Challenging Clinical Cases in Adult Immunization: Focus on Hepatitis B

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	Introduction Stanley C. Deresinski, MD Course Chair Clinical Professor of Medicine Stanford University Modical Center Redwood City, CA
	Case #1: Chronic Hepatitis C–Prevention of HBV and HAV Infection Raymond S. Koff, MD Clinical Professor of Medicine University of Connecticut, School of Medicine, Health Center Farmington, CT
	Case #2: Hepatitis B and the Traveler Bradley A. Connor, MD Clinical Associate Professor of Medicine Weill Medical College Cornell University Ithaca, NY
	Case #3: Hepatitis B Vaccine Nonresponder Robert G. Gish, MD Hepatologist & Medical Director, Liver Disease Management and Transplant Program, California Pacific Medical Center San Francisco, CA Division Chief of the Section on Hepatology and Complex Gastroenterology Physicians Foundation at California Pacific Medical Center Clinical Professor of Medicine, University of Nevada Reno, NV Clinical Professor of Medicine University of California, San Francisco San Francisco, CA

Introduction

Hepatitis B virus (HBV) causes significant morbidity and mortality worldwide. More than 350 million people are chronically infected with the virus, and an estimated2 billion have been infected at some time in their lives. Globally, HBV infection and its consequences cause an estimated 600000 to 1 million deaths per year. Chronic HBV infection, which affects approximately 1.25 million to 2 million people in the United States, has serious sequelae and is responsible for approximately one-third of cirrhosis cases and one-half of hepatocellular cancer cases.

HBV vaccines were first licensed in the United States in 1981 and, since then, more than 1 billion doses have been used worldwide. These vaccines have successfully prevented innumerable cases of HBV infection and its sequelae. However, issues related to the use of the vaccine in special populations, ie, patients with viral and/or other liver diseases, travelers, and nonresponders, require practitioners to consider their individual patients’ situations and needs.

In May 2009, Vindico Medical Education assembled a panel of experts in the field to address these issues. Three cases were presented to illustrate common situations that may be encountered, their interpretations, and appropriate responses. The results of these discussions provided material for this monograph. I thank the participants for sharing their expertise and experience, and for assisting with the preparation of this CME monograph.

Stanley C. Deresinski, MD

Course Chair

Case 1

Raymond S. Koff, MD

Chief Complaint

A 34-year-old musician was referred by his primary care physician to the liver clinic for management because of persistently elevated alanine aminotransferase (ALT) levels and positive antibodies to hepatitis C virus (HCV) and HCV RNA, supporting a diagnosis of chronic hepatitis C.

History

There was no history of blood transfusion. He did not work in a health care occupation and he denied cocaine use, body piercing, or tattooing. Also, to the best of his knowledge, there was no history of HCV infection in his mother. He admitted to frequent injection drug use from age 18 to 23 years and occasional use subsequently.

The patient was seen by his primary care physician approximately 1 year previously for community-acquired pneumonia that responded to a course of azithromycin. During that illness and evaluation, ALT was elevated (100 IU/L; normal <30 IU/L). Over the next 6 months, ALT levels remained elevated, aspartate aminotransferase (AST) was elevated to a lesser extent, and other liver chemistries were normal. He remained asymptomatic during the following 6-month period, and his physical examination was unremarkable.

Serologic studies were negative for hepatitis B virus (HBV) surface antigen, HBV surface and core antibodies, hepatitis A virus (HAV) antibodies, and human immunodeficiency virus (HIV) antibodies.

Assessment and Diagnosis

The physician in the liver clinic diagnosed the patient with chronic hepatitis C genotype 1, with an HCV load of 1.6 million IU/mL. The natural history of HCV infection, his diagnosis of chronic infection, and the possibility of infectivity were discussed with the patient.

Management

Options for treatment with pegylated interferon and ribavirin were discussed. New adjunctive treatments not currently available but that may receive FDA approval in the next 2 years were explained. As there was no serologic evidence of past exposure to HAV or HBV, and superinfection with either of these viruses might result in more severe liver injury, the combined hepatitis A/B vaccine was initiated that day. The recently approved accelerated schedule was followed, with the second dose given after 1 week and a third dose 3 weeks after the first. As part of the accelerated regimen, a booster dose was scheduled for 12 months after the first dose. High titers of both anti-HBV and anti-HAV were observed 2 months after the third dose.

