Hepatitis C Disease Progression
2016 NEWS AND UPDATES
Permanent Liver Damage May Be Avoided with Early Hepatitis C Treatment
In a study published in PLOS One, hepatitis C virus (HCV) patients saw a decrease in liver stiffness (LS) from pre-treatment to sustained virological response at 24 weeks (SVR24), and no significant decrease during the additional follow-up.
Hepatitis C Kills More Americans than Any Other Infectious Disease
New CDC studies underscore urgency of hepatitis C testing and treatment, especially for baby boomers
Deaths associated with hepatitis C reached an all-time high of 19,659 in 2014, according to new surveillance data released today by the Centers for Disease Control and Prevention (CDC).
A second CDC study, published online today in Clinical Infectious Diseases, shows that annual hepatitis C-related mortality in 2013 surpassed the total combined number of deaths from 60 other infectious diseases reported to CDC, including HIV, pneumococcal disease, and tuberculosis. Further, both studies use data from death certificates, which often underreport hepatitis C, so there likely were even more hepatitis C-related deaths than these numbers suggest.
The greatest hepatitis C burden falls on baby boomers – those born from 1945 to 1965 – many of whom have unknowingly been living with the infection for many years. According to a study published in The Lancet Infectious Diseases earlier this year, many baby boomers were infected during medical procedures in the years after World War II, when injection and blood transfusion technologies were not as safe as they are today. Without diagnosis and treatment, they increasingly develop liver cancer and other life-threatening hepatitis C-related diseases, and they may unknowingly transmit the disease to others.
“Why are so many Americans dying of this preventable, curable disease?” asked Jonathan Mermin, M.D., director of CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. “Once hepatitis C testing and treatment are as routine as they are for high cholesterol and colon cancer, we will see people living the long, healthy lives they deserve.”
The surveillance data released today also point to a new wave of hepatitis C infections among people who inject drugs. Acute cases of hepatitis C infection have more than doubled since 2010, increasing to 2,194 reported cases in 2014. The new cases were predominantly among young, white individuals with a history of injection drug use, living in rural and suburban areas of the Midwest and Eastern United States.
“Because hepatitis C often has few noticeable symptoms, the number of new cases is likely much higher than what is reported. Due to limited screening and underreporting, we estimate the number of new infections is closer to 30,000 per year,” said John W. Ward, M.D., director of CDC’s Division of Viral Hepatitis. “We must act now to diagnose and treat hidden infections before they become deadly and to prevent new infections.”
Addressing viral hepatitis risk among people who inject drugs is an important public health priority and a key concern for CDC. CDC recommends that comprehensive prevention programs be implemented to avert drug-related hepatitis C transmission. These prevention programs should include regular testing for hepatitis C (as well as hepatitis B and HIV); rapid links to medical care for people who test positive; and access to substance abuse treatment, sterile injection equipment, and other services.
About 3.5 million Americans are currently living with hepatitis C and roughly half are unaware of their infection. CDC and the U.S. Preventive Services Task Force recommend one-time hepatitis C testing for everyone born from 1945 to 1965 and regular testing for others at high risk. Once diagnosed, patients can take advantage of new, highly effective treatments that can cure the vast majority of infections in two to three months and take other steps to protect their health.
CDC is committed to helping communities use all effective tools to stop the spread of hepatitis C and reduce deaths associated with the disease. Through collaborative efforts, we can help reduce the rise in new infections and reverse trends in hepatitis C-related mortality, ultimately ensuring that far fewer people die of this disease.
Hepatitis C Deaths in U.S. Rose in 2014, but New Drugs Hold Promise
HCV infection in Baby Boomers with Medicare is associated with mortality
People treated for hepatitis C have unexpectedly high rate of liver cancer recurrence
aidsmap - 4 hours ago
Hepatitis C patients with cirrhosis who were treated with direct-acting antivirals had about twice the expected likelihood of developing hepatocellular carcinoma (HCC), with the excess risk seen in people with a previous history of HCC, according to ...
Association Between Hepatitis C Virus and Head and Neck ...
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Journal of the National Cancer Institute
Apr 14, 2016 - Abstract. Background: Hepatitis C virus (HCV) infection is associated with ..... of care for this infection and to prevent progression of underlying liver disease.
Does sustained virologic response represent a cure for hepatitis C virus infection?
BARCELONA — In this video perspective from the International Liver Congress 2016, Ronald Koretz, MD, Emeritus professor of medicine at University of California Los Angeles School of Medicine, discusses results of a systematic review that asks: Does sustained virologic response represent a cure for hepatitis C virus infection?
Alcoholic Hepatitis and HCV Interactions in Liver Disease
Apr 13, 2016 - Alcoholic liver disease and chronic HCV infection together are the most common causes of liver disease, and can promote rapid disease progression. ... Abstract. Most HCV-infected patients regularly consume alcohol. Alcoholic liver disease ...
