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Joining East and West: Coordinating HBV Management Between Western and Traditional Asian Medicine Practices Hello. I am Dr. Tram Tran, Associate Professor.

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Presentation on theme: "Joining East and West: Coordinating HBV Management Between Western and Traditional Asian Medicine Practices Hello. I am Dr. Tram Tran, Associate Professor."— Presentation transcript:

1 Joining East and West: Coordinating HBV Management Between Western and Traditional Asian Medicine Practices Hello. I am Dr. Tram Tran, Associate Professor of Medicine and Medical Director of Liver Transplantation at Cedars-Sinai Medical Center. I’d like to join you today in terms of talking about East and West, coordinating hepatitis B management between Western and traditional Asian medicine practices. This program is supported by an educational grant from

2 About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options ( Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3 Faculty David D. Liu, PhD, LAc, OMD Dean, Professor, Academic Advisor Departments of Acupuncture and Internal Medicine Academy of Chinese Culture and Health Sciences Oakland, California Director, Supervisor Departments of Acupuncture and Internal Medicine Chinese Medicine Clinic and Education Center San Francisco, California Tram T. Tran, MD Associate Professor of Medicine Geffen UCLA School of Medicine Division of Gastroenterology Medical Director of Liver Transplant Comprehensive Transplant Center Cedars Sinai Medical Center Los Angeles, California I am joined by Dr. David Liu, OMD, PhD, who is the Director of Chinese Medicine Clinic and Education Center in San Francisco, California, and a Professor at the Academy of Chinese Culture and Health Sciences, Oakland, California, to discuss traditional medicines.

4 Faculty Disclosures David D. Liu, PhD, LAc, OMD, has no significant financial relationships to disclose. Tram T. Tran, MD, has disclosed that she has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, and Vertex and contracted research support from Bristol- Myers Squibb.

5 HBV Epidemiology, Natural History, and Screening Recommendations
Tram T. Tran, MD So, first let’s talk about hepatitis B epidemiology, the natural history and the current screening recommendations.

6 IOM Report: Burden of HBV Disease
15% to 25% risk of early death caused by liver cancer or end-stage liver disease among patients with chronic HBV infection[1-3] WHO global HBV estimates[3] ~ 2 billion people infected with HBV ~ 350 million people living with chronic HBV infection ~ 600,000 deaths annually caused by HBV-related liver disease or HCC So, in 2010, the Institute of Medicine issued a report about the burden of hepatitis B disease, and they note 15% to 25% risk of early death by liver cancer or end-stage liver disease amongst patients who have chronic hepatitis B. So, that’s a very high number in terms of our overall world population, and the World Health Organization looked at the global health impact of hepatitis B, in that 2 billion people are infected with hep B, 350 million people live with chronic hepatitis B, and 600,000 deaths per year are caused by hepatitis B–related disease or liver cancer, as noted above. So, these are quite impactful numbers—really big numbers that we’re talking about and quite a global problem. 1. IOM. Hepatitis and liver cancer: a national strategy for prevention and control of Hepatitis B and C. Washington, DC: The National Academies Press; p Beasley R, et al. In: Hollinger FB, et al, eds. Proceedings of the 1990 international symposium on Viral Hepatitis and Liver Disease: Contemporary Issues and Future Prospects. Williams & Wilkins; WHO. Hepatitis B fact sheet N˚204.

7 Estimated Prevalence of HBsAg-Positive Persons in the US by Population Segment
Population Group HBsAg Prevalence, % US-born API[1] 1.40 Foreign-born API[1] 8.90 Non-Asian Americans*[1] 0.42 *Non-Asian Americans includes blacks, whites, and other ethnicities. Prevalence reflects patterns of HBV infection in regions of origin Potential for immigration from highly endemic countries to ↑ US HBV prevalence despite ↓ incidence of new infections Age-adjusted prevalence of anti-HBc and HBsAg in the US statistically similar during vs [2] ~ 40,000 persons with chronic HBV infection immigrate to US each yr[3] When we look at the estimated prevalence of surface antigen positivity in persons in the US by population, you can see here that your overall chronic hepatitis B prevalence is 1.4% if you were born in the US but you are an Asian-Pacific Islander. If, however, you were foreign born—born in another country, Asian-Pacific Islander—and immigrated here, the chronic hepatitis B prevalence is 8.9%, so that would be your answer of 9%. Non-Asian Americans, born here, the overall hepatitis B prevalence is pretty low at 0.42%. So, this prevalence definitely reflects patterns of hepatitis B infection in different regions of origin, so the country you come from is very important, and certainly the potential for immigration from highly endemic areas to the US increases the hepatitis B prevalence here, despite an overall decrease in incidence of new infection, so it’s not like hepatitis B is happening at a high rate in new patients here in the US; it’s because we’re getting a lot of immigration from highly endemic countries. 1. Cohen C, et al. J Viral Hepat. 2008;15: Wasley A, et al. J Infect Dis. 2010;202: Mast EE, et al. MMWR Recomm Rep. 2006;55(RR-16):1-33.

8 Impact of Immigration on HBV Prevalence in the US
Immigration Numbers by Continent: [1] ~ 3.9 million Asians ~ 1.2 million Europeans ~ 924,000 South Americans The impact of this immigration can be seen in this global map, which shows the impact of immigration in the US from You can see that 3.9 million Asians have immigrated, 1.2 million Europeans, 900,000 Africans—especially sub-Saharan Africa has very high prevalence rates—and over 900,000 South Americans. And if you see from the world map the areas that are in orange, those areas are considered high surface antigen prevalence of ≥ 8%, and you can see from the numbers that immigration from these countries is very high. HBsAg Prevalence[2] ≥ 8% (high) ~ 907,000 Africans 2% to 7% (intermediate) < 2% (low) 1. US Department of Homeland Security. Yearbook of immigration statistics: 2011. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. 8

9 Growth and Diversity of US Asian Population
Asian American population: 4.8% of the US population (14.7 million)[1] 1990 census: 2.9% total US population[2] 2000 census: 3.6% total US population[1,2] 43% growth since 2000[1] Projection for 2050: > 40 million (9.7% total population)[3] Extremely diverse 52 different countries[3] 100 languages and dialects[3] Religious, cultural, societal differences Immigrated in different eras The Asian US population is growing significantly, so the Asian American population is 4.8% of the US population, 14.7 million. In 1990, the census showed that the US Asian population was 2.9% of the total US population. In 2000, 10 years later, it was 3.6% and by 2050, it’s going to be estimated at a projection of 40 million. So, you can see here that the Asian population is growing significantly in the US, but we have to understand that the Asian population, when we refer to it, is extremely diverse. There are 52 different Asian countries, 100 or more languages and dialects, and all of these different countries and societies have different religious, cultural and societal differences, so we have to really be careful about lumping all Asian Americans together in terms of the cultural differences that we may see impact our clinical practices. 1. US Census Bureau. The Asian population: Issued March US Census Bureau. The Asian population: Issued February President’s Advisory Commission on Asian Americans and Pacific Islanders. Facts and data: critical issues facing Asian Americans and Pacific Islanders.

10 API Americans and Chronic Hepatitis B
Among API Americans, HBV transmission occurs most often at birth or in early childhood[1,2] Each yr, ~ 20,000 HBV-infected women give birth in the US[2] More than one half of these mothers are APIs Americans One of the most common forms of transmission, especially worldwide and in Asia, is perinatal hepatitis B transmission from mother to child. So, because she was born to a Chinese mother, even if she had been born in the United States, she should be screened for hepatitis B. Asian-Pacific Islander Americans and chronic hepatitis B—in general, transmission occurs most often at birth or in early childhood, so again, that maternal–fetal, or mother-to-child, transmission is very common. Each year, 20,000 hepatitis B–infected women give birth in the United States and 50% of these mothers are Asian-Pacific Islanders, so very high rates of potential transmission. We need to be diligent about the vaccinations, and we need to be aware that transmission occurs via this route. 1. Asian Liver Center, Stanford School of Medicine Physician’s guide to hepatitis B: a silent killer. 2. Asian Liver Center, Stanford School of Medicine. FAQ about hepatitis B.

