hepatitis B virus cells

Hepatitis B

Hepatitis B

Last Section Update: 09/2012

Contributor(s): Shayna Sandhaus, PhD

1 Overview

Summary and Quick Facts for Hepatitis B

  • Hepatitis B is an infectious liver disease caused by the hepatitis B virus (HBV). Chronic HBV infection often does not cause symptoms in its early stages, so only about 33% of adults with chronic hepatitis are aware they are infected.
  • Minimization of risk factors for HBV can reduce transmission of the virus, while new diagnostics and emerging treatments continue to advance the ability to combat this disease. This protocol will review these conventional treatments, as well as discuss nutritional approaches for addressing HBV infection and chronic liver disease progression.
  • Standard therapies for chronic HBV infection and hepatitis B are limited. Although research on specific nutritional strategies for HBV infection is not as broad as for hepatitis C (HCV) infection, evidence suggests that natural compounds can be of benefit for both conditions.

What is Hepatitis B?

Hepatitis B is an infectious liver disease caused by the hepatitis B virus (HBV). Most cases of HBV infection are acute and resolve on their own without medication. However, a small percentage of people infected with HBV will develop chronic hepatitis B, risking serious illness or death from cirrhosis, liver cancer, or liver failure.

HBV can be transmitted via injection or mucosal exposure to infected bodily fluids—sexual transmission and illicit IV drug use are leading causes of infection in the United States. Additionally, the virus can be transmitted from mother to fetus.

Natural interventions such as selenium and green tea may help protect the liver from damage.

What are the Risk Factors for Hepatitis B and HBV Infection?

  • Gender – progresses more rapidly in men than women
  • HIV infection
  • Alcohol use
  • Sexual behaviors including multiple or high-risk partners
  • Illicit intravenous drug use
  • Contact with infected fluids, such as may be encountered by healthcare workers, lab technicians, and patients requiring frequent transfusions
  • Parent-to-child transmission

What are the Signs and Symptoms of Hepatitis B?

Note: Most cases of acute hepatitis B are asymptomatic. Symptoms, if present, may include:

  • Loss of appetite
  • Fatigue
  • Nausea, vomiting
  • Abdominal pain
  • Joint pain
  • Mild fever
  • Dark urine
  • Jaundice

What are Conventional Medical Treatments for Hepatitis B?

Note: Acute hepatitis B usually resolves on its own without treatment. The goal of chronic hepatitis B treatment is to suppress viral replication, which may limit disease progression and lower risk of some complications.

  • Antivirals
  • Immune modulators (eg, Pegylated interferon, Interferon alpha)
  • Nucleoside and nucleotide analogs
  • Vaccination for prevention

What are Emerging Therapies for Hepatitis B?

  • Heteroaryldihydropyrimidines (HAPs)
  • RNA interference
  • Thymosin α1 (Tα1)

What Natural Interventions May Be Beneficial for Hepatitis B?

  • Selenium. Chronic hepatitis (B and C) is linked with selenium deficiency. The degree of deficiency relates to severity of the infection. Adequate selenium is also linked to reduced liver damage in HBV-infected patients.
  • Coffee. Coffee consumption may be linked to a reduced risk of liver cancer in HBV-infected patients.
  • Green tea. Green tea and its major antioxidant component epigallocatechin gallate (EGCG) reduced levels of HBV DNA and hepatitis B antigens in isolated liver cells. Some studies also suggest a decreased risk of cancer progression in those who consume green tea.
  • Zinc. Clearance of viral infection requires the activity of T cells, which are dependent on zinc. Some studies indicate higher serum zinc levels are linked with better response to interferon therapy.
  • Lactoferrin. Lactoferrin, a protein found abundantly in milk, has antibacterial and antiviral properties. In vitro studies indicate lactoferrin can inhibit HBV replication and prevent infection.
  • Vitamins C and E. Vitamin C and vitamin E levels are reduced in patients with chronic HBV. Several small studies suggest a role for these antioxidants in clearing HBV DNA.
  • Phyllanthus. Phyllanthus is a genus of plant used in traditional Chinese and Indian medicine to treat chronic liver disease. Several clinical trials indicate some Phyllanthus species can help improve response to conventional HBV medications.
  • Other natural interventions that may help patients with HBV include B vitamins, curcumin, N-acetylcysteine, resveratrol, whey protein, and others.

2 Introduction

Hepatitis B is an infectious liver disease caused by the hepatitis B virus (HBV) (A.D.A.M Editorial Board 2010; Merck 2007; Mayo Clinic 2011b). While most adults infected with HBV recover, a portion can develop chronic hepatitis B, risking serious illness or death from cirrhosis, hepatocellular carcinoma (liver cancer), or liver failure (El-Serag 2012; Nebbia 2012; WHO 2009; Lee 2008).

According to 2009 World Health Organization estimates, greater than 2 billion people have been exposed to the hepatitis B virus and 360 million are chronically infected worldwide (WHO 2009). It has been estimated that 12 million people In the U.S. have been exposed to HBV, with roughly 700,000 being chronically infected (Ioannou 2011).

Chronic HBV infection often does not cause symptoms in its early stages, so only about 33% of adults with chronic hepatitis are aware they are infected. Of those eligible for treatment for chronic HBV, only about 12.5% are receiving it (Scaglione 2012).

While the availability of HBV vaccination has decreased the incidence of HBV infection in the U.S., about 43,000 cases of acute hepatitis B still occur each year (Mitchell 2010). Rates of vaccination are relatively low among high-risk populations (eg, illicit IV drug users, individuals with HIV, and hemophiliacs); according to a 2007 CDC survey, over 51% of high risk adults remained unvaccinated in the U.S. (Ladak 2012).

Standard therapies for chronic HBV infection and hepatitis are limited, and are not effective in all cases (Scaglione 2012; Mutimer 2012). Additionally, the unique lifecycle of the HBV allows it to evolve and develop resistance to antiviral drugs (Billioud 2011).

Overlooked is an abundance of published research documenting potent anti-viral and liver-protecting properties of easy-to-obtain nutrients.

Fortunately, minimization of risk factors for HBV can reduce transmission of the virus, while new diagnostics and emerging treatments continue to advance the ability to combat this disease. This protocol will review these conventional treatments, as well as discuss nutritional approaches for addressing HBV infection and chronic liver disease progression.

3 Development and Progression of HBV Infection

HBV Biology. The hepatitis B virus infects humans and higher primates, entering and replicating within liver cells (hepatocytes), and secreting new virus particles into circulation (WHO 2009; Gish 2012). HBV is extremely effective at targeting hepatocytes; less than 10 individual virus particles are sufficient to establish an infection (Protzer 2012). Upon infection, HBV DNA enters the nucleus of the hepatocyte, where it serves as the reservoir for formation of virus particles for the lifetime of the cell and makes treatment of HBV challenging (Wilson 2009; Nebbia 2012). Replication of HBV requires the activity of a viral reverse transcriptase enzyme, which is prone to introducing mutations into the viral genome and potentially allowing the virus to become resistant to some treatments (Liaw 2009; Nebbia 2012).

