Kathleen N. Ly

The Increasing Burden of Mortality From Viral Hepatitis in the United States Between 1999 and 2007

BACKGROUND The increasing health burden and mortality from hepatitis B virus (HBV) and hepatitis C virus (HCV) in the United States are underappreciated. OBJECTIVE To examine mortality from HBV; HCV; and, for comparison, HIV. DESIGN Analysis of U.S. multiple-cause mortality data from 1999 to 2007 from the National Center for Health Statistics. SETTING All U.S. states and the District of Columbia. PARTICIPANTS Approximately 22 million decedents. MEASUREMENTS Age-adjusted mortality rates from HBV, HCV, and HIV. Logistic regression analyses of 2007 data generated 4 independent models per outcome (HCV- or HBV-related deaths) that each included 1 of 4 comorbid conditions and all sociodemographic characteristics. RESULTS Between 1999 and 2007, recorded deaths from HCV [corrected] increased significantly to 15,106, whereas deaths from HIV declined to 12,734 by 2007. Factors associated with HCV-related deaths included chronic liver disease, HBV co-infection, alcohol-related conditions, minority status, and HIV co-infection. Factors that increased odds of HBV-related death included chronic liver disease, HCV co-infection, Asian or Pacific Islander descent, HIV co-infection, and alcohol-related conditions. Most deaths from HBV and HCV occurred in middle-aged persons. LIMITATION A person other than the primary physician of the decedent frequently completed the death certificate, and HCV and HBV often were not detected and thus not reported as causes of death. CONCLUSION By 2007, HCV had superseded HIV as a cause of death in the United States, and deaths from HCV and HBV disproportionately occurred in middle-aged persons. To achieve decreases in mortality similar to those seen with HIV requires new policy initiatives to detect patients with chronic hepatitis and link them to care and treatment. PRIMARY FUNDING SOURCE Centers for Disease Control and Prevention.

Annual Report to the Nation on the Status of Cancer,1975-2012, Featuring the Increasing Incidence of Liver Cancer

Annual updates on cancer occurrence and trends in the United States are provided through an ongoing collaboration among the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR). This annual report highlights the increasing burden of liver and intrahepatic bile duct (liver) cancers.

Rising Mortality Associated With Hepatitis C Virus in the United States, 2003–2013

In the United States, hepatitis C virus (HCV)-associated mortality is increasing. From 2003-2013, the number of deaths associated with HCV has now surpassed 60 other nationally notifiable infectious conditions combined. The increasing HCV-associated mortality trend underscores the urgency in finding, evaluating, and treating HCV-infected persons.

Mortality Among Persons in Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study (CHeCS), 2006–2010

BACKGROUND The number of deaths in hepatitis C virus (HCV)-infected persons recorded on US death certificates has been increasing, but actual rates and causes of death in these individuals have not been well elucidated. METHODS Disease-specific, liver-related, and non-liver-related mortality data for HCV-infected patients in an observational cohort study, the Chronic Hepatitis Cohort Study (CHeCS) at 4 US healthcare systems, were compared with multiple cause of death (MCOD) data in 12 million death certificates in 2006-2010. Premortem diagnoses, liver biopsies, and FIB-4 scores (a noninvasive measure of liver damage) were examined. RESULTS Of 2 143 369 adult patients seen at CHeCS sites in 2006-2010, 11 703 (0.5%) had diagnosed chronic HCV infection, and 1590 (14%) died. The majority of CHeCS decedents were born from 1945 to 1965 (75%), white (50%), and male (68%); mean age of death was 59 years, 15 years younger than MCOD deaths. The age-adjusted mortality rate for liver disease in CHeCS was 12 times higher than the MCOD rate. Before death, 63% of decedents had medical record evidence of chronic liver disease, 76% had elevated FIB-4 scores, and, among those biopsied, 70% had moderate or worse liver fibrosis. However, only 19% of all CHeCS decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates. CONCLUSIONS HCV infection is greatly underdocumented on death certificates. The 16 622 persons with HCV listed in 2010 may represent only one-fifth of about 80 000 HCV-infected persons dying that year, at least two-thirds of whom (53 000 patients) would have had premortem indications of chronic liver disease.

Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988‐2012

The number of persons with chronic hepatitis B virus (HBV) infection in the United States is affected by diminishing numbers of young persons who are susceptible because of universal infant vaccination since 1991, offset by numbers of HBV‐infected persons migrating to the United States from endemic countries. The prevalence of HBV infection was determined by serological testing and analysis among noninstitutionalized persons age 6 years and older for: antibody to hepatitis B core antigen (anti‐HBc), indicative of previous HBV infection; hepatitis B surface antigen (HBsAg), indicative of chronic (current) infection; and antibody to hepatitis B surface antigen (anti‐HBs), indicative of immunity from vaccination. These prevalence estimates were analyzed in three periods of the National Health and Nutrition Examination Survey (NHANES): 1988‐1994 (21,260 persons); 1999‐2008 (29,828); and 2007‐2012 (22,358). In 2011‐2012, for the first time, non‐Hispanic Asians were oversampled in NHANES. For the most recent period (2007‐2012), 3.9% had anti‐HBc, indicating approximately 10.8 (95% confidence interval [CI]: 9.4‐12.2) million noninstitutionalized U.S. residents having ever been infected with HBV. The overall prevalence of chronic HBV infection has remained constant since 1999: 0.3% (95% CI: 0.2‐0.4), and since 1999, prevalence of chronic HBV infection among non‐Hispanic blacks has been 2‐ to 3‐fold greater than the general population. An estimated 3.1% (1.8%‐5.2%) of non‐Hispanic Asians were chronically infected with HBV during 2011‐2012, which reflects a 10‐fold greater prevalence than the general population. Adjusted prevalence of vaccine‐induced immunity increased 16% since 1999, and the number of persons (mainly young) with serological evidence of vaccine protection from HBV infection rose from 57.8 (95% CI: 55.4‐60.1) million to 68.5 (95% CI: 65.4‐71.2) million. Conclusion: Despite increasing immune protection in young persons vaccinated in infancy, an analysis of chronic hepatitis B prevalence in racial and ethnic populations indicates that during 2011‐2012, there were 847,000 HBV infections (which included ∼400,000 non‐Hispanic Asians) in the noninstitutionalized U.S. population. (Hepatology 2016;63:388–397)

Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006–2010

BACKGROUND & AIMS Persons chronically infected with the hepatitis C virus (HCV) may be at higher risk for developing and dying from non-liver cancers than the general population. METHODS 12,126 chronic HCV-infected persons in the Chronic Hepatitis Cohort Study (CHeCS) contributed 39,984 person-years of follow-up from 2006 to 2010 and were compared to 133,795,010 records from 13 Surveillance, Epidemiology and End Results Program (SEER) cancer registries, and approximately 12 million U.S. death certificates from Multiple Cause of Death (MCOD) data. Measurements included standardized rate ratios (SRR) and relative risk (RR). RESULTS The incidence of the following cancers was significantly higher among patients with chronic HCV infection: liver (SRR, 48.6 [95% CI, 44.4-52.7]), pancreas (2.5 [1.7-3.2]), rectum (2.1 [1.3-2.8]), kidney (1.7 [1.1-2.2]), non-Hodgkin lymphoma (NHL) (1.6 [1.2-2.1]), and lung (1.6 [1.3-1.9]). Age-adjusted mortality was significantly higher among patients with: liver (RR, 29.6 [95% CI, 29.1-30.1]), oral (5.2 [5.1-5.4]), rectum (2.6 [2.5-2.7]), NHL (2.3 [2.2-2.31]), and pancreatic (1.63 [1.6-1.7]) cancers. The mean ages of cancer diagnosis and cancer-related death were significantly younger among CHeCS HCV cohort patients compared to the general population for many cancers. CONCLUSIONS Incidence and mortality of many types of non-liver cancers were higher, and age at diagnosis and death younger, in patients with chronic HCV infection compared to the general population.