11 Burden of HBV Among API Americans
API Americans represent 4.8% of overall US population, but constitute > 50% of Americans with chronic HBV infection[1-3] 1 in 10 APIs Americans has chronic hepatitis B vs 1 in 1000 in the US general population[3] Birth in highly HBV endemic country a strong risk factor for chronic HBV infection among US API population[4] HCC is a leading cause of cancer mortality among API men in California[3] Ranks second in Vietnamese Americans and Cambodian Americans Ranks fourth in Chinese Americans and Korean Americans Asian Americans represent 4.8% of the overall US population but represent or constitute 50% of Americans with chronic hep B, so Asian Americans are disproportionately affected by chronic hep B. One in 10 Asian-Pacific Islanders has chronic hep B, compared to 1 in a thousand in the US general population, and birth in the highly endemic countries—the countries that we saw on that World Health Organization map—is a very strong risk factor for chronic hep B infection. And liver cancer, which is one of the scariest and worst outcomes of hepatitis B, is a leading cause of cancer mortality amongst Asian-Pacific Islander men in California and ranks second in Vietnamese Americans as a cause of death and Cambodian Americans, and fourth in Chinese Americans and Korean Americans for cause of death. So, all of these issues are of major concern. 1. US Census Bureau. The Asian population: Issued March CDC. MMWR Morb Mortal Wkly Rep. 2009;58: Asian Liver Center, Stanford University School of Medicine. FAQ about hepatitis B. 4. Lin SY, et al. Hepatology. 2007;46:

12 Relationship Between HBV DNA and HCC Development
54th AASLD Annual Meeting - SHOW 10/27/03 Relationship Between HBV DNA and HCC Development REVEAL: long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC among untreated HBsAg+ individuals in Taiwan 14 N = 3653 Taiwanese patients Baseline HBV DNA Level, copies/mL ≥ 1 million 100, ,999 10,000-99,999 < 300 12 10 8 Cumulative Incidence of HCC (%) 6 One of the major papers that have come out in the last several years on hepatitis B looked at the relationship between the hepatitis B virus and liver cancer, because we’ve known clinically that there was an association for many years. This paper was really important in that it looked at actual virus levels, the hepatitis B DNA levels, over a mean follow-up of 11.4 years. They looked at a very large cohort of 3,600 Taiwanese patients who had hepatitis B, and they followed these patients for 11 years and looked at their viral levels. Interestingly and very importantly, they found that the viral level of hepatitis B was very strongly associated with the development of liver cancer. So, you can see from the graph that the lower the viral level, the lower the cumulative incidence of liver cancer. If the virus level was ≥ a million, which is very common in hepatitis B, the cumulative incidence of liver cancer by years, you can see, approaches 10% to 14%. So, imagine how high that risk may be in regards to these patients who have hepatitis B over a relatively short period of time. Even patients that had > 10,000 copies of virus still were at significantly increased risk of developing liver cancer over this period of this study. So, this landmark study really solidified our understanding of the virus and how it’s associated so strongly with liver cancer and showed the gradient that the higher the virus, the higher the association or relationship with liver cancer. 4 2 1 2 3 4 5 6 7 8 9 10 11 12 13 Yrs of Follow-up Chen CJ, et al. JAMA. 2006;295:65-73. Satellite Symposium - Boston, MA

13 Screening and Diagnosis of HBV
So, what do we do in terms of screening and diagnosis of hepatitis B?

14 Candidates for HBV Screening
Persons born in high and intermediate endemic areas (≥ 2% prevalence) US-born children of immigrants from high endemic areas (≥ 8%; only if not vaccinated as infants in the US) Household and sexual contacts of HBV carriers Persons who have injected drugs Persons with multiple sexual partners or history of STDs Men who have sex with men Inmates of correctional facilities Individuals with chronically elevated ALT/AST Individuals infected with HIV or HCV Patients undergoing dialysis Patients undergoing immunosuppressive therapy All pregnant women Infants born to HBV carrier mothers Well, the candidates for hepatitis B screening have been broadened, so in the last several years, there have been wider and wider recommendations for screening. So at this point, these are the patients that can be candidates for hepatitis B screening—persons who are born in high and intermediate endemic areas. So it used to be that we would only recommend screening in patients who came from the highest areas of hepatitis B endemicity, but now the CDC is recommending that anybody who immigrates from an area of ≥ 2% prevalence should be screened for hepatitis B. Even if you are US-born children of immigrants—so just like our patient that we saw for her routine physical, if she was a US-born child of an immigrant from a highly endemic area like China, she should be screened for hepatitis B. Certainly, household and sexual contacts of people who are positive, persons who have used drugs, multiple sexual partners, high-risk groups like men who have sex with men, inmates in prisons, anybody who comes to you with elevated liver tests, you are going to screen for hep B. Coinfected patients with HIV or hepatitis C, patients who are undergoing dialysis, and then patients undergoing immunosuppressive therapies—it’s very important that anybody who gets chemotherapy should be screened for hep B because chemotherapy can make hepatitis B flare. In the US, all pregnant women are screened for hepatitis B during their first trimester, and then any baby born to a mom who is hepatitis B positive should also get screened as well. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. AASLD practice guidelines: chronic hepatitis B. September 2009.

15 AASLD Guidelines: Interpreting HBV Serology
HBsAg Anti-HBs Total Anti-HBc IgM Anti-HBc Indicates that the person is infected Indicates recovery and immunity from HBV infection Develops in a person who has been successfully vaccinated against hepatitis B Indicates previous or ongoing infection with HBV in an undefined time frame Appears at the onset of symptoms in acute hepatitis B and persists for life Indicates recent infection with HBV (≤ 6 mos) This test is used to distinguish acute from chronic HBV infection In terms of the guidelines, interpreting the serologies, if somebody is surface antigen positive, that means that they are infected. You then need to determine whether that infection has happened recently, acutely, or that infection is chronic. So, then you are going to go on to other tests to look for that. So, the screening test would generally be a surface antigen test to look for whether they are infected at all. Then you are going to look at antibodies, so if they have surface antibodies, that means that they’ve indicated recovery or immunity from hepatitis B infection. Core antibody or anti-HBC indicates ongoing infection with an undefined timeframe, and IgM core antibody indicates recent infection of ≤ 6 months. So, if someone is surface antigen positive, you may then check a core IgM antibody, and if that’s positive, that patient may have been acutely infected sometime within the last 6 months. If the core IgM is negative, then that patient may be surface antigen positive and may have chronic infection and been infected a long time ago and be chronically infected. CDC. Hepatitis B information for health professionals: FAQs. January 2012.

16 Overcoming Challenges to HBV Screening in the Traditional Chinese Medicine Setting
David D. Liu, PhD, LAc, OMD Hi, I’m Dave Liu and I have practiced Chinese medicine in the United States for more than 25 years. Before I immigrated to the United States, I worked at a hospital in China; I worked at a hospital which is called Shanghai ShuGuang Hospital, associated with Shanghai University Teaching Hospital. The university is one of the largest integrated medicine hospitals; that means they integrate Western medicine and Chinese medicine. I got a chance to learn both Western medicine and Chinese medicine, so today I will present some experiences and research to everybody. First, I just want to say that during the 25 years’ practice in the United States, I have also seen many chronic hepatitis patients, with hepatitis A, B, and C, especially Asian patients, Asian Americans, who have these conditions. But, during these patient consultations, we found that many patients may not have knowledge about hepatitis B or HBV screening. First, I want to talk about how to overcome these challenges to HBV screening in the traditional Chinese medicine setting, especially for the traditional Chinese medicine practitioner.

17 Potential Barriers to HBV Screening
Lack of healthcare coverage Makes screening process too expensive for many people For those who may not be staying in the US legally, fear of being caught by authorities No time to get screened due to busy work schedules Typically true for immigrants and their families HBV is silently transmitted and has a silent progression Many people with chronic HBV infection exhibit no symptoms and feel perfectly healthy First, we see the potential barriers to HBV screening. The first reason we saw may be a lack of healthcare coverage. Some new immigrants from countries such as the Asian countries may not have health insurance. That may be one of the reasons that they are missing a lot of chances; they don’t know how to go to the hospital and they don’t even known about insurance. Sometimes they might come to my clinic just to treat some symptoms and sometimes they might just go to hospital, the emergency room, when the symptoms are a very serious condition. But they never think about any minor condition, minor complaints or symptoms that may be related to hepatitis B. The second reason we can see is that some people may not have their green card. Of course, if they don’t have a green card, they don’t have health insurance and they maybe have no money; they go to the hospital and they have no money to take any blood exams or blood tests, including HBV testing and screening. Another big reason is when I practice in the Chinese medicine clinic, I see a lot of patients complain they are busy; they always complain they are busy and so if they have minor symptoms, they may not pay attention to them. Often they just continue to work. If a patient finds their liver area a little bit uncomfortable, with distension or sometimes even a little bit of pain, they may not go to hospital or for an examination immediately. Sometimes we know they have busy schedules, they have no vacations, and they have no time to take off to do that. I work for the Chinese community and find a lot of the group—especially the Chinese Asian immigrants—work so hard that they might not have time to take care of their body. The last reason we see is the most important reason for the patient missing this HBV screening. HBV is silently transmitted and has silent progress. That is very important because a lot of the time, patients have no symptoms, and even if they have symptoms, they might be similar to flu symptoms, such as a little bit of nausea, chills, fever, a little bit of an uncomfortable, upset stomach, or sometimes the liver area may feel a little bit distended and uncomfortable. But most people don’t think of this as related to hepatitis B; they think about it just like a common cold and maybe just take a rest. Even right now, we see in a common lab test that some people’s liver function is normal; ALT/AST and GGT is normal. But in this group of patients, their liver function tests may be normal, but they may be a virus carrier or they may have incubation. I have one patient who was a news reporter and worked for a TV station. It was pretty hard because his working schedule was not regular; sometimes he needed to work from 2 pm to midnight and sometimes overnight. He was just 30 years old. He says, “That’s fine. I’ll just take a break and sleep during the weekends to make up for it.” That is why he did not pay any attention to his condition. Until he found this liver problem, for half a year—almost 6 months—he had already had symptoms such as loss of appetite and continual loss of weight. His liver area and flank area had also been a little bit uncomfortable, but he had no time to have a check up and to do any virus screening. That is the missed chance. Finally, his symptoms got a lot worse so he went to the hospital and found he already had liver cancer. The doctor suggested chemo or surgery, but he also went to the Chinese medicine clinic as he wanted to know whether any other alternative medicine could help him. Unfortunately, I think it was too late. That was a very bad experience for us. Now we always caution the patient; be careful because HBV transmits silently and progresses silently.

