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Cigarette Smoking in Persons Living with Hepatitis C: The National Health and Nutrition Examination Survey (NHANES), 1999-2014

Published:February 03, 2018DOI:https://doi.org/10.1016/j.amjmed.2018.01.011

      Abstract

      Background

      Cigarette smoking is common in persons living with hepatitis C (hepatitis C+), but national statistics on this harmful practice are lacking. A better understanding of smoking behaviors in hepatitis C+ individuals may help in the development of targeted treatment strategies.

      Methods

      We extracted data from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2014. Hepatitis C+ were compared with hepatitis C− adults in the entire sample and in the subset of current smokers. Measures included demographics, current smoking, cigarettes/day, nicotine dependence, other tobacco use, substance use, and medical and psychiatric comorbidities.

      Results

      Complete smoking and hepatitis C virus (HCV) data were available for 39,472 (90.1%) of 43,793 adult participants in NHANES during the study years. Hepatitis C+ smoked at almost triple the rate of hepatitis C− adults (62.4% vs 22.9%), with no significant difference between hepatitis C+ men and women (64.5% vs 58.2%). Hepatitis C+ smokers were more likely to smoke daily than hepatitis C− smokers (87.5% vs 80.0%), but had similar levels of nicotine dependence. Hepatitis C+ smokers were more likely to be older (mean age: 47.1 vs 41.5 years), male (69.4% vs 54.4%), Black (21.2% vs 12.1%), less educated (any college: 31.8% vs 42.9%), poor (mean family monthly poverty index: 1.80 vs 2.47), uninsured (43.9% vs 30.4%), use drugs (cocaine: 11.1% vs 3.2%; heroin: 4.0% vs 0.6%), and be depressed (33.2% vs 13.5%). Multivariate analyses revealed significant associations of both hepatitis C infection and cigarette smoking with current depression and hypertension.

      Conclusions

      There is a cigarette smoking epidemic embedded within the hepatitis C epidemic in the United States. The sociodemographic profile of hepatitis C+ smokers suggests that the implementation of effective tobacco treatment will be challenging. Thoughtful treatment strategies that are mindful of the unique characteristics of this group are needed.

      Keywords

      Clinical Significance
      • Hepatitis C+ adults in the United States smoke cigarettes at almost 3 times the rate of hepatitis C− adults (62.4% vs 22.9%).
      • Hepatitis C+ smokers are more likely than hepatitis C− smokers to be older, male, black, poorly educated, poor, uninsured, drug-using, and depressed.
      • Hepatitis C+ smokers are more likely to be daily smokers than hepatitis C− smokers.
      • Hepatitis C is associated with depression and hypertension in US adult smokers.

