Fighting against viral hepatitis: Lessons from Taiwan

Authors

  • Ding-Shinn Chen

    Corresponding author
    1. Department of Internal Medicine, National Taiwan University College of Medicine, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
    • Section of Gastroenterology and Hepatology, Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan
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    • fax: 886-2-23317624


  • Potential conflict of interest: Dr. Chen is a consultant for, is on the speakers' bureau of, and received grants from Roche, GlaxoSmithKline, and Bristol-Myers Squibb, and Schering-Plough. He is a consultant for and is on the speakers' bureau of Novartis. He is also a consultant for Merck, Gilead, Chugai Pharmaceutical, and General Biologicals.

  • Supported by grants from Taiwan's National Science Council and Department of Health.

Abstract

Viral hepatitis and its sequelae are important health problems worldwide, including Taiwan. For the last 40 years, Taiwan's scientists and health care providers have worked hard to control these sequelae, and the results have been excellent. The author, Ding-Shinn Chen, had a key role in planning and establishing the control program in Taiwan, and participated in the endeavors from the very beginning. In this perspective, he describes how he became interested in research as a medical student, his encounters with hepatitis B and C, how he and his colleagues started early detection of hepatocellular carcinoma (HCC), how he helped Taiwan's government create and implement the Viral Hepatitis Control Program, and how the effectiveness of the program in the decrease of hepatitis B carriage and HCC was monitored. He also discusses how he pioneered the use of interferon-α plus ribavirin to treat chronic hepatitis C. Hepatitis B viral load as a risk factor for HCC and cirrhosis in hepatitis B surface antigen carriers is reviewed briefly, as is the prevention of sequelae by antiviral therapies. Finally, Dr. Chen discusses unresolved issues that must be addressed and predicts the changes of the patterns of liver disease in Taiwan beyond the mid-21st century, which is in part affected by the fight against viral hepatitis that was initiated in the early 1980s. Conclusion: Dr. Chen's perspective illustrates Taiwan's fight against viral hepatitis over the last 40 years. This experience can be shared by other countries in which the disease is equally prevalent. (HEPATOLOGY 2011;)

It is my great honor to contribute to the Master's Perspective series in HEPATOLOGY. I would like to thank Dr. Lindor for giving me this opportunity to describe my fight against viral hepatitis, extending to my views on the development of hepatology. I am fortunate to have encountered the discovery of Australia antigen as the biomarker of hepatitis B virus (HBV),1 the employment of recombinant DNA technology in producing hepatitis B surface antigen (HBsAg)2, 3 and interferon-α,4 and the application of molecular biology that led to the discovery of hepatitis C virus (HCV).5 The progress made enabled us to fight against viral hepatitis and its sequelae in Taiwan.6, 7

Abbreviations

CLD, chronic liver disease; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; NIH, National Institutes of Health; NTUCM, Natonal Taiwan University College of Medicine; NTUH, National Taiwan University Hospital; VHCP, Viral Hepatitis Control Program.

My Early Years

I entered National Taiwan University School of Medicine in 1961. In the third and fourth year of medical school, we studied basic medical science, and I realized the importance of research in the advancement of medicine. Without the pioneering work of our predecessors, it would not be possible for us to enjoy the knowledge we have today. I thought we should do the same by creating new knowledge for the benefit of future generations.

With this belief in mind, in 1965, my classmate Shin-Fu Hsu and I found a laboratory that accepted medical students to perform research. The laboratory was directed by Professor Kenneth S. S. Chang, an M.D. who had received research training abroad. Using a plaque-forming assay,8 we studied the antibody-forming cells (later called B cells) in two strains of mice, AKR/J and C57 BL/6J. We immunized the mice with sheep red blood cells and counted the number of hemolytic plaques in the agar plates containing a mixture of sheep red blood cells and mouse splenocytes in the presence of complement. We treated the mice with methotrexate, an anticancer and immunosuppressive drug, to explore whether there was a difference between the two strains of mice. At that time, the research infrastructure was poor. We had to prepare most reagents ourselves, including drawing blood from the sheep, taking blood from guinea pigs by cardiac puncture for complement, homogenizing mouse spleen to harvest splenocytes, making agar plates containing sheep red blood cells and mouse splenocytes at the right temperature, and so forth. It took us 2 years to complete the study. The work was published in the Journal of the Formosan Medical Association,9 the most prestigious medical journal in Taiwan. At that time, there was no computerized information system, and we had to spend long hours in the library to look into many volumes of Index Medicus to see whether our hypothesis had been studied before. The experience of performing research was enlightening and memorable for a young medical student like me. When I was Dean of National Taiwan University College of Medicine (NTUCM) from 2001 to 2007, I did all that I could to encourage students to perform research.

