Chari Cohen

Is chronic hepatitis B being undertreated in the United States

Summary.  Chronic infection with the hepatitis B virus (HBV) is a major risk factor for development of end‐stage liver disease, including cirrhosis, liver failure and primary liver cancer. There are now seven antiviral agents approved by the United States Food and Drug Administration (FDA) for the management of chronic HBV infection. Despite the fact that there are between 1.4 and 2 million chronic HBV infections in the United States, fewer than 50 000 people per year receive prescriptions for HBV antiviral medications. This report discusses possible explanations for the disparity between the number of people who are chronically infected and the number of people who receive treatment. Explanations for this incongruence include the potentially large number of infected persons who are unscreened and thus remain undiagnosed, and lack of access, including insurance, education and referral to appropriate medical care, particularly for disproportionately infected populations.

Underestimation of chronic hepatitis B virus infection in the United States of America

Dear Sir, In the December 2006 issue of Journal of Viral Hepatitis, Drs. Gish and Gadano made the important point that the current prevalence estimate of 1.25 million individuals in the USA with chronic hepatitis B virus (HBV) infection should be ‘corrected by taking into account HBV prevalence in immigrant populations and current estimates may be as high as 2 million’ [1]. The Hepatitis B Foundation (HBF) agrees with this statement, that the prevalence of chronic HBV infection in the United States is, in fact, significantly greater than the currently accepted estimate. We have performed our own calculation of the chronic hepatitis B prevalence estimate including the high prevalence rates of hepatitis B in immigrant populations. As a result, we estimate the current burden of chronic hepatitis B in the USA to be approximately 2 million people. We reason that an underestimation of the true number of infected individuals in the USA has occurred mostly because the highest-risk populations are under-represented in surveillance studies, and a large percentage of chronically infected individuals remain undiagnosed. Estimates of the number of HBV infections in the USA have been based on serosurvey data from the National Health and Nutrition Examination Surveys for the years 1976–1994 (NHANES II, III), which did not include significant numbers of Asians and Pacific Islanders (API, the ethnic groups most affected by hepatitis B), making it difficult to obtain accurate prevalence estimates [2]. Also, the large influx of foreign born individuals from countries with moderate or high incidence of hepatitis B increases the limitation of the NHANES estimate. Using Census data (2005 American Community Survey) and current prevalence estimates for chronic hepatitis B, we calculate that in APIs alone, there are approximately 832 433 individuals chronically infected with hepatitis B (Table 1). This number was reached using hepatitis B prevalence estimates of 8.9% for foreign and 1.4% for US born APIs [3], based on HBV survey data of API pregnant women. These estimates are conservative in comparison with recent studies, which have found the prevalence among foreign-born APIs to be between 10–15% [4, 5]. Table 1 Estimate of hepatitis B prevalence in the USA, based on census data and prevalence estimates, by ethnicity We calculated a chronic HBV burden of 1 157 137 individuals in the Caucasian, African American, and ‘other’ ethnicities, with a prevalence estimate of 0.42% in these groups (based on NHANES III data [6]) (Table 1). Adding our estimate for the API population (832 433) brings the total burden estimate to 1 989 570. This represents an increase of almost 800 000 individuals from the currently accepted HBV prevalence estimate, and it does not account for undocumented APIs, which could increase the number of chronically infected by another 100 000 (there are an estimated 1 500 000 undocumented APIs in the USA [7]). This calculation also does not include other high-risk groups, such as the incarcerated and homeless populations, which would increase the burden even further. While these calculations have limitations, they are provocative, in that they highlight the strong likelihood that chronic hepatitis B remains an under-recognized disease in the USA, one that deserves greater priority from public health leaders, research institutions and clinicians. The nation needs to support public health surveillance systems that yield reliable state and local data and can be used to calculate more accurate estimates of chronic hepatitis B. As the readers of JVH are aware, chronic hepatitis B infection leads to serious liver disease and early death in up to 25% of individuals [8], and the direct and indirect financial burden of chronic hepatitis B reaches

Hepatitis support groups: meeting the information and support needs of hepatitis patients.