      Introduction

      There are approximately 3,000,000 persons living with hepatitis C virus (hepatitis C+) in the United States.
      • Denniston M.M.
      • Jiles R.B.
      • Drobeniuc J.
      • et al.
      Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010.
      Hepatitis C recently surpassed all other notifiable infectious diseases as a cause of death in the United States.
      • Ly K.N.
      • Hughes E.M.
      • Jiles R.B.
      • Holmberg S.D.
      Rising mortality associated with hepatitis C virus in the United States, 2003-2013.
      Among hepatitis C+ individuals, mortality attributable to cardiovascular, respiratory, and nonhepatic cancers, all linked to tobacco use, exceeds that from liver-related causes.
      • Mahajan R.
      • Xing J.
      • Liu S.J.
      • et al.
      Mortality among persons in care with hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006-2010.
      Hepatitis C in the US is concentrated in substance users, non-Hispanic blacks, the poor, the undereducated, and those with mental health disorders,
      • Denniston M.M.
      • Jiles R.B.
      • Drobeniuc J.
      • et al.
      Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010.
      • Greene S.K.
      • Levin-Rector A.
      • Hadler J.L.
      • Fine A.D.
      Disparities in reportable communicable disease incidence by census tract-level poverty, New York City, 2006-2013.
      • Tohme R.A.
      • Xing J.
      • Liao Y.
      • Holmberg S.D.
      Hepatitis C testing, infection, and linkage to care among racial and ethnic minorities in the United States, 2009-2010.
      • Janjua N.Z.
      • Yu A.
      • Kuo M.
      • et al.
      Twin epidemics of new and prevalent hepatitis C infections in Canada: BC hepatitis testers cohort.
      all groups with high rates of cigarette smoking.
      • Agaku I.T.
      • King B.A.
      • Dube S.R.
      Centers for Disease Control and Prevention
      Current cigarette smoking among adults—United States, 2005-2012.
      National statistics on smoking rates among US hepatitis C+ persons are scarce, but one Veterans Administration study reported a smoking prevalence of 67% in >111,000 hepatitis C+ males in a 2001-2009 cohort.
      • Chew K.W.
      • Bhattacharya D.
      • McGinnis K.A.
      • et al.
      Short communication: coronary heart disease risk by Framingham risk score in hepatitis C and HIV/Hepatitis C-Coinfected persons.
      We have entered a new era in hepatitis C care with the advent of direct-acting antivirals (DAAs). These effective, but very costly, therapies cure the vast majority of recipients and reduce hepatitis C-related mortality.
      • Dieperink E.
      • Pocha C.
      • Thuras P.
      • Knott A.
      • Colton S.
      • Ho S.B.
      All-cause mortality and liver-related outcomes following successful antiviral treatment for chronic hepatitis C.
      The United States is poised to spend $27 billion annually on DAAs to improve the quality and quantity of life for hepatitis C+ individuals,
      • Chhatwal J.
      • Kanwal F.
      • Roberts M.S.
      • Dunn M.A.
      Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States.
      yet there is no organized strategy to combat the tobacco use that is destined to offset these benefits. We reviewed data from the National Health and Nutrition Examination Survey (NHANES), 1999-2014, with the aim of generating information that will inform the development of cessation interventions for hepatitis C+ smokers. Two sets of analyses are presented. First, we compared smoking prevalence in hepatitis C+ vs hepatitis C− persons. Second, we analyzed the subset of respondents who were current smokers, with the goal of identifying factors that distinguish hepatitis C+ from hepatitis C− smokers.

      Methods

      NHANES is a survey program conducted by the Centers for Disease Control and Prevention that assesses the health and nutrition of US adults and children.
      • Centers for Disease Control and Prevention
      National Center for Health Statistics.
      Since 1999, the survey has run continuously, and data are posted on a publicly available website. Participants include consenting, noninstitutionalized civilians located in counties (15 per survey) throughout the United States. Approximately 5000 individuals are included in each survey.

