Clinical Liver Disease
Volume 1, Issue 3, pages 65–68, July 2012
Ranjeeta Bahirwani M.D., K. Rajender Reddy M.D.*
Article first published online: 23 JUL 2012
Copyright © 2012 the American Association for the Study of Liver Diseases
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eRVR, early rapid virological response; HAV, hepatitis A virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IL-28B, interleukin-28B; SVR, sustained virological response.
Hepatitis C virus (HCV) is a major public health problem affecting more than 180 million people worldwide. The prognosis for patients with HCV depends on the progression of fibrosis; the risk of cirrhosis development is as high as 25% over a 25- to 30-year period and is influenced by cofactors, including human immunodeficiency virus coinfection, alcohol abuse, and hepatic steatosis.1 In patients with cirrhosis, hepatic decompensation, which can manifest as one or more clinical events (including variceal bleeding, ascites, and encephalopathy), occurs at a rate of 30% over a period of 10 years.2 Patients with HCV cirrhosis are at increased risk for hepatocellular carcinoma (HCC); the incidence is approximately 5% to 15% over a period of 10 years.3 Additionally, in patients undergoing liver transplantation for HCV-related liver failure (currently the leading indication for transplantation in the United States), graft reinfection is universal; progression to graft cirrhosis occurs in up to 30% of these patients within 5 years after transplantation and leads to compromised patient and graft survival.4 The eradication of HCV is the only therapeutic intervention that can halt disease progression and improve the quality of life in infected patients. A recent Markov model constructed for a cohort of 4000 patients with genotype 1 disease found that in comparison with no treatment, HCV therapy for patients with compensated cirrhosis (Child-Pugh class A) saved $55,314 and led to a 0.950 increase in quality-adjusted life years; this resulted in 119 fewer deaths, 54 fewer cases of HCC, and 66 fewer liver transplants.5 Successful antiviral therapy has been observed to reduce the incidence of complications from progressive disease both before and after liver transplantation.6
The care of patients with HCV cirrhosis involves the prevention and management of recognized complications (Fig. 1). Furthermore, those with advanced fibrosis and cirrhosis are most in need of HCV therapy; however, interferon-based antiviral treatment in these patients is challenging because of the frequent comorbidities affecting patient adherence and tolerance, the risk of serious adverse events, and the hyporesponsiveness to therapy. Bridging fibrosis and cirrhosis are negative predictors of HCV treatment outcomes. Additionally, patients with cirrhosis are often male and older and have comorbidities (including diabetes mellitus, obesity, and alcohol consumption) that adversely affect the efficacy of antiviral therapy.7 In patients with compensated cirrhosis, the sustained virological response (SVR) rates with pegylated interferon in combination with ribavirin range from 10% to 44% for genotypes 1 and 4 and from 33% to 72% for genotypes 2 and 3, whereas in patients with decompensated cirrhosis, the SVR rates drop to less than 16% for genotypes 1 and 4 and to 44% to 57% for genotypes 2 and 38 (Table 1).
Figure 1. Approach to the patient with HCV cirrhosis. Abbreviations: HAV, hepatitis A virus; HBV, hepatitis B virus; HE, hepatic encephalopathy.
Although pegylated interferon and ribavirin remain the backbone of HCV therapy, the emergence of two nonstructural protein 3/4A protease inhibitors, boceprevir and telaprevir, has led to a substantial improvement in SVR rates in patients with genotype 1 disease. In patients with cirrhosis, treatment with either boceprevir or telaprevir in combination with pegylated interferon and ribavirin is recommended for 48 weeks; the SVR rates in treatment-naive patients range from 50% to 60%. However, SVR rates are lower with triple therapy in treatment-experienced patients who have cirrhosis (primarily prior null and partial responders), whereas relapsers have SVR rates comparable to the rates of patients without cirrhosis9 (Table 2). Patients with cirrhosis are not eligible for response-guided therapy with nonstructural protein 3/4A serine protease inhibitors, and treatment is recommended in this cohort for a fixed duration of 48 weeks with both boceprevir and telaprevir regimens.9
*The data were taken from New England Journal of Medicine.10
†The data were taken from New England Journal of Medicine.11
‡The data were taken from New England Journal of Medicine.12
§Patients with undetectable HCV RNA at the end of treatment with pegylated interferon/ribavirin and without subsequent SVR.
∥The data were taken from New England Journal of Medicine.13
¶The data were taken from New England Journal of Medicine.14
#Patients with a ≥2-log drop in HCV RNA at week 12 with pegylated interferon/ribavirin but with detectable HCV RNA at week 24.
