TRMOME-938; No. of Pages 7
Review
Hepatitis C treatment: an incipient therapeutic revolution Andrew S. deLemos1 and Raymond T. Chung2 1
Department of Medicine, Center for Liver Diseases and Transplantation, Carolinas Medical Center, Charlotte, NC 28203, USA Department of Medicine, Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
2
An exciting paradigm shift is occurring in the treatment of hepatitis C virus (HCV). We now have the capacity to specifically target therapy to HCV proteins, and thereby directly interrupt the viral life cycle. The first direct-acting antivirals (DAAs), the NS3–4A serine protease inhibitors boceprevir and telaprevir, improved the rate of sustained virologic response (SVR), but their toxicities combined with PEG-IFN and RBV limited their overall efficacy. Sofosbuvir, a nucleotide HCV polymerase inhibitor, is now available and offers better tolerability and efficacy across all HCV genotypes. The next phase of therapy will be combining several classes of DAAs without IFN in order to make sustained clearance of hepatitis C deliverable to a much larger number of infected individuals. Hepatitis C infection: a glimpse back with a focus forward The scope of hepatitis C virus (HCV) infection is remarkably wide. Estimates suggest that up to 185 million people are infected worldwide, 3–4 million of whom reside in the USA [1,2]. Over 80% of patients develop a chronic, often asymptomatic, infection [3]. Furthermore, 5–30% of chronically infected patients will develop cirrhosis (see Glossary) and frequently will present with features of advanced liver disease such as variceal hemorrhage and hepatocellular carcinoma (HCC). Population-based studies indicate that the prevalence of decompensated cirrhosis has doubled over the past decade, whereas the prevalence of HCC has increased by 20-fold [4]. The annual mortality in the USA directly attributed to sequelae of end-stage liver disease (ESLD) due to hepatitis C infection was 16 627 in 2010 (http://www.cdc.gov/hepatitis/HCV/StatisticsHCV.htm), and this number is expected to double by 2030 [5]. ESLD due to HCV is the most common indication for liver transplant, which is itself complicated by universal allograft reinfection. Beyond the human cost, HCV infection is a tremendous economic burden, with total costs projected to peak at $9.1 Corresponding authors: deLemos, A.S. ([email protected]); Chung, R.T. ([email protected]). Keywords: hepatitis C; pegylated interferon; NS3–4A serine protease inhibitors; direct-acting antivirals (DAAs); sofosbuvir; simeprevir. 1471-4914/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2014.02.002
billion in 2024 [6]. Owing to these trends, coupled with the availability of increasingly effective and tolerated therapy, the Centers for Disease Control and Prevention (CDC) and the Department of Health and Human Services (DHHS) have now recommended universal testing for all US residents born between 1945 and 1964 [7], a group notable for being the largest epidemiologic risk group, and at highest risk for complications due to disease duration. Markov models suggest that this screening measure would be cost effective by preventing 84 000 cases of decompensated cirrhosis, 46 000 new cases of HCC, and 10 000 liver transplants [8]. Although the magnitude of HCV-related complications may be imposing to consider, a transformative period in treating HCV is now upon us. Caregivers, until very recently, had relied on pegylated interferon a (PEG-IFN) and ribavirin (RBV) to treat chronic hepatitis C (CHC) (Box 1). PEG-IFN/RBV produces a sustained virologic response (SVR) in approximately 50% of HCV genotype 1 patients Glossary Cirrhosis: a chronic liver disease that evolves often due to inflammation (e.g., alcoholism, viral hepatitis) in which the normal cellular architecture of the liver is replaced by nodular bands of fibrous tissue. Direct-acting antiviral (DAA): any drug within the class of HCV therapeutics with specific activity against a hepatitis C viral protein. Fibrosis: thickened connective tissue which forms as a response to injury to an organ. In chronic hepatitis C infection, liver fibrosis is staged on a continuum. The METAVIR system scores fibrosis on a liver biopsy from F0 to F4: F0, no fibrosis; F1, portal fibrosis; F2, portal fibrosis with few septa; F3, bridging