Bjorn Rembacken is at Leeds Teaching Hospitals NHS Trust, Leeds, UK. He was born in Sweden and qualified from Leicester University in 1987. He undertook his postgraduate education in Leicester and in Leeds. His MD was dedicated to inflammatory bowel disease. Dr Rembacken was appointed Consultant Gastroenterologist, Honorary Lecturer at Leeds University and Endoscopy Training Lead in 2005. Follow Bjorn on Twitter @Bjorn_Rembacken
In the UK, endoscopy is riding a wave of investment generated by population-level colorectal cancer screening. Now, it seems that hepatology is also planning to jump on the screening bandwagon.
In 2012 the US Centers for Disease Control and Prevention gave the go-ahead for population-level screening for chronic HCV infection.1 Then, in 2014, the World Health Organisation also recommended an expansion of the current screening strategy beyond those at high risk of HCV infection2.
Screening for HCV infection is a sizeable undertaking as up to 150 million people worldwide are thought to have the disease. Although most are asymptomatic, all studies have found that patients infected with HCV have a reduced life expectancy. Understandably, in those countries where most HCV infections result from intravenous drug use, there is not only an increased risk of liver disease, but also an increased risk of death from alcohol, HIV infection, smoking or drug-related events such as overdose, suicide, homicide and trauma.3 In patients with iatrogenic HCV infections, an excess mortality from nonhepatic causes such as renal and heart disease and cancer has also been described.4
What do people with HCV infection usually die from? I must admit that I find it difficult to understand research papers reporting on standardised mortality rates (SMR). It seems counterintuitive that patients who have an SMR of 16.8 of dying from a liver-related cause are still far more likely to die from heart disease (SMR of 1.25).5,6 However, a slightly increased risk of dying from something that is already a frequent cause of death will obviously have a great impact on the total number of deaths. I was surprised to find that up to 85% of patients with chronic HCV infections die from nonhepatic causes.7–14
Is there anything we can do to reduce the risk of progression to liver fibrosis, cirrhosis, liver failure or hepatoma? Yes! Beneficial lifestyle interventions could include attempts to reduce intravenous drug taking, tackle alcohol dependency, help with weight reduction in the obese and treat HIV co-infection aggressively, all of which may reduce the risk of progression.15 In fact, all of the above interventions would be beneficial for patients regardless of infection status.
The reason that hepatologists are so enthusiastic about screening for HCV infection is the fantastic sustained virologic response (SVR) rates achieved with the latest antiviral agents, which is now approaching 90%.16 However, it is worth pointing out that the SVR is a surrogate endpoint and sadly we don’t know if this translates into long-term clinical benefit.
I find it surprising that this fundamental issue has not yet been clarified. However, I do understand that the issues surrounding antiviral therapy are complex! For example, the patients who are the most likely to achieve an SVR are those who are least likely to have risk factors for progressive disease.17–19 In other words, those who do well on treatment would probably also do well even without treatment. In addition, a proportion of patients who achieve an SVR, nevertheless develop and die from liver-related causes. In one of the largest studies with the longest follow up (8 years), patients with severe hepatic fibrosis but with an SVR, were found to have annual risk of developing hepatocellular carcinoma of 1%.20 This sounded like a good result until I realised that the background incidence of hepatocellular carcinoma in patients with HCV cirrhosis is very similar (1.4–3.3%).21
Once population-level screening for chronic HCV infection has been rolled out there will be some difficult consultations during which unsuspecting people are told that they are now patients with a chronic disease, requiring lifelong monitoring and treatment. Although the long-term clinical benefit of antiviral therapy is uncertain, I would nevertheless expect these difficult conversations to be easier if a safe and well-tolerated treatment was on offer. Sadly this is not the case. The adverse effects of interferon are well known and it is associated with a 4% increase in all-cause mortality.22 Both the guanosine analogues and the protease inhibitors may cause bone marrow suppression, skin reactions, gastrointestinal upset and insomnia in a large proportion of patients.23.24 In 2012, the US Food and Drug Administration reported that telaprevir was the most common reported cause of severe and fatal skin reactions of any drug.25 In one trial, 3% of patients randomly allocated to receive sofosbuvir experienced serious adverse events, with 1% occurring in the peginterferon plus ribavirin arm.26 In a more recent study, combination therapy with sofosbuvir plus ledipasvir was associated with a 0.5–2% rate of serious adverse events.27 As up to 85% of HCV-infected people in the population will die from nonhepatic causes, the newer antiviral therapies must be safer and better tolerated; otherwise, people will conclude that such a government screening programme turns well people into poorly patients.
As an endoscopist, I find it reassuring to know that the benefit of colorectal cancer screening has been proven in several large, prospective studies. In view of the uncertainties surrounding population-level screening for HCV infection, I am not alone in wanting to see plans for large, prospective randomised controlled trials to prove it’s worthwhile.28 As a taxpayer, I would also like to be reassured that such screening would be money well spent.
