Chronic Hepatitis C (formerly called non-A, non-B hepatitis) is a low-grade viral infection in the liver for which treatments are now available. Interferon, a naturally occurring anti-viral agent, has been used for treatment of Hepatitis C since approved by the Food and Drug Administration in 1991. This short review highlights the nature of the virus, how it affects the liver, and how interferon and other drugs in combination are used to combat this virus. This is not a complete review of the topic, but tries to answer the most common questions patients raise concerning this illness.
Background
After the discovery of the Hepatitis B virus in 1965, blood banks began testing for this common blood-borne virus, and the blood pool was cleared of virtually all units capable of transmitting Hepatitis B infection. Even so, about 10% of patients receiving two or more units of blood continued to be infected with a virus which came to be known as non-A, non-B. The Hepatitis A virus is not blood-borne, and causes a limited illness after exposure to contaminated food. Hepatitis B, still a major health problem in many parts of the world, was no longer in the blood supply. For this reason the name non-A, non-B hepatitis was applied to this puzzling illness. Over the next 20 years, scientists sought to identify this second blood-borne virus without success. In 1989, through the use of advanced molecular biology techniques, the main non-A, non-B virus was identified and is now known as Hepatitis C. There may be other viruses remaining, but it appears that Hepatitis C, an RNA-containing virus, accounts for more than 90% of the cases of post-transfusion hepatitis which had remained unidentified. Initially, testing for the virus consisted of looking for antibodies which patients make when they have had the infection for several weeks. This is not an ideal test system since occasional patients in the early phases of the disease may remain unidentified; however, antibody tests currently identify virtually all patients found by other means to be chronically infected with this virus.
A positive antibody test for hepatitis C means that you have been exposed to the virus previously. However, for most patients, it also means on-going infection since the antibody tends to disappear in those who resolve their hepatitis. If you have elevated liver enzymes (evidence that liver cells are being damaged on a daily basis by some process) and you have a hepatitis antibody test positive, the chances are greater than 95% that the two are related and that you have chronic hepatitis C. Some antibody tests will be positive but in error, and are called "false positives." However, these will usually not be associated with elevated liver enzyme tests. Now, the actual level of hepatitis C virus RNA in the blood can be determined, and this is the "gold standard" for making the diagnosis. Determining the quantity of virus may also be helpful in predicting the likelihood of a favorable response to therapy. Lastly, a liver biopsy and other serological tests are used to exclude other similar diseases. The biopsy also allows your physician to determine how far the disease has progressed, and whether cirrhosis is already present.
The most common mode of transmission of hepatitis C has been blood transfusion, although illicit IV drug use is also a common way to spread the virus. Since it is blood-borne, other ways are possible including tattooing, and accidental needle-stick exposure of hospital personnel. "Spontaneous" cases account for 20% of patients and the route of exposure in such patients is unknown. Sexual contact is an unlikely but not impossible means of spread; casual household contact is not a problem. Hepatitis C appears to be spread from mother to infant only rarely.
What Does the Hepatitis C Virus Do?
Hepatitis simply means an inflammatory process in the liver and can be caused by chemicals, drugs or viruses. After blood transfusions prior to 1990 when hepatitis C testing began, about 10% of individuals, if followed carefully, would have liver enzyme abnormalities at some point as evidence of hepatitis. AST, (SGOT) and ALT (SGPT) or "transaminases" are all names for liver enzymes released into the blood with liver cell damage, and these enzyme tests provide a rough guide to the amount of hepatitis occurring at any one point in time. In some patients, these elevated enzymes will resolve in less than six months. Those who do not resolve their illness in six months make up about 85-90% of those infected, and these patients remain infected with the hepatitis C virus for years with inflammation continuing indefinitely. Therefore, prior to the recently instituted screening tests, approximately 5-10% of transfused patients on average developed chronic hepatitis C.
What is Hepatitis C Like?
