TESTIMONY OF

HAROLD S. MARGOLIS, M.D.

CHIEF

HEPATITIS BRANCH

DIVISION OF VIRAL AND RICKETTSIAL DISEASES

NATIONAL CENTER FOR INFECTIOUS DISEASES

CENTERS FOR DISEASE CONTROL AND PREVENTION

BEFORE THE

U.S. HOUSE OF REPRESENTATIVES

COMMITTEE ON GOVERNMENT REFORM

SUBCOMMITTEE ON CRIMINAL JUSTICE,

DRUG POLICY, AND HUMAN RESOURCES

MAY 18, 1999

Good morning, Mr. Chairman and members of the Subcommittee. I am Dr. Harold Margolis, Chief of the Hepatitis Branch at the National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC). I am joined by Dr. John Livengood, Director, Epidemiology and Surveillance Division, National Immunization Program, CDC. We are here this morning to discuss the importance of hepatitis B vaccination in the prevention of acute and chronic liver disease and liver cancer caused by hepatitis B and the safety of hepatitis B vaccine.

Like you, I have deep sympathy for the parents who testified on the previous panel. Like many of my CDC and Food and Drug Administration (FDA) colleagues, I, too, am a parent. I am also a pediatrician. As both a parent and a pediatrician, nothing matters more to me than the health and safety of my children and the children of others. Thus, while I am here to offer expert testimony on hepatitis B vaccine, my scientific and public health expertise is broadened by my responsibilities as a parent and pediatrician. All perspectives lead me to the same conclusions: (1) that hepatitis B is a real and serious risk to infants and young children; (2) that we have a safe, effective, and proven vaccine for addressing that risk; and, (3) that as scientists, physicians, policy makers, and parents, it is our responsibility to protect the current and future health of our children by broadly using this vaccine.

Hepatitis B Disease

Hepatitis B is a serious disease that kills 4,000 to 5,000 Americans each year and 1 million people worldwide. Of the 4,165 liver transplants performed in the United States in 1997, 332 (8 percent) were for acute liver failure; sixteen percent of these cases of liver failure were caused by hepatitis B. Approximately 220 people (5 percent) receive a liver transplant each year so that they may survive their hepatitis B end-stage liver disease.

In addition to the deaths that occur from chronic liver disease, 150 to 200 people in the U.S. die each year from hepatitis B-related acute liver failure. A patient in acute liver failure is one of the sickest persons for whom a physician will ever have to provide care. The liver does many things, including making blood clotting factors, storing sugar as energy reserves, digesting food, and removing waste products from the blood. When a person's liver is severely damaged from hepatitis B virus, all of these functions are lost. A person in acute liver failure bleeds into their skin and internal organs and from intravenous sites. Because of the build up of nitrogen wastes in the blood, the person becomes stuporous and eventually goes into coma.

Hepatitis B is caused by infection with the hepatitis B virus, abbreviated HBV. Persons with HBV infection have this virus circulating in their blood, much like hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Persons who become infected with HBV either recover from their infection in several months or they may remain chronically infected for most of their life. Persons with chronic HBV infection are at high risk of death from cirrhosis and liver cancer. In addition, they are likely to transmit their infection to other people. In the United States, 1.25 million persons are chronically infected with HBV.

Although HBV is a common infection, it often goes unnoticed. Only one-third of adults will have symptoms of hepatitis when they first become infected. More than 90 percent of young children who become infected will have no symptoms.

Chronic infection with HBV also often goes undetected for 20 to 40 years until the resulting liver disease makes the person ill. In essence, HBV is a silent, unnoticed killer destroying the liver or stimulating the development of liver cancer in someone who thinks they are completely well. The risk of chronic infection and death from cirrhosis and liver cancer is inversely related to the age when acutely infected. For children less than one year of age who become infected, 90 percent will remain chronically infected. A child less than 6 years of age who becomes infected has a 30 percent chance of remaining chronically infected. A teenager or adult who becomes infected with HBV has a 3 percent to 5 percent risk of chronic infection.