18 Potential Barriers to HBV Screening
Lack of education regarding the high rate of HBV in Asian populations Leads to lack of urgency to get screened For older populations, it may be more difficult for them to use modern technology to its fullest extent to learn more about HBV (eg, Web sites, videos, etc) Language and communication difficulties In the next slide, we see more barriers to HBV screening. We see the lack of education regarding the high rate of HBV in the Asian population. That is true. Some people may have a good degree and a very good background, but they don’t know about hepatitis B, transmission, that they are high risk. I find that many high schools and colleges don’t have this education for young people. Especially in schools like community colleges, I see a lot of immigrants there, but they do not provide a good education about hepatitis B. That is very challenging for us. Another group of people is the older population or elderly people who may not get a chance to learn this information through the computer, video, or Internet. They may not have the chance to learn from these high-tech things; maybe they only watch TV and read the newspaper, but unfortunately, TV and newspapers do not show any of this kind of educational material. Many of the older patients I saw in the community have this reason. We also find that this group of patients may not speak English very well, and they may be afraid of going to hospital or the clinic if this hospital does not translate. Right now, I think most hospitals and clinics have bilinguals who translate for these kinds of patients. The patient may communicate more with the doctor, and the doctor will have more chance to educate and have consultations with this group of patients.

19 How Can Traditional Chinese Medicine Specialists Encourage HBV Screening?
First, we talked about HBV screening, but now we will talk about how the traditional Chinese medicine specialist or practitioner can encourage the patient to do HBV screening.

20 Case Vignette The patient is a 35-yr-old Chinese male; he has 2 jobs
Visited Chinese Medicine clinic for chief complaint of sciatic pain During discussion of history and initial exam, the practitioner finds other symptoms of fatigue, bitter mouth, and flank distention pain How do you manage the patient? Firstly, I just want to present a case to everybody. The patient is a 35-year-old Chinese man. He is quite busy because, as he told me, he has 2 jobs: one is full-time and one is part-time. For one job, he is always driving—a lot of driving. That is why he first came to my clinic for sciatica pain. I think he was driving on average 16 hours per day and he had sciatic pain on the right side. For a new patient, we do a consultation and a history review. For the first visit, we always want to know detailed histories, and also especially with Chinese medicine, we need to ask the patient many questions including your energy levels, your appetite, your sleeping—even if your chief complaint is sciatica, we still ask these things for a Chinese medicine diagnosis. So, after I collect all of the information, I find this patient has some symptoms which are very typical in Chinese medicine called “damp heat” in the liver and the gallbladder. For example, he has a bitter taste in his mouth in the morning or especially when he is tired or after work. He also complains about the flank area, especially the liver area—sometimes there is distention pain, sometimes tingling pain; sometimes it disappears and sometimes it is worse, maybe related to fatigue and physical work or related to emotions. And he always feels fatigued because his sleeping is not good. Therefore, my experience from a Chinese medicine diagnosis, we diagnosed this damp heat in the liver and the gallbladder, but this is not the only thing that causes sciatica pain and fatigue. They also may be related to hepatitis. So, for this case I just want to ask you, if you are a Chinese medicine practitioner, how do you manage this patient from your experience?

21 Case Vignette: Management
Given his risk factors and mild symptoms, you suspect HBV infection You counsel the patient that screening would be warranted even in the absence of symptoms You suggest to the patient that he be given a blood test for HBV The patient is HBsAg positive, has high HBV DNA level Starts antiviral therapy and TCM practitioner manages sciatic pain I will share my experience with you. For this person, if I see any damp heat in the liver and the gallbladder, the first thing I will think about is any inflammation of the liver. What is “damp” and “heat”? In Chinese medicine, damp is when just a little bit of pathogenic fluid has come out. What is heat? Heat means you have some inflammation creating internal heat. That is very similar, the inflammation, if you think about their flank distension and also the damp heat, and so probably first I would think maybe this is a risk for B virus or the other types of hepatitis. So you need to suspect this patient may have HBV. And also from the CDC, also ask all of the Chinese medicine practitioners, especially acupuncturists, when you treat this kind of patient, always treat them like a hepatitis patient. All of the procedures and everything, you need to follow the hygienic procedures for that. So the only way we find it is from screening. Ask the patient to do the blood test and screening to get this correct diagnosis. No matter how much experience you have, no matter how much you suspect this patient may have HBV, for a diagnosis, you have to have a blood test. Even if the patient does not have any symptoms, but if there is a high risk, you still need to ask them to do the blood test because it is the only way if you suspect it. Finally, test results: This patient is positive. The virus DNA, I think, is pretty high and also he has over 1 million copies so usually the doctor will give antiviral treatment for that. So for that case, I will do it that way; I will treat the sciatica condition for this patient, but I will also ask this patient to follow up with the family doctor and continue the antivirus treatment.

22 Overcoming HBV Screening Barriers: Engaging At-Risk Patients
Ask at-risk patients if they are familiar with HBV Educate patients about HBV disease and potential consequences if left undiagnosed Explain the simple blood test needed to undergo screening Provide screening opportunities in Traditional Chinese Medicine practice or referral to a trusted colleague Overcoming HBV screening barriers and engaging the at-risk patient: I think ask all of the at-risk patients if they have family with HBV; if they have a high-risk chance, you have to do the test. Secondly, we need to educate patients through a different way to know this information and also educate about the risk from this disease. All of these potential at-risk patients, we need to give them more ways like education seminars, brochures, handouts, Internet—for different ways to educate them. And we also need to explain that this test is very simple—how to do it, where you need to do it—and just refer them to some lab tests and to do the testing. Also, after they have come back, to monitor this type of patient: Is it positive or is it negative?

23 Emphasize Key Points for Patients
Diagnosis is easily missed by both patients and their physicians due to asymptomatic nature of disease Thus, the only way to diagnose HBV infection is through a simple and inexpensive blood test: HBsAg Up to 1 out of every 4 chronic carriers will eventually die of liver failure or cancer caused by hepatitis B, if left untreated or unmonitored Hepatitis B takes a life every secs And emphasize the key points for the patient: Diagnosis is very easy to be missed by both the patient and the physician. That I have repeated very much because sometimes it is very confusing. That’s why we need to know, and even when the patient has no symptoms, we still need to pay attention and watch closely for that. Sometimes we still need a referral to see a Western doctor to continue watching, not to say, “Hey, your treatments are done, and the Chinese medicine—we can take care of the rest.” Studies show that up to one out of every 4 chronic carriers will eventually die of liver disease, such as cancer—or from the cancer—liver cirrhosis, hepatitis B. So, if left untreated or unmonitored—that’s why we need to know that studies show that hepatitis B takes a life every 30-45 seconds, and worldwide, every year, almost 1 million people die from hepatitis B because they develop liver cirrhosis and liver cancer. Asian Liver Center, Stanford School of Medicine. FAQ about hepatitis B.

24 Strategies to Increase HBV Screening in Traditional Chinese Medicine Practices
Lower cost of the screening process to make it more affordable Help alleviate fears regarding immigration status Make education on HBV more accessible in your practice Emphasize the higher rate of HBV cases in Asian populations[1] HBV can cause lifelong infection and can lead to cirrhosis of the liver, liver cancer, liver failure, and death[1] HBV often spread from mother to child but can be spread through contact with contaminated blood and body fluids, such as unprotected sex, drug use, shared razors or toothbrushes[1] We talked a little bit about strategies to increased HBV, the screening, and the TCM practitioners. We maybe try to lower the cost of the screening process and to make it more affordable and, for example, in the community clinic (and also I work for the Stanford University) and they also provide some very lower costs and tests. And we can refer all these patients to the clinic. And also we help all of the new immigrants how to get a good system to monitor or exam—this hepatitis B, to screen for that. And also educate regarding HBV from your clinic and from your practice and maybe emphasize the high rate. And we have emphasized it before: They are high risk. Present some cases to this Asian group of population for that. HBV often spreads from the mother to child, so also we suggest some of the pregnant women—or before they’re pregnant, if they’re preparing to get pregnant, if you treated some infertility case, you also maybe ask they do some blood tests. See the situation and condition, especially like new immigrants, if they want to have kids or are pregnant, better do the blood tests and look at that, especially the special Asian community. And also provide maybe an assessment and a resource for getting the screening. We maybe can connect to some of the local community clinics and hospitals, to ask if the they can refer or go there to do some more detailed exams, if you find this group of patients may have high risk for that. 1. Asian Liver Center, Stanford School of Medicine. Know HBV: what every Asian and Pacific Islander should know about hepatitis B and liver cancer

25 Strategies to Increase HBV Screening in Traditional Chinese Medicine Practices
Provide readily accessible resources for getting screened Provide translators for people who do not speak English (very well) Traditional Chinese Medicine providers can have available (translated) educational resources that they can provide to patients who are interested (eg, pamphlets, handouts) Many hospitals, many community clinics, they now provide different language, bilingual language to translate. It is now easier to communicate with you for that. Also we maybe can make some brochures and also hand out some education papers—the materials in your waiting room at the clinic when patients come in, they also can read it, and also this patient may also pass this information to the other patients. And even the patient doesn’t have this problem, but they’ve got education; they maybe can also educate others—their friends, their families. So from 2004, I worked with Stanford University Medical School, Liver Center. We promoted many big events and included a seminar, a fair, and also education. Also we printed a lot of books and brochures and handouts to the patients. And also we went to the TV station and radio stations. We had some call-in programs. We also had some education programs. They did very well—yes, they did very well.