1 billion each year [9]. It is a leading cause of primary liver cancer (hepatocellular carcinoma), which is rising in both incidence and mortality in the USA, and now ranks 8th among leading causes of cancer death for Americans [10]. In the API population, liver cancer ranks 3rd among causes of cancer death [11]. With the number of new infections remaining steady despite the availability of a vaccine, and the significant rise of primary liver cancer in the USA, it is imperative that hepatitis B be prioritized as an important public health concern. An accurate assessment of the true prevalence of chronic hepatitis B that includes updated estimates from high-risk, undercounted populations, is a crucial first step towards significantly reducing the burden of chronic hepatitis B in this country. The Hepatitis B Foundation calls for action to be taken to allow all individuals in the USA who are chronically infected with hepatitis B to be counted.

Eradication of Hepatitis B: A Nationwide Community Coalition Approach to Improving Vaccination, Screening, and Linkage to Care

An estimated 5 million Americans are chronically infected with hepatitis B or C. They face socially and clinically significant reductions in mental and physical health. Improved coping and compliance with clinical therapies and harm-reducing behaviors can improve quality of life and, potentially, treatment outcomes. Motivation to join, participation, use, and usefulness of online and in-person hepatitis support groups was examined through observation and survey of group members and group leaders. Members joined primarily to get information particularly about treatments, diet, and treatment side effects. They also joined to get support. All received support that was often hard to get elsewhere. Healthcare providers were generally the most used source of information, yet support groups were the most useful source of information. Members used the information and support obtained to make treatment and lifestyle changes such as initiating or ceasing treatment, eliminating alcohol consumption, increasing openness with family and friends, and discussing side effects with healthcare providers. Providers caring for hepatitis patients should consider recommending support groups to their patients and also participate in the groups to ensure that valid and reliable information is provided.

Data supporting updating estimates of the prevalence of chronic hepatitis B and C in the United States

Infection with the hepatitis B virus (HBV) is a significant public health concern in the US, disproportionately affecting Americans of Asian, Native Hawaiian and Pacific Islander descent, despite the availability of a simple blood test, approved treatments, and an effective vaccine. Hep B United, a national campaign to support and leverage the success of community-based HBV coalitions, convened a partner summit in 2012 to develop a strategic response to the HHS Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis. The resulting community action plan focuses on advancing three areas of the HHS plan: educating providers and communities to reduce health disparities; improving testing and linkage to care to prevent HBV-related liver disease and cancer; and eliminating perinatal HBV transmission.

