The liver-damaging Hepatitis C virus has infected more than four million Americans and hundreds of millions of people worldwide. The consequences of infection can be unpredictable, ranging from "silent" infection to liver failure and death. The ideal treatment remains elusive, and co-infection with the human immunodeficiency virus (HIV) compounds the treatment challenge. In the future, the most effective approach to defeating this virus will be prevention-but current vaccine candidates demonstrate mixed results. These topics were discussed as part of a symposium on Hepatitis C at the 38th Annual Meeting of the Infectious Diseases Society of America (IDSA).

Twenty-five percent of people who contract Hepatitis C (HCV), primarily through infected blood, develop immediate symptoms. For 75 percent of infected persons, the illness is not immediately apparent. In each of these groups, only ten percent of patients escape what the vast majority experience a slowly smoldering type of chronic illness that is either mild or moderate in severity. Five to 40 percent of these persons eventually develop cirrhosis of the liver (20 percent is the figure commonly cited), and about 25 percent of these cirrhotic patients develop liver cancer or liver failure, according to specialists on the panel.

Barbara Rehermann, MD, Liver Disease Section, National Institutes of Health (NIH), Bethesda, Maryland, is interested in understanding the mechanism by which some people completely eradicate HCV from their bodies while the majority becomes chronically infected. Recent research shows the key players in the defense against HCV to be HCV-specific antibodies and T-helper cells, which recognize and break up HCV in infected cells. "A strong T-helper cell response early in an acute infection appears to be associated with recovery from the virus, but loss of the T-helper cell response aids chronicity," she reported.

This hypothesis is supported by observations made in a group of people who were accidentally exposed to HCV 20 years ago. Those who completely recovered had T cells circulating in the peripheral blood, suggesting that if a strong T-helper immune response can be maintained, HCV might be fought off. To study whether the development of a strong T cell response might protect against future exposures to HCV, she inoculated chimpanzees (the only animal model of HCV) with HCV to produce infection, then reinoculated them one year later with the same strain of virus. The second exposure to the virus produced a shorter period of viral illness, less viral load, less elevation of liver enzymes, and more rapid clearance of the virus from the body-presumably because a strong immune response had been elicited and maintained by vaccination. The finding that a strong immune response upon initial HCV infection is associated with recovery from the virus has implications for future therapy, specifically with agents that might boost immunity, Dr. Rehermann indicated.

Current and Future Treatment of HCV

The goal of treating HCV by eradicating the virus is to prevent late-stage disease, especially cirrhosis of the liver and its complications, said Gary L. Davis, MD, University of Florida, Gainesville. Treatment with interferon-alfa (Roferon A®, Intron A®) alone has been disappointing. While about 30 percent of HCV-positive patients respond to 24 weeks of treatment (with undetectable virus and normalization of liver enzymes), only six percent have a sustained response at six months. The recent addition of ribavirin (Rebetron®) to the treatment arsenal, however, has proven very helpful. The combination of interferon-alfa and ribavirin produces higher response rates and more sustained responses, he said.

The interferons are natural glycoproteins produced by cells in response to infection. They have antiviral, immunostimulatory, and antiproliferative effects. Ribavirin is a guanosine analogue active against many viruses, but its mechanisms are largely unknown.

With combination therapy, 50 percent of patients respond to treatment after 24 weeks, and eradication is sustained in 26-34 percent of patients. Not all viral types respond equally well, however. For persons who have Type 1 HCV, the most common viral type, the response rate is 30 percent after one year of treatment and less than 20 percent after 24 weeks of treatment. Viral Types 2 and 3, on the other hand, which affect 20 percent of patients, respond quite well-65 percent of patients become permanently clear of the virus with 24 weeks of treatment, Dr. Davis reported.

Dr. Davis maintained that any patient with fibrosis or cirrhosis of the liver should receive 12 months of treatment with combination therapy, regardless of viral type. Without these late-stage conditions, the genotype should be taken into consideration before starting treatment, which can have some problematic side effects, such as fatigue.

