Progress in Hepatitis B: A 30-Year Journey Through Three Continents

Being asked to contribute a Master Perspective article in Hepatology is a great honor that I accepted with trepidation. In preparation for this article, I reviewed the previous ones and realized each tells a different story. I hope this article will illustrate how much progress we have made in our understanding of hepatitis B in the last 30 years. I also hope that my personal journey will inspire young readers to believe in their dreams and to strive towards their goals even when the path is tortuous and riddled with hurdles. I grew up in Hong Kong in a family where there had never been a physician. In fact, I was the first in my family to choose a science track in high school (we were forced to choose between science and humanity tracks at the end of 8th grade). My father cautioned that science is not for girls. When I got a “C” for my first physics test, I thought I should have listened to the old man. Fortunately, history did not repeat itself. After my “O Level” exam (an exam that kids from all schools take at the end of 11th grade), I applied to a boys' school with a reputation in science (a move from an all-girls' school strong in language and humanities) and was accepted as the only girl in a class of 31 boys. Being the odd person out, the boys were super nice and polite, and the teachers were so sympathetic that I ended up ranking top of the class 2 years in a row. When I announced that I would be applying for medical school at the end of 13th grade (college was an unnecessary waste of time), my father advised that nursing would be more appropriate for girls but he was delighted when I was accepted into medical school. The 5 years of medical school flew by quickly. After a year of internship, I was offered a lecturer position in the Department of Medicine, University of Hong Kong. There were very few faculty then and residents like myself were drafted to teach medical students (on top of all the clinical duties, there were no work-hour limits). Salaries were the same as other residents with no teaching duties but the perk was university sponsorship of overseas fellowship training. I fell in love with hepatology during my first rotation as a resident. Two people had a big influence on my decision to be a hepatologist. Dr. K.C. Lam1 was my attending and Dr. Rudi Schmid (Chief of Gastroenterology and Hepatology at University of California-San Francisco) was a visiting professor. Both were inspiring teachers who asked a lot of questions on rounds and made me think and want to know more. It is amazing how our lives are shaped by fate or chance encounter. As I mentioned earlier, the perk of taking on additional teaching duties as a resident was sponsorship of overseas fellowship training. Being a freebie made it easier for me to get into the best program. The Royal Free Hospital in London, headed by Dame Sheila Sherlock, was the mecca of hepatology at that time. My 2 years at the Royal Free were some of the best times in my life. The training and experience at the Royal Free provided solid foundations for my academic career. Just as important, if not more, I became a member of the Sherlock Hepatology Family (Fig. 1) and the Sherlock brand name was a major reason how I landed with a faculty position in the United States despite never having any training in the country. Hepatology was a fairly new specialty in the early 1980s (the Journal Hepatology was inaugurated in January 1981). Coming from Hong Kong, it was natural for me to choose hepatitis B as the research focus. Figuring out what topic to study was more difficult. I knew very little about hepatitis B (still don't know enough), had no research experience, and was not familiar with the research ongoing at that time. My first meeting with Professor Howard Thomas, my research mentor, did not go well. I was not able to articulate what topic I wanted to research on and how I would go about doing it. It took time, patience, and perseverance to prove that I was trainable. Hepatitis B in the early 1980s was fairly simple. Hepatitis B virus (HBV) had been established as a DNA virus that causes chronic hepatitis and cirrhosis but an etiological association with hepatocellular carcinoma (HCC) was still debated. Assays for HBV DNA were in its infancy. The assays used hybridization with limit of detection ∼1 million IU/mL. The results were usually scored from 0 to 4+. The natural history of chronic HBV infection was thought to comprise two distinct phases: hepatitis B e antigen (HBeAg)-positive when virus replication and liver inflammation are active and HBeAg-negative when virus replication ceases and liver inflammation subsides. Seroconversion from HBeAg to HBe antibody (anti-HBe) was thought to be an irreversible process. There was no approved treatment for hepatitis B. Although the tools were crude, the early 1980s was a golden era for HBV research. Molecular diagnostic tests were rapidly developing and there were few distractions. The latter changed by mid 1980s with the AIDS epidemic and the realization that it