Update on the Treatment of Hepatitis C
This report was reviewed for medical and scientific accuracy by William H. Stuart, MD , Director,Multiple Sclerosis Center of the Shepherd Center, Founding Partner Peachtree Neurological Clinic, Medical Director for Rehabilitation Services, Piedmont Hospital, Atlanta,GA; Chairman, HealthMed Advisory Board, webhealthsearch.com .
Nearly four million Americans are infected with the hepatitis C virus (HCV), 2.7 million of whom are chronically infected. It is estimated that 35,000 people become infected each year, primarily through intravenous (IV) drug use.
Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer. Most people who are infected with the virus have completely normal serum (blood) levels of liver enzymes and have no signs or symptoms of liver disease. However, the spectrum of the disease and its progression may vary widely among infected persons. Many people with HCV have very mild liver damage, and, interestingly, their overall prognosis is good.
At the other end of the spectrum are patients with severe hepatitis C and ongoing liver damage. These patients are at high risk for developing cirrhosis and end-stage liver disease. In the middle are many patients with lesser degrees of liver damage and an uncertain prognosis. At least 20 percent of patients with chronic hepatitis C develop cirrhosis within 20 years. Of those patients with cirrhosis, a small percentage develop liver cancer.
Recent findings with regard to this devastating disease-including new information about the disease process, advances in diagnosis and therapy, and areas of current controversy-were described in a special symposium held during the 65th Annual Meeting of the American College of Gastroenterology. The symposium was chaired by Mitchell L. Shiffman, Professor of Medicine, Chief, Hepatology Section, Medical College of Virginia, Richmond.
"There is a huge reservoir of individuals infected with the hepatitis C virus, and if we don't recognize them and effectively treat them, we will be inundated with cirrhosis and its complications within the next 20 years," Dr. Shiffman warned. "Death rates from cirrhosis and liver cancer will reach astronomical proportions."
New Insights into the Natural History of HCV
Clinicians detect hepatitis C through a blood test that shows antibodies to the virus-HCV ribonucleic acid (RNA), he said. In turn, analysis of HCV-RNA is used to confirm infection and to monitor response to interferon therapy. However, in the absence of treatment, the level of serum hepatitis C virus remains rather constant over time and does not increase with the severity of the disease. Thus, there is no reason to repeat the HCV-RNA test on a yearly basis.
A major consideration in the management of hepatitis C is the genotype (genetic makeup) of the virus. Patients with genotypes two and three respond very well to therapy, but, unfortunately, 72 percent of people infected with the hepatitis C virus are genotype one, which is more difficult to treat. In addition, the hepatitis C virus mutates frequently, thus evading the immune system and becoming chronic.
"Our challenge is to figure out specifically which mutations are associated with good outcomes and which are associated with bad ones," Dr. Shiffman noted.
Many patients with hepatitis C have normal liver transaminases (liver function tests). One recent study showed no link between genotype and elevation of transaminases (Hepatology 1999;30:1307-1311).
Another study showed that patients with normal liver transaminases tend to have milder disease, but not consistently (C.A. Stewart et al., submitted DDW, 1998).
The most important element in determining prognosis is the presence or absence of liver fibrosis.
"Any fibrosis on liver biopsy signifies that the individual will progress to cirrhosis," Dr. Shiffman confirmed.
In one study of patients whose original liver biopsies 20 years prior showed "bridging" (severe) fibrosis, all patients developed cirrhosis within ten years (Hepatology 1996;23:1334-1340).
Another study of more than 1,100 patients showed that the degree of inflammation in the liver remains constant over time. This suggests that only those persons with significant inflammation will develop progressive fibrosis (Lancet 1997;349:825-832).
"One thing we know clearly from multiple studies is that alcohol hastens the rate of fibrosis," Dr. Shiffman emphasized. "If you have hepatitis C, you should not consume alcohol on a regular basis." Once a person has cirrhosis, the natural history of the disease depends on whether the cirrhosis is compensated (stable) or decompensated (unstable). One study showed that in patients with decompensated cirrhosis, survival is only 50 percent in five years (Gastroenterology 1997;112:463-472).
Treatment of Chronic HCV
Therapy for hepatitis C is evolving rapidly, said Michael Fried, MD, Associate Professor of Medicine, University of North Carolina, Chapel Hill.
