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Unmet Needs of Chronic Hepatitis B
undetectable HBV DNA (74 versus 12%) and normalization of alanine patients with CHB with elevated ALT levels and significant HBV replication.
aminotransferase levels (69 versus 54%). Interestingly, HBsAg loss was The cut-off of ALT and HBV DNA levels for therapy are not well
observed in 3% of patients after 48 weeks of tenofovir therapy. Similar determined; however, there is some consensus that patients with ALT
results were observed in HBeAg-negative CHB patients. Tenofovir showed a levels higher than three times the upper limit of normal and HBV
higher antiviral efficacy than adefovir after 48 weeks of therapy. DNA levels over 100,000 copies/ml should be considered good candidates
Furthermore, no resistance was observed in both HBeAg-positive and for therapy. However, CHB is a heterogeneous disease with fluctuations
-negative CHB patients after 48 weeks of therapy. over time; therefore, there is no strong correlation between serum ALT
levels or serum HBV DNA levels and the severity of liver lesions. Indeed, a
Clevudine liver biopsy is often useful to determine the grade of necroinflammation
Clevudine (L-FMAU;1-(2-fluoro-5methyl-β-L-arabinosyl uracil) is a and the stage of fibrosis, as well as for the indication of treatment.
pyrimidine analog with marked in vitro activity against HBV but not against
HIV. The active triphosphate inhibits HBV DNA polymerase but is not an In patients with mild liver disease, treatment is not recommended unless
obligate chain terminator. In the woodchuck model, a daily dose of liver fibrosis deteriorates. It should be remembered that the best way to
10mg/kg of clevudine resulted in a 9 log
10
decrease in viral load. reduce the number of patients with resistance is to select the right
Interestingly, a delayed re-increase of viral load was observed after cessation patients for treatment: that is, those with active liver disease, who usually
of drug administration in a dose-dependent manner.
55
have relatively moderate levels of viral replication and who have a good
chance of responding well to therapy and a low risk of developing
An open-label phase I/II, non-randomized, dose-escalation study was resistance. For patients with mild disease, the treatment can be delayed
performed in 35 patients who received clevudine for 28 days at a daily dose with a regular follow-up.
of 10mg (n=10), 50mg (n=10), 100mg (n=10), or 200mg (n=5) followed by
a 20-week post-treatment period.
56
At the end of the dosing period, the PEG-IFN monotherapy should be considered in patients without
median reduction in serum HBV DNA was 2.48, 2.74, and 2.95 log
10
in contraindications since this treatment is not associated with resistance and
the 10, 50, and 100mg groups, respectively. Interestingly, as in the provides the best sustained response rate (about one-third after PEG-IFN
woodchuck model, there was a slow and delayed re-increase of serum HBV therapy) with a definite duration (48 weeks) of therapy. However, most
DNA levels at the end of the post-treatment follow-up and lower median patients with CHB (about two-thirds) do not develop a sustained response
HBV DNA levels compared with baseline. Clevudine was well tolerated, and therefore need prolonged therapy with an analog. During treatment
without serious adverse events. with an analog, the importance of good compliance and careful monitoring
(measurement of HBV DNA levels at least every three months) should be
Two 24-week phase III clinical trials have been conducted in both HBeAg- emphasized. Indeed, patients with HBV DNA levels higher than 1,000
positive and -negative patients in Korea.
57,58
Preliminary results of these copies/ml after six months of therapy are at high risk for the development
trials have indicated that clevudine reduced the HBV viral load to of resistance. Early diagnosis of resistance allows therapy to be adjusted by
undetectable levels after 24 weeks in 59 and 92% of trial participants. introducing a drug to prevent a flare of hepatitis. At present, no
Further studies are needed to assess the long-term efficacy and safety of combination has been shown to have a better antiviral effect or a reduced
this drug. risk of resistance compared with monotherapy. However, experimental
studies and uncontrolled clinical data suggest that combinations may
A Better Selection of Which Patients to Treat and How? decrease the incidence of resistance. Therefore, this strategy should
The decision of whether or not to treat patients with CHB is mainly based probably be considered in patients with cirrhosis to minimize the risk of liver
on the severity of the liver disease. It is generally recommended to treat failure, which may be associated with resistance. ■
1. World Health Organization, Hepatitis Fact Sheet, WHO/204, 19. Craxi A, Yurdaydin C, J Hepatol, 2006;44(6):1186–95. 39. Lai CL, et al., N Engl J Med, 1998;339:61–8.
