Over 90 percent of the ROC's people are exposed to hepatitis B during their lifetimes, but the disease poses special hazards for infants. If exposed in the first three years, most will become lifelong carriers of the virus and will have a high probability of dying of cirrhosis or liver cancer by the time they reach 50 to 60 years of age.
In response to the seriousness of the public health problem and to the discovery of a vaccine, the ROC launched an ambitious 10-year immunization program in July 1984. "During the first two years, we innoculated only the infants of hepatitis B carrier mothers," says Dr. C.H. Chuang, director of the Bureau of Disease Control (BODC) of the Department of Health. "Now the program includes all newborns. Next we will expand coverage to reach people in high risk professions—dentists, doctors, nurses, and blood bank workers." The effort will reduce the carrier rate on the island from 18 to 1 percent.
The ROC's medical statistics link hepatitis B with several fatal diseases. Cancer ranks as the number one killer and cirrhosis as number six. Of malignant tumors, liver cancer ranks first for men and third for women—and in Taiwan 80 percent of the victims of liver cancer and cirrhosis are hepatitis B carriers. In a sense, both maladies stem from carrier mothers in an earlier generation. In a recent study of 11 carriers with liver cancer, for example, eight had carrier mothers.
"The vaccine targets the virus, but in effect it is a vaccine against cancer," said Dr. Chen Ding-shinn, director of the Graduate Institute of Clinical Medicine at National Taiwan University Hospital. Results from two decades of research indicate that the risk of contracting liver cancer is 120 times higher for hepatitis B carriers than for the rest of the population. When compared with the highly publicized link between cigarette smoking and lung cancer—a factor of 20—the danger of chronic hepatitis B is clear.
If, for example, a nurse should prick her finger on a syringe of tainted blood, the first symptoms of hepatitis B—fever, fatigue, and mild chills—would not appear for about 90 days. The upper abdomen eventually becomes tender as the liver enlarges from the disease. Jaundice follows, and urine begins to discolor from bile pigments. Depending on her original physical condition, the bout with the virus could last from two to four weeks, or as long as six months. The only cure is bed rest and abstention from alcohol until liver tissues return to full functional capacity.
"People with healthy immune systems are relatively safe from hepatitis B," Chen says. "If infected, they produce antibodies to neutralize the virus and become immune for life. But those who have an insufficient response become carriers. The key point is the immune system, not the virus."
The immune system reacts in several steps when the hepatitis B virus enters the bloodstream. As soon as the host's heartbeat brings the virus to the liver, its dirty work begins. The virus evades the organ's defenses, penetrates the liver cells, then breaks into three fragments that scientists have labeled the surface, core, and e antigens. The virus pirates the metabolic machinery of the cells, forcing them to make new virus rather than performing their normal functions. As the liver cells die, these fragments of virus pulse throughout the body. To counter the infection, the immune system makes antibodies to match the three antigens. Later, when the disease passes and the antigens have been neutralized, the victim has an extra stock of antibodies to prevent future infection—at least this is what happens for three out of four people exposed to the virus on Taiwan. But the figures are misleading.
It is true, Chen says, that if 100 adults were injected with the virus nearly all would recover from the illness, with less than three percent becoming carriers. But if 100 newborn infants were injected, 85 to 95 percent would turn into carriers. No one yet knows why infants are so vulnerable, but researchers calculate that roughly 1.2 million of the 3 million hepatitis B carriers on Taiwan could trace their infection to their mothers.
Luckily, few babies are infected in the womb, for they are not exposed to blood contaminated with the virus until delivery. Researchers distinguish two types of carriers on the basis of blood tests. Pregnant women who test positive for the e antigen have 100 million times more virus in their blood than carriers of surface and core antigens, and their babies face an 86 to 96 percent of growing up as carriers, compared to 6 to 21 percent chance for the offspring of other carrier mothers. "That's a big dose of virus," said Dr. Chen, "even a single drop causes infection."