After the fifth year of medical school, we started our clinical training. The medical wards were full of patients with cirrhosis and hepatoma (hepatoma was the term used for hepatocellular carcinoma then). The diagnosis could only be made after overt symptoms appeared in the advanced stage. They died within 2-6 months.10 In surgical wards, splenectomy was commonly scheduled for patients with thrombocytopenia and leukopenia because of hypersplenism. Because of the lack of reliable imaging modalities for the liver, exploratory laparotomy was often used to diagnose hepatocellular carcinoma (HCC). However, due to the advanced stage of HCC and the coexisting cirrhosis, surgical resections could be performed in only a limited number of patients.11

It became obvious to me that chronic liver disease (CLD) and HCC were major diseases in Taiwan. In the meantime, I was depressed, because every day we watched patients die, and we could not do anything but inform the family or the patient of the grave prognosis. We were like judges announcing death sentences every day. This was not the purpose of my being a physician!

My Encounter with Hepatitis B

Around 1970, our understanding of CLD and HCC was limited. In 1965, Blumberg et al.12 (Fig. 1) found Australia antigen in leukemic sera, which was later proved to be a specific marker of HBV.1 When I was a third-year resident in 1972, in a journal meeting, I chose an article by Lander et al.13 for my presentation. This was my first encounter with HBV.

After I finished my training in general medicine, I decided to study liver diseases and entered the training program in the Division of Gastroenterology, National Taiwan University Hospital (NTUH). Professor Juei-Low Sung was Chairman of the Department and the Gastroenterology Division Chief. He became my mentor, and I worked with him for approximately 20 years until he retired in 1987. Dr. Sung is an excellent educator and researcher (Fig. 1). He is regarded as the father of hepatology and gastroenterology in Taiwan. In the late 1960s, Dr. Sung studied Australia antigen using micro-Ouchterlony double immunodiffusion and found a high prevalence in healthy people. However, the positivity rate in cirrhosis and HCC was not higher than that in healthy people.14 Because immunodiffusion assay was insensitive, Dr. Sung collaborated with Dr. Kusuya Nishioka of the National Cancer Center Research Institute, Tokyo, Japan (Fig. 1). With Nishioka's more sensitive immune adherence hemagglutination assay, 76% of Taiwanese patients with HCC were shown to be HBsAg-positive.15 Around the same time, Dr. Myron Tong collaborated with Dr. Kwang-Juei Lo of the Taipei Veterans General Hospital and detected HBsAg in 80% of HCC patients by testing 10-fold concentrated serum specimens.16 Both studies indicated a strong association of chronic HBV infection with HCC.

Figure 1.

Speakers of a symposium on liver disease commemorating the centennial anniversary of National Taiwan University Hospital, June 1995, Taipei, Taiwan. From left to right: Ding-Shinn Chen, Kusuya Nishioka, Baruch Blumberg, Kunio Okuda, Juei-Low Sung.

In the early 1970s, Dr. Yun-Fan Liaw and I joined Dr. Sung's research team. Because of the extremely limited space at NTUH, we had to take turns using a laboratory bench measuring about 3 feet in width! We not only discussed our research and clinical practice, but also chatted about trivial matters in our daily lives, and became close friends. Dr. Liaw has been devoted to studying chronic hepatitis since then. He moved to another hospital later and has made tremendous contributions. In 1975, Dr. Sung arranged for me to study in Dr. Nishioka's laboratory in Tokyo. I brought approximately 300 patient serum samples with me. Working with Dr. Teruaki Sekine, I learned passive hemagglutination assay for antibody to HBsAg, immune adherence hemagglutination and reversed passive hemagglutination for HBsAg, and serological subtyping of HBsAg. With these more sensitive assays, we demonstrated a high HBsAg-positivity rate in healthy people,17 CLD and HCC,18, 19 familial clustering of HBsAg,20, 21 and the importance of maternal HBV transmission in causing HCC.22 A geographical distribution of HBsAg subtypes implying the role of intrafamilial transmission was also documented.23

