Summer 1996 Volume 1, Number 2		Report from Rome: Special coverage of the IX Triennial International Symposium on Viral Hepatitis and Liver Disease (Rome) Thousands of hepatitis researchers gathered here from around the world for the ninth triennial conference on viral hepatitis. Conferees saw almost 1,500 presentations on subjects ranging from newly identified hepatitis viruses to success stories in the worldwide control of viral hepatitis. Here are the top disease control highlights: Hepatitis B control: success stories The big story from Rome was the tremendous success of hepatitis B control programs around the world. These programs have measurably reduced HBV infection, cut the prevalence of the hepatitis B carrier state, and, in a couple of early studies, decreased the incidence of hepatocellular carcinoma (HCC), the most serious sequela of chronic hepatitis B infection. Dr. D.S. Chen, from the Hepatitis Research Center in Taipei, Taiwan, fascinated conferees with his description of the Taiwanese hepatitis B control program. The program was launched in July 1984; universal vaccination of infants began in 1986. Prior to the program, Taiwan had a high hepatitis B carrier rate - about 7-10%. Dr. Chen and his colleagues recently evaluated their program using several methods. In one, they conducted random blood drawings of 3,000-4,000 children. In the 6-year-old cohort, the hepatitis B surface antigen (HBsAg) prevalence rate decreased from 10% for those born in 1983, to 0.7% for those born in 1987. In a second study done near Taipei city, researchers conducted follow-up serologic studies 5 and 10 years after the vaccination began. HBsAg prevalence decreased from 9.8% before the vaccination program began, to 4.8% in 1989, to 1.3% in 1994. Dr. Chen said it would take 50 years to see the full impact of the program on HCC rates, because the average age of Taiwanese HBsAg seropositive HCC patients is 55-60 years. But, he said, it is not too early to measure the program's effect on the HCC rate in young children. The annual incidence of hepatocellular carcinoma in Taiwanese children ages 6-14 has fallen from 4.5-7.1 per 100,000 children in 1981-91, to 1.7 per 100,000 in 1992 and 2.4 per 100,000 in 1993. Dr. Chen closed his talk by telling the entranced audience, only half jokingly, that the success of the Taiwan program means that "in the year 2040 or so, Taiwan oncologists will lose their jobs." Mainland China has long been recognized as an area of hyperendemic hepatitis B infection. Dr. Z.Y. Xu, of Shanghai Medical University, described the extraordinary progress in control of hepatitis B there. The Chinese program uses its own serum-derived vaccine, which is manufactured in six Chinese plants in huge quantities (75 million doses in 1995). In 1996, two more plants will open to produce recombinant vaccine using Merck technology. The Chinese vaccination program, begun in 1986, uses two alternate strategies: low dose vaccination of all newborns without serologic pre-screening of pregnant women, or high dose vaccination of infants born to HBsAg-seropositive mothers after maternal screening. Coverage rates are 98-100%. In areas using the first strategy, HBsAg carriage rates among children ages 0-9 have decreased from 16.3% to 1-2%. In areas using the second strategy, rates in the same age group have dropped from 8.8% to 0.4-0.5%. Dr. Xu said that "universal infant immunization may reduce the carrier state in the Chinese population to about 1% and lower in just one generation." In a related study of long-term vaccine efficacy, Dr. Xu told the conference that anti-HBs seroprevalence in vaccinees dropped from 96% to 68% in the ninth year after vaccination. But there was no accompanying increase in the HBV carrier rate. Furthermore, a small booster dose of only 2.5 micrograms caused rapid seroconversion in 80.8% of children who had lost antibody, indicating a strong immune memory-based response to exposure. He concluded that boosters are unnecessary so far. Dr. T. A. Ruff summarized the hepatitis B control situation in other Asian countries. HB vaccine is integrated into the WHO Expanded Programme on Immunization (EPI) schedule in all but 2 of 36 Western Pacific WHO countries. Some countries already have evidence of success. In Malaysia and Singapore, for example, HBsAg carrier rates have dropped from about 10% to 1-2% in just 3-5 years. In other countries, such as Cambodia and Indonesia, programs are only partly implemented. In the Americas, tremendous progress has been made in Alaska, where HBV infection was hyperendemic in the pre-vaccine era. A prevention program was started in 1983, which included