26 Antiviral HBV Therapies and Treatment Recommendations
Tram T. Tran, MD Next, we’ll move on to hepatitis B therapies and treatment recommendations.

27 Goals of HBV Therapy Primary goal Secondary goals in clinical practice
Prevention of cirrhosis, HCC, and death May be achievable by durable suppression of serum HBV DNA to low or undetectable levels Secondary goals in clinical practice Decrease serum HBV DNA Decrease or normalize serum ALT Induce HBeAg loss or seroconversion Induce HBsAg loss or seroconversion So, the goal with hepatitis B therapy once someone is diagnosed with chronic hepatitis B, surface antigen positive, you would look for the primary goal to be hopefully preventing cirrhosis, liver cancer, and death. This may be achievable by suppressing that virus long term to low or undetectable levels, but that’s going to be a long-term primary goal. In our real-life practice, how can we meet the goals of treatment? The secondary goals in clinical practice would be to decrease the serum HBV DNA or viral levels to undetectable; decreasing or normalizing their serum, ALT, or liver enzymes to normal; inducing E antigen loss or seroconversion (that means you lose the antigen and develop antibodies); and hopefully, inducing the surface antigen loss or seroconversion, so even better, losing the surface antigen. So, these would be the goals that we try to meet in our clinical practices on an everyday basis.

28 Chronic Hepatitis B Disease States
HBeAg positive Also known as “wild type” Negative for antibody to HBeAg (anti-HBe) HBV DNA generally > 20,000 IU/mL (> 105 copies/mL) HBeAg negative Also known as “precore mutant” Positive for antibody to HBeAg (anti-HBe) HBV DNA generally > 2000 IU/mL (> 104 copies/mL) It’s important to categorize if they are E antigen positive or E antigen negative because that determines the duration of therapy. So, if they are E antigen positive—that’s also known as the wild type—they would be negative for E antibody or anti-HBe, and their virus levels are generally on the high side, > 20,000 IU/mL or > 105 copies/mL, so this is known as the wild type—the regular virus. If somebody is E antigen negative, they may also still have active disease, so you need to make sure that you check their virus levels because these patients may also have a pre-core mutant. These patients are positive for antibody to E antigen, but when you check their HBV DNA levels, their virus levels, they still have active virus. These patients who are E antigen negative have lower viral levels because they are a mutated form of virus and don’t replicate as efficiently, so their viral levels may be > 2000 IU/mL or > 104 copies/mL. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6: Chu CJ, et al. Gastroenterology. 2003;125: Lok AS, et al. Hepatology. 2001;34;

29 4 Phases of Chronic HBV Infection
Current Understanding of HBV Infection HBeAg Anti-HBe ALT activity HBV DNA Phase Immune Tolerant Immune Clearance Inactive Carrier State Reactivation Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Active inflammation Understanding the natural history or the 4 phases of chronic hep B infection is important because it helps us determine when we should treat the patient. So, if someone is E antigen positive in the very beginning of infection—they are E antigen positive; they have the wild type—they may start out, if they’re young, as immune tolerant. They are tolerant to the virus, meaning their virus will be very high but their liver enzymes will be normal and they, on liver biopsies, would have very minimal inflammation and no significant damage to the liver. Those patients are currently not recommended for therapy. Some time in their life, they may go on to have immune clearance, where their immune system is no longer tolerant to the virus. It tries to clear the infection by creating immune activity in the liver, trying to clear those infected liver cells of the virus, and that immune reaction may cause damage to the liver. So, during that immune-clearance phase, you may see on a biopsy active inflammation, and if they are not able to clear the virus efficiently, then those patients go on to have significant injury or damage to the liver, histologically. If they are able, however, to immune clear their virus, they go into an inactive carrier state where they have minimal activity, their liver enzymes are normal, their virus is undetectable, and those patients should have minimal activity on their biopsy as well, and you wouldn’t treat those patients who are inactive. Unfortunately, sometimes they develop that pre-core or basal core promoter mutation. The virus comes back and becomes reactivated. So, even though they were E antigen negative and cleared or seroconverted during the immune-clearance phase, they may reactivate and develop active virus again, even though they are E antigen negative, E antibody positive. So, again, the 2 phases where you would treat would be somebody who has got immune activity, and they have a lot of active inflammation, elevated liver tests and active virus in the blood, or reactivation, where they have, again, elevated liver tests, high virus in the blood, and they may have active inflammation on biopsy. E antigen negative or positive would be dependent on which phase of the natural history they’re in. Optimal treatment times Yim HJ, et al. Hepatology. 2006;43:S173-S181. Copyright © John Wiley & Sons, Inc. All Rights Reserved.

30 Treatment Candidacy And when we look at treatment guidelines, we should first look at what is an elevated ALT.

31 What Is an Elevated ALT Level?
Increased levels of the ALT enzyme can indicate liver damage[1,2] Reference ranges for “normal” ALT vary between 2 most widely used commercial laboratories Men: 4-60 IU/L; women: 6-40 IU/L Men: 0-55 IU/L; women: 0-40 IU/L Most HBV treatment algorithms recommend lower ULN levels for ALT when making treatment-initiation decisions[1-3] 30 IU/L for men 19 IU/L for women Well, increased levels of ALT enzymes can be representative of liver damage because ALT spills out into the serum when liver cells are destroyed. Reference ranges for normal ALT vary between 2 most widely used commercial laboratories: men 4-60; women 6-40; and men 0-55 and women So, if you look at the reference ranges, the “normal ALT” by reference labs could be as high as 60. But both the AASLD and the Keeffe treatment algorithms have recommended looking at lower upper limit of normal levels for ALT when making treatment initiation and looking at really what is truly normal. And it’s determined by multiple studies that normal may be 30 for a man and 19 IU/L for a woman. So, when we look at our case of our 28-year-old Chinese immigrant, her ALT was in the 60s, so she clearly is abnormal because we would expect for a young, healthy woman that her ALT would be hopefully < 19, so she’s probably around 3 times the upper limit of normal. 1. Prati D, et al. Ann Intern Med. 2002;137: Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6: AASLD practice guidelines: chronic hepatitis B. September 2009.

32 HBV DNA Testing Indicates chronic hepatitis B when HBV DNA is still positive 6 mos after acute HBV infection Can differentiate among different states of infection HBV DNA level correlates with disease progression Change in HBV DNA level used to monitor response to therapy Increasing HBV DNA level during antiviral therapy indicates emergence of drug resistance DNA testing or viral load testing indicates chronic hepatitis B if the DNA is still positive after 6 months of having an acute infection. So, viral levels correlate with disease progression, as we saw from that REVEAL study, looking at those patients with the highest DNA levels showing a higher chance of liver cancer. And the change in viral levels can be used to monitor response to therapy, so we look at virus when we put them on therapy—we expect their viral levels are going to decrease on therapy to undetectable. If they are on therapy and we see their virus levels go up, that may be either a sign of noncompliance or nonadherence to medication or a sign of potential resistance to the medication, so virus levels or DNA testing is very important in our treatment parameters and paradigms. Adapted from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6: 32

33 Histology Liver biopsy
Establishes disease baseline before initiation of therapy Helps to exclude other causes of liver disease More sensitive and accurate than ALT May be considered in patients who meet criteria for chronic hepatitis B infection Limitations Invasive procedure Sampling error Interobserver variability Liver biopsy can be useful because a liver biopsy can help you establish how much disease or damage they’ve had before you decide to initiate therapy. It helps to exclude other causes of liver disease, like fatty liver or drug-induced liver disease, and in the end, it may be more sensitive and accurate than just an ALT because ALT levels can be elevated for many other reasons. But looking at a liver biopsy will help you really determine the underlying cause of a patient’s liver disease. It may be considered in patients who meet criteria for chronic hep B infection, but it’s limited because liver biopsies are an invasive procedure. There may be some sampling error because you’re missing one area that may have more disease than another area, and certainly the reading of the biopsy can be variable based on the pathologist and your particular pathology department. So, these are the caveats to liver biopsy, but liver enzymes, DNA or virus levels, and liver biopsy are the tools that you have to help decide disease activity and whether you want to treat a patient or not.

