Curr Gastroenterol Rep (2015) 17:20 DOI 10.1007/s11894-015-0443-3
LIVER (B BACON, SECTION EDITOR)
Management of HCV in Cirrhosis—a Rapidly Evolving Landscape Suraj A. Sharma 1 & Jordan J. Feld 1
# Springer Science+Business Media New York 2015
Abstract Despite the rapid progress in treatment, chronic hepatitis C virus (HCV) infection remains a growing cause of liver-related mortality globally. Patients who have been infected for decades are now presenting with advanced liver disease with the complications of cirrhosis and liver cancer. Early attempts at treatment with peginterferon and ribavirin were limited by toxicity, long treatment duration, and limited efficacy. This was especially relevant for patients with cirrhosis, where exposure to peginterferon-based therapy was relatively ineffective and led to high rates of toxicity. However, the recent development of multiple novel direct-acting antivirals (DAAs) has revolutionized the treatment of HCV. The majority of patients can now be cured with short courses of extremely well-tolerated all-oral regimens. However, the real test of these regimens comes in patients with more advanced liver disease, both in terms of safety and efficacy. Patients with cirrhosis have the greatest need for therapy and have traditionally been the most difficult to cure. The new therapies are rapidly changing this paradigm. Accumulating data suggest that high cure rates are achievable in patients with compensated cirrhosis and may even be possible in patients with signs of liver failure. This review will focus on the treatment of HCV in patients with cirrhosis, with an emphasis on
This article is part of the Topical Collection on Liver * Jordan J. Feld [email protected] 1
Toronto Center for Liver Disease, Sandra Rotman Centre for Global Health, University Health Network, University of Toronto, 6B-Fell Pavilion, Room 158, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada
the challenges that remain and strategies to deal with this important population. Keywords Hepatitis C . Sustained virologic response . Peginterferon . Epidemiology . Direct-acting antivirals (DAA) . Decompensation . Cirrhosis
Introduction Chronic hepatitis C (CHC) infection continues to be a common and growing cause of liver-related morbidity and mortality globally. The global prevalence of hepatitis C virus (HCV) infection is estimated to have increased from close to 122 million in 1990 (2.3 %) to 184 million people in 2005 (2.8 %), [1, 2] causing an estimated 350,000 deaths annually from the complications of end-stage liver disease and hepatocellular carcinoma (HCC) [3]. HCV causes slowly progressive liver injury over many years and even decades of infection. Life-threatening complications of the disease are rare until people progress to cirrhosis. The lifetime risk of cirrhosis is very difficult to estimate both at the population level and for the individual patient. It is commonly reported that cirrhosis occurs in approximately 20 % of infected individuals [4]. However, this figure is derived from risk estimates after 20 years of infection. Because many individuals contract HCV early in life through either contaminated medical equipment or injection drug use, the duration of infection is often much longer than 20 years. Modeling data suggest that the risk of cirrhosis may surpass 40 % by 30 years of infection [5]; however, accurate data on the lifetime risk of cirrhosis are lacking. For the individual patient, the risk of progressing to cirrhosis is determined by a combination of viral, host, and environmental factors. Genotype 3 HCV has been shown in recent
20
Page 2 of 11
