HepB Forum : Unofficial Research Thread (URT) Tx info

[stevenNYer]

I am reposting articles / summaries on the treatment management of chronic HepB.  "cajim" located these articles which are quite informative.  I thought about putting them on a seaprate Health Page but didn't think it was appropriate since we didn't write them.

Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information.  Let's keep this URT free of comments.  For comments, start a new thread indicating that it's in reference to URT.

We'll see how it goes.

[cajim]

Notes on “Approach to Managing the Pregnant Woman With Chronic Hepatitis B and Detectable Viral Load?” William F. Balistreri, from Medscape Gastroenterology, Ask the Experts about Liver Disease, Posted 07/09/2008

Question: Should pregnant women with chronic hepatitis B with detectable viral load be treated with antiviral agents during pregnancy to decrease the risk for transmission to the baby?

Response:

Let me first frame the question -- what problem are we trying to solve? Infection with hepatitis B virus (HBV) in infancy or early childhood often leads to persistent infection, as evidenced by the fact that in countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases.[1] Approximately 90% of untreated infants born to mothers positive for hepatitis B e-antigen (HBeAg) will develop "immune tolerance." This is traditionally explained by transplacental transfer of viral antigens, which induces a specific nonresponsiveness of helper T cells to HBeAg and hepatitis B core antigen (HBcAg). Spontaneous HBeAg seroconversion (to anti-HBe positive) may develop with time, but liver damage may occur during the process of immune clearance of HBeAg.[1] Screening for maternal hepatitis B surface antigen (HBsAg), followed by administration of HBV vaccine and hepatitis B-specific immunoglobulin (HBIG) to the newborn within 24 hours of birth, is the most effective way to prevent perinatal HBV infection. The first universal HBV immunization program in the world was launched in Taiwan over 20 years ago; thus, the HBV infection rate and the incidence of hepatocellular carcinoma and fulminant hepatitis in children have been reduced.[1] Current published guidelines state that newborns of HBV-infected mothers should receive passive-active immunoprophylaxis with HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series.[2] This strategy is approximately 95% effective in reducing the risk for HBV transmission, but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. Maternal serum HBV DNA concentrations>107 IU/mL have been associated with a 5% to 10% failure of immunoprophylaxis.[3]

In highly viremic HBsAg-positive mothers, reduction of viremia in the last month of pregnancy may be an effective and safe measure to decrease the risk for failure of prophylaxis. Two separate strategies have been used to reduce the "viral burden" during pregnancy: prenatal HBIG administration and specific antiviral therapy. However, prophylactic therapy is complex, controversial, and not well studied.

HBIG: In a prospective randomized controlled trial, Xu and colleagues[4] administered either placebo or HBIG (200 IU intravenously every 4 weeks for 3 times) from the 28th week of gestation in HBsAg-positive mothers. There was a significant difference in the rate of HBeAg and HBV DNA positivity in the newborns (positivity rates: 25% in those born to mothers who received HBIG vs 83% in placebo recipients). In addition, the HBV DNA load of newborns was lower than that of their treated mothers and significantly lower than that of untreated controls.

Specific Antiviral Therapy: The only oral antiviral agent studied in this setting is lamivudine. When given in the last 4 weeks of pregnancy, lamivudine has been shown to reduce high-level viremia. van Zonneveld and colleagues[5] treated 8 highly viremic (HBV DNA>1.2 x 109 IU/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. Children (n = 24) born to untreated HBsAg-positive mothers with similar HBV DNA levels served as controls. All children received passive-active immunization with HBIG and HBV vaccine at birth and were followed up for 12 months. Seven of the 8 lamivudine-treated mothers had a decrease in their serum HBV DNA concentrations. One of the 8 children (12.5%) in the lamivudine group remained HBsAg- and HBV DNA-positive at the age of 12 months; all other children seroconverted to anti-HBs. In the untreated control group, perinatal transmission occurred in 7 of 25 children (28%). Other studies have evaluated the efficacy and safety of lamivudine for the treatment of chronic hepatitis B in pregnancy.[6-9] Li and colleagues[6] investigated the effect of lamivudine vs HBIG on HBV intrauterine transmission. HBsAg-positive pregnant women (n = 56) were given either 200 IU of HBIG intramuscularly every 4 weeks from the 28th week of gestation, or lamivudine (n = 43) 100 mg orally every day from the 28th week of gestation until the 30th day after labor. Subjects in the control group (n = 52) received no specific treatment. The rate of neonatal HBV infection was significantly lower among those patients receiving HBIG (16%) or lamivudine (16%) compared with those in the control group (33%; P  .05). No side effects occurred in the pregnant women or their newborns.

