Hepatitis C genotype 1 virus with low viral load and rapid virologic response to peginterferon/ribavirin obviates a protease inhibitor


  • Potential conflict of interest: Dr. O'Brien is an inventor on patent applications filed by the National Cancer Institute for the IFNL4-ΔG (ss469415590) genotype-based test and for the IFNL4 protein. Dr. Morgan received grants from Bristol-Myers Squibb, Genentech, Gilead, Vertex, and Merck.

To the Editor:

Peg-interferon-α, ribavirin, and a first-generation protease inhibitor is currently the standard regimen for treatment of chronic hepatitis C in the United States. To examine whether the protease inhibitor may be superfluous for a selected subgroup of patients, Pearlman and Ehleben[1] conducted a randomized trial of 101 HCV genotype 1-infected patients with these favorable characteristics: treatment-naïve; noncirrhotic; pretreatment HCV RNA <600,000 IU/mL; achieved rapid virologic response (RVR) after 4 weeks of peg-interferon-α/ribavirin treatment. Overall rates of sustained virologic response (SVR) were: 88% in the arm receiving 20 additional weeks of peg-interferon-α/ribavirin alone (double therapy): 90% in the arm receiving 24 weeks of peg-interferon-α/ribavirin/boceprevir (triple therapy). These results support the authors' conclusion that there was no overall difference in treatment response between the two arms. Contrary to another conclusion of the authors, however, data from this trial indicate that even in this highly selected group of patients, host genotype identifies patients who are more likely to respond to therapy.

The authors examined rs12979860 genotype, which has been strongly associated with treatment response in numerous studies.[2] Although commonly referred to as “IL28B,” rs12979860 is actually located within IFNL4 and is highly correlated with the IFNL4-ΔG variant, an even stronger predictor of treatment response, especially for African American patients.[3] In the double therapy arm, 33/34 (97%; 95% confidence interval [95% CI], 85%-100%) patients with the rs12979860-CC genotype achieved SVR compared to 14/18 (78%; 95% CI, 52%-94%) in “non-CC” subjects. Nearly identical SVR rates were seen in the triple therapy arm: rs12979860-CC, 32/33 (97%; 95% CI, 84%-100%); “non-CC” 13/17 (76%; 95% CI, 50%-93%). While statistical power for the host genotype subgroup analysis was limited, by our calculations rs12979860-CC genotype was significantly associated with treatment response in each arm of the trial (P = 0.04, Fisher's exact test; Fig. 1).

Figure 1.

SVR-12 rates, by rs12979860 genotype, for HCV genotype 1-infected patients treated with double or triple therapy.[1] All patients were treatment-naïve and noncirrhotic, had a pretreatment HCV RNA <600,000 IU/mL, and achieved RVR after 4 weeks of peginterferon-α-2b/ribavirin treatment. 95% CIs (error bars) were calculated by the exact binomial method; P values were calculated with Fisher's exact test.

It appears, therefore, that a very high proportion of patients with a favorable host genotype who meet the selection criteria for this trial will achieve SVR with 24 weeks of peg-interferon-α/ribavirin alone. Otherwise similar patients with an unfavorable host genotype are less likely to respond to that regimen. Additional data, ideally based on genotype for IFNL4-ΔG, are needed to provide more precise estimates in that group.

Patients who are very likely to respond to a shortened course of peg-interferon-α/ribavirin may be more willing to undergo such treatment now rather than await development of interferon-free regimens. The authors assert host genotype has no role in identifying such patients once the HCV RNA level and RVR are considered.[1] Their data, however, indicate otherwise.


Supported by the Intramural Research Program of the National Institutes of Health (National Cancer Institute, Division of Cancer Epidemiology and Genetics). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

  • Alan S. Wang, B.A.1Ruth M. Pfeiffer, Ph.D.2Timothy R. Morgan, M.D.3Thomas R. O'Brien, M.D., MPH1

  • 1Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD

  • 2Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD

  • 3Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, CA, Division of Gastroenterology, University of California - Irvine, Irvine, CA