Causes of Death and Characteristics of Decedents With Viral Hepatitis, United States, 2010

BACKGROUND Previous research indicates that the mortality burden from viral hepatitis is growing, particularly among middle-aged persons. To monitor progress toward prevention goals, it is important to continue to document characteristics and comortalities of these deaths. This study sought to examine demographic characteristics and the most frequent causes of death among decedents with a viral hepatitis-related death. METHODS A cross-sectional study was performed on approximately 2.4 million death records from 2010. We calculated mortality rates for decedents with and without hepatitis A, B, and C virus (HAV, HBV, and HCV) and relative risks for the most frequently cited conditions in decedents with and without HBV and HCV. RESULTS In 2010, there were 18 473 (0.7%) deaths with HAV, HBV, and HCV listed among causes of death, disproportionately in those aged 45-64 years. Among the 10 frequent causes of death, decedents listing HBV or HCV died, on average, 22-23 years earlier than decedents not listing these infections. HBV- and HCV-infected decedents aged 45-64 years had an increased risk of having the following conditions reported than decedents without these infections: cancer of liver and intrahepatic bile duct; fibrosis, cirrhosis, and other liver diseases; alcohol-related liver disease; gastrointestinal hemorrhage; human immunodeficiency infection; acute and unspecified renal failure; and septicemia (HCV only). CONCLUSIONS Decedents with other causes of death that include HBV or HCV died 22-23 years earlier than decedents not listing these infections. These data suggest and support the need for prevention, early identification, and treatment of HBV and HCV.

Trends in Disease and Complications of Hepatitis A Virus Infection in the United States, 1999–2011: A New Concern for Adults

BACKGROUND In recent years, few US adults have had exposure and resultant immunity to hepatitis A virus (HAV). Further, persons with liver disease have an increased risk of adverse consequences if they are infected with HAV. METHODS This study used 1999-2011 National Notifiable Diseases Surveillance System and Multiple Cause of Death data to assess trends in the incidence of HAV infection, HAV-related hospitalization, and HAV-related mortality. RESULTS During 1999-2011, the incidence of HAV infection declined from 6.0 cases/100 000 to 0.4 cases/100 000. Similar declines were seen by sex and age, but persons aged ≥80 years had the highest incidence of HAV infection in 2011 (0.8 cases/100 000). HAV-related hospitalizations increased from 7.3% in 1999 to 24.5% in 2011. The mean age of hospitalized cases increased from 36.0 years in 1999 to 45.1 years in 2011. While HAV-related mortality declined, the mean age at death among decedents with HAV infection increased from 48.0 years in 1999 to 76.2 years in 2011. The median age range of decedents who had HAV infection and a liver-related condition was 51.0 to 68.0 years. CONCLUSIONS Although vaccine-preventable, HAV-related hospitalizations increased greatly, mostly among adults, and liver-related conditions were frequently reported among HAV-infected individuals who died. Public health efforts should focus on the need to assess protection from hepatitis A among adults, including those with liver disease.

Hepatitis C Virus Infection Among Reproductive-Aged Women and Children in the United States, 2006 to 2014

