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Hepatitis B (double stranded DNA virus)   RX    Hepatitis Markers  | hepatitisB_Rx2008.pdf  |

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1. Interferon alfa (IFN alfa) IFN alfa, 5 million units subcutaneously daily for 20 to 24 weeks
2. Lamivudine 25, 100, or 300 mg PO once daily for 24 weeks
3. New Treatment for Chronic Hepatitis B :  adefovir dipivoxil (Hepsera) 10 mg daily
4. Entecavir 0.5 mg once daily for a minimum of 52 weeks (NEJM Volume 354:1001-1010 March 9, 2006)

Hepatitis B Facts: Testing & Vaccination   (pdf file from Immunize.org)

Transmission:
Transmitted primarily through sexual contact, illicit intravenous drug use, and perinatal exposure of the newborn to mother's blood.  

Complications:
Although up to 95% of patients with acute hepatitis B recover, the development of chronic hepatitis can lead to cirrhosis, hepatocellular carcinoma, and death.   Approximately 10% of HBV-infected patients develop chronic hepatitis B.  Chronic hepatitis B is a progressive disease whose severity can be detected by liver biopsy. Median survival in patients with cirrhosis is approximately 5 years, and 80% of patients with chronic active hepatitis survive for 5 years.

During the acute prodrome, circulating immune complexes and a serum sickness-like illness can be seen.
Chronic carriers occasionally develop glomerulonephritis with nephrotic syndrome and polyarteritis nodosa.

Interferon alfa-2b (Intron A) for Chronic Hepatitis B with elevated ALT levels

The indication  for interferon Rx is

• histologically confirmed chronic hepatitis B, with 
• raised ALT levels, and
• positive HBeAg and HBV DNA.

Treatment:

• Interferon alfa (IFN alfa).  
  In controlled trials, therapy with IFN alfa, 5 million units subcutaneously daily for 20 to 24 weeks, clears HBeAg in 40% of patients but clears HBsAg in less than 10%. There are few relapses in patients who respond to IFN alfa, but no other treatment for those who fail to respond.
• Lamivudine 25, 100, or 300 mg PO once daily for 24 weeks decreased the serum HBV DNA levels (58%, 93%, & 88% respectively).  In most patients, however, markers of replication returned after therapy was stopped.  Adverse effects were minimal.  (Gastroenterology 1997;113:1258 Nevens F, Main J, Honkoop P, et al)
  In U.S. patients with previously untreated chronic hepatitis B, after 52 weeks of treatment, lamivudine 100 mg daily PO, recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01).
  (N Engl J Med Oct. 21,1999;341:1256-63.- Jules L. Dienstag)
• New Treatment for Chronic Hepatitis B :  adefovir dipivoxil (Hepsera) 10 mg daily
  Until recently, interferon and lamivudine were the only proven therapies for chronic hepatitis B virus (HBV) infection. But, many patients cannot tolerate interferon, and drug resistance develops frequently with lamivudine. Now we have a third option, the nucleotide analogue adefovir dipivoxil (Hepsera), which was evaluated in these 2 industry-sponsored, multicenter, randomized trials.
  In one trial, 515 hepatitis B e-antigen-positive viremic patients received daily oral doses of adefovir (30 mg or 10 mg) or placebo. At 48 weeks, patients in both adefovir groups were significantly more likely than patients in the placebo group to have histologic improvement on liver biopsy (59% and 53% vs. 25%), undetectable serum HBV DNA levels (39% and 21% vs. 0%), and normal serum transaminase levels. The 30-mg dose was associated with mild renal toxicity.
  In a second trial, 185 e-antigen-negative viremic patients, who often harbor HBV mutations, received daily doses of adefovir (10 mg) or placebo. At 48 weeks, adefovir recipients were significantly more likely than placebo recipients to have histologic improvement (64% vs. 33%), undetectable HBV DNA levels (51% vs. 0%), and normal transaminase levels. There were no major side effects.
  Comment: The findings of these 2 studies document that adefovir induces histologic, virologic, and biochemical improvements in patients with chronic HBV infection. The FDA-approved daily dose is 10 mg, because the 30-mg dose was only slightly more effective and carried a higher risk for nephrotoxicity. Importantly, no drug resistance was noted. Longer-term results will tell us whether sustained or additional improvements occur with continuation of therapy.   — Allan S. Brett, MD    Published in Journal Watch March 7, 2003
  Source  
  Marcellin P et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003 Feb 27; 348:808-16. [Full text of original article]
  Hadziyannis SJ et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003 Feb 27; 348:800-7.  [Full text of original article]  
• NEJM Volume 354:1001-1010 March 9, 2006
  Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir 0.5 mg than with lamivudine 100 mg once daily for a minimum of 52 weeks. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir.

