Malaysian Society of Gastroenterology and Hepatology

Management of Hepatitis C
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Adherence to treatment
As in prior trials, adherence or compliance to therapy was also associated with enhanced sustained response rates. Overall, 63% of patients who received more than 80% of both peginterferon alpha-2b 1.5 mcg/kg plus ribavirin achieved a sustained response compared to 54% in ITT. With the weight-based dosing regimen, the response rate is further increased from 63% to 72% (Figure 8). The impact of adherence to therapy was most notable in patients with genotype 1 infection(10).

Algorithm of Treatment
In the initial interferon monotherapy, most literature indicated that if serum HCV-RNA persistently detected in blood after 3 months of therapy, the chance of achieving sustained response will be very minimal and can be considered stopping therapy.

With interferon-ribavirin combination therapy, the recommendations were altered to test HCV-RNA at week 24 of therapy.

As for the new pegylated interferon-ribavirin therapy, using retrospective data from the Manns trial(9), it was suggested that the testing of HCV-RNA levels obtained during weeks 12 and 24 of therapy can be used to predict the treatment outcome(11) (Figure 9).

Early viral response (EVR), defined as a minimum of 2 log decrease in viral load during the first 12 weeks of treatment, is predictive of SVR and should be a routine part of monitoring patients with genotype 1. Patient who fail to achieve an EVR at week 12 of treatment have only a small chance of achieving an SVR even if therapy is continued for a full year. Treatment need not be extended beyond 12 weeks in these patients. The absence of detectable serum HCV RNA has been associated with resolution of liver injury, reduction in hepatic fibrosis and a low likelihood of relapse of the HCV infection.

Histological Effect of treatment on the liver
Chronic infection with HCV is associated with the typical histological features of chronic hepatitis including hepatocellular necrosis and inflammatory (activity and grade) and fibrosis (stage). The rate offibrosis progression varies markedly. In some individuals, fibrosis ultimately leads to cirrhosis; associated with major complications such as portal hypertension, liver failure and hepatocellular carcinoma while in others, fibrosis does not appear to progress even after decades of infection. Thus, liver biopsy remains the gold standard to assess fibrosis, and repeated liver biopsy is recommended every 3 to 5 years for untreated patients.

Most cross-sectional studies(12) of large numbers of liver biopsies have shown that the stage of fibrosis is associated with:

1. patient age (rate of fibrosis tend to be higher in older patients)
2. age at the onset of infection (rate of fibrosis is higher in patients who have been infected at adulthood than in children)
3. male sex
4. a history of heavy alcohol consumption
5. presence of immune deficiency, such as HIV co- infection or immunosuppressive therapy

Recently, it was discovered that metabolic factors (such as lipid disorders, obesity, insulin resistance(13,14) and diabetes) may also predispose to more rapid progression of fibrosis.

All regimens from interferon monotherapy to combination pegylated-interferon therapy significantly reduced the fibrosis progression rates in comparison to rates before treatment in most patients; regardless responders, non-responders or relapsers. From a pooled individual data of 3010 naive patients with pretreatment and and post-treatment biopsies from 4 randomized trials (Figure 10), necrosis and inflammation improvement ranged from 39% (interferon 24 weeks) to 72 % (pegylated interferon alpha-2b 1.5 mcg/kg/week plus ribavirin >10.6 mg/kg/day). Reversal of cirrhosis was observed in 75 patients (49%) of 153 patients with baseline cirrhosis(10). These patients whose cirrhosis was reversible tended to be younger, with early stage of cirrhosis. This reinforces the need for early diagnosis and treatment of HCV infection. Additionally, in two large but uncontrolled long-term follow-up studies from Japan, SVR after interferon therapy was associated with a lower risk of HCC(15,16).

Side-effects of therapy
Major side-effects of combination therapy includes:
- influenza-like symptoms (fatigue, headache, fever)
- decreases in haematological parameters (anaemia, neutrophil count, platelets, white blood count)
- gastrointestinal complaints (anorexia, nausea)
- dermatological symptoms (alopecia)
- psychiatric disturbances (depression, anxiety)
- hypo- and hyperthyroidism

Antidepressant therapy has found to be useful to reduce interferon-induced psychiatric or depressive symptoms(17) as well as in patients who have pre-existing risk of developing psychiatric disorders(18). Fluoxetine is stimulating and a good choice for patients with obsessions. Paroxetine tends to be sedating, stimulates appetite and is good for patients with anorexia. Sertraline is a good selection for patients with diminished energy or affect. Citalopram/escitalopram is good for elderly and medically compromised liver disease patients(15). Pre-treatment of patients with pre-existing risk of developing psychiatric disorders with antidepressants is able to reduce frequency and severity of depressive episodes during adjuvant interferon alpha treatment(16).

