Cco role of_hbv_downloadable

Editor's Notes

1. HBV, hepatitis B virus.   My name is Steven-Huy Han, MD, AGAF, and I am a Professor of Medicine and Surgery at the David Geffen School of Medicine at UCLA, Los Angeles, California. This presentation will review the role of hepatitis B virus (HBV) in the burden of hepatocellular carcinoma (HCC).
2. HCC, hepatocellular carcinoma.   The first topic is the public health burden of HCC in the United States.
3. HCC, hepatocellular carcinoma.   Hepatocellular carcinoma is common and the incidence is increasing. The number of deaths caused by liver cancer each year exceeds 660,000 worldwide, and the incidence in the United States has increased 2-fold from 1985-1998. It is estimated by the American Cancer Society that the number of new cases of liver cancer in the United States during 2010 will be more than 24,000, with approximately 18,500 estimated deaths caused by this disease. Hepatocellular carcinoma is currently the fifth leading cause of cancer deaths in males.
4. HCC, hepatocellular carcinoma; SEER, Surveillance, Epidemiology, and End Results.   In the United States, HCC accounts for a large proportion of medical healthcare expenditures with the per-patient cost estimated to be $32,907. Healthcare costs accounted for 89.2% of the total expense and lost productivity from HCC was responsible for the remaining 10.8%.
5. HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.   Viral hepatitis is an important risk factor for HCC. Worldwide, approximately 75% to 80% of HCC cases are attributable to chronic HBC or hepatitis C virus (HCV) infection. The graph on this slide shows the distribution of risk factors among HCC patients in the United States. Although HCV infection is present in the highest proportion of liver cancer cases, chronic HBV infection is nonetheless an important risk factor present in 15% of HCC cases. Both HBV and HCV are present in 5% of HCC cases.
6. HBV, hepatitis B virus.   Chronic hepatitis B is a predominant problem among Americans from Asia and the Pacific Islands. Although this group represents only 4.5% of the general US population, they constitute more than 50% of American chronic hepatitis B patients.
7. HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   Hepatitis B virus infection and HCC represent the greatest health disparity between Asian and white Americans. Among Asian men living in the United States, HCC is the second leading cause of cancer death. Furthermore, HCC incidence is 9 times higher in Asian American men than in white American men.
8. There has been an increase in the number of chronic hepatitis B patients in the United States mainly as a result of immigration from countries of high prevalence. Approximately 3.57 million Asians immigrated to the United States from 2000-2009 as well as approximately 3 million individuals from Europe, Africa, and South America. However, the United States is still considered to have a low prevalence of chronic hepatitis B.
9. API, Asia and Pacific Islands; CHB, chronic hepatitis B; HBV, hepatitis B virus.   Chronic hepatitis B has been called the “silent killer” because approximately 65% of Asian Americans who are infected with HBV are unaware of their infection. To reduce this proportion, primary healthcare providers should strive to educate patients and encourage HBV screening when any risk factors are present.
10. API, Asia and Pacific Islands; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma.   Diagnosing chronic hepatitis B is important because it is a predominantly asymptomatic condition that can result in the onset of serious liver disease if left untreated. Over time, progression of chronic hepatitis B can lead to liver cirrhosis, liver failure potentially requiring transplantation, and HCC.  
11. CHB, chronic hepatitis B; HBV, hepatitis B virus.   Individuals born in areas of high or intermediate HBV prevalence (≥ 2%) represent one of the most important high-risk groups who should be screened for chronic HBV infection. Such regions include all countries in Asia, Africa, and the South Pacific islands, most nations in the Middle East except Cyprus and Israel, Malta, and Spain in the European Mediterranean, indigenous people in the Arctic, many countries in South America and the Caribbean, all countries in Eastern Europe except Hungary, and Guatemala and Honduras in Central America.
12. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.   Other groups that have been recommended for chronic hepatitis B screening include: US-born persons not vaccinated as infants whose parents were born in regions of high HBV endemicity (≥ 8%); any person with household or sexual contact with HBV-infected individuals, injection drug users, men who have sex with men, persons who have elevated aminotransferases of unknown etiology, persons with selected medical conditions who require immunosuppressive therapy, pregnant women, infants born to hepatitis B surface antigen (HBsAg)–positive mothers, persons who are the source of blood or body fluid exposures that might warrant postexposure prophylaxis, and persons infected with HIV.
13. HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; STD, sexually transmitted disease.   Recommendations for HBV vaccination include universal vaccination of all infants at birth. Children who are not vaccinated as infants also should be vaccinated. Adult vaccination is recommended for individuals who are considered to be at risk for HBV infection, including adults who are traveling to regions of high or intermediate endemicity; susceptible sexual partners and household contacts of HBsAg-positive persons; persons seeking evaluation or treatment for sexually transmitted diseases; persons with behavioral or occupational exposure, including healthcare providers; persons with end-stage renal disease or chronic liver disease; and residents or staff in certain settings with clients who have known HBV risk factors.  
14. HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   The next topic is HBV treatment indications and the relationship with HCC.  
15. HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.   Several factors have been identified that increase the risk for HCC in HBsAg-positive individuals. Host-specific risk factors include age older than 40 years, male sex, Asian or African ancestry, and a family history of liver cancer. Viral risk factors include hepatitis B e antigen positivity, higher HBV DNA levels, infection with HBV genotypes B or C, and the presence of the precore or the basal core promoter mutation. Cirrhosis and coinfection with HCV are also associated with higher HCC risk. Finally, other potential risk factors for liver cancer in this population include smoking, alcohol use, obesity, and diabetes.  
16. HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   This slide summarizes the results of the REVEAL study, a prospective cohort analysis that assessed the risk of HCC according to baseline factors in 3653 HBsAg-positive individuals in Taiwan who were followed for a mean of 11.4 years. The graph on the left demonstrates that increasing baseline HBV DNA levels were associated with increasing risk of developing HCC. For example, the risk of HCC was significantly higher in patients with a baseline HBV DNA 10,000-99,999 copies/mL compared with patients having baseline HBV DNA < 300 copies/mL (adjusted hazard ratio: 2.3; P = .02). The graph on the right indicates that baseline liver cirrhosis was also significantly associated with a higher risk of developing HCC relative to patients with no cirrhosis (adjusted hazard ratio: 9.1; P < .001).  
17. CI, confidence interval; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   Among the subset of patients in the REVEAL study with follow-up HBV DNA assessments, persistent HBV DNA elevations during follow-up were also associated with an increased risk of HCC. The graph on this slide demonstrates that among patients with baseline HBV DNA ≥ 100,000 copies/mL, patients who maintained this HBV DNA level at follow-up had a 10-fold increased risk of developing HCC relative to patients who had baseline HBV DNA < 10,000 copies/mL. By contrast, patients with HBV DNA ≥ 100,000 copies/mL at baseline but < 10,000 copies/mL at follow-up had a 3.8-fold increased risk of HCC relative to patients with baseline HBV DNA < 10,000 copies/mL.
18. CHB, chronic hepatitis B; CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; LAM, lamivudine.   A randomized study conducted by Liaw and colleagues compared the impact of lamivudine (n = 436) vs placebo (n = 215) therapy in patients with advanced chronic HBV infection, defined by the presence of bridging fibrosis or cirrhosis at study entry. The results showed that the risk of disease progression was significantly lower in patients treated with lamivudine compared with patients who received placebo ( P = .001). These data provided proof of the concept that viral suppression using effective antiviral therapy could slow the progression of disease. In this trial, disease progression was defined as a ≥ 2 point increase in the Child-Turcotte-Pugh score, spontaneous bacterial peritonitis with sepsis, renal insufficiency, bleeding varices, liver-related death, or HCC.   Reference: Liaw YF, Sung JJY, Chow WC, et al. N Engl J Med. 2004;351:1521-1531.
19. AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ULN, upper limit of normal.   This slide addresses a frequently asked question: What role, if any, does HCC play in deciding whether to start a patient on treatment for chronic hepatitis B? The presence or absence of liver cancer or a family history of liver cancer is not currently a specific indication for starting hepatitis B therapy. However, there is some controversy surrounding this issue, particularly in patients with high HBV DNA levels. Based on evidence from the previously discussed REVEAL study showing that high HBV DNA is a risk factor for liver cancer and the potential that a positive family history of liver cancer may further increase this risk, many clinicians are inclined to initiate antiviral therapy in patients with a family history of HCC based on this family history alone, despite the fact that the data do not yet provide clear support for this strategy. Although the presence of a family history of liver cancer is not an independent indication for treating hepatitis B in any of the current treatment guidelines, in the subset of patients with immunotolerance, defined as having high HBV DNA levels but normal or low alanine aminotransferase levels, the American Association for the Study of Liver Diseases (AASLD) management guidelines recommend considering a liver biopsy to decide on treatment if the patient is older than 40 years of age, has persistent alanine aminotransferase levels in the high to normal range (2 times the upper limit of normal), or has a family history of HCC. However, the exact role of liver cancer in hepatitis B treatment indications has not been clearly defined as yet.
20. HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   The next section of this presentation reviews surveillance and diagnosis strategies for HCC in patients with chronic HBV infection.
21. HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   According to the current AASLD guidelines for HCC, patients with HBV for whom HCC surveillance is recommended include Asian males older than 40 years of age, Asian females older than 50 years of age, patients with a family history of HCC, African/North American blacks, and patients with established cirrhosis.  
22. AFP, alpha-fetoprotein; CI, confidence interval; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; US, ultrasound.   Zhang and colleagues conducted a clinical trial to assess the impact of routine HCC surveillance on HCC-related mortality. Investigators randomized 18,816 patients in Shanghai, China, with HBV infection or a history of chronic hepatitis to receive semiannual alpha-fetoprotein (AFP) and ultrasound screening (n = 9373) or no surveillance (n = 9443). The use of HCC surveillance was associated with a 37% reduction in the incidence of HCC-related mortality.
23. AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; PPV, positive predictive value.   What is the sensitivity of serum AFP surveillance in HCC? The table on this slide lists several studies addressing this question. The results of these analyses demonstrate that the sensitivity ranges widely from 41% to 97% between studies. The specificity of the test was fairly high overall in the studies in which it was calculated; however, the positive predictive values were quite low, ranging from 9% in one study to 46% in another analysis. These data indicate that serum AFP as a single test for the diagnosis of HCC has, in general, performed poorly and, as a result, is not recommended as a surveillance test in management guidelines.  
24. HCC, hepatocellular carcinoma; US, ultrasound.   The performance characteristics of ultrasonography as an HCC surveillance tool are superior to any serologic test—the sensitivity is 65% to 80% with a specificity > 90%. Therefore, management guidelines recommend that ultrasonography be considered the surveillance tool of choice in screening for HCC.
25. CT, computed tomography; HCC, hepatocellular carcinoma; NPV, negative predictive value; PPV, positive predictive value.   Computed tomography (CT) scanning has also been considered as an HCC surveillance tool. However, the positive predictive and negative predictive values of CT scanning for this indication are unknown, and there is currently no evidence to support the use of CT scanning for routine HCC surveillance. Although 4-phase contrasted CT is very accurate, it is associated with significant radiation exposure. In the absence of contrast, CT scans have a very high false positive rate primarily because the lack of contrast makes it difficult to distinguish small HCCs from dysplastic nodules or other vascular cirrhotic nodules.
26. AFP, alpha-fetoprotein; US, ultrasound.   Studies have demonstrated that combining serum AFP testing with ultrasonography for HCC surveillance increases the detection rate; however, this combination also increases the false positive rate and, consequently, is more expensive. False positive results lead to further testing with CT scans and/or magnetic resonance imaging, which contributes to the higher cost.   The false positive rate with AFP testing alone is 5%, with ultrasound alone is 2.9%, and with combination AFP and ultrasound is 7.5%. The resulting cost of ultrasonography surveillance is $2000 per tumor found whereas the combination of AFP and ultrasonography costs $3000 per tumor found. Therefore, the combination of AFP and ultrasonography is not recommended in current HCC guidelines.  
27. HCC, hepatocellular carcinoma.   Another important question regards the optimal HCC surveillance interval. The results of a retrospective analysis demonstrated that survival rates were similar with 6-month vs 12-month surveillance intervals. In addition, a separate study showed that the rate of detection of single nodules (vs multinodular HCC) was similar with 6-month vs 12-month surveillance intervals. However, a more recent nonrandomized, prospective cohort study involving patients infected with HBV found that 6-month surveillance intervals were associated with improved survival relative to 12-month intervals. Based on the known tumor doubling time, most physicians would recommend a 6-month surveillance interval.  
28. AASLD, American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma; US, ultrasound.   The AASLD HCC guidelines recommend surveillance in at-risk groups including certain hepatitis B carriers as outlined earlier in the presentation and patients with nonhepatitis B cirrhosis. According to these guidelines, HCC surveillance should be performed with ultrasound and patients should be screened at 6-month intervals. A surveillance interval shorter than 6 months in patients with a higher risk of HCC (ie, multiple risk factors) is not required.  
