Pharmacotherapy for Hepatitis C Virus Infection: Management
Although great strides have been made in the treatment of chronic HCV infection since the discovery of the virus in 1989, therapy remains problematic. Most patients with chronic infection (defined by the detection of HCV RNA for at least six months)45 have few signs and symptoms of disease. Infrequent signs and symptoms include fatigue, right upper-quadrant pain, nausea, and poor appetite. Selecting patients for treatment would be simpler if the current therapy (1) were less complicated, (2) carried high rates of sustained responses, (3) were simple to administer, (4) were required for a shorter time period, and (5) were easy to tolerate.
The duration of therapy is normally 24 or 48 weeks, and the goals of therapy are assessed by the end-of-treatment response (ETR) or by the sustained virological response (SVR).
Patients with undetectable viral loads (fewer than 100 copies/ml) at the cessation of therapy are said to have an ETR. The SVR can be defined as an HCV RNA viral load of 50 copies/ml or fewer, 24 weeks after treatment has stopped.
The primary goal of therapy is to decrease viral loads to undetectable levels and to achieve SVRs that will lead to histological improvement and a reduced risk of viral trans-mission. When patients do achieve SVRs, viral loads tend to remain undetectable for years.
Five distinct characteristics have been associated with SVRs:
- genotype 2 or 3
- viral loads below 3.5 million copies/ml at the baseline evaluation
- minimal or no portal fibrosis
- female sex
- age younger than 40
According to the National Institutes of Health consensus guidelines for the management of HCV infection, all patients with chronic HCV (detectable HCV RNA viral loads of 50 IU/ml or greater) and those at an increased risk for cirrhosis should be treated. Because therapy for chronic HCV infection is far from ideal, practitioners must consider many factors before making a final therapeutic decision for a given patient. In addition to receiving antiviral therapy for HCV, all patients should receive hepatitis A and B vaccine to decrease the incidence of morbidity and mortality.
Interferons (IFNs), which are glycopeptides derived from white blood cells in response to infection, have been the mainstay of HCV therapy since 1991; however, they yield poor virological response rates. At the beginning of the HCV epidemic, the initial treatment was IFN alfa-2b monotherapy, consisting of 3 million units (MU) three times weekly for 48 weeks or longer, depending on SVR rates at three months. However, because IFN alfa-2b did not show increased efficacy in induction trials, it is now reserved only for patients who cannot tolerate combination therapy with IFN alfa-2b, a nucleoside analogue with antiviral activity against several DNA and RNA viruses.
For patients who have received IFN monotherapy and have experienced a relapse (the re-emergence of HCV RNA after previous undetectable levels at the end of treatment), an increased dose of IFN or a combination product of IFN alfa-2b and ribavirin (Schering-Plough) has been found to be effective. Ribavirin canadian is well absorbed and is administered according to the patient’s weight; however, it has little to no activity against HCV when used as monotherapy. With this two-drug regimen, approximately 40% of patients achieve SVRs and the associated long-term benefits.
Two large, randomized, controlled clinical trials compared combination therapy with IFN alfa-2b monotherapy. Patients receiving the combination therapy had SVRs at 24 weeks (33%) and at 48 weeks (41%); patients receiving monotherapy had lower rates of SVRs at 24 weeks (6%) and at 48 weeks (16%). Genotype 1 patients, who received treatment for a longer period, had lower response rates than patients with genotypes 2 and 3.
Another interferon, IFN alfa-2a, also yielded low SVR rates in clinical trials. IFN alfa-2a differs from IFN alfa-2b in its peptide sequence by only one amino acid and demonstrates a safety and efficacy profile similar to that of other alpha interferons.
IFN alfacon-1 (Infergen®, Amergen) plus Consensus IFN (high-dose Infergen®, or CIFN) is a genetically engineered compound that shares 88% homology with IFN alfa and 30% with IFN beta. This agent has greater cytokine induction and antiviral activity than both IFN alfa-2a and 2b, but it is not commonly used because viral response rates have been similar to those achieved with standard IFN alfa monotherapy.