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Clearing Hep C

Several drugs that stop the virus by blocking different pathways are nearing FDA approval.

By Lauren Ware // Winter 2013
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The discovery of the hepatitis C virus in 1989, after more than five years of searching, used previously untried techniques and required frequent leaps of faith. It was one of the triumphs of molecular biology, and the years that followed saw the introduction of a treatment that cures about half of the patients who receive it as well as the possibility of a vaccine, as Proto related in Summer 2007 (“Out of the Shadows”). Developments on both the treatment and vaccine fronts are sorely needed, given that 170 million people worldwide are already afflicted with HCV, and a fifth of those will develop cirrhosis of the liver.

The current drug regimen for treating hepatitis C—interferon combined with ribavirin—is less than ideal: It must be injected, and it can elicit side effects so unpalatable that many asymptomatic patients choose to remain infected. Moreover, the drugs work better against some of the six HCV genotypes than others.

Now, several drugs that stop hepatitis C by blocking different pathways are nearing FDA approval. Rather than enduring weekly injections for a year, patients may swallow two to four pills daily for roughly 12 to 24 weeks. And the number of people who achieve a cure is far greater than with the previous generation of therapy. “For the typical patient who harbors the most common variant of HCV infection, genotype 1, we’re now looking at a sustained viral clearance rate of 90% or better,” says Raymond Chung, director of hepatology at Massachusetts General Hospital and a researcher of several such drugs.

The new drugs work by hitting three different targets in the viral replication pathway. When the hepatitis C virus enters the cell, it begins to translate its RNA, or genetic material, into a long polypeptide, or protein made of roughly 3,000 amino acids. Other proteins cleave the polypeptide into 10 shorter proteins, which are then responsible for replicating the viral genome. One type of drug blocks a specific viral enzyme, called protease, that is needed to cleave the polypeptide. A second class of drug blocks the action of a different enzyme, polymerase, that the virus needs to copy its RNA genome. One kind of polymerase inhibitor uses a molecule that resembles a building block of RNA, which inserts itself into the RNA strand and short-circuits the virus’s efforts to replicate itself. Another type of polymerase inhibitor works by binding to parts of the enzyme, changing its shape and thereby making it hard to add more RNA. The third class of drug binds tightly to a molecule called NS5A that is critical for aggregation of the viral proteins responsible for RNA replication. By combining drugs that inhibit different parts of the virus’s replication process, not only is effectiveness increased dramatically, but the likelihood of emergence of viral resistance to any one class of inhibitors is greatly reduced. “We may end up with several versions of successful combination therapy,” says Chung.

And on the vaccine front, in February 2012, Michael Houghton, a molecular biologist and Canada Excellence in Research Chair holder at the University of Alberta, and one of the team to discover the virus 24 years ago, presented data that shows the vaccine he and his colleagues have developed is effective at neutralizing the in vitro infectivity of every known strain of hepatitis C. Yet FDA approval, if it happens, could take as many as seven more years.

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