Immunization:
Hepatitis B can be prevented by active (vaccine) immunization and passively by administering hepatitis B immune globulin (HBIG) shortly after exposure. Both are effective when given together. The prevalence of HBV carriers in the United States is 0.2%, although some have only the empty HBsAg shell in serum and are minimally infectious.

Recently, recombinant interferon alfa  3 to 5 million units subcutaneously 3 times weekly for 6 months has been shown to reduce chronic hepatitis B replication and, in 20% to 30% of patients, to induce permanent clearance of HBeAg.  Responses are seen in 30% to 40% of patients; patients will gradually show decreases of hepatitis B DNA in serum, lose HBeAg, and develop anti-hepatitis B e antibodies during or after the course of therapy. They usually remain HBsAg-positive. Patients of Asian decent, those who have acquired infection at birth, those with serum hepatitis B DNA levels of greater than 100 pg/mL, and those with HIV infection respond poorly to interferon. Toxicity, including fatigue, malaise, headache, and myalgia, is frequent. Transaminases may rise during therapy, and pretreatment with corticosteroids before administration of interferon has been effective in a subset of patients.

Hepatitis B  &   Hepatitis B Vaccine General Info   (American Liver Foundation 7-1999)

ACP Library on Disk 2- (c) 1997 - American College of Physicians

Management of Apparently Healthy HBV Carriers

• Interferon alfa-2b (Intron A) 5 million units subc. three times a week for 16 to 24 weeks. or
• Lamivudine 100 mg tab (Epivir-HBV) 100 mg tab daily (or in 5 mg/mL solution)
• Should have Hepatitis A vaccination if no immunity to it yet.

Antiviral therapy is not indicated and in any case is not effective in eliminating HBV among apparently healthy carriers (those with normal ALT levels). Patients who are HBeAg-positive should be monitored a little more closely than HBeAg-negative patients because of the risk for developing chronic hepatitis. It is appropriate to perform liver tests and virus serology (especially HBeAg and anti-HBe) every 6 months.

Among HBeAg-negative patients, yearly monitoring of liver tests is all that is required until 40 years of age. After this, screening for HCC may be warranted, with measurements of serum alpha-fetoprotein every 6 months and hepatic ultrasonography each 12 months. Screening for Hepatocellular Carcinoma (HCC)  in this group remains contentious, as opposed to those known to have cirrhosis who are at higher risk, but it is particularly recommended in those with a family history of HCC. Conversely, it is not appropriate to screen HBV carriers if other medical disorders would contraindicate a curative procedure for HCC.

Hepatitis B Rx Update    
(Annals of Internal Medicine, 21 March 2000. 132:460-466)
(Annals of Internal Medicine, 2 May 2000. 132:723-731)

• Table for Rx of Chronic Hepatitis B  
• Table of Nucleoside Analogues
• Proposed algorithm for Rx of Chronic Hepatitis B (Figure)

Nucleoside analogues such as lamivudine exhibit antiviral activity against hepatitis B. They are orally active and lack the side effects caused by interferon. A 1-year double-blind, placebo-controlled trial of lamivudine in 358 Chinese patients with chronic hepatitis B, conducted by the Asia Hepatitis Lamivudine Study Group, demonstrated substantial histologic improvement in at least half the patients, especially those given Lamivudine 100 mg daily rather than 25 mg daily. Progression of fibrosis was slowed in patients given the higher dosage ( Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B.   Asia Hepatitis Lamivudine Study Group. NEJM 1998;339:61-8.).

Lamivudine has proved useful in patients not responding to interferon therapy. Perhaps 15% to 20% of patients with chronic hepatitis B will seroconvert after 1 year of lamivudine therapy, and one third of patients become negative for hepatitis B e antigen. About 30% develop a resistant variant of hepatitis B, which is not more aggressive than the "wild" type. It is resistant to lamivudine but may respond to other nucleoside analogues. In patients with hepatitis B surface antigen who require chemotherapy or immunosuppressive treatment, the virus may begin replicating again without immediately producing clinical illness. When chemotherapy ends, however, the high circulating viral load stimulates an immunologic attack that damages the liver and may cause life-threatening hepatitis. Prophylactic lamivudine, given until chemotherapy is concluded, should prevent this unfortunate occurrence.