References
- Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep 2012; 61(RR-4): 1–32. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm
- WHO. Guidelines for the screening, care and treatment of persons with hepatitis C infection. www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ (2014, accessed 28 January 2015)
- Grebely J and Dore GJ. What is killing people with hepatitis C virus infection? Semin Liver Dis 2011; 31: 331–333. https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0031-1297922
- Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 2012; 206: 469–477. http://jid.oxfordjournals.org/content/206/4/469.abstract?sid=bec80366-18a4-445c-bc76-e2378cd89f40
- Amin J, Law MG, Bartlett M, et al. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet 2006; 368: 938–945. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69374-4/abstract
- Butt AA, Xiaogiang W, Budoff M, et al. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 2009; 49: 225–232. http://cid.oxfordjournals.org/content/49/2/225.full?sid=88956f87-adc7-448a-9e91-964308329eb9
- Wiese M, Fischer J, Lobermann M, et al. Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection. Hepatology 2014; 59: 49–57. http://onlinelibrary.wiley.com/doi/10.1002/hep.26644/abstract
- Seeff LB, Hollinger FB, Alter HJ, et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001; 33: 455–463. http://onlinelibrary.wiley.com/doi/10.1053/jhep.2001.21905/abstract
- Vogt M, Lang T, Frosner G, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999; 341: 866–870. http://www.nejm.org/doi/full/10.1056/NEJM199909163411202
- Barrett S, Goh J, Coughlan B, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection. Gut 2001; 49: 423–430. http://gut.bmj.com/content/49/3/423.abstract?sid=fd8306e5-ae4e-464d-8941-ba8c6b308a2c
- Casiraghi MA, De Paschale M, Romano L, et al. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth. Hepatology 2004; 39: 90–96. http://onlinelibrary.wiley.com/doi/10.1002/hep.20030/abstract
- Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 2000; 132: 105–111. http://annals.org/article.aspx?articleid=713225&resultClick=1
- Locasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997; 90: 4628–4633. http://www.bloodjournal.org/content/90/11/4628
- Lai ME, Origa R, Danjou F, et al. Natural history of hepatitis C in thalassemia major: a long-term prospective study. Eur J Haematol 2013; 90: 501–507. http://onlinelibrary.wiley.com/doi/10.1111/ejh.12086/abstract
- Missiha SB, Ostrowski M and Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008; 134: 1699–1714. http://www.gastrojournal.org/article/S0016-5085(08)00348-X/abstract
- Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483–1493. http://www.nejm.org/doi/full/10.1056/NEJMoa1316366
- Stattermayer AF, Scherzer T, Beinhardt S, et al. Review article: genetic factors that modify the outcome of viral hepatitis. Aliment Pharmacol Ther 2014; 39: 1059–1070. http://onlinelibrary.wiley.com/doi/10.1111/apt.12717/abstract
- Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343: 1666–1672. http://www.nejm.org/doi/full/10.1056/NEJM200012073432301
- Koretz R. Chronic hepatitis: more quotes and misquotes. In: Gitnick G (ed) Current Hepatology. Vol 15. St. Louis: Mosby-Year Book Inc., 1995, pp.49–84.
- Van der Meer A, Feld J, Hofer H, et al. The risk for hepatocellular carcinoma among patients with chronic HCV infection and advanced hepatic fibrosis following sustained virological response. In: 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, USA, 1 November–5 November 2013. Abstract 143. http://onlinelibrary.wiley.com/doi/10.1002/hep.26814/full
- Everson GT. Management of cirrhosis due to chronic hepatitis C. J Hepatol 2005; 42 (suppl1): S65–S74. http://www.journal-of-hepatology.eu/article/S0168-8278(05)00056-5/abstract
- Di Bisceglie AM, Stoddard AM, Dienstag JL, et al. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon. Hepatology 2011; 53: 1100–1108. http://onlinelibrary.wiley.com/doi/10.1002/hep.24169/abstract
- Brok J, Gluud LL and Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database Syst Rev 2010; 1: CD005445. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005445.pub2/abstract
- Casey LC and Lee WM. Hepatitis C virus therapy update 2013. Curr Opin Gastroenterol 2013; 29: 243–249.
- Institute for Safe Medication Practices. Perspective on drug hypersensitivity. QuarterWatch 2013 Q1, www.ismp.org/quarterwatch/pdfs/2013Q1.pdf (2014, accessed 28 January 2015)
- Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878–1887. http://www.nejm.org/doi/full/10.1056/NEJMoa1214853
- Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–1888. http://www.nejm.org/doi/full/10.1056/NEJMoa1402355
- Koretz RL, Lin KW, Loannidis JPA, et al. Is widespread screening for hepatitis C justified? BMJ 2015; 350: g7809. http://www.bmj.com/content/350/bmj.g7809
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