In patients previously treated with interferon-alfa only-which is less effective-it is important to determine the best way to treat relapses in this group. Re-treatment with combination therapy has proven quite successful. Re-treatment with interferon alone clears the virus in only about five percent of patients, but 80 percent of patients respond to the combination, and almost half experience an eradication of the virus with combination therapy. The best response is seen in patients with Type 1 virus, who respond as well as patients treated for the first time. In patients who do not initially respond to interferon monotherapy, ten percent may respond to re-treatment with the newer combination regimen, he said.

Dr. Davis added that interferon maintenance treatment might suppress inflammation and perhaps, fibrosis (scarring of the liver), even without reducing the viral load, and it may even be a way of slowing the progression of HCV disease.

A newer form of interferon, called pegylated interferon (still under investigation), will require only once-a-week dosing-rather than three times a week-and is expected to be approved by the FDA within a year. The typical side effects, such as flu-like symptoms, will probably be similar to the current interferon preparation, but the pegylated form may produce better response rates because a more steady level of the drug is maintained.

Co-Infection with HCV and HIV

Intravenous drug users are much more likely to contract HCV before becoming infected with HIV, since HCV is about ten times more transmissible, said David L. Thomas, MD, Johns Hopkins University, Baltimore, Maryland. "By the time people get HIV through intravenous drug use, they usually already have HCV," he said. Some 240,000 Americans, and about one-third of HIV-infected persons, are co-infected with both viruses.

In the HIV-infected person, HCV is viewed as an opportunistic infection, making HIV infection even more difficult, he said. About 90 percent of persons infected with both viruses develop liver failure-a rate that is 100 times greater than the general population. HCV may also worsen the progression of HIV disease, and, correspondingly, HIV disease may accelerate liver damage from HCV, causing a more rapid progression to fibrosis. Furthermore, HCV appears to increase the risk of liver toxicity caused by standard antiretroviral HIV treatment. Dr. Thomas advised screening all HIV-positive persons for HCV by enzyme immunoassay. People who are diagnosed with HCV should be advised to decrease alcohol intake and stop illicit drug use, which further compound the already increased risk of fibrosis from HCV.

While the treatment of this co-infection is controversial and difficult, interferon-alfa has cured some patients and delayed the progression to liver fibrosis-even in patients not sustaining viral response. There are lifestyle issues that hinder therapy in many of these patients. Specifically, the "chaotic" lifestyle maintained by many HIV-infected persons makes it difficult to adhere to the rigid treatment regimen. Patients with "stable" HIV disease and a low level of "chaos" in their lives, however, may be candidates for hepatitis treatment, he maintained. Dr. Thomas' strategy for managing HCV and HIV co-infection is to try to prevent end-stage liver disease by treating HCV in patients who have significant fibrosis on liver biopsy and minimal lifestyle chaos. A "low chaos" patient with a lesser degree of fibrosis would also be a candidate for aggressive treatment. In this case, the goal would be not only to prevent disease progression, but to cure hepatitis.

Prospects for an HCV Vaccine

While the prevention of HCV is the ideal solution in terms of managing this difficult virus, the prospects for a vaccine any time soon are slim, said Robert Purcell, MD, National Institutes of Health. However, there are impediments to HCV vaccine development, which include: • Numerous variations in the virus exist. • Natural infection does not protect against reinfection with HCV. • Natural infection usually progresses to a chronic disease state. • Most infected persons develop chronic disease, which the host is unable to control. • Neutralizing antibodies and protective cellular immune responses are poorly characterized. • The virus does not grow well in cell cultures, and therefore, it is hard to manufacture the virus. • The chimpanzee is the only animal model of HCV. Nevertheless, some progress has been made. Chrion Corporation has protected some chimpanzees by vaccination; however, protection was limited to exposure with a viral strain that was the same as that used for the immunization. Viral challenges with even closely related HCV strains have resulted in infection. Other forms of immunization have been effective in laboratory studies, but such forms are not practical in humans, he said.

"A practical vaccine for Hepatitis C, like a practical vaccine for AIDS, will probably remain an unfulfilled goal for the foreseeable future," he concluded.