Researchers Using Lessons Learned From Anti-HIV Drugs To Develop Medications for Hepatitis C

Researchers are beginning to test treatments for hepatitis C similar to those used to treat HIV, the New York Times reports. Current hepatitis C treatments, a combination of ribavirin and the immune system protein alpha interferon, are not specifically designed to attack the virus itself but are designed to boost a patient's immune system to help it attack the virus. These treatments carry potentially severe side effects, such as anemia, depression, birth defects, flu-like symptoms and suicidal tendencies, and are only able to eliminate the virus in about half of the patients who take them, according to the Times. New treatments currently entering clinical trials use the tactics successfully employed for anti-HIV treatments, in which drugs specifically target the virus, interfering with the enzymes needed for the virus to replicate. Just as antiretroviral drugs interfere with protease and reverse transcriptase -- the enzymes needed for HIV to replicate -- new hepatitis C treatments are designed to interfere with protease and polymerase. While researchers say it will take years to determine if this tactic will work, evidence presented by German drug company Boehringer Ingelheim at the American Association for the Study of Liver Diseases conference in November 2002 showed that its experimental protease inhibitor succeeded in reducing hepatitis C viral loads by between 100 and 1,000 times in the small number of patients who took the drugs for two days. Other companies, including Idenix Pharmaceuticals, Japan Tobacco, Vertex Pharmaceuticals, Rigel Pharmaceuticals, Isis Pharmaceuticals and ViroPharma (in partnership with Wyeth), have started or will start trials on similar drugs this year.

Why Was The Technique Not Applied Sooner?
While some scientists blame the differences in HIV and hepatitis C drug development on the fact that hepatitis C was identified in 1988, four years after HIV, the first hepatitis C drugs are just now entering clinical trials -- 15 years after the virus' discovery -- and many anti-HIV drugs have been developed and approved in the same amount of time. Some scientists say that the comparatively larger federal government financing of HIV research and more vocal HIV patient advocacy speeded the development of HIV treatments. However, most scientists agree that the biggest obstacle in the development of hepatitis C drugs is the nature of the virus itself, which prevented scientists from being able to grow it in a test tube, making study of the virus and drug testing more difficult. In addition, scientists have had a hard time studying the virus and testing potential drugs in animals because chimpanzees, on whom testing is expensive, are the only animals who contract the virus.

Chiron Patents
Another factor in the delay, according to some scientists, is the amount of money that Chiron, the California-based biotechnology company that first identified the virus, charges for the license of its patents. "Chiron has been a little bit like a dog with a bone," Dr. Donald Payan, executive vice president and chief scientific officer of Rigel, said, adding, "I think they really slowed the field down." Gilead Sciences, which has developed successful HIV and hepatitis B drugs, dropped its hepatitis C research after being sued by Chiron, and Vertex is in the midst of a similar lawsuit. Robert Blackburn, Chiron's chief patent counsel, said that the company took a financial risk in the research that led to the discovery of the virus and deserved a share in the proceeds of drugs developed from its discovery. Blackburn added that the company's patents were available for a "modest upfront fee," as well as royalties if a drug made it to market, according to the Times.

Continued Developments
Recent scientific developments have begun to circumvent these problems. The development of a replicon, an artificial viral system, in 1999 by Dr. Ralf Bartenschlager, which was later improved by Dr. Charles Rice, has enabled scientists to study the hepatitis C virus. The replicon consists of RNA from the virus, including the protease and polymerase enzymes, which are put into liver cells to grow in culture. The replicon does not produce complete new hepatitis C virus; it reproduces using only the protease and polymerase enzymes, the parts needed for drug testing. Drug companies can now use the replicon to test if their enzyme inhibitors interfere with the replication of the replicon. In addition, as with HIV, scientists have had to contend with viral mutations, and it is likely that combinations of drugs will be needed. "No one really knows what it's going to take for the antiviral effect to outrun the resistance effect," Dr. Nathaniel Brown, vice president of hepatitis clinical research at Idenix, said. However, many researchers say that hepatitis C may be easier to treat than HIV. Unlike HIV, which turns its RNA into DNA, incorporating it into the chromosomes of the cells it infects and making it difficult to entirely eliminate the virus, hepatitis C does not use that process. Therefore, if an interferon can eliminate the virus, patients with hepatitis C can possibly be cured. "It does appear with the data we have to date it is possible to cure people with HCV, which has never been shown with HIV," Dr. Amy Weiner, director of hepatitis C research at Chiron, said (Pollack, New York Times, 3/11).