Most patients who become infected do not know they are sick. A few become jaundiced or are aware of fatigue or loss of appetite. The fatigue may continue intermittently for many years. These symptoms are not specific to hepatitis and are often attributed to other causes. If the disease remains mild but persists over many years, some individuals develop cirrhosis, which most simply means scarring and nodule formation in the liver. Not all patients will develop cirrhosis with its complications; however, many patients will have had their disease for ten or more years when it is first identified and the likelihood of serious complications increases with the length of time that the infection has been present. The good feature is that this is generally a mild disease and the length of time to development of cirrhosis, if it is going to occur, is most commonly after 20 or 30 years.
To summarize, chronic hepatitis C is a liver infection which is the result of exposure to an RNA virus. This virus is responsible for most cases of post-transfusion hepatitis over the past twenty years. The disease is usually mild and many patients remain without symptoms. It has been estimated that at least one in five eventually develop cirrhosis from this chronic infection and there is also an association with liver cell cancer. A treatment which would eradicate the virus would be predicted to halt the hepatitis and presumably stop the progression to cirrhosis and liver cancer.
Treatment with Interferon
Interferon alfa preparations which are short acting were given FDA approval for the indication hepatitis C in the early '90's, but their effectiveness for short treatment periods (6 months) were around 8-10%. Interferons are proteins made by white blood cells, which can now be produced in the laboratory through recombinant gene technology. Efforts to improve responses continued through the last decade and resulted in increasing the length of treatment for most patients to one year. In addition, ribavirin, a weak antiviral in capsule form was added to the regimen, with improvement in sustained viral responses (virus negative by sensitive techniques 6 months off treatment) to as high as 38%. But the most important recent breakthrough was the development of pegylated interferons, long acting preparations that require only a once a week injection. These maintain the interferon blood level nearly constant for the entire week and are easier to use since there is only one injection each week. Pegylated interferons can be used in combination with ribavirin and the response rates for this combination are in the range of 55% for naïve patients. Hepatitis C virus species are divided into several families called genotypes based on variations in the virus structure. Genotypes 1a and 1b make up about 70% of the US population and are somewhat less responsive to therapy than genotypes 2 or 3. As a result, the sustained response rate in genotype 1 is about 42% whereas for types 2 or 3 it is about 68%. Optimal dosing studies are still underway.
In summary, recombinant interferons are now available which can be used as a weekly injection that in combination with ribavirin yields sustained viral response of greater than 50%. There have been some availability issues in that there is only the Schering product Peg-Intron®, currently available. The Roche product, Pegasys®, is likely to receive Food and Drug Administration approval by the end of 2002.
Improving Response to Treatment
No patient features yet described accurately predict who will respond to treatment. Those with cirrhosis may be less likely to respond than those with milder, earlier disease. The problem is that some patients with cirrhosis respond completely, and probably "need" the drug more than those with earlier disease, therefore cirrhosis is not considered a reason not to treat. Typically, the evidence of a complete response which is detected at 12 weeks after institution of treatment (negative HCV RNA in serum, normal enzyme levels) will almost invariably confirmed by later evaluations. If there is failure to respond within this time interval, then additional months of treatment with the same dose or even with higher doses will not result in additional responses. A second problem in addition to failure to respond, is the high rate of relapses, once successful treatment is established, and this is being addressed in a trial in which we are engaged. Bottom line: there are no known criteria for predicting a favorable response to interferon treatment, therefore a clinical trial in each patient of the standard dose (three million units three times weekly) seems the only logical starting point, if blood studies, liver biopsy and patient interest warrants this treatment.
There are a variety of research protocols currently underway here at Southwestern. We are currently testing the efficacy of 1.5 µg/kg dose of Peg-Intron vs. 3.0 µg/kg dose in combination with ribavirin for naïve patients. This study should be open for enrollment by May 1st, and is being conducted on a national scale.
Side Effects of Interferon
The most striking initial effect is that of a flu-like syndrome which begins within hours of the first injection. Fortunately, the symptoms are greatly abated by taking acetaminophen (Tylenol®) at the time of the injection. Subsequent injections are usually much better tolerated. The first is truly the worst. We closely monitor white blood cell counts and platelet counts when treatment is started because these levels will almost always fall roughly 10-20%. We do not consider treatment with interferon if these numbers are already very low. Most patients tolerate the injections although many may continue to experience some sense of fatigue on the day following the shot. Late side effects include hair loss, abnormalities in thyroid blood tests, mental changes such as depression and difficulty concentrating, but these symptoms clear up if the medication is stopped. Those taking the drug who are of child-bearing age should use proven methods of contraception since interferon is not approved for use during pregnancy and may have harmful effects on the fetus.
