Clinical trial NCT01231685: Raltegravir Switch Study to Reduce Liver Fibrosis Progression in HIV-Hepatitis C Co-infection
Official title: A Randomized Prospective Open Label Study of Switching to Raltegravir Based ART Compared to Maintaining Ritonavir Boosted PI-based ART on Liver Fibrosis Progression in HIV-HCV Coinfected Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV
Hepatitis C
Liver Fibrosis
Keywords: Liver fibrosis
HIV
Hepatitis C Virus
Coinfection
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
name: CIHR Canadian HIV Trials Network
First posted: 2010-11-01
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: HIV infection exerts a negative impact on the course of HCV infection. Co-infected individuals progress more rapidly to liver fibrosis, cirrhosis and ESLD compared to those infected with HCV alone. Some of the this accelerated fibrosis may be related to longterm chronic toxicity from protease inhibitor based ART.

Hypothesis: 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).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. 18 years or older
2. Chronic HIV-HCV co-infection (HCV RNA + for at least 6 months and could have had previous HCV treatment).
3. Receiving ritonavir boosted PI-based ART for at least 6 months.
4. APRI score ≥ 1.5 (equivalent to liver biopsy score of ≥ F2) AND/OR Fibroscan \> 6.9KPa
5. HIV viral suppression (\<50 copies/mL) for at least 6 months.
6. No prior evidence of resistance to raltegravir or co-administered nucleoside backbone.
7. No prior history of virologic failure.

Exclusion Criteria:

1. Clinical evidence of decompensated liver disease (e.g., ascites, esophageal varices, or hepatic encephalopathy hepatoma or hepatocellular carcinoma).
2. Chronic Hepatitis B infection (defined as positive HBsAg or Hepatitis B viral load greater than 10,000 copies/mL).
3. AFP greater than or equal to 200 ng/mL at screening.
4. Known or suspected Wilson's disease, alpha-1-antitrypsin deficiency, celiac disease or other cause of chronic liver disease.
5. Chronic renal insufficiency (eGFR \< 20 mL/min) at screening.
6. Pregnancy and planned pregnancy (WOCBP not using adequate contraception).
7. Women who are breastfeeding.
8. Active opportunistic infection (except oral thrush) or neoplasm (except Kaposi's sarcoma, skin cancer, or cancer of the cervix or anus, unless known or suspected liver metastasis).
9. Patients intending to start HCV therapy within the treatment phase (within the year following the baseline visit).

Primary outcomes:
measure: To evaluate the effect of switch on change in liver fibrosis score
timeFrame: 48 weeks
Secondary outcomes:
measure: To evaluate inflammatory markers associated with liver fibrosis
timeFrame: 72 weeks
measure: To evaluate effect of switch on hepatic function
timeFrame: 72 weeks
measure: To evaluate effect of switch on metabolic parameters
timeFrame: 72 weeks
measure: Immunologic and virologic safety
timeFrame: 72 weeks
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: Providence Health Care- St. Paul's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: University Health Network - Toronto General Hospital Division
state: Ontario
city: Montreal
country: Canada
facility: Montreal Chest Institute
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Marina B Klein, MD. M.Sc.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vispo E, Mena A, Maida I, Blanco F, Cordoba M, Labarga P, Rodriguez-Novoa S, Alvarez E, Jimenez-Nacher I, Soriano V. Hepatic safety profile of raltegravir in HIV-infected patients with chronic hepatitis C. J Antimicrob Chemother. 2010 Mar;65(3):543-7. doi: 10.1093/jac/dkp446. Epub 2009 Dec 23.
citation: Eron JJ, Young B, Cooper DA, Youle M, Dejesus E, Andrade-Villanueva J, Workman C, Zajdenverg R, Fatkenheuer G, Berger DS, Kumar PN, Rodgers AJ, Shaughnessy MA, Walker ML, Barnard RJ, Miller MD, Dinubile MJ, Nguyen BY, Leavitt R, Xu X, Sklar P; SWITCHMRK 1 and 2 investigators. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010 Jan 30;375(9712):396-407. doi: 10.1016/S0140-6736(09)62041-9. Epub 2010 Jan 12.