During my 4-month stay in Japan, I was struck by the strong work ethic of the Japanese investigators. The interactions among them were very good. I visited Dr. Toshio Shikata at the Department of Pathology, University of Tokyo. Dr. Shikata was famous for the Orcein staining of HBsAg in hepatocytes and the experimental HBV infection in chimpanzees. We discussed the pathology of liver diseases, and my 1-hour visit unexpectedly extended into the evening and ended in a Japanese restaurant. I returned to Taipei in April 1975. Perhaps affected by the Japanese work ethic, I lost 8 kg during my visit.

Despite the aforementioned findings, how HBV causes HCC was still unclear. In 1978, Dr. Robert H. Purcell, Head of Hepatitis Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), discussed with us collaborative research on the etiologic role of HBV in HCC. I went to Dr. Purcell's laboratory in 1979. I brought with me 8 pairs of liver specimens, each composed of a resected HCC and the nontumor counterpart. I was assigned to Dr. John Gerin's laboratory in Rockville, MD, and worked on DNA extraction, restriction enzyme digestion, and Southern blotting, among other procedures. When I had my biochemistry course in 1963, my knowledge of DNA, RNA, and proteins was limited, so I had to reinforce my knowledge intensively. We were able to demonstrate integration of HBV DNA into the host genomes of the HCC in our patients,24 confirming the observations in African patients.25, 26

My 1-year experience at the NIH was eye-opening. The NIH was the Mecca of modern medicine; lectures given by scientists from all over the world were always listed fully in the “yellow pages.” Everything was well-organized, and the resources seemed unlimited. Investigators there worked very hard. In addition to Drs. Purcell and Gerin, I met Drs. Stephen Feinstone, Harvey Alter, Jay Hoofnagle, James Shih, and Mario Rizzetto. The discussion and interactions among the investigators were stimulating and productive. I also met Professor Hans Popper, who came to the NIH once a month to study the pathology of woodchuck hepatitis. While awaiting his ride to the airport, he sometimes shared with me the small office booth in Dr. Purcell's laboratory. As the guru of hepatology, he was accessible and kind to his colleagues. I still recall what he said to me in his strong German accent: “Dr. Chen, I know very little about the hepatitis in woodchucks, and I am learning from these animals”; “Dr. Chen, I saw molecules through my microscope.” He was extremely knowledgable about the structure, function, and pathobiology of the liver, as well as molecular pathology. Dr. Popper had an unbelievably good memory. He even remembered my work on α-fetoprotein when we first met. I was greatly inspired after interacting with him.

My exposure to molecular biology had a great influence not only on my own research, but also biomedical research in Taiwan. Realizing the power of molecular biology, after I returned to Taiwan in 1980, I convinced Dr. Sung and NTUH to let me set up a molecular biology laboratory, and started to recruit investigators with training in molecular biology. Pei-Jer Chen, M.D., Ph.D., a young and talented physician scientist, was the first with this background to join us in 1986. Molecular biological studies then became common in our research.27-31 In 1985, after I became the Director of Graduate Institute of Clinical Medicine, NTUCM, I included molecular biology as the primary course for graduate students. After their graduation, molecular biological approaches spread in the research community in Taiwan.