The Non-Responder Patient: The HALT C Study
Over the first ten years of study of the treatment of hepatitis C, it became apparent that patients could be divided into 4 groups based on response to treatment: sustained responders, relapsers non-responders and breakthrough patients. Although these definitions initially applied to biochemical improvement, viral clearance is more important than biochemical normalization. Viral clearance is associated with marked improvement in inflammation in the liver, and possibly even in a decrease in fibrosis. However, current treatment at best produces sustained virologic responses in 40%. Thus, a large segment of hepatitis C patients will be relapsers or non-responders.
What Characterizes A Non-Responder Patient?
A number of host and viral factors have been associated with failure to respond to therapy including male gender, African-American race, presence of cirrhosis, high viral titer and viral genotype 1. None of these are absolutes. Options for the true non-responder who has tolerated therapy well but just did not get the desired response, include repeat treatment with higher and more frequent doses, or consideration of maintenance therapy.
High dose therapy protocols have been in use for at least 5 years. Results suggest that as many as 1/3 of patients who had previously failed interferon monotherapy or combination therapy may respond to these more rigorous schedules. Side effects appear to be somewhat more severe than those observed with conventional dosing but are not different or intolerable for most patients.
Maintenance regimens have a different purpose and have been tested even less than high dose regimens. The National Institutes of Health is currently undertaking the HALT-C study: Hepatitis C Anti-viral Long Term Therapy Against Cirrhosis. This study is designed to test whether continued therapy with interferon, in this case a pegylated once weekly injection, can slow the progression of fibrosis to cirrhosis and the progression of asymptomatic cirrhosis to decompensation (ascites, variceal hemorrhage, encephalopathy, transplantation, death). More than 1,350 patients will be enrolled at 10 sites around the US, including UT Southwestern. Patients will have failed either monotherapy or combination therapy for a minimum treatment period of 12 weeks. There will be a lead-in phase of 24 weeks therapy with pegylated interferon plus ribavirin, to 'prove' with one added course of cutting edge therapy that the patient is truly a non-responder. At week 20, HCV RNA testing will determine whether the patient is truly a non-responder or can be continued on treatment for potential viral sustained response (48 wk total treatment). The main part of the trial then begins with the randomization (1:1) of the non-responders to receive a lower dose of peginterferon alone as a weekly injection for the next 3 1/2 years or no further treatment. Both groups will receive an identical follow-up protocol with 3-monthly visits, screening for hepatocellular carcinoma, presence of varices, and biopsies at yr 2 and yr 4. Features which need to be stressed if one is thinking of enrolling include the fact that patients may or may not receive the treatment, and that there will need to be close follow-up regardless of assignment. The overall aim is to establish whether prolonged treatment with interferon can slow or arrest disease progression absent a virologic response. A similar study is also under consideration in Japan.
New Drugs on the Horizon
Although many drugs have shown some initial promise, none has been tested to the extent that the present Pegylated interferons plus ribavirin has. We are evaluating a gamma interferon for improvement in fibrosis in patients with fibrosis or cirrhosis who have failed alpha interferon antiviral treatment. We are also evaluating the role of thymosin, an immune stimulant, in patients who have failed previous interferon based therapies.
Summary
This brief overview is meant to give you some basic information about hepatitis C and interferon therapy. As you can see, this is a rapidly evolving field where all the answers are not in. We wish we had a fool-proof medication with no side effects and a guaranteed high response rate but we do not. Nevertheless, interferon treatment offers the opportunity to improve or possibly cure this unusual virus infection in the liver. This document is not meant as a substitute for discussing your concerns with your doctor. If you are considering a course of interferon, this is meant to provide you with some fundamental information to help you decide whether interferon treatment is appropriate for you.
SPRI IDEAL Study
Hepatitis C Viral Kinetics Study