      Data Extraction and Definitions

      We collected 147 NHANES data files from 8 survey cycles spanning 1999-2014. Tobacco use questions were systematically administered to adults ≥20 years old, so data were filtered for age ≥20 years.
      Sociodemographic characteristics were defined by responses to single-item questions in the DEMO dataset, except for insurance status in the HIQ dataset.
      Cigarette smoking status was classified into 3 categories and 1 subcategory:
      • Jarvis M.J.
      • Giovino G.A.
      • O'Connor R.J.
      • Kozlowski L.T.
      • Bernert J.T.
      Variation in nicotine intake among U.S. cigarette smokers during the past 25 years: evidence from NHANES surveys.
      • 1)
        Current smoker – reports [smoking ≥100 lifetime cigarettes] AND [currently smoking cigarettes every day or some days OR smoking a cigarette in the past 5 days].
        • a.
          Current non-daily smoker—a current smoker who reports smoking cigarettes on some days (ie, not every day).
      • 2)
        Ex-smoker – reports [smoking ≥100 lifetime cigarettes] AND [currently not smoking at all AND does not report smoking a cigarette in the past 5 days].
      • 3)
        Never smoker – reports [smoking <100 lifetime cigarettes] AND [not smoking a cigarette in the past 5 days].
      Average number of cigarettes smoked per day, number of years smoking, use of menthol cigarettes, and use of other tobacco products were derived from single-item questions.
      Nicotine dependence was derived from average daily cigarette consumption and minutes after waking until first cigarette, that is, the Heaviness of Smoking Index,
      • Burling A.S.
      • Burling T.A.
      A comparison of self-report measures of nicotine dependence among male drug/alcohol-dependent cigarette smokers.
      with scores of 0-2 = very low, 3 = low-moderate, 4 = moderate, and 5-6 = high.
      Serum cotinine levels were derived from the laboratory dataset.
      Hepatitis C testing is completed in NHANES for all consenting participants aged 6 years or older. The initial screen is a chemiluminescent microparticle immunoassay for antihepatitis C virus immunoglobulin G and immunoglobulin M. Prior to 2013, all chemiluminescent microparticle immunoassay-positive samples were subjected to confirmatory recombinant immunoblot assay (RIBA). For RIBA+ and RIBA-indeterminate individuals, HCV-RNA nucleic acid amplification testing was performed. A positive HCV-RNA assay confirmed active hepatitis C infection. RIBA testing was not available for 2013-2014, so the HCV-RNA assay was conducted without the RIBA in this sample only. Reported prior hepatitis C treatment was relatively uncommon. A total of 34 participants reported prior treatment, and only 13 of them (38%) were HCV-RNA negative. Prior hepatitis C treatment was therefore not considered in our analyses. Active hepatitis C (hepatitis C+) was defined by a positive HCV-RNA test. Hepatitis C status was defined as uninfected (hepatitis C−) if either the antibody test/s were negative OR if the HCV-RNA test was negative.
      Medical history (eg, asthma, hypertension, lifetime substance use) was derived from single-item questions.
      Depression score was calculated from the Patient Health Questionnaire (PHQ-9), with a score of ≥10 signifying clinically relevant depression.
      • Wang Y.
      • Lopez J.M.
      • Bolge S.C.
      • Zhu V.J.
      • Stang P.E.
      Depression among people with type 2 diabetes mellitus, US National Health and Nutrition Examination Survey (NHANES), 2005-2012.
      Alcohol use was divided into 4 categories: 1) Never (<12 drinks ever); 2) Past only (≥12 drinks ever but no drinks in the past year); 3) Current nonexcessive (≤2 drinks per day for men and ≤1 drink per day for women AND never ≥5 drinks in a day for the past year); (4) Current excessive (>2 drinks per day for men and >1 drink per day for women AND/OR ≥ 5 drinks in a day in the past year).
      • Taylor A.L.
      • Denniston M.M.
      • Klevens R.M.
      • McKnight-Eily L.R.
      • Jiles R.B.
      Association of Hepatitis C Virus With Alcohol Use Among U.S. Adults: NHANES 2003-2010.
      Current marijuana, cocaine, and heroin use were defined as reported use within the past 30 days, past-only use was defined as any lifetime use but none in the past 30 days, and never use was defined as no lifetime use.

      Statistical Analysis

      When performing analyses for individual NHANES cycles, we used the 2-year sample weights. When performing pooled analyses of 8 NHANES cycles, we followed the NHANES guidance
      • Centers for Disease Control and Prevention
      National Health and Nutrition Examination Survey. When and how to construct weight when combining survey cycles.
      to calculate new survey weights, so that the estimates would be representative of the US population at year 2006, the midpoint of the combined survey period. Analyses used SPSS Version 24.0 (IBM, Armonk, NY) and the R Version 3.3.2. survey package.
      • Lumley T.
      Analysis of complex survey samples.
      In the first set of analyses, hepatitis C+ and hepatitis C− participants were compared for the entire NHANES sample. In order to better understand the contrasts between hepatitis C+ and hepatitis C− smokers, we conducted additional analyses that were restricted to current smokers.
      For dichotomous variables, we estimated prevalence (for clinical outcomes) or proportions (for sociodemographic or behavioral variables) among the hepatitis C+ and hepatitis C− groups. For each variable, we calculated the odds ratio between the 2 groups and the corresponding 95% confidence intervals. We tested for statistical significance (alpha <0.05, 2-tailed) using the Wald test. For categorical, nondichotomous variables, we estimated the proportion of population in each category according to hepatitis C status and performed the survey chi-squared test to assess for differences between groups. For continuous variables, we used a survey t-test to compare means between the hepatitis C+ and hepatitis C− groups.
      For certain medical diagnoses of interest, we also estimated adjusted odds ratios between the hepatitis C+ and hepatitis C− groups with survey multivariate logistic regression controlling for potential confounders including biologically important covariates: history of illicit drug use (ever/never), current smoking status, age, sex, and race.

