KEYNOTE ADDRESS - Hepatitis B: A Bright Future.doc.doc
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010KEYNOTE ADDRESS - Hepatitis B: A Bright FutureHie-Won Hann, M.D.Director, Liver Disease Prevention Center, Thomas Jefferson University, Philadelphia • The future of hepatitis B and liver cancer is much brighter today than in the past. Consider the stories of two young Asian men with chronic HBV who were both diagnosed with liver cancer: o In the early 1990’s, one man ultimately died within one year. o In 2000, the second man started antiviral therapy, and is still alive 10 years later. • Both of these men were my patients, and you can see how much progress there has been. • Treatment overview for primary Liver Cancer (or hepatocellular carcinoma, HCC). o HCC liver tumors have a lot of blood vessels in order to obtain oxygen to feed the tumor. o For Small tumors, generally TACE or RFA is considered to shrink and/or kill tumor cells: TACE (Transarterial chemoembolization) involves infusing chemotherapy drug directly into the hepatic artery to block the blood supply to the tumor. RFA (Radiofrequency ablation) is one treatment that is frequently used for HCC and is a type of heat therapy that “burns” the tumor tissue. Cryoablation involves injection of chemicals to freeze the tumor. PCEI (Percutanous ethanol injection) is an inexpensive method with a low rate of side effects where 100% ethanol is injected into the tumor. o For Large tumors, local therapies that were described above cannot be used; only systemic chemotherapy is effective. Unfortunately systemic chemo does not always work well and there are many side effects. o There is a recently approved oral drug that offers a new option for HCC – sorafenib - which seems to effectively arrest the tumor growth in many patients. o Liver transplantation is the final option for HCC that does not respond to medical treatment or surgical interventions. • Why are people living longer now, even those with small HCC tumors? The difference is antiviral therapy!! o 5 current antiviral FDA approved drugs (lamivudine, adefovir, entecavir, telbivudine, tenofovir). o There are more in clinical trials (visit the Hepatitis B Foundation’s Drug Watch at www.hepb.org . o There are two types of interferons that are approved for HBV (interferon alpha and pegylated interferon). o However, we need more therapeutic options as well. • Primary Liver Cancer (Hepatocellular Carcinoma – HCC) o 5th most common cancer in the world. o 3rd most common cause of cancer death in the world, because patients are diagnosed at advanced stages and there are few good treatment options at late stages. o Worldwide, 60% of HCC is caused by HBV and 25% is due to HCV (WHO, 2000) In endemic areas of Asia and Africa, the majority of HCC is due to HBV.
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010• The Liver o As the liver is damaged from a virus or other reason (drugs, injury, alcohol, etc.), liver cells die – this can be picked up by an ALT blood test (if AST is higher than ALT, it is usually alcohol-related cell death). o As the liver tries to heal itself, fibrous tissue begins to develop, and then liver cells grow up and out onto the surface of the liver, causing nodules – this leads to cirrhosis. o If a patient has HBV, how often do you see a normal liver? o Ultrasound cannot distinguish between the different types of liver damage (i.e. inflammation, fatty liver, cirrhosis), so an MRI is necessary. o When a person has HCC, the cancer cells “eat up” the normal liver cells, and the liver cannot function.• Discovery of the Hepatitis B virus (HBV) o Dr. Baruch Blumberg collected blood samples from Australian Aborigines, and found the “Australia Antigen” which he later identified as the hepatitis B virus (HBsAg), for which he won the Nobel Prize in Medicine. o Under electron microscope, Dr. Blumberg and his group saw particles of the HBsAg and whole virus particles. o When one of the researchers in his lab got hepatitis after a needle stick, they found that she had HBsAg circulating in her blood during illness and HBsAb after she recovered.• Dr. Hie-Won Hann’s research in Korea o Dr. Hann found so many people with jaundice, HCC and cirrhosis, but did not know why. o She drew blood, tested for HBsAg/HBcAb/HBsAb, and found that: HBsAg was found in 76% with “hepatitis” and 92% with cirrhosis and 72% with HCC. The culprit for these diseases was HBV – this was the first clear documentation that HBV caused all of these serious complications.• Dr. Palmer Beasley’s research in Taiwan o Conducted a study of 22,000 government workers in Taiwan and found that the risk of HCC was 60 times higher in HBV infected persons (which is much higher than the association between smoking and lung cancer, which is only 20-25 times). o Dr. Beasley’s research confirmed the link between chronic HBV infection and liver cancer! o His research also confirmed that perinatal transmission of HBV – that is, an infected woman could unknowingly pass the virus to her newborn during delivery.• Objectives of HBV treatment o Primary prevention: Stop infection with vaccine. o Secondary prevention: Stop progression of disease with management and treatment.• HBV Vaccine o First vaccine was invented by Dr. Baruch Blumberg and then licensed to Merck in 1983. o Once the vaccine was available, Drs. Blumberg, Hann and Tom London began to screen people in the Philadelphia region and established the Liver Cancer Prevention Center at Fox Chase Cancer Center.
