EXtended Therapy in Hepatitis C Genotype 3 Infected Patients — EXACT-R(3)  

Chronic Hepatitis C Clinical Trial

Official title: EXtended Therapy in Genotype 3 Infected Patients Who do Not AChieve a Treatment Response at Week 4 (RVR) But do Achieve a Complete Early Virologic Response (cEVR)

Status Terminated

Clinical Trial Summary

The purpose of this study is to evaluate the effect of 48 vs 24 weeks of treatment with Peginterferon alfa-2b plus weight-based ribavirin on Sustained Virologic Response (SVR) and relapse rates in patients infected with genotype 3 chronic hepatitis C (CHC) who do not achieve a Rapid Virologic Response (RVR) but attain a complete Early Virologic Response (cEVR).

Clinical Trial Description

This study plans to address the issue of whether increasing the duration of therapy from 24 weeks to 48 weeks with PegIFNα2b 1.5mg/kg/week and using weight-based ribavirin (15mg/kg) may reduce relapse rates and thereby increase SVR rates in patients infected with genotype 3 who fail to achieve an RVR but do achieve a complete cEVR defined as undetectable HCV RNA (ie. <50 or <15 IU/ml by 12 weeks). This study is necessary because although most patients with genotype 3 ultimately become HCV RNA undetectable during treatment, relapse after discontinuation of therapy remains a major cause of failure to achieve SVR. This is a very important issue given that to date none of the new small molecule drugs appear effective against genotype 3 meaning that at the present time patients with genotype 3 infection have no other options. Relapse is particularly common in patients with advanced liver disease but it has been shown that if SVR can be achieved in patients with advanced disease, the risk of liver failure is significantly reduced, as may be the risk of hepatocellular carcinoma (HCC). As a consequence the need for liver transplantation is diminished and survival is improved. Identifying strategies to reduce relapse and improve rates of SVR are therefore critical.

Certain individuals are at greater risk of infection with genotype 3. In the Western world, the main risk groups are current or former drug users (IDU) and immigrants raised in South Asia (India and Pakistan) where infection likely occurs early in childhood due to exposure to contaminated instruments, needles, etc.

A second potential benefit of achieving SVR is reduction in the rate of diabetes. Diabetes has been demonstrated to be more common in those infected with Hepatitis C than in the general population - this observation was made by examination of the NHANES population based database. The prelude to the development of Type 2 diabetes is insulin resistance. Insulin resistance (IR) is present in about one third of patients chronically infected with HCV - the rate being highest in those with cirrhosis and in those who are overweight or obese. Early data indicates that although the presence of insulin resistance impairs interferon responsiveness if SVR can be achieved, insulin resistance is lost. Studies of IR in individuals infected with genotype 3 HCV are lacking. Independent of HCV infection, being born South Asian is a risk factor for Type 2 diabetes.

The issue of insulin resistance and the effectiveness of antiviral therapy in chronic hepatitis C has been addressed exclusively in Caucasians infected with genotype 1. Recent data from Japan indicates that in patients with diabetes and hepatitis C successful eradication of HCV RNA may simultaneously prevent subsequent diabetes and presumably the systemic complications of this disease.

There is little data on the rate of RVR in the South Asian population as few therapeutic trials in patients with genotype 3 infections have been reported from Pakistan and India. Estimates can only be obtained from studies performed in Caucasians from Northern Europe and North America. In the trial by Shiffman the rate of RVR in those with genotype 3 infection was 62% and preliminary report from the trial of Albuferon in those with genotype 2 and 3 indicate RVR rates ranged from 44-60% in Asians -this figure included all Asians.

There are several reasons to specifically address ways to improve the outcome of antiviral therapy in patients infected with genotype 3 CHC. Firstly virtually all treatment studies report on a combined rate of SVR achieved in genotypes 2 and 3 even though the evidence has suggested that the response to therapy is different between these two genotypes. Within populations of patients with genotype 3 infection, there may be differences as well. South Asians are predominantly infected with genotype 3a, while injection drug users typically have genotype 3b infection. There are no formal trials published in the English literature of antiviral therapy in South Asians or comparing subtypes of genotype 3.

In patients infected with genotype 1 slow response to antiviral therapy i.e. lack of RVR, is associated with a significantly higher rate of relapse in those who go on to achieve undetectable HCV RNA at 12 weeks rather than at 4 weeks into treatment. Extending treatment for a further six months reduces this relapse rate considerably. By extending treatment in patients infected with genotype 3 who had previously relapsed following only 14 weeks of therapy to 24 weeks reduced relapse rates. Thus, it is anticipated that by extending treatment from 24 to 48 weeks in those who fail to achieve a RVR (i.e. slow responders) but who do achieve a complete EVR we hope to prevent relapse off treatment. A potential added benefit of achieving SVR in this patient population, many of whom are already at high risk of T2DM, is that it may reduce the virally mediated component of IR. ;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

• NCT number: NCT01095445
• Study type: Interventional
• Source: University Health Network, Toronto
• Status: Terminated
• Phase: Phase 3
• Start date: February 2010
• Completion date: June 2011