Early Detection of Hepatocellular Carcinoma

In 1970s, studies in Taiwan have shown a strong association of chronic HBV infection with HCC.7, 15, 16, 18, 19, 22 Nevertheless, it would be more convincing if a prospective study could be done to show a higher risk of HCC in HBsAg carriers. Dr. Sung and I had planned for such a study. Unfortunately, the National Science Council, the major research funding agency in Taiwan, could not support our proposal because of the limited budget. At that time, Dr. R. Palmer Beasley and colleagues at the University of Washington, Seattle, WA, had already received support from the US National Cancer Institute and had initiated a prospective study in Taiwan, which later provided strong evidence that HBV is the most important risk factor of HCC.32 They recruited 22,707 middle-aged men, 3,454 of whom were HBsAg-positive, and analyzed the occurrence of HCC. The relative risk of HCC in HBsAg carriers was 223 compared with non-HBsAg carriers.32 During the study, they encountered some asymptomatic HBsAg carriers with mildly elevated serum α-fetoprotein levels, and referred them to medical centers including NTUH to see whether they had HCC. At that time, the available imaging modalities for the liver were radionuclide scan, celiac arteriography, and peritoneoscopy. None were sensitive enough to detect small lesions, and we could not reach a diagnosis when the patients visited us. Sadly, after follow-up, some of them ended up with advanced HCC. This was truly frustrating. Around 1980, computed tomography and abdominal ultrasonography became available at NTUH. Dr. Jin-Chuan Sheu, who had a strong interest in abdominal ultrasonography, joined us. With his and our radiologic colleagues' efforts, we were finally able to diagnose HCC at an earlier stage. We defined HCC by its size and designated a tumor of ≤3 cm in diameter as small HCC, and reported 13 such patients in 1982.33 The reason for using 3 cm as the criterion was simple: if we had chosen 2 cm as the cutoff, there would have only been 7 patients in our first series.33

After we could diagnose small HCC, Dr. Sheu studied its growth rate.34 Accordingly, we proposed screening asymptomatic HBsAg carriers, patients with chronic hepatitis, and those with cirrhosis at defined intervals with serum α-fetoprotein and abdominal ultrasonography.34, 35 The screening yielded many patients with small HCC. Because of the smaller tumor size and a better liver function, the resectable cases increased remarkably. Alternatively, some patients were treated by local injection of absolute ethanol under ultrasound guidance, and the results were promising.36 I again thought of a prospective study to compare surgical resection and local ethanol injection for the treatment of small HCC. Unfortunately, our surgeons were not enthusiastic about undertaking such a study. It took me more than 10 years to persuade them to participate in the study, and the results were finally published in 2005.37 Dr. Guan-Tarng Huang coordinated the study. After a mean follow-up of 3 years, the results showed that for the treatment of small HCC, local ethanol injection and surgical resection had comparable outcomes.37 Nevertheless, in both groups of patients, HCC recurred in approximately 10% per year. Something must be done to halt this recurrence.

During the study of small HCC, I was greatly encouraged by Professor Kunio Okuda (Fig. 1). Dr. Okuda was an outstanding hepatologist with great contributions to the diagnosis and management of hepatobiliary diseases, and was an authority in early diagnosis of HCC. He sent us offprints of his papers regularly, shared with us his views unstintedly, and gave excellent advice.

The Universal Hepatitis B Mass Vaccination Program in Infants

The painful experience in treating patients with CLD or HCC made many of us believe that prevention was the way to go. When effective vaccines against HBV became available in adults,38, 39 investigators immediately thought of immunizing newborns, because mother-to-infant transmission of HBV was known to result in chronic infection.20-22, 40 Beasley et al.41 and Lo et al.42 performed such studies in infants, showing that passive and active immunization were effective in interrupting perinatal HBV transmission.

Because the disease burden caused by HBV was so severe in Taiwan,15-23 for several years, Dr. Sung and many of us had kept on lobbying the Taiwanese government to control HBV infection. In 1981, the government finally endorsed a 5-year Viral Hepatitis Control Program (VHCP).43 Under the direction of Kwoh-Ting Li, Minister without Portfolio of Taiwan's Executive Yuan, the VHCP was set at the Cabinet level (Fig. 2). Briefly, the National Science Council took charge of research and development, and the Department of Health was responsible for public education and hepatitis B immunization. The VHCP turned out to be extremely successful, and continues to this day. Each stage may have a slightly different focus. For example, universal vaccination was the focus in the early stages of the VHCP. In 2002, treatment of chronic viral hepatitides was added to the aim. At the time of this writing, we are proposing elimination and eradication of viral hepatitis in Taiwan as the ultimate goal in the next stages.

Figure 2.

Administrative system of Taiwan's Viral Hepatitis Control Program established in 1981.

After 3 years of preparation, on July 1, 1984, we launched a mass vaccination program.44 The top priority was to immunize newborns. Because of the complexity of this program, in 1984 and 1985, we targeted at the newborns of hepatitis B carrier mothers. From 1986, it was extended to all newborns.44 The efficacy of the program was seen 18 months later: 85% of the infants born to HBsAg carrier mothers were protected from chronic HBV infection.45 Hsu-Mei Hsu of the Department of Health did a superb job, and the program was very well implemented. The coverage rate of vaccination in newborns was always >95%, and recently even reached 98%.