Recent study has found that recombinant erythropoetin alfa is beneficial in the treatment of ribavirin induced anaemia and allows to maintain generally effective ribavirin dosage(19). Preliminary data from an on-going pilot study on vitamin C and E given concurrently with interferon alpha-2b and ribavirin has shown some encouraging results in decreasing the ribavirin-induced red blood cells haemolysis(20). This will provide an inexpensive method to optimize dosing of ribavirin without compromising the red blood cells.

Education of patients and caregivers about side-effects and their prospective management is an integral part of treatment. Frequent monitoring of HCV therapy is necessary(21).

References:
1. Malaysian Liver Foundation, Liver News; Vol 3(3); September-December 2001.
2. Malaysian Liver Foundation. Unpublished data.
3. National Institute for Clinical Excellence. Guidance on the use of ribavirin and interferon alpha for hepatitis C. October 2000.
4. Lachmanan SR and Merican I. An audit of Hepatitis C cases seen from 1990 to 2000. The Medical Journal of Malaysia; Vol 56 (2); June 2001 .
5. Esteban RM. New Advances in the treatment of Chronic Hepatitis C. Asia Pasific Association Study of Liver (APASL) 2002, Satellite Symposium; Chronic Hepatitis C in the New Millenium.
6. The French METAVIR cooperative study group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994:20:15-20.
7. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996:24-289-293.
8. National Institutes of Health (NIH); Consensus Development Conference Statement; Management of Hepatitis C: 2002;)une 10-12, 2002. Final Statement; Revisions September 12,2002.
9. Manns MP, McHutchinson JC, et. al. Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. The Lancet 2001;358:958-965.
10. McHutchison JG et. al. Adherence to Combination Therapy enhances sustained response in Genotype-1-infected patients with Chronic Hepatitis C. Gastoenterology 2002; 123:1061-1069.
11. McHutchison JG. New Algorithm predicts HCV Response to Combination Peginterferon alpha-2b plus ribavirin therapy. European Association of Study of Liver (EASL) 2002; Satellite Symposium.
12. Poynard T, McHutchison JG, Manns MP, et. al. Impact of pegylated interferon alpha-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303-1313.
13. Marcellin P. Fibrosis and Disease Progression. National Institute of Health (NIH) Consensus Guidelines, 2002 :Abstract; adapted from http://consensus.nih.gov/CONS/116/116cdcabstracts.pdf
14. Konrad T, Zeuzem S, Toffolo G et. al. Severity of HCV-Induced liver damage alters glucose homeostasis in non-cirrhotic patients with chronic HCV infection. Digestion 2002;62(1}:52-59.
15. Yoshida H et. al. Interferon Therapy reduces the Risk for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and Noncirrhotic Patients with Chronic Hepatitis C in Japan. Ann Intern Med 1999; 131:1 74-181.
16. Shiratori Y et. al. Histologic Improvement of Fibrosis in patients with Hepatitis C who have sustained response to Interferon therapy. Ann Intern Med 2000;132:517-524.
17. Kraus MR. Treating Psychiatric Side-effects in HCV patients on Peginterferon alpha-2b plus ribavirin therapy. Innovations in HCV Science, Clinical and Patient Management Initiatives. 8-10 September 2002; Vienna, Austria.
18. Schafer M. Treating Psychiatric Risk HCV Patients on Peginterferon alpha-2b plus ribavirin therapy. Innovations in HCV Science, Clinical and Patient Management Initiatives. 8-10 September 2002; Vienna, Austria.
19. Lunel-Fabiani F. Treatment of Ribavirin-induced anemia with erythropoietin in patients on Peginterferon alpha-2b plus ribavirin therapy. Innovations in HCV Science, Clinical and Patient Management Initiatives. 8-10 September 2002; Vienna, Austria.
20.Laughlin MA. Impact of Vitamin C and E therapy on anemia during Peginterferon alpha-2b plus ribavirin therapy. Innovations in HCV Science, Clinical and Patient Management Initiatives. 8-10 September 2002; Vienna, Austria.
21. Mazlam MZ. A new therapeutic approach to chronic hepatitis C virus infection with pegylaled interferon alpha-2b and ribavirin: Sustained virological response in two nairve patients. KPJ Medical Journal 2003; 1:41-44.


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