fibrosis; F4, cirrhosis. IL28B: gene encoding IFNl3, a type III interferon; genetic variation upstream of this gene was found to be important in both spontaneous and PEG-IFNinduced clearance of hepatitis C infection. NS3–4A protease inhibitors (PIs): includes the first generation DAAs, boceprevir and telaprevir, as well as the next generation agents, simeprevir, faldaprevir, asunaprevir, and ABT450. These DAAs specifically inhibit the NS3– 4A protease. NS5A: HCV protein required for viral particle assembly, and an attractive DAA target due to high potency, but low barrier to resistance. Examples of DAAs targeting NS5A include daclatasvir and ledipasvir. NS5B polymerase inhibitors: class of DAA with several pharmacologic targets on the NS5B polymerase protein, including the catalytic site (sofosbuvir) or allosteric sites away from the active site (e.g., ABT333) which inhibit viral replication Sustained virologic response (SVR): no detectable HCV RNA by PCR following cessation of antiviral therapy for HCV. This prespecified endpoint has been defined in clinical trials by study investigators. An SVR24, or undetectable HCV 24 weeks following completion of therapy, was the standard endpoint for early clinical trials. Subsequent studies have shown that SVR12 is essentially interchangeable with SVR24, and SVR12 has now been adopted as an endpoint for current clinical trials with DAAs. Triple therapy: a combination of PEG-interferon, ribavirin, and the addition of a direct acting antiviral.
Trends in Molecular Medicine xx (2014) 1–7
1
TRMOME-938; No. of Pages 7
Review Box 1. IL28B testing and next generation HCV therapy? Amid the flurry of activity to identify novel therapeutics to treat HCV, there has been a simultaneous pursuit to understand the role of human genetic variation in the natural history of HCV infection. SVR rates to PEG-IFN/RBV therapy are remarkably variable among genotype 1 HCV-infected patients. With this in mind, genome-wide association studies (GWAS) were conducted to investigate whether locus specific variation predicted response to PEG-IFN/RBV [36–39]. A highly significant haplotype of single nucleotide polymorphisms (SNPs) upstream of the interleukin-28B (IL28B) gene on chromosome 19 was identified. Homozygosity for the ‘C’ allele for rs12979860 is associated with a 2- to 3-fold higher SVR rate to PEG-IFN/RBV than either heterozygosity (CT) or homozygosity for the rarer ‘T’ allele [38]. Groups from Japan and Australia both reported genome-wide association between non-response to interferon and the presence of the minor ‘G’ allele for rs8099917 [36,39]. The presence of either the ‘C’ allele (rs12979860) or the ‘T’ allele (rs8099917) is also associated with spontaneous clearance of acute HCV infection [37,40,41]. Variation in IL28B genotype frequencies also explains a sizable basis of the difference in SVR rates seen in patients of different ethnic backgrounds [38,40]. IL28B encodes a type III interferon, IFNl3, which similar to type I IFN, activates the JAK–STAT pathway, leading to expression of interferon-stimulated genes (ISGs), which are integral for the host antiviral response. Although not in a coding region, the IL28B SNPs have been shown to be associated with differential ISG expression [42]. In the recent past, determining IL28B genotype for patients considering triple therapy with TVR or BOC was recommended, because retrospective analyses of the first generation PI registration trials found that IL28B status significantly impacted SVR rates (reviewed in [43]). In terms of the next generation DAAs with PEGIFN/RBV, IL28B genotype did not impact the response to 12 weeks of sofosbuvir/PEG-IFN/RBV in genotype 1 CHC patients [44], but did affect the response to simeprevir-based triple therapy in treatmentexperienced patients. In this group, IL28B genotype ‘TT’ was associated with a modest reduced benefit with SVR12 rates of 64.5% (‘TT’) versus 79.2% (‘CT and CC’) [17]. IL28B genotype may become inconsequential with future IFN-free treatment regimens, particularly in view of increasingly impressive SVR rates; to this end, preliminary analyses suggest no statistically significant difference [26,29]. As SVR rates continue to improve with more potent all-oral DAA regimens, it is increasingly apparent that IL28B genotype testing will have diminishing clinical utility.