Hepatitis C Deaths Up Sharply Over Past Decade
Natural History of Hepatitis C Infection - Hepatitis C Online
Background: Most persons who acquire hepatitis C virus (HCV) will develop chronic .... and HCV RNA level do not appear to influence progression of disease.
National Center for Biotechnology Information
Liver fibrosis progression in hepatitis C virus infection after seroconversion.
Butt AA(1), Yan P(2), Lo Re V 3rd(3), Rimland D(4), Goetz MB(5), Leaf D(5), Freiberg ...
HCV Most Common Infectious Cause of Death, Yet Still Underestimated
Watch Patients Treated For Hepatitis C: Studying possible regression in cirrhosis/ fibrosis
Nov 17 2015
SVR associated with improvement in fibrosis, cirrhosis
SAN FRANCISCO — Sixty percent of patients who reached SVR after treatment for hepatitis C virus infection demonstrated improvement in fibrosis or cirrhosis, according to findings presented at The Liver Meeting 2015.
Ana Maria Crissien, MD, of the departments of gastroenterology and hepatology at Scripps Clinic and Green Hospital in La Jolla, Calif., and colleagues, proposed that curing HCV could yield a regression of advanced fibrosis and/or cirrhosis. Additionally, she said FibroScan (EchoSens) may be a tool to determine the reversal of fibrosis..
Upsurge in HCV Deaths Despite New Treatments
Despite dramatic improvements in treatment, mortality from hepatitis C (HCV) continues to rise in the U.S., a researcher said here.
CDC reports rising number of hepatitis C-related deaths
Liz Highleyman Produced in collaboration with hivandhepatitis.com
The CDC analyzed death certificates in the US and found that hepatitis C-related deaths rose from about 11,000 in 2003 to 19,358 in 2013. Deaths related to other reportable infectious diseases decreased from about 25,000 in 2003 to 18,000 in 2013. After hepatitis C, the most commonly listed infectious diseases were HIV and Staphyloccus aureus. The findings were reported at the IDWeek 2015 meeting.
Full Story:Aidsmap -
Rising HCV -related mortality greater than all other infectious diseases.
Hepatitis C virus is now the most frequently recorded underlying or contributing infection on death certificates, superseding all 60 other infectious conditions reported to CDC combined and unabated by improving antiviral therapy, according to data presented at IDWeek 2015.
Hepatitis C virus (HCV) disease progression in people who inject drugs (PWID): A systematic review and meta-analysis - IDUs are not engaged in care resulting in increased infectiousness/costs/disease progression
Disease Progression: Acute Hepatitis C - HCV Advocate
This information is provided ... clear the virus (naturally rid the hepatitis C virus from their bodies). The reasons that some ...
What are the co-factors that increase severity of HCV disease and how should they be managed?
Long term changes in liver histology following treatment of chronic hepatitis C virus
Feb 25 2014
HCV increased risk for dying prematurely
Pinchoff J. Clin Infect Dis. 2014;doi:10.1093/cid/ciu075.
Adults with hepatitis C had an increased risk for dying and for dying prematurely compared with the general population, according to findings from a study conducted in New York.
They were particularly likely to die of HCV-associated conditions, such as HIV or drug use, researchers from the New York City Department of Health and Mental Hygiene reported in Clinical Infectious Diseases.
“Identifying HCV-infected persons earlier and linking them to comprehensive care and treatment services, and reducing new infections and preventing drug-related deaths through harm reduction, is likely to have long- and short-term benefits for reducing premature mortality and HCV-associated health care costs,” the researchers wrote.
They compared surveillance data from 2000 to 2010 with mortality data from 2000 to 2011. Both sets of data were maintained by the New York City Department of Health and Mental Hygiene. They cross-matched the data and analyzed factors associated with death and causes of death among those with HCV.
From 2000 to 2010, there were 128,444 people reported to have HCV, and of those, 18,291 (14%) of them also had HIV. Among those with HCV monoinfection, 13,307 died from 2000 to 2011, and of those, 8,525 (64.1%) died prematurely. Among adults with HIV/HCV coinfection, 5,475 died from 2000 to 2011 and 94% died prematurely. Among the 619,254 deaths of adults with neither disease, 25.3% died prematurely.
The median age of death among those with HCV monoinfection was 60 years, significantly younger than those with no infection, who died at a median age of 78 years. Adults with HIV/HCV coinfection died at a median age of 52 years, significantly younger than both those with HCV monoinfection and those with neither infection.
People with HCV monoinfection had higher odds of dying of liver cancer (OR=9.2), drug-related causes (OR=4.3) or cirrhosis (OR=3.7) compared with people with no infection. Those with HIV/HCV coinfection also had higher odds of dying of liver cancer (OR=2.2) or drug-related causes (OR=3.1), but 53.6% of people with HIV/HCV coinfection died of HIV/AIDS-related causes.