"Today we are in somewhat of a transition phase," he declared. "Combination therapy with interferon [alfa-2a or alfa-2b] (Roferon-A®, Intron® A) and ribavirin (Rebetron®, Virazole®) will remain the standard of care. Monotherapy [therapy with interferon alfa-2a or interferon alfa-2b alone] will be reserved for patients who are intolerant to ribavirin. The introduction of the new 'pegylated' interferons will significantly improve the sustained response rate. And we're very interested to see what happens when we combine pegylated interferon with ribavirin."
When patients are started on interferon alfa-2a or interferon alfa-2b alone, or on combination therapy, liver enzymes improve in 50-75 percent of cases. However, long-term improvement usually occurs only if HCV-RNA disappears during therapy and remains below detectable limits. Improvement is considered "sustained" if HCV-RNA remains below detectable limits for six months or more after therapy is stopped.
"Patients who have reached the six-month post-treatment point are very unlikely to have a relapse of their disease and can be considered viral-cured," Dr. Fried noted.
In two studies including more than 1,700 patients treated with combination therapy, 40 percent developed a sustained response (McHutchison 1999, Poynard 1999).
For genotype one patients, the sustained response at 48 weeks with combination therapy is only 29 percent. For patients with genotype two or three, response at both 24 and 48 weeks is about 66 percent.
New on the horizon are the longer-acting "pegylated" interferons. These are interferons that are modified by polyethylene glycol (PEG) so that they can be given once a week and yet provide a sustained level of interferon. Two are under development: pegylated interferon alfa-2a and pegylated interferon alfa-2b.
In a pilot study of patients who received standard interferon alfa-2b, the sustained response rate was only three percent, compared with a 36 percent response rate for patients who received pegylated interferon alfa-2b (Shiffman et al., submitted DDW 1999).
The largest trial so far of pegylated interferon alfa-2b showed a virologic response rate of about 39 percent for patients treated once a week, compared to 19 percent for those given standard interferon alfa-2b treatment three times a week (Zeuzem, EASL 2000). Pegylated interferon alfa-2b has been shown to be much more effective than standard interferon alfa-2b (Trepo, EASL 2000).
"These pegylated interferons have an acceptable safety profile," Dr. Fried added.
Two studies show that a combination of pegylated interferon with ribavirin improves sustained response to treatment. In one pilot study of patients given interferon plus ribavirin, the sustained response was 50 percent (Sulkowski et al., 1999). In another study, 64 percent of patients cleared HCV-RNA at 24 weeks, and the safety profile was very acceptable (Manns, AASLD 2000).
Patients Who Do Not Respond to Conventional Therapy
Patients with high viral loads in genotype one demonstrate a response rate to combination therapy of about 25 percent. But that leaves a large number of patients who do not have a sustained response, said Nezam Afdahl, MD, Director of Hepatology, Beth Israel Hospital, Boston, Massachusetts.
"Quite honestly, these non-responders are now becoming the predominant patients that many of us are seeing in our clinical practice," he said. One of the problems is viral breakthrough-when patients are on treatment, the virus disappears for a period, then reappears. The pegylated interferons, which offer better pharmacokinetics, may prevent these breakthroughs.
Some patients relapse after being treated, particularly those who have been on interferon alone. These patients are particularly distressing for physicians, who may have previously told their patients that they were having a great response and that the virus was gone.
Certain factors can predict who is unlikely to respond, Dr. Afdahl explained. These numbers include individuals with a high viral load, genotype one, long duration of disease, male sex, and-most importantly-liver fibrosis.
What is the best way to approach combination relapsers? "For patients who have mild disease, [a patient] can just wait for better agents to come along," he suggested. "Certainly, by giving a year of interferon plus ribavirin, you alter the natural history of the disease. Possibly, re-treatment will turn those relapsers into sustained responders. A third option is to put these patients into one of the studies of pegylated interferon plus ribavirin."
A study in France showed that with interferon treatment, the degree of fibrosis can be reduced to almost zero (Gastroenterology 1999;116:378).
Studies in Japan showed that interferon appears to slow the progression of liver cancer (Hepatology 1999;4:1124).
Should hepatitis C patients be given long-term interferon treatment for maintenance? In a study in which non-responders received 2 1/2 years of interferon therapy, Dr. Shiffman and his colleagues found that liver biopsies soon showed inflammation again when patients stopped taking interferon alfa-2b (Gastroenterology 1999;117:1164). If these patients stayed on treatment, however, inflammation continued to decline.
Fibrosis also progressed when interferon alfa-2b was stopped and declined when it was continued. Two large studies on fibrosis are currently in progress.