Hepatitis A and B Immunity and Vaccination in Chronic Hepatitis B and C Patients in a Large United States Cohort

Transcription

1 MAJOR ARTICLE Hepatitis A and B Immunity and Vaccination in Chronic Hepatitis B and C atients in a Large United States Cohort Emily Henkle, 1 Mei Lu, 2 Lora B. Rupp, 2 Joseph A. Boscarino, 3 Vinutha Vijayadeva, 4 Mark A. Schmidt, 1 and Stuart C. Gordon 2 ; for the Chronic Hepatitis Cohort Study (CHeCS) Investigators a 1 Center for Health Research, Kaiser ermanente Northwest, ortland, Oregon; 2 Henry Ford Health System, Detroit, Michigan; 3 Geisinger Health System, Danville, ennsylvania; and 4 Center for Health Research, Kaiser ermanente, Honolulu, Hawaii Background. Hepatitis A and B vaccines are effective in preventing superinfection and sequelae in patients with chronic hepatitis B or C. We describe immunity and vaccination against hepatitis A and B in chronic hepatitis patients from the US Chronic Hepatitis Cohort Study. Methods. We identified chronic hepatitis B and C patients with healthcare utilization during and 12 months of enrollment. We used electronic laboratory records to determine immunity and medical and billing records for vaccination history. Immunity against hepatitis A was defined by positive hepatitis A antibody or documented vaccination. Immunity against hepatitis B was defined as hepatitis B surface antibody level 10 miu/ml or core antibody positive, or by documented vaccination. Results. Among 1635 chronic hepatitis B patients, 978 (59.8%) were immune or vaccinated against hepatitis A, 122 (7.5%) had negative hepatitis A antibody tests, and 535 (32.7%) had no testing or vaccination record. Among 5328 chronic hepatitis C patients, 2998 (56.3%) were immune or vaccinated against hepatitis A, 659 (12.4%) had negative hepatitis A antibody tests, and 1671 (31.4%) had no testing or vaccination record. Additionally, 3150 (59.1%) chronic hepatitis C patients were immune or vaccinated against hepatitis B, 1003 (18.8%) had a negative test result, and 1175 (22.1%) were neither tested for nor vaccinated against hepatitis B. Conclusions. Approximately 40% of chronic hepatitis B and C patients are susceptible to or have no documented immunity or vaccination against hepatitis A or hepatitis B. Clinicians should consider antibody testing and vaccination for this vulnerable population. Keywords. chronic hepatitis; vaccination; hepatitis A; hepatitis B; hepatitis C. Adjusting for asymptomatic cases and underreporting, cases of acute hepatitis B infection and cases of acute hepatitis A infection occurred in the United States in 2010 [1]. Coinfection with chronic hepatitis C (CHC) and chronic hepatitis B (CHB) heightens an individual s risk for progressive liver disease and hepatocellular carcinoma [2, 3]. There is evidence of Received 29 May 2014; accepted 24 October 2014; electronically published 3 November a The CHeCS Investigators are listed in the Notes section. Correspondence: Emily Henkle, hd, MH, Oregon Health & Science University, 3375 SW Terwilliger Ave, ortland, OR (emhenkle@gmail.com). Clinical Infectious Diseases 2015;60(4): The Author ublished by Oxford University ress on behalf of the Infectious Diseases Society of America. All rights reserved. For ermissions, please journals.permissions@oup.com. DOI: /cid/ciu879 an increased risk of acute liver failure in CHC patients who have a superimposed acute hepatitis A infection [4, 5]. Hepatitis A infection in CHB patients carries a higher case fatality rate [6]. Therefore, the portion of the estimated million people with CHC and million people with CHB in the United States without prior immunity or history of vaccination are potentially vulnerable to sequelae of superinfection with these hepatotropic vaccine-preventable viruses [7, 8]. Hepatitis A and B vaccines are effective vaccines that can prevent superinfection in patients with CHB or CHC infection. Guidelines for their use in such populations are not consistent. While some rely on clinicians to identify patients with chronic liver disease or risk factors for hepatitis B infection, others broadly recommend 514 CID 2015:60 (15 February) Henkle et al