      Results

      Participant Sample

      In the pooled cohort from 1999-2014, a total of 43,793 adults ≥20 years of age were included, and 39,472 (90.2%) provided adequate information to define both their hepatitis C and smoking status. Of these, 524 (1.3%) were hepatitis C+, and 8820 (22.3%) were current smokers. Of the current smokers, 312 (3.5%) were hepatitis C+. Serum cotinine testing, a biochemical measure of current smoking status (>10 ng/mL = current smoker
      • Kim S.
      Overview of cotinine cutoff values for smoking status classification.
      ), was performed on 76.9% of the cohort, and it correlated moderately well with historical report: 92.2% of current, 8.0% of ex-, and 3.8% of never smokers had cotinine >10 ng/mL.

      Smoking Prevalence

      Hepatitis C+ individuals smoked at nearly triple the rate of hepatitis C− individuals (62.4% vs 22.9%, P < .001) in the 1999-2014 sample. Only 15.5% of hepatitis C+ individuals were never smokers compared with 52.6% of hepatitis C− individuals, P < .001. Smoking prevalence did not differ significantly between hepatitis C+ males and females (64.5% vs 58.2%, P = .27), but the difference between hepatitis C− males and females was statistically significant (26.0% vs 20.0%, P < .001).

      Demographics and Clinical Characteristics of Hepatitis C+ vs Hepatitis C− Smokers