Interferon alfa-2b (Intron A) for Chronic Hepatitis B with elevated ALT levels

The indication  for interferon Rx is

• histologically confirmed chronic hepatitis B, with 
• raised ALT levels, and
• positive HBeAg and HBV DNA.

Treatment is most strongly indicated in those with hepatic fibrosis; it is most likely to be effective if disease is of short duration, ALT levels are high (greater than three times the upper limit of normal), and HBV DNA levels are low (less than 200 pg per mL).

Interferon is less effective if ALT is mildly elevated (i.e., to less than twice the upper limit of normal or 100 IU per liter). It is also relatively ineffective in the presence of infection with HIV, particularly if the CD4+ cell count is low.

The contraindication for interferon Rx is patients with hepatitis B and cirrhosis who have poor liver function, as indicated by ascites, muscle wasting, coagulation disorder, or reduction of serum albumin concentration to below 32 grams per liter and elevation of serum bilirubin concentration above 1.5 mg per dL.

This is because the seroconversion illness that accompanies a response to interferon can precipitate fatal liver failure in those with poor hepatic "reserve" function and also because hematologic adverse effects are more severe in patients with cirrhosis.

The Dosage of Interferon Rx:

The usual treatment course is 5 million units subc. three times a week for 16 to 24 weeks. The patient should be monitored every 4 weeks for efficacy and safety. The best efficacy tests are HBV DNA, HBeAg, and anti-HBe. If HBV DNA is still present in serum after 8 weeks of interferon, the dose should be increased to 10 million units and treatment continued for another 8 to 16 weeks. The end point of treatment is loss of HBeAg with formation of anti-HBe.

This is achieved in 30 to 45% of cases. In the absence of interferon treatment, spontaneous loss of HBeAg occurs in 10 to 15% of patients during the first year of observation. Seroconversion (whether spontaneous or interferon induced) is preceded by a rise in ALT level (and rarely bilirubin concentration) and is followed by reduction in enzyme values toward normal. If HBeAg has not been lost at 24 weeks, there is no value in continuing treatment. Loss of HBV DNA and HBeAg after interferon treatment is permanent in most cases, but about 10% will relapse with reversion to HBeAg positivity and raised ALT levels. Conversely, about 30% of patients who lose HBsAg after a course of interferon treatment subsequently lose HBsAg and develop anti-HBs; this amounts to 10 to 15% of all treated subjects.

The Adverse Effects of Interferon Rx:
most effects are uncomfortable and transient, and it is uncommonly necessary to stop treatment. On the other hand, some adverse effects can be life-threatening or permanent.

In the early stages of treatment, patients usually experience an influenza-like reaction, with fever, myalgia, headache, sweating, rigors, and occasionally delirium. These symptoms begin about 2 hours after the interferon injection; they may be partly ameliorated by acetaminophen (1 gram) taken 2 hours before the injection and repeated once or twice as required. After 2 to 4 weeks, tachyphylaxis to these adverse effects develops, although intermittent or persistent headache and myalgia may occur.

The most common complaint during interferon treatment is fatigue, usually a minor reduction of physical and psychologic energy and well-being. However, more severe psychologic symptoms can occur and include profound lethargy and malaise, depression, irritability, and uncontrolled behavior. Those with a past history of depression or violent behavior may be at particular risk; if at all possible, interferon should be avoided in patients being treated with antidepressants.

The other adverse effects include weight loss, diarrhea, rash (including severe exacerbations of psoriasis), pruritus, hair loss, bad taste, paresthesias, neutropenia, leukopenia, and thyroid disorders (hypothyroidism and hyperthyroidism). Other rare effects include precipitation or exacerbation of other autoimmune diseases, including autoimmune hepatitis, worsening of epilepsy, diabetes mellitus, or unstable coronary heart disease.

Interferon predictably lowers both the leukocyte and platelet counts; patients with pre-existing abnormalities, such as those with advanced cirrhosis, are particularly at risk. Interferon should be stopped if the platelet count falls to below 50,000 cells per mm3 or if the neutrophil count is below 1000 cells per mm3 .  Values will return to pretreatment levels within days.