Following an incubation period of 1-4 months, acute symptomatic hepatitis occurs in about one-third of infected adults, 10% of young children, and rarely in infants (Nebbia 2012). Acute hepatitis B resolves on its own in over 95% of adult cases (Liaw 2009). The acute infection is considered resolved when hepatitis B surface antigen (HBsAg) can no longer be detected in the blood within 6 months of infection (Nebbia 2012). HBsAg, a lipoprotein that forms part of the protective coating of the virus particle, is a marker for disease progression. Many individuals with HBV infection (7–40%) who are HBsAg-positive may also carry the hepatitis B e-antigen (HBeAg), a viral protein associated with high infectivity (WHO 2009). After resolution of an acute infection, an individual generally develops lifelong immunity against HBV-associated hepatitis, although the virus itself is not cleared from the liver (Nebbia 2012). Small amounts of viral DNA can be detected in blood years after recovery from acute hepatitis B (Liaw 2009). Thus, immunosuppression (eg, corticosteroid therapy) has the potential to reactivate an HBV infection.

There are several genetic strains of HBV (genotypes A-H), which vary in geographic distribution, response to treatment, and risk of progression to advanced liver disease (Liaw 2009; Tanwar 2012). In the United States, HBV genotypes A and D are more common in African-Americans and Caucasians, whereas HBV genotypes B and C are more common among persons of Asian ancestry (El-Serag 2012). Severe liver disease and hepatocellular carcinoma is more likely from infection with genotypes C and D. Response to interferon treatment (a conventional therapy; see below) is greater in genotypes A and B (than C or D), and thymosin treatment (see below) is twice as effective in genotype B than C (Chien 2006; Tanwar 2012). Although not yet standard for HBV treatment, genotyping could enable clinicians to identify and provide appropriate therapy for those at increased risk of disease progression (Tanwar 2012).

Transmission and Infectivity. HBV is transmitted through the skin (eg, injection) or via mucosal exposure to infected blood or other body fluids, mainly semen or vaginal fluid (WHO 2009). In geographic areas with low HBV prevalence (such as the United States), sexual transmission and use of contaminated needles by illicit drug users are major risk factors for infection (Daniels 2009).

In areas of high HBV prevalence (such as the Asia Pacific region), the virus is most commonly spread from infected mother to child at birth or child to child during early childhood. About 90% of mothers with high viral load will infect their babies with HBV (Liaw 2009). HBV can also infect sperm, enabling possible transmission from infected father to embryo during conception (Kang 2012). The likelihood of parent-to-child transmission can be reduced by vaccination (Lee 2006) (see below).

Individuals with acute or chronic HBV infection should be considered infectious any time HBsAg is present in the blood. HBsAg can be found in blood and bodily fluids for 1–2 months before and after the onset of symptoms. HBsAg can be identified in serum 30 to 60 days after exposure to HBV. Other markers of infectivity include HBeAg (hepatitis B e antigen) and HBV DNA (Hepatitis B DNA). HBeAg is a viral protein that indicates ongoing viral replication and increased infectivity. HBV DNA is a marker of viral replication; higher viral loads correlate with greater infectivity (CDC 1990, WHO 2009, Byrd 2012).

Outcomes of HBV Infection:

Asymptomatic or acute HBV infection. Acute HBV infection is asymptomatic in most individuals (symptomatic acute hepatitis B occurs in only about one-third of infected adults, 10% of children, and rarely in infants) (Nebbia 2012). Symptoms are similar to other viral hepatitis’ and include loss of appetite, fatigue, nausea, vomiting, abdominal pain, joint pain, mild fever, dark urine, and jaundice (yellowing of the skin and eyes due to accumulation of bilirubin secondary to liver dysfunction) (Merck 2007). The majority of acute hepatitis cases resolve, and the infected person eventually develops immunity to the virus (Liaw 2009; Nebbia 2012).

Chronic HBV infection. Some acutely infected individuals will progress to chronic HBV infection. Chronic HBV carriers are identified by the presence of hepatitis B surface antigen (HBsAg) in their blood for over 6 months, a HBV DNA blood level of 2000-20 000 IU/ml, and persistent or intermittent increases in liver enzymes. People with viral DNA loads of less than 2000 IU/ml are considered inactive carriers (Chevaliez 2012).

Age of infection has a significant effect on persistence of HBV (WHO 2009; Nebbia 2012); 90% of children infected at birth will develop chronic HBV, compared to 20-30% of children aged 1-5 and 1-5% of adults (Nebbia 2012). Chronic HBV infection increases the risk of serious liver disease, including cirrhosis and hepatocellular carcinoma (El-Serag 2012). Dysbiosis (detrimental changes in intestinal flora) is also possible (Xu 2012).

Cirrhosis. Cirrhosis, the end stage of any chronic liver disease (Garcia-Tsao 2009), involves functional liver tissue being replaced by fibrous tissue and scarring. Ascites (buildup of fluid in the abdomen), hepatic encephalopathy (depressed brain function due to accumulation of toxins in the brain), bacterial infection of the abdomen, and cancer are complications of cirrhosis (Garcia-Tsao 2009; Mayo Clinic 2011a). Cirrhosis is generally irreversible, although studies suggest that some HBV-mediated cirrhosis may be reversible with treatment (Scaglione 2012).

Hepatocellular carcinoma. Liver cancer is the fifth most common cancer in men and seventh most common in women worldwide. Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Approximately 80% of HCC cases are associated with chronic HBV or HCV infection (El-Serag 2012). HCC risk increases with viral load. In the REVEAL-HBV study of liver disease in chronic HBV patients, individuals with the highest viral loads at study entry (over 1 million copies of HBV DNA per ml in blood) had almost 11 times the risk of HCC than those with viral loads of less than 10 000 copies/ml of blood (Chen 2006).

Fulminant Hepatitis. Fulminant hepatitis is an acute hepatitis leading to acute liver failure and hepatic encephalopathy within a rapid period of time (less than 8 weeks after the onset of jaundice) (Ichai 2011). Between 7 and 33.7% of fulminant hepatitis cases stem from HBV infection (Ichai 2011). Fulminant hepatitis is rare in HBV-infected children, and develops in 0.1-0.6% of acute hepatitis cases in adults (Nebbia 2012). HBV-mediated fulminant hepatitis has a mortality rate of about 70% (WHO 2009).

4 Causes and Risk Factors for Hepatitis B and HBV Infection

Risk factors for HBV transmission or the progression of HBV disease include:

Gender. Chronic hepatitis B progresses more rapidly in males than females; cirrhosis and HCC predominate in men and postmenopausal women (Shimizu 2007; El-Serag 2012). High serum levels of testosterone have been associated with increased HCC risk in HBV carriers (Yuan 1995). Additionally, among 42 men who underwent liver resection for HCC between 1995 and 1999, those whose preoperative testosterone levels were in the upper half of the distribution had greater disease recurrence and poorer survival rates over 5-year follow up (Lin 2007). In contrast, premenopausal women have lower liver iron stores and reduced production of pro-inflammatory cytokines, both reducing risk of liver disease; this also suggests a potential protective role of estrogens (Shimizu 2007).