Chronic Hepatitis C–Prevention of HBV and HAV Infection

Raymond S. Koff, MD

Chronic liver disease in the United States is estimated to affect 5.5 million people.¹ Of these, it is estimated that up to 5 million are chronically infected with hepatitis C virus (HCV), which is responsible for 8000 to 10 000 deaths each year, and 1.25 million have chronic hepatitis B virus (HBV) infection, 15% to 40% of whom will, in their lifetime, develop potentially lethal complications.^2,3 Co-infections are not uncommon, particularly with shared risk factors among the hepatic viral diseases. Accordingly, HBV must be considered in the setting of other chronic liver disease.

Discussion

Patients with chronic liver disease who are susceptible to hepatitis A virus (HAV) or HBV should be immunized against these viruses.^4,5 Case reports in the 1970s and 1980s were followed by a 1998 report of convincing data from 17 patients with chronic HCV who were superinfected with HAV.⁶ Seven of the 17 patients (41.1%) developed acute liver failure, of whom 6 (85.7%) died. There is also evidence that HAV superinfection of patients with chronic HBV increases the risk of more severe disease in these patients. Shared risk factors contribute to superinfection or co-infection; however, in approximately 50% of patients with HAV and 16% of patients with HBV infections, specific risk factors cannot be identified (Figure).^7,8 It is somewhat surprising that this patient who was an occasional injection drug user escaped superinfection with HAV or HBV and his history strengthens the recommendation for prompt vaccination.

Vaccination as early as possible after the diagnosis of chronic liver disease is warranted. In addition to reducing the likelihood that this patient acquires one of these infections, the immunogenicity of both HAV and HBV vaccines is impaired in patients who develop more advanced disease such as cirrhosis or hepatic decompensation or patients who require liver transplantation. As a consequence, postimmunization antibody testing is appropriate in such patients. The use of an accelerated dose schedule, as in this patient, should improve compliance and increase the likelihood that seroprotection will develop early. This is especially relevant for HAV, which has risk factors that can be encountered in daily living activities.

Vaccinating this patient is supported by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, which recommends the HBV vaccine for patients with chronic liver disease.^9,10 Furthermore, the American Association for the Study of Liver Diseases (AASLD) guidelines for the management of HCV recommends that all persons with HCV infection who lack antibodies to hepatitis A and B should be offered vaccination against these 2 viral infections.¹¹ Acute hepatitis B superimposed on chronic hepatitis C is a more severe illness, and individuals who are co-infected with HBV and HCV have a more progressive course and a higher risk of decompensation than those without HBV infection.

References

1. National Institute of Diabetes and Digestive and Kidney Diseases. Action Plan for Liver Disease. http://www2.niddk.nih.gov/NR/rdonlyres/8AB99610-4AA7-46E1-A306-0B976FF091C8/0/ldrb_executive_summary.pdf. Accessed July 15, 2010.
2. Centers for Disease Control and Prevention. Hepatitis C Information for Health Professionals. http://www.cdc.gov/hepatitis/HCV/index.htm. Accessed July 23, 2010.
3. Gish RG, Afdhal N, Dieterich D, Reddy K. Management of hepatitis C virus in special populations: patient and treatment considerations. Clin Gastroenterol Hepatol. 2005;3(4):311-318.
4. Koff RS. Risks associated with hepatitis A and hepatitis B in patients with hepatitis C. J Clin Gastroenterol. 2001;33(1):20-26.
5. Keeffe EB, Iwarson S, McMahon BJ, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology. 1998;27(3):881-886.
6. Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338(5):286-290.
7. Centers for Disease Control and Prevention. Hepatitis A. In: Atkinson W, Wolfe S, Hamborsky J, McIntyre L, eds. Epidemiology and Prevention of Vaccine Preventable Diseases. 11th ed. Washington DC: Public Health Foundation; 2009:85-98.
8. Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W, Wolfe S, Hamborsky J, McIntyre L, eds. Epidemiology and Prevention of Vaccine Preventable Diseases. 11th ed. Washington DC: Public Health Foundation; 2009:99-122.
9. Mast EE, Weinbaum CM, Fiore AE, et al; Advisory Committee on Immunization Practices Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33.
10. Centers for Disease Control and Prevention. Recommended adult immunization schedule-United States, 2010. MMWR. 2010;59(1).
11. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009; 49(4):1335-1374.