“It is important to continue to track mortality among people with HCV to assess changes in age at death and causes of death, as these important developments in the public health response to HCV unfold,” the researchers wrote.
Disclosure: The researchers report no relevant financial disclosures.
Source - Healio
Aug 12 2013
Hepatitis C - A Look At Disease Progression
The natural history of hepatitis C remains controversial. Among HCV-infected individuals progression to advanced liver
disease generally requires decades and is influenced by several host factors...
The High Comorbidity Burden of the Hepatitis C Virus Infected Population in the United States
Chronic hepatitis C (HCV) disease can be complicated with comorbid conditions that may impact treatment eligibility and outcomes. The aim of the study was to systematically review comorbidities and symptoms in an HCV infected population, specifically assessing comorbidities associated with HCV anti-viral treatment and disease, as well as comparing comorbidities between an HCV infected and uninfected control population
HCV Epidemiology, Diagnosis and Disease Progression
Higher serum testosterone is associated with increased risk of advanced hepatitis C-related liver disease in males
White DL, Tavakoli-Tabasi S, Kuzniarek J, Pascua R, Ramsey DJ, El-Serag HB; Hepatology (Aug 2011)
BACKGROUND: Males have strikingly increased risk of advanced liver disease. However, the association between testosterone and risk of hepatitis C virus (HCV)-related advanced liver disease is unknown.
METHODS: We performed a cross-sectional study in male veterans with chronic HCV. Blood samples were obtained to measure total serum testosterone and perform the FibroSURE-ActiTest. Other risk factor data were obtained through systematic questionnaires (e.g., alcohol), physical measurements (e.g., BMI) and serological tests (e.g., viral load). The association between total testosterone and risk of advanced hepatic fibrosis (F3 and F3/F4) and inflammatory activity (A3 and A2/3) measured by FibroSURE-ActiTest was evaluated with logistic regression.
RESULTS: A total of 308 eligible study participants were prospectively recruited (mean age 57, 52% African-American). There were 105 cases with advanced fibrosis and 203 mild fibrosis controls; and 88 cases with advanced inflammatory activity and 220 mild activity controls. Mean total serum testosterone was significantly higher in advanced fibrosis cases as well as advanced inflammatory activity cases compared to mild disease controls (6.0 ng/ml vs. 5.3 ng/ml and 5.9 ng/ml vs. 5.4 ng/ml, respectively). We observed a significant 27% increase in advanced fibrosis risk and 16% increase in advanced inflammatory activity risk for each 1 ng/ml increase in total serum testosterone. Total testosterone in the upper tertile was associated with an even greater excess risk of advanced fibrosis than advanced inflammatory activity (OR(adjusted advanced fibrosis) =3.78, 95% CI 1.88-7.61 vs. OR(adjusted advanced inflammatory activity) =2.64, 95% CI 1.29-5.45, respectively).
CONCLUSIONS: Total serum testosterone is associated with an increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV-infected men. Testosterone may be important in the pathogenesis of HCV-related advanced liver disease in males. (HEPATOLOGY 2011.)
From Clinical Gastroenterology and Hepatology
Prevalence and Challenges of Liver Diseases in Patients with Chronic Hepatitis C Virus Infection
Ira M. JAcobson; Gary L. Davis; Hashem El–Serag; Francesco Negro; Christian trépo
Authors and Disclosures
Posted: 11/09/2010; Clin Gastroenterol Hepatol. 2010;8(11):924-933. © 2010 AGA Institute
Abstract and Introduction
Hepatitis C virus (HCV) infections pose a growing challenge to health care systems. Although chronic HCV infection begins as an asymptomatic condition with few short-term effects, it can progress to cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and death. The rate of new HCV infections is decreasing, yet the number of infected people with complications of the disease is increasing. In the United States, people born between 1945 and 1964 (baby boomers) are developing more complications of infection. Men and African Americans have a higher prevalence of HCV infection. Progression of fibrosis can be accelerated by factors such as older age, duration of HCV infection, sex, and alcohol intake. Furthermore, insulin resistance can cause hepatic steatosis and is associated with fibrosis progression and inflammation. If more effective therapies are not adopted for HCV, more than 1 million patients could develop HCV-related cirrhosis, hepatic decompensation, or HCC by 2020, which will impact the US health care system. It is important to recognize the impact of HCV on liver disease progression and apply new therapeutic strategies.
