As is the problem with any drug that targets an HCV protein, viruses have emerged that are resistant to protease inhibitors. Because patients harbor a heterogeneous mix of HCV species, there could easily be a few in the population that are able to grow despite protease inhibitors, causing a so-called "viral breakthrough". This heterogeneity is due to the facts that HCV replicates at a high rate and the viral polymerase, which makes copies of the RNA genome, is prone to error. In fact, studies have estimated that, in a day's worth of gene replication, every site in the viral genome mutates at least once.
In the recent phase II study of telaprevir, viral breakthrough occurred in 7 percent of the patients that received triple treatment. "[But] the hope is that most of those [viruses that break through will] respond to the interferon and ribavirin," Alamo Medical's Lawitz says.
The protease inhibitors could be just the beginning of anti-HCV drugs that are added to the treatment regime. Compounds that inhibit the HCV polymerase are currently in phase II trials and, if all goes well, could get to market about a year after protease inhibitors. Although it would be less likely for a viral species to have mutations that made it resistant to both protease and polymerase inhibitors, the idea is that multidrug-resistant HCV strains could still emerge, as HIV strains have in spite of antiretroviral therapy.
Indirectly inhibiting HCV infection
To reduce the risk of viral resistance and give HCV-infected patients another treatment option, scientists are looking to inhibit cellular molecules that are important for HCV replication. In 2006 scientists discovered that HCV needs a microRNA, a regulatory RNA that does not get translated into protein, in order to replicate. Although this microRNA, called miR-122, binds directly to the viral genome, it is not entirely clear how miR-122 helps the viruses replicate.
Based on HCV's dependence on miR-122, scientists at Santaris decided to try a technology that they have also been developing to treat various cancers, such as leukemia and solid tumors. The team synthesized an RNA molecule called SPC3649 that is designed to base pair with miR-122 and has a chemical modification locking it in one of its two possible confirmations. Locking the molecule allows it to bind to miR-122 more effectively, thereby preventing miR-122 from binding HCV RNA.
The results that the Santaris group saw in HCV-infected chimpanzees, which were published November 30 in Science, encouraged the scientists to conduct phase I trials of SPC3649 that are currently ongoing. They found that the level of HCV plummeted in all four of the chronically infected chimpanzees that they injected with SPC3649 weekly for 12 weeks. These results do not resolve, however, whether SPC3649 can clear a chronic infection because the levels of virus rebounded after the scientists stopped treatment. "Future studies in human patients will be investigating that point further," says Orum, who is leader of the project, adding that "12 weeks is a fairly short period of time for eradicating HCV virus."