Case 2

Bradley A. Connor, MD

Chief Complaint

A 76-year-old man and his 74-year-old wife are planning a 50th wedding anniversary trip to Asia. Their plans include a flight from New York to Hong Kong, where they will embark on a 10-day cruise of Southeast Asia, stopping at various ports of call with several side trips into rural areas. The husband has a history of hypertension, hypercholesterolemia, and noninsulin-dependent diabetes mellitus. He is in good health with annual physical examinations and no other medical history of note. His wife has osteoarthritis but is otherwise healthy.

You were asked to see the couple 1 month prior to their departure to perform a pretravel consultation and make recommendations for prevention of vaccine-preventable disease, diarrhea, and malaria, and to discuss other destination-specific health risks. They are both up-to-date with routine immunizations including tetanus and diphtheria, receive annual influenza virus vaccines, and received pneumococcal vaccines in the past. You are being asked specifically to discuss their risk for hepatitis B virus (HBV). Acute HBV is not well tolerated in the elderly. Therefore, because of the rationale discussed below, you recommend HBV immunization.

The age of the couple suggests there is less than a 5% chance that they were previously infected.1 Unless they have a history of blood transfusion or other risk factors, prevaccination immunity screening is not necessary. In fact, studies have shown that prescreening is cost-effective only in populations with high prevalence (Table).^2,3

Table. Prevaccination Serological Testing

Reccomended for: Foreign-born people (including immigrants, refugees, asylum seekers, and internationally adopted children) born in Africa, Asia, the Pacific Islands, and other regions with high endemicity of HBV infection (HBsAg prevalence of 8% or higher) Household contacts, sex partners, and needle-sharing contacts of patients who are HBsAg positive People with HIV Usually cost-effective and should be considered for groups with a high risk for HBV infection (prevalence of HBV markers 20% or higher): Men who have sex with men Injection-drug users Incarcerated people Screening is usually not cost-effective for: Health professionals in their training years

Until recently, long-term travelers such as missionaries, expatriotes, and Peace Corps workers had a several percent annual seroconversion to hepatitis B.⁴ For an elderly monogamous couple on a short trip, the risk of contracting HBV infection would have been considered very low. In addition, HBV immunization required dosing at 0, 1, and 6 months, and most travelers do not plan health needs that far in advance of their travel.⁵ However, with the knowledge that more than 350 million chronic carriers of HBV provide a global reservoir for infection, the risk of direct or indirect contact with an infected individual through blood or body fluids must be considered a possibility.

uma due to accident or injury, medical or surgical intervention, cosmetic procedures, and sexual contact. In one study, 31% of travelers reported trauma during their trips, and incidents required hospitalization, instrumentation, and blood transfusions.⁶ The chance that this elderly couple may come in contact with local health care services, perhaps in a rural part of Asia, is not insignificant. For example, in one study, 64% of travelers reported being ill during their travels, 8% of whom sought medical care, with 17% of those patients receiving an injection.⁷ In many parts of the world, this may be done with unsterilized equipment, posing a risk for HBV infection. Finally, the most common cause of death among older travelers is cardiovascular disease,⁸ and for each of these deaths there is a multitude of people who are hospitalized and may be in a location where blood supplies are not screened and instruments are not sterilized.

In summary, this elderly couple has a risk of accessing medical care while traveling, and medical facilities may be risk factors for HBV transmission, particularly because the travelers will be making forays into rural areas. Vaccinating travelers is facilitated by the 2007 FDA approval of the accelerated 4-dose schedule at days 0, 7, and 21, followed by a 12-month booster.9 This couple, being seen 1 month before departure, will be able to complete the 3 initial doses prior to their short trip, which will not interfere with their receiving the final dose at 12 months.

