June 15-16, 2001
Reported by Jules Levin
Eugene Schiff, MD (University of Miami Center for Liver Diseases), known as the Dean of Hepatitis, opened the two day conference with a talk called "The Challenge of Hepatitis". He said safe and effective vaccines for Hepatitis A and B are readily available. Treatment for chronic hepatitis B is increasingly successful and for those with end stage liver disease, recurrent hepatitis B can be prevented. However, witness the recent case of HBV/HIV for Larry Kramer where he is facing a liver transplant, as reported recently in Newsweek.
Schiff said the overriding challenge in this decade is hepatitis C. This disease, with a worldwide prevalence of over 170 million, notoriously (85%) evolves into chronic hepatitis, which will progress to cirrhosis in about 20% of cases. Data from a number of studies shows HIV accelerates HCV progression substantially for many people. He warned that the aging cohort of more than 2 million people in the US can be anticipated to generate increasing numbers of patients with end stage liver disease, many of whom will develop fatal consequences including hepatocellular carcinoma. He also expressed a positive attitude by saying that the explosion of information from studies in molecular biology and gene therapy undoubtedly will result in the conquering of this disease. New antiviral, anti-fibrotic and immunostimulatory agents are in the pipeline, he said. And they appear to be. In the first of the two days conference we heard a number of talks about research programs into new drugs for hepatitis C.
Many drug companies and researchers are here at this conference, as the room is filled to capacity with about 300 people. Schiff said first and foremost is to prevent new cases of HCV, most effectively achieved with the development of a safe and effective vaccine. Second will be the advent of even more effective therapy than currently available for those with chronic HCV. Finally the patients with far advanced liver disease must have effective antiviral therapy that will prevent recurrent infection in the liver transplant graft.
Schiff reported that in the USA:
He showed data displaying how Japan has the most advanced death rate increase from HCV: 21% in 1980 to 51% in 1995. Three to 4 million have HCV in the US, 85% go on to chronic infection, and 10% develop decompensated cirrhosis ( 4% HCC, 6% decompensation, 3.6% death). He estimated that 61% would have cirrhosis by 2008, 68% HCC, and liver related death would increase 233%.
Hepatitis C Genetic Diversity and High Level of Viral Replication Pose a Challenge
Charles Rice, PhD (Rockefeller University) and Particia Farci (University of Cagliari, Italy) talked about hepatitis C viral diversity. Within an individual, the virus exists as a quasispecies (mutated forms) and among isolates worldwide 6 major genotypes and numerous subtypes are recognized. Virus replication is a dynamic process with virion half life of 2-3 hours and an estimated production rate of about 1012 virions per day. HCV RNA occurs via synthesis of a complementary negative-strand RNA intermediate and is error prone resulting in the generation of a large number of variants. Such high replication rates and the resulting genetic diversity pose important challenges for vaccination and treatment. Evidence is accumulating to suggest that the diverse genetic nature of HCV may have important biologic & clinical implications for viral persistence, for drug resistance and for vaccine failure, so said Farci. She continued that genetic variability is a critical mechanism for the virus to persist in the host (human) by escaping the immune system. Some patients can clear HCV but it remains unknown why. But recent evidence suggests that an increase in viral diversity during acute infection is associated with progression to chronicity, while self-limited clearance is associated with a virus which does not increase in diversity but remains stable. These data indicate that the early events of the virus-host interaction may determine the outcome of HCV infection. She said that patients who respond to interferon therapy with sustained HCV clearance exhibit a significant decrease in viral diversity and in the number of viral strains, with a similar pattern to that seen in patients who spontaneously clear the virus. By contrast, patients who do not respond to therapy show persistence of the original dominant viral strains, suggesting that resistant strains are already present prior to therapy.
David Ho talked about what has been learned in HIV saying that much less is known today about HCV. In HIV we know how HIV reproduces itself, but we dont know the process yet in HCV. Understanding this process has been limited by the fact that we do not have a cell culture system (test tube) where HCV can be placed to watch it replicate. Therefore, you cant place a drug in the test tube to see if and how the drug changes or inhibits replication. HCV disappears in the test tube. But it appears as though a new system is being developed and used in some labs that addresses some of the needs posed by the lack of such a system. Ho described daily production of HCV (1.3 x 1012 ), HIV (1010 ), and HBV 2.1 x 1012 ). In HIV, viral invasion into an infected call contributes to cell death and the immune system may play a role in killing off infected cd4 cells. In HCV it remains unknown why cells die off.
New Drugs In Development
The HCV gene was described and the various enzymes that comprise the gene were described as targets for which to develop drugs, as in HIV. The reverse transcriptase and protease enzymes are targets for HIV drug therapy. In HCV, the IRES, helicase, protease, and polymerase enzymes were discussed. Researchers described ongoing efforts to better understand how these enzymes assist in the process of virus replication, and at which points in these processes drugs can be developed for use. A few polymerase inhibitors are in development: two in clinical trials. But there is no data yet and speculation scuttle-but in the halls here was that these drugs may have limited antiviral activity. But hopefully more potent polymerase inhibitors will be developed. Several companies are researching the development of protease inhibitors for HCV. Boerhinger Ingleheim reports here of their HCV protease inhibitor going into phase 1 in uninfected in about 1 month. There is considerable controversy here about the viability of developing a protease inhibitor for HCV. Many researchers have been saying how difficult it is to develop a PI in HCV. But several researchers here reported that they feel encouraged that their HCV development program will be successful. Bear in mind that the Boerhinger PI is the first to go into humans and that none of the other PI programs are that far developed.
Also discussed were ongoing research into antisense and ribozymes. Larry Blatt from Ribozyme Pharmaceuticals discussed the drug they have in early human studies. He reported it to be well tolerated in animals, good safety profile so far in humans, potent in cell culture, well tolerated in humans in phase 1 by subcutaneous administration. He also said phase 2 in combination with interferon will be started and that the drug abundantly gets into liver cells.
John McHutchison (Scripps Clinic) reported on a dose escalation trial of ISIS 14803 in patients with chronic HCV. They are calling this an antisense inhibitor of HCV but one researcher told me he feels it works differently. In this initial study ISIS 14803 was administered three times weekly for 4 weeks either by 2 hour intravenous infusion or bolus subcutaneous injection following, by at least 7 days, a single dose. The first 11 patients in the study received ISIS 14803 by IV infusion. 10 had previously received interferon. Sequential groups of 3 patients were treated at 0.5, 1, and 2 mg/kg with another 2 patients receiving 2 mg/kg single doses and 1 mg/kg three times per week doses. Two out of 4 patients treated with 2 mg/kg for 30 days or more had decreases in plasma HCV RNA viral load greater than 1 log. Two others had reductions of 0.5 log or more. Of these, 3 experienced elevations in ALT >10 x upper limit of normal. Liver biopsies performed on 2 experiencing an ALT flare did not reveal evidence of drug induced hepatotoxicity. A 4th patient experienced an ALT elevation of <10 x ULN without a reduction in plasma HCV levels. Six patients were observed to have mild to moderate fatigue. No other clinical signs or lab evidence of toxicity were observed. Further evaluation of patients with the same administration routes is ongoing, and additional immunological studies of the ALT flares are planned.
Several researchers I spoke with estimated it will take 4-5 years for promising HCV antiviral drugs discussed above such as helicase, protease, and polymerase inhibitors to enter clinical trials in HCV infected.