Ask the Experts - How Do You Treat the Patient With Compensated...
Ask the Experts - How Do You Treat the Patient With Compensated...
Should genotype 1 compensated cirrhotics be treated? What probability for sustained response to combination therapy would you quote for such patients? Finally, would you commit to a 48-week treatment regimen, regardless of detectable viremia at week 24?
Paul Wilson, MD
It is estimated that 20% to 25% of patients with chronic hepatitis C will develop cirrhosis within the first 20 years of infection. However, predictions regarding whether cirrhosis will develop are difficult to make on an individual-case basis -- only 2% of women infected by hepatitis C virus (HCV)-contaminated anti-D immunoglobulin had cirrhosis 17 years after inoculation. Factors predictive of progression of chronic hepatitis C to cirrhosis include male gender, age > 40 years at the time of infection, alcohol consumption ≥ 50 g/day, and coinfection with the hepatitis B virus or HIV.
In patients with compensated chronic hepatitis C and cirrhosis, the risk of an initial episode of decompensation (ascites, variceal hemorrhage, hepatic encephalopathy) on prospective follow-up over 4-5 years is approximately 20%. On serial follow-up, a decrease in hepatocellular function based on a low serum albumin level, increase in prothrombin time, or elevation in serum bilirubin level is associated with subsequent clinical decompensation.
The management of compensated cirrhosis secondary to chronic hepatitis C should focus on therapy to induce a biochemical and virologic response, the prevention of complications, and on screening for hepatocellular carcinoma (HCC) with serial ultrasound and alpha-fetoprotein levels. The previously used regimen of interferon monotherapy (3 million units 3 times per week for 6-12 months) was rarely found to be effective in inducing a sustained response in patients with chronic HCV infection and cirrhosis. The sustained response to interferon monotherapy was found to range from 5% to 10% in cirrhotic patients, as opposed to the 15% to 25% obtained in patients without cirrhosis. In one analysis, genotype was, as expected, an important predictor of response; a sustained virologic response occurred in 4% of cirrhotic patients with genotype 1 vs in 10% of patients with genotypes 2 and 3.
Combination treatment with interferon and ribavirin has replaced interferon monotherapy as the preferred antiviral therapy for chronic hepatitis C. A meta-analysis of 6 randomized controlled trials of combination interferon and ribavirin therapy vs interferon monotherapy, which included 75 patients with compensated cirrhosis, showed a better sustained biochemical response with combination therapy in the cirrhotics (22% with combination therapy vs 4% with interferon monotherapy). In fact, only patients with cirrhosis who received combination therapy had a sustained virologic response (17% vs 0%). The sustained response was influenced by genotype (7% to 10% in patients with genotype 1 vs 24% to 33% in patients with genotypes 2 and 3). These studies indicate that combination interferon and ribavirin therapy can be recommended for all patients with compensated chronic hepatitis C and cirrhosis, including those with genotype 1. Patients with compensated chronic hepatitis C and cirrhosis and genotype 1 can expect a sustained response ranging between 7% and 10%.
Cumulative evidence also suggests that patients with cirrhosis who demonstrate a sustained virologic response have an improved prognosis, especially with respect to the development of HCC. Treatment with interferon can reduce the rate of fibrosis progression and also decrease the incidence of HCC by 13% and the mortality from cancer by 16%.
Data from the large trials of combination therapy for chronic hepatitis C provide important information about the timing of viral clearance in patients who have a sustained virologic response. In both large trials, persistence of serum HCV RNA at 24 weeks of therapy was predictive of a lack of sustained virologic response. In fact, most patients with a sustained response became HCV-RNA-negative very early in the course of therapy.
On the basis of these results, it is recommended that combination therapy be discontinued in patients with genotype 1 -- including cirrhotic and noncirrhotic patients -- who remain HCV RNA-positive after 24 weeks of therapy. Moreover, the long-term benefit of antiviral therapy in patients with chronic hepatitis C and cirrhosis occurs predominantly in those patients having a sustained response, and patients with persistent viremia at week 24 of combination therapy have virtually no chance of having a sustained response.
