need to be given with a muscarinic agonist, unlike anticholinesterase agents, eliminating the potential for further adverse events.

The drug is currently approved for use in Australia and the European Union; however, it is yet to be approved by the FDA in the United States. In August 2008, a not-approvable letter was issued not due to lack of efficacy but rather due to the risk of hypersensitivity and allergic reactions that had not been adequately determined. Further studies are currently being performed by Schering-Plough. [1]

The efficacy of sugammadex is well established by several significant studies. It has been shown to be a very effective NMBD reversal agent of non-depolarising NMB. Puhringer et al. (2010) reported an improvement in NMB reversal from rocuronium and vecuronium as compared with placebo, however these results represented trends and were not statistically significant. Mean rocuronium reversal times were 96.3 min with placebo and 1.5 min with sugammadex. Mean vecuronium reversal times were 79min and 3 min respectively. [20] One study by Lee et al. (2009) found that reversal of profound high dose rocuronium induced NMB with sugammadex reversal, and was substantially quicker than the use of the short acting suxamethonium. [18] Jones et al. (2008) found in a randomised comparison that sugammadex reverses profound rocuronium induced NMB significantly faster than that of neostigmine. [16] Alvarez-Gomez et al. (2007) made a similar finding in their study comparing the two drugs. [19] Sugammadex is also thought to halt relaxant induced anaphylaxis as it encircles the relaxant drugs theoretically preventing further immune reactions. However, this has not be sufficiently studied to confirm. [5] The drug has also been used successfully to reverse rocuronium induced NMB in a ‘can’t intubate can’t ventilate’ scenario. [21]

That being said there are adverse events as have been reported in 30 studies looking at 2000 patients. The most frequently reported side effects with an incidence greater than 2%, were hypotension, bronchospasm, QTc prolongation greater than 400msec, constipation, hyperactivity and altered taste sensation. Less common side effects included cough, dry mouth, temperature changes, parasthesia, parasomia, mild erythemia, abdominal discomfort, increased creatinine phosphokinase, bradycardia and dizziness. These adverse events did not appear to have a dose-response relationship. [1] While generally well tolerated, the adverse events one ought to be aware of are procedural pain, nausea and vomiting. [3]

Sugammadex can serve a purpose in rapid sequence induction. Traditionally, suxamethonium was used due to its quick speed of onset and short duration of action. However, this drug comes with a substantial list of side effects. [4] Instead, rocuronium can be given in high doses to quicken onset and can be quickly reversed at the close of the operation with sugammadex, although this is still considered second line.

The risks of residual NMB, as discussed previously, can be eliminated with the use of sugammadex. There are still some concerns for its regular use. Many studies have been conducted on the drug, looking at factors such as side effects and suitable dose ranges; however, more studies need to be conducted with larger cohorts to fully appreciate the risks. Patients with poorer health and who are more predisposed to adverse events have yet to be studied in great detail. [3]

While the cost of sugammadex is of no therapeutic relevance it needs to be taken into account from a health economics point of view. The cost is significant with a 200mg/2mL vial costing AUD188.90 and a 500mg/5mL vial costing AUD477.80 (cost sourced from FRED Dispense®, accessed 9th August 2013). It is not covered by the PBS and must be bought privately. Two systematic reviews have been performed in the UK on the cost benefit of sugammadex, both published in the British Journal of Anaesthesia. Both studies acknowledge that there could be cost benefit both from mortality and morbidity reduction point of views and with regards to optimisation of theatre time and post-anaesthetic care. However, the studies conclude that it would not be feasible to make an accurate economic assessment due to a lack of evidence. [14,15] It should be noted that these studies are UK relevant and apply differently to Australian practice. Zhang et al. (2008) found in their preliminary study of cost benefit that there is an appreciable decrease in postoperative time spent in an operating theatre improving cost efficiency; however, this failed to take into account the drug cost itself. Furthermore the study is applicable to the US health system and again may lack relevance to the Australian health system. [17]

The impetus for this paper came from an episode that occurred in theatre. A middle aged female due to receive a cholecystectomy was in an extremely anxious state before entering the operating theatre. She was convinced to go ahead with the procedure, which was uneventful. She was paralysed with rocuronium which was reversed with sugammadex. Upon reversal, the patient had a sudden severe reflexive episode going into a tonic-clonic contracture causing her jaw to occlude the endotracheal tube, in turn causing her oxygen saturation levels to fall. She had to be re-paralysed with suxamethonium to allow for manual respiration with bag and mask.

An episode as described above is not an uncommon event and can occur during the emergence from anaesthesia; however the episodes are rarely so severe. It is very possible the sugammadex can be partly blamed for the reflexive episode, with a sudden return of muscle tone increasing afferent input through the muscle and tendon stretch receptors causing the biting. Because the standard reversal agents are not as effective as sugammadex, similar reflexive episodes that have taken place will have not had the severity seen here. The drug is still very new and anaesthetists are perhaps yet to fully understand its use. With experience such events will become increasingly rare through improved use.

It has been shown convincingly that sugammadex is a superior NMB reversal agent to the cholinesterase inhibitors in terms of efficacy, although it has a significant side effect profile. Despite the considerable research that has been performed on the benefits and risks of the drug’s use, there are still many gaps in the literature which require further research.

There was no case report or evidence of similar cases to that in the clinical scenario discussed earlier. A case report of this incident may be of value. The patient’s response may have been due to incorrect dosing or indeed a rare reaction that is yet to be clinically identified.

Conclusion

This paper examined the use of sugammadex and its role in anaesthetic, focussing both on the risks and benefits of use. Having studied the available literature, there is a clear therapeutic benefit in the reduction of postoperative residual NMB, a preventable event that poses significant risk to patients. It presents a superior alternative to the current first line anticholinesterase NMB reversal agents. The benefit of the drug from a health economics point of view is yet to be determined, having regard to its high cost. Furthermore, the potential adverse effects and hypersensitivity reactions have not been adequately studied. The true side effect profile may require a very long period of testing or long term routine use before there is a good understanding. Sugammadex does have a role in very specific anaesthetic scenarios, however, given its significant cost and gaps in the literature, it cannot be recommended suitable for routine use.

Conflict of interest

None declared.

Correspondence

H Badgery: hebad2@student.monash.edu

References

[1] Kovac AL. Sugammadex: the first selective binding reversal agent for neuromuscular block. Journ Clin Anes.; 2009;21(6):444 – 453.

[2] Miller RD, Pardo M 2011 Basics of Anaesthesia. Sixth edition, pp 224-226

[3] Yang LPH, Keam SJ. Sugammadex: A review of its use in Anaesthetic Practice. Drugs; 2009;69(7):919 – 942.

[4] Rang HP, Dale MM, Ritter JM, Moore PK. 2003 Pharmacology, Fifth Edition. pp 149-154.

[5] McDonnell NJ, Pavy TGP, Green LK, Platt PR. Sugammadex in the management of rocuronium-induced anaphylaxis. Brit Journ Anaes; 2011;106(2):119-201.

[6] Eikermann M, Peters J, Herbstreit F. Impaired upper airway integrity by residual neuromuscular blockade: increased airway collapsibility and blunted genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiol; 2009;110(6):1253-1260.

[7] Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg; 2009;107(1):130-7.

[8] Mathias LAST, de Bernadis RCG. Postoperative Residual Paralysis. Rev Bras Anesthesiol; 2012;62(3):439-450.

[9] Butterly A, Bittner EA, George E, Sandberg WS, Eikermann M, Schmidt U. Postoperative Residual Curarization from intermediate-acting neuromuscular blocking agent delays recovery room discharge. Brit Journ Anaes; 2010;105(3):304-309.

[10] Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and postoperative residual curarisation: a meta-analysis. Brit Journ Anaes; 2007;98(3):302-316.

[11] Maybauer DM, Geldner G, Blobner M, Pühringber, Hofmockel R, Rex C, Wulf HF, Eberhart L, Arndt C, Eikermann M. Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaes; 2007;62(1):12-17.

[12] Abrishami A, Ho J, [12] Abrishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. Cochrane Database Syst Rev [Internet] 2009 [cited 15 Sept 2012]. Available from http://onlinelibrary.wiley.com.ezproxy.lib.monash.edu.au/doi/10.1002/14651858.CD007362.pub2/pdf

[13] Magorian T, Lynam DP, Caldwell JE, Miller RD: Can early administration of neostigmine in single or repeated doses alter the course of neuromuscular recovery from a vecuronium-induced neuromuscular blockade? Anesthesiol; 1990; 73(3):410-414.

[14] Chambers D, Paulden M, Paton F, Heirs M, Duffy S, Hunter JM, Sculpher M, Woolacott N. Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment. Brit Journ Anaes; 2010;105(5):568-575.

[15] Paton F, Paulden M, Chambers D, Heirs M, Duffy S, Hunter JM, Sculpher M, Woolacott N. Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular bloc: a systematic review and economic evaluation. Brit Journ Anaes; 2010;105(5):558-567.

[16] Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with Sugammadex. A randomized comparison with neostigmine. Anesthesiol; 2008;109(5):816-824.

[17] Zhang B, Menzin J, Tran MH, Neumann PJ, Friedman M, Sussman M, Hepner D. The potential savings in operating room time associated with the use of sugammadex to reverse selected neuromuscular blocking agents: findings from a hospital efficiency model. Val Health; 2008;11(3):244.

[18] Lee C, Jahr JS, Candiotti KA, Warriner B, Zornow MH, Naguib M. Reversal of Profound Neuromuscular Block by Sugammadex Administered Three Minutes After Rocuronium: A Comparison with Spontaneous Recovery from Succinylcholine. Anesthesiol; 2009;110(5):1020-1050.

[19] Alvarez-Gomez JA, Wattiwill M, Vanacker B, Lora-Tamayo JI, Khunl-Brady KS. Reversal of vecuronium-induced shallow neuromuscular blockade is significantly faster with Sugammadex compared with neostigmine. Euro Journ Anaes; 2007;24(suppl.39):124-125.

[20] Puhringer FK, Gordon M, Demeyer I, Sparr HJ, Ingimarsson J, Klarin B, van Duijnhoven W, Heeringa M. Sugammadex rapidly reverses moderate rocuronium- or vecuronium- induced neuromuscular block during sevoflurane anaesthesia a dose-response relationship. Brit Jour Anaes; 2010;105(5):610-619.

[21] Curtis R, Lomax S, Patel B. Use of Sugammadex in a ‘can’t intubate, can’t ventilate’ situation. Brit Journ Anaes; 2012;108(4):612-614.

[22] Appiah-Ankam J, Hunter JM. Pharmacology of neuromuscular blocking drugs Contin Educ Anaesth Crit Care Pain; 2004;4(1):2-7.

[23] Baldo BA, McDonnell NJ, Pham NH. Drug-specific cyclodextrins with emphasis on sugammadex, the neuromuscular blocker rocuronium and perioperative anaphylaxis: implications for drug allergy. Clin Exp Allergy; 2011;41(12):1663-1678.

 

Categories
Review Articles Articles

Examining the pathological nature of Hepatitis C and current drug therapies used in an Australian general practice context

Aim: This review aims to examine the pathological nature of Hepatitis C and review current drug therapies relevant to Australian health practitioners. Methods: Terms hepatitis C, Australia, pathogenesis and current treatment were searched using MEDLINE and CHINAL databases to identify research articles and systematic reviews. Constraints were used when researching drug developments to include only full-length papers, on humans published between 2009 and 2013.  Literature was analysed to identify shared themes. Sixty-eight articles were analysed and fifty-two chosen based on relevance to objective, reputable data sources and current information. Two websites and five books were included upon cross referencing data to journal articles. Four Australian guideline publications were included due to relevance to topic and general practitioners. Results: The aetiology, clinical significance and molecular pathogenesis of hepatitis C virus were examined to provide Australian practitioners with a basis of knowledge for presentation of both acute and chronic stages of hepatitis C infection. This understanding was further linked to current drug treatments available in Australia and potential future therapeutic options. Conclusion: The consequences of Hepatitis C infections will burden the Australian healthcare system in the next few decades as the chronic nature of HCV infection leads to complications of liver failure, cirrhosis and hepatocellular carcinoma in many patients. Practitioners must equip themselves with knowledge of HCV pathogenesis which forms the basis of current and future treatments in order to provide best quality care at all levels of prevention and management.