      Table 1 compares the sociodemographic characteristics of hepatitis C+ and hepatitis C− participants for both the overall sample and for the subset of current smokers. Hepatitis C+ respondents were more likely to be older, male, black, poorly educated, poor, and less likely to be married/partnered and privately insured than hepatitis C− individuals. Hepatitis C+ smokers were more likely to be older, male, black, poorly educated, poor, and less likely to be privately insured than hepatitis C− smokers.
      Table 1Sociodemographic Characteristics of Hepatitis C+ Versus Hepatitis C− Participants
      CharacteristicNHANES, 1999-2014NHANES, 1999-2014: Smokers Only
      HCV− (n = 38,983)HCV+ (n = 524)P-ValueHCV− (n = 8508)HCV+ (n = 312)P-Value
      Age (95% CI)46.7 (46.3-47.1)49.3 (48.350.3)< .00141.5 (41.1-41.9)47.1 (45.9-48.3)< .001
      % Male47.9%67.3%< .0154.4%69.4%< .001
      Race/ethnicity (%)
       White69.8%62.2%70.6%64.8%.002
       Black10.6%23.6%12.1%21.2%
       Mexican-American8.1%6.0%6.9%6.5%
       Other Hispanic5.3%4.2%4.9%2.9%
       Other
      Includes Asians, a category that was not included in all survey years.
      6.2%2.7%5.2%4.6%
      Education (%)
       <9th grade6.3%8.1%< .015.9%8.5%< .001
       Some HS12.1%21.2%20.4%23.6%
       HS Grad/GED23.9%31.8%30.9%36.0%
       Some college30.6%31.0%30.9%29.6%
       College grad27.1%7.9%12.0%2.2%
      Married/partnered64.1%52.8%< .00144.5%49.1%.25
      Medical insurance (%)
       Private64.7%40.4%< .00150.4%30.8%< .001
       Medicare7.0%5.5%4.8%4.9%
       Medicaid4.2%8.7%7.4%11.3%
       Medicare + Medicaid1.2%4.3%1.4%4.1%
       Other public insurance4.1%6.9%5.2%5.0%
       Other or unknown insurance0.3%0.2%0.4%0.0%
       Uninsured18.5%34.0%30.4%43.9%
      Family monthly poverty level index
      Ratio of monthly family income to the Department of Health and Human Services poverty guidelines specific to family size.
      (95% CI)
      3.00 (2.94-3.06)2.01 (1.83-2.20)< .012.47 (2.40-2.55)1.80 (1.57-2.04)< .001
      CI = confidence interval; GED = general educational development; HCV− = without active hepatitis C infection; HCV+ = with active hepatitis C infection; HS = high school; NHANES = National Health and Nutrition Examination Survey.
      * Includes Asians, a category that was not included in all survey years.
      Ratio of monthly family income to the Department of Health and Human Services poverty guidelines specific to family size.
      Table 2
      • Centers for Disease Control and Prevention
      National Health and Nutrition Examination Survey. When and how to construct weight when combining survey cycles.
      compares the clinical and behavioral characteristics of hepatitis C+ and hepatitis C− participants for both the overall sample and for the subset of current smokers. Histories of hypertension, illicit substance use, and injection drug use were more common in hepatitis C+ than hepatitis C− smokers. Current cocaine and heroin use were more common in hepatitis C+ than hepatitis C− smokers. Hepatitis C+ smokers were 2.5 times more likely to report clinically relevant depression than their hepatitis C− counterparts (P < .001). Although there was no difference in current excessive alcohol use by HCV status, the prevalences were high in both groups of smokers (58.7% and 55.4%).
      Table 2Clinical and Behavioral Characteristics Hepatitis C+ Versus Hepatitis C− Participants
      CharacteristicNHANES, 1999-2014
      Data were not available for the entirety of 1999-2014 for all listed variables. For variables with missing years, the data were aggregated for all years available.
      NHANES, 1999-2014: Smokers Only
      Data were not available for the entirety of 1999-2014 for all listed variables. For variables with missing years, the data were aggregated for all years available.
      HCV− (N = 38,983)HCV+ (N = 524)P-ValueHCV− (N = 8,508)HCV+ (N = 312)P-Value
      Medical history (%)
       Asthma13.6%15.1%.4713.1%24.4%.19
       Cancer8.9%7.8%.506.9%6.5%.82
       Diabetes8.3%9.7%.416.2%9.1%.17
       Emphysema1.8%4.5%< .0013.4%4.3%.50
       Hypertension29.8%41.1%< .00124.7%34.3%.006
       Cocaine, heroin, or methamphetamine use18.7%71.6%< .00135.1%80.1%< .01
       Injection drug use2.1%52.1%< .0014.8%53.6%< .001
       Myocardial infarction3.3%4.5%.283.5%5.0%.22
       Stroke2.7%4.7%.022.8%3.3%.65
      Depression score (95% CI)3.0 (2.9-3.1)5.6 (4.8-6.4)< .0014.1 (3.9-6.5 (5.6-7.4)< .001
      Current depression (PHQ score ≥10)7.4%25.3%< .0014.3)33.2%< .001
      Other (noncigarette) tobacco product use4.0%6.4%.0313.5%4.6%.58
      Current excessive alcohol use34.3%52.7%< .0013.7%58.7%.44
      Nontobacco substance use
       Alcohol (%)
        Current excessive34.3%52.7%< .00155.4%58.7%.23
        Current nonexcessive45.1%33.6%35.6%35.2%
        Past only7.5%8.7%5.4%5.3%
        Never13.1%4.9%3.5%0.7%
       Marijuana (%)
        Current9.5%21.2%< .00126.7%28.7%.32
        Past only50.2%66.5%56.3%60.6%
        Never40.3%12.3%17.1%10.7%
       Cocaine
        Current1.1%7.7%< .0013.2%11.1%< .001
        Past only16.9%60.1%30.3%63.6%
        Never82.0%32.2%66.6%25.2%
       Heroin
        Current0.2%2.4%< .0010.6%4.0%< .001
        Past only1.8%30.7%4.2%30.7%
        Never98.1%66.8%95.2%65.3%
      CI = confidence interval; HCV− = without active hepatitis C infection; HCV+ = with active hepatitis C infection; NHANES = National Health and Nutrition Examination Survey; PHQ = Patient Health Questionnaire – 9.
      • Centers for Disease Control and Prevention
      National Health and Nutrition Examination Survey. When and how to construct weight when combining survey cycles.
      * Data were not available for the entirety of 1999-2014 for all listed variables. For variables with missing years, the data were aggregated for all years available.

      Cigarette Smoking Behaviors in Hepatitis C+ vs Hepatitis C− Smokers (Table 3)

      There were no significant differences in daily cigarette consumption, nicotine dependence, or menthol cigarette usage by hepatitis C status. Hepatitis C+ smokers had been smoking for more years than their uninfected counterparts (30.4 vs 23.9 years, P < .001), and they were more likely to be daily smokers.
      Table 3Tobacco Use Characteristics of Hepatitis C+ Versus Hepatitis C− Participants
      CharacteristicNHANES, 1999-2014: Smokers Only
      HCV− (n = 8508)HCV+ (n = 312)P-Value
      Smoking frequency
       Daily80.0%87.5%.04
       Nondaily15.8%10.1%
       Not classifiable4.3%2.4%
      Nicotine dependence
      Derived from the Heaviness Smoking Index.15
       Very low45.7%39.1%.46
       Low-Moderate24.3%25.7%
       Moderate19.0%21.6%
       High11.0%13.6%
      Cigarettes per day (95% CI)14.4 (14.0-14.9)16.0 (14.2-17.7).09
      Cotinine level, ng/mL (95% CI)207 (202-213)264 (244-283)< .001
      Number of years smoking (95% CI)23.9 (23.4-24.3)30.4 (29.2-31.7)< .001
      Smokes menthol cigarettes (%)27.1%29.2%.54
      CI = confidence interval; HCV− = without active hepatitis C infection; HCV+ = with active hepatitis C infection.
      * Derived from the Heaviness Smoking Index.
      • Taylor A.L.
      • Denniston M.M.
      • Klevens R.M.
      • McKnight-Eily L.R.
      • Jiles R.B.
      Association of Hepatitis C Virus With Alcohol Use Among U.S. Adults: NHANES 2003-2010.