Hepatitis B and the Traveler

Bradley A. Connor, MD

Travel medicine began gaining importance in the United States in the mid-1980s, when it was realized that tropical medicine did not meet the needs of travelers going from developed countries to developing countries. Tropical medicine primarily involved infections in indigenous populations in less developed countries, but did not address specific issues related to how to prevent illness in people traveling there from developed countries. Consultation focused on vaccine-preventable disease, diarrhea, malaria, and, as warranted, other individual issues.

Most of the world outside of the United States, Canada, Western Europe, Australia, New Zealand, and Japan had either high or intermediate endemicity for hepatitis A virus (HAV). Therefore, HAV vaccine was the first vaccine considered. Other vaccines, for example, typhoid and yellow fever vaccines, were required for travel to certain countries. Until recently, hepatitis B virus (HBV) vaccination was not considered unless the travelers were going to be exposed to blood or body fluids. Due to the wide variety of circumstances that surround clinicians who deal with traveling patients, the following alternative scenarios are presented additionally to allow further insight into hepatitis B and the traveler.

Alternative Scenario 1

A 19-year-old college student is planning a semester in Antigua, Guatemala, where she will be studying Spanish. She states that she is up-to-date on all her immunizations and received HBV immunization as an infant. During her last visit with her physician, she asked to be tested for HBV antibodies in anticipation of her semester abroad. She was told that her antibodies to HBV were negative. She is concerned about the risk of hepatitis B and asks your advice.

She may have been seroprotected as an infant, but her antibodies have decreased to an undetectable level. Alternatively, she may have been a nonresponder. In the clinic, she was given 1 dose of HBV vaccine, which produced a very high antibody response. This suggests that she was seroprotected from her primary vaccination series and that this single dose is a sufficient booster. This anamnestic response also suggests that, if she had been exposed to live virus, she would have produced protective antibodies and would not have developed clinical disease. Individuals who respond appropriately to the vaccine may lose antibodies with time, to reach an undetectable titer after 15 or 20 years, yet they still are protected. In fact, clinical infection in these individuals is rare.¹⁰

Alternative Scenario 2

A 45-year-old man travels to Asia for business several times each year. He is a banker and stays in 5-star hotels in major cities. He is healthy but takes prescription medication for seasonal allergies.

Should he be protected against HBV? The simple answer is yes, everyone should be protected against hepatitis B. If he was 19, had tattoos and earrings, and was going to Bangkok for 6 weeks, his profile would warrant vaccination if he was not immune to HBV. However, in the travel clinic setting, profiling should be avoided. Travel medicine literature is replete with studies showing that the most virtuous travelers may be tempted to engage in behaviors they would not consider at home. In addition, this traveler’s destination meets the criterion of high-population seropositivity, at approximately 8%. Accordingly, it would be appropriate to suggest HBV immunization in a nonjudgmental way. This person makes multiple trips, and the immunization series becomes an investment in his health. Finally, 16% of HBV cases have unknown risk factors, although this rate may reflect the patient’s unwillingness to admit them. Other possible risk factors may be relevant for travelers. For example, the pedicurist, the manicurist, the barber who uses a straight razor, and the acupuncturist may contribute to transmitting blood-borne viruses.

References

1. Daniels D, Grytdal S, Wasley A. Surveillance for acute viral hepatitis -United States, 2007. MMWR Surveill Summ. 2009;58(3):1-27.
2. Centers for Disease Control and Prevention. Hepatitis B vaccination of inmates in correctional facilities-Texas, 2000-2002. MMWR Morb Mortal Wkly Rep. 2004;53(30):681-683.
3. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine Preventable Diseases. Atkinson W, Wolfe S, Hamborsky J, McIntyre L, eds. 11th ed. Washington DC: Public Health Foundation; 2009.
4. Frame JD, Lange WR, Frankenfield DL. Mortality trends of American missionaries in Africa, 1945-1985. Am J Trop Med Hyg. 1992;46(6):686-690.
5. Mast EE, Weinbaum CM, Fiore AE, et al; Advisory Committee on Immunization Practices Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33.
6. Fairhurst RJ. Accidents and the traveller. In: Cook GC, ed. Travel Associated Disease. London: Royal College of Physicians; 1995:61-71.
7. Hill DR. Health problems in a large cohort of Americans traveling to developing countries. J Travel Med. 2000;7(5):259-266.
8. Löscher T, Keystone JS, Steffen R. Vaccination of travelers against hepatitis A and B. J Travel Med. 1999;6(2):107-114.
9. CDC. Notice to readers: FDA Approval of an alternate dosing schedule for a combined hepatitis A and B vaccine (Twinrix). MMWR Morb Mortal Wkly Rep. 2007;56(40):1057.
10. McMahon BJ, Bruden DL, Petersen KM, et al. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up. Ann Intern Med. 2005;142(5):333-341.

