Raltegravir Switch Study to Reduce Liver Fibrosis Progression in HIV-Hepatitis C Co-infection

• To evaluate the effect of switch on change in liver fibrosis score [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

  Change in fibrosis will be assessed by:

  1. Change in Fibroscan® score (kPa) at 48 weeks from baseline
  2. Change in log transformed AST-to-platelt ratio (APRI) score at 48 weeks from baseline
  
  

• To evaluate inflammatory markers associated with liver fibrosis [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
  As a switch from protease inhibitors based regimen to a raltegravir based regimen may impact the liver through various potential mechanisms, we will explore the impact of treatment switching on inflammatory biomarkers.
  
  
• To evaluate effect of switch on hepatic function [ Time Frame: 72 weeks ] [ Designated as safety issue: Yes ]
  Liver enzymes, albumin, direct bilirubin and INR will be measured at week 0,2,4,8,12,24,36,40 and 72.
  
  
• To evaluate effect of switch on metabolic parameters [ Time Frame: 72 weeks ] [ Designated as safety issue: Yes ]
  Metabolic parameters, such as fasting glucose, lipid and insulin profiles will be measured at week 0,24 and 48 post switch
  
  
• Immunologic and virologic safety [ Time Frame: 72 weeks ] [ Designated as safety issue: Yes ]
  To ensure safety, with respect to control of HIV infection following a switch to raltegravir, HIV viral load and CD4 cell counts will be measured at weeks 0,4,8 12, 24, 36, 48 and 72 post switch.
  
  

Primary Objective-To assess if switching from ritonavir boosted-PI based ART regimen to a Raltegravir-based regimen will reduce the rate of hepatic fibrosis progression in HIV-HCV co-infected patients as measured by transient elastography (Fibroscan®) and the AST-to-platelet ratio index (APRI) after 48 weeks of treatment.

Secondary Objectives:

(i) To assess the safety and tolerability of switching from a ritonavir boosted-PI ART regimen to a raltegravir-based regimen for 48 weeks.

(ii) To evaluate hepatic function (liver enzymes) at weeks 0, 2, 4, 8, 12, 24, 36, 48 and 72 post switch.

(iii) To evaluate the effect of switching treatment on control of HIV infection (as measured by HIV viral load and CD4) at weeks 0, 4, 8, 12, 24, 36, 48, and 72 post switch.

(iv) To evaluate metabolic profiles (e.g, fasting lipid profiles, glucose and insulin) at weeks 0, 24, 48 and 72 post switch.

(v) To evaluate inflammatory markers associated with liver fibrosis at weeks 0, 2, 4, 8, 12, 24, 36, 48 and 72 post switch.

Population: Patients will be selected from CTN222; a Canadian National multisite prospective cohort of HCV-HIV infected persons (N=978) or from other eligible patients followed at participating sites. All patients recruited into the cohort are adults aged over 16 years old with documented HIV infection (ELISA with western blot confirmation) and with chronic HCV infection or evidence of HCV exposure (e.g. HCV-seropositive by ELISA with RIBA II or EIA confirmation, or if serologically false negative, HCV RNA+).

Study Design: A Randomized Prospective Open label study

Sample Size:

N = 40 This is a Phase II study designed to evaluate the safety and feasibility of a switch to raltegravir in HIV-HCV co-infected patients. As neither the duration of time required to improve fibrosis nor the potential impact of such a switch currently is known, this trial will provide important pilot data with which to estimate the true effect size and calculate the sample size required to conduct a larger definitive study on this question. It is hypothesized that switching therapy will lead to significant reduction in fibrosis as measured by APRI and FibroScan®. In other studies, for example, of successful HCV treatment using FibroScan®, a 34% reduction in fibrosis score was observed in those obtaining a sustained virologic response at 48 weeks (e.g., from mean baseline score of 10.3 kPa to 6.6 kPa at 48 weeks; s.d.= 5 kPa 1). We propose a sample size of 20 patients in each group, which would provide approximately 80% power to detect at least a difference of 5 kPa in fibrosis score change between the two groups assuming a similar standard deviation.