      Multivariate Analyses of Clinical Characteristics of Hepatitis C+ vs Hepatitis C− Individuals

      Medical diagnoses that were associated with hepatitis C infection in the overall NHANES sample and that are known to be associated with cigarette smoking (ie, emphysema, hypertension, stroke, current depression, and current excessive alcohol use) were subjected to logistic regression analyses in order to assess the relative associations of HCV status and current smoking with them. These analyses were adjusted for other biologically relevant covariates, that is, age, sex, race, and history of illicit substance use (Table 4). The multivariate analyses demonstrated significant associations of both hepatitis C+ status and current cigarette smoking with hypertension and current depression.
      Table 4Multivariate Logistic Regression for Medical Diagnoses Associated with Active Hepatitis C
      DiagnosisUnivariate OR for HCV + vs HCV−Multivariate logistic regression
      HCV + vs HCV−Current Smoker vs Current Nonsmoker
      ORadj95% CIORadj95% CI
      Emphysema
      Older age and ethnicity/race were also associated with emphysema.
      2.602.140.92–5.017.815.40–11.3
      Hypertension
      Older age and ethnicity/race were also associated with hypertension.
      1.641.651.20–2.271.131.01–1.27
      Stroke
      Older age and ethnicity/race were also associated with stroke.
      1.791.800.82–3.942.331.90–2.85
      Current depression
      Older age, ethnicity/race, history of use of cocaine, heroin, or methamphetamine, and female sex were also associated with current depression.
      4.212.471.69–3.602.632.28–3.05
      Current excessive alcohol‖2.141.120.69–1.812.141.81–2.54
      CI = confidence interval; HCV− = without active hepatitis C infection; HCV+ = with active hepatitis C infection; OR = odds ratio; ORadj = adjusted odds ratio.
      ‖Younger age, ethnicity/race, history of use of cocaine, heroin, or methamphetamine and male sex were also associated with excessive alcohol use.
      Ethnicity/race associated with the highest rates of the specific medical diagnoses were: White for emphysema and excessive alcohol use, Black for hypertension and stroke, and Hispanic (not including Mexican-American) for current depression.
      * Older age and ethnicity/race were also associated with emphysema.
      Older age and ethnicity/race were also associated with hypertension.
      Older age and ethnicity/race were also associated with stroke.
      § Older age, ethnicity/race, history of use of cocaine, heroin, or methamphetamine, and female sex were also associated with current depression.