was caused by a virus. Because of the high rate of mortality and devastating complications affecting mainly young people, a lot of funding and resources were earmarked for human immunodeficiency virus (HIV) research and many HBV investigators defected. Of those who stayed, many left in the early 1990s when the elusive non-A, non-B hepatitis virus was found. One of my first projects at the Royal Free was to study the use of interferon (IFN) in the treatment of chronic hepatitis B. In 1976, Tom Merigan and his colleagues at Stanford reported promising results in a study of four patients treated with IFN.2 The IFN we used was produced by a human lymphoblastoid cell line (recombinant DNA technology was not available yet) and administered as an intravenous infusion in doses of up to 100 million units/m2. Because of the intensity of the adverse reactions, the infusion had to be administered by a physician (yours truly) who would stay by the patient's bedside for the next few hours in case a catastrophic reaction occurred. This early experience spurred the evaluation of lower, better-tolerated doses. In a study of six patients given daily (n = 2), alternate day (n = 1), or thrice weekly (n = 3) intramuscular injections of IFN at 7.5-10 million units/m2, we found that thrice weekly administration of IFN was as effective as daily injections in inhibiting HBV replication, were associated with fewer side effects, and could be continued for up to 3 months.3 The rationale for thrice weekly (Monday, Wednesday, and Friday) versus alternate day administration was simply a matter of convenience because alternate day would require working over the weekend. Until pegylated IFN became available, thrice weekly administration of IFN was the norm for hepatitis B. I have always wondered why no one questioned the irregular spacing. In hindsight, we would not be able to tell whether HBV DNA levels crept up during the weekend gap because the HBV DNA assay used was not sensitive enough to detect <2-3 log changes. An “n” of 3 would be considered grossly inadequate nowadays but the concept of “sample size” had not been introduced into clinical trial designs in the early 1980s and a schedule designed to make the life of a young fellow easy was adopted worldwide with no questions asked. Following on the heels of the success of IFN, I led a randomized trial comparing IFN to another antiviral: adenine arabinoside monophosphate (ARA-AMP), which had been shown to inhibit HBV replication by Jay Hoofnagle at the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) and Tom Merigan at Stanford.4, 5 The intention of our trial was to compare the safety and efficacy of 12 weeks of IFN versus 4 or 12 weeks of ARA-AMP; however, during the course of the trial some patients in the 12-week ARA-AMP group developed peripheral neuropathy and the duration of treatment had to be shortened.6 A similar trial at Stanford was terminated early because of similar adverse events. Seeing young otherwise healthy patients came back to the clinic limping in severe pain is a sight that I would never forget. I am pretty certain we did not mention neuropathy was a possible adverse event in the consent forms and were lucky none of the patients pursued legal action. This experience taught me to be very cautious in reviewing everything that is known about an experimental drug before agreeing to be an investigator in any clinical trial and to have my eyes and ears open for unexpected events. This trial did show a benefit of IFN and was one of the studies that laid the foundation for subsequent multicenter trials leading to approval of IFN as treatment for hepatitis B. I presented the results of this trial during my debut at The Liver Meeting in 1983. The meeting was held in the Hyatt Hotel in Chicago with fewer than 1,000 participants. After a slow start, I was quickly swarmed. My 2-year fellowship at the Royal Free resulted in a total of 23 papers and book chapters, the meager support (one-third of my salary in Hong Kong while living in an expensive city, London) from the University of Hong Kong no doubt boosted my productivity. It was a lot more fun and relaxing to stay late at work than to return to a 90-sq. ft. room that I called home. One of the most interesting papers was in collaboration with Stephanos Hadziyannis in Greece. Stephanos was a Sherlock fellow and had observed that some HBeAg-negative patients continued to have elevated alanine aminotransferase (ALT) levels in serum and active inflammation in liver biopsies. He also found a high percent of these patients had detectable HBV DNA in serum (despite the insensitivity of the assays at that time). Unfortunately, reviewers and editors were not convinced. After the paper was rejected several times, Stephanos turned to Howard Thomas for advice. Howard in turn asked me (a rookie) to salvage the paper. We decided to add a control group of British patients and to retest all samples with the Royal Free (branded) HBV DNA assay. The paper was accepted by Gut on first submission.7 Perhaps the editors and reviewers recognized the significance of