TAG 2010 Pipeline Report
Characteristics of the Class: HCV Polymerase Inhibitors Nucleoside, nucleotide, and non-nucleoside polymerase inhibitors have been part of combination HIV treatment for years. Now, analogues of those drugs, made specifically for HCV, are in development. Nucleoside and nucleotide polymerase inhibitors are imperfect copies of nucleotides that insert themselves into hepatitis C RNA. Since they are faulty, other nucleotides cannot attach themselves; in other words, nucleoside and nucleotide polymerase inhibitors cause viral dead ends. Non-nucleoside polymerase inhibitors interfere with HCV replication by binding to the hepatitis C polymerase and preventing viral replication—it’s as if the virus is a car trying to park in a space that just got too small for it. Some nucleoside/nucleotide polymerase inhibitors have already been discontinued for toxicity, but other candidates in this promising class are moving forward. If these are safe, effective, and tolerable, nucleoside/nucleotide polymerase inhibitors are likely to become the backbone of HCV treatment, since they are active across genotypes and have a high genetic barrier to resistance (meaning that resistance to this family of drugs is less likely to develop than resistance to protease inhibitors and non-nucleoside polymerase inhibitors). So far, the hepatitis C non-nucleoside polymerase inhibitors in development are active only against HCV genotype 1, and resistance develops quickly. In fact, mutations that confer resistance to non-nucleoside polymerase inhibitors have already been detected in people who have never taken these drugs (Dryer 2009). It may be possible to combine non-nucleoside polymerase inhibitors, since the HCV polymerase has at least four binding sites. Side effects reported in trials of nucleoside/tide and non-nucleoside polymerase inhibitors include nausea, vomiting, diarrhea, fever, weakness, flatulence, chills, headache, fatigue, and rash.
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