      Discussion

      The Centers for Disease Control and Prevention identifies hepatitis C as the leading reportable infectious killer in the United States.
      • Ly K.N.
      • Hughes E.M.
      • Jiles R.B.
      • Holmberg S.D.
      Rising mortality associated with hepatitis C virus in the United States, 2003-2013.
      DAAs are destined to change the face of the hepatitis C epidemic, perhaps ending it altogether in the coming decades.
      • Kabiri M.
      • Jazwinski A.B.
      • Roberts M.S.
      • Schaefer A.J.
      • Chhatwal J.
      The changing burden of hepatitis C virus infection in the United States: model-based predictions.
      This will be a costly enterprise, with projected US medication expenses of $27 billion annually.
      • Chhatwal J.
      • Kanwal F.
      • Roberts M.S.
      • Dunn M.A.
      Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States.
      The American Association for the Study of Liver Diseases (AASLD) with the Infectious Diseases Society of America (IDSA),
      • American Association for the Study of Liver Diseases and the Infectious Diseases Society of America
      HCV Guidance: recommendations for testing, managing, and treating hepatitis C.
      the US Department of Health and Human Services (DHHS),
      • Centers for Disease Control and Prevention
      Viral hepatitis action plan for 2017-2020.
      and the World Health Organization (WHO)
      • World Health Organization
      Global health sector strategy on viral hepatitis 2016-2021.
      have all published hepatitis C treatment guidelines since 2016. A large majority of US hepatitis C+ adults smoke cigarettes, and we describe herein the first national sample of female persons living with hepatitis C, who reported a smoking prevalence of 58.2%. The average smoker loses more than 10 years of life to this behavior,
      • Jha P.
      • Ramasundarahettige C.
      • Landsman V.
      • et al.
      21st-century hazards of smoking and benefits of cessation in the United States.
      yet the aforementioned guidelines are largely silent on tobacco use. The AASLD/IDSA mention cigarettes as a possible cofactor in the progression of liver fibrosis,
      • American Association for the Study of Liver Diseases and the Infectious Diseases Society of America
      HCV Guidance: recommendations for testing, managing, and treating hepatitis C.
      the DHHS action plan does not discuss tobacco use,
      • Centers for Disease Control and Prevention
      Viral hepatitis action plan for 2017-2020.
      and the WHO strategy statement makes a single mention, stating that smoking “may complicate chronic infection.”
      • World Health Organization
      Global health sector strategy on viral hepatitis 2016-2021.
      Smoking cessation is not a recommendation within any of these guidelines.
      Heart disease, cancer, and stroke are the first, second, and fifth leading causes of death in the United States.
      • Centers for Disease Control and Prevention
      Mortality in the United States, 2014.
      The causal role of smoking in these health outcomes is firmly established. A meta-analysis of 22 studies (N = 69,725) showed that hepatitis C likewise increases the risk for cardiac death, myocardial infarction, and stroke even after adjustment for sex, body mass index, diabetes, hypertension, cholesterol, and smoking.
      • Petta S.
      • Maida M.
      • Macaluso F.S.
      • et al.
      Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies.
      Hepatitis C causes both hepatocellular carcinoma
      • El-Serag H.B.
      • Kanwal F.
      Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?.
      and non-Hodgkin lymphoma.
      • Peveling-Oberhag J.
      • Arcaini L.
      • Hansmann M.L.
      • Zeuzem S.
      Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management.
      It is also associated with cancers of the head and neck,
      • Mahale P.
      • Sturgis E.M.
      • Tweardy D.J.
      • Ariza-Heredia E.J.
      • Torres H.A.
      Association between hepatitis C virus and head and neck cancers.
      lung, pancreas, kidney, and anorectum.
      • Allison R.D.
      • Tong X.
      • Moorman A.C.
      • et al.
      Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006-2010.
      With the possible exception of lymphoma, all of these cancers are separately linked to tobacco exposure. There is some evidence that these risks may be additive. For example, tobacco use amplifies the risk for hepatocellular carcinoma in hepatitis C+ individuals,
      • Chuang S.C.
      • Lee Y.C.
      • Hashibe M.
      • Dai M.
      • Zheng T.
      • Boffetta P.
      Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis.
      and it also compounds the risk for carotid plaque formation.
      • Petta S.
      • Maida M.
      • Macaluso F.S.
      • et al.
      Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies.
      Widespread usage of DAAs promises increased longevity for those with HCV
      • Dieperink E.
      • Pocha C.
      • Thuras P.
      • Knott A.
      • Colton S.
      • Ho S.B.
      All-cause mortality and liver-related outcomes following successful antiviral treatment for chronic hepatitis C.
      and may ultimately render hepatitis C infection a rare disease.
      • Kabiri M.
      • Jazwinski A.B.
      • Roberts M.S.
      • Schaefer A.J.
      • Chhatwal J.
      The changing burden of hepatitis C virus infection in the United States: model-based predictions.
      Similar to HIV,
      • Helleberg M.
      • Afzal S.