Introduction

The recognition of viral hepatitis can be dated as far back as the fifth century BC to Babylonian records. [1] Our understanding of Hepatitis C gained remarkable ground when previously non-A non-B hepatitis infections were attributed to the hepatitis C virus discovered by Choo et al. in 1989. [1,2] Since then efforts have been made to develop drug treatments to combat the virus which progresses to chronic infection in up to 80% of patients, increasing their risk of cirrhosis, liver failure and hepatocellular carcinoma. [3,4,5] Chronic hepatitis C infection is currently the leading cause of liver transplantation in Australia. [6,7,8]

Hepatitis C is a major health concern for Australian practitioners with 260 000 Australians infected in 2010 and an estimated 12 000 new infections occurring annually. [4,7] The dominant mode of transmission of the hepatitis C virus (HCV) is parenteral exposure to infected blood and thus the epidemic of HCV infection in Australia continues to escalate predominantly through people who inject drugs (PWID). [7]

This review aims to summarise the aetiology, transmission and life cycle of HCV as well as examine the most recent literature regarding current and future drug therapies to provide the Australian general practitioner with a contemporary understanding in emerging hepatitis treatments.

Aetiology of Hepatitis C

Transmission in the Australian context

Hepatitis C is a blood-borne viral infection and is most commonly spread in Australia via shared injecting equipment (up to 80% acquiring the infection via this route). [7] Other means of transmission include unsterile tattooing, needle-stick injuries and vertical transmission from mother-to-infants from trauma during pregnancy and/or birth. [9,10] About 5% of all cases in Australia arise from HCV contaminated blood transfusions and blood products prior to screening introduced in February 1990. [7]

Virological Structure

Hepatitis C is caused by a small, positive-stranded RNA virus of the Flaviviridae family. The RNA strand is enveloped by a protein capsid which is further surrounded by a lipid bilayer envelope studded with E1 and E2 heterodimer proteins. The genome contains a 5’ noncoding region required for viral translation, followed by an open reading frame terminated by a 3’ noncoding region necessary for replication. The open reading frame translates into a 3000 amino acid polyprotein which is cleaved into structural (core, E1, E2) and non-structural (p7, NS3, NS4A, NS4B, NS5A, and NS5B) proteins. [11-15]

The NS5B protein is a RNA-dependent RNA-polymerase which lacks proofreading function. This combined with a high replication rate (1012 virions/day) results in rapid mutations driving genetic diversity. [16] Thus within a host, HCV circulates as a population of extremely closely related, but not identical variants called quasispecies. [17] This feature has contributed to difficulty in developing a vaccine as well as implications for pharmacological therapies. HCV is classified into seven major genotypes which differ genetically by at least 30% with over 100 subtypes. [11,13] The prevalence of genotypes differ with geographical distribution. Genotype 1 mostly dominates Australia, the Americas, Japan and Europe with genotypes 2 and 3 also prevalent in these areas. Genotype 7 was only recently discovered in a small proportion of people in Central Africa. Disease association is largely similar across genotypes, however genotype 3 has been correlated with a higher risk of hepatic steatosis and progressive liver disease. [13,18]

Life Cycle

The main stages of the HCV replication cycle are binding and entry, uncoating, translation and replication of RNA, assembly into new particles, maturation and secretion. [11,19] Several host factors have been identified aiding entry of HCV including heparan sulphate and low-density lipoprotein receptor. Other host factors CD81, scavenger receptor B1 and tight junction proteins claudin-1 and occludin allow for clathrin-dependent endocytosis which delivers the virus to early endosomes, which become acidified causing fusion of the viral envelope, uncoating and release of the viral RNA into the cytoplasm. [12,19] HCV replication induces a membranous web concentrating lipid-rich structures that aid the replication process. Hepatocyte -specific microRNA-122 has been shown to bind to target sites on the 5’ untranslated region of the HCV genome which forms a complex that protects the HCV genome from nucleolytic degeneration and innate host immune responses. [20] Lipid droplets interact with the core and NS5A viral proteins allowing viral assembly. The newly synthesised viral proteins can then exit the cell in a manner similar to the hosts’ very low-density lipoprotein (VLDL) export pathway by utilising cofactor ApoB and microsomal triglyceride transfer protein to form low-density viral particles termed lipo-viral particles. [11,12,18] ApoE is involved in HCV particle morphogenesis and infectivity. HCV particles exist in the serum as a mixture of complete low-density infectious lipo-viral particles and an excess of apoB-associated empty non-infectious particles complexed with anti-HCV envelope antibodies. [18]

The mechanism responsible for onset and progression of chronic hepatitis are not fully understood but it is currently believed that HCV establishes persistent infection by impairing host innate and adaptive immunity. [1,21] The infected hepatocytes recognise Pathogen Associated Molecular Patterns (PAMPs) through receptors known as Pattern Recognition Receptors (PRRs) which include Toll like receptors (TLRs) and RIG-1 like receptors (RLRs). Upon sensing HCV via TLR3 and RIG-1, intracellular signalling cascades result in the induction of type I and type III interferon and pro-inflammatory cytokines which establish an antiviral state in infected and neighbouring cells. [21,22] Resident antigen presenting cells, such as dendritic cells residing in the liver migrate from infected tissue to lymph nodes where they prime T and B cell activation to induce adaptive immunity. [11]

Recent studies have established multiple routes whereby HCV impairs immune functioning so as to coexist and replicate in the host. [23] NS3/4A protease cleaves intracellular pathway protein TRIF and CARDIF to impair TLR3 and RIG-1 receptors. [11] Furthermore, the HCV enveloped particle is not detected by TLR-2 and TLR-4 which also contribute to antiviral states. HCV has been shown to up regulate MHC Class I molecules on infected hepatocytes which suppresses Natural Killer cell activity. [23] Finally generation of quasispecies carry mutations to evade B and T-cell recognition as well induce hypermutation in B cell receptors to lower affinity allowing the virus to escape immune surveillance. [11]

Clinical Implications

The World Health Organisation estimates 170 million people are infected with Hepatitis C globally. [1,24] Hepatitis C is thus  the leading cause of chronic liver disease worldwide and is a growing burden on healthcare systems,  including within Australia. [3,25] Infection is characterised by a wide range of clinical manifestations and propensity to develop into chronicity. Up to 80% of infected patients will develop a chronic infection. [1,3] Persistent infection and chronic hepatitis are the hallmarks of HCV infection with severity varying widely from asymptomatic chronic infection with normal liver function tests to severe cases leading to cirrhosis and hepatocellular carcinoma. [2,14]

Acute Hepatitis

Acute HCV infection is often asymptomatic due to a mild immune response and reversible cellular injury seen at the microscopic level. [9] Where symptoms occur they tend to be minimal involving jaundice and flu-like malaise. [5] Strong immune responses during the acute infection are associated with clearance of the virus however in the majority of cases milder initial infections lead to chronic viral persistence. [5,26]

Chronic Hepatitis

Cirrhosis develops in as many as 20% of chronic HCV patients and is associated with hepatocellular failure. Patients may present with portal hypertension manifested as splenomegaly, variceal bleeding or ascites. [9,26] Primary hepatocellular carcinoma is thought to result from the continual division of infected hepatocytes attempting to regenerate in the presence of injury. [5] Once cirrhosis has established, patients have a 5% annual risk of developing hepatocellular carcinoma. [27] Extra-hepatic diseases such as mixed cryoglobulinemia and glomerulonephritis are also believed to be caused by HCV induced antibody complex depositions in small vessels causing vasculitis, however the pathogenesis of this is not fully understood providing an area for investigation in the future. [28,29]

Current drug therapies

Current standard of care treatment of HCV genotype 1 is triple therapy with pegylated interferon-α (cytokine), ribavirin (antiviral) and a direct acting antiviral (NS3/4A protease inhibitor) – either telaprevir or boceprevir. [2,8,30] The combination of pegylated interferon (PEG-IFN) and ribavirin remain the recommended treatment for HCV infection with genotypes 2, 3, 4, 5 and 6. [19] The aim of treatment is a sustained virological response (SVR), defined as the absence of detectable HCV RNA for 6 months after treatment cessation. [31] SVR is associated with crucial end points, particularly survival and protection from the complications of chronic hepatitis C such as cirrhosis and hepatocellular carcinoma. [19,30]

For reasons that remain elusive, interferon-based therapies result in a SVR of 80% in genotype 2 and 3 infections but only 45% in genotype 1 and 4 infections. [4,13] With the approval of boceprevir and telaprevir in 2011 by the US Food and Drug Administration, triple therapy has enabled the SVR to increase in patients with genotype 1 from 45% in 2010 to ~66% in 2011 and is expected to be >75% by 2014. [4,26]

The SVR is also influenced by a myriad of host factors such as ethnicity, gender, age and insulin resistance. [13,32] Furthermore, new biomarkers such as serum IP10 levels and genetic tests to determine polymorphisms in the gene encoding IFNL3 (formerly known as IL28B or IFN-λ3) and recently discovered IFNL4 show strong value with respect to interferon-based therapy as predictors of treatment outcome. [1,13,30]

In Australia, hepatitis C treatment is available for all eligible patients over 18 years of age who have chronic HCV infection with compensated liver disease and are using effective forms of contraception. Treatment is subsidised by the government under the Highly Specialised Drugs (HSD) program, section 100 (S100) of the National Health Act 1953 (Cwlth). [8]

Pegylated Interferon-α

Interferons are naturally produced by immunological cells in response to tumour or infectious organism. They are glycoproteins with antiviral, anti-proliferative and immunomodulatory functions. [31]

Upon administration of IFN- α, the type I interferon binds to IFNAR-1 and IFNAR-2 receptors on cell surfaces initiating a complex intracellular signalling pathway resulting in activation of genes coding for proteins which inhibit intracellular viral replication. Proteins include RNA-dependant protein kinase (PKR) which inhibits RNA translation and oligoadenylate synthetase (OAS) which mediates RNA degradation. IFN- α also stimulates TH1 cell production while reducing suppressor TH2 cells as part of its immunomodulation. [31,33]

Pathogenesis of HCV occurs as a result of the virus’ ability to prevent host cells from responding to natural levels of interferon. As previously discussed, HCV blocks TLR3 and RIG-1 receptors reducing type I IFN production. [5,11] Thus overwhelming host cells with high levels of injected IFN allow normal cellular mechanisms to control the virus. [5,13] Replacement of standard interferon with pegylated interferon (interferon-α conjugated to polyethylene glycol) improves pharmacokinetics and efficacy and has allowed its administration as a once weekly subcutaneous injection. [30]

Ribavirin

Unlike pegylated interferon-α, whose function was unravelled due to developments in cell culture models, the mechanism of action of ribavirin against HCV is unknown. [33] Ribavirin was originally synthesised as a guanosine analogue that could inhibit viral polymerases by chain termination. The process by which this is thought to occur is when the polymerase incorporates the nucleotide but cannot add more after inserting the analogue, hence preventing viral replication and transcription. [5]

However there is much debate about the mechanism of ribavirin activity in chronic hepatitis C.  Despite showing in vitro activity against some RNA and DNA molecules, studies conducted with ribavirin as a monotherapy against HCV reflect no effect on HCV RNA levels or improvement of hepatic histology following 12 months of therapy. [33] Yet analysis of the current literature shows multiple studies where combination therapy of IFN- α and ribavirin is significantly more effective then IFN- α alone. [34-36] Furthermore, the anti-HCV activity of ribavirin occurs at much lower doses then expected for the chain termination theory to occur. [5] This suggests other mechanisms of action are at work.

