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CHRONIC HEPATITIS C TREATMENT OVERVIEW

Therapy for chronic hepatitis C has evolved substantially in the 25 years since IFN-α was introduced for this indication in 1991. The therapeutic armamentarium grew to include PEG IFN with ribavirin and, then, in 2011, the introduction of the first protease inhibitors, telaprevir and boceprevir, used in combination with PEG IFN and ribavirin in patients with HCV genotype 1. The field of antiviral therapy for hepatitis C was transformed beginning in 2013, with the approval of the first nucleoside analogue, sofosbuvir. As of 2016, no fewer than six, all-oral, highly effective (>95%), low-resistance, well tolerated, short-duration (usually 12 weeks) combination regimens of DAA drugs are available. The remarkable historical evolution of antiviral therapy for hepatitis C is instructive.

THE INTERFERON ERA (1991-2011)

IFN-based therapy has been supplanted by DAA agents introduced in the second decade of the twenty-first century; however, many important lessons about antiviral therapy for chronic hepatitis C were learned from the experience with IFN-based treatment, and many of the limitations of—and disparities in responsiveness to—IFN-based therapy have been overcome by current-generation DAA treatments. When first approved, IFN-α was administered via subcutaneous injection three times a week for 6 months but achieved an SVR (Fig. 334-2) (defined then as a reduction of HCV RNA to undetectable levels by PCR when measured ≥24 weeks after completion of therapy) <10%. Doubling the duration of therapy—but not increasing the dose or changing IFN preparations—increased the SVR rate to ~20%, and addition to the regimen of daily ribavirin, an oral guanosine nucleoside, increased the SVR rate to 40%. When used alone, ribavirin is ineffective and does not reduce HCV RNA levels appreciably, but ribavirin enhances the efficacy of IFN by reducing the likelihood of virologic relapse after the achievement of an end-treatment response (Fig. 334-2) (response measured during, and maintained to the end of, treatment). Proposed mechanisms to explain the role of ribavirin include subtle direct reduction of HCV replication, inhibition of host inosine monophosphate dehydrogenase activity (and associated depletion of guanosine pools), immune modulation, induction of virologic mutational catastrophe, and enhancement of IFN-stimulated gene expression. Ribavirin, despite its poorly understood mechanism of action, retains a modest role in supporting DAA agents as well (see below). IFN therapy results in activation of the JAK-STAT signal transduction pathway, which culminates in the intracellular elaboration of genes and their protein products that have antiviral properties. Hepatitis C proteins inhibit JAK-STAT signaling at several steps along the pathway, and exogenous IFN restores expression of IFN-stimulated genes and their antiviral effects.

FIGURE 334-2

Classification of virologic responses based on outcomes during and after a 48-week course of pegylated interferon (PEG IFN) plus ribavirin antiviral therapy in patients with hepatitis C, genotype 1 or 4 (for genotype 2 or 3, the course would be 24 weeks). Nonresponders can be classified as null responders (hepatitis C virus [HCV] RNA reduction of ...

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