Persons who become chronically infected as adolescents or adults have a 15 percent chance of dying from liver disease. Persons who become chronically infected as young children or infants have a 25 percent chance of dying from hepatitis B-related cirrhosis or liver cancer. Thus, the youngest who are most likely to get a silent acute infection, if exposed, are also most vulnerable to silent chronic infection and death.

Prevention of chronic infection is of utmost importance because once a person is infected, there are few treatment options, and all are very expensive. Antiviral treatment with interferon or lamivudine is effective in approximately 40 percent of patients with chronic HBV liver disease, and not all infected persons are candidates for treatment. For persons with advanced liver disease, liver transplantation is an option. However, availability of organs is limited, and an organ recipient must remain on immunity suppressing drugs for the rest of his or her life and must take hepatitis B immune globulin to prevent reinfection of the liver and recurrence of severe chronic liver disease. The treatment of liver cancer is not very encouraging, with the average survival following diagnosis being less than one year. It is important to note that while the incidence of most cancers is declining in the United States, the rate of liver cancer has been increasing over the past 10 years.

Although most people do not have symptoms of HBV infection, blood tests can accurately identify persons with either a chronic or resolved infection. A number of studies were carried out prior to widespread use of hepatitis B vaccine in the United States to determine the burden or magnitude of this disease. National studies conducted by CDC have shown that 5 percent of Americans--12.5 million people--have been infected with HBV. In addition, these studies have shown that about 300,000 people have been infected with HBV each year for the two decades prior to 1990, and that the risk of infection is much higher among African-Americans than whites. These studies have shown that at least 25,000 children have been infected with HBV each year. These children acquire their infections in their households, as well as in the community. The virus is present in saliva and blood and is spread when these fluids come in contact with breaks in the skin or other body surfaces. Hepatitis B is approximately 100 times more contagious than HIV.

The importance of these childhood infections is illustrated in figure 1. Because infected children are at greatest risk of chronic infection, they contribute disproportionately to the number of persons with chronic HBV infection. Said another way, a large proportion of adults with chronic HBV infection got their infection as infants or children. If we do not prevent these childhood infections, especially the early childhood infections, we cannot effectively control hepatitis B liver disease in the United States.

It has been said that hepatitis B only affects certain groups of Americans, many of whom engage in activities that place them at risk. While there are high risk groups, many of the cases do not fit into these groups. Between 15 and 30 percent of cases in recent years, or about 45,000 to 90,000 newly infected persons annually, have no identified risk factors, and thus would not be preventable by programs targeted only to high risk groups.

Hepatitis B Vaccine

The hepatitis B virus was discovered in 1965, and by 1970 diagnostic tests were available for routine screening of blood donors to prevent this type of transfusion-transmitted hepatitis. The first vaccines to prevent hepatitis B were developed in the mid-1970's; clinical trials were conducted in the late 1970's that showed greater than 90 percent efficacy in preventing chronic infection; and hepatitis B vaccine was first licensed in the United States in late 1981.

Hepatitis B vaccine provides protection against infection with HBV by producing immunity or antibodies to the surface protein or outer coat of the virus. This outer coat is called hepatitis B surface antigen or HBsAg. The first vaccine was produced by purifying this surface protein from the plasma of chronically infected persons. Subsequently, this surface protein was produced in yeast by recombinant DNA technology. The vaccines used in the United States since about 1989 have only been produced by recombinant DNA technology. However, plasma-derived vaccines continue to be used widely throughout the world.

Hepatitis B vaccine provides greater than 90 percent protection to infants, children, and adults immunized before being exposed to the virus. The efficacy of plasma-derived and recombinant hepatitis B vaccine in preventing acute and chronic infection has been demonstrated in controlled clinical trials conducted with adults, children, and infants. In addition, a number of studies have examined various vaccination schedules and dosages and all have documented short-term vaccine safety.