Case 3

Robert G Gish, MD

Chief Complaint

A 32-year-old Chinese-American woman who works as a registered nurse at a major metropolitan hospital and medical center was asked to undergo hepatitis B virus (HBV) vaccination at her local occupational health clinic. The clinic tested for the presence or absence of HBV surface antibody. The patient had no known history of liver disease or elevated liver tests and had lived in the United States for 5 years after emigrating from mainland China. Because of her geographic origin, she is on the Centers for Disease Control and Prevention list of people who should be tested for chronic HBV infection1,²; however, she did not recall receiving HBV vaccine or testing in China or the United States. Recently, she underwent a series of standard HBV vaccinations with doses at 0, 1, and 6 months. As a health care worker, she was considered to be a high-risk individual, and was recommended to undergo serologic testing postvaccination at month 7. Importantly, the results of the hepatitis B surface antigen serology were negative.

The HBV vaccine is generally very effective with very high seroconversion rates; however, approximately 10% of healthy adults are nonresponders to the first series of vaccinations, and a decreased response rate occurs in some populations, including older individuals. In general, a vaccine nonresponder is defined as an individual who does not demonstrate protective antibodies after completion of 2 full series of vaccinations and who does not have chronic HBV infection.^3,4 The nonresponse rate decreases to lower than 5% after the 2 series have been given.² A variety of factors have been associated with nonresponse including older age (40 years), obesity, smoking, immunosuppressed status, and chronic illness. Up to 90% of patients who are nonresponders to the standard intramuscular vaccination route may respond to intradermal vaccination.^5,6 Paradoxically, nonresponders do not have a higher rate of chronicity after HBV exposure or acute infection compared with nonvaccinated individuals. The following scenarios present possible outcomes from a subsequent complete HBV panel that was performed by an infectious disease specialist to further evaluate her HBV status. Interpretation of the results⁷ and actions to be taken are summarized.

Hepatitis B Vaccine Nonresponder

Robert G. Gish, MD

Scenario 1

The results of the hepatitis B panel were negative for HBV surface antigen and core antibody and confirmed the lack of surface antibody. Although HIV status should be evaluated to determine whether she is immunosuppressed, the patient exemplifies nonresponse that may be due to a human leukocyte antigen phenotype.8 Vaccine nonresponse may also be experienced by individuals on dialysis, with older age (due to senescence of the immune system), and in other clinical settings of immunosuppression such as chronic prednisone therapy and in organ or tissue transplantation.

The best option for this patient would be 3 additional vaccinations accompanied by response monitoring. More than 65% of primary nonresponders will achieve a response ≥10 mIU/mL after 1 to 3 subsequent standard or double-strength vaccine doses. Interferon has also been used to boost vaccine response.^9,10 Those who do not respond to boosting with standard vaccine may be candidates for intradermal vaccination, which typically requires only one-fifth of the standard intramuscular dosing. The response mechanism following intradermal vaccination is proposed to comprise a unique set of antigen presenting cells, dendritic cells in the dermal space, that produce an immune stimulation different than that of the intramuscular vaccine. It is important to keep in mind that intradermal vaccination is off-label and should be performed as part of a protocol with immunogenicity follow-up testing. ¹¹

Scenario 2

The results of this patient’s serologic studies were positive for hepatitis B surface antigen and core antibody, which explains the lack of response to the hepatitis B vaccine. In this scenario, the patient does not need further vaccination as she is a chronic hepatitis B carrier; in fact, vaccinating people who are surface-antigen positive can give a false sense of protection. Importantly, follow-up should include secondary testing and ongoing surveillance for disease activity and development of adverse sequelae including liver cancer. Therefore, subsequent workups should include quantification of HBV DNA, determination of hepatitis B e-antigen and e-antibody status, and assessment for co-infection with hepatitis C virus (HCV) and HIV. In addition, despite its low prevalence, hepatitis delta virus (HDV) infection should also be investigated.