HIV infection. An estimated 10% of the 40 million people infected with HIV worldwide are also infected with HBV. HIV infection significantly increases the risk of developing cirrhosis and HCC in individuals carrying both viruses (WHO 2009), and HBV increases the rate of mortality in HIV patients on antiretroviral therapy (Nikolopoulos 2009).

Alcohol use. A few studies investigating the association between alcohol intake, HBV infection, and the progression of liver disease found a 1.2 to 3 times increased risk of HCC among heavy alcohol users (El-Serag 2012).

Sexual behavior. Hepatitis B is considered a sexually transmitted disease (STD), and in areas with low HBV incidence such as the U.S., sexual transmission represents a major route of infection. While homosexual men have the highest risk of infection (70% infected after 5 years of activity), heterosexual transmission has been increasing in frequency. In heterosexuals, multiple or high-risk partners (such as HBV carriers or illicit IV drug users), history of STD, and long duration of sexual activity all increase risk of transmission (Hou 2005).

Intravenous (IV) illicit drug use. Injection of illicit IV drugs is a major route of HBV infection in areas of low HBV incidence. In the U.S. and Western Europe, 23% of hepatitis B patients were infected by needles (Hou 2005).

Contact with infected fluids. Individuals in frequent contact with potentially contaminated blood products or bodily fluids (eg, health care workers, lab technicians, police, firefighters, and patients requiring frequent transfusions or hemodialysis) are at increased risk of HBV infection. Contaminated instruments (eg, those used for surgery, body piercing, acupuncture, or tattooing) also represent possible sources of infection (Hou 2005).

Parent-to-child transfer. As mentioned earlier, mother-to-child transfer is a significant source of viral transmission in both high-prevalence and low-prevalence geographic areas. In contrast to transmission by sexual contact, drug use, or contact with infected blood (which all have a <5% risk of chronic infectivity), infection at birth carries a 90% risk of chronicity (Nebbia 2012; Hou 2005).

5 Diagnosis

There are several tests for diagnosing HBV infection; the tests monitor either viral load or liver function.

Tests for HBV Viral Load. Quantification of HBV DNA in the blood by polymerase chain reaction (PCR) or newer real-time PCR tests are indicative of the activity of HBV replication. Levels above 2000 IU/ml indicate active or chronic infection, while levels below this indicate inactive carriage of the virus (Chevaliez 2012).

Serum hepatitis B surface antigen (HBsAg) level is also a marker of infected liver mass and the amount of HBV DNA in infected hepatocytes. When combined with PCR testing, a blood test for HBsAg levels can be used to monitor progression of chronic HBV infection or identify inactive carriers (Chevaliez 2012).

Other serological tests for viral load include quantification of HBeAg, a marker for high-infectivity HBV, as well as the detection of antibodies to HBV antigens (anti-HBs, anti-HBe, and anti-HBc, an antibody to the HBV core antigen), which can indicate a prior or chronic infection (WHO 2009; Chevaliez 2012). Testing for anti-HBc IgM antibody can identify acute HBV infection (Gitlin 1997).

Liver function tests. There are several blood tests that are not specific to HBV and nonspecifically assess liver function, but are important in the diagnosis of infection; these include ALT (alanine aminotransferase, a marker of liver cell damage), bilirubin (an indicator of liver excretion function), and albumin levels & prothrombin time (indicators of liver synthesis function) (Liaw 2009). Most of these markers can be measured in routine blood tests. Fibrometers (ie, liver-fibrosis-specific blood panels), which combine some of these markers with other liver-specific markers, are also available (Castera 2012).

Liver biopsy. Liver biopsy is an important, but invasive technique for grading liver damage. Newer non-invasive methods use imaging techniques to assess liver stiffness (a direct physical property of the liver that increases as the liver is filled with connective tissue during fibrosis). These include transient elastography (an ultrasound technique) and magnetic resonance elastography (Castera 2012).

6 Conventional Treatment for Hepatitis B

Acute hepatitis B typically resolves on its own and may not require treatment (Liaw 2009). The goal of chronic hepatitis B treatment is to suppress HBV viral replication, which may limit hepatitis progression and may lower the risk of some complications, such as cirrhosis or cancer (Gish 2012).

Antiviral therapy. There are 7 drugs approved for treatment of chronic hepatitis (Mutimer 2012). Interferon (IFN) is a signal protein produced by infected or cancerous cells to bolster the immune response of neighboring cells (Marieb 2010). Interferon alpha (IFN-α) therapy is an approved antiviral for HBV and HCV infection. Both standard IFN-α and pegylated IFN-α (an IFN derivative with a longer half-life in the body) (Grimm 2011) are administered via subcutaneous injection (Nebbia 2012). INF-α, either alone or in combination with the nucleoside analog lamivudine, lowers viral load and normalizes ALT levels (Scaglione 2012). IFN alone may reduce the incidence of cirrhosis, hepatocellular carcinoma, and liver-related deaths (Scaglione 2012). Side effects of IFN include fatigue, flu-like symptoms, mood changes, bone marrow suppression, and development or exacerbation of autoimmune illnesses (Scaglione 2012). IFN-α may be better for achieving a sustained virological response than nucleotide analogs (see below) (Nebbia 2012).

Nucleotide and nucleoside analogs. Nucleotide and nucleoside analogs (NUCs; lamivudine, telbivudine, entecavir, adefovir dipivoxil, and tenofovir disoproxil fumarate) interfere with HBV viral replication. Trials of NUCs in HBV patients demonstrate a decrease in viral load, ALT levels, and hepatocellular carcinoma incidence, as well as the possible reversal of HBV-mediated cirrhosis. As oral medications, NUCs are more convenient to take than IFN, but the eventual development of resistance to these drugs limits their long-term utility. Side effects, which vary by drug, include myopathy and peripheral neuropathy (telbivudine), kidney toxicity and dysfunction (tenofovir and adefovir), decreased bone mineral density (tenofovir), and lactic acidosis in patients with liver disease (entecavir) (Scaglione 2012).

7 Novel and Emerging Therapies

Heteroaryldihydropyrimidines. Heteroaryldihydropyrimidines (HAPs) are antiviral compounds that have been shown to inhibit HBV replication in isolated cells and animal models. In contrast to nucleotide and nucleoside analogs, which interfere with the replication of the viral genome, HAPs prevent the proper assembly of the protein capsule that surrounds the mature virus and serves as the site of DNA replication (Deres 2003; Stray 2005). They are effective against HBV mutant strains resistant to nucleotide/nucleoside analog drugs (Billioud 2011). Bay 41-4109, the best studied HAP, reduced HBV viral load by about 2 to 3-fold in a humanized mouse model (mice with livers that contain human liver cells) (Billioud 2011; Weber 2002). These compounds await human trials.

RNA interference (RNAi) is a cellular mechanism for controlling gene expression; it is used by cells to regulate cell development and metabolism, but can also be used to turn off the expression of foreign genes, such as those of an invading virus. Since the life cycle of HBV relies on RNA intermediates for its replication, it is sensitive to inhibition by RNAi (Grimm 2011). Therapeutic RNA inhibitors have been designed to interrupt HBV DNA replication, and turn off the genes that produce the structural and regulatory proteins required for assembly of infectious HBV particles. They have shown success in decreasing virus replication in cell cultures (Wilson 2009). Early results of a safety trial of the small interfering RNA NUC B1000 appear promising (Gish 2011).