2 vaccination for all CHC and CHB patients without evidence of immunity [4, 9 11]. The definition of chronic liver disease is not included in the guidelines. We describe the current recommendations for vaccination and the frequency of and factors related to immunity or vaccination and vaccination against hepatitis A in CHB and hepatitis A and B in CHC health plan members from US patients included in the Chronic Hepatitis Cohort Study (CHeCS). METHODS The CHeCS study population was drawn from 4 geographically disparate healthcare organizations: Kaiser ermanente Northwest (ortland, Oregon), Kaiser ermanente Hawaii (Honolulu, Hawaii), Henry Ford Health System (Detroit, Michigan), and Geisinger Health System (Danville, ennsylvania). We identified CHB and CHC patients with healthcare utilization between 2006 and 2008 using an algorithm of hepatitis and chronic liver disease, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and/or laboratory results (hepatitis C RNA alone or laboratory evidence of current hepatitis B [ positive hepatitis B surface antigen, hepatitis B e-antigen, or DNA serology]) as previously described [12]. All patients included in this analysis were confirmed to have CHB or CHC by chart review; we excluded patients coinfected with CHB and CHC. This analysis was restricted to health plan members with at least 12 months of continuous enrollment. All health plan and health record data were collected through 31 December We used electronic laboratory records to determine immunity, and electronic medical (CVX codes, which include history of vaccination) and billing records (Current rocedural Terminology codes) for vaccination history. atients were considered immune against hepatitis A if they had a positive hepatitis A antibody test (total hepatitis A antibody [anti-ha], immune from previous infection or vaccination). Evidence of immunity against hepatitis B was defined as a positive hepatitis B surface antibody (anti-hbs) (levels 10 miu/ml) or a positive hepatitis B core antibody (anti-hbc, immune from previous infection). We considered patients to be vaccinated against hepatitis A or B with documentation of at least 1 dose of the respective vaccine. Explanatory variables available in the medical record included age as of last encounter, sex, race, ethnicity, and length of time with a hepatitis B or C diagnosis. Median household income was estimated based on census tract data based on geocode. Duration of plan member coverage was reported as median years with standard deviation (SD). The severity of liver disease was classified as compensated cirrhotic, decompensated cirrhotic, or noncirrhotic based on ICD-9-CM codes as previously described [13]. The noncirrhotic group included those with no liver disease and those with no evaluation or documented ICD-9-CM code. In addition, the FIB-4 score was included as a noninvasive surrogate for liver fibrosis, validated against liver biopsy in these CHC and CHB cohorts [14, 15]. The FIB-4 score was calculated as age (years) aspartate aminotransferase (U/L) / (platelet count (10 9 /L) (alanine aminotransferase ½ (U/L)) and log-transformed for all analyses. A logistic regression model was applied given the binary outcome of immune or not immune. Analyses began with testing for univariate variable effect, followed by multivariable modeling. Given varied data availability status among the sites, all multivariate analyses were adjusted by site of enrollment. The final model would retain variables with a value <.05 and be assessed for the model goodness-of-fit (c-index). RESULTS Review of Current Recommendations Table 1 highlights the current recommendations for hepatitis A and B vaccinations. The Hepatitis C Task Force recommends both vaccines for newly diagnosed CHC patients without Table 1. Hepatitis A and B Vaccination Recommendations and Quality Measures for atients With Chronic Hepatitis B or C Recommending Agency Hepatitis A Vaccine Hepatitis B Vaccine Hepatitis C Task Force [11] Advisory Committee on Immunization ractices (ACI) [4, 10] American Association for the Study of Liver Diseases (AASLD) [9] European Association for the Study of the Liver (EASL) [16] Centers for Medicare & Medicaid Services (CMS) hysician Reporting Quality Measure [17] All CHC patients without evidence of immunity atients with chronic liver disease, but not routinely for CHC or CHB All CHC patients CHB patients with chronic liver disease CHB advised to be vaccinated if no hepatitis A antibody; not included for CHC One hepatitis A vaccine or evidence of immunity for CHC patients All CHC patients without evidence of immunity Adults with chronic liver disease or risk factors for hepatitis B (sexual behavior, blood exposure) Should be offered to CHC patients Not included Not included Abbreviations: CHB, chronic hepatitis B; CHC, chronic hepatitis C. Hepatitis A/B in Chronic Hepatitis B/C atients CID 2015:60 (15 February) 515

3 evidence of immunity to hepatitis A and/or B, based on expert opinion [11]. The Advisory Committee on Immunization ractices (ACI) recommends hepatitis A vaccine for susceptible patients with chronic liver disease but not routinely for CHB or CHC patients without chronic liver disease [4]. The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver both recommend hepatitis A vaccine for all CHC patients with no evidence of preexisting antibody, but the AASLD similarly recommends vaccinating CHB patients with chronic liver disease [9, 16]. AASLD guidelines state that hepatitis B vaccine should be offered to CHC patients. The ACI recommends hepatitis B vaccination of adults with chronic liver disease in addition to those at risk for infection by sexual exposure or exposure to blood [10]. The hysician Quality Reporting System quality indicator from the Centers for Medicare and Medicaid Services counts all CHC patients with at least 1 hepatitis A vaccine or documented immunity to hepatitis A [17]. Chronic Hepatitis B Infected atients We identified 1635 CHB-infected patients (Table 2). Half the population (50%) was years old, 49% were of Asian descent, and 55% were male. Most (78%) were classified as noncirrhotic. Among the 1635 patients, 978 (59.8%) had evidence of immunity or vaccination against hepatitis A infection, whereas 122 (7.5%) tested negative and were unvaccinated and 535 (32.7%) were neither tested for nor vaccinated against hepatitis A infection (Figure 1A). Among 1246 (76.2%) patients with no record of vaccination, 711 (57.1%) had an anti-ha test, and of these, 589 (82.8%) had a positive test. Of the 389 vaccinated, 242 (62.2%) received the complete hepatitis A vaccine series of 2 doses. In univariate analysis (Table 3), the oldest patients ( 80 years old) were less likely to have immunity or vaccination than any other age group (17% compared with 53% 65% per 10-year age strata). Native American (43%) and black (42%) patients were less likely to have immunity or vaccination (vs 51% 66% in other ethnic groups). atients with no immunity or vaccination had fewer months of member coverage (mean, 98 [SD, 43] months vs 90 [SD, 45] months for those with evidence). After multivariable adjustment (Table 4), factors significantly associated with immunity or vaccination included age 80 vs <30 years (odds ratio [OR], 0.15; 95% confidence interval [CI],.06.41), age vs <30 years (OR, 1.54; 95% CI, ), Asian vs white race (OR, 1.82; 95% CI, ), male sex (OR, 1.39; 95% CI, ), and months of member coverage (OR, 1.05/year; 95% CI, /year). Chronic Hepatitis C Infected atients Of the 5328 CHC-infected patients identified, 75% were aged years, 61% were male, and 63% were white. There was Table 2. Characteristics of Chronic Hepatitis B and C atients at 4 US Healthcare Organizations Characteristic Overall Chronic Hepatitis B Cohort (n = 1635) Overall Chronic Hepatitis C Cohort (n = 5328) Site ortland, Oregon 711 (43%) 2788 (52%) Honolulu, Hawaii 601 (37%) 949 (18%) Detroit, Michigan 286 (17%) 1174 (22%) Danville, ennsylvania 37 (2%) 417 (8%) Age group, y < (8%) 82 (2%) (19%) 170 (3%) (24%) 727 (14%) (26%) 2561 (48%) (16%) 1438 (27%) (5%) 268 (5%) (2%) 82 (2%) Sex Female 734 (45%) 2081 (39%) Male 901 (55%) 3247 (61%) Race Native American 7 (0%) 119 (2%) Asian 800 (49%) 