Approximately 180 million people worldwide are infected with hepatitis C virus (HCV) and are at risk of developing serious hepatic complications such as cirrhosis, hepatocellular carcinoma (HCC), or decompensation. In the United States, HCV-related end-stage liver disease is the most common indication for transplantation, and HCV markers are frequently found in cases of HCC.[3,4] Although some data suggest that hepatitis C does not increase overall mortality, it has been postulated that HCV infection could result in an 8- to 12-year reduction in life expectancy. It is estimated that HCV caused more than 86,000 deaths in the European region in 2002. The prevalence of hepatitis C–related cirrhosis and its complications is expected to continue to increase through the next decade. In addition, demographic changes are expected to result in an increasing incidence of severe HCV-related liver disease as the population ages.
Less than half (42%–46%) of patients infected with HCV genotype 1,[9,10] the major genotype in the USA, achieve a sustained virologic response (SVR) with currently available treatment (peginterferon/ribavirin for 48 weeks). There is also evidence to suggest that HCV infection is both underdiagnosed and undertreated.[12–14] The lack of access to effective, welltolerated therapies has serious implications for the current and future burden of HCV. A recent report commissioned by the Institute of Medicine (IOM) of the National Academies highlighted shortcomings in care for viral hepatitis, including the estimate that up to 75% of HCV-infected persons have not even been diagnosed. The report includes sweeping recommendations for prevention, identification, control, and surveillance of HCV in the general population and identifies major gaps in services for specific populations that are disproportionately affected.
In light of the public health threat posed by HCV, efforts are needed to heighten awareness of its impact on patients. Numerous extrahepatic morbidities are associated with HCV infection; these and their consequences are reviewed elsewhere. Here we summarize the latest evidence for the burden of chronic hepatitis C (CHC) in the United States, focusing on hepatic complications
This review reflects the detailed discussion and opinions of the authors (not the meeting sponsor, Vertex Pharmaceuticals Incorporated) on key articles from the published literature at an advisory board meeting on the burden of liver disease in HCV infection held in Boston, MA, in July 2007. Before the meeting, MEDLINE searches via the PubMed interface were designed and conducted by Paula Michelle del Rosario, a professional medical writer at Gardiner-Caldwell Communications. The searches encompassed the epidemiology and/or burden as a result of HCV-related liver disease by using the Medical Subject Headings (MeSH) [hepatitis C] and either [epidemiology], or [incidence], or [prevalence], or [fibrosis AND epidemiology], or [fibrosis AND mortality], or [liver cirrhosis AND epidemiology], or [liver cirrhosis AND mortality], or [carcinoma, hepatocellular AND epidemiology], or [carcinoma, hepatocellular AND mortality], or [cholangiocarcinoma OR intrahepatic cholangiocarcinoma AND epidemiology], or [fatty liver AND epidemiology], or [fatty liver AND mortality]. Articles not published in the English language and editorials, correspondence, letters, comments, and news articles were excluded. The authors received the search terms and results of the searches in advance of the meeting, and they selected relevant articles for discussion. The authors were responsible for several additions to content and topics covered. Throughout the development of the manuscript, the authors were personally responsible for a marked expansion in the scope of the article, including new references and concepts published since the original advisory board, making this essentially a new article. In addition, the manuscript was thoroughly updated with a repeated PubMed search by Gardiner-Caldwell Communications in September 2009 to capture articles published since the original search was conducted, and relevant publications were selected for inclusion by the authors.
Prevalence, Identification of at-risk Individuals, and Effects on Life Expectancy .
Various estimates of HCV prevalence in the US population place the number of infected individuals (as defined by anti-HCV antibody positivity) at between 4.1 and 5 million. Of these, 3.2–3.4 million are chronically infected.[17,18] During the first 10–20 years of infection HCV-infected individuals generally experience asymptomatic or mild illness, which explains why an estimated 75% of infections remain undiagnosed in the United States.[15,20] Despite a decline in the number of new US cases of HCV infection from a peak of an estimated 262,000/year in 1986 to 17,000/year in 2007, the prevalence of individuals infected with HCV for more than 20 years is expected to continue to increase until 2015. In the National Health and Nutrition Examination Survey (NHANES; 1999–2002), patients aged 40–49 years accounted for 66% of American HCVinfected patients, and the prevalence of HCV infection in the United States was 2.7 times higher among 40- to 49-year-olds than the general population (Figure 1). This "baby boomer" generation is particularly susceptible to blood-borne HCV transmission as a result of an increased lifetime risk of injection drug use (IDU), blood transfusion before 1992, or sexual activity with ≥20 partners, compared with older or younger patients.[23,24] The prevalence of HCV infection varies by age, sex, and race/ethnicity, and early identification of at-risk individuals through routine questioning by clinicians is critical, because management options are limited in late-stage disease.
