Dr Kenneth Siu Ho Chok
Consultant
Department of Surgery
The University of Hong Kong
In Hong Kong, about 8% of all liver transplants are done for diseases related to hepatitis C, which include decompensated liver cirrhosis and hepatocellular carcinoma. Treatment for hepatitis C before liver transplantation is notoriously difficult because the patients usually have poor liver function and thrombocytopenia. Moreover, the peg-interferon-based regimen, which is usually used in such treatment, has intolerable side effects. Reinfection of hepatitis C virus (HCV) is almost universal if the virus is not eradicated before reperfusion of the liver grafts.
Before 2011, the standard of care therapy for chronic hepatitis C featured the combination of peg-interferon and ribavirin. Among patients infected with HCV genotype 1, the rate of sustained virologic response (SVR) was around 50% after 48 weeks of therapy.
Therapy using direct-acting antivirals (DAAs) has emerged to bring about a new era in treating HCV infection by targetting specific components of the HCV that are important in its replication cycle. In 2011, two NS3 protease inhibitors, telaprevir and boceprevir, were approved. Both these agents still require the use of peg-interferon, with an improvement in the SVR rate to approximately 70%.
The recent approval for sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen) by the US Food and Drug Administration marks the beginning of a rapidly changing landscape defining the standard of care for patients with HCV infection. Sofosbuvir is a prodrug of a nucleotide analogue inhibitor of the HCV NS5B RNA-dependent RNA, whereas simeprevir is a specific inhibitor of the HCV NS3/4A serine protease.
Prior to the availability of DAAs, patients with established cirrhosis, especially those with advanced cirrhosis (such as those on the liver transplant waiting list), were not eligible for interferon-based antiviral therapy. Several studies using DAAs have shown the effectiveness of these agents in cirrhotic patients. In the COSMOS trial using simeprevir + sofosbuvir, the SVR rate in patients with HCV genotype 1 and F3/F4 disease was 94%.1 In the TURQUOISE II trial using a combination of ABT-450/r + ombitasvir + dasabuvir + ribavirin in cirrhotic patients, the SVR rate was 91.8% after 12 weeks (SVR12) of therapy and 95.9% after 24 weeks (SVR24).2 In another study on the combination sofosbivir and ribavirin for cirrhotic patients with portal hypertension with or without decompensation, 100% of the patients with Child-Pugh A disease and 93% of the patients with Child-Pugh B disease were negative for HCV RNA after 24 weeks of therapy.3 Obviously, if SVR can be achieved before liver transplantation, the risk of graft reinfection would be eliminated.
In patients with graft hepatitis from recurrent HCV infection after liver transplantation, the disease progression is often accelerated, with poor response and tolerance to previous interferon-based regimens. With the use of ABT-450/r + ombitasvir + dasabuvir + ribavirin, the SVR12 rate was 96.2%.4 The use of sofosbuvir + ribavirin for 24 weeks resulted in a SVR24 rate of 70%. It is likely that treatment using DAAs will become the mainstay of therapy after transplantation, and graft loss from recurrent hepatitis C will be a thing of the past.
An exciting prospect for all HCV-infected patients is the imminent availability of a powerful combination of DAAs in a single fixed-dose capsule. The combination of sofosbuvir and ledipasvir in a single capsule has shown to bring about a SVR12 rate close to 100% in non-transplant patients.
The main challenge is the cost issue. The daily cost for a 400mg sofosbuvir tablet is around 1000USD, making a 24-week course unaffordable for most patients. It is hoped that newer agents will come onto the market soon, so that the general cost will soon be lowered. In view that a SVR rate close to 100% has been achieved, we believe that hepatitis C will eventually follow smallpox into extinction.
References:
1. Lawitz et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. The Lancet, Early Online Publication, 28 July 2014
2. Poordad et al. ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis. N Engl J Med 2014; 370:1973-1982
3. Afdhal et al. Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety. J Hepatol 2014;60: S28
4. Kwo et al. Results of the phase 2 study M12-999: interferon-free regimen of ABT-450/R/ABT-267 + ABT-333 + ribavirin in livr transplant recipients with recurrent HCV genotype 1 infection. J Hepatol 2014;60:S47
5. Samuel et al. Sofosbuvir and ribavirin for the treatment of recurrent hepatitis C infection after liver transplantation: results of a prospective, multicenter study. J Hepatol 2014;40:S499