      • Kronborg G.
      • et al.
      Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study.
      it is possible, indeed likely, that effective antiviral therapy will allow tobacco use to emerge as the leading killer in the hepatitis C+ population. In order to avoid this undesirable outcome, public health authorities together with hepatitis C care providers, will need to make a concerted effort to combat tobacco use in this group.
      The national sample described herein and one earlier paper reporting on a small cohort from the Bronx, New York
      • Shuter J.
      • Litwin A.H.
      • Sulkowski M.S.
      • et al.
      Cigarette smoking behaviors and beliefs in persons living with hepatitis C.
      indicate that hepatitis C+ smokers possess various characteristics that may interfere with successful quitting. Black race, low socioeconomic status, lower educational attainment, psychiatric illness, and comorbid substance use are all associated with lower cessation rates, and these factors also suggest the need for intensive tobacco treatment rather than brief interventions.
      • Abrams D.B.N.R.
      • Brown R.A.
      • Emmons K.M.
      • Goldstein M.G.
      • Monti P.M.
      The Tobacco Dependence Treatment Handbook: A Guide to Best Practices.
      • Agrawal A.
      • Sartor C.
      • Pergadia M.L.
      • Huizink A.C.
      • Lynskey M.T.
      Correlates of smoking cessation in a nationally representative sample of U.S. adults.
      • Goren A.
      • Annunziata K.
      • Schnoll R.A.
      • Suaya J.A.
      Smoking cessation and attempted cessation among adults in the United States.
      • Jones M.R.
      • Joshu C.E.
      • Navas-Acien A.
      • Platz E.A.
      Racial/ethnic differences in duration of smoking among former smokers in the National Health and Nutrition Examination Surveys (NHANES) [e-pub ahead of print].
      • Smith P.H.
      • Homish G.G.
      • Giovino G.A.
      • Kozlowski L.T.
      Cigarette smoking and mental illness: a study of nicotine withdrawal.
      We found that a larger proportion of hepatitis C+ smokers compared with hepatitis C− smokers use cigarettes daily, and they had significantly higher cotinine levels. The multivariate analyses demonstrated that hepatitis C infection and smoking have independent, significant associations with both depression and hypertension. The emerging profile of hepatitis C+ smokers in the United States suggests that this is a population bearing a heavy burden of psychiatric illness, other substance use (including alcohol), socioeconomic disadvantage, and important medical comorbidities.
      The groups with the highest rates of hepatitis C in the United States are also at risk for inconsistent care.
      • Sarpel D.
      • Baichoo E.
      • Dieterich D.T.
      Chronic hepatitis B and C infection in the United States: a review of current guidelines, disease burden and cost effectiveness of screening.
      DAA therapy, including pretreatment evaluation and posttreatment monitoring, typically lasts at least 12-24 weeks, during which time hepatitis C+ individuals interact frequently and predictably with the medical system, and this may represent a golden opportunity to promote cessation. Our findings suggest that interventions designed for this population should be mindful of the educational status, cultural background, poverty, reliance on public insurance, and hyperprevalence of depression and other substance use that characterize the group. The medical community has abundant experience treating tobacco use in depressed
      • Gierisch J.M.
      • Bastian L.A.
      • Calhoun P.S.
      • McDuffie J.R.
      • Williams Jr, J.W.
      Comparative Effectiveness of Smoking Cessation Treatments for Patients With Depression: A Systematic Review and Meta-analysis of the Evidence.
      and substance-using populations,
      • Apollonio D.
      • Philipps R.
      • Bero L.
      Interventions for tobacco use cessation in people in treatment for or recovery from substance use disorders.
      and this collective experience should inform the development of treatment strategies for hepatitis C+ smokers.
      Our study has certain limitations. Like all surveys, the NHANES dataset is restricted to those interview and laboratory data that were collected from the participants. We cannot rule out residual confounding by unmeasured variables. Although completion rates were high, there were missing data for all of the analyzed variables, and we cannot ensure that the “missingness” was randomly distributed. We did not systematically verify smoking status with biochemical markers, although cotinine levels correlated well with reported smoking status in the 77% of the overall sample who provided specimens.
      Sixteen years of experience from a nationally representative sample confirms the existence of a cigarette smoking epidemic embedded within the hepatitis C epidemic in the United States. Hepatitis C+ individuals smoke at nearly triple the rate of the general population, and we describe herein a sociodemographic profile of this group that will be helpful in developing effective tobacco treatment strategies for them. It is public health folly to spend tens of billions of dollars annually on antiviral hepatitis C medications and ignore the lethal addiction affecting more than 60% of them. As we enter a new era of hepatitis C treatment, it is a public health imperative to research, develop, and implement tobacco treatments for the hepatitis C+ community.

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