Chinese Medical Information Portal Website (Taiwan Medical Network-TMN) - OldDoc Wu's Series
(Established in March 1996)
Dr. Wu's Liver diseases
|Treatment of Viral Hepatitis |
for professionals (medical students and residents)
(Posted Sep. 16, 1996; Updated May 14, 2009)
Treatment of Viral Hepatitis
(Key words: treatment, viral hepatitis, HBV, HCV, lamivudine, adefovir, interferon)
[Dr. Wu's Health Note- Home]
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- Both hepatitis B and hepatitis C infection can persist in the body and become longstanding infections (chronic hepatitis).
- The two most common forms of chronic hepatitis are caused by hepatitis B and C.
- Many people with chronic hepatitis B and C can lead normal lives without developing problems from liver disease, however, chronic hepatitis B and hepatitis C can also lead to cirrhosis, liver failure, liver cancer, and even death.
- While there is no way for complete cure for Hepatitis B and C, treatment can be used to reduce the liver damage that may result in cirrhosis, liver failure and liver cancer.
- There are six FDA approved treatments for chronic hepatitis B.
- Lamivudine (Epivir, approved 1998): an antiviral drug that inhibits the viral replication.
- Adefovir (Hepsera, approved 2002): an oral antiviral drugs that inhibits the HBV virus replication.
- Entecaviri (Baraclude, approved 2005): an oral antiviral drug that inhibits the HBV virus replication
- Telvibudine (Tyzeka approved 2006): an oral antiviral drug that inhibits the HBV virus replication
- Interferon alpha-2b (Intron A, approved 1961): stimulate the immune system to kill the hepatocytes infected with HBV virus. Subcutaeous injection 3 times a week.
- Peginterferon alpha-2b (Pegasys, approved 2006): Subcutaneous injectin once a week.
- Favorable responses to treatment include:
- Normalization of ALT.
- Loss or marked reduction in HBV-DNA.
- Anti-HBe conversion (loss of HBeAg and development of anti-HBe).
- (2009) hepatitis B Infection. by Yun-Fan Liaw and Prof Chia-Ming Chu. The Lancet, Volume 373, Issue 9663, Pages 582 - 592, 14 February 2009
- (2007)Physician's guide to chronic hepatitis B. by the Asian Liver Center at Stanford University.
- (2006)A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B
by TT Chang, M.D., et al. NEJMed, 354:1001-1010 (2006)
- (2005)Long term therapy with Adefovir Dipivoxil for HBe-Negative chronic hepatitis B. by SJ Hadziyannis et al. NEngJMed 352:2673-81(2005)
- (2005)NEJM Article on Peginterferon Alfa-2a, Lamivudine, and the Combination for HBeAg-Positive Chronic
Hepatitis B by Geoge KK Lau et al. NEngJMed 352:2682-95(2005)
- (2004)AASLD practice guideline (US government work). Chronic hepatitis B: Update of recommendation. by Lok ASF and McMahon BJ. Hepatology March 2004
- (2003) Asian-Pacific concensus statement on the management of chronic hepatitis B: An update. by Liaw YF, Leung N, Guan R, Lau GKK, Merican I. J Gastroenterol and Hepatol, 18: 239-245.
- The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998. Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments, and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts disease progression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during long term therapy. The development of new drugs and strategies is needed to improve treatment outcomes. (Liaw YF, 2009)
- Indication for treatment
- Recommendation 2.1
Patient with persistently normal ALT should not be treated but need adequate follow-up and HCC surveilance every 3-6 months.
- Recommendation 2.2
Liver biopsy is recommended in viraemic patients with raised ALT prior to therapy.
- When to start treatment ?
- Recommendation 2.3
HBV-DNA seropositive patients with ALT > 2 x ULN should be considered for treatment.
Patients with rising ALT (from normal or minimally elevated levels) or with ALT > 5 x ULN may be developing an exacerbation and severe hepatitis or hepatic decompensation may follow, particularly in patients with advanced fibrosis. Therefore, they should be monitored closely with weekly or biweekly serum bilirubin level and prothrombin time measurements. Treatment must be initiated in time to prevent thedevelopment or deterioration of hepatic decompensation. Conversely, such exacerbations may also precede spontaneous HBeAg seroconversion and may be followed by disease remission. Because of this, it is acceptable to delay treatment for an observation period of 3 months if there is no concern about hepatic decompensation.
