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HCC Tripled in USA/Treatment Normalized Survival,
would Reduce HCC by 60%-new studies
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"......incidence of HCC has almost tripled......HCC cases increased from 37,697 between 1990 and 1999..... to 130,366 cases between 2010 and 2019.....treatment of all infected individuals would reduce the risk by 60.4% after just 10 years. Thus, a reduction in the incidence of HCC may not be achieved unless an increasing number of patients are diagnosed and treated...."
Changing Hepatocellular Carcinoma Incidence and Liver Cancer Mortality Rates in the United States..[Am J Gastro 2014 ...http://www.natap.org/2014/HCV/050514_01.htm]..... "Incidence rates only increased among blacks, Hispanics, and white men and women aged 50+ years........US liver cancer mortality rates increased with age in all racial/ethnic groups..... Among individuals aged 50-64 years, blacks had the highest mortality rate (18.6), followed by Hispanics (13.5), Asians/Pacific Islanders (13.0), and whites (7.7)......overall liver cancer mortality rates significantly increased during 2000-2010 (APC=2.1%, annual percent change), with a less rapid increase among individuals aged 65+ years (APC=1.1%) than among individualss aged 50-64 years (APC=5.6%)."
The incidence of HCC has almost tripled since the early 1980s in the United States where it is the fastest rising cause of cancer-related deaths......The risk of developing HCC in cirrhosis patients varies with the underlying condition. The highest 5-year cumulative risks are seen in HCV cirrhosis (17% in the West and 30% in Japan), hemochromatosis (21%), HBV cirrhosis (10% in the West and 15% in Asia), alcoholic cirrhosis (8%-12%), and biliary cirrhosis (4%)......co-infected with HCV (and to a lesser extent HBV) and HIV have faster progression to cirrhosis and decompensated liver disease, especially during immunosuppression, than patients with mono infection.......For both HBV and HCV, men have 2-4 times greater risk of HCC across almost all liver disease etiologies than women......A recent mathematical model based on the prevalence and natural history of HCV in the U.S. general population of HCV-infected individuals estimated that the
number of HCC cases increased from 37,697 between 1990 and 1999 to 86,765 (+130%) between 2000 and 2009, with a projected increase to 130,366 (+50%) cases between 2010 and 201954. We found similar time trends in the prevalence of HCC in a national cohort of Veterans with HCV55. Among HCV infected Veterans who visited the VA in a given calendar year, the prevalence of HCC increased 19-fold from 0.07% (95% CI, 0.04% to 1.0%) to 1.3% (95% CI, 1.23% to 1.35%) from 1996 to 2006 (p<0.0001).Recent data show that approximately 45%-70% of individuals with HCV in the United States remain unaware of their infection STATUS53. Based on the mathematical model by Davis et al.54, assuming an SVR rate of ~80%, antiviral treatment will decrease cases of cirrhosis by a mere 5% in 2020. However, extending the treatment of half of infected persons would reduce HCC by 30.2%; treatment of all infected individuals would reduce the risk by 60.4% after just 10 years. Thus, a reduction in the incidence of HCC may not be achieved unless an increasing number of patients are diagnosed and treated.
HCV Viral Load Suppression Reduced Death, Risk for Liver Events: new study http://www.natap.org/2013/HCV/111413_02.htm
SVR Normalized Survival in Dutch Study AASLD: Comparison of the overall survival between patients with HCV-induced advanced hepatic fibrosis and the general population - (05/15/14)
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Epidemiology of Hepatocellular Carcinoma in the United States: Where Are We?
Where Do We Go?
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record.
Hepatology May 17 2014
Hashem B El-Serag, Fasiha Kanwal
1,2 Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs
Medical Center, Baylor College of Medicine; 1,2 Houston VA HSR&D Center of
Excellence Houston, Texas, USA.
Excerpts.......
Hepatocellular Carcinoma (HCC) in the United States: Current Epidemiological
Trends:
The incidence of HCC has almost tripled since the early 1980s in the United States where it is the fastest rising cause of cancer-related deaths1. According to population based Surveillance Epidemiology and End Results registry data, the overall HCC age adjusted incidence rates for liver and intrahepatic ducts cancer is as high as 8 per 100,000 underling population in 2010 (Fig. 1) of which at least 6 per 100,000 related to HCC. Men are at approximately three times higher risk than women. Asian men (i.e., Chinese, Korean, Filipino, and Japanese) have the highest age-adjusted incidence rates. However, the largest proportional increases have occurred among Hispanics followed by blacks and non-Hispanic whites, whereas the lowest proportional increases have occurred among Asians. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics2. HCC incidence rates have increased in each successive birth cohort born between 1900 and 1959 3(Fig. 2). In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45-60 years old (Fig. 2). There is a south to north gradient in the incidence and mortality of HCC; Southern states including Texas, Louisiana, and Mississippi have some of the highest HCC incidence rates in the nation (Fig. 3). In one study, Texas Latino and especially South Texas Latinos had the highest age-adjusted HCC incidence rates (as high as 10.6/100,000)4.
