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Original Research |

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

Kathleen N. Ly, MPH; Jian Xing, PhD; R. Monina Klevens, DDS, MPH; Ruth B. Jiles, PhD, MPH; John W. Ward, MD; and Scott D. Holmberg, MD, MPH
[+] Article and Author Information

From the Centers for Disease Control and Prevention, Atlanta, Georgia.

Acknowledgment: The authors thank Dr. Tara Vogt for her technical assistance early in the analysis and Drs. Richard Selik, Division of HIV/AIDS Prevention, and Deborah Holtzman, Division of Viral Hepatitis, Centers for Disease Control and Prevention, for their helpful review and suggestions for the manuscript.

Grant Support: By the Centers for Disease Control and Prevention.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1649.

Reproducible Research Statement:Study protocol and data set: Available at www.cdc.gov/nchs/data_access/Vitalstatsonline.htm. Statistical code: Available from Ms. Ly (e-mail, kathleenly@cdc.gov) or Dr. Xing (e-mail, jxing@cdc.gov).

Requests for Single Reprints: Kathleen N. Ly, MPH, Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mailstop G-37, Atlanta, GA 30333; e-mail, kathleenly@cdc.gov.

Current Author Addresses: Ms. Ly and Drs. Xing, Klevens, Jiles, Ward, and Holmberg: Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mailstop G-37, Atlanta, GA 30333.

Author Contributions: Conception and design: K.N. Ly, J. Xing, R.M. Klevens, R.B. Jiles, J.W. Ward, S.D. Holmberg.

Analysis and interpretation of the data: K.N. Ly, J. Xing, S.D. Holmberg.

Drafting of the article: K.N. Ly, R.M. Klevens, J.W. Ward, S.D. Holmberg.

Critical revision of the article for important intellectual content: K.N. Ly, R.M. Klevens, J.W. Ward, S.D. Holmberg.

Final approval of the article: R.M. Klevens, R.B. Jiles, J.W. Ward, S.D. Holmberg.

Statistical expertise: J. Xing.

Obtaining of funding: R.B. Jiles, J.W. Ward, S.D. Holmberg.

Administrative, technical, or logistic support: R.B. Jiles, S.D. Holmberg.


Ann Intern Med. 2012;156(4):271-278. doi:10.7326/0003-4819-156-4-201202210-00004
Text Size: A A A

This article has been corrected. The original version (PDF) is appended to this article as a supplement.

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 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.

Figures

Grahic Jump Location
Figure.

Annual age-adjusted mortality rates from hepatitis B and hepatitis C virus and HIV infections listed as causes of death in the United States between 1999 and 2007.

Because a decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection.

Grahic Jump Location

Tables

References

Letters

July 17, 2012
Edward L. Murphy, MD, MPH
AIM. 2012;157(2):149-150  doi:10.7326/0003-4819-157-2-201207170-00021



July 17, 2012
Scott D. Holmberg, MD, MPH; Kathleen N. Ly, MPH; Jian Xing, PhD
AIM. 2012;157(2):150  doi:10.7326/0003-4819-157-2-201207170-00022



NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Non-Liver Mortality in HCV Seropositives
Posted on March 16, 2012
Edward L., Murphy, Professor
University of California San Francisco
Conflict of Interest: None Declared

To the Editor,

Although the data on mortality associated with hepatitis C virus (HCV) are certainly important to public health, Ly et al. present them in a way that may lead to overestimation of HCV related mortality. First, the authors define HCV deaths as those with a death certificate mentioning HCV as either a contributing or underlying cause of death, and they do not present a breakdown of cause specific mortality among these "HCV deaths". In our own analysis of HCV mortality, liver related deaths represented only 20% of deaths in a large cohort of HCV seropositive former blood donors #1#. Most of the mortality in our HCV cohort was related to trauma or suicide #23%#, drug or alcohol causes #14%#, cardiovascular causes #13%# and cancer excluding hepatocellular carcinoma #12%#. Ascertainment of HCV serostatus from blood donor records is probably more complete than from death certificates, providing more accurate estimate of attributable mortality than studies based upon the latter method.

