Cutting edge

September 3, 1999

Lorne Tyrrell saw his idea for a treatment for hepatitis B through from conception to introduction

Hepatitis B virus is a common infection worldwide that causes acute or chronic infections. There are an estimated 300 million HBV carriers. Each day, about 1,500 people die from cancer of the liver and 2,000-3,000 from cirrhosis of the liver as a result of chronic HBV infection. There is a vaccine to prevent infection, but there has been no effective therapy for chronic HBV.

In 1986, I became fascinated by the discovery of the virus's unique replication mechanism and thought there were potential "targets" for antiviral therapy. I met Morris Robins, a nucleoside chemist at the University of Alberta (now at Brigham Young University in Provo, Utah), who saw the potential of the collaboration and began supplying nucleoside analogues to be tested in the system on which I was working.

At that time, it was not possible to grow human HBV in cell cultures. However, a virus very similar to the human virus exists in ducks. I used liver cell cultures from congenitally infected ducklings to screen compounds for antiviral activity. Robins and I soon discovered and patented several compounds with potent antiviral activity.

In 1989, Canada was restoring appropriate patent protection for pharmaceutical agents, and industry began to invest in university research. My laboratory was one of the first to obtain substantial industry support, in our case from Glaxo Canada, now Glaxo Wellcome Canada.

Through the Glaxo Wellcome collaboration, many compounds were screened for antiviral activity against hepatitis B. Lamivudine, a compound synthesised by Bernard Belleau, was licensed to Glaxo Wellcome. I discovered the potent antiviral activity of lamivudine against duck HBV. The collaboration with Glaxo again proved fruitful as Ron Keeney, a physician and medical director with Glaxo Inc. in the US, identified a chimpanzee colony in Louisiana that had been used in the early vaccine studies. I and my student Karl Fischer found six animals that were chronic carriers of HBV. This provided an opportunity to test lamivudine in a primate carrying the human strain of the virus. We added lamivudine to their drink and saw within three days that the virus in the blood fell to undetectable levels.

Three studies paved the way for human trials - the first completed in 1993 in three centres in Europe and two in North America. They were exhilarating. The patients on placebo had no change in the levels of virus in their blood, whereas patients receiving 100mg per day or more by mouth had more than a 99.9 per cent drop in the amount of virus in their blood. In addition, lamivudine's safety profile was excellent. An added benefit of this therapy was the treatment of patients with end-stage liver disease from hepatitis B who undergo liver transplants. A big problem had been infection of the transplanted liver within days by HBV. In the early 1990s, this was so significant that many medical centres would not do liver transplants in patients with HBV in their blood. The use of lamivudine before and after transplanting has given these patients new hope.

It is rare in science that we have the experience of conceiving a concept, synthesising many of the compounds, developing the tools to test the concept, and proving the utility of an agent in animal models and humans. But that was the case for me and Robins. A concept that began in teaching was put into practice by a research team that included many excellent technicians, graduate students, postdoctoral fellows, research nurses and clinical fellows. Lamivudine is now widely approved as the first oral antiviral agent for the treatment of chronic hepatitis B infection.

Lorne Tyrrell is dean of medicine at the University of Alberta in Edmonton, Canada.

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