Thymosin α1. Thymosin α1 (Tα1) is an immunomodulatory peptide derived from the thymus that stimulates T-cells (one of the principle immune cells) to mature and produce cytokines, as well as increases the ability of the immune system to recognize invading pathogens (Delaney 2002; Yang 2008). In several studies of Tα1 therapy in chronic, HBeAg-negative (low-infectivity) HBV patients, thymosin lowered the liver enzyme ALT and increased the rate of HBV DNA clearance (Yang 2008). It is better tolerated than IFN-α. While treatment with Tα1 alone does not appear to be superior to current HBV therapies (Grimm 2011), it may enhance the effectiveness of antivirals and IFN when used as a combination therapy (Mao 2011; Zhang 2009), especially in difficult-to-treat HBeAg-positive patients. Tα1 is approved for use as a hepatitis B treatment in 30 countries, but is not yet available in the U.S. (SciClone 2012).

8 Prevention

Vaccination. The availability of HBV vaccine and anti-HBV antibodies has significantly lowered HBV infection rates throughout the world. The first HBV vaccine was introduced in 1982, along with official recommendations for its use in high-risk groups (Rich 2003). Recommendations for childhood (CDC 1991) and adolescent (CDC 1996) vaccination programs were published within the decade. A synthetic version of the vaccine was introduced in 1986, replacing blood-derived versions of the vaccine (WHO 2009), and a thimerosal-free version has been available since 1999 (CDC 1999).

Immunization may be one way to prevent mother-to-child transmission of HBV. In an analysis of several trials of children born to infected mothers, immunization reduced likelihood of mother-to-child transfer by 72% (Lee 2006). This protective effect decreased significantly when the initial dose of vaccine was delayed more than 7 days following birth (Marion 1994, WHO 2009).

As mentioned above, rates of vaccination are relatively low among high-risk populations in the U.S. (Ladak 2012). Healthcare workers at risk of HBV infection are recommended to receive the vaccine. However, in a study of matriculating healthcare students at U.S. University, only about 60% had been vaccinated (Tohme 2011).

9 Nutrients

Although research on specific nutritional strategies for HBV infection is not as broad as for HCV infection, evidence suggests that natural compounds can be of benefit for both conditions (See the Hepatitis C protocol for more information).

Selenium. Selenium is an essential trace element with protective roles in the defense against free radicals, liver detoxification reactions, and immunity (Rauf 2012). Chronic hepatitis patients (as well as those infected with hepatitis C virus) tend to be selenium deficient compared to their uninfected counterparts. The degree of deficiency relates to the severity of HBV infection (in one study, selenium levels dropped by 50% in HBV-infected men) (Khan 2012). Adequate selenium may also be associated with less liver damage in HBV-infected patients (Abediankenari 2011). It is suggested that HBV and HCV patients be tested for selenium adequacy and supplemented if deficient (Khan 2012). Long-term selenium treatment reduced HBV infection by 77% and liver lesions by over 75% in an animal model. In an 8-year trial, treatment reduced the incidence of liver cancer in HBV patients by 35% (Yu 1997).

Coffee and related compounds. Evidence from several European and Japanese studies suggests coffee consumption is associated with reduced risk of liver cancer in. Heavy coffee consumption (defined in the studies as over 3 cups daily by Europeans, or over 1 cup daily by Japanese) reduced hepatocellular carcinoma (HCC) risk by an average of 55% over 10 observational studies (Bravi 2007; Larsson 2007). Moderate coffee consumption (4 or more cups weekly) in HBV carriers reduced hepatocellular cancer incidence by almost 60% in a separate study (Leung 2011). Chlorogenic acid, a compound isolated from coffee, was shown to inhibit HBV viral replication in isolated liver cells, and reduce blood levels of HBV in an animal model. Its efficacy was comparable to the nucleoside analog lamivudine (Wang 2009a). Special coffee roasting procedures can retain chlorogenic acid, which is normally depleted by Dian roasting procedures. Chlorogenic acid is also supplied by green coffee extract supplements.

Green tea. Green tea and its major antioxidant component epigallocatechin gallate (EGCG) reduce the levels of HBV DNA and hepatitis B antigens in isolated liver cells by inhibiting the replication of HBV DNA (Xu 2008; He 2011). A study of 204 HCC cases in Chinese individuals with HBV infection revealed that green tea consumption reduced the risk of cancer progression by nearly half (Li 2011). But a Japanese study of 110 cases of HCC could not determine any effect of green tea consumption on cancer risk (Inoue 2009).

Zinc. Zinc, which is found in various enzymes, has a role in immunoregulation (Balamtekin 2010). Clearance of viral infection requires the activity of T-cells, which are highly dependent on zinc (Kuloğlu 2011). Levels of zinc (as well as molybdenum, manganese, and selenium) are reduced in HBV-infected children compared to healthy subjects (Balamtekin 2010). Low serum zinc is associated with elevated blood levels of liver enzymes (aspartate aminotransferase and alanine aminotransferase; markers of liver damage) in adults (Abediankenari 2011). In one study, children with higher serum zinc levels had a better response to interferon (IFN) therapy (Ozbal 2002). In another study, the response to combination therapy of zinc and IFN-α in HBV infection was not significantly different than IFN-α alone. However, researchers speculate that the lack of response may have been due to the low dose of zinc administered (7.5 – 10 mg) (Kuloğlu 2011).

Lactoferrin. Lactoferrin is an antimicrobial protein with inhibitory activity against several viruses, possibly through interactions with host cells or direct binding to the invading virus. The antiviral activity of lactoferrin (a major protein in milk) may partially explain the low incidence of mother-to-child transfer of HBV through breastfeeding in humans (Petrova 2010). Isolated human liver cells pre-treated with bovine or human lactoferrin were resistant to HBV infection (Hara 2002). Bovine lactoferrin, as well as zinc- and iron-saturated lactoferrin, inhibited HBV replication in infected human liver cells in culture (Li 2009).

Iron-sequestering compounds. High serum and hepatic iron have been associated with a reduced response to IFN treatment and increased risk of disease progression in chronic hepatitis B patients (Fiorino 2011). While their efficacy in HBV treatment has not been examined, several compounds have been shown to reduce iron absorption from the gut or chelate iron from cells or body fluids; these include several flavonoids (Mladěnka 2011), pectin (Monnier 1980), silybin from milk thistle (Borsari 2001) and curcumin (Thephinlap 2011). Lactoferrin (Brock 1980) and green tea (Mandel 2006) may also have iron-sequestering activity in addition to their anti-viral activity. More information is available in the Iron Overload Disorders protocol.