34 AASLD Guidelines: Treatment Candidacy for HBeAg-Positive Patients
< 1 x ULN 1-2 x ULN > 2 x ULN ALT: and and and < 20,000 IU/mL > 20,000 IU/mL > 20,000 IU/mL HBV DNA: MONITOR Q3-6 mos ALT Q6-12 mos HBeAg MONITOR Q3 mos ALT Q6 mos HBeAg Consider biopsy if persistent or aged > 40 yrs and TREAT as needed MONITOR Q1-3 mos ALT and HBeAg and TREAT if elevations persist Liver biopsy optional TREAT immediately if jaundice or decompensated APPROACH: So, looking at AASLD guidelines on treatment candidacy for E antigen–positive patients, you look at their ALT. If their ALT is > 2 times the upper limit of normal and their virus levels are > 20,000 IU/mL, the column furthest on the right, those patients can be monitored and if they are repeatedly the same after 1-3 months, you would treat them because they meet treatment criteria. Again, high ALT, high virus, repeat the test. If it’s still elevated, you can treat that patient because they meet criteria. A liver biopsy would be optional in that case. You don’t have to do it because they meet 2 of the criteria for disease activity. If they have an ALT that’s < 1 times the upper limit of normal, meaning the ALT is completely normal, and the virus is < 20,000 IU/mL, meaning low virus, you would just monitor that patient because that patient doesn’t seem to have disease activity. Normal ALT, low virus: just monitor every 3-6 months with an ALT and every 6-12 months with an E antigen status. If they’re somewhere in between where their ALT is 1-2 times the upper limit of normal and their virus is elevated—they meet viral criteria but their ALT is borderline—those are the patients you may want to consider a biopsy in, especially if they are over 40, and then the biopsy can help you determine treatment options. AASLD practice guidelines: chronic hepatitis B. September 2009. 34

35 AASLD Guidelines: Treatment Candidacy for HBeAg-Negative Patients
< 1 x ULN 1-2 x ULN ≥ 2 x ULN ALT: and and and < 2000 IU/mL ,000 IU/mL ≥ 20,000 IU/mL HBV DNA: MONITOR Q3 mos ALT x 3, then Q6-12 mos if ALT still < 1 X ULN MONITOR Q3 mos ALT and HBV DNA Consider biopsy if persistent and TREAT as needed TREAT if elevations persist Liver biopsy optional APPROACH: If a patient is E antigen negative, the treatment criteria are essentially the same: again, high ALT > 2 times the upper limit of normal and > 20,000 IU/mL. You would treat if the elevations persist. A liver biopsy is optional. If the ALT is low and the DNA is low as well, you would just monitor those patients, and if there’s any borderline case where the ALT is between 1-2 times the upper limit of normal and the DNA is fluctuating—it’s between 2000 and 20,000—you can monitor those patients and then consider a biopsy that will help you determine again what’s really happening in the liver and help you decide if you’re going to treat or not. So, E antigen–positive and E antigen–negative patients have very similar criteria and that sort of borderline case is where you would consider a liver biopsy to help you determine treatment. AASLD practice guidelines: chronic hepatitis B. September 2009. 35

36 HBV Antiviral Therapies
So, what are the current hepatitis B antiviral therapies?

37 FDA-Approved HBV Therapies
Schering-Plough PPT Template 4/10/ :14 PM FDA-Approved HBV Therapies Peginterferon alfa-2a Lamivudine Entecavir Tenofovir 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Adefovir Telbivudine So, FDA-approved therapies go back to 1990 when we first had standard interferon alfa-2b. In 1998, we had lamivudine, which was the first oral drug approved for hepatitis B, and at the time, it was really remarkable. We used it and it worked, but we found that lamivudine resistance became a problem shortly thereafter, but at least we had an oral drug that was easy to take for hepatitis B. It wasn’t until 2002 that we had adefovir, and that improved things because the resistance rates were a little bit lower. But in 2005, we really started to see a lot of developments in hepatitis B with pegylated interferon approval alfa-2a, entecavir in 2005, telbivudine in 2006, and then tenofovir in So, we’ve had 5 oral therapies and 2 injectable therapies that are FDA approved for hepatitis B. 37

38 Current Guideline Recommendations for First-line HBV Antiviral Therapy
Use ONE of the following[1-3]: Weekly injectable medication: pegIFN alfa-2a Exceptions: pregnancy, chemotherapy prophylaxis, decompensated cirrhosis or autoimmune disease, acute infection, uncontrolled severe depression or psychosis Daily oral nucleos(t)ide analogue; either Entecavir or Tenofovir Older drugs no longer recommended for first-line therapy due to high rates of resistance (eg, lamivudine, adefovir)[1,3] But the current first-line recommendations make things pretty easy because of all of those therapies that I just discussed, really there are only 3 first-line therapies for hepatitis B. One is injectable medication with pegylated interferon alfa-2a. It’s done weekly; given for 1 year. Interferon has its side effects, as related to the interferon’s flulike symptoms, anemia, etc, and you wouldn’t treat with pegylated interferon in patients that are pregnant; anybody for chemotherapy prophylaxis, you wouldn’t use. You wouldn’t use interferon in somebody with decompensated cirrhosis because it may make them worse, and somebody with an acute infection also you wouldn’t use interferon. The 2 oral therapies that are recommended first line are entecavir or tenofovir, and both of those are highly efficacious at suppressing the virus with low resistance rates. The older drugs that we talked about—lamivudine, adefovir—are no longer recommended first-line therapy because of the issues of resistance and potency. We wouldn’t be using those older medications now, so again, simplifying the first-line therapies to 3: one is peginterferon, one is entecavir, and one is tenofovir. 1. EASL. J Hepatol. 2012;57: Liaw YF, et al. Hepatol Int. 2012;6: AASLD practice guidelines: chronic hepatitis B. September 2009.

39 Comparison of PegIFN vs Nucleos(t)ide Analogues
Pros Cons Finite course of therapy No resistance Higher rate of HBeAg loss in 1 yr Higher rate of HBsAg loss with short duration therapy* SQ administration Frequent AEs Contraindicated in patients with cirrhosis, in pregnancy, with acute hepatitis B, and who are immunosuppressed PO administration Infrequent AEs Safe at all stages of disease, including decompensated cirrhosis† Safe in immuno-compromised populations Selected drugs probably safe in pregnancy Need for long-term or indefinite therapy Potential for drug resistance Unknown long-term safety When you compare peg vs oral therapies—nucleoside, nucleotide analogues—certainly the pros of pegylated interferon are that you only need treatment for 1 year. There’s a finite course of therapy. There’s no resistance, and because it’s an immune modulator, you have a higher chance of developing surface antigen loss or losing surface antigen with peginterferon. The cons are certainly that you have to do an injection, and the patients certainly have the side effects related to the peginterferon. Then the pros of the oral therapies are certainly that it’s oral. It’s a pill that you take once a day with either tenofovir or entecavir. There are rare side effects related to the oral therapies, and it usually is safe in pretty much all stages of disease of hepatitis B. We can use oral therapies in severely ill, decompensated, cirrhotic hepatitis B patients, and it should be well tolerated, and it’s safe in immunocompromised patients and has some safety data in pregnancy as well. The con is certainly that once you take an oral therapy, you are probably going to be on that oral therapy for quite some time, if not indefinitely, so for E antigen–negative patients, the length of treatment is indefinite for E antigen–negative oral therapy treatment, and there is some theoretical chance of drug resistance with antiviral therapies. *Particularly for HBeAg-positive patients with genotype A infection. †Recent case report of lactic acidosis in severe liver failure. EASL. J Hepatol. 2012;57: Lok AS, et al. Hepatology. 2009;50: Lok AS. Hepatology. 2010;52: Buster EH, et al. Gastroenterology. 2008;135: Lange CM, et al. Hepatology. 2009;50: AASLD practice guidelines: chronic hepatitis B. September 2009.

40 Treating Asian Patients With HBV: Special Considerations
High rate of HBeAg-negative chronic hepatitis B Long-term therapy often required Increased risk for HCC Treatment-induced drug resistance mutations Loss of treatment efficacy Possible flares resulting in serious complications, including HCC and death Poor response to treatment Poorer response to interferon in patients with genotype C Poor response in patients with normal ALT levels In Asian patients with hep B, there are some special considerations. The high rate of E antigen–negative chronic hepatitis B often means that they need long-term therapy and that there’s increased risk for liver cancer, and E antigen–negative patients may not respond as well to interferon. Asian patients also have potentially treatment-induced drug resistance mutations, so therefore the loss of treatment efficacy and flares when they develop resistance mutations, especially if they’ve been on previous lamivudine or other medications that had higher resistance. And then some Asian patients may have a poor response to therapy, so if they are genotype C, they may have a poor response to interferon, and certainly patients with normal ALTs are not always candidates for therapy as per the AASLD guidelines, and they may not have as good of a chance of responding to therapy in terms of seroconversion with therapies.

41 Overview of Traditional Chinese Medicine Beliefs
David D. Liu, PhD, LAc, OMD So now let me introduce some very simple TCM theories regarding the liver and liver diseases.