Lamivudine therapy may not prevent perinatal transmission of HBV infection in every newborn. Kazim and colleagues[8] reported the development of chronic HBV infection in a newborn despite suppression of HBV DNA to undetectable levels in the mother by prolonged lamivudine therapy. The newborn received neonatal vaccination and treatment with HBIG, yet had still had increased aminotransferase levels and was persistently positive for HBV DNA. On HBV DNA sequencing, complete sequence homology and a similar precore mutation was found in the mother and child, indicating vertical transmission.

A major question, in addition to efficacy, is, of course, safety. Again, to place the issue in perspective, it is important to remember that hepatitis B during pregnancy does not increase maternal morbidity or mortality or the risk for fetal complications.[1,3] In addition, the use of lamivudine did not directly lead to adverse events in the infected mothers. However, in one study, when compared with untreated women, there was a significant increase in liver disease activity after delivery in those patients treated with lamivudine.[9] And what about the potential effects of these drugs on the fetus? Lamivudine, adefovir, and entecavir are designated as category C drugs, which indicates that these drugs are capable of exerting teratogenic or embryocidal effects in animals; however, there are no controlled studies in humans.[3] With the emergence of additional nucleos(t)ide analogs (telbivudine and tenofovir [currently undergoing review by the FDA for use in chronic hepatitis B], which are category B drugs), studies are needed to evaluate their role in reducing viral burden during pregnancy.[3,10]

The bottom line: The strategy of using antiviral therapy to reduce viremia during pregnancy to decrease the risk for transmission of HBV to the baby is reasonable. However, at present, the data are not sufficient to make broad recommendations. The approach should be evaluated in a large controlled trial using new antiviral agents in combination with HBIG to prevent intrauterine HBV infection.

[cajim]

Notes on “CHINA:   "China Cuts Off Hepatitis Patients" Toronto Star, (07.11.08

On May 29, a popular Web site for people in China living with hepatitis B went silent, at least, for people in China. It has not been seen there since.  "At first I thought it was just a technical glitch, maybe a problem with the server," said Lu Jun, a former IT specialist who devotes his time to helping people with hepatitis B. But the site may be another victim of Chinese government efforts to heighten social control before the Beijing Olympic Games in August.  The Web site offered support to hepatitis B virus (HBV) patients, and it also informed patients about their rights. Though about 95 million people live with HBV in China, discrimination against patients is widespread, HBV awareness is poor, and many believe the infection can be casually transmitted.  From 2005, government departments have been prohibited from barring applicants with HBV. "Still, today there are 20 different laws that contain articles that discriminate against [HBV] carriers," Lu said. For example, people with HBV cannot work as teachers, bus drivers or as department store shop assistants.  Under Lu's nonprofit Beijing Yirenping Center, 40 lawsuits have been filed on behalf of HBV patients since 2003, and 10 of the last 13 have been successful.  "Many people have told me the government doesn't want any 'noise,' either before or during the Olympic Games," said Lu. The shutdown of the Web site "has caused a lot of anger among the HBV community," he said, "toward the Games, the government and the [Communist] Party." Some expressed their frustration at the popular Tianya Web site.  The Olympics is making it difficult for all non-governmental organizations, said Nicholas Bequelin of the Human Rights Watch Hong Kong office. "People pointing to a defect in the public health system, or issues of discrimination" would annoy the government, he said.

[cajim]

Notes on “VIRAL LOAD IS A STRONG PREDICTOR OF LIVER CIRRHOSIS RISK IN PEOPLE CHRONICALLY INFECTED WITH HEPATITIS B VIRUS REGARDLESS OF HEPATITIS B E ANTIGEN STATUS,” C.J. Chen, et al.  2005.

Introduction: HBeAg is considered a marker of active viral replication often associated with high levels of viremia. This study was carried out to examine the impact of HBV DNA level on the risk of disease progression to cirrhosis stratified by HBeAg status.

Methods: A population based prospective cohort of 3,851 subjects chronically infected with HBV was established was from seven townships in Taiwan between 1991 and 1992. Subjects were prospectively followed by hepatologists by clinical examinations including ultrasonography through June 30th 2004. The diagnosis of cirrhosis was based on ultrasonographic findings. All cirrhosis cases diagnosed within 6 months of enrollment were excluded from analyses. Multivariable adjusted relative risks (RRadj) were derived using Cox proportional hazard models.