Ref:

Rakel: Conn's Current Therapy 1998, 50th ed

*

http://www.cdc.gov/hepatitis Interferon Rx in Hepatitis C and Hepatitis B (American Liver Foundation 1999) Advances in the Rx of Chronic Viral Hepatitis - JAMA, Aug.11, 1999;282:511- Raymond Koff http://www.aasld.org/   http://www.gastro.org/ J of  Hepatology   REVIEW Chronic Hepatitis B Ann Internal Med, 2 May 2000. 132:723-731.   Advances in the Rx of Chronic Viral Hepatitis - JAMA, Aug.11, 1999;282:511- Raymond Koff Prevention of Hepatitis B (Patient Info Sheet from AMA Nov. 10, 1999 Pdf file)

*  ABSTRACTS

. Hepatitis B e Antigen and the Risk of Hepatocellular Carcinoma   NEJM  July 18, 2002, Volume 347:168-174   Hwai-I Yang,, etc. - Taiwan Community-Based Cancer Screening Project Group   There were 111 cases of newly diagnosed hepatocellular carcinoma during 92,359 person-years of follow-up. The incidence rate of hepatocellular carcinoma was 1169 cases per 100,000 person-years among men who were positive for both HBsAg and HBeAg, 324 per 100,000 person-years for those who were positive for HBsAg only, and 39 per 100,000 person-years for those who were negative for both. After adjustment for age, sex, the presence or absence of antibodies against hepatitis C virus, cigarette-smoking status, and use or nonuse of alcohol, the relative risk of hepatocellular carcinoma was 9.6 (95 percent confidence interval, 6.0 to 15.2) among men who were positive for HBsAg alone and 60.2 (95 percent confidence interval, 35.5 to 102.1) among those who were positive for both HBsAg and HBeAg, as compared with men who were negative for both. . Adefovir Dipivoxil for the Treatment of Hepatitis B e Antigen–Negative Chronic Hepatitis B    NEJM Feb. 27, 2003, Volume 348:800-807   S. J. Hadziyannis and Others - the Adefovir Dipivoxil 438 Study Group   RESULTS:  At week 48, 64 percent of patients who had base-line liver-biopsy specimens available in the adefovir dipivoxil group had improvement in histologic liver abnormalities (77 of 121), as compared with 33 percent of patients in the placebo group (19 of 57, P<0.001). Serum hepatitis B virus (HBV) DNA levels were reduced to fewer than 400 copies per milliliter in 51 percent of patients in the adefovir dipivoxil group (63 of 123) and in 0 percent of those in the placebo group (0 of 61, P<0.001). The median decrease in log-transformed HBV DNA levels was greater with adefovir dipivoxil treatment than with placebo (3.91 vs. 1.35 log copies per milliliter, P<0.001). Alanine aminotransferase levels had normalized at week 48 in 72 percent of patients receiving adefovir dipivoxil (84 of 116), as compared with 29 percent of those receiving placebo (17 of 59, P<0.001). No HBV polymerase mutations associated with resistance to adefovir were identified. The safety profile of adefovir dipivoxil was similar to that of placebo. Conclusions:   In patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo. There was no evidence of the emergence of adefovir-resistant HBV polymerase mutations. . Adefovir Dipivoxil for the Treatment of Hepatitis B e Antigen–Positive Chronic Hepatitis B   NEJM Feb.27, 2003,  Volume 348:808-816   P. Marcellin and Others - the Adefovir Dipivoxil 437 Study Group   Results:  After 48 weeks of treatment, significantly more patients who received 10 mg or 30 mg of adefovir dipivoxil per day than who received placebo had histologic improvement (53 percent [P<0.001], 59 percent [P<0.001], and 25 percent, respectively), a reduction in serum HBV DNA levels (by a median of 3.52 [P<0.001], 4.76 [P<0.001], and 0.55 log copies per milliliter, respectively), undetectable levels (fewer than 400 copies per milliliter) of serum HBV DNA (21 percent [P<0.001], 39 percent [P<0.001], and 0 percent, respectively), normalization of alanine aminotransferase levels (48 percent [P<0.001], 55 percent [P<0.001], and 16 percent, respectively), and HBeAg seroconversion (12 percent [P=0.049], 14 percent [P=0.01], and 6 percent, respectively). No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene. The safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo; however, there was a higher frequency of adverse events and renal laboratory abnormalities in the group given 30 mg of adefovir dipivoxil per day. Conclusions:  In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a favorable risk–benefit profile for long-term treatment. No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.

2008