42 Basic Concepts of TCM Theory
TCM syndrome: a profile of symptoms and signs as a series of clinical phenotypes Guides understanding of the human homeostasis Basis for the applications of Chinese herbs and acupuncture Heat, cold, excess, and deficiency are the 4 basic syndromes of maladjustment nature in TCM One study found 47 syndromes related to CHB[1] Majority among individuals without cirrhosis: Liver Depression and Spleen Deficiency or Liver-Gallbladder Dampness Heat/Dampness-Heat Obstructing Middle Energizer Common in those with severe CHB: Liver-Kidney Yin Deficiency and Spleen-Kidney Yang Deficiency Let me also introduce a little bit of the basic concept of the TCM theory. The TCM usually diagnosis based on the syndrome. What does syndrome mean? Syndrome means the patient complained about symptoms, plus the signs from the doctor’s exam. So that’s why the symptom and the patient complaint, plus the sign—the evidence—the doctor sees the evidence such as from the pulse, from the tongue. We can see any evidence, plus the patient complaint together, then this is what we call the pattern—one pattern. This pattern we call the syndrome. So the TCM treat any disease, including hepatitis B based on the syndrome, not based on the symptom; yes, this is a little bit different from the Western medicine. So we don’t really see this patient has a headache—give the headache a relief medicine—nor constipation, give the constipation medicine. We need to see the whole thing so that they belong to which pattern, then we give this treatment for that. Zeng XX, et al. Am J Chin Med. 2011;39:

43 TCM Theories Regarding Etiology and Pathology
Toxin: pathogenic factors that cause acute contagious and infectious diseases and their complications Special pathogenic factors in the theory of etiology of TCM, which is either included in the 6 exogenous causes of disease—wind, cold, summer heat, dampness, dryness, and fire—or dissociates itself from them Accumulation of damp heat in the liver External invasion of damp heat Damp heat food over time The TCM theories regarding the etiology and the pathology. When we say you have acute hepatitis, even A or B, and this is a usual infection stage; most TCM theorists say because you catch the toxin. It’s toxin from the external—it’s external pathogenic factor, but this factor was the toxin and the heat. This is the first factor we can see for toxins, usually for the acute infection area. They maybe the patient has symptoms throughout the whole body related to the liver. Another factor we see is dampness. The dampness is a very strange factor to Western medicine but to TCM, the dampness is a very common factor, either from the external or the internal. What is a dampness? Basically TCM say, just like a pathogenic water, they don’t circulate very well. From Western medicine, the dampness is very similar to inflammation or infection. We say infection may be damp and heat. How do you know you’re this person with dampness? Usually they show the very thick coating on the tongue, and also the patient may have digestive system disorder, such as lost appetite, such as nausea. And then the final results is qi stagnation—your energy (qi means vital energy), not moving very well. That’s why the patient mostly feel the liver area a little bit distended and little bit of enlargement, and also they say qi energy not flowing very well. And finally they also affect the digestive system, and the patient may have some stomach bloating and maybe the flank area, a little bit of distention pain, and a little bit of bitter taste and bitter mouth or bad breath. In some severe cases, they may also have nausea and vomiting. The last one for the chronic condition, if you find this is hepatitis B, if you are already doing the treatment, from research, if you use long-term medication they may get a chance—it’s a may, not everybody, maybe got an injury after your yin fluid. When you go to the yin deficiency, that means already, you have already developed to the chronic. If you continue to develop, as you know, the yin deficiency, you draw more dryness; your liver will become more fibrosis, and the fibrosis—final, the end—they will develop liver cirrhosis and will develop liver cancer. This is the way we find, in China; many patients follow this progress. That’s why yin deficiency is usually for chronic condition. Proceedings of TCM Conference at West China University of Medical Science

44 TCM Theories Regarding Etiology and Pathology
“Qi is an infinitesimal substance by which the human body is nourished. It is the basic substance that sustains life and is vital to the function of the internal organs” -- cen yuefang Qi and blood stagnation[1] Theory that all diseases originate from an imbalance of qi and blood flow, leading to stagnation and blockage Restoring balanced flow can restore health Upright qi (body’s resistance to disease) and yin (that which maintains and endures) deficiency[1] What is the qi? Qi usually is a vital energy. But for liver—hepatitis or liver disease—they usually have the qi stagnation because they have inflammation, they are swollen. That’s the energy, stagnation—not moving very well. Or at the later stage, maybe got a blood stasis and more severe. The last one I will talk about: the upright qi. The upright qi actually—this is very important for both Western medicine and TCM. This, we say, is just like immunity, your resistance to the disease. And the TCM, we have a special theory; we say when you know this patient may develop some condition, you need to treat earlier. That’s why we have a special, called a third medicine, called preventive medicine. What does preventive medicine mean to the TCM? First, we need to raise this patient or boost this patient’s immunity, healthy qi. We have—through many different ways, such as you have good lifestyle, you’re sleeping well, you’re eating healthy, you exercise, you do also some nutrition or herbal preventive treatment. All of these can boost your upright qi. So, most TCM, they know how to protect themselves. I think the Western medicine—same as the TCM—Western medicine now use immuno shots, the vaccine. This is right now from the experiments that proved, scientific research already proved, this is the best way to prevent hepatitis B. We also encourage all of the patients or practitioners’ patients better; we need to raise your upright qi before they get sick. If their screen is negative, we better ask this patient to do immuno shots. If you can prevent hepatitis B, then we will never gather any liver cirrhosis or liver cancer. 1. Xutian S, et al. Am J Chin Med. 2012;40:

45 TCM Theories Considered During Management of HBV Patients
Eliminate pathogenic factors and toxin for acute stage Drain dampness and clear heat for infection stage Open and soothe liver to overcome qi stagnation for relief of symptoms Invigorate the blood for late stage Tonify (nourish and replenish) healthy qi and yin for chronic stage TCM nutrition therapy for recover stage The next one we talk about is TCM, the theories concerned with the management of HBV in patients. I just list these methods from my experience. Also, these methods I learned from my teacher and also from my practice experience. I just give you a summary, but this is just the principal management, just the principal methods. For TCM, and the treatment and management of HBV, we say to eliminate the pathogenic effects and the toxins for the acute stage. The second one is we try to drain the dampness, and I tell you the truth: The dampness is not easy to clean. Dampness we usually consider as very dirty, like oil, and dirty like water or the dampness. It is very different to clean it, just like your kitchen. When you’re cleaning, you take a little bit of time to complete the cleaning. That’s why for hepatitis B, you usually have a long time from the positive and the DNA to the negative. You have your symptom to relieve—your symptom is usually a long process. The next one is open and through liver qi stagnation. That means, in Western terms, promoting secretion, with the idea that if secretion gets better; your symptoms will be getting better too. That’s why we open and clear your stagnation, your flanks pain, your nausea feeling, your bloated feeling, all your digestive disorder symptoms. The next method just remove the blood stagnation. Invigorate the blood because your blood got stasis. Earlier, I talked about the later stage, like liver cirrhosis, liver cancer. They usually have a blood-stasis stage. The liver also started getting harder; it’s not soft anymore. This time, we need to try to move the old blood—the poisoned blood—and let the new blood come in to refresh your liver and maybe also help your condition and constitution and symptoms. The next one is for the chronic stage. That is the need to tonify the healthy qi and yin. I emphasize this stage because, in the United States in my clinic, I saw many of these cases. Usually in hepatitis B, their first priority should be to see the Western doctor, and it should be antiviral treatment, but during this treatment or after treatment, I saw many patients who had the qi and the yin deficiency condition. We can work with Western medicine. We can integrate Western medicine therapy, and we can complement the Western medicine together. Personally, I got a lot of good feedback from the patient, and the patient usually feels a lot of improvement, especially for the symptoms. Most antiviral treatment only emphasizes control of the virus. TCM, their advantage is treat these symptoms based on your diagnosis. That’s where we can work together. Finally, also for the recovery stage, the patient also needs TCM nutrition therapy. In TCM, we have a theory that says you may not take too much damp heat in the food because damp heat of food—such as spicy food, oily foods, smoke, and alcohol—all of these things about damp heat products may increase your conditions and symptoms. At these times, we may be limited to eat these kinds of foods. This is what we call TCM nutrition therapy. We have certain herbs, foods, and lifestyles for this recovery stage, such as we ask that they do minor exercise, the tai chi or the meditation, easy to digest food. TCM Internal Medicine, by Dave Liu, 1992

46 Overview of Barriers to Treatment and Engagement in Care
Tram T. Tran, MD So, moving on to the overview to barriers to treatment. Once we’ve decided to treat a patient, what are the barriers to treatment and engagement in the care of these patients long term?

47 Causes for Health Disparities
Chronic HBV infection and liver cancer is the greatest health disparity between APIs and white Americans[1,2] Health disparities between APIs Americans and the US general population can be attributed to[1] Communication challenges[1] Cultural differences[1] Socioeconomic factors[1] Lack of awareness and misinformation[1] Potential for more aggressive HBV progression among APIs Americans (higher rate of genotype C HBV infection)[3] So, liver cancer is one of the greatest healthcare disparities between Asian Americans and Caucasian Americans. One in 10 Asian Americans may be positive for hepatitis B as opposed to one in 1000, so we know that that is a healthcare disparity, and liver cancer is a contributor to that. So, the healthcare disparities may be attributed to communication challenges, cultural differences, socioeconomic factors, lack of awareness, and more aggressive hepatitis B progression amongst Asians as well, so these are some of the concerns in regards to Asian Americans and to healthcare disparities. 1. Bailey MB, et al. J Community Health. 2011;36: Asian Liver Center, Stanford University School of Medicine Colvin HM, et al, eds. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC: The National Academies Press; 2010.

48 Asian Health Beliefs About Wellness and Disease
Western Cultures Asian Cultures Separate mind and body Embrace a holistic approach to health Strive toward movement and exploration Cultivate “what is” Dissect and analyze the body Restore body functioning Asian health beliefs about wellness and disease—we have to certainly be sensitive to the Western culture vs Asian culture. In Western culture, we may have more of a predisposition to separating the mind and the body, whereas Asian cultures may embrace a more holistic approach to health. The Western culture may strive towards movement and exploration, whereas the Asian culture may cultivate a “whatever it is, it is.” And then Western cultures may be more prone or more likely to dissect and analyse the body, whereas Asian cultures talk about more restoring body function, so some of these different cultural beliefs may play a role in management of these patients.

