Pilot HCV Direct Acting Antiviral Therapy and Metabolism
Pilot HCV Direct Acting Antiviral Therapy and Metabolism
There is compelling data supporting the pursuit of research into the effects of HCV
 antivirals on metabolic homeostasis. As a further rationale and justification, the experience
 with HIV antiretrovirals has clearly demonstrated that antiviral medications can produce
 profound changes in glucose metabolism, lipid profile and other measures of metabolic
 homeostasis. This establishes biological plausibility for this focus of research in HCV.

 The new knowledge created from this research will:

 1. Provide new information on the metabolic effects of the Abbvie 3D HCV antiviral regimen.

 2. Provide insight as to whether there are metabolic advantages with RBV-free compared to
 RBV-containing HCV regimens. This is particularly relevant given the current uncertainty
 regarding the need for RBV in IFN-free, oral DAA regimens.

 3. Provide insight into the impact of cirrhosis on metabolic milieu before, during and
 after HCV antiviral therapy
There is a heavy burden of metabolic disease in hepatitis C infected populations Allison et
 al (1994) were the first to identify an interaction between chronic hepatitis C virus (HCV)
 infection and diabetes, demonstrating an increase in the prevalence of type 2 diabetes among
 HCV-infected patients with cirrhosis compared to patients with cirrhosis from other causes
 (50% versus 9%, respectively).1 Subsequent studies have found the prevalence of type 2
 diabetes among this population to range between, 7.6% to 50%.2 The presence of insulin
 resistance and type 2 diabetes in HCV has been associated with poor HCV antiviral treatment
 response,3,4 acceleration of liver fibrosis,5 increased risk for hepatocellular carcinoma
 (HCC),6 higher transplant complication rates7 and possibly increased morbidity from
 cardiovascular and metabolic complications.8 Early intervention with lifestyle modification
 and/or metformin in patients with pre-diabetes can delay or prevent the onset of type 2
 diabetes in high risk populations. It is unknown whether this benefit extends to those
 infected with HCV.9 [see Appendix I for definitions of insulin resistance, impaired fasting
 glucose, and diabetes] There is lack of agreement on how to manage insulin resistance in
 HCV-infected patients. There may be risks with some diabetes medications in this population.
 Sulfonylureas and insulin may be associated with an increased risk of developing HCC in this
 population. Additional evaluation of the risks and benefits of diabetic medications in HCV
 are required.10 HCV is also known to induce changes in lipid metabolism. The HCV life cycle
 is dependent on the VLDL pathway. Viral replication involves the formation of complexes
 termed lipoviral particles resulting in decreased secretion of VLDL. The assembly of these
 lipoviral particles is believed to facilitate binding with LDL receptor and considered a
 mechanism by which HCV gains entry to the hepatocyte. Numerous studies have demonstrated
 lower total cholesterol, triglycerides (TG), HDL-C and LDL-C levels in patients with chronic
 hepatitis C infection. Lower lipid levels correlate with higher HCV viral load,11 decreased
 antiviral virological cure rates12 [A.K.A Sustained Virological Response (SVR)] and increased
 hepatic steatosis.13,14 Successful treatment of HCV with IFN/Ribavirin is typically
 associated with the reversal of hypolipidemia yet in some patients lipid levels may increase
 to levels associated with increased cardiovascular risk.15,16

 The metabolic effects of new HCV therapies are unknown in HCV-Infection Three HCV protease
 inhibitors (simeprevir, telaprevir, boceprevir) have been approved for the treatment of
 genotype 1 infection in combination with interferon and ribavirin. Telaprevir and simeprevir
 are dosed in combination with PEG-IFN and ribavirin for the initial 12 weeks of treatment.
 Interferon and ribavirin are dosed for 12 to 36 additional weeks based on early virological
 response and patient characteristics including liver fibrosis stage. Sofosbuvir is a
 nucleotide dosed in combination with pegylated interferon and ribavirin for 12 weeks in
 genotype 1 infected individuals. It can also be used in combination with simeprevir +/-
 ribavirin for 12 weeks without interferon. Sofosbuvir and ribavirin for 24 weeks is a third
 viable option of sofosbuvir-containing therapy in genotype 1 infection. Other orally
 administered HCV antivirals (protease inhibitors, nucleosides, non-nucleosides, assembly
 inhibitors) in development are effective against genotype 1 and other genotypes as well.
 Abbvie has developed a 12-week combination DAA regimen consisting of a HCV protease inhibitor
 (ABT-450 based with ritonavir), a NS5a inhibitor (ABT-267; Ombitasvir), a polymerase
 inhibitor (ABT-333; Dasabuvir) with or without ribavirin. This regimen was licensed in Canada
 in December 2014.

 There are limited data evaluating the influence of HCV protease inhibitors, nucleotides and
 other direct acting antiviral (DAAs) drug classes on the metabolic milieu of HCV treatment
 recipients. In one study of HCV mono-infected study participants receiving 14 days of
 monotherapy with the protease inhibitor danoprevir, serum HCV RNA and HOMA-IR [Appendix I]
 correlated significantly (Spearman rho=0.379, p<0.0001).17 At baseline, mean serum HCV-RNA
 level and mean HOMA-IR score were 6.2±0.5 log10 IU/ml and 3.8±1.9, respectively. At the end
 of 14 days of Danoprevir monotherapy the mean decrease in HCV RNA was 2.2±1.3 log10 IU/ml
 (p<0.0001) in patients who received the active drug (n=40). Concurrent with this, the mean
 HOMA-IR score decreased by 1.6±1.1 (p<0.0001), with a close correlation between HOMA-IR
 improvement and viral load decline. In contrast, HCV-RNA and HOMA-IR remained unchanged in
 placebo recipients. The effect of HCV-protease inhibitors and other DAAs on glucose
 metabolism beyond 14 days of treatment has not been established.

 With the development of DAA, the predictors of treatment response have evolved. However,
 phase 3 studies suggest that lower baseline LDL-C levels continue to be a predictor of
 treatment response to telaprevir triple therapy. The effect of interferon and ribavirin free
 regimens on lipid homeostasis has not been established and it is not known if baseline
 cholesterol levels remain a predictor of treatment outcomes with these regimens.

 Why conduct this research? The above is compelling data supporting the pursuit of research
 into the effects of HCV antivirals on metabolic homeostasis. As a further rationale and
 justification, the experience with HIV antiretrovirals has clearly demonstrated that
 antiviral medications can produce profound changes in glucose metabolism, lipid profile and
 other measures of metabolic homeostasis. This establishes biological plausibility for this
 focus of research in HCV.

 The new knowledge created from this research will:

 1. Provide new information on the metabolic effects of the Abbvie 3D HCV antiviral regimen.

 2. Provide insight as to whether there are metabolic advantages with RBV-free compared to
 RBV-containing HCV regimens. This is particularly relevant given the current uncertainty
 regarding the need for RBV in IFN-free, oral DAA regimens.

 3. Provide insight into the impact of cirrhosis on metabolic milieu before, during and
 after HCV antiviral therapy
Inclusion Criteria:

 -  HCV RNA evidence of HCV infection

 -  Documented history of chronic HCV RNA infection with Genotype 1

 -  Able to provide informed consent

 -  Available for ongoing follow-up if required

 Exclusion Criteria:

 -  <18 years old

 -  Evidence of decompensated liver disease

 -  HOMA IR< 2.0

 -  HIV seropositivity

 -  Chronic HBV/HIV infection

 -  Use of immune suppressing medications

 -  Active malignancy