Effectiveness of Mass Hepatitis B Vaccination in the Decrease of HBsAg Carriage and Liver Disease

To evaluate the vaccination program, seroepidemiologic surveys were performed once every 5 years. The HBsAg carrier rate in the children of Taipei City decreased from 11% in 198446 to approximately 1% in 1989,47 1994,48 1999,49 and 2004.50 Results of the 2009 survey showed this figure to be 0.9%, and the decrease in the population has extended to adults 25 years of age (unpublished results). Similar results were also found in other places of Taiwan.51 In 2005, a study on 1,545 randomly sampled first graders of elementary schools found 12 HBsAg carriers (0.78%) only.52

Although HBsAg carriage has decreased, the most important issue is whether the diseases caused by HBV have decreased. After universal vaccination in newborns, the mortality rate of fulminant hepatitis in infants reduced from 5.36 per 100,000 infants to 1.71 per 100,000,53 and fulminant hepatitis B in children >1 year nearly disappeared.54 Nevertheless, fulminant hepatitis is far less common than cirrhosis and HCC, so we were more eager to know the effects of hepatitis B vaccination on these two diseases. Because both are sequelae of long-term HBV infection, it takes 50-60 years for them to manifest clinically55 (Fig. 3). Hence, we have to wait until 2035-2045 to see the effects on cirrhosis and HCC. Fortunately, we found a proxy that may disclose the results earlier. In Taiwanese children, HCC can be seen at a prevalence comparable to that of Wilms' tumor or neuroblastoma. In 1987, two studies showed that HBsAg was positive in 100% of childhood HCC in Taiwan.56, 57 Therefore, there is a chance that the effects of hepatitis B vaccination might be disclosed earlier by studying HCC in children. Dr. Mei-Hwei Chang, my pediatric team member, took this opportunity and made seminal discoveries. Ten years after the universal vaccination in infants, she analyzed the incidence of HCC in children 6-9 years of age, and found it was 0.52 per 100,000 children in those born before the vaccination program, and decreased to 0.13 per 100,000 in those born after the Program.58 Sixteen years after the vaccination program, the results again revealed the decline in 6- to 14-year-old children, from 0.54 to 0.20 per 100,000.59 Twenty years after universal vaccination, the decrease of HCC had extended to young adults.60 This is the first time that a human cancer was prevented by vaccination. I estimate that in the last 27 years in Taiwan, the program has prevented at least 700,000 HBV carriers, and this will avert 175,000 deaths from the sequelae caused by hepatitis B. For other parts of the world where hepatitis B is endemic, our experience provides an example showing that liver diseases caused by HBV can be controlled by mass vaccination. I strongly believe that vaccination is the key to the elimination and eradication of HBV.51, 61

Figure 3.

Natural history of chronic hepatitis B virus infection in Taiwan. AC, Active cirrhosis; CAH, Chronic active hepatitis; CPH, Chronic persistent hepatitis; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IC, Inactive cirrhosis; LH, Lobular hepatitis; NSRH, Nonspecific reactive hepatitis. **, Reactivation of HBV. (Modified from Chen.55)

The success of the VHCP can be attributed to the Taiwanese government's determination, a well-designed program, effective implementation, and appropriate assessment (Table 1). Other factors have also contributed to the success, including the fact that Taiwan is a small island country with a good public health delivery system and household registration, that its people are well-educated and understand the importance of vaccination, and so forth.

Table 1. Steps Taken in Taiwan's Effort to Control Hepatitis B
YearStep TakenFacts
Before 1965Identify problemsCLD, HCC are very common
1965-1972Find causes80%-90% of such patients are positive for HBsAg
  Half of chronic HBV infections are caused by mother-to-infant transmission; the rest are due to early infection (<2 years of age)
1975-1981Find solutionsImmunoprophylaxis can interrupt the transmission
1980-1983Form policyGovernment decides to control hepatitis B
1984Begin implementationMass immunization launched on July 1, 1984
1985Make assessmentSeroepidemiologic study every 5 years
  Surveillence of acute hepatitis B and HCC
  Identify problems that remain to be addressed
2003Begin treatmentTherapies for chronic hepatitis B reimbursed by National Insurance