49 Healthcare Practices Among API Patients
Many API patients adhere to Eastern healthcare practices[1,2] How many patients used herbal remedies? 38% of Vietnamese patients[2] 36% of Japanese patients[2] 1 in 4 Koreans used acupuncture[2] 14% of Chinese patients saw traditional Chinese healers[2] And how many patients use herbal remedies? In one study, 38% of Vietnamese patients use Eastern healthcare practices, 36% of Japanese patients, 1 in 4 Koreans used acupuncture, and in one study, 14% of Chinese patients saw a traditional Chinese healer, so you can see that these numbers are quite high. 1. Ahn AC, et al. Am J Public Health. 2006;96: The Commonwealth Fund 2001 health care quality survey: quality health care for Asian Americans.

50 Healthcare Practices Among API Patients
Two thirds of Vietnamese and Chinese patients have used complementary or alternative medical therapies[1] Only 7.6% had discussed these with their Western physicians[1] Many APIs do not see a doctor unless they are sick No screening during pregnancy Insufficient screening for chronic HBV infection In other statistics, two thirds of Vietnamese and Chinese patients had used complementary or alternative medical therapies and very interestingly, in this study only 7% of patients had discussed this with their western physicians. So, we should be more open to the dialogue about complementary or alternative medical therapies because it’s clear from many studies that many of these patients are using them; they just don’t talk about it with us. Many Asian-Pacific Islanders do not see a doctor unless they are sick. 1. Ahn AC, et al. Am J Public Health. 2006;96:

51 Barriers to Treatment: Language
Ability to speak English tremendously affects healthcare access[1,2] Communication with providers[1,2] Accessing services (eg, Medicare/Medicaid)[1,2] Impact of limited English Less likely to have routine preventive care[1,2] Their children also less likely to receive care[3] Limits ability to understand and comply with medication use[1] So, when we really delve into the barriers to treatment or adherence, let’s look at language. The ability to speak English tremendously impacts healthcare access here in the United States, because if you don’t speak English, it’s hard to communicate with your providers, you can’t access services like Medicare or Medicaid or other services that are available, and the impact of limited English is they are less likely to have routine preventative care and their children unfortunately are also less likely to receive care if they have limited English. It also limits their ability to understand and comply with medication, so imagine starting a patient on an antiviral therapy where you need to monitor viral levels. They need to take the medications regularly every day, but if they didn’t really understand what you were explaining or why they are taking their medications or how often they need to take it, the chance of adherence to the medications goes down significantly. 1. Ngo-Metzger Q, et al. J Gen Intern Med. 2007;22: Fiscella K, et al. Medical Care. 2002;40: Weinick RN, et al. Am J Pub Health. 2000;90:

52 Barriers to Treatment: Language
Limited English proficiency definition: does not speak English “very well” Legal implications Linguistic isolation: no one in household aged 14 yrs or older speaks English at least “very well” More than one third of Korean, Taiwanese, Chinese, Hmong, and Bangladeshi households[1] 45% Vietnamese households[1] So, when you have limited English proficiency, which is defined as not speaking English “very well,” there are some legal implications to that as well. And linguistic isolation—no one in the household older than 14 who speaks English—more than one third of Korean, Taiwanese, Chinese, Hmong, and Bangladeshi households have linguistic isolation, and 45% of Vietnamese households are linguistically isolated. So, that makes a huge impact in their ability to receive appropriate therapies. 1. US Census Bureau. Census 2000 brief: language use and English speaking ability: Issued October 2003.

53 Barriers to Treatment: Communication Challenges
Most API patients report lower satisfaction in communication with their physicians < 50% of API patients said that their physician “listened to everything”[1] Of Asian patients with limited language skills, large proportions report Dissatisfaction with their involvement in healthcare decisions That they did not spend enough time with their physician Most Asian patients report unsatisfactory communication with their physicians and < 50% of Asian patients said that their physician listened to everything. So, maybe part of it is on our end because if there is a communication issue, we are less likely to delve into the subtleties of their concerns, about their complementary medicines; we are less likely to ask the more detailed question. Ngo-Metzger Q, et al. J Gen Intern Med. 2004;19:

54 Barriers to Treatment: Religious Perspectives on Health and Well-being
Buddhism Suffering as an integral part of one’s life Confucianism Worship of ancestors Family well-being more important than individuals Taoism Perfection is achieved when things are allowed to take the more natural course When we also look at barriers to treatment we look at religious perspectives, so Buddhism will view suffering as an integral part of one’s life. So, if you tell a patient, “Well, listen, you might get liver cancer from hepatitis B,” they may view that from a religious standpoint as part of just the natural history of one’s life and may be more resistant to therapy because they don’t really feel like it should be changed. Confucianism looks at the worship of ancestors and family well being is more important than that of individuals. So, what does that mean? That may mean that they don’t want the diagnosis of hepatitis B to be known, so they don’t screened because they don’t want their family to be labelled with the stigma of having somebody with hepatitis B. So, instead of looking at their individual health, they say, “For my family’s well being or for my family’s name, I don’t want to have it out there that I have hepatitis B,” so they don’t want to get screened. Taoism believes that perfection is achieved when things are allowed to take the more natural course. So, again, just letting things be as the natural way is perhaps one of the religious beliefs that we need to be aware about, and we need to be sensitive to this but also probe a little bit more deeply into how we can work with the patient and their family in these regards. Tran TT. Cleve Clin J Med. 2009;76:S10-S13.

55 Barriers to Treatment: Poverty
Perception of increasing per capita income[1] Asians more likely to be living in poverty compared with whites (12% vs 10%) and lower per capita income[2] Disaggregated data: Asian subpopulations particularly affected by poverty[3] Hmong: 37.8% Cambodian: 29.3% Laotian: 18.5% Vietnamese: 16.6% Certainly, poverty is a big part of a barrier, so the perception of Asians is that they have increased per capita income—Asians are the “model minority.” Asians, however, may be more likely to be living in poverty compared to Caucasians and they have a lower per capita income. 1. Tran TT. Cleve Clin J Med. 2009;76:S10-S US Census. Income, poverty, and health insurance coverage in the United States: September President’s Advisory Commission on Asian Americans and Pacific Islanders. Facts and data: critical issues facing Asian Americans and Pacific Islanders.

56 Barriers to Treatment: Health Insurance Coverage
Uninsured by subgroups Korean: 25.5% Vietnamese: 19.8% Native Hawaiian and Pacific Islander: 16.7% Chinese: 13.4% Asian Indian: 11.8% Filipino: 10.9% Japanese Americans: 6.6% And when you look at some subpopulations in terms of insurance coverage, many of these Asian groups come over, are small business owners, and don’t pay for health insurance because they are really trying to get their small business up and going, and they may not have full health insurance coverage, so it’s something to keep in mind. US DHHS. ASPE research brief: the Affordable Care Act and Asian Americans and Pacific Islanders. April 2012.

57 Barriers to Treatment: Educational Attainment
Educational achievement is associated with attainment of financial security and health insurance[1] 86% of Asians complete high school (general US population 85%, white 90%)[2] Southeast Asians much lower rates of HS completion (between 61% and 72%, depending on subgroup) [2] Asians more likely to have bachelor degree (49% vs 28% overall) except certain subgroups (ie, Southeast Asians) [2] Bimodal distribution is seen in some subgroups regarding educational attainment[1] Educational attainment is also important. So even though there’s that perception of a model minority, there are Asians who don’t complete high school, and especially South East Asians may have lower rates of high school completion. 1. Tran TT. Cleve Clin J Med. 2009;76:S10-S13. 2. US Census Bureau American community survey, 3-year estimates.

58 Barriers to Treatment: Educational Attainment
Less Than HS Education (%) 20 40 60 80 Hmong Cambodian Laotian Vietnamese Tongan Fijian Bangladeshi Chinese Korean Filipino Japanese Taiwanese 59 53 49 38 33 33 23 And these barriers—you can see that 59% of Hmong have a less than high school education—impact our ability to really get through to the patients in terms of awareness about hepatitis B, literature about hepatitis B, understanding treatments, etc. 23 14 13 9 7 US Census Bureau, 2000.

59 Barriers to Treatment: Health Workforce
IOM: “Racial concordance is associated with greater patient participation, higher patient satisfaction, and greater adherence”[1] US physician diversity[2] 75% of physicians in the US are white whereas Asians are the largest minority group of physicians (12.8%) Among Asian subgroups, Japanese, Filipino, Vietnamese, Korean are least represented US nursing diversity[3] 11 of the 16 Asian subgroups underrepresented When we look at barriers to treatment, we are looking also at the health workforce. The Institute of Medicine says that being racially concordant is associated with a greater patient participation, higher patient satisfaction and greater adherence. So, being the same race as your patient actually helps a lot in terms of getting patients to do what we recommend. So, US physician diversity amongst Asian subgroups, their ability to find a doctor who speaks their language or understands their culture is much, much lower, so we need to do the best we can at bridging this divide in terms of the healthcare workforce. And then certainly nurses are greatly underrepresented: 11 out of 16 Asian subgroups are underrepresented in terms of nursing diversity as well. 1. IOM. Unequal treatment: confronting racial and ethnic disparities in healthcare. Washington, DC: National Academies Press; March AAMC. Diversity in the physician workforce: facts and figures Summer APIAHF. Diverse communities diverse experiences. The status of Asian Americans and Pacific Islanders in the US

60 David D. Liu, PhD, LAc, OMD Tram T. Tran, MD
Building Partnerships and Overcoming Barriers: Integrating Western and Traditional Chinese Medicine David D. Liu, PhD, LAc, OMD Tram T. Tran, MD Now we do the final parts: Build the partnership and overcoming the barriers and integrating Western with traditional Chinese medicine.