Second, in considering secular trends in HCV mortality, the authors do not mention the possible contribution of a birth cohort effect which has been well described for HCV infection #2,3#. Since most HCV infected persons in the United States probably acquired their infection due to injection drug related activity in the 1960s and 70s, they constitute a cohort which is now aged 45 to 64 years. Therefore it is reasonable that all-cause mortality will increase as this cohort ages, independent of a possible increase in HCV related liver mortality. Ly et al. could perform age-adjusted analyses to address this issue in their data.

Finally, the abstract's conclusion that "By 2007, HCV has superseded HIV as the cause of death in the United States, ..." gives the misleading impression that there is an epidemic of HCV deaths. In fact, even with the loose definition of HCV deaths used in this report, the rate is increasing gradually and the rate of HIV deaths is declining, as the authors note presumably due to successful treatment of HIV disease. While the authors are correct that HCV deaths may be underestimated due to lack of recording HCV status on the death certificate, the fact that many HCV infected persons die of causes unrelated to HCV may counterbalance this possible underestimation. Physicians treating HCV infected persons should be aware of potentially preventable, non-liver related mortality due to trauma, suicide and substance abuse in their patients.

References

1# Guiltinan AM, Kaidarova Z, Custer B, Orland J, Strollo A, Cyrus S, Busch MP, Murphy EL. Increased all-cause, liver and cardiac mortality among Hepatitis C Virus seropositive blood donors. Amer J Epidemiol 2008;167:743-50.

2) Murphy EL, Bryzman S, Williams AE, Co Chien H, Schreiber GB, Ownby HE, Gilcher RO, Kleinman SH, Matijas L, Thomson RA, Nemo GJ. Demographic determinants of hepatitis C virus #HCV# seroprevalence in United States Blood Donors. JAMA 1996;275:995-1000.

3) Murphy EL, Fang J, Tu Y, Cable R, Hillyer CD, Sacher R, Triulzi D, Gottschall JL, Busch MP for the Retrovirus Epidemiology Donor Study II #REDS-II#. Hepatitis C virus prevalence and clearance among U.S. blood donors, 2006-2007: associations with birth cohort, multiple pregnancies and body mass index. J Infect Dis 2010;202:576-584.

Conflict of Interest:

None declared

Author's Response
Posted on April 4, 2012
Scott D., Holmberg, MD, MPH, Kathleen N. Ly, MPH, Jian Xing, PhD
Centers for Disease Control and Prevention, Atlanta, GA 30333
Conflict of Interest: None Declared

IN RESPONSE:

Our analysis of approximately 22 million multiple-cause-of death certificates from 1999 to 2007 showed increasing mortality among those noted to have hepatitis C virus (HCV) infection; by 2007 there were more recorded deaths among HCV-infected than among HIV-infected persons (1). We have since received data on deaths in 2008 and record an extension of the same trends as shown in that article.

Dr. Murphy and colleagues analyzed a small sample of 453 HCV-infected blood donors who died between 1991 and 2002; this analysis was of only a single cause of death and found a very high rate of trauma and suicide in persons who died at an average age of 50 years (2). This does not appear to be a representative sample (3), and we think comparison of that study with ours is not appropriate. In any case, such deaths among HCV-infected blood donors would be subsumed in our analysis of all deaths in US residents for the years of study. As in Table 1 of our article, national death certificates indicate that 57% of decedents who had hepatitis C noted as an underlying or contributing cause of death also had a diagnosis of "chronic liver disease (1)."

In answer to Dr. Murphy's question about a cohort effect, our analyses showed age-adjusted mortality rates, as clearly indicated in the text and in the figure and table legends.

We respectfully assert that there is indeed "an epidemic of HCV deaths" in the United States, especially among persons of the "Baby Boom" generation now aged 47- 66 years. Rate increases only appear gradual because they are 'flattened' by using 100,000 population as a denominator for the rates. More importantly, as we noted in our Discussion, death certificates actually under-enumerate HCV (or HBV)-related deaths as various studies now show that hepatitis C is diagnosed in half or fewer of patients before death. Even when persons are diagnosed, physicians and others filling out death certificates are often not the primary clinicians and may not be aware of the decedent's HCV infection. ]

We do agree that non-hepatic mortality among persons with HCV infection--including from trauma, suicide and substance abuse, as well as from effects of the virus on other organ systems--may not be adequately appreciated.

Scott D. Holmberg, MD, MPH

Kathleen N. Ly, MPH

Jian Xing, PhD

Centers for Disease Control and Prevention, Atlanta, GA 30333

References

1. Ly KN, Xing J, Klevens M, LJIles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012; 156:271-8

2. Guiltinan AM, Kaidarova Z, Custer B, et al. Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors. Am J Epidemiol 2008; 167:743-50.

