Central nervous system involvement in patients with HCV-related
NATURAL HISTORY OF HCV INFECTION AND APPROACH TO THE PROBLEM Aggressive Approach Leads to Better Response Rates. Better Therapies, Head to Head Studies of Existing Treatments Are Necessary. Progression of the Disease "Evidence is accumulating that hepatitis C patients that are identified early, before they've developed very progressive disease, are more likely to respond to therapy," says Dr. Raymond Koff, Professor of Medicine, University of Massachusetts, and Chairman, Department of Medicine, Metro-West Medical Center, Framingham, Massachusetts. "That's one of the reasons that doctors are becoming more aggressive about identifying patients, getting them into treatment programs, and advising them against drinking," he adds. The evidence is also strong that individuals who drink alcohol are at increased risk of developing cirrhosis and the rate of progression is more rapid in those who continue to drink while they have hepatitis C. Some controversy exists around the amount of alcohol that is safe for hepatitis C patients, but Dr. Koff's view is that no specific level is safe. "If a person has chronic hepatitis C," he says, "giving up alcohol makes good sense. If you are treated and cured, then maybe you can drink socially again, but it's more realistic to assume that you should not continue to drink. "Some factors that seem to be involved in the rate of hepatitis C progression are beyond our control," says Dr. Koff. For example, it appears that if transmission of the disease was through a blood transfusion, the risk of progression may be higher. Patients who develop the disease after the age of 40 or who are immunosuppressed, as in HIV, may also experience a faster progression rate, as do men in general. According to Dr. Koff, the disease exhibits a variable rate of progression. In some instances, it appears to rapidly go from chronic hepatitis to cirrhosis; but in many individuals, the disease is slowly progressive. In general, it progresses slowly enough that over the first twenty years of infection minimal morbidity or mortality is observed. Results of Treatment Studies Treatment studies are showing some interesting results, as well, especially those comparing monotherapy to combination therapy in specific patient groups. Dr. Koff described two studies of patients who had initially responded to an interferon and then had relapsed. When those patients were retreated either with interferon alfa-2b (Intron A) plus ribavirin or with the 15 microgram dose of consensus interferon (Infergen) alone, the results were comparable. In fact, the Infergen sustained response rate was 58% whereas the response rate for the combination therapy was about 46%. The only difference was that the combination therapy lasted six months and the Infergen was continued for a year. Furthermore, the side effects of ribavirin can be troublesome and are additive to those from an interferon. Ribavirin's major side effect is a hemolytic anemia that can be disabling and which leads to greater fatigue than when taking interferon alone. Dr. Koff suggests that what is needed now is a head-to-head comparison of combination therapy versus high dose Infergen in previously untreated patients. A similar comparison trial in patients who have not responded to lower dose interferon would also provide valuable information. "Only a minority of currently treated patients do respond," says Dr. Koff. "We need better therapies that are different than what we have now. It's clear that interferon alone is not going to be the answer nor is interferon plus ribavirin. I think we'll end up treating hepatitis C the same way we treat HIV, using multiple drugs and tailoring therapy to specific characteristics of the patient." As an example, Dr. Koff cites patients with genotype-1 virus (one of the three major genetic variants HCV), who are the least responsive to therapy. "They might need longer treatment periods, higher dose therapy, or daily treatments. People with a higher viral load are also less likely to respond. It's becoming clear that we may need to determine a patient's viral genotype along with their viral load and factor in any negative liver histology before we tailor therapy to the specifics of that patient." Another study showed that for the relapsing patient, one year of Infergen alone, especially for genotype-1 patients, appeared to provide a little better result than six months of combination therapy. Dr. Koff cautions that straight statistical comparisons between the studies are not valid because the drugs were not directly compared in the same study and, therefore, the methodologies may have differed somewhat. "In the literature that will be published in the next several weeks," Dr. Koff says, "it's clear that even in so-called naive [previously untreated] patients, combination therapy in genotype-1 still doesn't help the majority. We have a way to go in terms of therapies." One of the problems for researchers is that they don't know enough about the differences of genotype-1 from other genotypes to design drugs that will attack those differences. "We know that the individual genotypes differ from each other in their nucleotides by about 20 or 30%, but what is it about the particular structure of that genotype? I don't think we have a clue," Dr. Koff says. Treatment Side Effects Dr. Koff voices strong cautions about treatment side effects. "No patient who has serious depression should be treated with an interferon-like drug until they have been treated for their depression, are in counseling, and can be judged to be as non-depressed as possible. For individuals who have a history of suicidal attempts or suicidal ideation, the drug is probably contra-indicated," he says. Doctors should be cautious about using combination therapy in anyone who starts off being anemic because ribavirin may induce anemia. Caution is also advised when prescribing combination therapy for patients with cardiovascular disease. If their hemoglobin drops as a result of the anemia, they are at risk of developing a coronary event, such as a heart attack. "We are also very concerned that ribavirin is teratogenic," Dr. Koff adds. "Women who are taking this drug during their reproductive years should be on some form of contraception and should not conceive a baby. This is also true for men. We don't know exactly what the risks are but we assume they continue for at least six months after therapy has been stopped. If a physician recommends combination therapy, he must counsel the patient that fetal abnormalities are a risk. Teratogenicity apparently can be transmitted through sperm, but we are not quite sure and don't want to take any chances." Definition of Cure Current thinking, according to Dr. Koff, is that as many as 95% of individuals who have a sustained viral response, defined as virus-negative six months after ending therapy, will continue to be virus-negative, have normal ALT, and improved or normal liver biopsies on follow-up. Two different studies have followed patients for about ten years, and Dr. Koff says he would cautiously refer to them as cured. "If you've gone nine years after ending therapy, your virus is negative, negative, negative, and we can't find it in the liver biopsy, I think it means it's been cleared and you should be home free." Dr. Koff says that by eliminating the virus, treatment greatly reduces the probability of developing cirrhosis and hepatocellular carcinoma. "Virtually all such cancers in hepatitis C patients occur in individuals with cirrhosis so if we can prevent the development of cirrhosis, we should be able to prevent hepatocellular carcinoma. If you are a sustained responder, your risk of developing cirrhosis is so small that, in effect, your risk of hepatocellular carcinoma is also very small." Liver Transplants Another difficult problem is the length of time hepatitis C patients wait for liver transplants. Some are on the transplant list so long that they are almost too sick to withstand the surgery once a liver is available. Additionally, if they have hepatitis C with cirrhosis and end-stage liver disease and they are transplanted, there is a real risk that the new liver will be infected. "Fortunately, the infection is very well tolerated, at least for the first five years after transplantation," Dr. Koff says. "We don't have data much beyond five years but those who have transplants for hepatitis C are doing as well as patients who have transplants for other diseases. Should we treat people before they have their transplant or afterwards? Some of the most recent data indicate that if you treat a patient for chronic hepatitis C following transplantation, you may reduce his risk of infection and the development of liver disease. It's not perfect, however, so chronic hepatitis in the new graft continues to occur in a substantial proportion of patients. We need better therapies."