61 Example Case Vignettes of HBV Patients Seeking TCM Therapy
Case 1: HBV patient with suppressed HBV DNA on antiviral therapy still experiencing symptoms of fatigue, loss of appetite, etc Seeks TCM for symptom relief Case 2: HBV patient seeking TCM for infertility issues TCM provider asks her to initiate antiviral HBV medication treatment first 1 yr later, her HBV DNA levels are negative and after discussion with HBV doctor, she starts TCM treatments for infertility First, I want to present some example cases. The case 1, I have one patient: his HBV DNA, it’s very high. That’s why they started getting treatment, and especially used antiviral therapy but, during the treatment, he complains of sleeping problems or fatigue and also lost his appetite. He saw the doctor, and the doctor said maybe it’s normal, but this is many years ago. I think maybe new generation, the medication may have less of a side effect. He asked the TCM practitioner to help him, so after I received this patient, I added some TCM therapy and treatment. I had a lot of experience with that—people having insomnia, people losing hair, people with depression, headaches. All of them can use acupuncture and herbal medicine to help that. This time, I used acupuncture more because I didn’t want to use herbs, which interact with the medication. He got on much better. His condition was improved from all of these complaints and symptoms. The second case, I saw this female patient and asked her—like around 35 years old. She just wanted to get pregnant. They tried, but they’re not successful. That’s why she’s an infertility patient in my clinic. After the consultation and after this exam, I asked that they do maybe the lab tests first. Then she finds the HBV screen is positive. That’s—I say, maybe you need to treat this condition first. She’s back to the primary doctor for 1-year treatment with antiviral therapy. It works very well and the DNA is inactive. She asks the medical doctor, “Can we start the infertility treatment—the herbal or the acupuncture?” Her doctor says, “Yes, you can do right now. Your virus is controlled very well right now.” That’s why she came back. We gave her infertility treatment. Actually, this patient may have only taken a couple of months before she was pregnant. Actually, she was very successful in both: the hepatitis B and also infertility. TCM has a principle. We say that, if you have an urgent, acute, or serious condition, we treat that condition first. When you have a minor chronic condition, maybe it’s later. For this case, she must have the healthier liver and the virus should be under control, and then become pregnant

62 Role of TCM Provider as a Trusted Healthcare Provider: Encouragement
Screening for HBV HBV vaccination Antiviral therapy Management of chronic HBV infection Screening for liver cancer Eliminating HBV myths In the next one, we talk about the role of the TCM provider as the trusted healthcare provider, encouragement. We would do the pretty same as Western medicine from TCM. First, we would ask a patient to do a screen for HBV. Screening for HBV, this is a priority. I think all of the practitioners should have their first priority to do this, if this patient has a risk for that. Then we also emphasize HBV immune shots, vaccinations. That’s also the best way to prevent if your test is negative. If you have started for antiviral therapy—even TCM also has some antiviral therapy with the herbs, but we suggest you use new medication because new-generation medication is so good. It’s easier. Manage the chronic condition of HBV. Screening for liver cancer: We also ask the patient, if you have hepatitis B as a positive, we also need to do, every 6 months or 1 year, especially for high risk, to screen for liver cancer. Finally, we also need to eliminate some patients’ mistaken thoughts or thinking. First, they say—we have patients who say, “Oh, I’m the carrier. The carrier is not really serious. Usually chronic hepatitis is more serious. Carriers are inactive and should be okay.” This is a popular mistake because a lot of carriers have no symptoms, but they still can develop. Another thing is some patients say, “Oh, I just take herbal medicines. I don’t need medication. Herbal medicine also can treat it, from a few thousand years’ history.” This is also a mistake. Herbal medicine cannot be instead of Western medicine or drugs. It’s the same thing: Western medicine cannot be instead of herbal medicine. They have different ways. I suggest that Western medicine does antiviruses very well, and Chinese medicine just can help relieve some side effects or relieve some symptoms. That’s for me, and also I never ask the patients to stop taking medication without any permission from their primary doctor.

63 TCM Approaches That May Be Used in Patients Receiving Antiviral Medication
Use of TCM in China is based on clinical observations and wisdom accumulated > 2000 yrs of use and practice[1] Addressing symptoms in HBV in hopes of improving quality of life[1,2] Fatigue and depression Sleep difficulties Promoting kidney health Headaches and muscle pain Strategies aimed at boosting immune function, promoting liver health, resisting liver fibrosis[1-3] TCM has a few thousand years’ history, but when it’s used for this hepatitis condition, I think an advantage is most times there are no side effects from acupuncture. We can use acupuncture treatment during their medication time because acupuncture doesn’t have any chemicals to interact with any medications. We can use acupuncture therapy to treat many side effects such as fatigue, depression, and sleeping problems. If the patient wants to use herbal medicine, I suggest the patient will find it looking for an experienced (or specialist in liver experience) TCM practitioner. Because the practitioner may have a different education or degree background or a different specialty, you have to find these people who have experience in using herbal medicine. For TCM, we can also help boost their immunity during their treatment with Western medicines. We can also work complementarily with Western medicine. The last one is we also can resist liver fibrosis. From research, we found that most chronic liver disease slowly develops through liver fibrosis and through liver cirrhosis and goes to liver cancer. Western medication mostly treats chronic liver disease with antivirals or treats liver cancer with surgery and chemo, but not many medications focus on fibrosis and cirrhosis. From TCM’s advantage, we find that TCM has a good advantage for these 2 stages: fibrosis and cirrhosis. Most of the hepatitis B patients, if they are not under good treatment control, will usually develop fibrosis. We use herbs and we use acupuncture. This is a way we also can work with Western medicine to prevent the patient’s case developing to liver cancer. We especially find some patients stop the medication treatment after the HBV DNA becomes negative. Later, they will rebound and develop again. This we saw many times. That is why the virus being negative does not mean it’s gone; it’s just inactive. If you forgot that and do still not take care of your patient very well, then maybe it will develop again. That’s how TCM can help in this condition. This is my thought and my experience of how to integrate with Western medicine and work together for hepatitis B patients. 1. Zhang L, et al. Hepatology. 2010;51: Wang BE. J Gastroenterol Hepatol. 2000;15(suppl): E67-E Feng Y, et al. Chin Med. 2009;4:16.

64 Role of Western Medicine Providers in Overcoming Barriers
Interactions with patients Reassure Educate on disease and transmission Be sensitive to cultural attitudes Refer for assistance to access programs Have in-language materials and interpreter So, the role of us in terms of Western medicine providers in overcoming these barriers, as I’ve talked about, is interacting with the patient. We can be more reassuring, and we can certainly educate on disease and transmission. And it’s been shown in many studies again that using a professional interpreter is better than using a family member as an interpreter because there’s a dynamic that changes when you use a family member to interpret what you are discussing in terms of disease and transmission. We clearly need to be sensitive to cultural attitudes. If they don’t understand the disease or we’re not spending enough time with them or really understanding their cultural and religious beliefs, that’s going to impact their long-term management. And then refer them to access programs, so there are a lot of social workers and other local community centers and programs that may have educational programs for patients and certainly having readily available in your office in-language materials with an interpreter in all steps along the way in terms of the screening, the diagnosis, the discussion about treatment, would be key.

65 Role of Western Medicine Providers in Overcoming Barriers
Cultural training Education programs specific to their needs for their particular community Provide in-language materials to use/distribute Overcoming barriers: You may want to think about cultural training, especially if you practice in an area where you are seeing Asian patients who have cultural differences from you, so undergoing a lot of cultural training programs that are out there, educational programs specific to their needs in a particular community, and providing in-language materials.

66 Bridging the Gap With TCM and Western Medicine
Be open and nonjudgmental regarding concomitant TCM usage Overall better reported quality-of-care ratings if discussions are initiated Open dialogue and collegiality among Western clinical team and TCM practitioners, preferably in-language Team approach to treatment rather than “us vs them” or “right vs wrong” And I think being open and nonjudgemental regarding concomitant use of traditional or alternative therapies is important because I think the judgemental aspect—we may end up driving the patient away and not really being able to then have the appropriate therapy. So, patients overall reported better quality-of-care ratings if discussions are initiated, so we should initiate the discussion in a nonjudgemental way, leaving open the idea of maybe they can continue their herbal medication, if they are already on it, while you are also doing the recommended oral therapy for hepatitis B. And over time, as your relationship improves with that patient, you may discuss the discontinuation risk or benefit of continuing the alternative or complementary medicine. We should have an open dialogue and collegiality with the Western clinical team and the traditional or alternative medicine practitioners. I think that we should perhaps consider them colleagues, and preferably in-language, maybe approach these traditional medicine practitioners or alternative medication practitioners in a team approach to treatment. So we should talk to them as part of the team, as compared to an us vs them or a right vs wrong strategy, so having that sort of collegiality and teamwork approach to the patient may be more beneficial for the patient long term. Ahn AC, et al. Am J Pub Health. 2006;96: Ngo-Metzger Q, et al. J Gen Intern Med. 2003;18:44-52.

67 Go Online for More Information on Management of Hepatitis B

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