3. El-Kamary SS, Jhaveri R, Hardell MD. All-cause, liver-related, and non-liver-related mortality among HCV-infected individuals in the general US population. Clin Infect Dis 2011; 53:150-7.

Conflict of Interest:

None declared

Failing to Take Action Will Contribute to Increasing the Burden of Morbidity and Mortality from Viral Hepatitis in Latin America
Posted on August 17, 2012
Jose Ramiro Cruz, DSc., Independent Consultant
44408 Maltese Falcon Sq., Ashburn, VA. 20147. USA
Conflict of Interest: None Declared

Dear Sirs,

The article by Ly and collaborators on the mortality from viral hepatitis (1) showed the importance of hepatitis C virus (HCV) infections and raised issues on their surveillance and treatment, and on the quality of death certificates in the United States. That decedents who were Hispanic or 45-54 years old had the highest risks of HCV-related death foreshadows the future of HCV infections and liver disease in Latin America, where efforts to control HCV are limited and where the information on HCV epidemiology and causes of death needs to be improved (2, 3). In Latin America and the Caribbean there were 6,170,260 deaths in 2008, 68,605 of which were associated with HIV/AIDS, 10,785 with HCV and 4,374 with hepatitis B (4). These may be underestimates and probably represent flawed data. Quality of mortality records was adequate in only seven of the Latin American countries (3) in 2007. Focused cohort studies showed that liver disease was the cause of death in 6.5% to 29.0% decedents older than 65 years in Cuba, Venezuela, Peru and Mexico (5).Kershenobich et al reported that epidemiological data on HCV infections in Latin America need to be improved (6). Trends and projections of HCV epidemiology, however, could be developed by using blood bank data to calculate the numbers of HCV-infected individuals. These authors estimated that 6.8-8.9 million Latin American adults are currently anti-HCV positive (6). This figure, compared with the 3.2 million persons with chronic hepatitis in the United States referenced by Ly (1), raises the possibility that complications of HCV chronic infections will become a major health issue in Latin America in the near future. Measures to prevent and control HCV infections should be established by the health systems in Latin America. Blood banks can participate in such efforts. Over 12 million individuals who attempt to donate blood in Latin America each year are asked about their risks for HIV, HBV and HCV before blood donation; 9 million units of blood collected for transfusion are screened to detect those infections (7). Blood donors are more likely to be infected with HCV than with HIV and HBV (8, 9; Table) and not all blood units collected in 2005-2009 were tested for viral markers. The numbers of unscreened units for that period were 196,330 for HIV, 267,173 for HBV and 252,185 for HCV. The high prevalence of infection (Table) and the untested units result in transmissions of viral infections through transfusions (10.) Wendel and colleagues reported that, between 2008 and 2011, the likelihood of blood being donated during the window period was 1:124,844 for HIV, 1:49,751 for HBV and 1:68,965 for HCV in selected Latin American countries (11). It is not surprising, therefore, that a multicenter study in nine Latin American countries found 20.0% of polytransfused individuals infected with HCV, while 14.5% had HBV and 2.1% had HIV (12). These data strongly suggest that HCV-associated morbidity and mortality will rise in the next few years in Latin America.In 2009, 47,638 Latin American blood donors were HCV-positive; 29,182 and 35,276 were reactive for HBV and HIV, respectively (9). It was estimated that 575,000 potential donors were deferred from donating because of HCV, HBV or HIV risk (9). Further analyses of these individuals –who attempt to donate blood because they are healthy and unaware of risky behaviors-, would shed light on the epidemiology of HCV. Adequate management of those who are infected would contribute to preventing future clinical complications and new infections. Failing to take action will definitely contribute to increasing the burden of morbidity and mortality from viral hepatitis in Latin America.