(which accounts for 75% of HCV infections in the USA), whereas SVR rates approach 80% for genotypes 2 or 3. These response rates successfully forestall complications of CHC; however, PEG-IFN/RBV therapy is cumbersome and frequently produces unacceptable toxicities. For example, PEG-IFN is associated with flu-like symptoms, cytopenias, autoimmunity, and depression. RBV causes hemolysis and symptomatic anemia, particularly in patients with advanced fibrosis who are most in need of therapy. Many patients either refuse therapy or are unwilling to continue owing to side effects. This quandary has spurred tremendous research into understanding the virology and pathogenesis of hepatitis C infection to develop therapeutics that specifically target antiviral proteins. The first of these direct-acting antivirals (DAAs), the HCV protease inhibitors telaprevir (TVR) and boceprevir (BOC), gained FDA approval in May 2011 for the treatment of genotype 1 CHC. The next wave of DAAs, with improved efficacy and tolerability, are now available and promise to dramatically alter the natural history of CHC infection. 2
Trends in Molecular Medicine xxx xxxx, Vol. xxx, No. x
The first-in-class HCV protease inhibitors: boceprevir and telaprevir The first generation protease inhibitors (PIs) had a positive impact for genotype 1 CHC patients. The pivotal registration trials with TVR (ADVANCE [9]) and BOC (SPRINT 2 [10]) in treatment-naı¨ve CHC patients randomized to triple therapy found overall SVR rates of 75% (TVR) and 67% (BOC), compared with less than 50% for PEG-IFN/RBV. However, the toxicities associated with PEG-IFN/RBV were more pronounced with triple therapy, particularly in patients with underlying cirrhosis, who stood the most to gain with successful treatment. In the combined TVR trials, 6% of all patients enrolled withdrew owing to the development of a rash, which in some cases was serious. The CUPIC trial investigators reported a 44.1% risk of death or significant complications, such as hepatic decompensation or serious infection, with triple therapy in cirrhotic patients with a platelet count
Review
Hepatitis C treatment: an incipient therapeutic revolution Andrew S. deLemos1 and Raymond T. Chung2 1
Department of Medicine, Center for Liver Diseases and Transplantation, Carolinas Medical Center, Charlotte, NC 28203, USA Department of Medicine, Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
2
An exciting paradigm shift is occurring in the treatment of hepatitis C virus (HCV). We now have the capacity to specifically target therapy to HCV proteins, and thereby directly interrupt the viral life cycle. The first direct-acting antivirals (DAAs), the NS3–4A serine protease inhibitors boceprevir and telaprevir, improved the rate of sustained virologic response (SVR), but their toxicities combined with PEG-IFN and RBV limited their overall efficacy. Sofosbuvir, a nucleotide HCV polymerase inhibitor, is now available and offers better tolerability and efficacy across all HCV genotypes. The next phase of therapy will be combining several classes of DAAs without IFN in order to make sustained clearance of hepatitis C deliverable to a much larger number of infected individuals. Hepatitis C infection: a glimpse back with a focus forward The scope of hepatitis C virus (HCV) infection is remarkably wide. Estimates suggest that up to 185 million people are infected worldwide, 3–4 million of whom reside in the USA [1,2]. Over 80% of patients develop a chronic, often asymptomatic, infection [3]. Furthermore, 5–30% of chronically infected patients will develop cirrhosis (see Glossary) and frequently will present with features of advanced liver disease such as variceal hemorrhage and hepatocellular carcinoma (HCC). Population-based studies indicate that the prevalence of decompensated cirrhosis has doubled over the past decade, whereas the prevalence of HCC has increased by 20-fold [4]. The annual mortality in the USA directly