CLEARANCE OF GENOTYPE 2A IN MIXED GENOTYPE HEPATITIS C VIRAL INFECTION

R Thornburg, MD, TA Shaw-Stiffel, MDCM

Strong Memorial Hospital, University of Rochester, Rochester, NY, and Center for Liver Diseases, UPMC Presbyterian Hospital, University of Pittsburgh, Pittsburgh, PA

INTRODUCTION: It is now well established that current treatment with interferon (IFN) and ribavirin (RBV) is more likely to achieve a sustained response in patients with chronic hepatitis C viral (HCV) infection if they are infected with genotypes (GT) 2 or 3 rather than GT1. The mechanism(s) for this are not yet known. Mixed genotype infections (e.g. GT1/2) are uncommon and the immunologic events during antiviral treatment have not been studied. We report 2 cases in which GT2a but not GT1b was cleared with IFN and RBV.
CASES: (1) A 54 yo man with GT1b/2a and prior non-response to IFN monotherapy, was re-treated with standard IFN and RBV for 6 months. His viral load fell from 1 million copies/mL (c/mL) to 517,000 c/mL. RBV was continued for another 4 months after IFN was stopped. One year later, his viral load was 377,000 copies/mL and only GT1b was detected. (2) A 58 year-old man with GT1b/2a and naif to antiviral treatment was given standard IFN and RBV for 1 year. His viral load fell from 306,030 c/mL to 35,800 c/mL. Only GT1b was detected.
DISCUSSION: The mechanism(s) for enhanced clearance of GT2/3 with IFN and RBV therapy remain uncertain. One thought is that mutations in the IFN-sensitivity determining region (ISDR) of NS5A in the HCV genome alter early viral response to IFN, since this region has been shown to bind to host RNA-dependent protein kinase (PKR) which normally inhibits viral protein translation and thus viral replication. Second envelope viral glycoprotein (E2) may have the same effect. Other factors likely play a role: more quasispecies are found in GT1; GT1 may replicate faster than GT2; and GT1 may infect a site not accessible to IFN or RBV (e.g. the microglial cells of the CNS).
CONCLUSION: Our cases illustrate the preferential clearance of one GT over another GT in a single individual. Such cases should be the focus of further studies to elucidate the mechanism(s) of viral resistance.