Systematic Review

Current Concepts and Challenges for the Direct-acting Antiviral Era in Hepatitis C Cirrhosis

A. Majumdar; M. T. Kitson; S. K. Roberts


Aliment Pharmacol Ther. 2016;43(12):1276-1292. 

In This Article

Abstract and Introduction


Background The burden of HCV cirrhosis is high and projected to increase significantly over the next decade. While interferon therapy is problematic in HCV cirrhosis, the era of direct-acting anti-viral (DAA) therapy provides effective treatment for patients with cirrhosis.

Aim To systematically review the results of DAA therapy to date in patients with HCV cirrhosis, and highlight the ongoing challenges for DAA therapy in this population.

Methods A structured Medline search was conducted to obtain phase II and III HCV trials in patients with cirrhosis. Citations from review articles were cross-referenced and conference abstracts from EASL and AASLD liver meetings for the preceding 3 years were reviewed manually. Keywords used included hepatitis C, cirrhosis and the DAA's: sofosbuvir, ledipasvir, velpatasvir, grazoprevir, elbasvir, daclatasvir, beclabuvir, asunaprevir, simeprevir, paritaprevir, ombitasvir and dasabuvir.

Results Successful direct-acting anti-viral treatment is now possible in patients with HCV-related cirrhosis including those with liver decompensation with several regimens now offering sustained virological response (SVR) of 90–95%. Overall success rates in GT1 cirrhosis are excellent while GT3-infected patients with cirrhosis remain hard to cure. The pangenotypic combination of sofosbuvir and velpatasvir holds promise for GT3 cirrhosis achieving SVR of ~90%.

Conclusions Potent DAA therapies provide much needed, safe and highly effective treatment options for persons with HCV cirrhosis including those previously deemed unsuitable for treatment. Combination therapy with two or more classes of drug is essential to achieve high efficacy and minimise viral resistance, with the role of ribavirin still under evaluation. However, several challenges remain including the hard-to-cure groups of GT3 cirrhosis and direct-acting anti-viral failures, and managing drug–drug interactions.


Globally, chronic hepatitis C virus (HCV) infection affects over 180 million people. The resultant burden of liver disease is significant, with HCV remaining a major cause of cirrhosis and the leading indication for liver transplantation (LT).[1–3] Across Europe, HCV seroprevalence rates are as high as 3.3% in some regions while chronic HCV infection currently affects an estimated 8.5 million persons.[4] In the United States, around 2.7 million individuals have chronic HCV infection with HCV accounting for up to 13 000 deaths annually.[5,6] Furthermore, the prevalence of HCV-related cirrhosis is estimated to be 25%, which is projected to increase to 37% by 2020.[7,8]

Chronic HCV infection leads to cirrhosis in approximately 16% over 20 years of infection. Once cirrhosis is established, there is an estimated 3–5% annual risk of developing hepatocellular carcinoma (HCC) and a 3–6% annual risk of hepatic decompensation. Moreover, the risk of death within 1 year following hepatic decompensation is 15–20%.[9–11] The successful endpoint of HCV treatment is sustained virological response (SVR). Achieving an SVR is associated with regression of hepatic fibrosis and in patients with cirrhosis, a reduction in portal hypertension, and attenuated risk of development of hepatic decompensation and HCC.[12–16] These clinical outcomes have been shown to translate to a reduction in both liver and non-liver-related mortality and improvements in quality of life.[17–21] Furthermore, it has been suggested that even those with advanced fibrosis or cirrhosis who achieve an SVR have an overall survival similar to the general population.[22]

Peginterferon (PegIFN)-based therapy has been the mainstay of HCV treatment for over a decade. However, treatment in patients with cirrhosis has been difficult due to low SVR rates and higher risks of serious adverse events compared to those without cirrhosis.[23–25] Additionally, those with advanced or decompensated liver disease, who arguably need treatment most, are unable to tolerate interferon-based therapy due to the significant risk of sepsis, liver failure and death.[26–28] The direct-acting anti-viral (DAA) era of HCV therapy arrived in 2011 following the introduction of the protease inhibitors (PIs) boceprevir, telaprevir and subsequently simeprevir for HCV genotype 1 patients. Despite increasing SVR rates in combination with PegIFN and ribavirin (RBV), important real-world data from Europe reporting the use of these agents identified significant safety concerns in patients with advanced chronic liver disease.[29]

Thus, the major focus in recent years has been the pursuit of safe and effective interferon-free drug regimens, particularly for those with advanced chronic liver disease and/or those who have failed interferon-based therapy. The rapid development of highly efficacious and well-tolerated, all-oral, interferon-free treatment for patients with cirrhosis is becoming a reality in many European countries as well as the USA. Currently, approved DAA regimens in Europe and/or the USA include the sofosbuvir/ledipasvir co-formulation, daclatasvir combined with sofosbuvir, simeprevir plus sofosbuvir, and the three DAA regimen of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir. However, the optimal duration of therapy, the ideal combination of drug classes and the role of RBV are some of the areas that are yet to be fully understood. Furthermore, many challenges remain, specifically regarding costs, reduced SVR rates for those with genotype 3 infection, the potential for viral resistance, drug–drug interactions and determining treatment algorithms for those who do not respond to DAA therapy. The aim of this review is to summarise the progress made in the treatment of patients with HCV-related cirrhosis to date, including results from conference abstracts awaiting peer-reviewed publication.