237 (4%) Black 125 (8%) 881 (17%) Hawaiian/acific Islander 177 (11%) 165 (3%) Unknown 244 (15%) 572 (11%) White 282 (17%) 3354 (63%) Hispanic or Latino ethnicity No 1195 (73%) 4177 (78%) Yes 24 (1%) 236 (4%) Unknown 416 (25%) 915 (17%) Median household income (census tract geocode) <$ (1%) 63 (1%) $ $ (10%) 725 (14%) $ $ (42%) 2612 (50%) $ $ (35%) 1541 (29%) $ (12%) 311 (6%) Months of health plan coverage through 31 December (43.61) 99.3 (44.68) Months since hepatitis B or 91.3 (46.80) 104 (44.48) C diagnosis Liver disease measures FIB-4, median (IQR) 1.1 ( ) 1.7 ( ) Cirrhotic, decompensated 288 (18%) 1421 (27%) Cirrhotic, compensated 74 (5%) 449 (8%) Noncirrhotic 1273 (78%) 3458 (65%) Data are presented as No. (%) unless otherwise specified. Abbreviation: IQR, interquartile range. documented decompensated cirrhosis in 27% and compensated cirrhosis in 8%. Of the 5328 patients, 2998 (56.3%) had 516 CID 2015:60 (15 February) Henkle et al

4 Figure 1. A, Hepatitis A testing and immunity in patients with chronic hepatitis B. B, Hepatitis A testing and immunity in patients with chronic hepatitis C. C, Hepatitis B testing and immunity in patients with chronic hepatitis C. Abbreviations: anti-ha, hepatitis A antibody; anti-hbc, hepatitis B core antibody; anti-hbs, hepatitis B surface antibody. immunity or vaccination against hepatitis A, whereas 659 (12.4%) tested negative and were unvaccinated and 1671 (31.4%) were neither tested for nor vaccinated against hepatitis Ainfection(Figure1B). Among 3393 unvaccinated participants, 1722 (50.8%) had an anti-ha test, and of these, 1063 (61.7%) were positive. Of the 1935 vaccinated, 1355 (70.0%) received the complete hepatitis A vaccine series of 2 doses. In univariate analysis (Table 3), immunity or vaccination against hepatitis A varied between 41% and 58% by 10-year age strata, and those with immunity or vaccination had longer member coverage (105 [SD, 44] months compared with 92 [SD, 46] months in nonimmune patients). atients with an income of <$ had less immunity or vaccination than those $ Non-Hispanic patients (56%) were less likely to be protected than Hispanic patients (68%; =.001). Black patients (44%) were least likely and Asian patients (73%) were most likely to have immunity or vaccination. atients with compensated cirrhosis also had significantly more immunity or vaccination (64%) than those with no documented cirrhosis (55%; <.001). After multivariable adjustment, compensated cirrhosis (OR, 1.52; 95% CI, vs no cirrhosis), increased time of member coverage (OR, 1.08/year; 95% CI, ), and increased FIB-4 score (log OR, 1.06 per 1-point increase; 95% CI, ) were significantly associated with immunity or vaccination. A total of 3150 of 5328 (59.1%) CHC patients had evidence of immunity or vaccination against hepatitis B infection, whereas 1003 (18.8%) tested negative and were unvaccinated and 1175 (22.1%) were neither tested for nor vaccinated against hepatitis B(Figure 1C). Of the 1871 vaccinated, 1275 (68.1%) received the complete hepatitis B vaccine series of 3 doses or shots. Among 3457 patients without evidence of vaccination, 2282 (66.0%) were tested for either anti-hbs or anti-hbc, and 1279 (56.0%) tested positive to either or both. Among 665 patients who tested negative for anti-hbs and had a test for anti-hbc, 304 (45.7%) had a positive test for anti-hbc only. Among 445 patients who tested positive for anti-hbs and had a test for anti- HBc, 340 (76.4%) also had a positive anti-hbc result. In univariate analysis (Table 3), patients and 80 years of age had the lowest rates of immunity (51% and 50%, respectively). In addition, patients without immunity or vaccination had a shorter duration of membership (mean, 104 [SD, 44] Hepatitis A/B in Chronic Hepatitis B/C atients CID 2015:60 (15 February) 517