**Patients with a <2-log drop in HCV RNA at week 12 with pegylated interferon/ribavirin.
Testing for single-nucleotide polymorphisms in the interleukin-28B (IL-28B) gene on chromosome 19 may be helpful in determining the likelihood of achieving an SVR. Among the baseline host and viral factors, the predictive value of the IL-28B genotype is superior to the fibrosis stage, HCV RNA, age, and sex with respect to SVR, and it is useful even in patients on triple therapy with protease inhibitors. A recent cost-effectiveness study of the utility of protease inhibitor therapy for HCV revealed that both universal triple therapy and IL-28B–guided triple therapy were cost-effective for patients with advanced fibrosis: the costs were $51,500 per quality-adjusted life year for universal triple therapy and $36,300 per quality-adjusted life year for IL-28B–guided triple therapy in comparison with standard therapy with pegylated interferon and ribavirin.15
Pegylated interferon and ribavirin are associated with a host of adverse effects, which include a flulike syndrome, depression, fatigue, and hematological abnormalities (neutropenia, thrombocytopenia, and anemia). HCV therapy in patients with compensated cirrhosis is safe with a discontinuation rate of approximately 10%. Completing the full dosing and duration of therapy, however, is difficult for genotype 1/4 patients with cirrhosis because of the longer course of therapy (48 weeks) in comparison with patients with genotype 2 or 3 (24 weeks). Dose modifications are required for 30% of the patients with compensated disease, mainly because of the increased rate of cytopenias in the setting of portal hypertension, with rates of anemia, thrombocytopenia, and neutropenia ranging from 20% to 35%. Ribavirin dose reduction and the addition of erythropoiesis-stimulating agents are suggested for patients with hemoglobin levels of 10 g/dL or less; granulocyte colony-stimulating factors can be used in those with an absolute neutrophil count less than 750/mm3. Interferon dosing can be reduced for patients with platelet counts less than 70,000 × 103/μL; more recently, the thrombopoietin agonist eltrombopag has been shown to prevent severe thrombocytopenia in patients on antiviral therapy.16 The threshold for treatment discontinuation for thrombocytopenia has varied, with the lower limit being approximately 20,000 × 103/μL. Because antiviral therapy presents a potentially increased risk of bacterial infections in patients with cirrhosis, spontaneous bacterial peritonitis prophylaxis with norfloxacin is advised for patients with cirrhosis who are receiving interferon and ribavirin therapy.17 Adverse events occur more frequently in patients with genotype 1 disease with the addition of protease inhibitors to pegylated interferon and ribavirin (Table 3). Overall, the adverse events reported with telaprevir include rash (56% versus 34% with pegylated interferon/ribavirin alone), anemia (36% versus 17% with pegylated interferon/ribavirin alone), and nausea (39% versus 28% with pegylated interferon/ribavirin alone). Boceprevir use has been associated with higher rates of anemia (45%-50% versus 20%-30% with pegylated interferon/ribavirin alone) as well as dysgeusia (35%-44% versus 11%-16% with pegylated interferon/ribavirin alone). Although there are no data in the registration trials on the rates of rash and anemia in patients with cirrhosis, recent data from a French observational study of triple therapy in patients with advanced fibrosis and cirrhosis showed high rates of cytopenias and an increased need for blood transfusions.20
The rate of decompensation in patients with compensated cirrhosis enrolled in randomized clinical trials of HCV therapy has been reported to be 0% to 3% and likely reflects careful patient selection. HCV therapy is poorly tolerated in patients with Child-Pugh class C cirrhosis because of the high risk of cytopenias and hepatic decompensation as well as the increased risk of infection21, 22 and is, therefore, considered investigational and not recommended in this patient population.
Treatment-induced improvements in liver histology and lower rates of hepatic decompensation have been reported in multiple studies examining the favorable impact of SVR in the context of HCV cirrhosis. Rates of liver-related complications, mortality, and HCC are lower in SVR patients versus non-SVR patients. Importantly, the risk of HCC is not eliminated in patients who achieve viral eradication, so continued HCC surveillance is critical in these patients.23
In summary, HCV eradication is associated with lower mortality and fewer liver-related complications; this is particularly important for patients with cirrhosis because of the lower rates of decompensation and HCC development once SVR is achieved. Treatment in patients with cirrhosis poses significant challenges because of the inferior SVR rates, the higher rates of adverse events, and the lower tolerance to therapy. Nonetheless, aggressive therapy in such patients is strongly supported and leads to improved outcomes.