Interferon has served for many years as the backbone of chronic hepatitis C therapy,
despite the dismal success rate of early therapies (<10% for genotype 1b). While the
introduction of peg-interferon and the addition of ribavirin improved the sustained
viral response (SVR) rate, the therapy was still ineffective for about half of the
patients infected with genotype 1b, providing a strong impetus for the development
of innovative therapeutic options for HCV. In stark contrast to the system-wide
innate immune activation induced by interferon, the next major advance in HCV
therapy employed a far more directed strategy. Direct acting antiviral agents (DAAs)
have been designed to interfere with HCV replication by directly targeting HCV
proteins. Administered as part of a triple therapy along with peg-interferon plus
ribavirin, protease inhibitors, the fi rst DAAs to be approved, signifi cantly improved
the SVR rate. However, interferon’s broad activity has always exacted a high cost
in terms of side effects, including fever, malaise, anorexia, and thrombocytopenia,
and ribavirin poses a high risk of anemia, as well, requiring frequent dose reductions.
These risks put interferon-based therapy out of the reach of many of Japan’s
patients, many of whom are elderly. Furthermore, patients with mental illness, cirrhosis,
or other comorbidities are ineligible for interferon-containing therapies.
However, protease inhibitors used in monotherapy would rapidly select for antiviral
resistance and lead to viral breakthrough and discontinuation of therapy. The race
was on for a safe and effective alternative to interferon. Studies using the human
hepatocyte chimeric mouse as a model system for HCV infection demonstrated that
the combination of two DAAs with different targets (telaprevir, an NS3/4A protease
inhibitor, and MK-0608, an NS5B polymerase inhibitor), could successfully eliminate
HCV without interferon or ribavirin. Clinical trials in humans using the combination
of a protease inhibitor (asunaprevir) and an NS5A inhibitor (daclatasvir)
showed great success, especially against genotype 1b, the predominant genotype in
Japan. In 2014, Japan became the fi rst country to approve an interferon-free therapy
for HCV and has since successfully treated tens of thousands of patients. Not all
patients achieve SVR, however, and pre-existing or treatment-emergent resistanceassociated
variants contribute to treatment failure in an important subset of patients.
Therefore, clinicians attempting to apply DAA therapy treatment must understand
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