People infected with hepatitis C virus (HCV) face a long road of drug treatment that, in the best cases, can cure their infections and allow their livers to recover from HCV-associated liver disease, whose symptoms range from scarring and cancer to organ failure. Unfortunately, for nearly half of those treated for the most common strain of HCV, the standard antiviral drugs do not succeed in clearing the virus. And, even in cases where the drug regime is effective, flulike symptoms, depression and anemia are common side effects during the 48-week treatment period.
Here is the crux of the current treatment dilemma: When John McHutchison, a liver specialist at the Duke Clinical Research Institute (DCRI) in Durham, N.C., discusses with his patients whether to begin treatment for their chronic HCV infections, he tells them that it would give them about a 40 percent chance of curing their infection. The HCV regime contains two nonspecific antiviral drugs called interferon and ribavirin. But, he also tells his patients nowadays that in about 18 months new treatments could be available that improve their chances. "Many of them who have not responded to our current treatment are waiting for these new [HCV] drugs," he says.
The World Health Organization estimates that about 170 million people worldwide have chronic HCV infection—resulting from their bodies not having been able to fight off the acute onset—and are thus at risk of developing potentially fatal liver disease. Approximately 3.2 million people in the U.S. are chronically infected with HCV, according to the U.S. Centers for Disease Control and Prevention. In the U.S. patients have between a 38 and 41 percent likelihood of responding to the combination of interferon and ribavirin, depending on the level of virus in their bodies as well as the drug dosages. McHutchison says that the likelihood of responding to HCV treatment is higher among European than American patients, but as low as 25 percent among African-Americans, because of differences in mutations in immune genes between these groups.
How long patients like McHutchison's and others will have to wait for new HCV medication depends on the success of the drug candidates that are currently in large-scale phase III clinical trials. The strategy of these pharmaceuticals is to directly undermine HCV's ability to replicate inside cells. In contrast, interferon nonspecifically boosts the immune system (the mechanism of ribavirin is not well understood). One of the new anti-HCV drugs, when given in combination with interferon and ribavirin, increases the percentage of patients who are cured of the virus to 60 and reduces overall treatment time. If the drug, called telaprevir, performs well in the phase III trials that are underway, it could be approved for patients by 2011, says McHutchison, who leads the telaprevir trials.
Although it is at an earlier stage in clinical development, a second type of HCV drug could also become part of the treatment strategy. Rather than going after the virus itself, these compounds would inhibit molecules native to the patient. The right type of cellular target "needs to be mandated by the virus, and then it needs to be dispensable for the host during the duration of treatment," says Henrik Orum, chief scientific officer at Santaris Pharma in Denmark. Orum's group demonstrated that a type of RNA molecule called a microRNA could be that kind of target in a study that was published December 3 in Science. Whereas this microRNA is necessary for HCV replication, its absence does not seem to cause harm to the host.
Of course, the best way to handle HCV infection is to prevent it altogether. T. Jake Liang, chief of the Liver Disease Research Branch at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), says that even if HCV therapy became an effective cure for everyone, "there are still cases of new infections through various means," such as intravenous drug use, sexual and close personal contacts, and tainted medical products or instruments. Because injecting drugs is also a major risk factor for HIV, between 50 and 90 percent of injecting drug users that are HIV-positive are also infected with HCV. Co-infection with HIV accelerates the progression of HCV-associated liver disease, and may compromise the effectiveness of HCV treatment.