years to lead to more progressive liver injury, possibly due to the steatogenic effect of this viral strain [6]. Although some more recent studies suggest that higher viral titers may lead to more progressive disease [7, 8], most data suggest that viral load is not a major determinant of fibrosis progression [9]. Of host factors, age and age at infection are important with the 20-year cumulative incidence of cirrhosis in chronic HCV varying from 5 % in patients infected before age 40 [10] to 20 % in patients infected after age 40 [4]. Other host risk factors include male gender [11], ongoing chronic inflammation (with elevated ALT) [12], coinfection with HBV or HIV [13, 14], and development of steatosis and insulin resistance [15]. A set of single nucleotide polymorphisms has also been reported to be associated with more rapid fibrosis progression; however, the mechanisms remain obscure [16]. The most important environmental cofactor in disease progression is concomitant heavy alcohol consumption (>50 g/day) [11, 17], which may significantly accelerate disease progression. HCV prevalence peaked in the early 2000s and has been slowly declining since that time [18•, 19]. However, as the cohort of individuals infected decades ago through experimentation with injection drug use or via contaminated blood products ages, the prevalence of cirrhosis continues to increase. Even with declining HCV prevalence, mortality related to complications of cirrhosis and HCC is anticipated to continue rising until at least 2027 [20]. However, the remarkable therapeutic developments of the past few years raise the prospect of a very altered and hopefully much more favorable future for patients with CHC. Viral eradication with effective antiviral therapy halts disease progression and may lead to regression of established fibrosis, with the potential to even reverse cirrhosis [21]. If patients achieve a sustained virological response (SVR) prior to the development of cirrhosis, they are truly cured with no risk of future hepatic sequelae [22]. For those with established cirrhosis at the time of treatment, SVR still markedly reduces the risk of HCC and effectively eliminates the risk of liver failure [23, 24]. Clearly, the optimal way to prevent complications of cirrhosis is to prevent cirrhosis altogether by treating patients early in the disease process. However, for those who present with cirrhosis, treatment still has major impact [24]. Traditionally, patients with cirrhosis have presented the greatest challenge, as they are the patients who need therapy the most and tolerate and respond to it the least well. The recent development of extremely well-tolerated, highly effective direct-acting antivirals (DAAs) has changed the prospect for those with cirrhosis dramatically (Table 1). In patients with compensated cirrhosis, treatment success rates are comparable to those without cirrhosis and early reports of treating even those with signs of liver failure are surprisingly favorable. As with all aspects of treatment for CHC, treatment of patients with cirrhosis is in rapid flux. This review will focus on the treatment of HCV in patients with cirrhosis in the context of this rapidly evolving treatment landscape.
Curr Gastroenterol Rep (2015) 17:20
Interferon-Based Treatment in Cirrhosis Prior to the development of DAAs, treatment of CHC consisted of peginterferon and ribavirin. Ribavirin was noted to have antiviral activity against HCV in small pilot studies performed in the early 1990s [43] and was studied in combination with interferon beta by 1993 [26]. By 1995, interferonalfa was combined with ribavirin to treat patients who had relapsed on interferon monotherapy in small studies [25]. In 1998, this result was corroborated in a large randomized trial [44]. By 2002, pegylated interferon (peginterferon) was developed and tested, allowing for reduced frequency of injections (weekly rather than three times per week) [45]. In large RCTs, SVR rates of 40 % were obtained in genotype 1 (G1) treatment-naïve patients treated with peginterferon and ribavirin [27]. However, among patients with advanced fibrosis or cirrhosis (F3/4), SVR rates dropped substantially. For example, a study of 271 patients with F3/4 showed SVR rates of only 30 % after 