the finding—one of the earliest descriptions of the clinical entity “HBeAg-negative chronic hepatitis.” As I was planning my trans-Atlantic trip to my first American Association for the Study of Liver Diseases (AASLD) meeting, I thought I should take the opportunity to visit some of the famous hepatologists and academic centers that I read so much about. Within 3 weeks I received return mail (this was before faxes and emails) from NIDDK, Massachusetts General Hospital, Mayo Clinic, Albert Einstein Medical Center, and Rockefeller University inviting me to visit and to present my research findings. There was no doubt the Sherlock brand to the In I to Hong Kong and was to everything I in The first I was a with we established a Hepatitis B and a and serum and I the hybridization assay for HBV to a of patients and the of an approved treatment for hepatitis B provided a golden opportunity to study the natural history of chronic hepatitis B. We the different of chronic HBV the of HBeAg and and and causes of of chronic hepatitis B. In one of the early we that young with chronic hepatitis B have despite high levels of HBV One of the reviewers that this clinical not in patients and the should these findings. As mentioned in his The for a when one the one to be that it would be with and be to by our I was that when are an entity it more to that and be of the and of in group made some of the most to our understanding of the natural history of chronic hepatitis B. Following the success of IFN in my we two randomized trials of IFN in and but only of and of results led some to that the in patients was and patients should not be considered for IFN Because IFN was the only available treatment at that time, I a to the I A at the patients in these two trials that most had and were in the This led to another trial in which patients with and those with were randomized to IFN with or The of to our young readers but this was the in the late 1980s when it was realized while HBV replication, of is by an and in some HBeAg The was that treatment be more effective if it was when there is a in by of a course of We that patients with elevated had to IFN than those with and their were on with that of that the of HBV to HBV and not for the we reported in our and had a benefit on an of not only to IFN but also to this none of our patients had liver and were observed in some studies that the concept of The of liver associated with of was first reported in the After several patients who of liver despite of their I a study on HBV in patients This was the first study on HBV and it was possible because the at the University of Hong Kong recognized the of the and the of the of HBV in patients years the case this be by of patients for HBV infection to of and in those with of HBV In I left Hong my and for the I was advised to take it easy I was to in to Professor in the was on back of some more colleagues I was advised to slow The that I had an academic when I was still in my the I have no family and had never had any training in the and took the first position that offered me a and a medical I had at several in the in the late 1980s but none of those out because I was not doing science research and had never and would never have a in or I was not the a and a medical were by my while thought the move was to many hepatologists that with the of and effective HBV hepatitis B would be and the of hepatitis B in the is so that that it would not be possible to any funding for hepatitis B would there be enough patients to my My first in the was in at Two people were in that of Gastroenterology and a medical who the and the late of and a provided for the of the hepatitis virus the of hepatology research rapidly to hepatitis only was there a in research and there was also an of hepatitis B It was to but my to hepatitis B research is Hepatitis B is a with many and important, hepatitis B and I have always a to that would the of hepatitis B I mentioned that one of my first was on “HBeAg-negative chronic hepatitis.” In working with Howard Thomas, found that patients with HBeAg-negative chronic hepatitis a of HBV with a in the of the HBV which HBeAg This the how HBV to and hepatitis B antigen despite not able to but it did not why HBeAg-negative chronic hepatitis was more in and One I on an article the of a in the as a for of the HBV After at one of the for an I a and realized that the back as a and while the when the at position is a as in the case of HBV and some of it when there is a at position as in the case of HBV A and some of It out that the of HBV in different of the is to the of its HBV and whether the is a or We this the same as I in who was working with in The 1990s was an of drug for The resources and in drug over to HBV which of the In I was asked to in a multicenter trial of which was shown to have HBV in After reviewing the I because some of the and me of When that caused and liver I was that the I from ARA-AMP me and my patients from to this in the was not as as I had but it took some to from a where I never had to any patients to a in the more than 100 papers before