Study of Ezetimibe for Chronic Hepatitis C Virus (HCV) Infection in Liver Transplant Candidates (EZE-2)
Study of Ezetimibe for Chronic Hepatitis C Virus (HCV) Infection in Liver Transplant Candidates (EZE-2)
NPC1L1 is a key transporter in the enterohepatic cycle of cholesterol. Initial in vitro and
 in vivo data show that blocking this receptor with ezetimibe results in delaying infection in
 these models. The investigators hypothesize that HCV has an enterohepatic cycle, being
 secreted in bile and reabsorbed either in the canalicular membrane or in the intestine by
 association with NPC1L1, following a path similar to the cycle of cholesterol in humans. To
 prove this hypothesis the investigators propose to assess the effect of ezetimibe treatment
 in HCV infected individuals undergoing liver transplantation to avoid or delay HCV infection.
 For this purpose, the investigators propose to administrate ezetimibe 10 mg/d for 12 weeks to
 12 patients with chronic hepatitis C infection listed for a liver transplantation.
Infection by hepatitis C virus (HCV) affects more than 170 million people in the World and
 80.000 in Chile. It causes more deaths than HIV infection in the US and is a leading cause of
 liver transplantation in Chile. Even though treatments are evolving with new direct antiviral
 agents (DAAs) with increasing response rates, there are several issues with these new
 approaches, including toxicity, need for using interferon and ribavirin, complex algorithms
 of treatment, high cost, limited effectivity in certain groups (liver transplant patients)
 and drug interactions. Treatments targeted at host factors required for the viral cycle are
 becoming increasingly explored as an alternative or complement to DAAs. HCV has a very
 intimate connection with host lipidic pathways, altering the lipid profile, circulating bound
 to lipoproteins and using cholesterol receptors and intracellular mechanisms of fat
 metabolism. It has been recently described that NPC1L1 (Niemann-Pick C1-like 1), the
 intestinal receptor of cholesterol, serves as an entry factor for HCV. Interestingly, this
 receptor is not only expressed in the enterocytes (absorbing both endogenous and dietary
 cholesterol), but also in the canalicular membrane of the hepatocyte, where it functions
 absorbing cholesterol secreted into the canalicular lumen. NPC1L1 is, therefore, a key
 transporter in the enterohepatic cycle of cholesterol. Initial in-vitro and in-vivo data show
 that blocking this receptor with ezetimibe results in delaying infection in these models.
 Moreover, it has reported the case of a patient that after 3 unsuccessful treatment attempts,
 cleared HCV RNA with ezetimibe treatment, being the first report of the effect of ezetimibe
 in humans. In view of these observations, the investigators hypothesize that HCV has an
 enterohepatic cycle, being secreted in bile and reabsorbed either in the canalicular membrane
 or in the intestine by association with NPC1L1, following a path similar to the cycle of
 cholesterol in humans.

 This possibility is further supported by the observation that HCV RNA has been detected in
 bile and feces of infected humans. To prove this hypothesis, the investigators propose to
 assess the effect of ezetimibe treatment in HCV-infected individuals. Ezetimibe is an
 approved and generally safe drug used for the management of hypercholesterolemia. HCV RNA and
 core antigen in plasma and feces will be assessed. An increase in bile or fecal HCV load
 after antagonizing NPC1L1 with ezetimibe will support the notion that HCV is reabsorbed in
 the canalicular membrane or at the intestinal level. The second part of the proposed study
 will be conducted in 12 patients who have chronic hepatitis C and are listed for a liver
 transplantation. Graft reinfection after liver transplant is universal. Here the
 investigators anticipate that the use of ezetimibe will directly impact on the reinfection
 time of the graft, by delaying or even preventing liver reinfection in some patients. Should
 this study be successful it will for sure have enormous implications for the design of novel
 management strategies for liver transplant patients.
Inclusion Criteria:

 -  Chronic hepatitis C defined as detectable HCV RNA for more than 6 months.

 -  Age > 18 years old.

 -  No current HCV antiviral treatment.

 -  No medications for dyslipidemia in the preceding 2 months.

 -  Listed in the national waiting list for liver transplant with an estimated time to
 transplantation of 3 months or less, either for complications of cirrhosis or for
 hepatocellular carcinoma.

 -  No abdominal surgery that could alter biliary or intestinal anatomy.

 -  HCV RNA level > 10.000 IU/mL.

 -  No evidence of sitosterolemia.

 -  Negative pregnancy test in urine (for females).

 -  Signed informed consent document.

 Exclusion Criteria:

 -  Hepatitis B or HIV co-infection.