Ignite Creation Date:
2024-05-06 @ 8:25 AM
Last Modification Date:
2024-10-26 @ 12:00 PM
Study NCT ID:
NCT02734173
Status:
COMPLETED
Last Update Posted:
2019-08-13
First Post:
2015-10-21
Brief Title:
Pilot HCV Direct Acting Antiviral Therapy and Metabolism
Sponsor:
Ottawa Hospital Research Institute
Organization:
Ottawa Hospital Research Institute
Study Overview
Official Title:
Pilot Evaluation of the Influence of ABT450r Ombitasvir Dasabuvir - Ribavirin HCV Therapy on Insulin Resistance and Lipid Profile
Status:
COMPLETED
Status Verified Date:
2019-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
3D
Brief Summary:
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
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
Detailed Description:
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 respectively1 Subsequent studies have found the prevalence of type 2 diabetes among this population to range between 76 to 502 The presence of insulin resistance and type 2 diabetes in HCV has been associated with poor HCV antiviral treatment response34 acceleration of liver fibrosis5 increased risk for hepatocellular carcinoma HCC6 higher transplant complication rates7 and possibly increased morbidity from cardiovascular and metabolic complications8 Early intervention with lifestyle modification andor 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 HCV9 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 required10 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 load11 decreased antiviral virological cure rates12 AKA Sustained Virological Response SVR and increased hepatic steatosis1314 Successful treatment of HCV with IFNRibavirin is typically associated with the reversal of hypolipidemia yet in some patients lipid levels may increase to levels associated with increased cardiovascular risk1516
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 rho0379 p0000117 At baseline mean serum HCV-RNA level and mean HOMA-IR score were 6205 log10 IUml and 3819 respectively At the end of 14 days of Danoprevir monotherapy the mean decrease in HCV RNA was 2213 log10 IUml p00001 in patients who received the active drug n40 Concurrent with this the mean HOMA-IR score decreased by 1611 p00001 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
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 rho0379 p0000117 At baseline mean serum HCV-RNA level and mean HOMA-IR score were 6205 log10 IUml and 3819 respectively At the end of 14 days of Danoprevir monotherapy the mean decrease in HCV RNA was 2213 log10 IUml p00001 in patients who received the active drug n40 Concurrent with this the mean HOMA-IR score decreased by 1611 p00001 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None