Greenblatt presents two possibilities. [5] One involves ribavirin as depleting the cell’s reservoir of normal guanosine to interfere with viral RNA synthesis. Secondly she proposes a mutagenic theory in which ribavirin incorporation into viral genomes renders them funtionless. [5] Other theories propose that ribavirin induces IFN-stimulated genes or may have immunomodulatory functions which like IFN- α, push patient cytokine profiles towards TH1 types which are more effective against viral infections then type 2 Helper T cells. [13,31]

Telaprevir and Boceprevir

Telaprevir and boceprevir are first generation peptidomimetic, reversible inhibitors of NS3/4A protease. [30] The HCV NS3/4A serine protease is essential for viral replication by cleaving polyproteins into mature non-structural proteins. [13] Thus by inhibiting this protease, telaprevir and boceprevir are the first direct-acting antivirals (DAAs) approved for use against HCV genotype 1.

Despite both drugs having similar mechanisms of action and thus sharing most clinically relevant strengths and weaknesses, there are discrepancies between telaprevir-based regimens and boceprevir-based regimens. [1,30] These differences are in the timing and duration of combined therapy. Typically, telaprevir is given in triple therapy with PEG-IFN and ribavirin for the first 12 weeks of therapy, PEG-IFN and ribavirin are then continued for the remainder of treatment (either 24 or 48 weeks) without the protease inhibitor. Duration of treatment is dependent on virological response (response-guided therapy). Boceprevir, however is started 4 weeks after commencement with PEG-IFN and ribavirin and is continued for the remaining treatment duration of 28 or 48 weeks depending on response. [19] Telaprevir-based regimen is stopped in patients with a HCV RNA level greater than 1000 IU/ml at week 4 or 12 and all three drugs should be discontinued. For the boceprevir-based regimen, patients with HCV RNA levels greater than 100 IU/ml at week 12 should discontinue treatment. For both treatments, if HCV RNA is detectable at 24 weeks of therapy, all three drugs should be stopped. [19]

Side effects profile – pegylated interferon-α and ribavirin

These can be quite distressing and contribute to low tolerance and compliance in patients. The major effects of interferon include depression, constant flu-like symptoms, thrombocytopenia, leucopenia, thyroid dysfunction, retinopathy and alopecia. [25,37] Ribavirin is highly teratogenic and can lead to haemolytic anaemia and autoimmune disorders. [37]

Psychiatric status as well as full blood count, kidney and liver function tests should be monitored continuously throughout therapy. Furthermore, precautions should be taken with patients with depressive histories, thyroid dysfunctions, diabetes, autoimmune disorders and renal impairment. [38] Finally pregnancy in female patients or the partners of male patients must be avoided during treatment, and owing to the long half life of ribavirin, also 6 months after cessation of treatment. [39]

Side effects profile – telaprevir and boceprevir

Although triple therapy is more efficacious in HCV genotype 1 infections, there are additional side effects compared to traditional dual therapy and thus management of hepatitis C patients has become more complex. Common side effects of telaprevir include rash and anorectal discomfort while dysgeusia (altered taste sensation) and neutropaenia are associated with boceprevir. The most challenging side effect of both drugs is marked anaemia (haemoglobin level < 10 g per decilitre) occurring in 36-50% of patients. [19,30] Erythrocyte-stimulating agents have some success in managing this complication however are not approved for routine use in chronic hepatitis C patients due to serious side effects and cost. Some studies have shown that reduction in the dose of ribavirin can effectively manage anaemia in this setting and this is the current recommended first line approach. [19]

Due to the highly variable nature of HCV with the error-prone RNA polymerase, drug resistance is also an issue with these protease inhibitors and can develop as early as day 4 upon use in monotherapy. Consequently, these drugs are not to be used in isolation. Because of the similar mechanism of action, resistance to one protease inhibitor can result in other drugs within the same class to be ineffective.  Once the drug is stopped, the frequency of resistance-associated variants within the quasispecies slowly decreases until they disappear, most likely because they do not replicate as effectively as the wild-type virus. [19,30] General practitioners can play a crucial role in patient education to ensure adherence to the prescribed regimen in order to limit the development of resistance-associated variants.

The third major consideration with these new drugs is the issue of drug-drug interactions. Both telaprevir and boceprevir are inhibitors of the cytochrome P450 3A (CYP3A). CYP3A enzymes are involved in the metabolism of numerous drugs such as statins, antidepressants, antiarrhythmics, anticonvulsants, analgesics and sedatives. [19] As such, these are all contraindicated in patients undergoing treatment with telaprevir and boceprevir. This has important implications for general practitioners who are frontline prescribers of such agents. Efforts are being made to make such complex information widely available to the medical community through platforms such as the ‘Hepatitis Drug Interactions’ website from the University of Liverpool, UK. [30,40]

The future of hepatitis C

With the exponential increase in knowledge of life cycle and replication of HCV due to breakthroughs in cell culture systems in 2005, there is fierce competition to develop medicines that will replace PEG-IFN, ribavirin and first generation protease inhibitors. [30] About two-thirds of agents in Phase II and III trials are directed against the NS3/4A and NS5B viral proteins called second generation protease inhibitors and polymerase inhibitors respectively. [19,30] The current challenges in drug development are decreasing side effects and drug interactions, exploring combinations for genotypes 2-6, exploring individualised drugs to specific genetic polymorphisms, and eradicating the need for interferon and ribavirin in treatment.

A number of drugs are currently being developed for genotypes 2-6. A preliminary phase 2a study in New Zealand involved combining sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, and ribavirin in various interferon and interferon-sparing regimens for 12 weeks. [41] Patients with HCV genotype 1, 2 and 3 were investigated. In this early trial sofosbuvir showed a promising result with 100% rate of SVR among patients with genotype 2 or 3 infection. [19,26,41] However phase 3 studies of sofosbuvir fall short of the results produced by the phase 2a study. [42,43,44] One noninferiority trial looked at sofosbuvir plus ribavirin compared to standard peginterferon alfa-2a plus ribavirin in 499 patients with HCV genotype 2 or 3 infection. The results revealed the same SVR rate of 67% in both the sofosbuvir-ribavirin and peginterferon-ribavirin group at 12 weeks after cessation of therapy. [43] Two further phase 3 trials (POSITRON and FUSION studies) investigated sofosbuvir-ribavirin therapy in patients for whom peginterferon treatment was not an option (due to pre-existing psychiatric or autoimmune disorders) and in those who did not have a response to previous interferon treatment. The POSITRON trial was a randomized, blinded, placebo-controlled study that compared 12 weeks of sofosbuvir-ribavirin treatment with matching placebo in patients who had previously discontinued interferon therapy due to adverse events or concurrent medical condition. In this group, 78% had a SVR at 12 weeks after treatment compared to 0% in the placebo group. [42] The FUSION study looked at patients who had failed a sustained response to interferon-based therapy and compared 12 and 16 week regimens of sofosbuvir-ribavirin therapy. Results showed that four additional weeks of therapy made a difference with an increase in the SVR from 86% to 94% in patients with genotype 2 infection and from 30% to 63% in genotype 3 infections. [42,44] All three phase 3 studies with sofosbuvir-ribavirin showed better SVR rates in genotype 2 infections compared to genotype 3 infections. [42,43,44]

Nonstructural 5A (NS5A) protein is also a target of recent drug development. [45] The functions of the NS5A protein are not yet fully understood with in vitro studies suggesting is has a role in viral replication and assembly and release of infectious particles. [45] Daclatasvir is a potent NS5A inhibitor which has shown early promising results for use in interferon-free combinations with rapid decline of extracellular HCV titres upon administration. [45] In a phase 2a trial, patients who had not had a response to previous therapy received daclatasvir and a protease inhibitor (asunaprevir) for 24 weeks. [46] Four out of eleven patients had a SVR at 12 and 24 weeks after treatment ended, suggesting a cure may be possible with an all-oral interferon-ribavirin free treatment. [45,46]

Another group of host targeting antiviral agents are arising. Miravirsen is a drug undergoing development which targets miR-122. Liver specific miR-122, as discussed previously is a microRNA which all strains of HCV use to survive and replicate in liver cells. [11,12] A recent phase 2a study by Janssen et al, dose-dependent reductions in HCV RNA levels were found without viral resistance. [20] The study was limited by a small sample of 36 patients and only moderate levels HCV RNA reduction which rebounded once miravirsen was stopped in patients who had not begun interferon and ribavirin. [20,47] Normally miR-122 is involved in controlling cholesterol levels independent of its effect on HCV. In the study, there was a sustained decrease of serum cholesterol levels by ~25% which lasted 14 weeks after the final injection. [47] Given statins are contraindicated in the current triple therapy treatment of HCV genotype 1 infections, there is potential in the future to develop liver-targeting nucleic acid drugs which can be used intermittently for both HCV treatment and other co-morbid conditions.

Furthermore, the future of HCV treatment is trending towards highly individualised regimens which consider not only the viral genotypes but also the patient’s genetic polymorphisms. For instance, easy-to-treat patients have been identified as treatment-naïve, IL28B CC. [30] Patients with a favourable interlukin-28B genotype (CC variant as opposed to CT or TT) have shown sustained virologic responses up to 80%. [19] It is theorised that these patients could receive PEG-IFN and ribavirin first, minimising the adverse effects of triple therapy. [19] Although testing for the IL28B genotype is not currently the approved standard of care, in the future Australian general practitioners may be managing care of these ‘easy-to-treat’ patients while more complex cases, such as patients with IL28B TT with decompensated cirrhosis are managed at tertiary centres using a cocktail of tailor made drug regimens. [30]

Implications for Australian health practitioners

Accessing and treating hepatitis C infection in PWID – the role of the general practitioner

Advances made in the development of better tolerated interferon free HCV treatment will remain negligible as long as access to therapy cannot be expanded to the most affected and underserved risk groups. [48,49,50] People who inject drugs act as a virus reservoir, as the burden of HCV-related liver disease in this group is increasing but treatment uptake remains low. [49,50] There are a number of barriers to accessing care at the level of the patient, practitioner and system. [48,50,51] New guidelines have been published with recommendations for the management of HCV infection among PWID which aim to overcome these barriers by providing evidence-based treatment recommendations.[50] Analysis of the literature revealed a common theme supported by high quality evidence which was the use of multidisciplinary care teams in enhancing treatment uptake in PWID. [49,50] General practitioners can play a crucial role in co-ordinating multidisciplinary care between specialists, drug and alcohol support services, psychiatric services, social work and other social supports such as peer-based groups. [49] In an Australian community-based study, hepatitis C positive patients who had seen a general practitioner about HCV in the last 6 months were four times more likely to be assessed for therapy by a specialist. [50] Furthermore, a prospective cohort study using telehealth technology in supporting and training GPs was compared to HCV treatment provided at a tertiary centre. Similar rates of treatment success were achieved in both groups. [49,51] From these studies, it was seen that general practitioners not only co-ordinated care but provided a more patient-centred approach necessary in dealing with the complex psychiatric and substance abuse co-morbidities which required individualised models of care. Enhanced personal contact provides an ideal environment for pre-therapeutic assessment of housing, education, cultural and social issues, supports, finances, nutrition, drug and alcohol use and psychiatric evaluation. [50] Merging different disciplines into one general practice model may be a simple and effective model in the future for a sub-population of PWID with HCV but will require commitment by motivated and supported GPs who have undergone further training in addiction and HCV medicine. [49]

The role of general practitioners in assessment and management of HCV infection

As stated previously, hepatitis C may be present in patients unknowingly for decades before symptoms of liver failure prompt a seeking of treatment. At this stage of irreversible cellular damage, treatment options are limited, often associated with distressing side effects and yield less efficient results in certain genotypes. The onus is on health practitioners, armed with an understanding of the pathogenesis of HCV, to identify high risk patients and test for anti-HCV antibodies and HCV RNA levels as a secondary preventative strategy to provide early detection and referral. There are a number of useful international guidelines which can assist general practitioners in managing newly diagnosed hepatitis C patients in regards to indications for treatment as well as first-line treatment recommendations. [3,24] Furthermore, primary prevention strategies whereby educating the public about transmission, symptoms and progression of the disease can be effectively implemented in a consultation setting.