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010 o Dr. Hann also tested and vaccinated people at Korean churches in Philadelphia. o More than 25,000 Korean Americans were tested and vaccinated! o In a study published in 2007 of 6,130 HBV tests, Dr. Hann found a carrier rate of 8-10% in males and 4-6% in women. o Of this group, 139 (42%) already had cirrhosis – why? They were infected at birth (i.e. they were unknowingly infected by their mothers; newborns who are exposed to the hepatitis B virus have a 90% risk of developing a chronic infection, which is why infant HBV vaccination is so important). o People infected at birth are at high risk for developing cirrhosis and liver cancer. • The HBV vaccine brought the incidence of chronic infection rates way down in Taiwan, China, Thailand, and U.S. • Universal HBV vaccination at birth and in young children removes the virus from the next generation. • Unfortunately, though, the vaccine does not help the 400 million people already infected. • We need to make sure to not forget these patients – it is our task to help them! • The “REVEAL” study showed that the most important risk factor for HCC is the hepatitis B virus itself! Those with high viral loads are at highest risk for progression to cirrhosis and HCC. • We can suppress viral replication with the antiviral drugs, which can also reverse non-severe cirrhosis. • Dr. Hann has a new paper published in the International Journal of Cancer, 2010 that reports: o Antiviral therapy reduces recurrence & improves survival in those diagnosed with HCC. o After the antiviral era, all of her chronic HBV patients - without cirrhosis - remain well without developing HCC while on antiviral therapy. • Risk factors for HCC o Cirrhosis, male, age over 40, Asian, chronic hepatitis, alcoholism, sustained serum ferritin (iron levels) higher than 300 nm/mL. • Who should receive therapy? o People who are HBsAg+ and are scheduled for chemotherapy need antiviral treatment HBV status can be a predictor of reactivation as can the type of cancer (i.e. lymphoma has the highest rate of reactivation). o Case study – pregnant woman with HBV High ALT during pregnancy when they stopped antiviral treatment – started treatment again during third trimester and ALT went down and baby was healthy. ALL antiviral agents are stopped during pregnancy until the 3rd trimester to avoid any potential problems. o Asian patients who have a family history of liver cancer. o There are also clear treatment guidelines developed by the American Association for the Study of Liver Diseases (AASLD).Questions and Answers o Is the hepatitis B virus genetically passed?