48 weeks of peginterferon alfa2a [28]. These results have been corroborated in other studies, including both Asian and European cohorts [29, 30]. Similar results have been obtained in patients with genotype 4 cirrhosis. A meta-analysis of 1536 patients with advanced (F3-4) fibrosis across 14 studies reported an SVR rate of 39 %, compared to 66 % among patients with mild fibrosis [46]. Even in patients with the more Binterferon-sensitive^ genotypes (G2 and G3), cirrhosis was a strong predictor of reduced treatment efficacy. In those with G2 infection, SVR rates as low as 50 % [47] have been reported in patients with cirrhosis, compared to the 80–95 % rates reported in noncirrhotic cohorts [31]. The effect of cirrhosis appeared to be even greater in those with genotype 3 infection, with rates of SVR as low as 17 % reported and most studies finding that fewer than 50 % achieved SVR [47]. Whether the steatosis associated with genotype 3 or some other viral factors affect the response to peginterferon and now to new DAAs remains unclear. Besides limited efficacy, peginterferon and ribavirin also led to an increased risk of adverse events in patients with cirrhosis, particularly those with any signs of decompensation (Table 2). Everson and colleagues pioneered the lowaccelerating dosing regimen in an attempt to improve tolerability for patients with cirrhosis [32]. In a study of 124 patients with cirrhosis, 55 % of whom had Child’s-PughTurcotte (CPT) B or C, significant adverse events were very frequent, including 4 deaths. Sepsis, worsening ascites, and encephalopathy were the most common serious complications. Notably, 21 of the 22 serious adverse events were seen in patients with CPT B or C cirrhosis and the SVR rates were extremely low (13 % G1 and 50 % non-G1). A systematic review of 1133 patients with cirrhosis showed that 14.5 % discontinued therapy due to severe adverse events
Curr Gastroenterol Rep (2015) 17:20 Table 1
Page 3 of 11 20
Summary of SVR rates for selected interferon-containing and interferon-free regimens in patients with cirrhosis
Regimen
Interferon-containing regimens PegIFN-RBV (24–48 weeks) PegIFN-RBV + telaprevir/ boceprevir (48 weeks)
PegIFN-RBV + simeprevir (24–48 weeks) PegIFN-RBV + sofosbuvir (12 weeks) Interferon-free regimens Simeprevir + sofosbuvir (12 weeks) Sofosbuvir + ledipasvir +/− RBV (12–24 weeks)
Sofosbuvir + ledipasvir + RBV (12 weeks) Sofosbuvir + RBV (12–24 weeks)
Genotype 1 SVR (%)
Genotype 2 SVR (%)
Genotype 3 SVR (%)
Genotype 4 SVR (%)
20–30 [22, 23] 42–62 (naïve) 77–84 (relapser) 14–15 (null-responder) [27–30] 60 [31, 32]
50 [25]
17 [25]
40 [26]
80 [33]
93 [34]
83 [34]
93 (treatment-naïve, 12 weeks) 60 (treatment-experienced, 12 weeks) 78 (treatment-experienced, 16 weeks) [33, 39, 40]
31 (treatment-naïve, 12 weeks) 19 (treatment-experienced, 12 weeks) 92 (treatment-naïve, 24 weeks 60 (treatment-experienced, 24 weeks) [33, 39, 40] 58 (treatment-naïve, 12 weeks) 69 (treatment-experienced, 12 weeks) [41]
93 [35] 97 (treatment-naïve, 12 weeks) 96 (treatment-experienced with RBV, 12 weeks 98 (treatment-experienced, 24 weeks) [36•, 37] 87 (CPT B or C) [38••]
Sofosbuvir + daclatasvir (12 weeks) Paritaprevir/ritonovir + ombitasvir + dasabuvir + RBV (12–24 weeks)
92 (12 weeks) 96 (24 weeks) 80 (G1a, null responder, 12 weeks) 93 (G1a, null responder, 24 weeks) [42]
References for SVR rates are shown in square brackets PegIFN-RBV pegylated interferon + ribavirin, CPT Child-Pugh-Turcotte score
[48], and the rate of treatment discontinuation was significantly higher in patients with CPT B or C cirrhosis. In addition, approximately 25 % of patients required dosereductions due to severe side effects and ultimately the SVR rate was only 20.5 % in patients with genotypes 1 or 4 and 56.5 % in those with genotypes 2 or 3. With this high risk to benefit ratio, peginterferon-based therapy effectively became contraindicated in patients with any signs of decompensation.