Hepatitis B immunization has been ongoing in a number of childhood and adult populations in the United States and other countries since the vaccine was first licensed in 1981. CDC and others have conducted studies to evaluate both the effectiveness of hepatitis B immunization and the long-term protection provided by the initial 3-dose vaccine series. Infant immunization has been ongoing for 14 years among Alaska Natives, who have higher rates of HBV infection than found in much of the United States. Previous studies have shown that 8 percent to 13 percent of Alaska Native children were chronically infected with HBV, and Alaska Natives have had the highest rate of liver cancer in the United States. Since 1983, all Alaska Native infants have been routinely vaccinated with the available licensed hepatitis B vaccines, beginning at birth. In a study conducted in 1993, it was shown that among the children less than 11 years of age -- that is, children routinely vaccinated since 1983 -- none had chronic HBV infection.

Other studies conducted among American Samoan children, children in the Gambia and children in China have shown that routine hepatitis B immunization lowers the HBV infection rates by more than 90 percent. In addition, studies in Taiwan have shown that there has been a significant reduction in cases of liver cancer among children since the introduction of routine hepatitis B immunization over 10 years previously. These studies provide evidence that hepatitis B immunization will prevent liver cancer and chronic liver disease.

Concerns have been raised about how long protection will last. In other words, will vaccinated infants be protected when they are adolescents and adults? A number of follow-up studies have also shown that the initial 3-dose immunization series provides protection from HBV infection for years. These studies have followed more than 2,000 persons vaccinated either as infants, children, or adults, and the periods of follow-up have ranged from 5 to 15 years. All studies indicate that immunity is long-term and may be lifelong. While immunized people may lose antibody circulating in their blood, they still retain protection from chronic HBV infection because their immune cells remember that they were vaccinated -- we call this "immune memory." The immune cells of a person immunized with hepatitis B vaccine and who has lost antibodies in their blood will remember that they were immunized and rapidly make antibodies when they are exposed to HBV. In the case of hepatitis B, the long incubation period for HBV infection allows enough time for the immune system to mount a protective response.

Vaccine Recommendations

CDC vaccine recommendations are made through a careful, deliberative process involving advice and guidance from the Advisory Committee on Immunization Practices (ACIP). The ACIP is a Federally chartered advisory committee with the goals of providing to the Director, CDC, and the Secretary, Department of Health and Human Services (HHS), advice on decreasing disease through the use of vaccines and other biological products, and on improving the safety of their use.

The ACIP currently includes 12 voting members selected based on their infectious disease expertise, experience in the evaluation of vaccine performance and safety, and knowledge about the implementation of immunization programs. Members of ACIP come from academia, clinical practice and State and local health departments. In addition, ACIP meetings are attended by ex officio members who represent Federal agencies, liaison members who represent professional societies and groups implementing vaccination programs, and the general public. A list of the organizations that are liaison members of the ACIP is attached in Appendix 1. All ACIP meetings are open to the public. Agendas are published before each meeting in the Federal Register and time for public comment is included at each meeting. Vaccine manufacturers are represented at ACIP meetings by the liaison representative from the Pharmaceutical Research and Manufacturers of America. Manufacturer representatives may be invited to present data that are not yet published, for example, from recent clinical trials, and also can make statements during the public comment period.

Vaccine recommendations initially are drafted by a working group that includes ACIP members and ex officio and liaison representatives, assisted by CDC experts. Vaccine manufacturers may participate in this process because not yet published and proprietary data often are useful in developing appropriate recommendations. Draft recommendations are sent to all ACIP members for comment, discussed during multiple public meetings, finalized, and adopted by vote of ACIP members.

Federal advisory committee members are subject to Federal conflict of interest laws, which are modified to take into account the nature of their service. Since vaccine research is largely funded by vaccine manufacturers, some advisory committees inherently have members who may have potential financial conflicts of interest because members are chosen for service based on their expertise in the areas in which advice is sought by the government. Congress has recognized the need for service by these experts on Federal advisory committees, despite the potential for conflicts of interest, by providing under 18 U.S.C. 208(b)(3) for waivers of the conflict of interest prohibitions when "the need for the individual's services outweighs the potential for a conflict of interest created by the financial interest involved." CDC is sensitive to concerns about potential conflicts of interest. Therefore, rather than issuing blanket waivers to members of the ACIP, CDC has chosen to grant only limited waivers as follows: an ACIP member with a conflict of interest is granted a waiver to participate in all committee discussions, but only if the member (1) publicly discloses all relevant interests at the beginning of each ACIP meeting and (2) abstains on votes pertaining to entities with which the member has a financial interest. In this manner, the agency can fully utilize the expertise of the committee member, with the assurance that CDC, fellow committee members and the public are aware of each individual member's related financial interests and ultimately the formal recommendation of the committee is only made by members without any kind of financial conflict.

