TAG 2010 Pipeline Report
Oral drugs (known as direct-acting antivirals, or DAAs) that specifically target certain steps in the hepatitis C virus life cycle are in late-stage development. In 2011, the U.S. Food and Drug Administration (FDA) approval of two HCV protease inhibitors, boceprevir and telaprevir, is expected. But pegylated interferon (also known as peginterferon) and ribavirin—the current standard of care for hepatitis C—will remain as the therapeutic backbone for the first few generations of HCV drugs. Peginterferon and ribavirin work by killing infected cells (immunologic effect) and protecting new cells from hepatitis C by preventing HCV replication (antiviral effect). Nobody knows whether a combination of DAAs will cure HCV by preventing the virus from reproducing (an approach that has been successful for treating, but not eradicating, HIV). Peginterferon (or another therapy that stimulates the immune response to HCV) may still be required to cure HCV. Everyone would like to be rid of interferon. It is a huge barrier to HCV treatment access, uptake, and completion because of its cost (~$25,000 per year), medical contraindications, and many side effects. Even when HCV treatment is readily available at no cost, tolerability is a problem: only one out of 56 people who received HCV treatment through the Veteran’s Administration completed their regimen (Butt 2009). Hopefully, DAA combinations will become the standard of care. By 2013, results from a trio of groundbreaking trials will be available. These studies combine two DAAs, with or without peginterferon and ribavirin. Study populations and drugs differ (in treatmentnaive people, a protease inhibitor/non-nucleoside polymerase inhibitor combination; in prior null responders, a protease inhibitor plus an NS5a inhibitor), but if successful, these trials will provide initial proof-of-concept for peginterferon-free regimens. In the meantime, results from the first phase III study of a DAA (telaprevir, an HCV protease inhibitor) plus SOC were reported in May 2010, and others are nearing completion. Several ongoing triple therapy trials—adding a single DAA to SOC—are exploring treatment strategies and duration, and evaluating early predictors of successful treatment. Quad trials—two DAAs plus SOC—will soon be underway as well. The biggest limitation to DAAs is the emergence or development of drug resistance. Drug resistance means that an organism—such as HCV—is able to grow or reproduce despite presence of levels of a drug that would normally stop it from doing so. HCV makes billions of copies of itself each day. They are not identical; some individual virus particles (virions) have structural changes (mutations). Some mutations may allow the virus to escape from drug pressure, leading to drug resistance. In fact, resistance to one or more DAA classes has already been detected in people who have never used these drugs (Kuntzen 2008; Legrand-Abravanel 2009). 78