Hepatitis-Associated Liver Cancer: Gaps and Opportunities to Improve Care

T he current estimates of chronic hepatitis B (CHB) and chronic hepatitis C (CHC) prevalence that are widely used by the press and cited in many publications and presentations are 805,0001,405,000 persons with CHB (prevalence 0.8%-1.2%) and 2.7 million (confidence interval 2.2 million-3.2 million) with CHC (prevalence 0.3%-0.5%). Although these figures accurately represent findings from national prevalence studies, we believe that because of underrepresented or excluded populations they should be revised upward to increase public awareness about viral hepatitis and to support increasing funding for both the National Institutes of Health’s viral hepatitis research and the Centers for Disease Control and Prevention’s (CDC’s) Division of Viral Hepatitis, which has by far the smallest budget in the National Center for HIV/ AIDS, Viral Hepatitis, STD, and TB Prevention. The CHC estimate is based entirely and the CHB estimate in large part (with some adjustments) on data from the National Health and Nutrition Examination Survey (NHANES), which the CDC is careful to point out excludes some populations with increased infection risk, including the incarcerated, the homeless, and institutionalized persons, and does not adequately represent multiple racial/ethnic groups with higher infection rates, including Native Americans, Alaskan Natives, and Asians and Pacific Islanders. Using the same approach the CDC uses to estimate CHB prevalence in the foreign-born, a meta-analysis of hepatitis B surface antigen seroprevalence rates in 102 countries multiplied country-specific CHB prevalence rates by the number of foreign-born in the United States by country of birth. This study estimated 1.32 million foreign-born persons with CHB and, adding the current prevalence estimates for the general population and institutionalized persons, a total CHB population of up to 2.2 million. A similar estimate of 2.09 million was calculated by Hepatitis B Foundation researchers, using NHANES and 2005 census data, with an estimated additional 100,000 CHB persons among undocumented Asians and Pacific Islanders. The current CHB estimate for institutionalized persons, which includes residents both of correctional settings (2.0% estimated prevalence) and of other group living quarters, and the homeless (0.5%) may be too low. US incarcerated population prevalence estimates range from 0.9% in Tennessee to 8.7% in Maryland. The current 2.0% estimate considered only five peer-reviewed studies reporting 0.9%-3.1% prevalence rates. Because 20% of state and 13% of federal inmates are injection drug users, CHB prevalence is likely much higher. Similarly, prevalence in the homeless may be much higher than 0.5%. An estimated 24.2% of those in homeless shelters are current or former injection drug users. One study found that 32.5% of homeless persons with mental illness and substance use disorders were positive for antibody to hepatitis B core antigen and 29.8% were anti– hepatitis C virus–positive (HCV). Taking all of this into consideration, we believe that the 2012 estimate of 2.2 million US CHB persons may be the most accurate. In the NHANES-based study that provides the CHC prevalence estimate that is currently most often used by the press and cited in many journal publications and conference presentations, the CDC researchers state, “A major limitation of NHANES is that it does not include Abbreviation: CDC, Centers for Disease Control and Prevention; CHB, chronic hepatitis B; CHC, chronic hepatitis C; HBV, hepatitis B virus; HCV, hepatitis C virus; NHANES, National Health and Nutrition Examination Survey. Received January 23, 2015; accepted July 30, 2015. Address reprint requests to: Robert Gish, M.D., 6022 La Jolla Mesa Drive, San Diego, CA 92037. E-mail: rgish@robertgish.com; tel: 11-858-229-9865; fax: 11-858-886-7093. Copyright VC 2015 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.28026 Potential conflict of interest: Dr. T. Block is employed by and owns stock in Contravir. He consults, advises, and holds intellectual property rights with OnCore-Tekmira. Dr. J. Block consults for Arrowhead. Dr. Brosgart consults, owns stock in, and is on the board of directors for Tobira. She consults, owns stock in, and is on the scientific advisory board for Contravir. She consults for Dynavax. Dr. Cohen advises Gilead. Dr. Sandt advises and received grants from Gilead, Bristol-Myers Squibb, Merck, Genentech, AbbVie, AbbVie Foundation, and Janssen. Dr. Gish consults, advises, and is on the speakers’ bureau for Gilead, AbbVie, and Merck. Dr. Kowdley consults, advises, and received grants from Gilead. He consults for AbbVie and advises Achillion, BristolMyers Squibb, and Merck.

Chronic HBV infection outside treatment guidelines: is treatment needed?

The global burden of hepatocellular carcinoma (HCC; primary liver cancer) is increasing. HCC is often unaccompanied by clear symptomatology, causing patients to be unaware of their disease. Moreover, effective treatment for those with advanced disease is lacking. As such, effective surveillance and early detection of HCC are essential. However, current screening and surveillance guidelines are not being fully implemented. Some at-risk populations fall outside of the guidelines, and patients who are screened are often not diagnosed at an early enough stage for treatment to be effective. From March 17 to 19, 2015, the Hepatitis B Foundation sponsored a workshop to identify gaps and limitations in current approaches to the detection and treatment of HCC and to define research priorities and opportunities for advocacy. In this Commentary, we summarize areas for further research and action that were discussed throughout the workshop to improve the recognition of liver disease generally, improve the recognition of liver cancer risk, and improve the recognition that screening for HCC makes a life-saving difference. Participants agreed that primary prevention of HCC relies on prevention and treatment of viral hepatitis and other underlying etiologies. Earlier diagnosis (secondary prevention) needs to be substantially improved. Areas for attention include increasing practitioner awareness, better definition of at-risk populations, and improved performance of screening approaches (ultrasound, biomarkers for detection, risk stratification, targeted therapies). The heterogeneous nature of HCC makes it unlikely that a single therapeutic agent will be universally effective. Medical management will benefit from the development of new, targeted treatment approaches.