screening of all Alaskan Natives for HBV seromarkers followed by vaccination of susceptibles, routine vaccination of all newborns, and screening of all HBV carriers with alpha-fetoprotein to detect hepatocellular carcinoma at a potentially treatable stage. Dr. Brian McMahon, from the Arctic Investigations Program, CDC, told the conference that about 52,000 Alaskan Natives have been screened and over 60,000 have been vaccinated. In the highest prevalence area of Alaska, the incidence of acute hepatitis B has fallen from 200 per 100,000 per year to zero. Dr. McMahon told conferees that "we have created a generation of hepatitis B-free individuals." In the Alaska program, none of the 60,000 persons who received HBV vaccine since 1981 has had icteric hepatitis B or become a carrier, although a few recipients have converted from negative to positive anti-HB core antibody. Dr. McMahon interprets this to mean that the protection afforded by HBV vaccine lasts at least ten years. In a poster presentation, F. Hofmann and colleagues from Freiburg, Germany cited success in reducing the prevalence of HBV seromarkers in hospital workers (Changes in HBV-prevalence due to hepatitis B vaccination: Results of three prevalence studies in 1984/85, 1989/90 and 1994/95. F Hofmann, HM Hasselhorn, N Krall, M Michaels, H Berthold). In another poster, RPB Larke and colleagues from Alberta, Canada reviewed their success in screening prenatal women for HBV and delivering vaccine to newborns. In Alberta, of 685 infants born to HBsAg-seropositive mothers, 95.5% have been given HBIG and 3 doses of vaccine. In 1994, the group was unable to find a single HBsAg-seropositive infant born to a carrier mother (A decade of success for Canada's earliest province-wide program to prevent mother-to-infant transmission of HBV infection. RPB Larke, JR Waters, JS Pagnucco). In the U.S.: Why the ACIP draft guidelines on hepatitis A do not recommend routine vaccination for health care workers The recent draft guidelines of the Advisory Committee on Immunization Practices on prevention of hepatitis A (see related story "ACIP HAV recommendations still in press") do not recommend routine hepatitis A vaccination for health care workers. At a plenary session, Dr. Eric Mast, of the CDC Hepatitis Branch, explained the Committee's reasoning and explored the issue of nosocomial hepatitis A. Dr. Mast said that the operative question for the ACIP drafters was: are health care workers at increased risk for hepatitis A? Before writing the guidelines, CDC epidemiologists reviewed two sources of data: outbreak reports and seroprevalence studies. At least 20 outbreaks have been recorded in hospitals - in neonatal intensive care units (attributable to transfusion of HAV-contaminated blood), or on the wards. The attack rate has ranged from 2 to 15%. Outbreaks on the wards have been traced to source patients unwittingly hospitalized during the disease's prodrome, when virus is present in stool, or to source patients with diarrhea or incontinence. The drafters also reviewed seven studies of anti-HAV prevalence in health care workers. Prevalence varied from 11% to 72%, but no study demonstrated a higher risk of infection for health care workers over controls. In the 1989 NHANES III population-based seroprevalence survey, health care workers had an anti-HAV prevalence of 46.2%; non-health care workers had a prevalence of 47.7%. The drafters concluded that the risk of HAV infection in health care workers is low and that routine vaccination of health care workers is not warranted. Handwashing and barrier precautions are still the best modes of defense. In a question-and-answer period after the presentation, the discussion turned to universal hepatitis A vaccination in the U.S. CDC staff and other experts have advocated universal vaccination as the best ultimate strategy, but obstacles remain - the need for better immunogenicity data in infants under two years old, and the need for combination vaccines in order to reduce the number of needle sticks received by children. Dr. Mast also stressed the need for good cost-effectiveness studies. Until these obstacles can be overcome, ACIP has adopted an interim strategy of vaccinating high-risk groups. A member of the audience pointed out that vaccination of high-risk groups was not a successful strategy for hepatitis B, and it was not likely to be successful for hepatitis A. A lively debate ensued as the audience and panelists exchanged views about the role that cost-effectiveness analysis should play in the decision to universally vaccinate. Some argued that limited national resources for prevention make cost-effectiveness