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010 o No, hepatitis B is an infectious disease. It can, however, be transmitted from an infected mother to her newborn during birth. But the newborn can be protected by giving one dose of HBIG and the first dose of the HBV vaccine in the delivery room (these medications must be given within the first 12 hours of life to prevent chronic infection!).o Do patients often need to change medications? o Sometimes they develop resistance to one drug, so then you need to add another drug or switch; as long as the viral load is going down (as opposed to being undetectable), one may want to keep the drug before switching.o When someone goes off treatment, and then the DNA climbs again years later, when do you treat? o If the virus is climbing, you treat immediately – it is a sign that the virus is actively replicating.o When do you recommend liver biopsy? o Now that we have good imaging studies and good biological markers (ALT, DNA), there is less need to biopsy. o Liver biopsy is a debate among specialists, so each patient and doctor needs to make the decision that is right for their situation.o Is it possible to remain a carrier for HBV and never develop symptoms? o Yes, only 25-40% develop any liver damage.o What are the symptoms of chronic HBV? o There are not many. Some people talk about fatigue, but most do not have symptoms.o For the future – how can we prevent resistance, and shorten the duration of therapy? o We need new therapies for this.
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010LIVING WITH LIVER CANCERSantiago Munoz, M.D.Medical Director, Liver Transplantation, Temple University, Philadelphia o Primary liver cancer has become more and more common – every week he sees several new patients who have been diagnosed, mostly due to HBV and HCV infections. o Primary liver cancer is the 6th most common cancer in the world. o There is Primary vs. Secondary liver cancer. o Primary begins in the liver (hepatocellular carcinoma, HCC). o Secondary is metastasis from another site. o 22,000 people in the U.S. diagnosed with primary liver cancer in 2009. o 20,000 people die each year in the U.S. (3,100 Hispanics diagnosed each year and 2,400 die). o African American men mortality rate from HCC is twice the rate of Caucasian men. o U.S. rates more than doubled between 1985-2002. o Hispanic women – fastest growth rate compare to others (63%). o There may be some environmental factors that change the risk for some groups (American-born Hispanic men are more likely develop HCC than immigrant Hispanic men). o HCC rates are highest among Asian and Pacific Islanders worldwide and in the U.S. o HCC risk goes up by age: it starts to increase at about 35 years of age in Asians and about 45 in African American and whites. o People with HBV need to be screened for HCC beginning at about 30 years of age. o Risk factors for HCC Hepatitis Cirrhosis NASH (non-alcoholic steatohepatitis) NAFLD (non-alcoholic fatty liver disease) Diabetes Mold poisoning (aflatoxin) Family history Alcohol consumption (excessive) o Goal of HCC screening o To detect HCC as early as possible, for the best treatment and cure options. o Ultrasound of the liver every 6 months and AFP both (and CBC). o Other options would include a CT-Scan or MRI. o Screening is key to every diagnosis!!! o A single CT-scan gives you as much radiation as 500 x-rays. This is one reason you would not necessarily use it as a first line screening for HCC – however, when an ultrasound shows some irregularity, the CT scan or MRI will show the exact dimension/location. o Symptoms of liver cancer
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010 o Most have no symptoms when the tumor is small. o When the tumor is larger, it blocks other structures and symptoms can develop: jaundice, bleeding, itching, ascites (abdominal bloating), and weight loss. These are all very late stage symptoms associated with large tumors and immediate medical attention is required.o The good news is that the liver can regenerate itself.o But with chronic HBV, this regeneration is disorganized and abnormal, leading to liver damage, fibrosis, cirrhosis.o Eventually, these abnormalities can develop into HCC.o There have been recent tremendous advances in the treatment of HCC – previously there was very little to offer.o Now, if picked up early, it can be cured.o Once liver cancer is diagnosed, then it needs to be staged – this determines how far the cancer has progressed, the extent of the cancer, how big it is, if it has spread and to where.o The treatment is tailored to the stage, or the extent of the cancer. o Stage 1 – single, very small tumor. o Stage 2 – several small tumors or single tumor that has spread to nearby blood vessels. o Stage 3 – one or more tumors that might have spread to other close body parts. o Stage 4 – spread to distant parts of the body.o Treatment is based upon several factors o How well the liver is working in the person who is diagnosed. o Stage of liver cancer. o Overall health of the person.o Treatment is best handled by a team approach. o Hepatologist, surgeon, pathologist, radiologist, medical oncologist, radiation oncologist.o Treatment Options o Transplantation – when tumors are small and few (less than 6.5cm) and the cancer has not spread, this is the treatment of choice. Today, about 1/3 of liver transplants in the U.S. is for HCC. o Resection – taking out part of the liver. If tumor is small, there is good liver function, and the tumor is right under the surface of the liver – if the tumor is deep in the liver, you would need to remove too much liver and the liver could not function.o Loco-regional treatment options These are done for tumors that cannot be removed, when cancer has spread, or to prepare someone for transplant (shrink the size of the tumor while they are on waiting list), which can buy precious time for a person, either time of life or until a liver transplant is possible. Cryotherapy – freeze/destroy tumor with chemicals. Radiofrequency Ablation (RFA) – high heat to destroy. Transarterial chemoembolization (TACE) – block use blood supply of the tumor by injecting local chemotherapeutic agents into the blood system; this targeted approach reduces the side effects of systemic chemo. Ethanol injection directly into tumor.