After 30 years of infection, an estimated 15%–35% of patients will develop cirrhosis (5-year survival, 75%–80%); after 40 years, up to 60% could have cirrhosis. . Given the high prevalence of HCV infection among 40- to 49-year-olds and that Americans are now expected to live into their mid-70s or beyond, the incidence of complications of HCV infections can be expected to further increase in coming years. In fact, from 1995–2004, US HCV-related mortality already increased 123% from 1.09/100,000 to 2.44/100,000 persons, although this study has some limitations. Furthermore, the proportion of CHC patients in the United States with cirrhosis is projected to rise from 25% in 2010 to 45% in 2030. Projections also estimate that without effective treatment, the annual number of US patients with cirrhosis, hepatic decompensation, or HCC will roughly double by 2020, and liver-related deaths will almost triple (Table 1). Although not all data agree with these estimates, several studies have suggested that HCV infection could have a deleterious effect on population mortality rates and life expectancy.[27,28] HCV increased the risk of death in several analyses, irrespective of comorbidities such as coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV)[30,31] and even after adjustment for alcohol consumption. Furthermore, numerous studies[33–37] and a Cochrane review indicated that achievement of an SVR through effective antiviral therapy can significantly reduce mortality in patients with chronic HCV. If all HCV-infected patients were treated with currently available treatment in 2010, liver-related HCV-associated deaths could be reduced by 36% by 2020, whereas antiviral treatment rates are currently declining. Improvements in diagnosis and treatment are therefore necessary to reduce the associated public health burden.[15,39]
Individuals with CHC are at increased risk of liverrelated morbidity and mortality. HCV infection was associated with 27% of all US liver transplants performed in 2007, and US-based studies demonstrated that up to 51%–55% of HCC patients have anti-HCV antibodies.[3,4] There is also a link between steatosis and liver fibrosis in HCV-infected patients, as well as a potential association between HCV infection and HCC or, as described more recently, of intrahepatic cholangiocarcinoma (ICC).[41–45] In some ethnic groups such as Latinos the course of HCV infection is more aggressive, with a higher risk of cirrhosis than other ethnic groups. Furthermore, disease progression is more rapid in patients who are coinfected with HCV and HIV. Coinfected patients have approximately double the risk of cirrhosis or decompensation than those infected with HCV alone.
Fibrosis and Cirrhosis
Progressive hepatic fibrosis leading to cirrhosis is the major complication of chronic HCV infection and accounts for almost all HCV-related morbidity and mortality. Early studies suggested little, if any, fibrosis progression during the first decade of infection, followed by a slow, regular progression during the next 15 years, increasing to an intermediate rate during the subsequent decade.[48,49] In a German cohort study of 1833 women infected with HCV-contaminated immunoglobulin, 0.5% of patients developed cirrhosis after 25 years. Similarly, in a study of 376 HCV-infected women conducted by the Irish Hepatology Research Group, 51% of patients had fibrosis after 17 years, but only 2% had probable/definite cirrhosis. These estimates of cirrhosis rates are considerably lower than those from the US multicohort study and the widely cited US military study (approximately 35%). Fibrosis outcomes of 184 women from the same cohort were followed up for the subsequent 5 years; 49% showed no change in fibrosis, 24% showed regression, and 27% showed progression.
Recent data reinforce the potential for severe liver disease to develop in some patients. Among 485 plasma donors infected during the early 1970s, 34% had stage F3/F4 fibrosis (bridging fibrosis), cirrhosis, or HCC after 31 years; their 35-year cumulative survival was 84% versus 91%–95% for the general population. Similarly, a study of 300 black and white Americans with untreated HCV infection found that 29% of patients had stage F3/F4 fibrosis after 20 years, and 4.7% had confirmed cirrhosis. It should be noted, however, that these studies could have selected patients with severe disease.
The nonlinear progression of fibrosis was recently confirmed in a meta-analysis of 111 HCV studies. The mean annual stage-specific transition probabilities were 0.117 for stage F0 to F1, 0.085 for F1 to F2, 0.120 for F2 to F3, and 0.116 for F3 to F4. Although the estimated prevalence of cirrhosis was 16% after 20 years, there was wide variation between studies, suggesting that fibrosis is a highly unpredictable process.
Infection duration is a major risk factor for severe fibrosis, with the progression rate in a 50-year-old being almost 3 times that in a 20-year-old. Age at time of infection is also important. In a biopsy analysis of 247 treatment-naïve HCV patients, progression rates were 0.13, 0.14, 0.27, and 0.36 fibrosis units/year for patients aged ≤19, 20–24, 25–36, and >36 years at infection, respectively. Age >36 years (vs ≤36 years) at time of infection was independently associated with faster progression. Men infected before age 50 have been identified as comprising the majority of cases of cirrhosis today (73.6%), whereas men aged >50 years when infected have faster disease progression compared with other age groups.