In regards to treating chronic hepatitis C patients, this review aims to equip the general practitioner with an up-to-date understanding of the molecular and immunological aspects of HCV pathogenesis to aid in diagnostic tools as well as provide a platform of knowledge for future pharmaceuticals. We are entering an exciting new era of hepatitis C treatment where interferon-free therapies are likely to dominate the therapeutic landscape within the next 5 years [19] and so an understanding of their mechanism of action in hepatitis C is crucial for continuing treatment and management.

Conclusion

From the ancient observations to the discovery of hepatitis C virus 24 years ago, up until recent advances in cell model systems, our understanding of the pathological nature of hepatitis C has grown exponentially. With this growth have come parallel developments in treatment, both in understanding mechanisms behind current drug therapies but also providing a platform for future pharmaceuticals to target aspects of HCV pathogenicity. These developments come at a timely point, as the burden of an escalating epidemic of hepatitis C in Australia will have major impacts on our healthcare system within the next few decades as the chronic nature of the disease will come into play.

Conflict of interest

None declared.

Correspondence

J Aslanidis: jaimie.aslanidis@gmail.com

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Categories
Review Articles Articles

Is plasmapheresis the optimal treatment option for acute pancreatitis secondary to hypertriglyceridemia? A systematic review

Background: Hypertriglyceridemia is an uncommon cause of acute pancreatitis, which is a life-threatening illness. Conventional management involves fasting, lipid-lowering medication, insulin and heparin. Plasmapheresis is an approach which is used occasionally to achieve rapid lowering of triglyceride levels in patients where conventional management is unsuccessful. It is currently unclear whether plasmapheresis improves outcome in patients with hypertriglyceridaemia-induced pancreatitis. Aim: A literature review and critical analysis was conducted to assess the effectiveness of plasmapheresis in improving patient outcomes in patients with acute pancreatitis secondary to hypertriglyceridemia Methods: The PICO model (Population, Intervention, Comparator, Outcomes) was used to synthesise a research question. Thereafter, a search was conducted through the Scopus database (includes complete MEDLINE coverage) applying the terms ‘plasmapheresis’ OR ‘plasma exchange’ OR ‘lipid apheresis’ AND ‘pancreatitis’ AND ‘hypertriglyceridemia’ OR ‘hyperlipidaemia’ OR ‘hyperlipidemia’. Article titles and/or abstracts were screened for relevance to the topic. Original research articles assessing the efficacy of plasmapheresis in hypertriglyceridaemia-induced pancreatitis were included. Results: To date, no randomised controlled trials have been published assessing the efficacy of plasmapheresis in this population. Two retrospective primary research studies were identified. Both studies demonstrated a rapid reduction in triglyceride levels following plasmapheresis in the magnitude of 65.8-80%. The studies showed no significant clinical benefit in terms of mortality and morbidity, but were limited by small sample size and study design. Conclusion: Current evidence demonstrates that plasmapheresis in the setting of hypertriglyceridemia-induced pancreatitis reduces triglyceride levels by 46-80%. [1] However there is insufficient data to suggest a beneficial effect on clinical outcomes. Well-designed prospective studies with adequate follow-up are required to elucidate whether plasmapheresis is associated with reduced morbidity and mortality in this population.

Introduction

Hypertriglyceridemia is an uncommon cause of acute pancreatitis, accounting for 1.3-3.8 % of cases with an incidence of 18/100,000 per year in the United States of America. [1,2] Primary (genetic) and secondary causes, such as uncontrolled diabetes mellitus, hypothyroidism, alcohol, obesity, certain medications, and pregnancy, are associated with hypertriglyceridemia-induced pancreatitis. [1,3] The mechanism for severe hypertriglyceridemia-inducing pancreatitis remains unclear, [3] although triglyceride levels exceeding 10 mmol/l (1000 mg/dl) can trigger a bout of pancreatitis. [3,4] One postulated theory involves the idea that pancreatic lipase hydrolyses excess triglycerides to produce free fatty acids around the pancreas. These free fatty acids can damage the pancreatic acinar cells and pancreatic vascular endothelium, resulting in ischaemia and inflammation. The acidic environment can further amplify the free fatty acid toxicity in a vicious cycle. [3,4]

Hypertriglyceridemic pancreatitis is a life-threatening illness with a mortality rate of 7-30%. [5] Complications include sepsis, pancreatic necrosis, abscess formation and renal insufficiency; which account for the high mortality seen in this disease. [3] Optimal management of hypertriglyceridemia-induced pancreatitis is essential to reduce morbidity and mortality. Current management includes fasting, lipid-lowering medication (such as fenofibrate), and insulin and heparin, used to ‘accelerate lipoprotein lipase activity’. [2,4] These interventions have shown limited efficacy in reducing inflammation and life-threatening complications associated with severe acute pancreatitis. Novel therapies are needed to improve patient outcomes. [5]

Plasmapheresis is defined as ‘removing the plasma and replacing it with donor plasma or a plasma substitute’. [6] The term plasmapheresis is used interchangeably with the term ‘therapeutic plasma exchange’. The use of plasmapheresis in patients with hypertriglyceridemia can be traced back to a case report in 1978. [3] However, it is not widely utilised in this patient population at present. Given that plasmapheresis provides rapid removal of the triglycerides responsible for underlying inflammation in hypertriglyceridemia-induced pancreatitis, it is expected that this intervention may prove highly effective in reversing this sub-type of acute pancreatitis. The aim of this review was to assess the effectiveness of plasmapheresis in achieving positive patient outcomes (as per Table 1) in patients with acute pancreatitis secondary to hypertriglyceridemia.

Methods

The PICO model was used to synthesise the research question. [7]

Search Methodology

The literature search was conducted on Scopus, which is one of the largest databases of abstracts and citations of research literature, and includes complete coverage of the MEDLINE database. [8] The following search terms were used: (“plasmapheresis” OR “plasma exchange”) AND “pancreatitis” AND (“hypertriglyceridemia” OR “hyperlipidaemia” OR “hyperlipidemia”). The initial database search yielded a total of 139 documents, of which 110 were written in English. After further limiting the search query to include only ‘articles’ or ‘reviews’, a total of 86 documents were found. The documents were then sorted by relevance, and titles and abstracts were screened to identify articles that reported on the use of plasmapheresis in the management of hypertriglyceridemia-induced acute pancreatitis. A total of 28 relevant articles were identified: one primary research study, one review paper, one guideline (the 2010 American Society for Apheresis (ASFA) guideline), eleven case-series (62 patients), and fourteen individual case studies (Figure 1). Review of the references and citations of these studies yielded an additional two articles: one original retrospective study and one review. Focused searches revealed no additional relevant articles. The inclusion criterion for this review was limited to primary research studies only.

Results

Two cohort studies meeting the pre-specified inclusion and exclusion criteria were included. No randomised-controlled trials were identified, and are probably not feasible given the low incidence of hypertriglyceridemia-induced pancreatitis.

Chen et al. [9] conducted a retrospective cohort study to compare the mortality and morbidity in patients with hyperlipidaemic pancreatitis before and after the introduction of plasmapheresis in Shin kong Wu-Ho-Su Memorial Hospital, Taiwan, in August 1999. This study separated the patients into two cohorts: group I (pre-August 1999) and group II (post-August 1999). There were 34 patients in group I and 60 patients in group II, of which twenty patients received plasmapheresis. The cohort was recruited appropriately with all patients fitting the time-frame criteria (pre- or post-August 1999). There was no statistical difference between the demographics of group I and group II, including mean age, gender distribution, initial mean triglyceride level, diabetes mellitus, alcohol consumption, Ranson’s score ≥ 3 and Balthazar grade D or E. [9]

Furthermore, patients with severe hypertriglyceridemic pancreatitis (defined by Ranson’s score ≥ 3) were analysed separately, comparing Group A (those who received plasmapheresis) and Group B (those who did not receive plasmapheresis). There were ten patients in Group A and nineteen patients in Group B. Morbidity was defined in terms of systemic complications, including acute renal failure, upper gastrointestinal bleeding, shock and acute respiratory distress syndrome; and local complications, in particular abscess and pseudocyst formation.

The results were analysed using a t-test and chi-square test. There was no statistical significance (defined as p<0.05) between the mortality and complications of patients with severe pancreatitis who received plasmapheresis, compared to those who received conventional therapy. Similarly, there was no significant difference (defined as p<0.05) between the clinical outcomes of pre-August 1999 and post-August 1999 samples. Interestingly, Chen et al. found that the mean serum concentration of triglycerides and lipase were markedly reduced after plasmapheresis, with a 65.8% reduction of triglyceride levels and 88.8% reduction of lipase levels. [9]

Gubensek et al. [4] also carried out a retrospective cohort study. They looked at two sets of patients. The first sample consisted of 50 patients who were treated with plasmapheresis between 1992 and 2008 at a tertiary-care hospital (University Medical Center Ljubljana, Slovenia), and the triglyceride and total cholesterol levels before and after plasmapheresis were compared. The demographic characteristics of these patients revealed a gender bias, with 92% of the sample being male. The second set of patients included 40 patients treated between 2003 and 2008 with plasmapheresis. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was used as a prognostic tool, with a score of < 8 indicating mild pancreatitis and a score of ≥ 8 indicating severe pancreatitis. A comparison of mortality rates was made between these two groups. The mortality rate was 4% and 42% respectively, with statistically significant differences between the two groups (p<0.001).

The results of the first cohort in the study by Gubensek et al. [4] showed a statistically significant (defined as p<0.001) reduction in triglyceride and cholesterol levels after plasmapheresis within 24 hours. On average, a reduction in serum triglyceride levels of approximately 80% was achieved by plasmapheresis. The analysis of the second cohort showed a significantly higher mortality in patients who had an APACHE II score of ≥ 8 (42% vs. 4%). The overall mortality was 15%, which the authors acknowledged as ‘considerable’.

Discussion

The efficacy of plasmapheresis in hypertriglyceridemia-induced pancreatitis has been unclear. In an attempt to clarify this, we conducted a systematic review of published studies and guidelines investigating the benefits of this therapy. Studies by Chen et al. and Gubensek et al. reported on different populations; however both highlighted that a significant reduction in serum triglyceride levels can be achieved by plasmapheresis in patients with hypertriglyceridemic pancreatitis. Chen et al. [9] showed a reduction in triglyceride levels by 65.8%, and Gubensek et al. [4] demonstrated an average reduction of 80% in triglyceride levels. It should be highlighted that a rapid reduction in triglyceride and cholesterol levels does not necessarily imply a clinical benefit to the patient. The exact pathophysiology of hypertriglyceridemia-induced pancreatitis remains unclear. During a prolonged episode of acute pancreatitis cellular injury can occur which may remain irreversible regardless of lowering of triglyceride levels, although further pancreatic destruction and recurrent episodes may be reduced. [5,10-11] Admission triglyceride levels have not been associated with severity, complication rates or clinical course. [5] Therefore more research is required to look at the effect of the rapid lowering of triglyceride levels on patient outcomes.

The weaknesses of both studies are the small sample size and sub-optimal study design. Chen et al. only looked at a small number of patients from a single hospital, and no definitive conclusions could be reached based on the limited statistical power of the study. Moreover, Chen et al. [9] compared group I and group II outcomes, despite group II comprising of 40 patients who had not received plasmapheresis in addition to the twenty patients who had received plasmapheresis. Therefore, since group II comprised of a mixed sample of patients receiving plasmapheresis and those receiving conventional treatment, the outcomes do not give a true picture of the effect of plasmapheresis only. A statistical comparison between group I and group II only accentuates that there was no benefit in terms of mortality and morbidity between patients presenting with acute pancreatitis secondary to hypertriglyceridemia before August 1999 or after August 1999 at that specific hospital. Thus, any conclusion on the effectiveness of plasmapheresis at reducing patient morbidity and mortality using these statistical results is invalid.