B Vitamins. Patients with chronic hepatitis B exhibit marked increases in oxidative stress and lipid peroxidation along with decreased antioxidant status (Duygu 2012). Vitamin B1 (thiamine) is required for the formation of dihydrolipoate, an important antioxidant and cofactor in iron metabolism, two functions with relevance to HBV disease mitigation. A small study on Chinese children with chronic HBV demonstrated similar reductions in HBV DNA and hepatitis B e-antigen (HBeAg) between thiamine and standard IFN therapies. But a second study in the same population showed no effect of thiamine on HBV (Fiorino 2011). Chronic HBV infection reduces levels of vitamins B2 (riboflavin) and B6 (pyridoxine) in red blood cells (Lin 2011). Supplementation with these vitamins may be helpful in HBV patients, although their effects on mitigating HBV disease are unknown (Lin 2011).

Vitamins C and E. Vitamin C and E stores are also reduced in chronic HBV patients (Tasdelen Fisgin 2012). Three small studies of vitamin E therapy in HBV-infected children and adults suggest a possible role for the antioxidant in the clearance of HBV DNA, adaptation of immune response to the viral antigen, and normalization of liver enzymes levels (Fiorino 2011).

Resveratrol. In an animal model of HBV-associated liver disease resveratrol reduced fatty changes in the liver and structural alterations of liver cells (such as degradation of mitochondria), raised cellular glutathione levels, and decreased reactive oxygen species. Additionally, resveratrol reduced incidence of HCC by 5-fold, and enhanced liver cell proliferation and liver regeneration (Lin 2012).

Curcumin. Curcumin reduces viral replication and expression of HBV genes in isolated human hepatocytes by inhibiting the activity of the metabolic regulator PGC-1α (Kim 2009; Rechtman 2010). PGC-1α, which is activated during starvation and turns on genes involved in glucose production, also increases the replication of HBV (Rechtman 2010).

N-acetyl-cysteine. N-acetyl-cysteine (NAC) is derived from L-cysteine, a conditionally essential amino acid. This powerful antioxidant diminishes free radicals and raises glutathione levels (Nguyen-Khac 2011). It reduces viral load in experimental models by disrupting the assembly of HBV virus particles (Weiss 1996). The few studies of NAC in HBV patients have had mixed results. Dosages of 1200 to 8000 mg/day were able to raise glutathione levels in chronic HBV patients or lower levels of bilirubin (high bilirubin can indicate liver dysfunction), but did not significantly affect most other markers of liver function (Shohrati 2010; Wang 2008; Shi 2005). Neither oral nor intravenous NAC significantly affected HBV viral load or time to patient recovery, although differences in dosages and small study populations may preclude any conclusions about NAC therapy for HBV (Gunduz 2003; Weidenbach 2003).

Phyllanthus. Phyllanthus, a genus of plant used to treat chronic liver disease in traditional Chinese and Indian medical systems, has demonstrated inhibition of HBV viral replication and antigen synthesis in isolated cells as well as in animal models (Cui 2010). A review of several small clinical trials suggests some positive effects of Phyllanthus on parameters of HBV infection and significant reductions in serum HBV antigen. Several species of Phyllanthus were used in these trials; one of the most commonly used is Phyllanthus amarus at a dose of 600 to 1200 mg daily (Liu 2001). Fifteen trials have investigated combinations of Phyllanthus and antiviral drugs (INF-α, lamivudine, adefovir dipivoxil, thymosin, vidarabine), and demonstrated significant improvements associated with combination therapy over antiviral drugs alone, such as reducing blood levels of HBV DNA & HBV antigen, and increasing immune response to HBV (Xia 2011).

Whey protein. In addition to its anabolic benefits, long-term supplementation with whey protein may increase antioxidant status and reduce markers of liver damage (Marshall 2004). An open label study of 8 chronic hepatitis B patients revealed that 12 grams twice daily of undenatured whey protein reduced alanine aminotransferase (ALT) activity in 6 of the patients and raised glutathione in 5 after 12 weeks of supplementation. Additionally, markers of lipid oxidation significantly decreased, while interleukin-2 levels and natural killer (NK) activity (both involved in immune response) significantly increased (Watanabe 2000).

Astragalus. Astragalus root has a history of traditional usage in Chinese medicine for immune and liver health. It inhibited secretion of HBV antigens from isolated human liver cells infected with the virus, and reduced levels of HBV DNA in a hepatitis B animal model (Wang 2009b). A mixture of astragalus polysaccharide and another plant extract called emodin demonstrated significant reductions in HBV DNA and HBV antigens (HBsAg, HBeAg and HBcAg) in a hepatitis B mouse model (Dang 2009). A Chinese study examined the effectiveness of astragalus and adjuvant compounds (Bupleurum chinense, Salviae miltiorrhizae, curcumin, peony and paeoniae) (116 grams daily as a tea) in 116 chronic HBV patients. Two months of treatment with the tea was clinically effective (defined as improvement in clinical symptoms -- fatigue, anorexia, abdominal distension, jaundice -- and partial or full recovery of liver function) in 91% of patients, compared to 70% of controls (who took a low-dose mixture of silibinin, oleanic acid, and the herb Yi-Gan-Ling) (Tang 2009).

Schizandra. Members of the genus Schizandra inhibited the secretion of virus antigens from isolated human liver cells by up to 76.5% in one experiment (Ma 2009a,b; Wu 2003). A Schizandra-containing herbal formulation reduced the production and secretion of HBsAg and HBeAg surface antigens (a measurement of virus particle secretion) from isolated liver cells, and reduced the growth of isolated hepatocellular carcinoma cells (Loo 2007). In a Phase I trial, 23 volunteers with HBV infection took the herbal formulation daily for 10 weeks. The average number of monocytes (a type of circulating immune cell) in the blood decreased over the course of the study, which the authors suggested may lower self-inflicted host immune response and liver cell destruction (Yip 2007).

Milk Thistle. Milk thistle is a traditional liver tonic; the active compound in milk thistle (silymarin) has antioxidant and antifibrotic activity (Abenavoli 2010). Although it does not affect HBV viral replication, and has yet to demonstrate a significant effect on virus-related mortality in clinical trials (Rambaldi 2005), milk thistle may be beneficial in reducing the inflammation inherent to hepatitis that may precipitate complications such as cirrhosis or cancer (Abenavoli 2010). Silibinin, a component of silymarin, slows the growth of isolated human hepatocellular carcinoma cells, and exhibits the strongest inhibition towards cancer cells positive for the hepatitis B virus (Varghese 2005). In an animal model of hepatitis B infection, silymarin prevented the progression of pre-cancerous lesions into hepatocellular carcinoma, but had no effect on existing cancer. Cancer developed in 80% of control animals (Wu 2008). A small trial in mixed hepatitis patients demonstrated that 480 mg silibinin daily for 7 days could significantly reduce aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltranspeptidase (GGT), and bilirubin, all markers of liver dysfunction (Buzzelli 1993).