Several other factors, including sex, baseline fibrosis, HCV genotype, HIV/HBV coinfection, and alcohol consumption, also influence fibrosis progression (Table 2).[54–69] Identifying these factors can be useful when determining prognosis and advising patients on minimizing liver damage. Indeed, a recent study suggested that HCV genotype 3 might pose a particularly high risk of progressive fibrosis. Insulin resistance has been linked with fibrosis,[70,71] and several studies have reported that this relationship remains significant, irrespective of HCV genotype.[62,72,73] In addition, serum aminotransferase level elevations and the degree of hepatocellular necrosis/inflammation on biopsy have been found to predict fibrosis progression. Genetic factors might also play a role in fibrosis progression.[75,76] Recent data indicate that the cirrhosis risk score, which is based on the association of 7 host genes, might help to differentiate HCV patients at high versus low risk of progressing toward cirrhosis, including those with early or mild CHC.[76–78] Steatosis has also been linked to fibrosis progression,[40,67,79] as has regular cannabis use.[68,80] There is evidence of an association between cigarette smoking and hepatitis fibrosis, but not all studies have verified such an association.
The greatest increase in US cancer deaths from 1995–2004 was in those caused by cancers of the liver and bile duct, of which HCC comprised about 76%. This might be attributed to the increasing incidence of HCV-related HCC because rates for HBVrelated and alcohol-related HCC have remained stable during recent years.[84,85] The incidence of HCV-related HCC in the United States is projected to peak in 2019 at 14,000 cases/year. In a large US database, the proportion of HCV-related cases of HCC among HCC patients aged ≥65 years doubled from 11% in 1993–1996 to 21% in 1996–1999. During the past decade, the fastest increase in HCC incidence has affected Hispanics and whites. In multivariate analysis HCV infection was an independent predictor for the development of HCC. Furthermore, maintenance therapy with peginterferon did not reduce the 5-year incidence of HCC in the HALT-C cohort.
Comparisons of US and Japanese HCV strains suggest that the US HCV epidemic began about 2 to 3 decades after that in Japan.[89,90] This has led to speculation that the burden of HCC in the United States might eventually equal that currently seen in Japan as HCV-infected individuals age and their infection duration increases. In Japan, HCV-related HCC accounts for 80% of all HCC cases, and the rate of HCC among HCV-infected men has risen from 17.4/100,000 in 1972–1976 (32,335 deaths) to 27.4/100,000 in 1992–1996 (109,365 deaths).
A recent Italian study of 214 HCV-infected patients with Child–Pugh class A cirrhosis showed that HCC developed at a rate of almost 4%/year. HCC was the first complication to occur in 55 (27%) patients; after 17 years, HCC had developed in 68 (32%) patients. In another cohort of 416 patients with uncomplicated Child–Pugh class A HCV-related cirrhosis, the incidence of HCC was 13.4% at 5 years, and the 5-year HCC death rate was 15.3%, with the hazard rate of HCC tending to increase over time.
Several factors influence the risk of HCC in patients with HCV-related cirrhosis. Generally, HCC risk is increased in patients aged >50 years or those infected when aged >50 years, patients with longer duration of infection, men, overweight or diabetic patients, and patients with advanced cirrhosis or elevated alpha-fetoprotein.[8,95,96] Other possible risk factors include the presence of steatosis, HCV genotype 1b, Asian/African American race, and occult HBV infection. As for hepatic fibrosis, an association between cigarette smoking and HCV-related HCC has been suggested in some studies but not others.
Chronic HCV-related inflammation might increase HCC risk by shifting hepatocytic transforming growth factor– beta signaling from tumor suppression to fibrogenesis. HCC generally develops after cirrhosis is established, signifying the likely importance of long-standing necrosis and regeneration, an environment of extensive scarring, in its pathogenesis. HCV might influence hepatocarcinogenesis through the oncogenic effects of its core protein, which might augment oxidative stress. It might also alter the signaling cascade of mitogen-activated protein kinase and activating factor 1, thereby activating cellcycle control. Liver angiogenesis and the neovascular response,[104,105] plus genomic changes that deregulate components of the Jak/STAT pathway in early carcinogenesis, might also promote HCV-related hepatocarcinogenesis. Additional mechanisms have also been proposed.
Various small studies have demonstrated a link between HCV and ICC.[42–45] A recent large cohort study of >140,000 HCV-infected military veterans showed a >2-fold increase in ICC risk in HCV-infected patients versus noninfected controls. However, many of these hospital-based, case-control studies are limited by the potential for selection or ascertainment bias, and some studies have failed to observe any association between HCV and ICC.[109,110] The association of HCV infection with susceptibility to ICC, and the pathogenetic basis for such an association, warrant further investigation. Chronic HCV infection was not a risk for extrahepatic cholangiocarcinoma (ECC).