First-Generation Direct-Acting Antivirals—Boceprevir and Telaprevir Boceprevir and telaprevir were the first approved DAAs— both first-generation NS3 HCV protease inhibitors (PI), with
a low genetic barrier to resistance and activity limited to G1 HCV. Both drugs were licensed for use in combination with peginterferon and ribavirin, with a total treatment duration of 48 weeks for patients with cirrhosis. The initial studies of both agents generated much enthusiasm, with SVR rates ranging from 63 to 72 % among cirrhotic patients receiving 48 weeks of therapy [33, 35, 49, 50]. The addition of the PI significantly increased SVR rate when compared to peginterferonribavirin therapy alone. These data led to changes in the HCV treatment guidelines both in Europe and North America. However, these recommendations were based on very small (
LIVER (B BACON, SECTION EDITOR)
Management of HCV in Cirrhosis—a Rapidly Evolving Landscape Suraj A. Sharma 1 & Jordan J. Feld 1
# Springer Science+Business Media New York 2015
Abstract Despite the rapid progress in treatment, chronic hepatitis C virus (HCV) infection remains a growing cause of liver-related mortality globally. Patients who have been infected for decades are now presenting with advanced liver disease with the complications of cirrhosis and liver cancer. Early attempts at treatment with peginterferon and ribavirin were limited by toxicity, long treatment duration, and limited efficacy. This was especially relevant for patients with cirrhosis, where exposure to peginterferon-based therapy was relatively ineffective and led to high rates of toxicity. However, the recent development of multiple novel direct-acting antivirals (DAAs) has revolutionized the treatment of HCV. The majority of patients can now be cured with short courses of extremely well-tolerated all-oral regimens. However, the real test of these regimens comes in patients with more advanced liver disease, both in terms of safety and efficacy. Patients with cirrhosis have the greatest need for therapy and have traditionally been the most difficult to cure. The new therapies are rapidly changing this paradigm. Accumulating data suggest that high cure rates are achievable in patients with compensated cirrhosis and may even be possible in patients with signs of liver failure. This review will focus on the treatment of HCV in patients with cirrhosis, with an emphasis on
This article is part of the Topical Collection on Liver * Jordan J. Feld [email protected] 1
Toronto Center for Liver Disease, Sandra Rotman Centre for Global Health, University Health Network, University of Toronto, 6B-Fell Pavilion, Room 158, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada
the challenges that remain and strategies to deal with this important population. Keywords Hepatitis C . Sustained virologic response . Peginterferon . Epidemiology . Direct-acting antivirals (DAA) . Decompensation . Cirrhosis
Introduction Chronic hepatitis C (CHC) infection continues to be a common and growing cause of liver-related morbidity and mortality globally. The global prevalence of hepatitis C virus (HCV) infection is estimated to have increased from close to 122 million in 1990 (2.3 %) to 184 million people in 2005 (2.8 %), [1, 2] causing an estimated 350,000 deaths annually from the complications of end-stage liver disease and hepatocellular carcinoma (HCC) [3]. HCV causes slowly progressive liver injury over many years and even decades of infection. Life-threatening complications of the disease are rare until people progress to cirrhosis. The lifetime risk of cirrhosis is very difficult to estimate both at the population level and for the individual patient. It is commonly reported that cirrhosis occurs in approximately 20 % of infected individuals [4]. However, this figure is derived from risk estimates after 20 years of infection. Because many individuals contract HCV early in life through either contaminated medical equipment or injection drug use, the duration of infection is often much longer than 20 years. Modeling data suggest that the risk of cirrhosis may surpass 40 % by 30 years of infection [5]; however, accurate data on the lifetime risk of cirrhosis are lacking. For the individual patient, the risk of progressing to cirrhosis is determined by a combination of viral, host, and environmental factors. Genotype 3 HCV has been shown in recent
20
Page 2 of 11