Approximately 3.5 million U.S. residents are estimated to have hepatitis C virus (HCV) infection (1, 2). After years of declining incidence (3), the number of newly detected and reported HCV cases in the United States increased from 781 in 2009 to 2194 in 2014 (3), suggesting that after adjustment for underascertainment and underreporting (4), about 30000 incident infections occurred in 2014 (3). This rise in incidence is thought to result from an overall national increase in injection drug use among young persons, albeit with a much greater concentration in some geographic areas (57). Among young persons who inject drugs, about half are women of reproductive age (57). Thus, concerns have arisen about the risk for vertical transmission to infants born to HCV RNApositive mothers (8), especially because an increase in the HCV detection rate has been observed in recent years among reproductive-aged women (8), but in the absence of standard interventions to prevent HCV transmission to infants. Although birth to an HCV-infected mother is a known risk factor for HCV infection in the infant, perinatal transmission is infrequent. Only 5% to 6% of women transmit HCV to their infants, although rates are higher among women with HIV co-infection or very high HCV viral loads (>6 log) (912). The prevalence of HCV infection among pregnant women has been difficult to determine, because HCV screening is not performed routinely in this population but rather is risk based. As a result, many HCV infections may go undetected because of underrecognition of risk behaviors, as well as concerns about stigmatization or legal consequences if risk behaviors are disclosed. Even when HCV infection is detected, 1 study concluded that most at-risk children born to known HCV RNApositive women are not screened subsequently (13) and therefore do not receive appropriate medical care. To assess the extent of HCV infection in reproductive-aged and pregnant women, as well as in infants born to them, we analyzed 2 of the largest population data sets available in the United States. Methods Data Sources Data were analyzed from the National Notifiable Diseases Surveillance System (NNDSS) of the Centers for Disease Control and Prevention (CDC) and the Quest Diagnostics Health Trends database. The NNDSS is a nationwide collaboration that enables public health agencies at local, state, territorial, federal, and international levels to share notifiable disease-related health information. Because the great majority of HCV infection cases are asymptomatic and are detected sporadically over time, the NNDSS tracks those that meet a specific definition for reporting according to state and local statutes and requirements. No new enhancements in detection and reporting or substantial changes in HCV surveillance case definitions were made during the period from which these NNDSS data were drawn (Appendix Tables 1 and 2). The current analysis used NNDSS data to evaluate trends in (rather than the prevalence of) HCV infection in reproductive-aged women and children aged 2 to 13 years from 2006 to 2014. Follow-up investigations are performed by state and local health jurisdictions with the resources available to collect extended data elements, such as injection drug use behavior, by using standard case report forms. Forms for reporting viral hepatitis cases are available from the CDC Division of Viral HepatitisStatistics and Surveillance Web site (www.cdc.gov/hepatitis/statistics/) in the Surveillance Guidelines and Forms section. Appendix Table 1. Comparison of the 2004, 2007, 2011, and 2012 CDC/Council of State and Territorial Epidemiologists Surveillance Case Definitions: Acute HCV* Appendix Table 2. Comparison of the 2005, 2010, 2011, and 2012 CDC/Council of State and Territorial Epidemiologists Surveillance Case Definitions: Past/Present and Chronic HCV* Quest Diagnostics is a commercial laboratory system serving approximately one third of the U.S. adult population annually and approximately one half over a 3-year period. It receives specimens from an estimated one half of all physicians and hospitals in the United States (14). Quest Diagnostics data were obtained through a multiyear contractual agreement between the CDC and Quest Diagnostics Health Trends (15). Data on HCV infection (prevalence) in reproductive-aged women, pregnant women, and children aged 2 to 13 years were analyzed for 2011 through 2014. Cases Standard HCV surveillance case definitions are used by jurisdictions to classify cases of acute and past or present HCV infection in accordance with the Council of State and Territorial Epidemiologists in collaboration with the CDC. Laboratory data on HCV are not submitted to the NNDSS; therefore, parsing current HCV infection cases from the pool of past and present cases in that database was not possible. To ensure consistency over time, we verified that these HCV case definitions did not change substantively during the NNDSS study period (Appendix Tables 1 and 2). We considered that ascertainment and reporting of cases may be affected by changes in surveillance resources over time. However, reporting has remained a mainly unfunded mandate for the state health departments over the years, without the federal resources to increase numbers of reported cases nationally. We included all reports in the NNDSS of HCV cases in females aged 15 to 44 years that met the criteria for either confirmed acute or past or present infection. For children, we assumed that maternal antibodies and, consequently, anti-HCV assay positivity could persist for 18 months after birth and that infection might resolve spontaneously in about half of infected infants up to 3 years after occurrence (12). Given that most infections that resolve do so before the age of 2 years, we limited our analysis to children aged 2 years (24 months) through 13 years, almost all of whom would be infected perinatally. The pediatric cases examined met the definition for either confirmed acute or past or present HCV infection. To ensure consistency, we applied the age criteria of the NNDSS definitions to the Quest laboratory data: 15 to 44 years for reproductive-aged women and 2 to 13 years for children. Persons who tested positive for HCV antibody were identified as having a past or present HCV infection, whereas those who tested positive for HCV RNA or had a genotyped HCV infection were considered to have a current HCV infection. Persons who tested negative for HCV antibody or RNA were considered not currently infected. Statistical Analyses For HCV cases reported to the NNDSS from 2006 to 2014, the number and proportion of reproductive-aged women and children overall and of those with information on demographic characteristics (geographic location, age, sex, race/ethnicity) and injection drug use (women only) were calculated. From Quest data, the following laboratory tests were included: HCV antibody, HCV RNA, and HCV genotype. Among persons without a current HCV infection, the number and proportion of women or children with each demographic characteristic (year of service, geographic region of the provider ordering the test, and age group) were examined, where the denominator for calculating the proportions for each characteristic was the number of women aged 15 to 44 years and the number of children aged 2 to 13 years who had any HCV testing performed by Quest in 2011 through 2014. We also examined pregnancy status, type of insurance, provider setting, and specialty of provider ordering the test. We calculated 95% CIs around each proportion to measure variability. Interquartile ranges (IQRs; first to third quartiles) for the median age of acute versus past or present HCV-infected women and children for the NNDSS and HCV-infected versus nonHCV-infected women and children for Quest were calculated to assess the range of the middle 50% of the age distribution. To estimate the number of HCV-infected women who gave birth in the United States, we multiplied the Quest HCV infection prevalence in pregnant women by the average annual number of births that occurred in the United States from 2011 to 2014, which was obtained from National Vital Statistics Reports (1619) (Supplement). The Quest HCV infection prevalence in pregnant women was calculated by dividing the annual number of pregnant women with HCV infection by the annual number of unique women who had 1 or more HCV tests performed by Quest. ClopperPearson 95% CIs were calculated for the HCV infection rate among these pregnant women. To estimate the number of infants with HCV infection, we multiplied the overall perinatal HCV infection rate of 5.8% (95% CI, 4.2% to 7.8%), determined recently by Benova and colleagues (9) on the basis of a thorough systematic review and meta-analysis of HCV perinatal transmission rates in 109 studies, by the calculated number of parturient women. Supplement. Calculation of the Estimated Average Annual Number of HCV-Infected Parturient Women and Infants, United States, 2011 to 2014 Because all data were obtained from secondary sources without patient-identifying information, the study did not require approval by an institutional review board. All analyses were performed by using SAS software, version 9.3 (SAS Institute). Role of the Funding Source This work was done by a CDC employee as a part of her routine work. Results HCV in Reproductive-Aged Women Of 425322 women with confirmed HCV infection reported to the NNDSS from 2006 to 2014, 171801 (40.4%) were of reproductive age (15 to 44 years) (Table 1). The reported number of acute cases in these women increased 3.4-fold, and the reported number of past or present cases doubled from 2006 to 2014 (Table 1); by 2012, the total number of cases reported in reproductive-aged women surpassed that of women aged 45 to 64 years (Figure). Non-Hispanic white women accounted for about half (2342 [57%]) of all acute infections; for the 2069 women with available risk information, 1310

