Current treatment for Hepatitis C infection is aimed at suppressing viral load, and consequently slowing the progression of disease. Three markers are used are used as diagnostic tools to monitor effectiveness of treatment and track progress of the disease (2):

• Liver Biopsy -- This is considered the most dependable indicator of disease progression. Studies show that rate of progression to cirrhosis is higher in those with initial biopsies that demonstrate high-grade or high-stage lesions. Liver biopsy is considered to be important before beginning treatment, in order to  determine current stage of disease and to adjust treatment accordingly.
• HCV RNA -- Assays to test for the presence of viral load are in their third generation. While earlier tests had a two to three month blind period, new assays can detect HCV infection almost immediately after contact with the virus. HCV RNA titers are taken throughout treatment. Maintained absence of detectable HCV RNA is the requirement for the remission classification of HCV, and is the aim of current therapy.
• Alanine Aminotransferase (ALT) Activity -- ALT is an important biological marker for liver function.  Elevated levels indicate HCV-related hepatocyte death but are not prognostic, and should not be used to measure the effectiveness of anti-viral therapy.

The best anti-viral therapy currently available is the combination of interferon-alpha and ribavirin (1). The Schering-Plough Pharmaceutical Company currently owns the patent on this treatment, and distributes the two drugs packaged together under the name Rebetron. Treatment is expensive; amounting to approximately $1,440 per month, or $17,300 per year (3). A high economic cost, coupled with the complicated diagnostic tools needed to monitor the response to treatment, make combination therapy ineffective for use in developing countries.

Combination treatment is only used in patients that present both elevated levels of ALT concentration, as well as  signs of nephron necrosis in liver biopsy. Patients demonstrating liver necrosis and normal levels of ALT, present a problem for current therapy -- treatment with interferon and ribavirin has been largely ineffective in such patients, and is therefore no longer advised (1). Interferon/Ribavirin therapy has also proven to be ineffective against patients infected with HCV Genotype 1 (see Virology). 

Consumed independently, interferon-alpha has been effective in reducing viral load and suppressing the progression of HCV infection. Conversely, ribavirin has proven to have no therapeutic value exclusive of interferon-alpha. A cocktail of the two drugs, however, is effective in reducing viral load, as well as maintaining remission after therapy is ceased (1). Although its mechanism of action is poorly understood, ribavirin has wide-ranging anti-viral effects and may partially inhibit HCV protease (3).

The duration of a typical course of combination therapy ranges from six to eighteen months, with interferon and ribavirin being administered in 3 nine-million-unit doses, three times a week (6). Side effects of the treatment include flu-like symptoms, bone marrow suppression, irritability, anxiety, depression, autoimmune reactions, and -- perhaps most seriously -- hemolysis. The course of therapy appears manageable with the occasional dose reductions, and the relatively infrequent treatment for symptoms; but it requires constant monitoring by a physician. A small percentage of patients receiving combination therapy experience severe hemolysis, resulting in profound symptomatic anemia (5). For patients who are already anemic, use of ribavirin is often avoided, and this has been shown to prevent hemolysis. Roughly 20% of patients receiving interferon/ribavirin therapy for a full year require some dose reduction, and a small subset of these require complete cessation of treatment (5).

Efficacy of Treatment:

 The most discouraging aspect of current interferon/ribavirin combination therapy has been its high relapse rate (as demonstrated by elevated ALT and detectable HCV RNA levels) after cessation of therapy (5). The graph below outlines the efficacy of interferon treatment, as measured by serum concentrations of alanine aminotransferase: 

Most studies have shown combination interferon/ribavirin therapy to have a 40% remission rate six months after cessation of therapy (about twice that achieved with interferon alone). This six-month long post-therapy window is considered crucial, as recent studies have indicated that less than 3% of the patients who relapse after treatment do so at, or beyond, six months after therapy. The conclusion is that very few patients who are HCV RNA-negative six months after treatment will tend to relapse in the long term.

Future Therapies:

Recent interest in therapies for HCV-infection has centered on developing ways by which to maintain high blood levels of circulating interferon-alpha, and consequently maintaining the maximum possible pressure against HCV replication (3). Administration of the combination drug regimen three times a week leads to fluctuating levels of interferon in the blood, peaking when the drugs are administered, and plummeting when the medication is  cleared. This point is illustrated in the following graph:

To counteract this natural clearing effect, new interferon-based medications are being developed, which are pegylated with proteins of varying mass. Clinical trials with pegylated interferon-a2b (PEG-Intron) have been completed, and a large clinical trial of PEG-Intron plus ribavirin is currently underway (3). The graphs below demonstrate how pegylation can reduce the clearing of interferon:

In the future, researchers hope to be able to selectively inhibit the viral replication and assembly of HCV. The internal ribosomal entry site (IRES), which represents a crucial step in HCV translation, has been targeted as a potential site for an anti-HCV agent (4). Inhibition of the HCV post-translational processing could be accomplished by competitively binding the NS3 protease or NS5b polymerase & helicase (see Virology). This type of therapy would be analogous to current protease inhibitor medications used for HIV treatment. Also like the case for HIV, it is anticipated that these anti-viral drugs will not be used as monotherapies, but in combination with other treatments. 

References:

1.  Davis G, McHutchison J, et al:  Durability of Viral Response to Interferon Alone or in Combination with Oral Ribavirin in Patients with Chronic Hepatitis C, HepNet, Schering Canada Inc., 1995-200. http://www.hepnet.com

2. Davis G, Combination Treatment with interferon and ribavirin for chronic Hepatitis C. Clinics in Liver Disease, W.B. Saunders Company, volume 3, number 4, 1999

3. Fried M, et all: Aggressive Interferon Therapies, Combination Therapies and Newer Long-Acting Interferons in Hepatitis C.HepNet, Schering Canada Inc., 1995-200.  http://www.hepnet.com

4. Glue P, et al: Hepatitis C Treatment Beyond 2000, Schering-Plough Research Institute, HepNet, Schering Canada Inc., 1995-200.  http://www.hepnet.com

5. Russel H. Wiesner, MD,  Overview of Controversies in the Management of Hepatitis C. HepNet, Schering Canada Inc., 1995-200.  http://www.hepnet.com

6. Wong J, et al: Pharmacoeconomics of Combination Therapy for HCV, HepNet, Schering Canada Inc., 1995-200. http://www.hepnet.com