I to the my research but there were times when I had to prove myself Fortunately, there were more than After years in I accepted a position as the of Hepatology at the University of in had a strong but hepatology received very little most of my life in many I would not last more than The Hepatology from 5 to faculty with in of liver and many faculty and have investigators with and It been a lot of work and there have been many trials and but this been an and journey and I like a with to about my the it was shown that several for are and have In the and approved the first drug for This was an time. we were able to patients with hepatitis B with one a only were serum HBV DNA levels levels and liver In patients who presented with liver and some patients who were for liver to be the The about as a drug was quickly by the realization that drug quickly. the lives of many hepatitis B In most of the been by and which have to years approval of the first for hepatitis we have that clinical of of liver and and the for liver The of not only the for liver also the of hepatitis B liver In the late 1980s and early hepatitis B was considered a to liver because HBV in of patients and hepatitis B was associated with rapidly liver in mortality years of Although the of and his colleagues in that intravenous infusion of hepatitis B from the the of HBV and mortality from this was very expensive and in patients who were HBV DNA by hybridization at the of This changed so much in the last years that my in leading an multicenter study in early to the most to hepatitis B liver was when new and more sensitive HBV DNA assays became available during the course of the We ended up the of the randomized trials for a study which that when appropriate were administered before and liver and was available for HBV be of the and duration of hepatitis B of HBV and in have resulted in a in the of HBV infection as as a in the of chronic HBV infection in and in the however, the of chronic HBV infection in because of the of from The is known to be a In the case of hepatitis it is not a of of different and but also a of HBV at infection and and and on the natural history of HBV infection from studies in other not be applied in the because of in over the of HBV infection in the in the not to the In early with the that to treatment of HBeAg-negative chronic hepatitis from that of chronic to have for treatment of and HBeAg-negative chronic hepatitis B. In several were from the trials for HBeAg-negative chronic hepatitis because it was thought that HBV A and HBeAg-negative chronic hepatitis is in the As a physician who patients in the it was that these were these I led a study in to the of HBV and in the This study that A was present in of patients and B and in in of from other studies that of patients with chronic HBV infection in the are This study also that were present in and in of that HBeAg-negative chronic hepatitis was not a entity in the years I to the and was that hepatitis B will be it is as many as million living in the have chronic HBV and many questions natural and treatment of hepatitis B It was very that in established the Hepatitis B which and clinical in the and in The more than and with chronic HBV infection in the studies and clinical trials of The of the patients and of HBV from A to a opportunity to the of and on the of HBV infection that is not possible with studies in where most patients are of the same and only one or two HBV It been an honor and a to the from the are to and we these will our understanding of the and natural history of HBV infection not only in the but worldwide because of the were As the first and only physician in the this been a There were many the but also a lot of and the I have made many to many of the and many at of and collaboration on I got to know many in hepatology who have and me in my and made many who not research and but also life and I have also many and many of have the and have recognized to name a My is the of the Hepatology Family the and success of the kids who stay in an family during The Liver I have been to be recognized by my and to have received many a and an book The for a by the late from the Hepatitis B in and a from in a lot to be recognized by the that I am most with and to be other in hepatology I and After as at of in I was to be as in and will as in I to the and of leading the of our As a of the of the of hepatology and hepatitis B been an amazing the major in HBV progress and 2 how we have in the last As a of the on HBV for a I the opportunity to the of hepatitis B the last 30 there have been of investigators and funding from HBV to and then the of it is to a back to HBV and a from the and the to a for In I want to the Hepatology editors for the honor to contribute this in HBV progress and many people who have to the progress and who have me the could not be to There are a few people I my who girls be my who me I to work I was and my who the of taking of our me to my dreams I would not be where I am the and support from and in Hong Kong, the late Dame Sheila Sherlock in London, and Jay Hoofnagle in the