  • Sept: Comprehensive update & review

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A.D.A.M Editorial Board.Hepatitis B. Pubmed Health. 2010; Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002139/ [Accessed August 26, 2012]

Abediankenari, S., Ghasemi, M., Nasehi, M. M., Abedi, S., and Hosseini, V. Determination of trace elements in patients with chronic hepatitis B. Acta Med Iran. 2011;49(10):667–9

Abenavoli, L., Capasso, R., Milic, N., and Capasso, F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24(10):1423–32

Balamtekin, N., Kurekci, A. E., Atay, A., Plasma levels of trace elements have an implication on interferon treatment of children with chronic hepatitis B infection. Biological Trace Element Research. 2010;135(1-3):153–61

Billioud, G., Pichoud, C., Puerstinger, G., Neyts, J., and Zoulim, F. The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication. Antiviral Res. 2011;92(2):271–6

Borsari, M., Gabbi, C., Ghelfi, F., et al. Silybin, a new iron-chelating agent. J. Inorg. Biochem. 2001;85(2-3):123–9

Bravi, F., Bosetti, C., Tavani, A., et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology. 2007;46(2):430–5

Brock, J. H. Lactoferrin in human milk: its role in iron absorption and protection against enteric infection in the newborn infant. Arch. Dis. Child. 1980;55(6):417–21

Buzzelli, G., Moscarella, S., Giusti, A., Duchini, A., Marena, C., and Lampertico, M.A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis.Int J ClinPharmacolTherToxicol. 1993;31(9):456–60

Byrd KK, Murphy TV, and Hu DJ. MD Consult. DNA Viruses: Hepadnaviridae. In: Long: Principles and Practice of Pediatric Infectious Diseases, 4th ed. 2012. Available at: http://www.mdconsult.com/books/page.do?sid=1357739703&eid=4-u1.0-B978-1-4377-2702-9..00215-4&isbn=978-1-4377-2702-9&uniqId=365677148-16. Accessed September 21, 2012.

Castera, L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology. 2012;142(6):1293–4

Centers for Disease Control and Prevention (CDC). Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep. 1991;40(RR-13):1–25

Centers for Disease Control and Prevention (CDC).Availability of hepatitis B vaccine that does not contain thimerosal as a preservative.MMWR Morb.Mortal. Wkly. Rep. 1999;48(35):780–2

Centers for Disease Control and Prevention (CDC).Hepatitis. MMWR Recomm Rep. 1990;39(RR-2):1–22.

Centers for Disease Control and Prevention (CDC).Immunization of adolescents. Recommendations of the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American Medical Association. MMWR Recomm Rep. 1996;45(RR-13):1–16

Chen, C.-J., Yang, H.-I., Su, J., et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006;295(1):65–73

Chevaliez, S., Rodriguez, C., and Pawlotsky, J.-M.New virologic tools for management of chronic hepatitis B and C. Gastroenterology. 2012;142(6):1303–1313.e1

Chien, R.-N., Lin, C.-Y., Yeh, C.-T., and Liaw, Y.-F. Hepatitis B virus genotype B is associated with better response to thymosin alpha1 therapy than genotype C. J. Viral Hepat. 2006;13(12):845–50

Cui, X., Wang, Y., Kokudo, N., Fang, D., and Tang, W. Traditional Chinese medicine and related active compounds against hepatitis B virus infection.Biosci Trends. 2010;4(2):39–47

Dang, S.-S., Jia, X.-L., Song, P., et al. Inhibitory effect of emodin and Astragalus polysaccharide on the replication of HBV.World J Gastroenterol. 2009;15(45):5669–73

Daniels, D., Grytdal, S., Wasley, A., Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis - United States, 2007.MMWR SurveillSumm. 2009;58(3):1–27

Delaney, W., Bartholomeusz, A., and Locarnini, S. A. Evolving therapies for the treatment of chronic hepatitis B virus infection.Expert OpinInvestig Drugs. 2002;11(2):169–87

Deres, K., Schröder, C. H., Paessens, A., et al. Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids. Science. 2003;299(5608):893–6

Duygu, F., Karsen, H., Aksoy, N., and Taskin, A. Relationship of Oxidative Stress in Hepatitis B Infection Activity with HBV DNA and Fibrosis. Ann Lab Med. 2012;32(2):113

El-Serag, H. B. Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology. 2012;142(6):1264–1273.e1

Fiorino, S., Conti, F., Gramenzi, A., et al. Vitamins in the treatment of chronic viral hepatitis.Br J Nutr. 2011;105(7):982–9

Garcia-Tsao, G., Lim, J. K., Lim, J., Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol. 2009;104(7):1802–29

Gish, R. G., Satishchandran, C., Young, M., and Pachuk, C. RNA interference and its potential applications to chronic HBV treatment: results of a Phase I safety and tolerability study. Antivir.Ther.(Lond.). 2011;16(4):547–54

Gish, R., Jia, J.-D., Locarnini, S., and Zoulim, F. Selection of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis. 2012;12(4):341–53

Gitlin, N. Hepatitis B: diagnosis, prevention, and treatment. Clin Chem. 1997;43(8 Pt 2):1500–6

Grimm, D., and Thimme, R. Hepatology International, Volume 5, Number 2 - SpringerLink. Hepatol Int. 2011;

Gunduz, H., Karabay, O., Tamer, A., Ozaras, R., Mert, A., and Tabak, O. F. N-acetyl cysteine therapy in acute viral hepatitis.World J Gastroenterol. 2003;9(12):2698–700

Hara, K., Ikeda, M., Saito, S., et al. Lactoferrin inhibits hepatitis B virus infection in cultured human hepatocytes. Hepatol. Res. 2002;24(3):228

He, W., Li, L.-X., Liao, Q.-J., Liu, C.-L., and Chen, X.-L.Epigallocatechingallate inhibits HBV DNA synthesis in a viral replication - inducible cell line. World J Gastroenterol. 2011;17(11):1507–14

Hou, J., Liu, Z., and Gu, F. Epidemiology and Prevention of Hepatitis B Virus Infection. Int J Med Sci. 2005;2(1):50–7

Ichai, P., and Samuel, D. Epidemiology of liver failure.Clin Res HepatolGastroenterol. 2011;35(10):610–7

Inoue, M., Kurahashi, N., Iwasaki, M., et al. Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1746–53

Ioannou, G. N. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a nationally representative survey. Ann Intern Med. 2011;154(5):319–28

Kang, X., Xie, Q., Zhou, X., et al. Effects of hepatitis B virus S protein exposure on sperm membrane integrity and functions.PLoS ONE. 2012;7(3):e33471

Khan, M. S., Dilawar, S., Ali, I., and Rauf, N.The possible role of selenium concentration in hepatitis B and C patients.Saudi J Gastroenterol. 2012;18(2):106–10

Kim, H. J., Yoo, H. S., Kim, J. C., et al. Antiviral effect of Curcuma longa Linn extract against hepatitis B virus replication. J Ethnopharmacol. 2009;124(2):189–96

Kuloğlu, Z., Kırbaş, G., Erden, E., and Kansu, A. Interferon-alpha-2a and zinc combination therapy in children with chronic hepatitis B infection.Biological Trace Element Research. 2011;143(3):1302–9

Ladak, F., Gjelsvik, A., Feller, E., Rosenthal, S., and Montague, B. T. Hepatitis B in the United States: ongoing missed opportunities for hepatitis B vaccination, evidence from the Behavioral Risk Factor Surveillance Survey, 2007. Infection. 2012;40(4):405–13

Larsson, S. C., and Wolk, A. Coffee consumption and risk of liver cancer: a meta-analysis. Gastroenterology. 2007;132(5):1740–5

Lee HC. Acute liver failure related to hepatitis B virus. Hepatologyresearch : the official journal of the Japan Society of Hepatology. Nov 2008;38Suppl 1:S9-S13.