Patients with HCV-associated cirrhosis are at high risk of developing hepatic decompensation, manifesting as hepatic synthetic dysfunction or complications of portal hypertension. Clinical signs of decompensation include ascites, encephalopathy, and upper gastrointestinal hemorrhage caused by variceal bleeding.[93,112]
In an analysis of data from 1000 HCV patients with mild to advanced fibrosis, the incidence of decompensated cirrhosis after 5–7 years of follow-up was 43.5/10,000 person-years or about 1 in 230 patients/year. Similarly, a retrospective study reported the 5-year risk of decompensation to be 18% in 384 HCV patients with compensated cirrhosis (incidence, 3.9%/year), and a recent estimate suggests decompensation is currently present in 11.7% of CHC patients with cirrhosis. Decompensation has become more common since 1995, and because the proportion of CHC patients with cirrhosis is expected to increase through 2030, the incidence of decompensation can be expected to increase accordingly. It should be noted, however, that this model estimates that the majority of cirrhotic patients with chronic HCV infection will not develop decompensation during the first 3 decades of infection. Annual incidence rates for ascites (2.9%), jaundice (2.0%), upper gastrointestinal bleeding (0.7%), and encephalopathy (0.1%) were established in a later prospective study of 214 HCV-RNA seropositive patients after 114 months of follow-up.
Age at HCV acquisition is relevant, with decompensation risk as high as 133/10,000 person-years in patients infected after 39 years of age. In addition, the presence of the human leukocyte antigen DRB1*1201–3 allele might be associated with a higher rate of progression toward decompensated cirrhosis and HCC. The identification of reliable proteomic/genomic markers for risk of advanced HCV-related liver disease would aid prognostication and therapeutic decision-making.
Steatosis occurs to some degree in about half of all patients with chronic HCV infection.[40,113] In a meta-analysis of data from >3000 patients, steatosis was independently associated with the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, overweight (body mass index >25), age ≥45 years, and genotype 3 infection. Among 101 HCV-infected patients with no factors predisposing to fatty liver, steatosis was found in 41% of patients, irrespective of sex, age, or infection route.
Two main mechanisms underlie the pathogenesis of steatosis in HCV-infected patients who abstain from alcohol, a direct viral effect and a metabolic mechanism. Viral steatosis is associated with genotype 3 HCV infection,[40,114–117] where the severity of steatosis correlates with serum[71,115] and intrahepatic viral load. This type of steatosis often resolves after viral eradication.[116–118] It is believed that HCV genotype 3 has a direct effect on hepatocyte lipid metabolism, resulting in fat accumulation. Interactions involving the HCV genotype 3 core protein, such as enhanced fatty acid synthase promoter activation and increased lipid affinity, are being investigated in vitro.
Metabolic steatosis is seen primarily in patients infected with genotype non-3 HCV[40,72] and is largely due to insulin resistance,[62,72,121] characterized by hyperinsulinemia and free fatty acid overflow to organs and non-adipose tissues. These alterations give rise to triglyceride accumulation in hepatocytes, resulting in steatosis.[40,70,71,123]
Steatosis might reduce the likelihood of achieving SVR with HCV treatment, even when other steatosis-inducing factors are accounted for. In one study, SVR rates were 18%–32% lower in people with steatosis versus those without steatosis after adjusting for other potentially confounding cofactors such as genotype, fibrosis score, and viral load.
Reducing the Impact of Infection
About 85% of HCV-positive persons in the United States general population can be identified on the basis of 3 characteristics: IDU history, blood transfusion before 1992, or abnormal serum alanine transaminase levels. In selected populations, other characteristics might also be useful for screening. A retrospective study of 5400 US veterans found that the following factors predicted HCV infection: IDU, blood transfusion before 1992, service during the Vietnam war, tattoo, and a history of abnormal liver test results. However, HCV risk factor histories are rarely documented in clinical practice. Infected patients can thus remain undiagnosed until they present with hepatic complications. Recent guidelines issued by the American Association for the Study of Liver Diseases (AASLD) make recommendations for diagnosis and counseling of HCV-infected patients on alcohol, weight loss, and treatment to prevent the development of cirrhosis and other complications.
Diagnosis and Screening
Figure 2 summarizes the clinical management of patients at risk of HCV infection. Asking patients about their transfusion history and high-risk drug/sexual behavior during health care visits should be routine, and high-risk patients (history of IDU, blood transfusion before 1992, or HIV-positive) should be tested, with cognizance of the higher prevalence rates in men, "baby boomers," and African Americans. The AASLD guidelines promote screening in at-risk populations to reduce HCV transmission rates. The recent IOM report on viral hepatitis includes a recommendation that federally funded US health care insurers improve access to HCV screening as part of preventative care for the general population, so people at risk of HCV infection can be identified.