On the other hand, Chen et al. [9] should be commended on their detailed explanation of the apheresis procedure performed, which was well controlled. However, replacement fluid was either fresh frozen plasma (N=8) or isovolumetric 5% albumin solution (N=12). The authors did not adjust their results for this potentially confounding variable. The mean serum concentration of triglycerides and lipase were markedly reduced after plasmapheresis, with a 65.8% reduction of triglyceride levels and 88.8% reduction of lipase levels. However, the time period in which these reductions occurred post-procedure is unclear, and no comparisons were made with the reduction in serum lipase and triglycerides in patients presenting pre-August 1999. The authors did not follow the patients over a considerable time period and were unable to assess recurrence of acute pancreatitis or mortality between patient samples.

The research study by Chen et al. [9] is essentially the only study comparing the use of plasmapheresis and conventional treatment in acute pancreatitis due to hypertriglyceridemia. This study found no differences in mortality and morbidity between conventional therapy and plasmapheresis, but the results need to be carefully evaluated, as mentioned above. A review of this study by the 2010 ASFA Guidelines highlight that ‘adequate information was not provided to ascertain the comparability of the two groups’. [1] Chen et al. stated that earlier intervention might provide positive outcomes for plasmapheresis, given that the median time for starting plasma exchange was three days for their patients. [9] This is a possible explanation for the results, and further studies are needed to evaluate the relationship between the time of initiating plasmapheresis and patient outcomes. A review by Tsuang et al. reported that ‘early initiation of treatment for hypertriglyceridemic pancreatitis is likely to be beneficial’, [3] based on findings from the retrospective case series by Kyriakidis et al., who reported positive patient outcomes in eight out of nine patients treated with plasmapheresis within 48 hours of diagnosis. [2]

The study by Gubensek et al. is also limited, in that it did not compare the effect of plasmapheresis with conventional treatment options.  No comparison was made with the mortality rate of patients who were treated conventionally. The study makes a strong point on the effectiveness of plasmapheresis in acutely reducing serum triglyceride and cholesterol levels, but does not determine whether there is any clinical benefit of this to the patient.

The indications and criteria for applying plasmapheresis was not consistent across the literature. Plasmapheresis is commonly used in settings where there is inadequate outcomes achieved using conventional management. [5] However, the patients treated with plasmapheresis in Chen et al. [9] and Gubensek et al. [4] include those with mild to moderate pancreatitis as well as severe pancreatitis (evaluated using Ranson’s scores or APACHE II score), but no information was given about any conventional treatment prior to the initiation of plasmapheresis. Therefore, it is unclear whether any prior conventional treatment had an effect on patient outcomes.

Neither study reviewed the potential symptomatic relief from plasmapheresis. A possible reason could be due to the subjectivity in measuring this outcome and the retrospective nature of the studies. Evaluation of potential symptomatic relief from plasmapheresis may be useful in minimising the severe pain associated with hypertriglyceridaemic pancreatitis.

ASFA [1] conducted a literature review to evaluate the rationale for plasmapheresis in patients with hypertriglyceridemic pancreatitis. This review is consistent with the findings of studies by Chen et al. and Gubensek et al., and reported no randomised controlled trial evaluating the effectiveness of plasmapheresis in these patients.  Their search on PubMed yielded twelve case-series and 28 case reports, with sample sizes ranging from 100-300. The ASFA have given a Category III indication to the use of plasmapheresis in patients with hypertriglyceridemic pancreatitis, which implies that the optimum role of apheresis therapy in these patients is not established. ASFA highlight the role of clinicians in making individualised decisions due to the weak evidence in this area. [1]

There is clearly a need for stronger evidence to determine the effectiveness of plasmapheresis in patients with hypertriglyceridemic pancreatitis. However, the low incidence of this disease means that randomised controlled trials may not be feasible. Gubensek et al. [4] argue that it would be questionable to perform a randomised controlled trial, given the large reduction in triglyceride levels by plasmapheresis. The ethical issues and feasibility of performing a randomised controlled trial on a small sample are barriers in answering this question. Nevertheless, large cohort studies with sufficient follow-up and appropriate adjustments for population stratification should provide immense support either in favour or against the use of plasmapheresis. Furthermore, appropriate studies assessing the effectiveness of rapidly lowering triglyceride levels on patient outcomes should be conducted.

Conclusion

There is insufficient evidence to confirm that plasmapheresis is a beneficial treatment option for patients with acute pancreatitis secondary to hypertriglyceridemia. Current literature shows that plasmapheresis promotes a rapid reduction in triglyceride levels of 46-80% [1], however its effect on patient outcomes remains unclear. Adequately powered prospective studies with long term follow-up are recommended to elucidate whether plasmapheresis is associated with reduced morbidity and mortality in this population.

Acknowledgements

Thank you to Dr Channa Perera, Endocrinologist at Campbelltown Hospital, for the inspiration to research and write up on this topic.

Conflict of interest

None declared.

Correspondence

M Rehmanjan: mrehmanjan@gmail.com

References

[1] Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberfer ML, Marques MB, et al. Guidelines on the use of therapeutic apheresis in clinical practice. Journal of Clinical Apheresis 2010; 25:83-177.

[2] Kyriakidis AV, Raitsiou B, Sakagianni A, Harisopoulou V, Pyrgioti M, Panagopoulou A, et al. Management of Acute Severe Hyperlipidemic Pancreatitis. Digestion 2006; 73(4):259-64.

[3] Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A. Hypertriglyceridemic Pancreatitis: Presentation and Management. The American Journal of Gastroenterology 2009;104:984-91

[4] Gubensek J, Buturovic-Ponikvar J, Marn-Pernat A, Kovac J, Knap B, Premru V, et al. Treatment of hyperlipidemic acute pancreatitis with plasma exchange: A single-center experience. Therapeutic Apheresis and Dialysis 2009;13(4):314–17.

[5] Lebenson J, Oliver T. Acute pancreatitis [Internet]. Rijeka, Croatia: InTech; 2012. Chapter 16, Hypertriglyceride Induced Acute Pancreatitis [cited 2013 Aug 25]. Available from: http://www.intechopen.com/books/acute-pancreatitis/hypertriglyceride-induced-acute-pancreatitis

[6] Brooker C. Medical Dictionary. Philadelphia. Churchill Livingstone Elsevier; 2008.

[7] University of Warwick Library. The Pico Method [Internet]. 2010 Sep 1 [cited 2012 Aug 6]. Available from: http://www2.warwick.ac.uk/services/library/tealea/sciences/medicine/evidence/pico/

[8] Elsevier. Scopus Database [Internet]. 2012 [cited 2012 Aug 6]. Available from: http://www.scopus.com/home.url?null

[9] Chen JH, Yeh JH, Lai HW, Liao CS. Therapeutic plasma exchange in patients with hyperlipidemic pancreatitis. World Journal of Gastroenterology 2004; 10(15):2272-74.

[10] Banks PA, Conwell DL, Toskes PP. The Management of Acute and Chronic Pancreatitis. Gastroenterol Hepatol 2010; 6(2 Suppl 5):1–16.

[11] Piolot A, Nadler F, Cavallero E, Coquard JL, Jacotot B. Prevention of recurrent acute pancreatitis in patients with severe hypertriglyceridemia: value of regular plasmapheresis. Pancreas 1996; 13(1):96-9.

Categories
Review Articles Articles

A systematic review evaluating non-invasive techniques to diagnose genetic disorders in a human fetus and the ethical implications of their use

Introduction: Genetic disorders are a significant cause of neonatal morbidity and mortality. [1] Diagnosing a genetic disorder currently involves invasive tissue sampling which carries an increased risk of miscarriage. The discovery of cell-free fetal DNA (cffDNA) in maternal plasma has enabled the development of non-invasive prenantal diagnostic tests (NIPD). [2,3] The scientific and ethical implications are examined. Methods: Medline, PubMed and Cochrane Library were searched for original research articles, review articles and meta-analyses focussed on screening and diagnosis of fetal genetic disorders. Results: 422 original research and review articles were assessed using processes in the Cochrane Handbook for Systematic Reviews of Interventions. [4] Using maternal plasma obtained during the second trimester, researchers were able to sequence the fetal genome with up to 98% accuracy. Clinicians reported the test will improve prenatal screening uptake, and reduce morbidity and mortality associated with genetic disorders. Ethicists argue it has implications for informed consent, rates of termination, reliability of future applications, inadvertent findings in clinical settings, commercial exploitation and inconsistent use of the technology internationally. Conclusions: Once NIPD tests utilising cffDNA are refined and costs reduced it is likely its implementation will affect both specialist genetic and routine antenatal services. However, given the complex set of ethical, legal and sociocultural issues raised by NIPD, professional education, public engagement, formal evaluation and the development of international standards are urgently needed. Health systems and policy makers must prepare to respond to cffDNA technology in a responsible and effective manner.

Introduction

Most pregnant women wish to be reassured that their unborn baby is healthy. [5] The aim of antenatal care is therefore to select screening and diagnostic tests that are accurate, safe and can be performed sufficiently early to allow parents to plan ahead or terminate the pregnancy in the event that fetal abnormality is diagnosed. [6] Genetic disorders are a significant cause (20%) of neonatal mortality. [1] At present, maternal serum screening, alone or in combination with ultrasound, is used to identify fetuses at risk of aneuploidy and other disorders. [7] Unfortunately, neither maternal serum screening nor ultrasound provide information on the genetic constitution of a fetus or allow a definitive diagnosis to be made. [8] For this, fetal cells must be invasively sampled from the placenta (chorionic villus tissue), amniotic fluid or fetal blood – all of which increase the risk of miscarriage. [9,10] This increased risk makes the decision to use invasive prenatal diagnosis difficult, particularly as there are still only very limited treatment options. [11] As a result, the medical community has sought to develop reliable and safe methods for achieving non-invasive prenatal diagnosis (NIPD), in addition to future treatment options. [12] Through NIPD, researchers hope to improve screening uptake, and reduce morbidity and mortality associated with genetic disorders. [1] Ethicists argue that NIPD transects existing distinctions between screening and diagnostic tests, and has implications for informed consent or choice. [12]

Methods

MEDLINE, PubMed and Cochrane Library were searched weekly between September 2012 and April 2013 for original research articles, review articles and meta-analyses focussed on screening and diagnosis of fetal genetic disorders. MeSH headings used were: Genetics, Medical, Genetics Testing and Fetus. Search terms used were: non-invasive, whole-genome and sequencing. Results were limited to human studies written in English between 1995 and 2013.

Results

The search resulted in 422 articles being identified; these were subsequently examined. The majority of publications were original research and review articles, although there was one meta-analysis by Alfirevic et al. (2003). [6] Many publications (217) were excluded for their limited scope or irrelevance.

Maternal serum screening and ultrasound are current methods of choice for screening pregnancies at risk of genetic disorders. [8,13] However, both methods rely on measuring epiphenomena rather than core pathology. Consequently, both tests have limited sensitivity and specificity and can only be used within a relatively narrow gestational period. [14] To achieve a definitive diagnosis chorionic villi sampling (CVS), amniocentesis or cordocentesis must be used. [6,8]

CVS is an invasive diagnostic procedure performed after 10 weeks gestation that is used for karyotyping when first trimester screening suggests a high risk of aneuploidy. [8] It is also used for fetal DNA analysis if the parents are known to be carriers of an identifiable gene mutation, such as cystic fibrosis or thalassaemia. [9] The procedure involves ultrasound-guided aspiration of trophoblastic tissue using either the trans-cervical or trans-abdominal routes. The tissue is then analysed with fluorescence in situ hybridisation polymerase chain reaction (FISH PCR). Like CVS, amniocentesis involves ultrasound-guided aspiration of amniotic fluid but is performed after 15 weeks gestation. [6] Cordocentesis involves direct sampling of fetal blood from the umbilical cord but is rarely performed and will not be discussed further in this article.