But prevention is possible because the virus needs three months to incubate. As a result, ROC health authorities are now racing against time to inoculate a whole generation of babies. To meet this goal, an island-wide program has been set in motion with firm guidelines. Within 24 hours of birth, infants born of highly infectious mothers receive hepatitis B immune globulin. This provides only temporary immunity, however, making it necessary for high-risk infants to be inoculated with the vaccine in their fifth and ninth weeks, and once more on their first birthday. These four shots are the foundation of the immunization program.
Even for the babies of uninfected mothers, speedy vaccination is critical. Young children cannot properly fight the hepatitis B virus until the age of three, when their immune systems catch up with those of adults. For toddlers, the home is a dangerous place. "Hepatitis B is a family disease," says the BODC's Chuang. "We don't know exactly how it is spread, but the evidence is strong that it is passed from one member of the family to another."
Hepatitis B is sometimes called the "Chinese disease" because of its high incidence in Chinese communities. In mainland China, 8 to 10 percent of the people north of the Yangtze River carry the virus, and in the south the rate is 15 to 20 percent. Overseas Chinese are prone to the disease as well. In Singapore, for example, 9 percent of the Chinese are carriers, compared to 3 to 5 percent for the Malays. It is symbolic, perhaps, that Sun Yat-sen, the father of modern China, died of liver cancer, a disease tied to the hepatitis B virus.
In the West, the spread of hepatitis B shows the same pattern as AIDS, striking drug users, male homosexuals, and medical professionals, while in Asia these vectors account for only a small part of the transmission of the disease. Researchers believe that breaking the link between mother and child will solve half of the problem, and education may well solve the other half. Newspapers, TV, and radio all warn the public of questionable practices such as sharing razors, toothbrushes, and chopsticks; they also recommend avoiding ear piercing, tattooing, and unnecessary injections.
The task of stamping out hepatitis B on Taiwan will require substantial funds and coordinated effort. More than 350,000 babies are born on the island each year, and although most families live in or near cities with up-to-date health care, many others still reside in remote mountain villages and in fishing hamlets along the coast. For the program to succeed, all expectant mothers must be screened for the virus, then be convinced to bring their infants in for all four shots. Besides the daunting obstacles in communication and public education about the necessity for all these arrangements, the government itself has another significant challenge—distributing at least 1.4 million doses of the vaccine in a single year.
The Immunization program began shortly after the hepatitis vaccine went on the market for the first time in 1981. "If we had waited to develop the vaccine ourselves, it would have delayed the program two or three years," Chen says, "We thought about the number of carriers that would be born during that time and eventually decided to start by importing the vaccine."
In 1983, a steering committee sent booklets introducing the immunization program to health personnel around the island, workers readied laboratories and clinics, and by the early months of 1984 the media were broadcasting the hazards of hepatitis B and giving information on details of the project. By July, babies began receiving their first free shots. Due to the high cost of imported vaccine, only the newborns of carrier mothers received vaccine during the first 15 months of the program. Roughly 70 percent of the pregnant women on Taiwan were screened for the virus in the first year. Of the 27,375 infants of highly infectious mothers, 21,178 were inoculated. Of these, only five babies suffered adverse reactions, none of them serious. By 1986, the program was expanded to include all newborns.
Costs for the continuing program dropped precipitously last year. Beginning in July, Lifeguard Pharmaceutical, a local biotech firm in the Hsinchu Science-based Industrial Park, began supplying inexpensive vaccine. It is now estimated that before the 10-year program ends in 1993, all residents on the island will have an opportunity to be vaccinated.
There has been little opposition to the ambitious program thus far. "In fact, consumers want the program expanded," Chuang says. "They want elementary and secondary school children vaccinated right away." One reason for popular support of the program is financial. The cost of injections for newborns is covered by central, county, and municipal government funds, while individuals in other age groups must pay NT$300 just over US$10) for each shot.
Chen has high praise for those officials who had the foresight to promote the immunization project. "It's not like building a highway which voters can see," he says. "To enjoy the results, one must wait 50 or 60 years. That's when liver cancer and cirrhosis will no longer appear on death certificates as a leading cause of death."