Genotypes of HBV

In the early 1990s, Dr. Jia-Horng Kao joined our team and studied the quasispecies and other virological characteristics of HCV. One day in the summer of 1998, during a lunch break in the basement of NTUH, we discussed with Dr. Kao that in hepatitis C, genotypes of HCV are important in clinical and virological aspects—but what, then, of HBV? There were few studies. We decided to investigate HBV genotypes and their possible implications. After the genotypes in about 300 patients were studied, Dr. Kao found that in Taiwan genotype B was more common than genotype C, and HBV genotype C infection was associated with severe liver disease62 and a poor response to interferon-α therapy.63 That HBV genotype is important in determining natural course of HBV infection and treatment response is now widely accepted.

My Encounter with Hepatitis C

Around 1975, despite screening blood donors with HBsAg, posttransfusion hepatitis still occurred frequently, and the hepatitis did not belong to hepatitis A or hepatitis B. Non-A, non-B hepatitis was coined for this disorder.64 The etiologic agent was not found until 1989, when Choo and colleagues identified a fragment of complementary DNA derived from the parenterally transmitted non-A, non-B hepatitis virus5 and designated it HCV.65 We soon learned that HCV infection was also prevalent in Taiwan, and HCV was a common cause of CLD and HCC, second only to HBV.66 Led by Dr. Pei-Jer Chen, we also cloned and sequenced the whole genome of HCV.67 Based on these efforts, blood donors were screened with antibody to HCV in Taiwan beginning in 1992, and transfusion-transmitted hepatitis C has been effectively prevented thereafter.68

By 1990, the only treatment for chronic hepatitis C was interferon-α, and the effects were unsatisfactory.69 In early 1991, the Roche Far East representatives asked me to conduct a clinical trial of their interferon-α (Roferon) for the treatment of chronic hepatitis C. There were two arms in the protocol, one treatment group and a control group. After reviewing the protocol, I concluded the study would not generate anything new. It replicated what had already been done in other countries, and was merely a formality so that the company could apply for a license in Taiwan. I told the Roche representatives that, as a professor, I had to strive to pursue new knowledge, and I insisted on another arm with a novel treatment. Around that time, Reichard et al.70 reported transient decrease of serum aminotransferase activities during treatment of chronic hepatitis C with ribavirin. Because different kinds of drugs are frequently combined in anticancer and antimicrobial therapies, another arm with the combination of interferon-α and ribavirin was added in our study. Roche reluctantly agreed with me, and we started to enroll patients in 1991. I asked Dr. Ming-Yang Lai to handle this trial. It turned out that the combination therapy had a much better end-of-treatment response (combination therapy versus interferon monotherapy 76% versus 32%). Two years after cessation of the treatment, the responses were still better sustained in the combination therapy group (43% versus 6%).71 In the sustained responders, HCV RNA was not detected in serum, liver, or peripheral blood mononuclear cells. We therefore used “eradication” of chronic hepatitis C instead of “remission” in that paper.71 The beneficial results of this combination therapy were confirmed by others, and the regimen has since evolved into a standard-of-care treatment for chronic hepatitis C. Encouraged by the good results in chronic hepatitis C, we also tried the regimen for chronic hepatitis B. However, adding ribavirin did not increase the efficacy of interferon in this setting.72

In clinical practice, I found that a group of patients was being neglected: those who are infected simultaneously with both hepatitis B and C virus.73 Worldwide, the coinfection is estimated to be present in 7-20 million people,74 and there may be a quarter million in Taiwan. In clinical trials for the treatment of chronic hepatitis B, we excluded patients with HCV infection, and in clinical trials for hepatitis C, patients infected with HBV were excluded. Hence, the treatment modality for patients who have HBV/HCV coinfection was virtually unknown. To solve this issue, in 2000, we initiated an open trial by treating 24 HBV/HCV coinfected patients with regular interferon-α2a and ribavirin. The pilot study suggested that in the coinfected patients, interferon-α plus ribavirin could achieve a sustained clearance of HCV comparable with those infected with hepatitis C alone.75 We then proceeded to perform a multicenter randomized control trial with more patients by using pegylated interferon-α2a and ribavirin in 161 HBV/HCV coinfected patients compared with 160 HCV monoinfected patients. I asked Dr. Chun-Jen Liu to coordinate the study. With his and our collaborators' efforts, we concluded that combining peginterferon-α2a and ribavirin was equally effective in patients with chronic HBV/HCV coinfection and in patients with HCV monoinfection.76

