Management of Hepatitis C
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Liver biopsy
Liver biopsy is an invasive procedure that provides a unique source of information on fibrosis and histologic assessment of the liver injury due to HCV but cannot be used to diagnose HCV infection. It is also the only procedure or tool that provides information on possible contributions of iron, steatosis, and concurrent alcoholic liver disease to the progression of chronic hepatitis C towards cirrhosis. The information obtained on liver biopsy allows affected individuals to make more informed choices about the initiation or postponement of antiviral treatment, especially in those infected patients with persistently normal to slightly elevated ALT level (< 2x upper limit normal). A baseline assessment of liver histology offers a valuable standard for subsequent comparisons. Thus, liver biopsy is an absolute requisite before antiviral treatment(5) except in certain conditions such as haemophilias.

Activity and fibrosis are the 2 major histologic features of chronic hepatitis C. One of the few validated scoring systems for these histologic features is METAVIR(6,7) scoring system. This system assesses histologic lesions in chronic hepatitis C using 2 separate scores, one for necro-inflammatory grade (A for activity); and another for stage of fibrosis (F). These scores were defined as follows: stages of fibrosis (F) (Figure 4); FO = no fibrosis, F1 = portal fibrosis without septa, F2 = portal fibrosis with rare septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis. Grade for activity (A): AO = no histologic activity, At = minimal activity, A2 = moderate activity, A3 = severe activity. The degree of activity was assessed by integration of the severity of the intensity of both piecemeal (periportal) necrosis and lobular necrosis as described in a simple algorithm (Figure 5). Intra- and inter-observer variations of METAVIR scoring system are lower than those widely used Knodell scoring system.

Activity grade, which represents the necrosis feature, is not a good predictor of fibrosis progression. In fact, fibrosis alone is the best marker of ongoing fibrogenesis.

Treatment of HCV
All patients with chronic hepatitis C are potential candidates of antiviral therapy(8). Treatment is recommended for patients with an increased risk of developing cirrhosis. These patients are characterized by:

a) detectable HCV RNA levels higher than 50 IU/ml
b) a liver biopsy with portal or bridging fibrosis and
c) at least moderate inflammation and necrosis

The majority of these patients tended to have persistently elevated ALT values.

For those patients with normal ALT levels (30% of HCV patients) or mild elevation of ALT level (<2x upper limit normal) (40% of HCV patients), indications for treatment is less clear. This is where liver biopsy is useful to determine initiation of treatment or deferring antiviral treatment. It has been found that at least 30% of these patients will progress and show liver fibrosis in a second liver biopsy. Thus, initiating treatment in this group of patients should be on an individual basis.

In some patient populations (such as children and adolescent and active injection drug users [IVDU]), the risks and benefits of therapy are less clear and should be determined on an individual basis or in the context of clinical trials. Small studies of interferon monotherapy in children has shown a SVR rates better than adults ranging from 26% for genotype 1 to 70% for other genotypes(8).

All HIV-infected persons should be screened for HCV. Patients with chronic hepatitis C and concurrent HIV infection may accelerate the course of HCV disease. Thus, these patients should be considered for treatment. The primary aims' of treatment of patients of hepatitis C are:

a) to achieve acceptable ALT levels at least 6 months after treatment cessation
b) clearance of HCV virus (defined as undetectable HCV-RNA in the serum) at least 6 months after treatment cessation
c) improve liver histology, thus reduced risk of cirrhosis and hepatocellular carcinoma.

Treatment of hepatitis C has advanced tremendously since the discovery of hepatitis C virus in 1989 (Figure 6). Since then, interferon monotherapy 3 MIU three times a week is the only approved treatment available, but with a disappointing sustained response rate of 5% and a high rate of relapse. In 1997, oral ribavirin was found to decrease the relapse rate and produces a synergistic effect with interferon alfa. This lead to the recommendation by the National Institute for Clinical Excellence, UK on the use of ribavirin and interferon alpha for hepatitis C in 2000 as the gold therapy(3). Recently, pegylated interferon alfa was developed and with combination oral ribavirin produces a higher overall sustained response rate which made it the most current recommended gold therapy(8). There are two forms of pegylated interferon available, pegylated interferon- alpha 2a and pegylated interferon- alpha 2b.

Several factors were associated with successful therapy which includes:
a) genotypes other than 1
b) lower baseline viral load
c) less fibrosis or inflammation on liver biopsy
d) age less than 40 years

The new pegylated-interferon in combination with ribavirin is the new treatment of choice for patients with chronic hepatitis C(5) It is superior to the standard interferon, with a single injection per week, easier to adjust the dose per body weight and a very similar profile of adverse events. In addition, cirrhotic patients do as well as non-cirrhotic patients with pegylated interferon and for this reason, this group will be part of the standard indication. The antifibrotic effect of the drug, irrespective of the antiviral effect is important for those especially with severe liver disease, in an attempt to slow down the progression and reduce the risk of complications. Therefore, maintenance therapy using interferon or pegylated interferon may play a role to slow disease progression and prevent complications such as HCC. Retreatment of patients who does not response or relapsed after combination of standard interferon-ribavirin is much warranted for patients with advanced fibrosis or cirrhosis who have an increased risk of hepatic decompensation. Preliminary results suggest that overall, 15 to 20% of non-responders achieved an SVR on re-treatment using pegylated interferon-ribavirin(8).

The current dosage recommendation for chronic hepatitis C treatment is pegylated-interferon 1.5 mcg/kg/week with combination of ribavirin > 10.6 mg/kg/day in two divided doses(9). Both drugs are dosed according to weight to optimize the response and at the same time, to minimize
the unwanted effects of the drugs.

In a study by Manns et al (Lancet 2001)(9) with 1530 patients from 62 centers in nine countries demonstrated a sustained virologic response (SVR) for all genotypes (using intention-to-treat, ITT analysis) of 54% for pegylated interferon alpha-2b 1.5 mcg/kg + ribavirin versus 47% for standard interferon alpha-2b 3 MIU tiw + ribavirin.

Reanalysing the data above using weight-based dosing for ribavirin, the regression analyses demonstrated that the optimal response was achieved in those patients treated with ribavirin >10.6 mg/kg/day (Figure 7).

Genotype 1 patients has the most apparent benefit with pegylated-interferon-ribavirin combination therapy with a sustained virological response of 48% versus 34% with standard interferon-ribavirin combination. Genotype 2 and 3 patients obtained a sustained virological response of 88% for pegylated-interferon combination versus 81% for standard interferon combination(9).

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