- Which drugs or strategy ?
- Recommendation 2.4
Patients can be treated with either lamivudine or interferon. Lamivudine is recommended if there is a concern about hepatic decompensation.
- How to monitor therapy ?
- Recommendation 2.5
During therapy, ALT, HBeAg and/or HBV-DNA (quantitative method) should be monitored at least every 3 months. During interferon therapy, the monitoring of adverse effects is mandatory.
- Recommendation 2.6
After the end of therapy, ALT and HBV markers (including HBV DNA) should be monitored monthly for the first 3 months for early relapse and then every 3 months (for cirrhotic patients and those who remain HBeAg/HBV-DNA positive) to 6 months (for responders). For non-responders, further monitoring is requirred to recognize a delayed response and to plan retreatment when indicated.
- When to stop therapy ?
- Recommendation 2.7
For interferon, the current recommended duration of therapy is 4-6 months.
- Recommendation 2.8
Forlamivudine in HBeAg positive patients, treatment can be stopped when HBV DNA loss with HBeAg seroconversion is doccumated on two seperate occasions 6 months apart.
- What to do for patients in special circumstances ?
- Recommendation 2.9
Lamivudine is the agent of choice for patients with impending or bovious features of hepatic decompensation.
HBV reactivation is well recognized as a serious complication in immunosuppessed patients, including those undergoing chemotherapy and taking immunosuppressives. It commonly occurs after the first 2-3 cycles of chemotherapy. Lamivudine therapy is effective when instituted early before there is obvious jaundice and decompensation. Prophylactic suppression of HBV during the course of chemotherapy is a feasible approach.
- Recommendatio 2.10
For immunosuppressed patients, Lamivudine is the preferred treatment and interferon is usually ineffective or even contraindicated in the setting of organ taransplantation. HBsAg positive patients undertaking immunosuppressives or chemotherapy need close monitoring for reactivation and must start lamivudine therapy promptly before decompensation develops.
For the treatment of those with concurrent HCV and/or HDV infection, data are limited and futher studies are required.
For those patients treated with lamivudine in whom YMDD mutants have emerged, current practice is usually to continue lamivudine therapy in order to further suppress or prevent the return of wild type HBV. However, recent studies indicate that this practice dose not always seem to benefit patients. Studies have shown that adefovir dipivoxil and entecavir are effective for patients with YMDD mutants. Adefovir dipivoxil will be availabe shortly and can be used to 'rescue' such paatients. If these 'rescue' drugs are not available, stopping lamivudine therapy with close monitoring may be an option in patients who develop YMDD mutants. Further studies of the long-term outcome of such cases and the efficacy of adding a second antiviral agent are ongoing.
- AASLD Practice guideline for trreatment of chronic hepatitisLok ASF and McMahon BJ: Hepatology, (2001) December, pp:1225
- Long-term therapy with adefovir dipivoxil for the hepatitis BeAg-negative chronic hepatitis B. by
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. N Engl J Med 2005 June 30;352(26):2673-81
- Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. by
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL; Adefovir Dipivoxil 438 Study Group. N Engl J Med 2003 Feb 27;348(9):800-7
- Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. by
Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL; Adefovir Dipivoxil 437 Study Group. N Engl J Med 2003 Feb 27;348(9):808-16.
- Interferon: immunomodulator
1) 3 MU / t.i.w.
2) 3 MU / q.d.
3) 6 ~ 10 MU / t.i.w.
1) 6 months
2) 12 months
- Lamivudine: virus suppressor
1) 3 MU / t.i.w.
2) 3 MU / q.d.
3) 6 ~ 10 MU / t.i.w.
1) 6 months
2) 12 months
- Combination therapy:
- For HCV:
- 3 MU/t.i.w. for 6 months:
1) End-of-treatment response: 50% (Biochemical response--ALT recover to normal)
2) 40 ~50% of the responder: relapse soon after discontinuation of interferon.