Prevention of HCC by Antiviral Therapies

Because chronic HBV or HCV infection can cause HCC, when effective therapies for these infections became available, investigators were eager to know whether antiviral therapy could affect the occurrence of HCC. Because cirrhosis is the most dominant risk factor of HCC,35, 55 HBsAg-positive cirrhosis is an ideal target to explore. Dr. Yun-Fan Liaw led a randomized study showing that lamivudine could reduce the occurrence of HCC in HBsAg-positive patients with cirrhosis.77 I assigned Dr. Chia-Ze Lee from our team to join this important study.

For hepatitis C, because we used the combination of interferon and ribavirin as early as 1991,71 we were perhaps the first to learn that treatment of chronic hepatitis C with this combination therapy could decrease the occurrence of HCC. Dr. Ming-Yang Lai had analyzed our data and obtained the results in 2002 (Fig. 4). Regretfully, due to personal reasons, he did not manage to publish them. In 2006, Yu et al.78 from Kaohsiung Medical University proved it in a large series of patients.

Figure 4.

Cumulative incidence of hepatocellular carcinoma (HCC) among different groups of non-cirrhotic patients treated for chronic hepatitis C in National Taiwan University Hospital. The patients were enrolled from 1991. Left panel: Results of the four groups of patients. IFN mono: interferon-α monotherapy; Combine: Combination therapy with interferon-α plus ribavirin; Combine-IFN fail: Combination therapy in patients who failed previous interferon mono-therapy, Combine naïve: combination therapy in patients who were not treated before. Right panel: Results of interferon-α monotherapy (IFN mono) and those treated with combination therapy (two groups together, a: combine-IFN fail and b: naïve). Patients in the no-treatment group were informed of the effective therapy of interferon-α plus ribavirin when it became available, but they could not afford to receive the therapy because of the high cost. The therapy was finally reimbursed by Taiwan's National Health Insurance in 2003.

Risk Factors of Liver Diseases in HBsAg Carriers

Possibly enlightened by Dr. Palmer Beasley's earlier study of HBsAg carriers in Taiwan,32 Chien-Jen Chen, Sc.D., then at the Department of Public Health, NTUCM, undertook a community-based cohort study in Taiwan. In 1991-1992, they collected biological samples from 23,820 Taiwanese subjects (11,973 men and 11,847 women) from seven townships. Of them, 4,155 (2,445 men and 1,710 women) were HBsAg carriers. The long-term cohort study has revealed many key factors of chronic hepatitis B in causing HCC79-82 and cirrhosis.84

In the beginning, hepatitis B e antigen (HBeAg) was used to indicate the replication of HBV, and in 92,359 person-years of follow-up, the relative risk of HCC was 60.2 among HBsAg/HBeAg-positive men and 9.6 among those who were positive for HBsAg only.79 We measured serum HBV DNA in 120 HBsAg carriers of this study, and the level at recruitment was found to correlate with the risk of HCC. This finding was later confirmed in larger series.80, 81 There was a dose-response relationship to the occurrence of HCC, ranging from 108 per 100,000 person-years for levels of HBV DNA <300 copies/mL to 1,152 for those with levels of >106 copies/mL.81 Basal core promoter mutations (A1762 T/G 1764A) and HBV genotype C infections were also demonstrated to have an increased risk of HCC,80, 82 results that were consistent with our clinical observations.83 In addition, the cohort study also revealed the relationship between HBV viral load and the progression to cirrhosis. During a mean follow-up of 11 years, 365 of 3,582 chronic hepatitis B patients were newly diagnosed with cirrhosis. Serum HBV DNA level was the strongest predictor for progression to cirrhosis.84

Although these epidemiologic studies yielded excellent results, the underlying mechanisms and the host genetic factors remain to be investigated.