The benefit of CVS is that it can be performed at an earlier gestation, facilitating earlier diagnosis and providing the opportunity to terminate the pregnancy by suction curettage of the uterus. The benefits of amniocentesis include the lower background rate of miscarriage and the avoidance of isolated placental mosaicism occurring in 1% of samples. [8] The primary risk with CVS and amniocentesis is miscarriage. The level of risk is similar for the two tests (reported risk ranges from 1% to 1 in 1600) and is operator dependent. [6,7] Researchers have attempted to reduce this risk by developing a NIPD that allows the direct analysis of fetal genetic materials. [2,12,14-22] Better screening tests will achieve a higher detection rate combined with a lower false positive rate, resulting in less invasive testing and fewer procedure-related miscarriages.

Much of the early work on NIPD focussed on the isolation of fetal nucleated cells that had entered into the maternal blood. [14] However, the concentrations of these cells were low, meaning the tests had low sensitivity and specificity. [15,22] Later methods were inspired by the presence of tumour-derived DNA in the plasma of cancer patients. [23,24] In 1997, Lo et al. (1997) observed an analogous phenomenon was present in pregnancy by identifying Y chromosomal DNA sequences in plasma of women carrying male foetuses. [25] Replication of this study has concluded that 10% of cell-free DNA (cffDNA) in a pregnant woman’s plasma originates from the fetus she carries. [14,17,18,20] Since then, several groups have developed NIPD tests but most were only capable of detecting gross abnormalities such as aneuploidies, and were limited by small sample size and substandard accuracy. [17,18,22,26,27] In June 2012, Kitzman et al. (2012) reconstructed the whole-genome sequence of a human fetus using samples obtained relatively noninvasively during the second trimester, including paternal buccal DNA and maternal and cffDNA from the pregnant mother’s plasma. [2] Predicting which genetic variants were passed from mother to fetus was achieved by resolving the mother’s haplotypes – groups of genetic variants residing on the same chromosomes – and combining this result with shotgun genome sequencing of the father’s DNA and deep sequencing of maternal plasma DNA. [19] Comparing the results of this method with cord blood taken at delivery found inheritance was predicted with 98.1% accuracy. The study sequenced only two fetuses at a cost of $50,000 each, and is yet to be reproduced. Researchers from Stanford University were able to sequence the fetal genome without a paternal saliva sample although this was less accurate than the method used by Kitzman et al. (2012). [18] This latter method forms the basis of commercially available NIPD tests being offered by laboratories. [28] In Australia, NIPD testing is currently limited to Trisomy 21, 18, 13 and abnormalities of sex chromosomes, is not eligible for a Medicare rebate and costs upwards of $1,250. [29] It is anticipated that analysing samples for NIPD locally will reduce the cost and drive demand. [30,31]

Discussion

Clinicians report that non-invasively diagnosing genetic disorders will reduce infant mortality and morbidity. [31] Ethicists argue the technology raises concerns for informed consent, rates of termination, reliability of future applications, inadvertent findings in clinical settings, commercial exploitation and inconsistent use of the technology internationally [12,32-36].

Informed Consent and Informed Choice

Ethicists believe NIPD testing transects existing distinctions between screening and diagnostic tests and has implications for informed consent and choice. [12] An example is screening for Down’s syndrome, a common genetic disorder. Although a significant number of women may not already achieve informed choice for screening, at least a subsequent invasive diagnosis provides another opportunity for reflection as they consent to the procedure (CVS or amniocentesis). [34,35] Replacing this multi-step screening process with highly-predictive cffDNA testing may reduce opportunities for exercising informed choice. [12] In addition, despite the belief that introducing cffDNA testing will promote parental reproductive choice, it may indeed make proceeding with an affected pregnancy more difficult for two reasons: First, the decreased risks associated with cffDNA might lead women to feel ‘pressured’ into agreeing to the tests, or undergoing testing without informed consent, even if they potentially lead to outcomes with which they disagree. [33,36] Second, the lower risks might cause a shift in the extent to which society is supportive of those who chose to have disabled children. [10] In turn, worries over social disapprobation could prompt a loopback effect, where women feel more pressured to test and to terminate their pregnancies.

Termination of pregnancy (TOP)

In Australia, there is broad agreement that TOP is ethically and legally permissible in some circumstances. [11,33,37] However, the laws are notoriously unclear, outdated and inconsistent between states and territories. [38,39] In many jurisdictions it is legally defensible for a clinician to perform a TOP at any gestation if they can justify the harms of continuing with the pregnancy outweigh the risks of termination. [40] For this reason, access to TOP is very much dependent on the clinician, which may be problematic if cffDNA testing becomes more widespread and moves outside the existing setting of medical genetics, where high standards of relevant ethical practice and the professional duty of non-directive counselling are firmly entrenched. [12]

Accuracy and reliability of NIPD

Despite improved accuracy by utilising fetal nucleic acids, the sensitivity and specificity of even the most accurate method is still less than 100%. [2] Maintaining an acceptably high sensitivity and specificity will also be a challenge, as researchers discover an ever-increasing number of sequences associated with pre-existing diseases. [12] To do this will require careful monitoring within different applications. [33] Without it, the personal, sociocultural, legal and ethical ramifications of false positives and negatives may be devastating. For example, additional invasive testing may be undertaken, healthy fetuses may be terminated, and children may suffer psychologically should they discover their parents would have terminated them if they had known of their diagnosis. [34]

Inadvertent findings in clinical settings

The Kitzman et al. method requires paternal buccal DNA to sequence the fetal genome and may therefore inadvertently disclose misattributed paternity. [41] However, so too may the Stanford University method that forms the basis of commercially available NIPD but that does not require paternal buccal DNA. [18] In a trial of 18 subjects, researchers using the latter method were able to predict 70% of the paternally inherited haplotypes in the fetus with 94–97% accuracy. [18] Of course, the correlation of these findings to the clinical setting would likely still require paternal buccal DNA to confirm paternity. The potential for inadvertent disclosure of misattributed paternity would be a particular concern if cffDNA testing were ever incorporated into routine antenatal screening as a greater number of women who may not have been adequately forewarned would be exposed to the risks such information may bring.

Commercial and international uses

The likely increase in the accessibility of NIPD using cffDNA tests made available via the internet has major implications, particularly for fetal sex selection. [12] In China [42] and India, [43] population skewing has already been observed as a result of unlawful sex selection practices favouring male children. Some ethicists believe cffDNA could significantly aggravate or extend this problem. [44] The development of cffDNA technology within the commercial sector is also a concern as some companies choose only to sell the service rather than invest in research and development eg: babygendermentor.com. The provision of testing direct-to-consumers raises a complex set of issues relating to the role of ‘gatekeepers’ in prenatal testing and access to non-clinical applications of the technology. [33] In addition, it may even impact upon the provision made through Medicare for ongoing care, including diagnostic confirmation, interventional procedures (such as TOP) and medical advice. [5] Having commercial players involved may result in elements of professional practice, including informed consent and counselling, being difficult to enforce considering international legislative and regulatory boundaries. [12] The cultural context is also highly relevant to how consumers access cffDNA testing. For example, its use in countries where access to safe TOP is limited or absent is ethically questionable and could cause significant social and medical problems. [45]

Conclusion

The utilisation of cffDNA for safe and reliable NIPD has opened the way for accurate sequencing of the fetal genome and the ability to diagnose an ever-increasing number of genetic anomalies and their clinical disorders. Once methods such as those by Kitzman et al. and researchers at Stanford University are refined and costs reduced it is likely the implementation of cffDNA testing will affect both specialist genetic and routine antenatal services, improve screening uptake, and reduce morbidity and mortality associated with genetic disorders. As a result of the pace of development, there is concern that cffDNA testing transects existing distinctions between screening and diagnostic tests, having implications for informed consent, termination rates and commercial. Given the complex set of ethical, legal and sociocultural issues raised by NIPD, both professional education and public engagement are urgently needed. Formal evaluation of each test should be required to determine its clinical accuracy, and laboratory standards should be developed alongside national best practice guidelines to ensure that cffDNA testing is only offered within agreed and well-supported pathways that take account of the aforementioned issues. This development has the potential to deliver tangible improvements in antenatal care within the next 5-10 years, and health systems and policy makers around the globe must now prepare to respond to further developments in cffDNA technology in a responsible, effective and timely manner.

Conflict of interest

None declared.

Correspondence

M Irwin: matt@irwinmd.com.au

References

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[11] van den Berg, M., et al., Accepting or declining the offer of prenatal screening for congenital defects: test uptake and women’s reasons. Prenat Diagn, 2005. 25(1): p. 84-90.

[12] Hall, A.B., A; Wright, C F, Non-Invasive Prenatal Diagnosis Using Cell-Free Fetal DNA Technology: Applications and Implications. Public Health Genomics, 2010. 13(4): p. 246-255.

[13] Wieacker, P. and J. Steinhard, The prenatal diagnosis of genetic diseases. Dtsch Arztebl Int, 2010. 107(48): p. 857-62.

[14] Lo, Y.M., Non-invasive prenatal diagnosis by massively parallel sequencing of maternal plasma DNA. Open Biol, 2012. 2(6): p. 120086.

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[36] van den Berg, M., et al., Are counsellors’ attitudes influencing pregnant women’s attitudes and decisions on prenatal screening? Prenat Diagn, 2007. 27(6): p. 518-24.

[37] Drabsch, T., Abortion and the law in New South Wales, N.P.L.R. Service, Editor 2005, NSW Parliamentary Library Research Service: Sydney. p. 1-33.

[38] de Costa, C.M., et al., Introducing early medical abortion in Australia: there is a need to update abortion laws. Sex Health, 2007. 4(4): p. 223-6.

[39] De Crespigny, L.J. and J. Savulescu, Abortion: time to clarify Australia’s confusing laws. Med J Aust, 2004. 181(4): p. 201-3.

[40] Cica, N., Abortion Law in Australia, D.o.t.P. Library, Editor 1998, Department of Parliamentary Library: Canberra.

[41] Lucast, E.K., Informed consent and the misattributed paternity problem in genetic counseling. Bioethics, 2007. 21(1): p. 41-50.

[42] Cecilia Lai-wan, C., B. Eric, and C. Celia Hoi-yan, Attitudes to and practices regarding sex selection in China. Prenatal Diagnosis, 2006. 26(7): p. 610-613.

[43] George, S.M., Millions of missing girls: from fetal sexing to high technology sex selection in India. Prenat Diagn, 2006. 26(7): p. 604-9.

[44] Van Balen, F., Attitudes towards sex selection in the Western world. Prenat Diagn, 2006. 26(7): p. 614-8.

[45] Ballantyne, A., et al., Prenatal Diagnosis and Abortion for Congenital Abnormalities: Is It Ethical to Provide One Without the Other? The American Journal of Bioethics, 2009. 9(8): p. 48-56.

Categories
Review Articles Articles

The role of viruses in carcinogenesis

It is accepted that populations in the so-called developed world have gone through an ‘epidemiological transition’ where chronic disease has replaced infection as the primary cause of death. However, there is mounting evidence that infections play a key role in certain chronic diseases such as cancer. Cancers of infectious origin provide the perfect opportunity for harnessing the advances that have been made in the control of communicable diseases to attempt the control of noncommunicable diseases. Worldwide, one in every five malignancies can be attributed to infections: this figure is considered conservative and expected to rise. About two-thirds of these cancers occur in less developed countries. The majority of these malignancies are recognised to be caused by viruses via mechanisms of chronic inflammation, immunosuppression or the expression of oncogenic proteins. An understanding of virally mediated carcinogenesis may provide new targets for the development of specified viral therapy that not only impacts on viral infections but human cancer as well. From a public health perspective, viral carcinogenesis is important because it shows potential for preventative and therapeutic programmes to reduce the burden of cancer, particularly in less developed countries.

Introduction

The process of carcinogenesis involves multiple contributing factors. These include environmental, lifestyle, host factors, genetically inherited traits and infectious agents. Infectious agents are important from a public health aspect as they represent a significant and preventable cause of cancer. The infection-attributable cancer burden has been estimated at 1.9 million cases, or 17.8% of the total global cancer burden. [1] The percentage of infection-attributable cancer is higher in developing countries (26.3%) than in developed countries (7.7%), reflecting the higher prevalence of infectious diseases. Of these infection-associated cancers, viruses are the most common causative agents with 12.1% of cancers worldwide attributed to viral infections. [1]

This article aims to outline current knowledge of the role of viruses in mediating cancer, explore the main mechanisms involved and propose exciting preventative and therapeutic approach for virus-associated cancers in the 21st century.