 

Table. Prevalence (%) of HIV, HBV and HCV markers among blood donors. Latin American countries, 2005 and 2009

 

Country

HIV

HBV

HCV

2005

2009

2005

2009

2005

2009

Argentina

0.25

0.24

0.39

0.27

0.98

0.67

Bolivia

0.19

0.11

0.47

0.31

0.75

1.07

Brazil

0.46

0.56

0.50

0.22

0.52

0.34

Chile

  0.06*

 0.04*

  0.04*

 0.02*

 0.17*

0.04*

Colombia

0.34

0.25

0.39

0.20

0.54

0.45

Costa Rica

 0.03*

0.12

 0.10*

0.13

 0.09*

0.93

Cuba

 0.02*

 0.02*

 0.51*

0.44

 0.60*

1.56

Ecuador

   0.006*

0.54

0.34

0.44

 0.01*

0.40

El Salvador

0.09

0.08

0.28

0.15

0.19

0.12

Guatemala

0.61

0.60

0.80

0.64

0.93

0.89

Honduras

0.24

0.27

0.30

0.29

0.99

0.48

Mexico

0.29

0.30

0.22

0.19

0.64

0.59

Nicaragua

0.80

0.08

0.03

0.21

0.73

0.31

Panama

0.07

0.05

0.27

0.20

0.67

0.24

Paraguay

0.28

0.61

0.31

0.42

0.58

0.32

Peru

0.51

0.54

0.62

0.45

0.92

1.06

Dominican Republic

0.42

0.22

1.66

1.08

0.66

0.54

Uruguay

  0.05*

0.14

0.17

0.20

0.30

0.35

Venezuela

0.35

0.43

1.25

1.53

0.37

0.70

Median

0.25

0.24

0.34

0.27

0.60

0.48

Mean

0.2666

0.2734

0.4553

0.3890

0.5600

0.5819

Standard Deviation

0.2219

0.2090

0.4070

0.3612

0.3020

0.3806

*Confirmed positive

References.

1. Ly KN, Xing J, Klevens M, Jiles RB, Ward JW and Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012; 156:271-8

2. Pan American Health Organization 2012. Informe sobre la reunion regional sobre hepatitis virales. Bogota, Colombia. Marzo 2012. In www.new.paho.org/hq/index.php?option=com_docman&task=doc_view&gid=18288&Itemid=

3. Alonzo-Gonzalez M, Martinez L, Munoz S and Jacobson JO. Patterns, trends and sex differences in HIV/AIDS mortality in Latin American countries: 1996-2007. BMC Public Health 2011:605. In http://www.biomedcentral.com/1471-2458/11/605

4. World Health Organization. Global burden of disease. Mortality and burden of disease statistics. Cause-specific mortality: regional estimates for 2008. In www.who.int/healthinfo/global_burden_disease/estimates_regional/en/index.htlm

5. Ferri CP, Acosta D, Guerra M, Huang Y, Llibre-Rodriguez JJ, Salas A et al. Socioeconomic factors and all cause and cause-specific mortality among older people in Latin America, India and China: A population-based cohort study. PLoS Medicine 2012, 9(2):e1001179. Doi:10.1371/journal.pmed.100179

6. Kershenobich D, Razavi HA, Sanchez-Avila JF, Bessone F, Coelho HS, Dagher L, et al. Trends and projections of hepatitis C virus epidemiology in Latin America. Liver Inter 2011; 31 Suppl 2:18-29. doi: 10.1111/j.1478-3231.2011.02538.x.

7. Pan American Health Organization, 2011. Regional Initiative and plan of action for transfusion safety 2006-2010. CD51/INF/5 pp 30-45.

8. Pan American Health Organization, 2007. Supply of blood for transfusion in the Caribbean and Latin American countries. Base line data for the Regional Plan of Action for Transfusion Safety 2006-2010.

9. Pan American Health Organization, 2010. Supply of blood for transfusion in the Caribbean and Latin American countries 2006, 2007, 2008, and 2009. Progress since 2005 of the Regional Plan of Action for Transfusion Safety.

10. Schmunis GA and Cruz JR. The safety of the blood supply in Latin America. Clin Microbiol Rev. 18 (1):12-29. 2005. Erratum Clin Microbiol Rev 18 (3):582. 2005

11. Wendel S, Acevedo CE, Baungarten C, Benati FJ, Bravo A, Camacho B, et al. The ISBT Working Party for transfusion-transmitted infectious disease (WP-TTID) survey for NAT testing in Latin America. Vox Sang 2012; 103(Suppl 1): 10 (Abstract).

12. Cruz JR. El estudio EPISANGRE. Editorial. Boletin Grupo Cooperativo Iberoamericano de Medicina Transfusional GCIAMT 2006; 5-8. 

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