Should genotype 1 compensated cirrhotics be treated? What probability for sustained response to combination therapy would you quote for such patients? Finally, would you commit to a 48-week treatment regimen, regardless of detectable viremia at week 24?
Paul Wilson, MD
It is estimated that 20% to 25% of patients with chronic hepatitis C will develop cirrhosis within the first 20 years of infection. However, predictions regarding whether cirrhosis will develop are difficult to make on an individual-case basis -- only 2% of women infected by hepatitis C virus (HCV)-contaminated anti-D immunoglobulin had cirrhosis 17 years after inoculation. Factors predictive of progression of chronic hepatitis C to cirrhosis include male gender, age > 40 years at the time of infection, alcohol consumption ≥ 50 g/day, and coinfection with the hepatitis B virus or HIV.
In patients with compensated chronic hepatitis C and cirrhosis, the risk of an initial episode of decompensation (ascites, variceal hemorrhage, hepatic encephalopathy) on prospective follow-up over 4-5 years is approximately 20%. On serial follow-up, a decrease in hepatocellular function based on a low serum albumin level, increase in prothrombin time, or elevation in serum bilirubin level is associated with subsequent clinical decompensation.
The management of compensated cirrhosis secondary to chronic hepatitis C should focus on therapy to induce a biochemical and virologic response, the prevention of complications, and on screening for hepatocellular carcinoma (HCC) with serial ultrasound and alpha-fetoprotein levels. The previously used regimen of interferon monotherapy (3 million units 3 times per week for 6-12 months) was rarely found to be effective in inducing a sustained response in patients with chronic HCV infection and cirrhosis. The sustained response to interferon monotherapy was found to range from 5% to 10% in cirrhotic patients, as opposed to the 15% to 25% obtained in patients without cirrhosis. In one analysis, genotype was, as expected, an important predictor of response; a sustained virologic response occurred in 4% of cirrhotic patients with genotype 1 vs in 10% of patients with genotypes 2 and 3.
Combination treatment with interferon and ribavirin has replaced interferon monotherapy as the preferred antiviral therapy for chronic hepatitis C. A meta-analysis of 6 randomized controlled trials of combination interferon and ribavirin therapy vs interferon monotherapy, which included 75 patients with compensated cirrhosis, showed a better sustained biochemical response with combination therapy in the cirrhotics (22% with combination therapy vs 4% with interferon monotherapy). In fact, only patients with cirrhosis who received combination therapy had a sustained virologic response (17% vs 0%). The sustained response was influenced by genotype (7% to 10% in patients with genotype 1 vs 24% to 33% in patients with genotypes 2 and 3). These studies indicate that combination interferon and ribavirin therapy can be recommended for all patients with compensated chronic hepatitis C and cirrhosis, including those with genotype 1. Patients with compensated chronic hepatitis C and cirrhosis and genotype 1 can expect a sustained response ranging between 7% and 10%.
Cumulative evidence also suggests that patients with cirrhosis who demonstrate a sustained virologic response have an improved prognosis, especially with respect to the development of HCC. Treatment with interferon can reduce the rate of fibrosis progression and also decrease the incidence of HCC by 13% and the mortality from cancer by 16%.
Data from the large trials of combination therapy for chronic hepatitis C provide important information about the timing of viral clearance in patients who have a sustained virologic response. In both large trials, persistence of serum HCV RNA at 24 weeks of therapy was predictive of a lack of sustained virologic response. In fact, most patients with a sustained response became HCV-RNA-negative very early in the course of therapy.
On the basis of these results, it is recommended that combination therapy be discontinued in patients with genotype 1 -- including cirrhotic and noncirrhotic patients -- who remain HCV RNA-positive after 24 weeks of therapy. Moreover, the long-term benefit of antiviral therapy in patients with chronic hepatitis C and cirrhosis occurs predominantly in those patients having a sustained response, and patients with persistent viremia at week 24 of combination therapy have virtually no chance of having a sustained response.
