October 21, 2001
Dr. Eugene Schiff, Professor of Medicine and Director of the Center for Liver Disease at the University of Miami presented an overview of the current status of hepatitis C treatment and discussed some of the treatments that are being developed to control this disease.
The main goal of treatment for hepatitis C infection is to induce a sustained viral response, defined as no detectable virus in serum using sensitive polymerase chain reaction (PCR) assays 6 months after completion of therapy. Long-term studies have shown that patients that can achieve this goal have a greater than 98% chance of staying free of detectable virus for over 10 years. For those who did not have cirrhosis (scarring) prior to therapy, the liver biopsy returns to normal. A second important goal of antiviral therapy is to improve liver inflammation and enhance liver repair. This outcome is particularly important for those patients who already have fibrosis or cirrhosis of the liver at the time of diagnosis. This goal can be achieved in many patients even if total viral eradication is not achieved.
Great progress has taken place over the last decade in the treatment of hepatitis C infection. In the early 1990s, the only available treatment consisted of interferon monotherapy for six months with sustained response rates of less than 10%. Increasing length of treatment to 12 months and adding ribavirin to interferon therapy greatly increased the efficacy of therapy with sustained response rates in the 40% to 45% range. Among individuals infected with the hepatitis C virus genotype 2 or 3, sustained viral response can be achieved in 70% of cases. The recent introduction of pegylated interferon in combination with ribavirin achieves a sustained response in over 50% of patients treated and increases quality of life during treatment compared to regular interferon. When weight-adjusted dosing for pegylated interferon and ribavirin is used, as many as 61% can achieve a sustained viral response.
Despite these advances in the treatment of hepatitis C, current medications can be associated with significant side effects. The quality of life during treatment is reduced and significant neuropsychiatric side effects such as depression, irritability and aggressive personality disorders limit the usefulness of therapy. Moreover, among genotype 1 infected individuals (the most common genotype in the U.S.), sustained viral eradication is achieved in only 42% of those treated with pegylated interferon and ribavirin.
According to Dr. Schiff, research is actively ongoing in several areas that can enhance the efficacy of hepatitis C treatment. Newer therapeutic agents in development attempt to a) inhibit the host-virus interactions that promote viral replication, b) stimulate host mechanisms that have antiviral activity and c) inhibit viral replication.
The development of a vaccine to prevent hepatitis C infection is the ultimate goal. Unfortunately, the hepatitis C virus has the ability to mutate rapidly and escape detection by neutralizing antibodies. The rapid formation of these "escape mutants" makes development of a vaccine very difficult. There is ongoing research in this area, but Dr. Schiff noted it is unlikely that we will have an effective vaccine available in the near future.
Passive immunization by the administration of gamma globulin active against hepatitis C is another area of research. The utility of this approach is limited, as it would be useful only for documented cases of recent exposure, a situation that rarely occurs in hepatitis C infection, as most infections are inadvertent or asymptomatic. Human gamma globulin injection using high titer anti-HCV antibody has been used with limited success in animal studies.
Dr. Schiff considers that therapeutic DNA vaccines that can be used to treat established hepatitis C infection rather than prevent the infection hold some promise. These vaccines introduce a component of the virus into a vehicle that is delivered in a vaccine form. Once injected it triggers a vigorous immune response in the host that could successfully attack the virus and eliminate the infection. Trials are currently ongoing with these types of vaccines.
The most promising agents for the future are those that inhibit the ability of the virus to replicate. Ribozymes attach to one end of the viral genome and act as "scissors" cutting up the genome of the virus at set locations, effectively destroying the "brain" of the virus and inhibiting viral replication. While ribozymes have been shown to be effective in the laboratory, it is not yet known if they are capable of reducing viral load in humans. Trials are currently in progress.
The hepatitis C virus has several key proteins that allow it to replicate. Inhibiting these proteins will likely result in a marked reduction in viral load. The HCV protease inhibitors target the HCV proteases, enzymes that are critical for viral replication. Unfortunately, the protease receptor site is very shallow and an unusually large inhibitor molecule is required to block it, this has resulted in disappointing results in using this approach.
Helicase is a protein used by the virus to "unwind" the RNA once it is produced. Helicase inhibitors hold promise in reducing viral load, but researchers are having difficulty developing an inhibitor that will bind strongly to the helicase, thus a clinically useful product has yet to be developed.
According to Dr. Schiff, the most promising agents in development are the HCV RNA polymerase inhibitors. There is prior experience with polymerase inhibitor development in the treatment of HIV and hepatitis B, and several pharmaceutical companies are developing this type of compound. While this appears to be the most promising approach, it will take three to five years before these products are available for clinical use.
Dr. Schiff discussed the ongoing developments of anti-fibrotic agents, another promising area of research. The hepatitis C virus causes liver damage by allowing deposition of collagen or scar tissue that eventually leads to cirrhosis. Prevention of collagen formation or deposition would prevent most of the serious consequences of hepatitis C infection or any other type of chronic liver disease. The messengers that lead to formation of scar tissue in the liver have been identified. Among these, tumor necrosis alpha (TNF-alpha), PDGF and TGF-beta are the most active messengers. Even though we have currently available inhibitors of TNF-alpha for the treatment of other diseases, it appears that this messenger is mainly involved in triggering inflammation and not fibrosis. In contrast, TGF-beta appears to be mostly involved in the formation and deposition of collagen and research is ongoing in developing inhibitors for TGF-beta.
In summary, although a lot of progress has been achieved in the treatment of hepatitis C in the recent past, ongoing research promises even better results in the future. Newer therapies, however, are unlikely to become available for the next three to five years. For now, aggressive use of pegylated interferon products in combination with ribavirin remains the most effective therapy against hepatitis C infection, achieving long-term response in 40% to 80% of patients depending on pre-treatment characteristics.
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