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010 Radiotherapy – high energy radiation to shrink tumor. o Systemic treatment options o Involves the whole body. o Targeted biological therapies have been developed that help block the growth and spread of cancer without killing healthy cells. o The only oral medicine approved for HCC that cannot be removed surgically is sorafenib. o Sorafenib blocks the chemical process that the tumor needs and it cuts off blood supply. o In clinical trials, 33% who received placebo and 44% of people who received the drug were alive at one year (clinically significant difference). o Compared with systemic chemo, it is very well tolerated. o It is also approved for primary kidney cancer. o Side effects can include high BP, hand and foot skin rash, bowel perforation, wound healing problems.Questions and Answers o For consistent screening for HCC, is ultrasound accurate enough and is one place better than another (hospital vs. radiology center)? Yes, ultrasound technique is well established in the U.S. and outside facilities should be just as good as hospital-based. All are reviewed by radiologists. If a person is obese, an MRI is better. What are the thresholds for AFP that should cause concern? • In someone with HBV or HCV, the AFP does go up and down. Normal is less than 5 or 6. • The AFP will fluctuate over time because in hepatitis, the liver cells are constantly trying to regenerate, and are secreting AFP into the blood. • There is no real fixed number to worry about – look at the track record – if there is a big difference at some point, you would follow-up with something else (MRI). • Most liver cancers do not produce AFP, and it is not by itself a very good screening test – it needs to be used with ultrasound. Please explain liver regeneration. In a healthy person, 80% of the liver can be removed and it will grow back within a few weeks. In a person with HBV or HCV, the regeneration leads to cirrhosis (abnormal or disorganized regeneration). Why aren’t liver transplants used more often to treat HCC? Donor availability is a problem – 18,000 people in the U.S. are on the waiting list, and there are only 5,000 donors each year. We need to promote organ donation. For HBV, transplant is a good option for HCC because after transplant, them antivirals drug therapies can be given, which are very good in preventing the HBV from returning.
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010 There is more of a problem with HCV, since there are not really good treatment options for HCV post-transplant to prevent re-infection. How are decisions made as to who gets a liver? There is a protocol – before 2002, it was very subjective – now, there are government guideline . Organs are distributed by how sick a person is – those with the worst liver function are at the top of the list – this helped to level the playing field. Those with HCC are put into a special category because HCC is so fatal, so these patients are put higher on the waiting list; this why 1/3 of liver transplants are for HCC. What happens to the tumor after RFA or TACE? The therapies injure or kill 80-90% of the cancer, but they are not cures – they can buy a lot of time, though. The tumor just becomes dead tissue which you can see on a CT-scan - the body then develops inflammation around that area which turns into scar tissue – however, whatever cells are left will start to grow eventually. When do you use the oral drug as opposed to the loco-regional options? o The official FDA indication for using sorafenib is when HCC is unresectable (that is, cannot be removed surgically because it is too large. o It is used for multi-modal treatment with the locoregional options (RFA, TACE) – so they might start on sorafenib right away and then schedule a TACE and be evaluated for transplant as well.