attributed to sequelae of end-stage liver disease (ESLD) due to hepatitis C infection was 16 627 in 2010 (http://www.cdc.gov/hepatitis/HCV/StatisticsHCV.htm), and this number is expected to double by 2030 [5]. ESLD due to HCV is the most common indication for liver transplant, which is itself complicated by universal allograft reinfection. Beyond the human cost, HCV infection is a tremendous economic burden, with total costs projected to peak at $9.1 Corresponding authors: deLemos, A.S. ([email protected]); Chung, R.T. ([email protected]). Keywords: hepatitis C; pegylated interferon; NS3–4A serine protease inhibitors; direct-acting antivirals (DAAs); sofosbuvir; simeprevir. 1471-4914/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2014.02.002
billion in 2024 [6]. Owing to these trends, coupled with the availability of increasingly effective and tolerated therapy, the Centers for Disease Control and Prevention (CDC) and the Department of Health and Human Services (DHHS) have now recommended universal testing for all US residents born between 1945 and 1964 [7], a group notable for being the largest epidemiologic risk group, and at highest risk for complications due to disease duration. Markov models suggest that this screening measure would be cost effective by preventing 84 000 cases of decompensated cirrhosis, 46 000 new cases of HCC, and 10 000 liver transplants [8]. Although the magnitude of HCV-related complications may be imposing to consider, a transformative period in treating HCV is now upon us. Caregivers, until very recently, had relied on pegylated interferon a (PEG-IFN) and ribavirin (RBV) to treat chronic hepatitis C (CHC) (Box 1). PEG-IFN/RBV produces a sustained virologic response (SVR) in approximately 50% of HCV genotype 1 patients Glossary Cirrhosis: a chronic liver disease that evolves often due to inflammation (e.g., alcoholism, viral hepatitis) in which the normal cellular architecture of the liver is replaced by nodular bands of fibrous tissue. Direct-acting antiviral (DAA): any drug within the class of HCV therapeutics with specific activity against a hepatitis C viral protein. Fibrosis: thickened connective tissue which forms as a response to injury to an organ. In chronic hepatitis C infection, liver fibrosis is staged on a continuum. The METAVIR system scores fibrosis on a liver biopsy from F0 to F4: F0, no fibrosis; F1, portal fibrosis; F2, portal fibrosis with few septa; F3, bridging fibrosis; F4, cirrhosis. IL28B: gene encoding IFNl3, a type III interferon; genetic variation upstream of this gene was found to be important in both spontaneous and PEG-IFNinduced clearance of hepatitis C infection. NS3–4A protease inhibitors (PIs): includes the first generation DAAs, boceprevir and telaprevir, as well as the next generation agents, simeprevir, faldaprevir, asunaprevir, and ABT450. These DAAs specifically inhibit the NS3– 4A protease. NS5A: HCV protein required for viral particle assembly, and an attractive DAA target due to high potency, but low barrier to resistance. Examples of DAAs targeting NS5A include daclatasvir and ledipasvir. NS5B polymerase inhibitors: class of DAA with several pharmacologic targets on the NS5B polymerase protein, including the catalytic site (sofosbuvir) or allosteric sites away from the active site (e.g., ABT333) which inhibit viral replication Sustained virologic response (SVR): no detectable HCV RNA by PCR following cessation of antiviral therapy for HCV. This prespecified endpoint has been defined in clinical trials by study investigators. An SVR24, or undetectable HCV 24 weeks following completion of therapy, was the standard endpoint for early clinical trials. Subsequent studies have shown that SVR12 is essentially interchangeable with SVR24, and SVR12 has now been adopted as an endpoint for current clinical trials with DAAs. Triple therapy: a combination of PEG-interferon, ribavirin, and the addition of a direct acting antiviral.