Prevalence of Hepatitis B Virus Infection in Kenya, 2007

Current estimates put the prevalence of hepatitis B virus (HBV) infection in Kenya at 5-8%. We determined the HBV infection prevalence in the human immunodeficiency virus (HIV)-negative Kenyan adult and adolescent population based on samples collected from a national survey. We analyzed data from HIV-negative participants in the 2007 Kenya AIDS Indicator Survey to estimate the HBV infection prevalence. We defined past or present HBV infection as presence of total hepatitis B core antibody (HBcAb), and chronic HBV infection (CHBI) as presence of both total HBcAb and hepatitis B surface antigen (HBsAg). We calculated crude and adjusted odds of HBV infection by demographic characteristics and risk factors using logistic regression analyses. Of 1,091 participants aged 15-64 years, approximately 31.5% (95% confidence interval [CI] = 28.0-35.3%) had exposure to HBV, corresponding to approximately 6.1 million (CI = 5.4-6.8 million) with past or present HBV infection. The estimated prevalence of CHBI was 2.1% (95% CI = 1.4-3.1%), corresponding to approximately 398,000 (CI = 261,000-602,000) with CHBI. CHBI is a major public health problem in Kenya, affecting approximately 400,000 persons. Knowing the HBV infection prevalence at baseline is important for planning and public health policy decision making and for monitoring the impact of viral hepatitis prevention programs.