3) 6~12 months post-treatment sustained rsponder: 20~25% for biochemical response and 10~15% for virological response (elemination of HCV-RNA)
- 3 MU/t.i.w. for 12 months:
1) 28~38% sustained response (by Kao, J.H. -- NTUH)
2) Increase in side effects and cost.
- For HBV:
- 5 ~ 10 MU/t.i.w. or q.d. for 3 ~ 6 months
1) 25 ~ 50% : clearance of serum HBeAg and HBV-DNA
2) few cases with disappearance of HBsAg
3) Poorer HBeAg/HBV-DNA clearance rate --- 20% --- in Taiwan and Japan
4) with steroid withdrawal before IFN --- response rate rise to 50%
- Cytosine dideoxynucleoside analogue --- potent reverse transcriptase inhibitor of HIV and HBV.
- Lai, C-L et al.
One year trial of Lamivudine for chronic hepatitis B: (N Engl J Med 1998;339:61-8.)
- Double-blind trial of lamivudine in 358 Chinese patients with chronic hepatitis B.
- The patients were randomly assigned to receive 25 mg of lamivudine (142 patients), 100 mg of lamivudine (143), or placebo (73) orally once daily.
- The patients underwent liver biopsies before entering the study and after completing the assigned treatment regimen.
In a one-year study,
- lamivudine was associated with substantial histologic improvement in many patients with chronic hepatitis B.
- A daily dose of 100 mg was more effective than a daily dose of 25 mg.
- Hepatic necroinflammatory activity improved by two points or more in 56 percent of the patients receiving 100 mg of lamivudine, 49 percent of those receiving 25 mg of lamivudine, and 25 percent of those receiving placebo (P<0.001 and P=0.001, respectively, for the comparisons of lamivudine treatment with placebo).
- Necroinflammatory activity worsened in 7 percent of the patients receiving 100 mg of lamivudine, 8 percent of those receiving 25 mg, and 26 percent of those receiving placebo.
- The 100-mg dose of lamivudine was associated with a reduced progression of fibrosis (P=0.01 for the comparison with placebo) and with the highest rate of hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg, development of antibody to HBeAg, and undetectable HBV DNA) (16 percent), the greatest suppression of HBV DNA (98 percent reduction at week 52 as compared with the base-line value), and the highest rate of sustained normalization of alanine aminotransferase levels (72 percent).
- Ninety-six percent of the patients completed the study.
- The incidence of adverse events was similar in all groups, and there were few serious events.
- Conclusions. In a one-year study, lamivudine was associated with substantial histologic improvement in many patients with chronic hepatitis B. A daily dose of 100 mg was more effective than a daily dose of 25 mg.
- A synthetic guanosine analogue with activity against a broad spectrum of DNA and RNA viruses, but its molecular mechanism of action remains unclear.
- Like other nucleoside analogues, ribavirin may have a direct antiviral effect, but it may also have an immunomodulatory effect.
- 1, 200 mg/d oral
- in combination therapy, for 24, 48 wks
- How long will the effects last ?
- The chief and most frequent side effect of ribavirin is hemolytic anemia, which in rare instances can be severe enough to require the discontinuation of treatment.
- This side effect, in conjunction with the bone marrow suppression that is commonly observed with interferon treatment, excludes as candidates for combination therapy many patients at risk for heart disease. How ribavirin causes hemolytic anemia is not known; therefore, this side effect cannot be predicted or prevented. In addition,
- Anemia --- hemolytic
- Birth defect -- teratogenic --- birth control during and after treatment.
- Difficulty breathing, insomnia, sore throat, rashes, itching, nausea and anorexia.
- Combination therapy:
Interferon + ribavirin in HCV infection
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(By Jau-Shin Wu, M.D.; Posted Sep. 16, 1996; Revised May 12, 2009)
(TMN) Since June 09, 2002
(Dr. Wu's Liver D) Since Jan. 01, 2008
(Olddoc)Since Jan. 01, 2008
(TMN) Since Jan. 01, 2008