Mechanisms by which viruses mediate cancer

The International Agency for Research on Cancer (IARC) recognises seven viral agents that have been linked with cancer: Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV), Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), Karposi-Sarcoma Herpes Virus (Human Herpes Virus 8), Human T-cell leukemia virus type I (HTLV-1) and Human Immunodeficiency Virus type 1 (HIV). [2] These seven viruses classified as ‘carcinogenic to humans’, and the recently discovered Merkel Cell Virus which has not yet been included by the IARC, are summarised in Table 1.

The induction of cancer development by viruses requires persistent infection of the host.  It is hypothesised that long-term infection initiates cellular changes that predispose to cancer progression. [3]

In addition to persistent infection, the specific actions of these viruses are discussed below and can be broadly grouped into viruses that induce cancer by (i) chronic inflammation (eg. HCV), (ii) immunosuppression (eg. HIV) and by (iii) direct actions of viral oncogenic proteins (eg. EBV, HPV). [3]

(i) Cancer associated with chronic inflammation: Hepatitis B and C Viruses

Once a viral infection is initiated, recovery requires the activation of the innate and adaptive arms of the immune system. Acute inflammation is usually a short process that eliminates the pathogen. However, chronic inflammation may result if acute inflammation continues unresolved and fails to eradicate the pathogen. Chronic inflammation itself may promote carcinogenesis via the release of many factors including nitric oxide, cytokines and chemokines thus mediating DNA damage and effecting cell proliferation and neoangiogenesis. [3]

HBV and HCV infections are examples of chronic infections associated with ongoing inflammation. HBV and HCV are responsible for 54% and 31% of human hepatocellular carcinoma (HCC) cases worldwide. [4,5] These hepatotropic viruses can induce cirrhotic livers from which HCC can arise. This review will focus on HCV.

In those infected with HCV, 80% will develop chronic infection, and in 30 years 10-30% of these chronic HCV infections will develop cirrhosis. The subsequent rate of cirrhotic HCV liver disease developing HCC is 1-3% per year. [6] Since current WHO estimates suggest that 3% of the world’s population, or 150 million people, are HCV infected, this represents a significant virus-associated cancer burden.

HCV is a RNA virus of the hepacivirus family of the genus Flaviviridae. HCV does not integrate itself into the host genome and several viral proteins (core protein and the NS3, NS4B and NS5A) have been suggested as potential oncogenic candidates in-vitro. For example, the HCV NS5A protein has been shown to bind and sequester the cellular p53 protein to the perinuclear membrane, and it may be the be key to HCC development. [7] However, it is thought that HCC primarily occurs due to repeated rounds of hepatocyte destruction and regeneration from chronic inflammation, producing a procarcinogenic cirrhotic microenvironment, [3,8] rather than through the action of viral oncogenes. Cirrhosis appears to be the main risk factor for HCC, but exogenous factors could also play a role, such as chronic alcohol consumption, viral co-infection (such as HIV modulating immunosuppression), diabetes and obesity [4] highlighting the multifactorial triggers for the induction of cancer. [9]

HCV is also a well-established cause of essential mixed cryoglobulinemia, a lymphoproliferative disease that can evolve into B-cell non-Hodgkin lymphoma (NHL). [10] HCV has been suggested to be lymphotropic, but this is not well defined. [11] Again, since HCV has not been demonstrated to encode direct oncogenic proteins, the mechanisms of HCV-induced NHL are likely to be via chronic inflammation.

(ii) Cancer associated with immunosuppression and insertional mutagenesis: HIV

It is estimated that there are approximately 34.2 million individuals worldwide living with HIV infection, two-thirds of these being in sub-Saharan Africa. [12] People with HIV have a substantially higher risk of certain cancers compared with uninfected people of the same age. These cancers are termed AIDS-defining malignancies and include: Kaposi sarcoma, a mesenchymal tumour originating from lymphatic endothelial cells, cervical cancer and NHL. [13] Additionally, other types of cancer, such as Hodgkin’s disease (HD), anal cancer, lung cancer and testicular germ cell tumours appear to be more common among HIV-infected subjects compared to the general population and are termed AIDS-associated cancers. [14]

HIV is an RNA lentivirus of the Retroviridae family. The members of this family all integrate into the host chromosome and thus have the potential to cause direct insertional mutations or activation of cellular oncogenes.  Other members of the Retroviridae family, such as Mouse mammary tumour virus (MMTV) have a well-defined link with tumours in mice, which are likely mediated by insertional activation of cellular genes in breast tissue through hormone responsive elements in the MMTV promoter. [15] Similarly, insertional mutagenesis and the induction of lymphoma has been identified in humans treated with gammaretrovirus [16] and lentivirus vectors used in gene therapy. [17] In contrast, there is little evidence for an HIV oncogenic protein, although studies have suggested that the transactivator protein of viral gene expression, Tat, which has oncogenic potential, is secreted by HIV. It has also been suggested that Tat can re-enter non-infected cells blocking apoptosis and accelerating tumour formation. [18]

The above described AIDS-associated cancers are linked with low CD4+ T-cell counts, and this may lead to co-infections with other oncogenic viruses such as HPV (cervical cancer) and Kaposi’s sarcoma-associated herpesvirus (Kaposi’s sarcoma), or the reactivation of existing infections with opportunistic oncogenic viruses such as EBV (Burkitt’s lymphoma). [18] However, the specific mechanisms by which depressed immunity may increase the risk for cancer are unclear, except for KS and most subtypes of NHL that are strictly associated with a low CD4 count. [19] Supporting the link between cancer and immunosuppression, the pattern of cancers in immunosuppressed organ transplant recipients is similar to people with HIV/AIDS. [20]

Thus, the evidence suggests that HIV can be associated with carcinogenesis through insertional mutagenesis. Moreover, HIV may indirectly cause cancers by inducing a chronic state of immunosuppression, reducing immunosurveillance for neoplastic cells, and increasing the risk of reactivation of latent oncogenic viruses as well as the risk of acquiring new oncogenic viral infections.

(iii) Cancer associated with Oncogenic viruses

Of the identified and accepted carcinogenic viruses, EBV, HHV-8, HTLV-1and HPV are tumour viruses that express viral oncogenic proteins to exert carcinogenesis. HBV also produces the HBx protein that disrupts signal transduction and deregulates cell growth: however, HBV-associated carcinogenesis is believed to be mainly mediated through chronic inflammation as described for HCV. [3] Oncogenic viruses can transform cells by carrying viral oncogenes into a cell or by activating cellular proto-oncogenes. [5] The virally derived oncogenes produce transforming growth factors that deregulate growth control and proliferation, leading to malignant transformation. Specific examples are discussed below, with the oncogenic viruses divided into DNA and RNA tumour viruses.

DNA Tumour Viruses

EBV best illustrates DNA tumour viruses. EBV is a double-stranded DNA virus of the herpesviridae family, and causes infectious mononucleosis. Like all herpesviruses, EBV causes a life-long latent infection, and EBV is the primary cause of B-cell transformation in Burkitt’s lymphoma. [14] This was the first human tumour associated with an infectious agent. Since then, EBV has been implicated in a number of other cancers (see Table 1).

In the case of EBV-lymphoma, expression of the viral oncogene, latent membrane protein-1 (LMP1), transforms cells into lymphoblasts by the disruption of cellular signal transduction. [3] In contrast, in most NPCs, the viral BamHI-A reading frame-1 (BARF1) gene is expressed. BARF1 has been identified as an important oncogene in NPC pathology. [21] Thus, EBV has a number of different oncogene expression profiles associated with different cancers. EBV is extremely widespread in prevalence affecting more than 90% of the world’s population, [22] yet only a small fraction of the infected populations have a cancer attributable to EBV.  Therefore, beside viral factors, host responses also play a role in the neoplastic transformation of EBV-infected cells.

HHV-8 is a DNA virus of the herpesviridae family, and HHV-8 infection is strongly associated with Kaposi’s sarcoma. The mechanism, however, of HHV-8-induced carcinogenesis is very different to that of the related virus, EBV. HHV-8 infects endothelial cells and encodes a viral G protein-coupled receptor (vGPCR). This vGPCR has dysregulated signalling function and acts as an oncogene, inducing angioproliferative tumours. [23]

HPV is a DNA virus of the papillomavirus family, and there are 30-40 types. Approximately fifteen types of HPV are oncogenic viruses, causing 5.2% of total human cancers. [24] These cancers include those of the ano-genital mucosae (cervix, vagina, vulva, anus and penis), and the mouth and the pharynx. [24,25] The predominant transmission of these HPV infections is sexual. [26] While HPV is an accepted aetiological factor for oral and pharyngeal cancers, the major risk factors are tobacco and alcohol, with the effects of these exposures being multiplicative. [25] Oncogenic HPV can be detected by PCR in virtually all cases of cervical cancer, with specific genotypes HPV16 and 18 identified as the primary causes of cervical cancer. These viral genotypes have also been associated with 86-95% of HPV-associated non-cervical cancers. [26,27] These viruses infect the basal layer of the stratified epithelium and express two important viral oncoproteins, E6 and E7. [23] These proteins destabilise the cellular tumour suppressor genes, p53 and the retinoblastoma protein (RB). [28] This dysregulation of cellular growth directly leads to cell transformation and cancer.

RNA Tumour Viruses

HTLV-I is a retrovirus related to HIV, which is associated with adult T-cell leukaemia. Only 1% of HTLV-I infected individuals will develop leukaemia, and only after a long latency period of 20-30 years. [29] HTLV-I infection rates are elevated in certain Indigenous populations of Central and Northern Australia, as well as the southern islands of Japan, the Caribbean basin and South Africa. [14] Unlike HIV, HTLV-I infections are not associated with immunosuppression, but HTLV-I encodes an oncogenic protein; the viral Tax protein. [30,31] Tax is a transcription factor and is known to bind to a number of cellular genes involved in cell cycle progression and growth regulation, such as NFkB and p53. [32] Via promotion of transcription and cell cycle progression, Tax is proposed to set up a self-stimulating loop that causes continuous proliferation of infected T-cells, and ultimately leukaemia.

The growing cancer burden attributable to viruses

While there are only seven viruses clearly recognised as carcinogenic to humans, this is conservative, with the discovery of new associations between infections, particularly viruses, and cancer anticipated.

MCV is a recently discovered DNA virus that is found to be associated with approximately 80% of Merkel Cell Carcinomas, an aggressive form of skin cancer. [33] MCV is a relatively common virus, yet only leads to cancer in rare circumstances. It is thought that this is because for MCV to become carcinogenic, two rare mutagenic steps must occur:  viral integration and T antigen mutation. Integration of MCV is not a regulated event, unlike for HIV and HTLV-I, and occurs rarely. The integration, probably of only parts of the MCV genome into cells, renders the virus replication-incompetent, but allows parts of the virus, such as the T-antigens, to be maintained in these cells. [34] MCV T antigens can be oncogenic, and target cellular tumour suppressors and cell cycle regulatory proteins. Thus, the whole replicative virus may not be present, but the residual oncogenic T-antigen is, and can promote transformation of the cell leading to cancer.