A research agenda for curing chronic hepatitis B virus infection

BACKGROUND There are now seven antivirals approved for use in the management of chronic HBV infection in the US. Current professional guidelines recommend the use of antiviral treatment in only a distinct subset of the total HBV chronically infected population, estimated to be more than 350 million worldwide. The subset of chronically HBV-infected individuals for whom the antivirals have been demonstrated to produce desirable outcomes are those with abnormal liver enzymes and a viral load above a defined threshold, presumably identifying those at highest risk for development of cirrhosis and hepatocellular carcinoma. However, some individuals whose clinical features place them outside these guidelines, for whom treatment is not recommended, are also at significant risk for liver disease complications and liver-related death. METHODS In this report, we produce new estimates of the age-specific risks of liver-related death in people outside the current treatment guidelines using published data from multiple populations. RESULTS Our results indicate that the age-specific 10-year risks of liver-related mortality in these individuals range from 0.3-4% in the West to 0.3-20% in Asia. CONCLUSIONS The magnitude of these risks and the estimated size of the global population that falls outside of current treatment guidelines have led us to consider whether medical interventions are also needed for these individuals, either with currently approved therapeutics or yet-to-be-discovered medications targeting new mechanisms of antiviral effect. Potential targets for development of new medications are discussed.

Prevention of perinatal hepatitis B transmission in Haimen City, China: Results of a community public health initiative

Harvey Alter, Timothy Block, Nathaniel Brown, Alan Brownstein, Carol Brosgart, Kyong-Mi Chang, Pei-Jer Chen, Francis V. Chisari, Chari Cohen, Hashem El-Serag, Jordan Feld , Robert Gish , Jeffrey Glenn, Tim Greten, Haitao Guo, Ju-Tao Guo, Yujin Hoshida, Jianming Hu, Kris V. Kowdley, Wenhui Li, Jake Liang, Stephan Locarnini, Anna S. Lok, William Mason, Brian McMahon, Anand Mehta , Robert Perrillo, Peter Revill, Charles M. Rice, JoAnn Rinaudo, Raymond Schinazi, Christoph Seeger, Kirty Shetty, John Tavis, and Fabien Zoulim

Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop.

In regions where hepatitis B virus (HBV) is endemic, perinatal transmission is common. Infected newborns have a 90% chance of developing chronic HBV infection, and 1 in 4 will die prematurely from HBV-related liver disease. In 2010, the Hepatitis B Foundation and the Haimen City CDC launched the Gateway to Care campaign in Haimen City, China to improve awareness, prevention, and control of HBV infection citywide. The campaign included efforts to prevent perinatal HBV transmission by screening all pregnant women for hepatitis B surface antigen (HBsAg), following those who tested positive, and administering immunoprophylaxis to their newborns at birth. Of 5407 pregnant women screened, 185 were confirmed HBsAg-positive and followed until delivery. At age one, 175 babies were available for follow up testing. Of those, 137 tested negative for HBsAg and positive for antibodies to HBsAg, indicating protection. An additional 34 HBsAg-negative babies also tested negative for antibodies to HBsAg or had indeterminate test results, were considered to have had inadequate immune responses to the vaccine, and were given a booster dose. A higher prevalence of nonresponse to HBV vaccine was observed among babies born to hepatitis B e antigen (HBeAg)-positive mothers and mothers with high HBV DNA titers. The remaining 4 babies tested positive for HBsAg and negative for antibodies, indicative of active HBV infection. The mothers of all 4 had viral loads ≥8×10(6) copies/ml in the third trimester. Although inadequate response or nonresponse to HBV vaccine was more common among babies born to HBeAg-positive and/or high viral load mothers, these risk factors did not completely predict nonresponsiveness. All babies born to HBV-infected mothers should be tested upon completion of the vaccine series to ascertain adequate protection. Some babies of HBeAg-positive mothers with high viral load may still become HBV infected despite timely immunoprophylaxis with HBV vaccine and HBIG.