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Early Diagnosis
Liver cancer is a major threat to Taiwan's 3 million carriers of the hepatitis B virus. Only two decades ago, the disease was nearly always fatal. Patients came to complain of painful, distended bellies, the result of liver tumors sometimes as large as an orange. Few cases were operable, and most victims died within a few months. But today, through the efforts of specialists like Dr. Lee Chue-shue, who is perhaps National Taiwan University Hospital's leading liver surgeon, early detection has become the rule rather than the exception.
To detect tumors in the earliest stages of growth, Lee administers blood tests to all his patients once a year, and scrutinizes the samples for unusual proteins. Two-thirds of his patients' cancers are identified before the tumors grow much larger than a toy marble. When the test is positive, Lee uses ultrasound and CT exams to locate and measure the tumor. Within a few days the surgical staff has evaluated the data and decided whether or not to operate.
Leading liver surgeon Dr. Lee Chue-shue explains a point to interns.
Patients placed on the hospital's regular Monday or Friday morning operating schedule for this category of surgery face a set of refined procedures. By 9:00 a.m. the first patient is wheeled to the operating theater where two anesthetists, four surgeons and two nurses await his arrival. Lying face up on the table, he is anesthetized and attached to monitors that measure his vital signs, and final preparations are made for surgery.
After the incision is made, the skin and muscle are pulled away to expose the liver. It is an angry purple, and dealing with its puddling-like consistency is a challenge to surgeons. In the operating room, the team must still make a final decision about proceeding. They check for the telltale striations of cirrhosis, then place an ultrasound probe directly on the liver to remeasure the tumor. If everything agrees with the diagnosis, surgery follows with few complications. The whole procedure takes 90 to 120 minutes from initial incision to final stitch. Afterwards, the patient spends the afternoon in the recovery room before being transferred to his bed in the ward. That night the pain begins, gradually subsiding in a few days. In two weeks, the patient returns home.
Despite the seriousness of the surgery, only six out of 100 patients do not survive; the vast majority leave the hospital with a 50 percent chance of at least another five years of life. Surgery only removes the cancer, not the conditions that led to it. After the operation, cancer victims still face life with a liver ravished by five decades of viral infection. Relapses are common. To date, the only sure treatment for liver cancer is prevention. On Taiwan, that means inoculation against the hepatitis B virus.
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Reliable Vaccine
The key to any mass immunization program is a reliable and inexpensive source of vaccine. On Taiwan, that source is Lifeguard Pharmaceutical, a 10,000 square meter factory located in the Hsinchu Science-based Industrial Park. Established in August 1984, Lifeguard imported technology from Sanofi and Pasteur Vaccins of France to become the ROC's first biotech firm. Today, the plant's annual capacity of hepatitis B vaccine is four million doses, enough to supply one million people.
To make the vaccine, Lifeguard extract an inert fraction of the virus from carriers' blood. Thus, its first task was to enlist a pool of suitable plasma donors. "No one had done this before," says Pen-tui Lai, director and vice president. "In France, the U.S., and elsewhere, plasma is purchased from hospitals. In Taiwan, you can't do this. It is illegal to buy and sell infected blood." The company set up collection centers in Taipei, Kaohsiung, and Taichung, and eventually recruited 3,000 volunteers.
Meanwhile, in early 1985, seven prefabricated workshops arrived in Hsinchu from France. Ten months later, in November, construction was completed and work began on producing and testing vaccine. The plant ran batch L001, and sent a 43-liter stainless steel drum of the finished vaccine to New York's Laboratory for Experimental Medicine and Surgery in Primates. There it was injected into chimpanzees. L001 passed with flying colors. "In the past, we imported the vaccine," Lai said. "Now we can make it."
Sales began in July 1987. Influenced by the government groups that own a majority of its stock, Lifeguard must supply under-priced vaccine to satisfy the needs of the ROC's immunization program before it can export the product at market value. According to the Program for Appropriate Technology in Health, an international nonprofit organization based in Seattle, the demand for vaccine during the next five to ten years will hit an annual peak of 350 million doses as countries throughout the Third World establish their own immunization programs. Twelve companies around the world already market the vaccine and 20 more are setting up production facilities in order to penetrate the market. "And if we do our job well," says David T.W. Chang, deputy plant manager at Hsinchu, "we will all go out of business."