Early Metabolic and Hepatic Lipid Gene Expression Changes in Chronic Hepatitis C Patients Treated with an Interferon-free Regimen

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1830. Early Metabolic and Hepatic Lipid Gene Expression Changes in Chronic Hepatitis C Patients Treated with an Interferon-free Regimen

Session: Oral Abstract Session: Hepatitis C

Saturday, October 5, 2013: 3:15 PM

Room: The Moscone Center: 250-262

Background: Hepatitis C (HCV) modulates the intrahepatic VLDL synthetic pathway as part of its natural life cycle. Chronic HCV (CHC) infection is associated with an altered metabolic state including dyslipidemia and insulin resistance, contributing to disease progression and reduced response to therapy. The interactions between HCV replication and host lipid pathways are incompletely understood.

Methods: Sixty CHC genotype-1, treatment-naive patients were treated with 24 weeks of the HCV NS5B inhibitor sofosbuvir in combination with low or full dose ribavirin. Serum lipids and hemoglobin A1C (HbA1c) were measured at various time points. Targeted quantitative RT-PCR for lipid and glucose metabolism related genes was performed on paired liver biopsy specimens obtained from 7 patients before and at end-of treatment (EOT). 

Results: Of 55 patients who completed the study, 38 patients achieved a sustained virologic response (SVR₂₄) and 17 patients relapsed after EOT.  Between baseline and week 4 of therapy, LDL significantly increased (91 ± 4 to 104 ± 5 mg/dl, p=.0027) and triglycerides decreased (137 ± 10 to 98 ± 8 mg/dl, p<.0001) which persisted through EOT. Compared to patients who achieved SVR₂₄, LDL was significantly lower in patients who eventually relapsed both at baseline (97 ± 5 vs 78 ± 7 mg/dl; p=0.031) and at week 48 (109 ± 6 vs 82 ± 7mg/dl; p=0.005), while there was no difference during or at EOT (Fig 1A). Triglycerides differed by treatment outcome only after EOT (Fig 1B). No changes in HDL were observed. HbA1C decreased significantly (5.58 to 5.45) in the 39 patients with paired values obtained at baseline and 24 weeks after EOT (p=0.0033) and this was independent of treatment outcome (Figure 1C). Intrahepatic gene expression of lipid transport genes (APOB, APOC3, APOL3) was significantly up-regulated, while lipid assembly and signaling genes (LEPR, MTTP) were down-regulated at EOT in 7 patients with paired liver biopsies (all achieved SVR₂₄).    

Conclusion: Our data demonstrate changes in lipid metabolism pathways and glucose homeostasis in CHC genotype-1 infection following interferon-free antiviral therapy.  The early changes in LDL and triglycerides associated with treatment implicate a direct effect of viral clearance on lipid homeostasis.    

Eric Meissner, MD, PhD¹, Anu Osinusi, MD, MPH^1,2, Jing Qin, PhD³, Yu-Jin Lee, BA³, Susanna Naggie, MD⁴, Keyur Patel, MD⁴, John Mchutchison, MD⁵, Henry Masur, MD, FIDSA⁶ and Shyam Kottilil, MD, PhD¹, (1)NIAID/NIH, Bethesda, MD, (2)Clinical Research Directorate/Cmrp, Saic-Frederick, Inc., Frederick, MD, (3)Niaid/NIH, Bethesda, MD, (4)Duke University Medical Center, Durham, NC, (5)Gilead Sciences, Foster City, CA, (6)National Institutes of Health - Dept of Critical Care, Bethesda, MD

Disclosures:

E. Meissner, None

A. Osinusi, None

J. Qin, None

Y. J. Lee, None

S. Naggie, Gilead Sciences: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient

K. Patel, Gilead Sciences: Consultant and Scientific Advisor, Consulting fee

J. Mchutchison, Gilead Sciences: Employee and Shareholder, Salary

H. Masur, None

S. Kottilil, None

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