In the long run, Liang says, drug treatment is more expensive and complicated than vaccination, adding that it is difficult for developing countries to afford the cost of a 48-week treatment, which currently runs up to $20,000 in the U.S. With current HCV vaccine candidates in the early stages of clinical testing, however, anti-HCV drugs will probably beat vaccines to the marketplace.
Attacking HCV head-on
The forerunners among the new drugs tailored to stem HCV infection are telaprevir and boceprevir. Both drugs are currently in their last, or phase III, trials. If the tests are successful, the companies that developed them will file with the U.S. Food and Drug Administration for approval. Telaprevir, designed by Vertex Pharmaceuticals in Cambridge, Mass., and boceprevir, by Schering–Plough in Kenilworth, N.J., also share a similar mechanism of action and efficacy. Eric Lawitz, president and medical director of Alamo Medical Research in San Antonio, Tex., expects that boceprevir, like telaprevir, should increase the number of patients that respond to interferon and ribavirin by 20 percent. Lawitz has worked with McHutchison at the DCRI on some of the early clinical telaprevir studies.
These drugs target the HCV protease—one of the virus's enzymes. When the virus infects a cell its RNA genome gets translated into one long polyprotein. The HCV protease, along with some cellular proteases, must cleave this polyprotein into distinct viral proteins that can carry out other jobs in the viral life cycle, such as making more copies of the viral genome. Lab strains of HCV that harbor mutations crippling the protease fail to replicate in cells in a petri dish and cannot establish an infection in chimpanzees, the animal model for studying HCV. Because of the importance of the HCV protease, scientists at Vertex and Schering designed small molecules, based on the structure of the protease protein, that could fit into the protease's active site. They then tested them for their ability to disarm the enzyme. The winners were telaprevir and boceprevir.
In the most recent phase II clinical trial, a team of investigators, which included McHutchison, found that 61 percent of patients who received a triple treatment of telaprevir with interferon and ribavirin responded to treatment compared with 41 percent in the control group that received the usual 48-week regime of interferon and ribavirin. Treatment response meant that the patient had undetectable levels of virus for at least 24 weeks after the end of treatment, indicating that they could be cured of HCV. Moreover, instead of 48 weeks, patients were on the triple therapy for 12 weeks, followed by 12 weeks of double therapy (interferon and ribavirin). The results of the trial were published in the April 30 issue of The New England Journal of Medicine.
The drawback of triple therapy, however, is its side effects. Rash was the most common as well as an overall heightened degree of the nausea and anemia associated with double therapy. Because of such effects, 21 percent of the triple-therapy group dropped out of the study, compared with 11 percent of the control group.
McHutchison attributes the success of triple therapy at bringing down the level of virus to the fact that "we're just attacking viral replication another way." But there could be some overlap between the action of the protease inhibitors and that of interferon. Along with cleaving the viral polyproteins, which benefits the virus, the HCV protease also cleaves cellular proteins involved in the immune response, which may compromise patient immunity. Interferon treatment restores some of this innate immune response. And, if a protease inhibitor were added in the treatment mix, it could prevent some of the destruction of the host's immune response.