Results: Overall, 3774 subjects with 42,115 person years of follow up contributed data to this analysis. There were 395 cases of cirrhosis. Of the 3774 participants, 3,214 (85%) were seronegative for HBeAg, of which 1082 (34%) had serum HBV DNA level ³104 copies/mL; 560 (15%) were HBeAg positive of which 538 (96%) had serum HBV DNA ³104 copies/mL at enrollment. There was a dose dependent relationship between HBV DNA and cirrhosis risk within the HBeAg strata. With the HBeAg negative undetectable DNA group as reference, the highest risk of progression was found in the HBeAg positive group with HBD DNA over 105 copies/mL.

Conclusion: Elevated serum HBV DNA is a strong predictor of cirrhosis risk in HBV infected persons regardless of HBeAg status. Effective suppression of HBV DNA to very low levels especially in HBeAg negative persons could reduce progression of CHB to cirrhosis.

[cajim]

Notes on “Milk thistle does not reduce deaths from liver diseases,” best studies find, Center for the Advancement of Health, 2-May-2005.

Milk thistle, a widely used alternative medicine, is not proven effective in lowering mortality in alcoholic or hepatitis B or C liver disease, according to a systematic review of current evidence.While some studies found that liver-related mortality may be significantly reduced in patients treated with milk thistle, these findings were not duplicated in the higher quality clinical trials.

However, milk thistle was found safe to us with no serious side effects and with participants perceiving improvement in symptoms -- although no more than with placebo.

Dr. Andrea Rambaldi, visiting researcher at the of the Centre for Clinical Intervention Research at Copenhagen University Hospital, led a team that reviewed 13 randomized clinical trials involving 915 patients who were treated with milk thistle or its extracts.

Participants had acute or chronic alcoholic liver cirrhosis, liver fibrosis, hepatitis and/or steatosis, and viral-induced liver disease (hepatitis B and/or hepatitis C). Patients with rarer specific forms of liver disease were excluded.

All the trials compared the efficacy of milk thistle or any milk thistle constituent versus placebo or no intervention in patients with liver disease. "There is no evidence supporting or refuting milk thistle for alcoholic and/or hepatitis B or C virus liver diseases," the authors found.

The review appears in the most recent issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

According to the Centers for Disease Control and Prevention, 170 million people worldwide are infected with hepatitis C, and 2 billion are infected with hepatitis B.

While a vaccine exists to prevent hepatitis B, there is no vaccine for hepatitis C.

Although the virus can be cleared in a handful of patients, many strains are resistant to treatment. Drug therapies that focus on long-term suppression of the virus are expensive, and many patients develop a resistance. The current gold standard treatment, which combines injections of interferon and ribavirin, has serious side effects and is hard for patients to tolerate.

With lack of effective treatment for liver disease, researchers have been looking for alternative therapies that curb symptoms with minimum adverse effects on patients. Milk thistle and its extracts have been used since the time of ancient Greece for medicinal purposes, are currently widely used in Europe for liver disease, and are readily available in the United States at alternative medicine outlets and outdoor markets.

G. Thomas Strickland, M.D., Ph.D., professor at the University of Maryland School of Medicine, has been studying the role of silymarin, an extract of milk thistle, in preventing complications of chronic hepatitis virus infection. Strickland says that the exact mechanism of action of silymarin is unclear.

A problem with current trials, according to Dr. Strickland, is that the dose of silymarin administered, typically 140 mg three times daily, is too low. "I would certainly double it," he says, "especially since at the current dose we're not seeing any improvement in acute viral or chronic hepatitis, and we've shown that silymarin is totally safe."

"The problem is, there is no cure for viral hepatitis except bed rest and diet, and treatments like silymarin are worth pursuing," Strickland says, calling for more research funding.

"We should consider doing randomized clinical trials with higher doses of silymarin," Dr. Rambaldi concurs.

According to the National Center for Complementary and Alternative Medicine , a part of the National Institutes of Health, studies in laboratory animals suggest that silymarin may benefit the liver by promoting the growth of certain types of liver cells, demonstrating a protective effect, fighting oxidation (a chemical process that damages cells) and inhibiting inflammation.

In their review, Dr. Rambaldi and colleagues conclude, "Milk thistle could potentially affect alcoholic and/or hepatitis B or C virus liver diseases. Therefore, large-scale randomized clinical trials on milk thistle for alcoholic and/or hepatitis B or C liver diseases versus placebo may be needed."

[cajim]

Notes on “Your Child's Immunizations,” KidsHealth.org, 2005.

When a child is born, she usually has immunity to certain diseases. This is a result of the disease-fighting antibodies that have passed through the placenta from the mother to the unborn child. After birth, the breastfed baby gets the continued benefits of additional antibodies in breast milk. But in both cases, the immunity is only temporary.