Lee, C., Gong, Y., Brok, J., Boxall, E. H., and Gluud, C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database Syst Rev. 2006;(2):CD004790

Leung, W. W.-M., Ho, S. C., Chan, H. L. Y., Wong, V., Yeo, W., and Mok, T. S. K. Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study. Journal of Epidemiology & Community Health. 2011;65(6):556–8

Li, S., Zhou, H., Huang, G., and Liu, N. Inhibition of HBV infection by bovine lactoferrin and iron-, zinc-saturated lactoferrin. Med. Microbiol. Immunol. 2009;198(1):19–25

Li, Y., Chang, S.-C., Goldstein, B. Y., et al. Green tea consumption, inflammation and the risk of primary hepatocellular carcinoma in a Chinese population. Cancer Epidemiol. 2011;35(4):362–8

Liaw, Y. F., and Chu, C.-M.Hepatitis B virus infection.Lancet. 2009;373(9663):582–92

Lin MC, Wu CC, Cheng SB, Liu TJ, P'Eng F K. The influence of high serum testosterone levels on the long-term prognosis in male patients undergoing hepatectomy for early stage hepatocellular carcinoma without vascular invasion. World journal of surgery.Jul 2007;31(7):1469-1473.

Lin, C.-C., Liu, W.-H., Wang, Z.-H., and Yin, M.-C.Vitamins B status and antioxidative defense in patients with chronic hepatitis B or hepatitis C virus infection.Eur J Nutr. 2011;50(7):499–506

Lin, H.-C., Chen, Y.-F., Hsu, W.-H., Yang, C.-W., Kao, C.-H., and Tsai, T.-F. Resveratrol Helps Recovery from Fatty Liver and Protects against Hepatocellular Carcinoma Induced by Hepatitis B Virus X Protein in a Mouse Model. Cancer Prevention Research. 2012;5(7):952–62

Liu, J., Lin, H., and McIntosh, H. Genus Phyllanthus for chronic hepatitis B virus infection: a systematic review. J. Viral Hepat. 2001;8(5):358–66

Loo, W. T. Y., Cheung, M. N. B., and Chow, L. W. C. Fructusschisandrae (Wuweizi)-containing compound inhibits secretion of HBsAg and HBeAg in hepatocellular carcinoma cell line. Biomed Pharmacother. 2007;61(9):606–10

Ma, W.-H., Huang, H., Zhou, P., and Chen, D.-F.Schisanwilsonenes A-C, anti-HBV Carotanesesquiterpenoids from the fruits of Schisandrawilsoniana. J. Nat. Prod. 2009a;72(4):676–8

Ma, W.-H., Lu, Y., Huang, H., Zhou, P., and Chen, D.-F.Schisanwilsonins A-G and related anti-HBV lignans from the fruits of Schisandrawilsoniana.Bioorg. Med. Chem. Lett. 2009b;19(17):4958–62

Mandel, S., Amit, T., Reznichenko, L., Weinreb, O., and Youdim, M. B. H. Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol. Nutr. Food Res. 2006;50(2):229–34

Mao, H.-Y., and Shi, T.-D. [Treatment with interferon and thymosin alpha-1 versus interferon monotherapy for HBeAg positive chronic hepatitis B: a meta-analysis]. ZhonghuaGanZang Bing ZaZhi. 2011;19(1):29–33

Marieb, E., and Hoehn, K. Human anatomy & physiology. 8th ed. San Francisco: Pearson Benjamin Cummings. 2010.

Marion, S. A., TommPastore, M., Pi, D. W., and Mathias, R. G. Long-term follow-up of hepatitis B vaccine in infants of carrier mothers. Am. J. Epidemiol. 1994;140(8):734–46

Marshall, K. Therapeutic applications of whey protein.Altern Med Rev. 2004;9(2):136–56

Mayo Clinic.Cirrhosis.2011a Mayo Clinic. Available at: http://www.mayoclinic.com/health/cirrhosis/DS00373 [Accessed August 26, 2012].

Mayo clinic.Hepatitis B. 2011b. Available at: http://www.mayoclinic.com/health/hepatitis-b/DS00398 [Accessed August 26, 2012].

Merck. Acute Viral Hepatitis: Hepatitis: Merck Manual Professional. merckmanuals.com 2007. Available at: http://www.merckmanuals.com/professional/hepatic_and_biliary_disorders/hepatitis/acute_viral_hepatitis.html [Accessed August 28, 2012].

Mitchell, A. E., Colvin, H. M., and Palmer Beasley, R. Institute of Medicine recommendations for the prevention and control of hepatitis B and C. Hepatology. 2010;51(3):729–33

Mladěnka, P., Macáková, K., Filipský, T., et al.In vitro analysis of iron chelating activity of flavonoids. J. Inorg. Biochem. 2011;105(5):693–701

Monnier, L., Colette, C., Aguirre, L., and Mirouze, J. Evidence and mechanism for pectin-reduced intestinal inorganic iron absorption in idiopathic hemochromatosis.Am J ClinNutr. 1980;33(6):1225–32

Mutimer, D. J., and Lok, A. Management of HBV- and HCV-induced end stage liver disease. Gut. 2012;61Suppl 1:i59–67

Nebbia, G., Peppa, D., and Maini, M. K. Hepatitis B infection: current concepts and future challenges. QJM. 2012;105(2):109–13

Nguyen-Khac E, Thevenot T, Piquet MA, et al. Glucocorticoids Plus N-Acetylcysteine in Severe Alcoholic Hepatitis. N Engl J Med. 2011;359(19):1781-9. Available at: http://www.med.upenn.edu/gastro/documents/NACinAlcHep.pdf. Accessed August 30, 2012.

Nikolopoulos, G. K., Paraskevis, D., Hatzitheodorou, E., et al. Impact of hepatitis B virus infection on the progression of AIDS and mortality in HIV-infected individuals: a cohort study and meta-analysis. Clin. Infect. Dis. 2009;48(12):1763–71

Ozbal, E., Helvaci, M., Kasirga, E., Akdenizoğlu, F., and Kizilgüneşler, A. Serum zinc as a factor predicting response to interferon-alpha2b therapy in children with chronic hepatitis B. Biological Trace Element Research. 2002;90(1-3):31–8

Petrova, M., and Kamburov, V. Breastfeeding and chronic HBV infection: clinical and social implications. World J Gastroenterol. 2010;16(40):5042–6

Protzer, U., Maini, M. K., and Knolle, P. A. Living in the liver: hepatic infections. Nat. Rev. Immunol. 2012;12(3):201–13

Rambaldi, A., Jacobs, B. P., Iaquinto, G., and Gluud, C. Milk Thistle for Alcoholic and/or Hepatitis B or C Liver Diseases-A Systematic Cochrane Hepato-Biliary Group Review with Meta-Analyses of Randomized Clinical Trials. Am J Gastroenterol. 2005;100(11):2583–91