years to lead to more progressive liver injury, possibly due to the steatogenic effect of this viral strain [6]. Although some more recent studies suggest that higher viral titers may lead to more progressive disease [7, 8], most data suggest that viral load is not a major determinant of fibrosis progression [9]. Of host factors, age and age at infection are important with the 20-year cumulative incidence of cirrhosis in chronic HCV varying from 5 % in patients infected before age 40 [10] to 20 % in patients infected after age 40 [4]. Other host risk factors include male gender [11], ongoing chronic inflammation (with elevated ALT) [12], coinfection with HBV or HIV [13, 14], and development of steatosis and insulin resistance [15]. A set of single nucleotide polymorphisms has also been reported to be associated with more rapid fibrosis progression; however, the mechanisms remain obscure [16]. The most important environmental cofactor in disease progression is concomitant heavy alcohol consumption (>50 g/day) [11, 17], which may significantly accelerate disease progression. HCV prevalence peaked in the early 2000s and has been slowly declining since that time [18•, 19]. However, as the cohort of individuals infected decades ago through experimentation with injection drug use or via contaminated blood products ages, the prevalence of cirrhosis continues to increase. Even with declining HCV prevalence, mortality related to complications of cirrhosis and HCC is anticipated to continue rising until at least 2027 [20]. However, the remarkable therapeutic developments of the past few years raise the prospect of a very altered and hopefully much more favorable future for patients with CHC. Viral eradication with effective antiviral therapy halts disease progression and may lead to regression of established fibrosis, with the potential to even reverse cirrhosis [21]. If patients achieve a sustained virological response (SVR) prior to the development of cirrhosis, they are truly cured with no risk of future hepatic sequelae [22]. For those with established cirrhosis at the time of treatment, SVR still markedly reduces the risk of HCC and effectively eliminates the risk of liver failure [23, 24]. Clearly, the optimal way to prevent complications of cirrhosis is to prevent cirrhosis altogether by treating patients early in the disease process. However, for those who present with cirrhosis, treatment still has major impact [24]. Traditionally, patients with cirrhosis have presented the greatest challenge, as they are the patients who need therapy the most and tolerate and respond to it the least well. The recent development of extremely well-tolerated, highly effective direct-acting antivirals (DAAs) has changed the prospect for those with cirrhosis dramatically (Table 1). In patients with compensated cirrhosis, treatment success rates are comparable to those without cirrhosis and early reports of treating even those with signs of liver failure are surprisingly favorable. As with all aspects of treatment for CHC, treatment of patients with cirrhosis is in rapid flux. This review will focus on the treatment of HCV in patients with cirrhosis in the context of this rapidly evolving treatment landscape.
Curr Gastroenterol Rep (2015) 17:20
Interferon-Based Treatment in Cirrhosis Prior to the development of DAAs, treatment of CHC consisted of peginterferon and ribavirin. Ribavirin was noted to have antiviral activity against HCV in small pilot studies performed in the early 1990s [43] and was studied in combination with interferon beta by 1993 [26]. By 1995, interferonalfa was combined with ribavirin to treat patients who had relapsed on interferon monotherapy in small studies [25]. In 1998, this result was corroborated in a large randomized trial [44]. By 2002, pegylated interferon (peginterferon) was developed and tested, allowing for reduced frequency of injections (weekly rather than three times per week) [45]. In large RCTs, SVR rates of 40 % were obtained in genotype 1 (G1) treatment-naïve patients treated with peginterferon and ribavirin [27]. However, among patients with advanced fibrosis or cirrhosis (F3/4), SVR rates dropped substantially. For example, a study of 271 patients with F3/4 showed SVR rates of only 30 % after 48 weeks of peginterferon alfa2a [28]. These results have been corroborated in other studies, including both Asian and European cohorts [29, 30]. Similar results have been obtained in patients with genotype 4 cirrhosis. A meta-analysis of 1536 patients with advanced (F3-4) fibrosis across 14 studies