Immunization (vaccination) is an artificial way of creating immunity to certain diseases - by using relatively harmless substances called antigens that come from or are similar to the components of microorganisms that cause the diseases.

Microorganisms can be viruses, such as measles virus, or they can be bacteria, such as pneumococcus. Vaccines stimulate the immune system into reacting as if there were a real infection. The immune system then fights off the "infection" and remembers the organism so it can fight it off quickly if it enters the body at some future time.

Some parents may hesitate to give their children a vaccine because they are concerned about complications or their children developing the illness the vaccine is supposed to prevent. Although it's true that some vaccines could have these effects, the likelihood of that happening is very small. Not immunizing your child exposes her to greater health risks associated with contracting the disease the vaccine is intended to prevent.

Immunization is one of the best means of protecting your child against contagious diseases. The following vaccinations and schedule are recommended by the American Academy of Pediatrics (AAP). Please note that some variations are acceptable and that changes in recommendations frequently occur as new vaccines are developed; your child's doctor will determine the best vaccinations and schedule for your child.

Hep B
Hepatitis B (HBV) is a virus that infects the liver. Those who are infected can become lifelong carriers of the virus and may develop long-term problems such as cirrhosis (liver disease) or cancer of the liver.

Immunization Schedule
Hepatitis B vaccine usually is given as a series of three injections. The first shot is given to infants shortly after birth. If the mother of a newborn carries the hepatitis B virus in her blood, the infant needs to receive the first shot within 12 hours after birth. If a newborn's mother shows no evidence of HBV in her blood, the infant may receive the shot any time prior to leaving the hospital. It also may be deferred until the 4- or 8-week visit to the child's doctor.

If the first shot is given shortly after birth, the second shot is given at 1 to 2 months and the third at 6 months. For infants who do not receive the first shot until 4 to 8 weeks, the second shot is given at 3 to 4 months and the third at 6 to 18 months. In either case, the second and third shots usually are given in conjunction with other routine childhood immunizations.

Why Receive the Vaccine?
The hepatitis B vaccine probably creates lifelong immunity. Infants who receive the HBV series should be protected from hepatitis B infection not only throughout their childhood but also into the adult years. Eliminating the risk of HBV infections also decreases risk for cirrhosis of the liver, chronic liver disease, and liver cancer. Young adults and adolescents should also receive the vaccine if they did not as infants.

Possible Risks
Serious problems associated with receiving the HBV vaccine are rare. Problems that do occur tend to be minor, such as fever or redness or tenderness at the injection site.

When to Delay or Avoid the Immunization
if your child is currently sick, although simple colds or other minor illnesses should not prevent immunization
if severe allergic reaction (anaphylaxis) occurs after an injection of the HBV vaccine

How to Care for Your Child After the Immunization
The vaccine may cause mild soreness and redness at the place the shot was given; this may be treated with pain relievers like acetaminophen or ibuprofen.

When to Call Your Child's Doctor
if you are not sure of the recommended schedule for the hepatitis B vaccine
if you have concerns about your own HBV carrier state
if moderate or serious adverse effects appear after an HBV injection has been given to your child.

[cajim]

Notes on “Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications,” Yuen Mf. et al. Gut. 2005 May 4.

BACKGROUND: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria.

AIM: To determine risk factors for the development of complications in Asian CHB patients.

PATIENTS AND METHODS: 3,233 Chinese CHB patients (mean follow-up 46.8 months) were monitored for liver biochemistry, viral serology, HBV DNA levels, acute exacerbation, HBeAg seroconversion, and development of cirrhotic complications and hepatocellular carcinoma. RESULTS: The median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years respectively. Patients with alanine aminotransferase (ALT) levels of 0.5 - 1 X upper limit of normal (ULN) and 1 - 2 X ULN had increased risk for the development of complications compared to patients with ALT levels < 0.5 X ULN (p<0.0001 for both). HBeAg/ anti- HBe status, and the number of episodes, duration and peak ALT levels of acute exacerbations were not associated with increased risk of complications. In patients with complications, 43.6% had the HBV DNA levels less than 1.42 X 105 copies/ml. Male gender, stigmata of chronic liver disease, old age, low albumin and high AFP levels on presentation were independently associated with increased cumulative risk of complications. Male gender, presence of hepatitis symptoms, old age, low albumin level and presence of complications on presentation were independently associated with shorter survival.

CONCLUSION: Prolonged low-level viremia causing insidious and continual liver damage as reflected by ALT levels of 0.5 - 2 X ULN is the most likely pathway for the development of complications in Asian CHB patients.