Rauf, N., Tahir, S. S., Dilawar, S., Ahmad, I., and Parvez, S. Serum selenium concentration in liver cirrhotic patients suffering from hepatitis B and C in Pakistan.Biological Trace Element Research. 2012;145(2):144–50

Rechtman, M. M., Har-Noy, O., Bar-Yishay, I., et al. Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1alpha. FEBS letters. 2010;584(11):2485–90

Rich, J. D., Ching, C. G., Lally, M. A., et al. A review of the case for hepatitis B vaccination of high-risk adults. Am. J. Med. 2003;114(4):316–8

Scaglione, S. J., and Lok, A. S. F. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology. 2012;142(6):1360–1

SciClone.Zadaxin Product Monograph. 2012:1–58

Shi, X.-F., Guo, S.-H., Wu, G., et al. [A multi-center clinical study of N-acetylcysteine on chronic hepatitis B].ZhonghuaGanZang Bing ZaZhi. 2005;13(1):20–3

Shimizu, I., Kohno, N., Tamaki, K., et al. Female hepatology: favorable role of estrogen in chronic liver disease with hepatitis B virus infection. World J Gastroenterol. 2007;13(32):4295–305

Shohrati, M., Dermanaki, F., Babaei, F., and Alavian, S. M. Evaluation of the effects of oral N-acetylcysteine and a placebo in paraclinical and oxidative stress parameters of patients with chronic hepatitis B. Hepat Mon. 2010;10(2):95–100

Stray, S. J., Bourne, C. R., Punna, S., Lewis, W. G., Finn, M. G., and Zlotnick, A. A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly. ProcNatlAcadSci USA. 2005;102(23):8138–43

Tang, L. L., Sheng, J. F., Xu, C. H., and Liu, K. Z. Clinical and experimental effectiveness of Astragali compound in the treatment of chronic viral hepatitis B. J. Int. Med. Res. 2009;37(3):662–7

Tanwar, S., and Dusheiko, G. Is there any value to hepatitis B virus genotype analysis? CurrGastroenterol Rep. 2012;14(1):37–46

TasdelenFisgin, N., Aydin, B. K., Sarikaya, H., et al. Oxidative stress and antioxidant defense in patients with chronic hepatitis B. Clin. Lab. 2012;58(3-4):273–80

Thephinlap, C., Phisalaphong, C., Lailerd, N., et al. Reversal of cardiac iron loading and dysfunction in thalassemic mice by curcuminoids. Med Chem. 2011;7(1):62–9

Tohme, R. A., Ribner, B., Huey, M. J., and Spradling, P. R. Hepatitis B vaccination coverage and documented seroprotection among matriculating healthcare students at an academic institution in the United States. Infect Control HospEpidemiol. 2011;32(8):818–21

Varghese, L., Agarwal, C., Tyagi, A., Singh, R. P., and Agarwal, R. Silibinin efficacy against human hepatocellular carcinoma.Clin Cancer Res. 2005;11(23):8441–8

Wang, G.-F., Shi, L.-P., Ren, Y.-D., et al. Anti-hepatitis B virus activity of chlorogenic acid, quinic acid and caffeic acid in vivo and in vitro. Antiviral Res. 2009a;83(2):186–90

Wang, N., Shi, X.-F., Guo, S.-H., Zhang, D.-Z., and Ren, H. [A clinical study of N-acetylcysteine treatment in chronic hepatitis B patients].ZhonghuaGanZang Bing ZaZhi. 2008;16(7):487–9

Wang, S., Li, J., Huang, H., et al. Anti-hepatitis B virus activities of astragaloside IV isolated from radix Astragali. Biol. Pharm. Bull. 2009b;32(1):132–5

Watanabe, A., Okada, K., Shimizu, Y., et al. Nutritional therapy of chronic hepatitis by whey protein (non-heated). J Med. 2000;31(5-6):283–302

Weber O, Schlemmer KH, Hartmann E, Hagelschuer I, Paessens A, Graef E, . . . Wohlfeil S. Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antiviral research.May 2002;54(2):69-78.

Weidenbach, H., Orth, M., Adler, G., Mertens, T., and Schmid, R. M. Treatment of chronic hepatitis B with high-dose intravenous N-acetyl-L-cysteine.Hepatogastroenterology. 2003;50(54):2105–8

Weiss, L., Hildt, E., and Hofschneider, P. H. Anti-hepatitis B virus activity of N-acetyl-L-cysteine (NAC): new aspects of a well-established drug. Antiviral Res. 1996;32(1):43–53

Wilson, R., Purcell, D., Netter, H. J., and Revill, P. A. Does RNA interference provide new hope for control of chronic hepatitis B infection? Antivir.Ther.(Lond.). 2009;14(7):879–89

World Health Organization.Hepatitis B vaccines. Wkly. Epidemiol. Rec. 2009;84(40):405–19

Wu, M.-D., Huang, R.-L., Kuo, L.-M.Y., Hung, C.-C., Ong, C.-W., and Kuo, Y.-H.The anti-HBsAg (human type B hepatitis, surface antigen) and anti-HBeAg (human type B hepatitis, e antigen) C18 dibenzocyclooctadienelignans from Kadsuramatsudai and Schizandraarisanensis. Chem. Pharm. Bull. 2003;51(11):1233–6

Wu, Y.-F., Fu, S.-L., Kao, C.-H., et al. Chemopreventive effect of silymarin on liver pathology in HBV X protein transgenic mice. Cancer Res. 2008;68(6):2033–42

Xia, Y., Luo, H., Liu, J. P., and Gluud, C. Phyllanthus species for chronic hepatitis B virus infection. Cochrane Database Syst Rev. 2011;(4):CD008960

Xu, J., Wang, J., Deng, F., Hu, Z., and Wang, H. Green tea extract and its major component epigallocatechingallate inhibits hepatitis B virus in vitro. Antiviral Res. 2008;78(3):242–9

Xu, M., Wang, B., Fu, Y., et al. Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus-induced chronic liver disease. Microb. Ecol. 2012;63(2):304–13

Yang, Y.-F., Zhao, W., Zhong, Y.-D., et al. Comparison of the efficacy of thymosin alpha-1 and interferon alpha in the treatment of chronic hepatitis B: a meta-analysis. Antiviral Res. 2008;77(2):136–41

Yip, A. Y. S., Loo, W. T. Y., and Chow, L. W. C. FructusSchisandrae (Wuweizi) containing compound in modulating human lymphatic system - a Phase I minimization clinical trial. Biomed Pharmacother. 2007;61(9):588–90

Yu, S. Y., Zhu, Y. J., and Li, W. G. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biological Trace Element Research. 1997;56(1):117–24

Yuan, J. M., Ross, R. K., Stanczyk, F. Z., et al. A cohort study of serum testosterone and hepatocellular carcinoma in Shanghai, China.Int J Cancer. 1995;63(4):491–3

Zhang, Y.-Y., Chen, E.-Q., Yang, J., Duan, Y.-R., and Tang, H. Treatment with lamivudine versus lamivudine and thymosin alpha-1 for e antigen-positive chronic hepatitis B patients: a meta-analysis. Virol. J. 2009;6:63.