Scenario 3

The results of this patient’s hepatitis B panel were positive for HBV core antibody. This commonly indicates a history of exposure to HBV, and the patient is most likely a very low-level carrier. In fact, studies of liver transplant organ donors showed that 70% of donors who are core-antibody positive will transmit HBV to an immunosuppressed recipient.¹² Seventy percent of core-antibody positive patients, however, have had exposure to HBV, and a subset of those have cleared the infection.⁴ Although these patients are considered “cleared” of the HBV infection, they are not “cured” of their infection, and thus there is a low probability of reactivation of hepatitis B if the patient is treated with an immunosuppressant.

In the clinical setting, considering the possibility of a false-positive anti-HBc result, an additional dose of the vaccine can be given. If the patient has a blunted response after 1 dose; that is, the surface HBV antibody level is higher than 10 mIU/mL but lower than 100 mIU/mL, the patient should finish the vaccine series or receive a booster. If after 1 dose the response is at least 100 mIU/mL, either the anti-HBc results were false-positive or the HBV had cleared and the patient had an appropriate anamnestic response to the vaccine booster.

These individuals who have isolated anti-HBc should be educated about their risk of reactivation and monitored during any type of immunosuppression and, if there is an increase in liver enzymes, then they will need immediate HBV DNA quantitative testing. If the results of HBV DNA quantification are positive, then nucleoside or nucleotide analog therapy should be started immediately to suppress the reactivation of HBV; these patients would not benefit from further hepatitis B vaccination.

References

1. Weinbaum CM, Williams I, Mast EE, et al; Centers for Disease Control and Prevention. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1-20.
2. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine Preventable Diseases. Atkinson W, Wolfe S, Hamborsky J, McIntyre L, eds. 11th ed. Washington DC: Public Health Foundation; 2009.
3. Lai CL, Lau JY, Yeoh EK, Chang WK, Lin HJ. Significance of isolated anti-HBc seropositivity by ELISA: implications and the role of radioimmunoassay. J Med Virol. 1992;36(3):180-183.
4. McMahon BJ, Parkinson AJ, Helminiak C, et al. Response to hepatitis B vaccine of persons positive for antibody to hepatitis B core antigen. Gastroenterology. 1992;103(2):590-594.
5. Choy BY, Peiris JS, Chan TM, Lo SK, Lui SL, Lai KN. Immunogenicity of intradermal hepatitis B vaccination in renal transplant recipients. Am J Transplant. 2002;2(10):965-969.
6. Playford EG, Hogan PG, Bansal AS, et al. Intradermal recombinant hepatitis B vaccine for healthcare workers who fail to respond to intramuscular vaccine. Infect Control Hosp Epidemiol. 2002;23(2):87-90.
7. Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev. 2006;28:112-125.
8. Thio CL, Thomas DL, Karacki P, et al. Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection. J Virol. 2003;77(22):12083-12087.
9. Goldwater PN. Randomized comparative trial of interferon-alpha versus placebo in hepatitis B vaccine non-responders and hyporesponders. Vaccine. 1994;12(5):410-414.
10. Long JE, Huang LN, Qin ZQ, Wang WY, Qu D. IFN-gamma increases efficiency of DNA vaccine in protecting ducks against infection. World J Gastroenterol. 2005;11(32):4967-4973.
11. Mast EE, Weinbaum CM, Fiore AE, et al; Advisory Committee on Immunization Practices Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33.
12. Dickson RC, Everhart JE, Lake JR, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology. 1997;113(5):1668-1674.