Other Hepatitis Viruses

My studies on hepatitis A and E are limited. Nevertheless, we have studied hepatitis D virus (HDV). HDV infection was present in <5% of HBsAg-positive patients with severe parenchymal liver disease and HCC in Taiwan.85 In HBsAg-positive intravenous drug users, despite the high anti-HDV prevalence (85%), only 4% had active HDV replication.86 Studies in HBsAg-positive intravenous drug users showed a steady decrease of HDV infection from 85% in 198687 to 39% in 1997.88 The decrease was attributed to active education programs in illicit drug users.89 We also elucidate the mechanisms of the assembly of HDV by showing the crucial role of large form of δ antigen in the assembly of HDV,90 and the sufficiency of small HBsAg in HDV packaging.91

After identification of HCV5 and hepatitis E virus,92 the fervor of finding new hepatitis viruses was intense around 1990. However, because the existing hepatitis viruses could already explain the etiology in >95% of CLD and HCC in our patients, I decided not to go with the fervor, but instead kept an eye on the development. In case a new agent is identified, we will immediately explore its role with our well-characterized specimens. Indeed, this happened in 1995, when Simons et al.93 identified new virus-like sequences (GB virus C) associated with non-A–E human hepatitis. In 1996, Linnen et al.94 claimed they found a new RNA virus, designated hepatitis G virus. Actually, these two viruses are identical. On our team, Dr. Jin-Town Wang examined the role of the virus with serum samples collected in our prospective studies for posttransfusion hepatitis and found that GB virus C or the so-called hepatitis G virus did not cause hepatitis.95 Similar stories happened with TT virus and SEN virus subsequently. All are passenger viruses.

The Future

Despite the progress that has been made over the last 40 years, the following unresolved issues remain.

Although current immunoprophylaxis can interrupt most mother-to-infant transmission of HBV, approximately 10% of cases will fail if the mother is highly infectious.59 At present, the infectivity is defined by HBeAg; however, this is inadequate. Better infectivity markers, such as serum HBV DNA, should be applied on a large scale. By way of analogy to the effective intervention of giving antivirals to pregnant women infected with human immunodeficiency virus,96 lowering the maternal hepatitis B viral load with antivirals may reduce perinatal HBV transmission. Indeed, some pilot studies have suggested this possibility.97 More studies are needed to justify the use of antivirals in this setting.

Currently, chronic hepatitis B is treated with interferon or direct antivirals. The former has a response rate of approximately 30%, and nucleos(t)ide analogs need to be taken for prolonged duration. More effective therapies are needed. Treatments targeting covalently closed circular HBV DNA should be investigated. Other innovative approaches are also needed. Although quite effective, for the treatment of chronic hepatitis C the combination of pegylated interferon and ribavirin has to be given for 6-12 months, and the treatment has unpleasant adverse effects. An effective treatment with less adverse reactions and shorter treatment duration will be greatly appreciated.

Hepatic fibrosis is the major cause of morbidity and mortality of CLD. The pathway and the genetic determinants related to mechanisms of hepatic fibrosis are being increasingly clarified.98 After these advances are translated into antifibrotic therapies, hepatic fibrosis and cirrhosis will hopefully be managed effectively and become reversible.

Recurrence of HCC after curative therapy is a serious challenge, and specific therapy to reduce the recurrence of HCC is desperately needed. In addition, because cirrhosis is the most dominant risk factor for HCC, chemoprevention to stop hepatocarcinogenesis in cirrhosis is also warranted.

After chronic hepatitis B and C are controlled, liver diseases associated with metabolic syndrome will become dominant, as has begun to happen in Japan.99 In Taiwan, I anticipate that nonalcoholic fatty liver disease, drug-induced liver injury, and several other biliary diseases will increase after the mid-21st century (Table 2).

Table 2. Prediction of Changes in Prevalence of Liver Disease in Taiwan After 2050
Less Common than in 20th CenturyMore Common than in 20th Century
Acute viral hepatitis (A–E)Drug-induced liver injury
Chronic viral hepatitis (B, C, D)Nonalcoholic fatty liver disease
Hepatic cirrhosis, HCCAlcoholic liver disease
 Metastatic malignancies of the liver
 Cholangiocarcinoma, bile duct cancers, gallbladder cancers
 Gall stones

Acknowledgements

I thank all my team members and collaborators, mentioned or not mentioned in this article, for their continued efforts and invaluable contribution. I am grateful to my close friends and colleagues at NTUCM and NTUH for stimulating interactions and warm encouragement, and to my family for their considerate understanding and unfailing support over the last 40 years.

Ancillary

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