Upon being finalized by the ACIP, a vaccination recommendation is submitted to CDC for consideration. If the agency accepts the recommendations, the document is edited and published in the Morbidity and Mortality Weekly Report (MMWR) as an ACIP recommendation. As new data become available on the effectiveness of disease prevention or on adverse events, these also may be discussed and may lead to published updates or revisions of previous recommendations.

Hepatitis B Recommendation

Recognizing the severity of hepatitis B infection and the availability of a safe and effective vaccine, the first recommendations on hepatitis B vaccine by the US Public Health Service's Advisory Committee on Immunization Practices (ACIP) were published in June 1982. The available epidemiologic data at the time indicated that infections among adults contributed almost all of the disease burden in the United States. Groups for whom vaccination was recommended included health care workers and hospital staff, clients and staff of institutions for the developmentally disabled, hemodialysis patients, hemophiliacs, men who have sex with men, household and sex contacts of HBV carriers, injection drug users, and inmates of long-term correctional facilities. In addition, vaccination of Alaskan Eskimos was recommended along with postexposure immunization of infants born to women with chronic HBV infection.

Since 1982 a large amount of new information has become available on the epidemiology of HBV infection; HBV disease burden; hepatitis B vaccines; vaccine immunogenicity, schedules, doses and safety; long-term efficacy of immunization and hepatitis B immunization practices and strategies. As information has become available, presentations were made to the ACIP by staff from CDC, FDA, and other government agencies, non-government investigators, and vaccine manufacturers. Hepatitis B immunization issues were on the ACIP agenda on 20 occasions during the 40 meetings that were held from 1986 to 1999. As sufficient new information became available, hepatitis immunization recommendations were updated and revised.

Beginning in 1990 presentations were made to the ACIP describing the increase in incidence of hepatitis B that occurred during the early 1980's despite the availability of hepatitis B vaccine. Other data presented demonstrated that few adults at risk of infection were being vaccinated and that perinatal and early childhood infections contributed to a substantial proportion of the chronic hepatitis B disease burden in the United States. As part of the June 1990 recommendations, Protection Against Viral Hepatitis, the ACIP stated that "For vaccine to have an impact on the incidence of hepatitis B, a comprehensive strategy must be developed that will provide hepatitis B vaccine to persons before they engage in behaviors or occupations that place them at risk of infection." In addition, the ACIP stated that "As an alternative to high-risk group vaccination, universal vaccination of infants and adolescents needs to be examined as a possible strategy to control transmission of disease."

Such a comprehensive strategy was developed by the ACIP over the next year and published in November 1991, and subsequently was endorsed by the American Medical Association and the American College of Obstetricians and Gynecologists. At about the same time, the American Academy of Pediatrics, and the American Academy of Family Physicians developed and endorsed the same comprehensive hepatitis B immunization strategy. The objective of the strategy is to eliminate transmission of HBV infection. The components required to achieve this objective are (1) prevention of perinatal HBV infection by screening all pregnant women and providing postexposure immunization to at-risk infants of chronically infected mothers; (2) routine hepatitis B vaccination of infants as part of the childhood immunization schedule; (3) routine vaccination of adolescents; and (4) vaccination of adolescents and adults in groups at increased risk of infection.

Routine maternal screening to prevent perinatal HBV infection has been successfully implemented with greater than 85 percent of pregnant women being screened. Similarly, 84 percent of children born in 1996 have been fully vaccinated against hepatitis B, which is particularly important since young children are most at risk from chronic infections, complications, and death if exposed to the hepatitis B virus. Routine vaccination of adolescents has been widely accepted; however, we do not know what percent of teenagers have been immunized. High-risk adult immunization has only been effective among persons at occupational risk of HBV infection. It is estimated that over 70 percent of health care workers have been vaccinated, and almost all new health care workers are being immunized. In the mid-1980's it was estimated that 18,000 health care workers were infected each year with HBV. This has dropped to fewer than 1,000 today. Only limited success has been achieved in the immunization of high risk adolescents and adults in settings including public health clinics, correctional facilities, drug treatment centers, and physicians' offices.