Revised October 2000. Available at: http://www.who.int/inf- 20. Sangiovanni A, et al., Gastroenterology, 2004;126(4):1005–14. 40. Liaw YF, et al., N Engl J Med, 2004;351(15):1521–31.
fs/fact204.html (accessed September 23, 2005). 21. Rajendra A, Wong JB, J Hepatol, 2007;47(4):608–17. 41. Marcellin P, et al., N Engl J Med, 2003;348:808–16.
2. Shepard CW, et al., Lancet Infectious Diseases, 2005;5:558–67. 22. de Jongh FE, et al., Gastroenterology, 1992;103:1630–35. 42. Hadziyannis SJ, et al., N Engl J Med, 2003;348:800–807.
3. Ganem D, et al., N Engl J Med, 2004; 350:1118–29. 23. Fattovich G, et al., Gut, 1991;32:294–8. 43. Hadziyannis SJ, et al., N Engl J Med, 2005;352(26):2673–81.
4. Lok AS, N Engl J Med, 2002;346:1682–3. 24. Brunetto MR, et al., J Hepatol, 2002;36:263–70. 44. Marcellin P, et al., J Hepatol, 2005;43:920–23.
5. Fattovich G, J Hepatol, 2003;39(Suppl. 1):S50–S58. 25. Iloeje UH, et al., Gastroenterology, 2006;130:678–86. 45. Schiff ER, et al., Hepatology, 2003;38:1419–27.
6. Brown RE, et al., J Clin Gastroenterol, 2004;38:S169–S174. 26. Yang HI, et al., N Engl J Med, 2002;347:168–74. 46. Benhamou Y, et al., Lancet, 2001;358:718–23.
7. Yuen MF, Lai CL, J Clin Gastroenterol, 2004;38(Suppl. 10): 27. Chen CJ, et al., JAMA, 2006;295:65–73. 47. Lai CL, et al., N Engl J Med, 2006;354(10):1011–20. Erratum in:
S134–S135. 28. Lok AS, McMahon BJ, Hepatology, 2007;45(2):507–39. N Engl J Med, 2006;354(17):1863.
8. Custer B, et al., J Clin Gastroenterol, 2004;38:S158–S168. 29. Marcellin P, et al., J Viral Hepat, 2005;12(4):333–45. 48. Chang TT, et al., N Engl J Med, 2006;354(10):1001–10.
9. Lavanchy D, J Viral Hepat, 2004;11:97–101. 30. EASL International Consensus Conference on Hepatitis B, 49. Pierra C, et al., Antiviral Res, 2000;45:169–83.
10. Funk ML, et al., J Viral Hepat, 2002;9:52–61. Consensus Statement (long version), J Hepatol, 50. Lim SG, et al., Arch Intern Med, 2006;166(1):49–56.
11. Zarski JP, et al., J Hepatol, 2006;45(3):355–60. 2003;39(S1):S3–S25. 51. Lai CL, et al., Gastroenterology, 2005;129(2):528–36.
12. Fattovich G, et al., Gastroenterology, 2004;127(5 Suppl. 1): 31. Keeffe EB, et al., Clin Gastroenterol Hepatol, 2007;5(8):890–97. 52. Lai CL, et al., N Engl J Med, 2007;357(25):2576–88.
S35–50. 32. Wong DKH, et al., Ann Intern Med, 1993;119:312–23. 53. Heathcote EJ, et al., Hepatology, 2007;46:861A.
13. Bruix J, et al., J Hepatol, 2001;35:421–30. 33. Cooksley G, et al., J Viral Hepat, 2003;10:298–305. 54. Marcellin P, et al., Hepatology, 2007;46:290A.
14. Chang MH, et al., N Engl J Med, 1997;336:1855–9. 34. Janssen HL, et al., Lancet, 2005;365(9454):123–9. 55. Peek SF, et al., Hepatology, 2001;33:254–66.
15. Perz JF, et al., J Hepatol, 2006;45(4):529–38. 35. Lau GK, et al., N Engl J Med, 2005;352(26):2682–95. 56. Marcellin P, et al., Hepatology, 2004;40(1):140–48.
16. Marcellin P, et al., J Hepatol, 2008; in press. 36. Marcellin P, et al., N Engl J Med, 2004;351(12):1206–17. 57. Yoo BC, et al., Hepatology, 2007;45(5):1172–8.
17. Bruno S, et al., Hepatology, 2007;45(3):579–87. 37. Chan HL,et al., Ann Intern Med, 2005;142(4):240–50. 58. Yoo BC, et al., Hepatology, 2007 Jul 23 [Epub ahead of print].
18. Hoofnagle JH, et al., Hepatology, 2007;45(4):1056–75. 38. Marcellin P, et al., J Hepatol, 2007;46(S1): abstract 53.
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