29. AFP, alpha-fetoprotein; CT, computed tomography; ICC, intrahepatic cholangiocarcinoma; HCC, hepatocellular carcinoma; MR, magnetic resonance; MRI, magnetic resonance imaging; US, ultrasound.   Regarding the tools for diagnosing HCC, serum AFP alone is no longer recommended because of difficulties with specificity, in particular, distinguishing HCC from intrahepatic cholangiocarcinoma. Diagnosis currently relies mainly on radiologic imaging or histology via biopsy. A diagnosis of HCC is possible with radiologic imaging alone if contrast-enhanced CT or magnetic resonance is used. If the lesion is < 1 cm on ultrasound, it is recommended that the lesion be followed every 3-6 months with ultrasound. If the tumor or lesion is > 1 cm on ultrasound, then it is recommended that further characterization with contrasted CT or magnetic resonance is undertaken. Biopsy is still definitive, although small lesions require evaluation by expert pathologists. If a biopsy is negative for HCC, the lesion should be followed by imaging every 3-6 months.
30. HCC, hepatocellular carcinoma.   The next section addresses HCC staging and treatment considerations.
31. HCC, hepatocellular carcinoma.   Treatment for HCC is often suboptimal. A study by El-Serag and colleagues examined the use of potentially curative therapy according to disease stage in a cohort of 2963 Medicare patients with HCC. Among patients with single lesions or patients with lesions < 3 cm, only 34% received potentially curative therapy. The rate of potentially curative treatment use was 19.2% in patients with lesions > 10 cm and 4.9% in patients with metastatic disease. Among patients who were ideal candidates for transplantation, 11.5% received transplantation. Similarly, among ideal candidates for surgical resection, 12.9% received surgical resection.   For more information, please online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Articles/El-Serag-JHepatol-2006-01/Capsule.aspx
32. HCC, hepatocellular carcinoma.   The treatment options available for HCC fall into 3 categories: surgical, locoregional, and systemic. Surgical options include resection of the tumor and liver transplantation. Locoregional therapies include percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization, and yttrium-90 spheres. Finally, patients with HCC can be treated systemically with sorafenib.
33. AASLD, American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma; PEI, percutaneous ethanol injection; PST, performance status; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.   This slide depicts the AASLD guidelines regarding the staging and treatment of patients with HCC. Patients with very early­–stage disease consisting of a single lesion < 2 cm in size and no evidence of portal hypertension or liver dysfunction are candidates for potentially curative resection. However, in patients with early-stage disease who have 1-3 lesions ≤ 3 cm in size or evidence of portal hypertension or liver synthetic dysfunction, liver transplantation may be an option for cure.   Among patients with Child-Pugh A-B disease and higher performance score (up to 2), patients with early-stage disease defined as 1-3 lesions ≤ 3 cm in size with evidence of liver synthetic dysfunction are also eligible for potentially curative liver transplantation with the addition of local-regional therapy as necessary to restrict tumor size.   Patients who have intermediate-stage, multinodular, or multifocal HCC who are not considered resection or transplantation candidates can only receive palliative treatment modalities. Such patients may be eligible for chemoembolization.   Patients who have advanced-stage disease, as defined by either portal invasion or lymph node metastases, are best served by systemic, palliative treatment with sorafenib.   Finally, for patients who have markedly advanced, terminal-stage HCC, treatment is purely symptomatic.
34. HCC, hepatocellular carcinoma.   Eligibility for liver transplantation for HCC according to the Milan criteria includes patients who have a single tumor ≤ 5 cm or up to 3 tumors all ≤ 3 cm, in the absence of macroscopic vascular invasion or extrahepatic spread.  
35. Patients with confirmed liver cancer should be referred to a tertiary care center with specific expertise in the management of this disease. In most of these centers, patients with HCC are treated by a multidisciplinary team of specialists that includes a hepatologist, a pathologist, an interventional radiologist, a surgeon, and an oncologist.
36. HCC, hepatocellular carcinoma.   An important component of managing patients with chronic HBV infection is the development of a patient and family teaching plan. This plan should include a discussion of the mode of transmission and how to prevent the spread of viral infection. Hepatitis B virus is parenterally transmitted, meaning that it requires blood-to-blood contact. Therefore, modes of transmission include injection drug use and sexual contact. In addition, there is a high rate of vertical transmission from mother to child at birth; indeed, this is the most common mode of transmission among Asians and Pacific Islanders. Other risk factors for parenteral transmission that should be avoided include sharing of razors and toothbrushes. However, the most effective method of preventing hepatitis B infection is vaccination, and it is recommended that family members and close contacts of any patients with hepatitis B infection should be vaccinated.   It is also important to discuss the value of maintaining a healthy lifestyle, including a healthy diet and exercise, to promote immune health and protect against viral disease progression.   The signs and symptoms of hepatitis B infection should be reviewed with patients. In the early stages of disease, most patients are asymptomatic. At more advanced stages, patients may describe symptoms of fatigue, muscle wasting, water retention, and clinical jaundice or yellowing of the eyes and skin; however, most of these symptoms are associated with late-stage disease.   There are several US Food and Drug Administration–approved treatments for chronic HBV infection currently available, including oral and injectable medications. Patients should be informed that the general goal of treatment is to decrease viral replication and suppress the virus to undetectable levels to prevent or delay progression of disease to cirrhosis and liver cancer.   It is critical that patients are educated on the importance of strict treatment adherence to antiviral therapy. Inadvertent interruptions in therapy can be harmful because they can lead to the development of viral resistance to medication.   Chronic hepatitis B even without the development of cirrhosis is a very important risk factor for the development of HCC; therefore, many patients with chronic hepatitis B should undergo regular screening with periodic abdominal ultrasound to look for any new lesions developing in the liver.  
37. HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   The next section of this presentation reviews HBV management in patients with HCC.
38. CI, confidence interval; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio; LAM, lamivudine; RFA, radiofrequency ablation.   Antiviral therapy following HCC treatment has been shown to reduce HCC recurrence. A study by Kubo and colleagues compared treatment with lamivudine (n = 14) vs no antiviral therapy (n = 10) following resection for liver cancer. Patients who received lamivudine after resection experienced a significant improvement in tumor-free survival vs patients who were untreated ( P = .0086).   The results of a retrospective study involving 103 patients who received radiofrequency ablation for initial liver cancer showed that a high HBV DNA level ( P = .007) and the absence of antiviral therapy ( P = .005) were independent risk factors for HCC recurrence by multivariate analysis.
39. ADV, adefovir; CHB, chronic hepatitis B; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LAM, lamivudine; TDF, tenofovir.   The impact of HBV therapy on recurrence and survival following HCC treatment was also assessed in a study conducted by Hann and colleagues. In this trial, 15 patients with chronic HBV infection and early-stage HCC, defined as single nodules ≤ 4 cm, received local ablative therapy. All patients had a complete response to HCC therapy, and no antiviral therapy was given before the HCC diagnosis. Following diagnosis, 9 patients received antiviral therapy with lamivudine with or without the addition of tenofovir or adefovir. The remaining patients did not receive antiviral therapy. Among patients who received antiviral therapy, HCC recurrence occurred in only 2 patients, and the median survival in this group was 60 months. By contrast, in the untreated control group, all 6 patients experienced HCC recurrence, and median survival was significantly shorter at 12.5 months ( P = .006).  
40. HBV, hepatitis B virus.   An important point regarding the management of HBV infection during chemotherapy or immunosuppressive therapy is that 20% to 50% of patients experience HBV reactivation during such treatment. Therefore, prophylactic antiviral therapy is recommended in HBV patients at the onset of chemotherapy or immunosuppressive therapy. If the baseline HBV DNA is < 2000 IU/mL, it is recommended that treatment be continued for 6 months. If the baseline HBV DNA is > 2000 IU/mL, treatment should be continued until they reach treatment endpoints for hepatitis B. Entecavir or tenofovir are preferred agents for antiviral therapy in this setting, particularly if treating for longer periods of time, based on the low risk of viral resistance associated with these agents.  
41. AASLD, American Association for the Study of Liver Diseases; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   To conclude this presentation on HBV and HCC, there are several important take-home messages. The first key point is that hepatitis B is prevalent among Asian Americans, and it is important to screen patients who are considered at risk for chronic HBV infection because it is an important risk factor for the development of HCC. Diagnosing hepatitis B carriers enables subsequent surveillance for HCC.   Another important point is that increasing data support the importance of HBV replication in the pathogenesis of HCC. Therefore, in addition to diagnosing hepatitis B, patients need to be regularly monitored for increasing HBV DNA levels and treated with anti-HBV agents as appropriate.   Hepatocellular carcinoma surveillance should be performed in certain patients with chronic HBV infection as recommended by the AASLD guidelines. These patients include Asian men older than 40 years of age, Asian women older than 50 years of age, patients who have a family history of HCC, patients with cirrhosis, and African/North American blacks.   Finally, treatment for HCC is evolving. Potentially curative treatments include resection or liver transplantation. Following the diagnosis of HCC, patients must be accurately staged to determine the optimal treatment approach. Palliative treatments are recommended for patients with later stages of disease; these therapies also can be used as a prelude to possible transplantation. The use of sorafenib for systemic therapy is an option for patients with advanced or metastatic disease. Hepatocellular carcinoma is a difficult disease entity to treat, and most patients should be referred to expert tertiary care centers that offer a multidisciplinary approach to treatment.