Dr. Eric Yoshida (biography and disclosures)
What I did before
As most health-care professionals, are well aware, the natural history of Hepatitis C Virus (HCV): can end with cirrhosis and hepatocellular cancer (HCC) as the final outcome. After 20-30 years of chronic HCV infection, anywhere from 20-30% of those with chronic HCV will develop cirrhosis. Once cirrhosis has developed approximately 30% of these will then face the risk of decompensation over the next 5 to 7 years requiring either a life-saving liver transplant or face premature mortality. Once cirrhosis develops in HCV infected patients, the risk of HCC is approximately 3-5% per year which means that after 5 years, the cumulative risk of developing HCC is 15-20%.
British Columbia, unfortunately, has a very heavy burden of HCV. Although the exact prevalence is not known, it is estimated that anywhere from 40-80,000 (or more) residents of BC suffer from chronic HCV and many remain undiagnosed. Across Canada, over a quarter of a million people are estimated to have the infection (1) and the mortality from HCV, based on the premise of no improvements in the current licensed therapy (ie. peginterferon and ribavirin), has been projected to continue to increase.
In BC as in all provinces, HCV dominates the wait-list of those in need of a liver transplant and 35% of all transplants are performed for end-stage liver disease caused by HCV (2). Although liver transplantation in BC has been associated with an excellent post-transplant survival, the truth remains that there is a tragic discrepancy between the need for transplantation and its availability, as cadaveric organ donation remains the main source of donor organs. The mortality on the wait list, i.e. death from end-stage liver disease before a suitable donor organ becomes available, remains approximately 30% per year (1).
It is very clear to the gastroenterologists/hepatologists at the Vancouver General Hospital (VGH), that to ameliorate the many clinical tragedies associated with treating dying cirrhotic patients, awaiting a life-saving transplant, is to reduce the need for transplantation over the long-term. In this regard, over the past dozen years, we have seen the hepatitis C antiviral agents that we offer our patients, outside of transplantation, evolve and improve.
Hepatitis C is not a homogenous virus. Although all strains have equal virulence, response to treatment differs amongst the 6 genotypes (G), of which only three (G 1,2 and 3) are common in North America. With genotype 1 (the most common genotype in North America and Europe, and the most frustrating genotype to treat), the likelihood of a sustained virologic response (SVR) has improved from 30% with standard three times a week non-pegylated interferon in combination with ribavirin (3) to 40-50% with pegIFN and ribavirin (4,5). Patients with G2 and G3 infections have a much greater chance of clearing the virus (approximately 70%) and the duration of therapy is half that of the G1 patients (24 weeks vs. 48 weeks) (4).The combination pegIFN and ribavirin has been the standard in our clinical practice since 2003. For the G1 patients, the difficulty of taking a 48 week therapy with many side-effects, as well as the need to monitor the hematologic profile and thyroid function, is compounded by the fact that the overall odds of achieving a successful outcome is at best, a flip of a coin (in actuality, for those with advanced liver fibrosis and high viral loads, it is far less than a coin toss).
What changed my practice
Until this year, however, there was no other choice open to these patients. This year, based on the phase III studies, published in the New England Journal of Medicine (6, 7), confirming earlier clinical trials, the American regulatory body, the Food and Drug Administration (FDA) approved the new protease inhibitors, telapravir (7) and boceprevir (6) in combination with pegIFN and ribavirin for patients with HCV G1 infections. Telapravir (7) for 12 weeks and pegIFN with ribavirin for 24 or 48 weeks, depending on whether or not the HCV disappeared from the blood stream in the early weeks, has a likelihood of HCV sustained clearance of 75%. Similarly, the triple combination of bocepravir, pegIFN and ribavirin for 24-48 weeks, depending on whether early clearance is achieved or not, is associated with a 68% likelihood of sustained clearance (8). Considering that a sustained clearance has been demonstrated to be associated with cure in almost all patients, this is, for health-care professionals and hepatitis C patients alike, a reason for extreme optimism. It should be noted, that the likelihood of a sustained clearance with these new drugs is less in those of African background but this is still far superior than anything that came before. Although Canadian approval for these new drugs is still pending (as of this writing, July 01, 2011), it is very likely that Health Canada will act similarly to the FDA and allow the same antiviral benefits to Canadians that Americans now enjoy.
What I do now
Although it may seem unusual to write about “changing practice” with drugs that are not yet on the market in Canada, in actuality, myself, and my colleagues at the BC Hepatitis Program at VGH, have been using telapravir since 2007 and boceprevir since 2008 as part of our clinical trials program. We can confirm the outstanding efficacy of these drugs against HCV G1 infection and our patients are very appreciative. We have found the side-effect profile of the new protease inhibitors to be very manageable with the outstanding help of our excellent hepatitis nurses. We no longer offer patients with HCV G1 infections the “standard of therapy” as currently available because we know that it suboptimal and obsolete. We advise our patients to either wait for telapravir or boceprevir to become available (and for the majority, this also means waiting for BC Pharmacare to cover these antiviral agents) or to consider entry into a clinical trial with these agents or similar agents that we are also finding to be efficacious.
Lastly, we have reported that fewer patients infected with HCV G2 (the “easy to treat” genotype) are being sent for transplant assessment because this genotype is amenable to pegIFN and ribavirin therapy (8). This is clear epidemiologic evidence that effective antiviral therapy can decrease the need for liver transplantation and save lives. We expect that telapravir and boceprevir will be able to have the same epidemiologic effect over the long-term for G1 patients. The “future is now” and victory in the war against HCV is finally in sight. For the sake of our patients, it has to be.
References: (Note: Article requests require a login ID with CPSBC or UBC)
- Sherman M, Shafran S, Burak K et al. Management of chronic hepatitis C: consensus guidelines. Can J Gastroenterol 2007; 21 (suppl C): 25C-34C. (View article with CPSBC or UBC)
- Haque M, Scudamore CH, Steinbrecher UP et al. Liver transplantation: current status in British Columbia. BC Med J 2010; 52: 203-10. (View article with CPSBC or UBC)
- McHutchinson JG, Gordon SC, Schiff ER et al. Interferon alfa 2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998: 339: 1485-92. (View article with CPSBC or UBC)
- Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346-55. (View article with CPSBC or UBC)
- McHutchinson JG, Lawitz EJ, Shiffman ML et al. Peginterferon alpha-2b or alpha-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580-93. (View article with CPSBC or UBC)
- Poordad F, McCone J Jr, Bacon BR et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 31: 364: 1195-06. (View article with CPSBC or UBC)
- Jacobson IM, McHutchinson JG, Dusheiko G et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405-16. (View article with CPSBC or UBC)
- Hashim A, Haque M, Krajden M et al. Shift in HCV genotype in a liver transplant referral centre over 10 years: the British Columbia experience. Can J Gastroenterol 2010; 24 (suppl A): 158 A (abstract). (View article with CPSBC or UBC)