The goal in the hepatitis B prevention program is to achieve high levels of immunization coverage to stop transmission within the United States. This will protect not only the children who are vaccinated, but children who cannot be protected by vaccination, such as children with leukemia who cannot mount adequate immune responses to the vaccine. A decision to vaccinate a child protects that child and the community. A decision not to vaccinate a child not only puts that child at risk for hepatitis B, but others in the community as well.

Information for Parents

In addition to any disclosure that may be required by State medical consent laws, all health care providers, both public and private, are required to provide parents/patients with vaccine information materials before administering particular vaccines. As required by the National Childhood Vaccine Injury Act of 1986, the Secretary, HHS must develop vaccine information materials for all vaccines covered by the National Vaccine Injury Compensation Program. This authority has been redelegated to the CDC. Vaccine Information Statements (VIS) are developed after notice to the public and a 60 day comment period, and in consultation with the HHS Advisory Commission on Childhood Vaccines, the Food and Drug Administration, and health care provider and parents' groups. VIS must include a concise description of the benefits and risks associated with a vaccine. Information is included on risks that have been scientifically established as published in the ACIP statement, the Institute of Medicine report on vaccine adverse events, and expert evaluation of the peer-reviewed medical literature. Alleged adverse events that have not been scientifically associated with a vaccine, as reviewed by the ACIP, are not included in the VIS.

Safety of hepatitis B vaccine

CDC is strongly committed to assuring the safety of the vaccination program. This is especially important because many vaccines are administered widely to children and are mandated by States for children entering school. Reflecting this commitment to safety, recent changes in the vaccination program to decrease the occurrence of adverse events have been made, such as recommendation of acellular pertussis vaccines to replace more reactive whole cell vaccines and use of inactivated polio vaccine to diminish use of oral polio vaccine which very rarely causes polio itself. Carefully considered recommendations by the ACIP, information on vaccine benefits and risks based on Vaccine Information Statements, and compensation for those injured by vaccines under the National Vaccine Injury Compensation Program are important components of a system where optimal disease prevention is achieved when vaccination rates in a community are high and where risks to the individual are minimized and, injuries, should they occur, are compensated.

Before licensure, vaccines are rigorously evaluated for possible adverse events. Because severe adverse events may occur rarely and the population included in pre-licensure studies is relatively limited, post-licensure safety evaluation of widely administered vaccines is important. Hepatitis B vaccines are among the safest vaccines we have. In pre-licensure studies, severe adverse events were not detected and local reactions were no greater in persons receiving hepatitis B vaccine than persons who received a placebo or another vaccine.

Since licensure, the safety of the vaccine has continued to be monitored. Several reviews have occurred and have not shown a scientific association between hepatitis B vaccination and severe neurological adverse events such as optic neuritis and Guillain-Barré syndrome. In addition, preliminary data from French and British studies have shown no significant association between hepatitis B vaccination and multiple sclerosis. On August 21, 1998, the National Multiple Sclerosis Society reported, "In the view of the medical advisory board of the National Multiple Sclerosis Society, there is no current evidence of a link between hepatitis B vaccination and MS." Similar conclusions were reached by the European Viral Hepatitis Prevention Board and the World Health Organization.

Allegations have been made that hepatitis B vaccination of infants causes Sudden Infant Death Syndrome (SIDS). Because almost 10 million doses of hepatitis B vaccine are administered to infants each year, some infants will die shortly after vaccination by coincidence alone. Available scientific data do not support any causal role of vaccination in the deaths. In fact, in 1992, the first full year after the hepatitis B vaccine was first recommended universally for infants, there were 4,800 SIDS deaths, and hepatitis B vaccination coverage was 8 percent. In contrast, as shown in figure 2, by 1996 when coverage had risen to 82 percent, the number of SIDS deaths had actually decreased to 3,000 deaths. These data are reassuring because if Hep B vaccine were a major cause of SIDS, we would have expected an increase in SIDS, not a decrease. SIDS deaths have continued to decrease as a result of the effort to change infant sleep position despite a marked increase in hepatitis B vaccination coverage.