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010Current Hepatitis B TreatmentKenneth Rothstein, M.D.Chief, Division of Gastroenterology and Hepatology, Drexel University, Philadelphia o Everyone at risk for HBV should be screened. o It is important to have at least one, if not two, opinions on whether you need biopsy or treatment. o HBV is very complicated. It keeps changing, and everyone has different opinions about who should be biopsied and treated (best two out of three opinions!). o Anyone who has HBV is at increased risk for liver cancer. o Interferon is likely more effective than the oral agents. o Side effects and injection are negatives. o Defined treatment period and success rates are potential benefits. o Cascade of HBV o Virus replicates, causes inflammation, leads to cirrhosis/fibrosis, HCC, can lead to the need for transplant or death. o Important to keep your weight down, exercise, watch your diet, and limit alcohol. o Acute HBV is most likely asymptomatic – most patients do not know they are sick and don’t seek medical attention – there might be flu-like symptoms, jaundice, fatigue (may lose their urge to smoke). o From his practice, HCV patients have many more symptoms than his HBV patients – this might have to do with the mode of acquisition (psychological components), but they don’t know why it really occurs. o HCV patients also tend not to tolerate interferon as well as HBV patients – it could be that people who have addictive personalities might just have a lower threshold for pain (physical and emotional). o The liver is the only organ we can’t live without!! It is the most important organ in your body! o Microscopic cirrhosis will not always show up on the surface of the liver, but most of the time a cirrhotic liver will not look normal.Liver Cancer o Any cirrhotic patient of any type has a 3% chance of developing liver cancer every year. o With HBV, you do not need to have cirrhosis to develop HCC. o Even patients who recover from HBV have some increased risk of developing HCC – however, there is no feasible way of screening all of them for HCC.
B INFORMED NOW! PATIENT WORKSHOP Holiday Inn Express Midtown, Philadelphia, PA Saturday April 24, 2010 Even if someone is treated, responds, and becomes HBsAg-, they need to be screened every 6 months for HCC – they can still develop HCC – although there are no guidelines for this population. o There is evidence that the more HBV virus you have in your body, the worse your outcome will be (REVEAL) – this is the evidence for treatment to reduce the amount of virus you have.Treatments o In his experience, adefovir is not very helpful – but, both entecavir and tenofovir are very safe and effective. o Lamivudine can still be very effective against HBV reactivation – chemotherapy, other immune depressing treatments, steroids. o Pegylated interferon FDA approved. More effective in resulting in eAg- and sAg- seroconversion than antivirals. Not for use in individuals with decompensated cirrhosis. eAg loss following treatment with interferon increases possibility of losing HbsAg. Because of side effects from interferons, more patients choose oral antivirals. Interferon is the only treatment for HBV/HDV co-infection. Pegylated interferon with eAg- disease • At end of follow-up (wk 72), pegylated interferon had better outcomes than lamivudine and there was no difference from combination treatment. • In those with combined result (ALT normal and dropped DNA), 2% lost sAg with Peg and 0% lost sAg with lamivudine. • eAg+ disease o eAg conversion 32% with PEG, 27% with combination, 19% with lamivudine alone. o In those with ALT that is greater than 5 times the ULN, lamivudine is an option because it works well. o Using DNA and ALT levels, one can tell what chance a person has of seroconverting with interferon (very high ALT and low DNA has 52%). o In eAg+ patients and Peg, 30% lost eAg, 10% lost sAg. o PEG can be a first line therapy for both eAg+ and eAg- HBV. • Two new techniques are coming on the market to replace biopsy – MRI and ultrasound that are more specific and will be able to tell the degree of liver damage. Questions and Answers • Are there any studies that include longer durations of pegylated interferon? o He hasn’t seen anything published on this, but these studies should be done. • Patients with genotype C do not respond to pegylated interferon, is that correct? o Yes, that is true, but he makes decision independent of genotype.