Cancerous cells themselves are generally not transmissible. In humans, during the two known physiological routes for tumour cell transmission (pregnancy and organ transplantation), the immune system is altered.  Transplacental transmission of lymphoma, acute leukaemia, melanoma and carcinoma have been observed, as well as acute leukaemia cells transmitted to the foetuses in multiple case pregnancies with the subsequent disease development in the newborn. [35] Similarly, in organ transplantation, donor derived tumour cells have been observed, with the immunosuppressive therapy following transplantation potentially facilitating the engraftment and growth of donor derived tumour cells. [35] Fortunately, these transmissible tumours are rare, with the development of donor-derived tumours in solid organ transplant recipients at 0.04%. [15] Additionally there have been rare case reports of human contagious cancers documented via needle stick (colonic adenocarcinoma), [36] and a surgeon contracting a malignant fibrous histiocytoma from a patient following an intraoperative cut to his left palm. [37]

Cancer prevention and public health strategies

In theory, the cancers resulting from viral infections represent an exciting potential for public health intervention strategies and therapeutics to prevent these cancers.  In particular, the high number of cancers attributable to viral infections in developing countries presents a real need and opportunity for public health programs to reduce both infectious disease and cancer burden. [38]

The mode of transmission of the seven IARC-recognised carcinogenic viruses is provided in Table 2. The implementation of public health education, awareness, treatment and prevention programs to reduce the horizontal spread of these viruses and manage these viral infections in patients is a public health priority, but has the additional benefit of reduction in the associated cancer risks.

Public health programs should be prioritised to target vertical transmission of viral infections such as HBV and HIV. The WHO outlined targets and recommendations in 2010 with the prevention of mother to child transmission (PMTCT) strategy, targeting anti-retroviral therapy (ART) in pregnant women and providing guidelines for HIV in relation to infant breastfeeding. [39] Similar guidelines may be applicable to our Indigenous population afflicted by HTLV-I, which has a well described increased mother to child transmission rate associated with breastfeeding. [40] However, breastfeeding recommendations in resource poor settings need careful consideration. [41]

More outstanding, are the successful programs for screening and management of viral infections associated with cancer. For example, the National Cervical Screening Program (NCSP) in Australia has had a huge benefit in reducing the mortality rates from cervical cancer from 3.9/100,000 in 1991 to 1.9/100,000 in 2007, [42], demonstrating that cancer prevention via monitoring oncogenic viral infections is a real possibility. [43] Additionally, such programs as the NSW Cancer Council ‘B positive’ program, implemented in 2008 aims to increase HBV awareness and the treatment and management of chronic HBV infection to reduce the risk of HCC. [44]

Vaccination and treatments to prevent cancer-associated viral infections

Historically, the world has experienced, with polio and smallpox, elimination or virtual elimination of viral diseases through vaccination. There are now vaccines available for both HBV and HPV, two major infectious causes of HCC and cervical cancer, respectively. The HBV surface antigen is the basis for the vaccine against the HBV, which was first available in the 1980s, and is the first vaccine for prevention of a human cancer. [45] Vaccination programmes of children with the HBV vaccine have already proved successful in protecting against chronic carriage and HCC, [46,47] and HBV vaccination has now been introduced into the Australian childhood immunisation schedule. Long-term and full coverage of newborns against HBV has the potential of reducing HCC by approximately 85%. [14]

The two currently marketed vaccines for HPV utilise the L1 coat protein in the form of virus-like particles to prevent persistent infection with HPV16 and HPV18. [48-50] These viral subtypes are estimated to cause 71.8% of all HPV-related cancers, cervical and non-cervical. [25] These vaccines need to be administered prior to exposure to HPV16 and 18, which makes delivery in a public health setting more difficult than an infant setting. In Australia in 2007, the National HPV vaccination Program was made available to teenage women, and is now part of the school age vaccination program. From 2013 will also be made available to 12-13 year old males. [51] However, the current cost is not practical for all groups, especially those in developing countries, [14] and although the HPV vaccination program in developing countries is supported by the WHO, the applicability and benefits of HPV vaccination have been queried and recently suspended in India. [52] The efficacy of these HPV vaccines in preventing infections at sites other then the cervix, vagina and vulva should be assessed. [27] Specifically, research is required on the administration to high-risk groups (e.g. men who have sex with men and HIV positive people) for anal cancer. [24]

Unfortunately, the described RNA viruses associated with cancer, HIV and HCV, are highly genetically variable and therefore prove to be difficult candidates for prophylactic vaccines. For these viruses, anti-viral therapy appears to be more successful. For example, the risk of infection-associated cancers in HIV positive individuals is related to ongoing HIV replication. The use of suppressive highly active antiretroviral therapy (HAART) has dramatically reduced the risk for opportunistic infections and improved overall life expectancy in patients with HIV-infection and AIDS. [53] A significant decrease in the incidence of KS has been observed in patients treated with HAART. [19] Moreover, HAART and preserved CD4 count preferentially reduces the risk of malignancies associated with oncogenic infections. [54] Similarly, patients with HCV who were prescribed the anti-viral agent, interferon, showed regression of their splenic lymphoma. [55]

Recently approved HCV NS3-4A protease inhibitors are proving effective in clearing and curing HCV infection. In the future, this may significantly impact on HCV infection rates and subsequent incidence of HCC.

Exciting Therapeutic Targets

Our understanding of mechanisms of viral initiation of carcinogenesis has provided the opportunity to design innovative, targeted cancer therapies based on the pathways disrupted by the transforming viral genes.

For example, recent studies reveal that the cellular survivin oncoprotein is activated by MCV large T antigen protein via targeting the cellular Rb (p53) protein, and that survivin inhibitors can delay MCV-induced tumour progression in animal models. [56] Clinical trials are now in progress to determine whether these survivin inhibitors have any therapeutic benefits. Additionally, MCV is a target for cell-mediated immune responses, and so important research efforts are being focused on immunologic therapies that may benefit MCC patients. [56] These findings provide a proof of principle for specifically treating virus-associated cancers by targeting the mechanisms by which they induce oncogenesis. In the case of MCV, a promising rational drug target has been uncovered within only four years of the initial discovery of MCV as a causative cancer agent. Similarly, other new treatments for cancer might be rapidly developed should we identify new viral associations with malignancies.

Conclusion

Viruses are an important aetiological cause of human cancers, especially in the developing world where they lead to a significant burden of disease.  Although viruses make an important contribution to human cancer development, it is often difficult to prove the association of viral infections with cancer, due to latency in tumour development and the multifaceted interaction with the host.  It is reasonable to think that the calculations of cancers attributable to viruses are underestimates and that cancers other than the ones described may also be associated with viral infections. The viruses in this review exemplify the best-established human tumour viruses, but there are many other potential candidates.  Undoubtedly, as our knowledge of carcinogenesis and viruses expand, further cancer-associated viruses will be discovered. From a public health point of view, infectious diseases are often preventable or treatable; therefore, cancers associated with infections are, or may become, preventable.  Prevention may be in the form of vaccination, novel therapies to target the immune system or oncogenic proteins, or education and public health interventions.

Conflict of interest

None declared.

Correspondence

V Boon: boon0035@flinders.edu.au

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Categories
Letters Articles

End-of-life issues in the emergency department

In AMSJ Vol. 3, Issue 2, Michael Li provided an insightful and personal dissertation on the futility of medical treatments and the potential of students to relate to and support patients and their families. [1] Li’s article captures one of the most confronting situations faced by all health professionals, in acknowledging the futility of aiming for a cure, and instead allowing the patient to succumb to their illness. In these situations, clinicians may experience thoughts of frustration, feelings of being powerless, guilt, a sense of professional or personal failure, and an awakened sense of human fragility and mortality. [2] However, the challenges posed by end-of-life decision making across the divergent fields of medicine are not identical. Emergency medicine has long been held as a field of medicine centred upon recognising, treating and stabilising patients with acute illness before they receive definitive care. This is now changing and emergency physicians are experiencing an increasing responsibility for patients with acute, sometimes terminal, exacerbations of chronic, incurable disease.  [3,4] Awareness of the values pertinent to end-of-life care, specifically within the emergency department setting, is critical to maintaining patient dignity and preventing unnecessay distress to the patient and their families.

The 24/7 availability of emergency departments and their functioning as the point of access to a range of hospital services, both therapeutic and diagnostic, often result in emergency doctors being the first medical personnel confronted by new or worsening symptoms in patients with advanced or terminal medical conditions. [3,5] Rosenwax et al. (2011) illustrated that emergency providers feature prominently in the care of patients with terminal illness, with 70%  of a Western Australian cohort of 1071 patients with terminal illness visiting the emergency department at least once in their last year of life and 4% on their final day of life. [4] Such exposure provides emergency physicians the opportunity to apply the tenants of palliative care in relation to patients with incurable, terminal disease, who are clearly suffering.[3] Despite its need, the decision regarding the extent of treatment appropriate is often a challenging one to make in the emergency setting. Emergency medicine is a field characterised by limited continuity of care and a highly mobile patient population, as highlighted by the national four-hour benchmark. [6] Consequently, emergency physicians rarely have the advantage of knowing a patient or their family and lack the background knowledge and unique rapport of a long-term therapeutic relationship. Physicians must also struggle against some ingrained cultural aspects and expectations tied to emergency medicine, where when in doubt aggressive resuscitation is the default. [7,8]

Strategies to increase the ability and confidence of emergency departments to manage patients nearing the end of life include increasing training and protocols around end-of-life care, improving the utilisation of palliative care services and improving access to palliative management information for novel situations. [3,9] Tasmania has recently instituted the Healthy Dying Initiative, a state-wide policy that includes ‘Goals of Care’ documentation. [10] A patient’s Goals of Care are documented on admission and range from ‘for all active treatment measures’ to ‘terminal’, with a range of medical and surgical management options in between. They aid after-hours patient management, clearly outlining treatment expectations and goals, and provide a link between hospitals and the community. As always, clear communication between medical practitioners, patients, families and allied health professionals is an essential component of providing good medical care.

In some situations, treating with curative intent may be futile, even harmful, but emergency doctors still have a major role to play in optimising patients’ overall quality of life and relieving suffering. Worthwhile goals that may outweigh the simple prolongation of life include reducing pain or preserving a patient’s independence, dignity or good neurological functioning. As Australian medical students, we are always progressing towards the moment when we take the lead responsibility for our patients. Considering how we can best benefit patients and their families when a cure is no longer an option and death appears imminent is a vital, if challenging, aspect of medical training. The emergency department is a setting we will all encounter during some stage of our training. While there may be unique challenges to achieving optimal end-of-life care in the emergency environment, awareness of these challenges and of the continuing importance of symptom relief across all domains of medicine will aid our practice as we endeavour to provide the best possible care and achieve the best possible outcome for each and every patient.

Conflict of interest

None declared.

Correspondence

C Ellis: cellis2@utas.edu.au

References

[1] Li, M. Dealing with futile treatment: A medical student’s perspective. AMSJ. 2012; 3(2): 8-60.

[2] Meier, D, Back, A, Morrison, R. The inner life of physicians and care of the seriously ill. JAMA. 2001; 286(23):3007-14.

[3] Forero, R, McDonnell, G, Gallego, B, McCarthy, S, Mohsin, M, Shanley, C, Formby, F & Hillman, K. A Literature Review on Care at the End-of-Life in the Emergency Department. Emerg Med Int. 2012; 2012

[4] Rosenwax, L, McNamara, B, Murray, K, McCabe, R, Aoun, S &Currow, D. Hospital and emergency department use in the last year of life: a baseline for future modifications to end-of-life care. MJA.  2011; 194(11): 570-73.

[5] O’Connor, A, Winch, S, Lukin, W & Parker, M. Emergency medicine and futile care: Taking the road less travelled. Emerg Med Australs. 2011; 23: 640-43.

[6] Indraratna, P &Lucewicz, A. In and out in four hours: The effects of the four-hour emergency department target on patients, hospitals and junior doctors. AMSJ. 2011; 2(2): 9-10.

[7] Smith, A, Fisher, J, Schonberg, M, Pallin, D, Block, S, Forrow, L, Phillips, R, MCCarthy, E. Am I doing the right thing? Provider perspectives on improving palliative care in the emergency department. Ann Emerg Med. 2009; 54(1):86-93

[8] Marco, CA. Ethical issues of resuscitation: an American perspective. Postgrad Med Journ.  2005; 81(959):608-12.

[9] Grudzen, C, Stone, S & Morrison, R. The palliative care model for emergency department patients with advanced illness. J Palliat Care Med. 2011; 14(8): 945-50.

[10] Department of Health and Human Services. Goals of care plan. http://www.dhhs.tas.gov.au/palliativecare/health_professionals/goals_of_care (accessed 8 March 2013).