analyses a necessity. Others said that the U.S. should adopt a bold position and not wait for cost-effectiveness analyses, pointing out that the medical profession often adopts technologies that are not cost-saving. HAV seroprevalence is falling worldwide Hepatitis A transmission is undergoing a fundamental shift around the globe, especially in rapidly developing countries, according to several presentations at the meeting. In one presentation, Dr. G. J. Papaevangelou, from the University of Athens, Greece, showed data illustrating the dramatic fall in anti-HAV prevalence in Athens. From 1977 to 1992, the prevalence fell from 30% to 2% in the 5-9 age group, from 63.2% to 4.8% in the 10-18 age group, and from 69% to 13% in the 19-22 age group. Similarly, in Saudi Arabia, a recent serosurvey in children showed that, from 1985 to 1995, the seroprevalence fell from 38% to 14.6% in the 1-5 age group, from 61% to 32% in the 6-10 age group, and from 81% to 48% in the 11-15 age group. The authors attributed these decreases to improvements in health standards and general hygiene (Serosurvey of hepatitis A antibody among Saudi children. M Khali, Y Al Mazrou, Al Howasi M, Al Jeffri). Similar declines were shown in presentations from several cities in Italy and in Rio de Janeiro. These findings agree with trends reported elsewhere. For example, the Viral Hepatitis Prevention Board, based in Antwerp, noted in 1994 that "improvements in standards of hygiene and sanitation worldwide during the last 20 years - as well as a reduction in family size in developed countries - are responsible for reducing the circulating levels of HAV and the emergence of a growing population of non-immune subjects. This causes an epidemiological shift of HAV prevalence to older age groups" (Viral Hepatitis, VHPB, 1994). This shift has occurred in several European countries and in Asia. As HAV infection is delayed to adulthood in these countries, the number of clinical hepatitis A cases may increase. Paradoxically, while the overall burden of infection decreases, the incidence of symptomatic disease may increase. HAV economics: vaccination in community-wide outbreaks In a later poster session, Dr. Mast and his CDC colleagues showed a cost- effectiveness analysis for the use of hepatitis A vaccine in controlling community wide outbreaks. The study evaluated the use of routine vaccination of 2-year-olds and catch-up vaccination of 3-12 year-olds in a hypothetical U.S. community of 20,000 people experiencing an annual hepatitis A incidence rate of 150 per 100,000 over 10 years. It assumed 85% coverage for routine vaccination and 50% for catch-up, a case-fatality rate of 0.1%, and a 75% reduction in disease attributable to the vaccination program. Additionally, it assumed a vaccine cost of $11 per dose (3 dose series), administration costs of $5 per dose, medical and work loss costs of $4,160 for a hospitalized case and $1,400 for a non-hospitalized case, and a death-associated cost of $780,000. All costs were discounted at 5% per year. From the societal perspective, the model showed cost savings of $362 for every case prevented or $22,000 per year of life saved. The vaccination program would be cost saving in the hypothetical community for disease rates of more than 112 per 100,000. If the vaccine's cost were reduced by 50%, the program would be cost-saving for rates of more than 80 per 100,000 (An economic analysis of the use of hepatitis A vaccine to control communitywide epidemics. C Shapiro, E Mast, B Bell, P Coleman, A Haddix, H Margolis). U.S. trends in hepatitis C Linda Moyer and colleagues from CDC reported on a review of acute hepatitis C cases in the CDC Sentinel County Study (a high-intensity surveillance system in four U.S. counties). The trend in incidence is down - acute HC rates dropped by 63% from 1983-89 to 1990-94, from 8 per 100,000 to 3 per 100,000. Cases are getting older, too. In 1983-89, the highest incidence was in the 15-29 age group. By 1990-94 the highest rate had shifted to the 30-44 age group. The number of HC reports associated with blood transfusions or intravenous drug abuse has been decreasing. Only 4% of case reports are now associated with blood transfusions. The number of cases associated with intravenous drug abuse has dropped 80% since 1989, although it still accounts for 25-38% of cases. The authors conclude that most of the decrease in acute HC incidence in the Sentinel Counties is due to a decrease in drug abuse-associated cases (Recent trends in the epidemiology of acute hepatitis C in the United States. L Moyer, M Alter, H Margolis, and the Sentinel Counties Viral Hepatitis Study Group).