reported an SVR rate of 39 %, compared to 66 % among patients with mild fibrosis [46]. Even in patients with the more Binterferon-sensitive^ genotypes (G2 and G3), cirrhosis was a strong predictor of reduced treatment efficacy. In those with G2 infection, SVR rates as low as 50 % [47] have been reported in patients with cirrhosis, compared to the 80–95 % rates reported in noncirrhotic cohorts [31]. The effect of cirrhosis appeared to be even greater in those with genotype 3 infection, with rates of SVR as low as 17 % reported and most studies finding that fewer than 50 % achieved SVR [47]. Whether the steatosis associated with genotype 3 or some other viral factors affect the response to peginterferon and now to new DAAs remains unclear. Besides limited efficacy, peginterferon and ribavirin also led to an increased risk of adverse events in patients with cirrhosis, particularly those with any signs of decompensation (Table 2). Everson and colleagues pioneered the lowaccelerating dosing regimen in an attempt to improve tolerability for patients with cirrhosis [32]. In a study of 124 patients with cirrhosis, 55 % of whom had Child’s-PughTurcotte (CPT) B or C, significant adverse events were very frequent, including 4 deaths. Sepsis, worsening ascites, and encephalopathy were the most common serious complications. Notably, 21 of the 22 serious adverse events were seen in patients with CPT B or C cirrhosis and the SVR rates were extremely low (13 % G1 and 50 % non-G1). A systematic review of 1133 patients with cirrhosis showed that 14.5 % discontinued therapy due to severe adverse events
Curr Gastroenterol Rep (2015) 17:20 Table 1
Page 3 of 11 20
Summary of SVR rates for selected interferon-containing and interferon-free regimens in patients with cirrhosis
Regimen
Interferon-containing regimens PegIFN-RBV (24–48 weeks) PegIFN-RBV + telaprevir/ boceprevir (48 weeks)
PegIFN-RBV + simeprevir (24–48 weeks) PegIFN-RBV + sofosbuvir (12 weeks) Interferon-free regimens Simeprevir + sofosbuvir (12 weeks) Sofosbuvir + ledipasvir +/− RBV (12–24 weeks)
Sofosbuvir + ledipasvir + RBV (12 weeks) Sofosbuvir + RBV (12–24 weeks)
Genotype 1 SVR (%)
Genotype 2 SVR (%)
Genotype 3 SVR (%)
Genotype 4 SVR (%)
20–30 [22, 23] 42–62 (naïve) 77–84 (relapser) 14–15 (null-responder) [27–30] 60 [31, 32]
50 [25]
17 [25]
40 [26]
80 [33]
93 [34]
83 [34]
93 (treatment-naïve, 12 weeks) 60 (treatment-experienced, 12 weeks) 78 (treatment-experienced, 16 weeks) [33, 39, 40]
31 (treatment-naïve, 12 weeks) 19 (treatment-experienced, 12 weeks) 92 (treatment-naïve, 24 weeks 60 (treatment-experienced, 24 weeks) [33, 39, 40] 58 (treatment-naïve, 12 weeks) 69 (treatment-experienced, 12 weeks) [41]
93 [35] 97 (treatment-naïve, 12 weeks) 96 (treatment-experienced with RBV, 12 weeks 98 (treatment-experienced, 24 weeks) [36•, 37] 87 (CPT B or C) [38••]
Sofosbuvir + daclatasvir (12 weeks) Paritaprevir/ritonovir + ombitasvir + dasabuvir + RBV (12–24 weeks)
92 (12 weeks) 96 (24 weeks) 80 (G1a, null responder, 12 weeks) 93 (G1a, null responder, 24 weeks) [42]
References for SVR rates are shown in square brackets PegIFN-RBV pegylated interferon + ribavirin, CPT Child-Pugh-Turcotte score
[48], and the rate of treatment discontinuation was significantly higher in patients with CPT B or C cirrhosis. In addition, approximately 25 % of patients required dosereductions due to severe side effects and ultimately the SVR rate was only 20.5 % in patients with genotypes 1 or 4 and 56.5 % in those with genotypes 2 or 3. With this high risk to benefit ratio, peginterferon-based therapy effectively became contraindicated in patients with any signs of decompensation.
First-Generation Direct-Acting Antivirals—Boceprevir and Telaprevir Boceprevir and telaprevir were the first approved DAAs— both first-generation NS3 HCV protease inhibitors (PI), with
a low genetic barrier to resistance and activity limited to G1 HCV. Both drugs were licensed for use in combination with peginterferon and ribavirin, with a total treatment duration of 48 weeks for patients with cirrhosis. The initial studies of both agents generated much enthusiasm, with SVR rates ranging from 63 to 72 % among cirrhotic patients receiving 48 weeks of therapy [33, 35, 49, 50]. The addition of the PI significantly increased SVR rate when compared to peginterferonribavirin therapy alone. These data led to changes in the HCV treatment guidelines both in Europe and North America. However, these recommendations were based on very small (