Nevertheless, the CDC is committed to continuing the evaluation of the safety of hepatitis B vaccine in a careful, scientific fashion. Ongoing studies are investigating whether other alleged adverse events are associated with vaccination, including multiple sclerosis and other demyelinating diseases, diabetes mellitus, rheumatoid arthritis and other autoimmune disorders.

Case reports of adverse events following vaccination rarely provide a convincing link between the event and vaccination. While reports to the Vaccine Adverse Event Reporting System (VAERS), jointly managed by FDA and CDC, can provide valuable information regarding serious adverse events that may be associated with a vaccine and are useful for generating hypotheses, they only rarely can be used to determine whether a vaccine actually caused the adverse event. Moreover, case reports of serious adverse events obtained through VAERS often do not represent true consequences of vaccination -- they may be temporally linked but causally unrelated -- they may not represent the correct diagnosis and they may be duplicate reports. By chance alone, some patients who develop symptoms of illness, will do so within several days of receiving a vaccine. Or in some cases, a vaccine may lead to the earlier recognition of an illness without increasing the overall risk of that illness occurring. Because of the limitations of VAERS, other systems have been developed to evaluate whether vaccines are scientifically associated with an adverse event.

To determine the association between vaccination and a potential adverse event requires documenting that the event is more likely in someone who recently has received vaccine than in someone who has not. Because serious potential adverse events are uncommon, documenting a statistical association of an adverse event with vaccination requires a large population of vaccinated and unvaccinated persons. In 1990, CDC established the Vaccine Safety Datalink (VSD) which links computerized vaccination, hospitalization, and outpatient medical records for members of four large managed care organizations serving about 2 percent of the U.S. population. VSD evaluations include identifying the health outcome of interest (i.e., the potential adverse event), linking these data with vaccination records, and comparing the frequency of the health event in persons who recently were vaccinated with those who are unvaccinated or had been vaccinated at a different time. All analyses must carefully be controlled for other factors that may be associated with disease occurrence or with the likelihood of being vaccinated. Several ongoing studies using the VSD are investigating whether a link exists between potential adverse events and hepatitis B vaccination.

Conclusion

In summary, as my testimony has noted, hepatitis B causes approximately 4,000 to 5,000 deaths per year in the United States. If exposed to the virus, infants and young children are most at risk from chronic infections, complications, and death. Further, in most children, the virus is a silent killer. It destroys the liver or induces liver cancer often over 20 to 40 years or more. Fortunately, we have a safe and highly effective tool to prevent the transmission of this destructive and often deadly virus. We have a vaccine that provides long-term protection and prevents liver cancer. Both pre- and post-licensure reviews have shown that hepatitis B vaccines are among the safest vaccines we have.

Immunization of infants and children is supported by the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, the American Medical Association, the Infectious Diseases Society of America, the Hepatitis Foundation, the American Liver Foundation, and virtually all other medical authorities and their professional organizations.

Routine infant immunization is a proven strategy to prevent the transmission of serious infection and chronic liver disease. Only by achieving high vaccination rates, can we optimally protect all children and all communities. We would be remiss in our responsibilities as public health professionals, policy makers, and parents if we did not take all the steps necessary to control, eliminate, and hopefully, one day eradicate this virus.

APPENDIX I

Advisory Committee on Immunization Practices

Liaison Representatives

American Academy of Family Physicians

American Academy of Pediatrics

American Association of Health Plans

American College of Obstetricians and Gynecologists

American College of Physicians

American Hospital Association

American Medical Association

Association of Teachers of Preventive Medicine

Canadian National Advisory Committee on Immunization

Hospital Infection Control Practices Advisory Committee

Infectious Diseases Society of America

Mexico's Health Secretariat

National Medial Association

Pharmaceutical Research and Manufacturers of America