Summary of the screening, diagnosis, and treatment of patients at risk of HCV infection . Once diagnosed, patients should be evaluated for HCV RNA, genotype, and serologic exclusion of common liver diseases. Baseline imaging (ultrasound) might also be useful. Assessing fibrosis by liver biopsy can be used to estimate prognosis, treatment urgency, and necessity of HCC screening. Surrogate methods, including serum fibrosis markers, imaging techniques, and indirect methods to measure liver stiffness such as transient elastography, might have a future role.
Because insulin resistance enhances fibrosis progression, monitoring insulin resistance, fasting glucose, or insulin levels is advisable. In addition, lifestyle modifications, including weight loss and dietary changes, might reduce insulin resistance and slow the fibrosis rate. All patients should be assessed for immunity against hepatitis A/B by assessment of disease markers and vaccinated if seronegative. Counseling should be offered regarding alcohol consumption, if appropriate.
Currently, the only drugs available to treat HCV are peginterferon and ribavirin. SVR rates associated with peginterferon/ribavirin are suboptimal, particularly for genotype 1–infected patients.[9,10] The AASLD guidelines recommend an individualized treatment approach based on assessment of comorbidities, likelihood of response, and side-effect potential. Although more effective options are needed, successful treatment can eradicate the virus and thereby minimize complications and possibly improve mortality rates.[126,127] Nearly all patients (99.2%) maintain undetectable HCV loads 5 years after attaining SVR, representing a "virologic cure." Some patients with fibrosis who achieve SVR demonstrate an improvement in necroinflammatory activity and fibrosis regression.[128 –130] Furthermore, the 5-year survival of SVR patients is similar to that of the overall population. The role of interferon in preventing HCC is controversial. A reduced risk of HCC has been noted in patients achieving SVR; however, reports of HCC after SVR was achieved in cirrhotic patients indicate a need for surveillance and reinforce the importance of viral eradication before cirrhosis develops.[131,132] Long-term maintenance therapy with peginterferon does not appear to affect the incidence of HCC.
Davis et al extended their multicohort model to include an assessment of treatment effects, predicting that an increase in the proportion of treated patients (or use of treatment with improved viral clearance rate) would result in reduced rates of cirrhosis, liver failure, HCC, and liver-related death.
Education and Counseling
A lack of knowledge about HCV among health care providers, social service providers, and the public is identified by the IOM as a major challenge to controlling the disease. Education and outreach programs for these audiences feature among the recent IOM recommendations for comprehensive viral hepatitis services aimed at preventing viral transmission, missed diagnosis, and poor health outcomes in HCV.
Increasing access to treatment and providing support to optimize therapeutic adherence might help to improve outcomes. This requires a greater emphasis on early detection along with careful, individualized diagnostic assessment and therapeutic decision-making. Many physicians have adopted a "watch-and-wait" approach, particularly for patients with minimal liver disease. Although this might sometimes be appropriate, patients should be advised of the possibility of unexpectedly rapid disease progression and the need for regular follow-up, including repeat biopsies every 3–5 years. The pros and cons of deferring therapy should be discussed in the context of the patient's clinical and histologic profile.
Many eligible patients decline antiviral treatment. In a study of 280 US patients, 41% declined treatment, citing no symptoms and concerns about side effects. Information provided by health care providers is critical; in 3 US cities, interest in HCV treatment among injection drug users was 7-fold higher among patients who were told that they were at risk for cirrhosis or cancer. Patients under regular review are also more likely to be interested in receiving treatment, emphasizing the importance of communication and continuity of care. Several promising agents, including HCV protease and polymerase inhibitors (eg, telaprevir, boceprevir, and R7128), are in phase 2 or phase 3 trials, with a hope of availability within 2–3 years and beyond.
Changing our Views
The impact of HCV infection on the burden of liver disease is becoming evident as individuals unknowingly infected decades ago age and develop severe sequelae of advanced liver fibrosis. Up to 1 million Americans are predicted to develop HCV-related hepatic complications during the next 2 decades. Persons born between the 1940s and 1960s account for most infections, with the highest risk among those with a history of IDU or blood transfusions before 1992. Once chronic infection is established, disease progression is variable and dependent on several factors. Cirrhosis, liver failure, and HCC might occur at a faster rate and in more patients than previously believed.
HCV infection is a health care priority. Increasing access to treatment might significantly reduce the morbidity and mortality burden of HCV infection. Other measures to tackle the challenge of HCV include improving surveillance, screening and identifying patients at risk of progression, and optimizing therapy. We now need to capitalize on what we know about HCV and formulate strategies to address the anticipated surge in HCV-related morbidity and mortality. New HCV treatments are in development that might increase SVR and potentially decrease the burden of hepatic complications in populations with significant unmet need.
Abstract and Introduction
Prevalence, Identification of at-risk Individuals, and Effects on Life Expectancy
Reducing the Impact of Infection
Changing our Views
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