Future Burden of HCC
In the US, the incidence of HBV-related HCC is likely to remain steady. Though vaccination against HBV could prevent HCC, it does not prevent cancer in persons with chronic infections. A larger proportion is chronically infected with HCV-most of them are unaware of their infection status53. Testing persons at high risk for infection, educating patients, and administering effective therapies for treating HBV and HCV is therefore an important component of prevention against HCC.
A recent mathematical model based on the prevalence and natural history of HCV in the U.S. general population of HCV-infected individuals estimated that the
number of HCC cases increased from 37,697 between 1990 and 1999 to 86,765 (+130%) between 2000 and 2009, with a projected increase to 130,366 (+50%) cases between 2010 and 201954. We found similar time trends in the prevalence of HCC in a national cohort of Veterans with HCV55. Among HCV infected Veterans who visited the VA in a given calendar year, the prevalence of HCC increased 19-fold from 0.07% (95% CI, 0.04% to 1.0%) to 1.3% (95% CI, 1.23% to 1.35%) from 1996 to 2006 (p<0.0001).
Collectively, these data show that number of individuals with HCV related HCC has continued to rise and is projected to peak in 2019.
Although the incidence of HCV-related HCC is expected decline after 2020, this may not translate into a parallel decrease in the number of overall HCC cases. NASH-related cirrhosis is rapidly becoming an important cause of HCC. Given the very high prevalence of the metabolic syndrome in the U.S., even small increases in risk related to NASH could translate into a large number of cases of HCC.
The recent breakthrough in the management of HCV may indeed change the trajectory of HCC in the U.S. However, data show that the benefit of antiviral treatment
is primarily limited to patients with successful eradication of the virus. Recent data show that approximately 45%-70% of individuals with HCV in the United States remain unaware of their infection STATUS53. Based on the mathematical model by Davis et al.54, assuming an SVR rate of ~80%, antiviral treatment will decrease cases of cirrhosis by a mere 5% in 2020. However, extending the treatment of half of infected persons would reduce HCC by 30.2%; treatment of all infected individuals would reduce the risk by 60.4% after just 10 years. Thus, a reduction in the incidence of HCC may not be achieved unless an increasing number of patients are diagnosed and treated.
The Centers for Disease Control and Prevention (CDC) recently recommended to test all persons in the United States born between 1945 and 1965 with the hope that
this will identify 400,000 new persons with HCV56. However, issues related to patient consent, buy-in, and reimbursement may reduce its overall effectiveness. Furthermore, the degree to which increased identification will result in treatment with new, highly potent yet expensive treatment remains to be seen57.
The success of the CDC's plan will likely be contingent upon the use of efficient and effective means of entering and retaining individuals in HCV care-steps that will need more focused efforts in the near-term.
Prevention of HCC
Prevention of HCC focuses on preventing these risk factors from ever developing (primary prevention) or, once developed, treating them at an early enough stage (secondary prevention) in order to reduce the risk of HCC. On the other hand surveillance in patients at risk for HCC is intended to detect small, treatable cancer (tertiary prevention). The section below focuses on primary and secondary prevention.
Antiviral Treatment
There is moderately strong evidence that successful antiviral therapy for HBV or HCV substantially reduces but does not eliminate the risk of HCC in patients with viral hepatitis who already developed cirrhosis; the residual annual HCC risk in those patients may exceed the 1.5% threshold required by some cost-effectiveness models for HCC surveillance.
HCV Treatment
A recent systematic review of observational studies examined the risk of HCC among HCV-infected adults who had been treated and either achieved a sustained virology response (SVR) or did not respond to therapy47. SVR was associated with a reduction in the relative risk for HCC for patients at all stages of liver disease (hazard ratio, 0.24, 95% CI = 0.18 to 0.31, P < 0.001). Approximately 1.5% of patients responding to treatment develop HCC, compared with 6.2% of those who did not respond. SVR was associated with a similar reduction in the risk for HCC (hazard ratio, 0.23, 95% CI= 0.16 to 0.35, P < 0.001) in patients with advanced liver disease or cirrhosis; approximately 4.2% of patients with SVR developed HCC compared to 17.8% of those without SVR.