Trends in Molecular Medicine xx (2014) 1–7
1
TRMOME-938; No. of Pages 7
Review Box 1. IL28B testing and next generation HCV therapy? Amid the flurry of activity to identify novel therapeutics to treat HCV, there has been a simultaneous pursuit to understand the role of human genetic variation in the natural history of HCV infection. SVR rates to PEG-IFN/RBV therapy are remarkably variable among genotype 1 HCV-infected patients. With this in mind, genome-wide association studies (GWAS) were conducted to investigate whether locus specific variation predicted response to PEG-IFN/RBV [36–39]. A highly significant haplotype of single nucleotide polymorphisms (SNPs) upstream of the interleukin-28B (IL28B) gene on chromosome 19 was identified. Homozygosity for the ‘C’ allele for rs12979860 is associated with a 2- to 3-fold higher SVR rate to PEG-IFN/RBV than either heterozygosity (CT) or homozygosity for the rarer ‘T’ allele [38]. Groups from Japan and Australia both reported genome-wide association between non-response to interferon and the presence of the minor ‘G’ allele for rs8099917 [36,39]. The presence of either the ‘C’ allele (rs12979860) or the ‘T’ allele (rs8099917) is also associated with spontaneous clearance of acute HCV infection [37,40,41]. Variation in IL28B genotype frequencies also explains a sizable basis of the difference in SVR rates seen in patients of different ethnic backgrounds [38,40]. IL28B encodes a type III interferon, IFNl3, which similar to type I IFN, activates the JAK–STAT pathway, leading to expression of interferon-stimulated genes (ISGs), which are integral for the host antiviral response. Although not in a coding region, the IL28B SNPs have been shown to be associated with differential ISG expression [42]. In the recent past, determining IL28B genotype for patients considering triple therapy with TVR or BOC was recommended, because retrospective analyses of the first generation PI registration trials found that IL28B status significantly impacted SVR rates (reviewed in [43]). In terms of the next generation DAAs with PEGIFN/RBV, IL28B genotype did not impact the response to 12 weeks of sofosbuvir/PEG-IFN/RBV in genotype 1 CHC patients [44], but did affect the response to simeprevir-based triple therapy in treatmentexperienced patients. In this group, IL28B genotype ‘TT’ was associated with a modest reduced benefit with SVR12 rates of 64.5% (‘TT’) versus 79.2% (‘CT and CC’) [17]. IL28B genotype may become inconsequential with future IFN-free treatment regimens, particularly in view of increasingly impressive SVR rates; to this end, preliminary analyses suggest no statistically significant difference [26,29]. As SVR rates continue to improve with more potent all-oral DAA regimens, it is increasingly apparent that IL28B genotype testing will have diminishing clinical utility.
(which accounts for 75% of HCV infections in the USA), whereas SVR rates approach 80% for genotypes 2 or 3. These response rates successfully forestall complications of CHC; however, PEG-IFN/RBV therapy is cumbersome and frequently produces unacceptable toxicities. For example, PEG-IFN is associated with flu-like symptoms, cytopenias, autoimmunity, and depression. RBV causes hemolysis and symptomatic anemia, particularly in patients with advanced fibrosis who are most in need of therapy. Many patients either refuse therapy or are unwilling to continue owing to side effects. This quandary has spurred tremendous research into understanding the virology and pathogenesis of hepatitis C infection to develop therapeutics that specifically target antiviral proteins. The first of these direct-acting antivirals (DAAs), the HCV protease inhibitors telaprevir (TVR) and boceprevir (BOC), gained FDA approval in May 2011 for the treatment of genotype 1 CHC. The next wave of DAAs, with improved efficacy and tolerability, are now available and promise to dramatically alter the natural history of CHC infection. 2
Trends in Molecular Medicine xxx xxxx, Vol. xxx, No. x
The first-in-class HCV protease inhibitors: boceprevir and telaprevir The first generation protease inhibitors (PIs) had a positive impact for genotype 1 CHC patients. The pivotal registration trials with TVR (ADVANCE [9]) and BOC (SPRINT 2 [10]) in treatment-naı¨ve CHC patients randomized to triple therapy found overall SVR rates of 75% (TVR) and 67% (BOC), compared with less than 50% for PEG-IFN/RBV. However, the toxicities associated with PEG-IFN/RBV were more pronounced with triple therapy, particularly in patients with underlying cirrhosis, who stood the most to gain with successful treatment. In the combined TVR trials, 6% of all patients enrolled withdrew owing to the development of a rash, which in some cases was serious. The CUPIC trial investigators reported a 44.1% risk of death or significant complications, such as hepatic decompensation or serious infection, with triple therapy in cirrhotic patients with a platelet count
![[Treatment of hepatitis C - an imminent revolution].](/assets/img/hold.png)