Most studies included in this systematic review were from Asia. Given the fact that rates of HCC are higher in Asian populations than in European or U.S. populations, the absolute benefit of SVR on HCC risk may have been overestimated. Collectively however, these data show a moderate protective effect of treatment-related SVR on the development of HCC among HCV-infected persons. However, the absolute risk of HCC does not revert to baseline levels among those with cirrhosis, older age, high α-fetoprotein levels, low platelet counts, high fibrotic stage and diabetes48;49.
Furthermore, HCC incidence in nonresponders to initial antiviral therapy is not reduced by maintenance IFN therapy. Newer and more effective therapies may further stem the risk of HCC in HCV infected persons.
Risk factors for HCC
Most HCC risk factors (chronic infection with hepatitis B (HBV) and/or C virus (HCV) and alcoholic liver disease) operate by promoting the development of cirrhosis.
Exceptions are rare in HCV-related HCC and mostly represent cases with at least bridging hepatic fibrosis5. While most cases of HBV-related HCC also occur in the
background of cirrhosis (as high as 85% in some studies)6, HBV can cause HCC in the absence of advanced fibrosis or cirrhosis. Although there are several mechanisms for non-alcoholic fatty liver disease-non-alcoholic steatohepatitis (NAFLD-NASH) related HCC conceivably in the presence of mild or no fibrosis7, there are no systematic studies to confirm or quantify this contention8. Indirect measures of severity of hepatic fibrosis such as degree of liver stiffness using elastography is associated with risk of HCC9.
The risk of developing HCC in cirrhosis patients varies with the underlying condition. The highest 5-year cumulative risks are seen in HCV cirrhosis (17% in the West and 30% in Japan), hemochromatosis (21%), HBV cirrhosis (10% in the West and 15% in Asia), alcoholic cirrhosis (8%-12%), and biliary cirrhosis (4%) 10,11.
HCV: HCV infection is associated with a 15- to 20-fold increase in risk for HCC compared with HCV-negative subjects. The rate of HCC in cohort studies of HCV-infected persons ranges from 1% to 3% over 30 years of chronic infection. Once HCV-related cirrhosis is established, HCC develops at an annual rate of 1%-8% (average 3.5%). Risk factors for HCC in HCV-infected individuals include male sex, co-infection with HBV or HIV, diabetes, obesity, and high level of alcohol consumption.
HCV viremia of any level is a strong risk factor for HCC compared to no viremia, however, while few studies reported a correlation between HCV viral load levels and risk of progression to cirrhosis 18 or HCC, most studies did not find such an association18. Reports of the association between HCV genotype and HCC risk are
inconsistent but suggest a slightly greater risk of developing HCC in patients with HCV genotype 1b, and possibly genotype 3, than patients with other HCV genotypes19.
Meta-analyses of observational studies from various countries20 report additive effects of HBV and HCV on risk for HCC (35- to 165-fold increase), although a sub-additive effect has been suggested based on more recent studies, cohort studies, and studies conducted in areas in which HBV and HCV infection were not common21. Persons co-infected with HCV (and to a lesser extent HBV) and HIV have faster progression to cirrhosis and decompensated liver disease, especially during immunosuppression, than patients with monoinfection.
For both HBV and HCV, men have 2-4 times greater risk of HCC across almost all liver disease etiologies than women. Gender-based differences in behavior and environmental exposures such as alcohol use might explain some of this difference. However, male and female sex hormones may also play a role. Nested case-control studies in China reported that baseline testosterone levels were higher in HBsAg positive males compared to age-matched controls 22. There is a functional polymorphism, a trinucleotide polyglutamine (CAG) short tandem repeat, in exon 1 of the AR gene, where increasing number of CAG repeats results in decreased androgen receptor (AR) signaling. Carriage of the high risk AR allele (i.e., fewer CAGs) conveyed greater risk of HBV-related HCC in Taiwanese males22;23, whereas increased AR CAG repeats were associated with greater HCC risk in females24. Molecular data indicate that androgens contribute to the HCC development by acting as tumor promoters via induction of DNA damage and oxidative stress while estrogens may act as general suppressors of HCC through reduction in the proinflammatory effects of MyD88-mediated secretion of IL625.
Alcohol: Heavy alcohol intake, defined as ingestion of >50-70 g/day for prolonged periods, is a well-established HCC risk factor. However, even moderate alcohol consumption may increase the risk of HCC in women33. There is evidence for a synergistic effect between heavy ingestion of alcohol and HCV infection and, to a lesser extent, HBV infection on HCC risk; similar synergism may be present with diabetes. These factors presumably operate together to promote cirrhosis and further increase the risk in individuals with cirrhosis34;35.
Cigarette Smoking: The association between cigarette smoking and HCC has been inconsistent with few studies finding a positive association and others finding no associations. Among studies reporting positive associations, several found that effects were limited to only those with HBV or HCV infection36.
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