5 518 CID 2015:60 (15 February) Henkle et al Table 3. Characteristics Associated With Hepatitis A and B rotection in Chronic Hepatitis B and C atients Chronic Hepatitis B atients Chronic Hepatitis C atients Characteristic HAV Immune or (n = 978) HAV Not Tested or (n = 657) HAV Immune or (n = 2998) HAV Not Tested or (n = 2330) HBV Immune or (n = 3150) HBV Not Tested or (n = 2178) Age group, y <30 69 (53%) 61 (47%) < (41%) 48 (59%) (66%) 28 (34%) < (57%) 133 (43%) 83 (49%) 87 (51%) 86 (51%) 84 (49%) (65%) 138 (35%) 409 (56%) 318 (44%) 414 (57%) 313 (43%) (62%) 157 (38%) 1453 (57%) 1108 (43%) 1494 (58%) 1067 (42%) (61%) 100 (39%) 840 (58%) 598 (42%) 915 (64%) 523 (36%) (57%) 38 (43%) 138 (51%) 130 (49%) 146 (54%) 122 (46%) 80 6 (17%) 30 (83%) 41 (50%) 41 (50%) 41 (50%) 41 (50%) Sex Female 416 (57%) 318 (43%) (55%) 928 (45%) (58%) 866 (42%).382 Male 562 (62%) 339 (38%) 1845 (57%) 1402 (43%) 1935 (60%) 1312 (40%) Race Native American 3 (43%) 4 (57%) < (60%) 48 (40%) < (61%) 47 (39%) <.001 Asian 532 (67%) 268 (34%) 173 (73%) 64 (27%) 167 (70%) 70 (30%) Black 52 (42%) 73 (58%) 391 (44%) 490 (56%) 563 (64%) 318 (36%) Hawaiian/acific Islander 98 (55%) 79 (45%) 114 (69%) 51 (31%) 116 (70%) 49 (30%) Unknown 150 (61%) 94 (39%) 308 (54%) 264 (46%) 281 (49%) 291 (51%) White 143 (51%) 139 (49%) 1941 (58%) 1413 (42%) 1951 (58%) 1403 (42%) Hispanic or Latino ethnicity No 711 (59%) 484 (41%) (56%) 1844 (44%) (60%) 1661 (40%) <.001 Yes 14 (58%) 10 (42%) 160 (68%) 76 (32%) 146 (62%) 90 (38%) Unknown 253 (61%) 163 (39%) 505 (55%) 410 (45%) 488 (53%) 427 (47%) Median household income <$ (59%) 7 (41%) (49%) 32 (51%) < (65%) 22 (35%).154 $ $ (57%) 66 (43%) 364 (50%) 361 (50%) 419 (58%) 306 (42%) $ $ (60%) 274 (40%) 1479 (57%) 1133 (43%) 1551 (59%) 1061 (41%) $ $ (61%) 219 (39%) 890 (58%) 651 (42%) 894 (58%) 647 (42%) $ (61%) 76 (39%) 196 (63%) 115 (37%) 202 (65%) 109 (35%) Years of health plan membership through 31 December 2010, mean ± SD 97.7 ± ± ± ± 46.0 < ± ± 45.5 <.001 Years since hepatitis B or C diagnosis, mean ± SD 91.3 ± ± ± ± 45.4 < ± ± 45.1 <.001

6 Table 3 continued. Chronic Hepatitis B atients Chronic Hepatitis C atients HBV Not Tested or (n = 2178) HBV Immune or (n = 3150) HAV Not Tested or (n = 2330) HAV Immune or (n = 2998) HAV Not Tested or (n = 657) HAV Immune or (n = 978) Characteristic Liver disease measures FIB-4, median (IQR) 1.1 ( ) 1.0 ( ) ( ) 1.6 ( ) < ( ) 1.7 ( ) <.001 Cirrhotic, decompensated 153 (53%) 135 (47%) (57%) 609 (43%) < (65%) 494 (35%) <.001 Cirrhotic, compensated 47 (64%) 27 (36%) 288 (64%) 161 (36%) 314 (70%) 135 (30%) Noncirrhotic 778 (61%) 495 (39%) 1898 (55%) 1560 (45%) 1909 (55%) 1549 (45%) Data are presented as No. (%) unless otherwise specified. Abbreviations: HAV, hepatitis A virus; HBV, hepatitis B virus; IQR, interquartile range; SD, standard deviation. months) and shorter time since hepatitis C diagnosis (106 [SD, 44] months) compared to those with immunity (93 [SD, 46] and 100 [SD, 45] months, respectively). Asian and Hawaiian/ acific Islander patients had the highest rate of protection (70% each). After multivariable adjustment, factors significantly associated with an increased immunity or vaccination include black race (OR, 1.37; 95% CI, vs white), compensated and decompensated cirrhotic liver disease vs no documented cirrhosis (OR, 1.60; 95% CI, and OR, 1.37; 95% CI, , respectively), increased FIB-4 score (log OR, 1.03 per 1-point increase; 95% CI, ), and increasing years of member coverage (OR, 1.08; 95% CI, ). Every age group >40 had significantly less immunity or vaccination compared to the reference group of patients <30 years of age. DISCUSSION A small but significant percent of patients with CHC and CHB remain susceptible to infection with hepatitis A, and at least 19% of CHC patients are susceptible to hepatitis B infections across geographically diverse patients, despite access to care. Contrary to vaccination guidelines targeting patients with chronic liver disease, we did not observe a higher level of immunity or vaccination against hepatitis A among CHB patients with cirrhosis or among CHC patients with decompensated cirrhosis compared to those without cirrhosis. However, CHC patients with compensated cirrhosis were more likely to be immune or vaccinated against hepatitis A and hepatitis B, and those with decompensated cirrhosis more likely to be immune or vaccinated against hepatitis B than those without cirrhosis. To our knowledge, this is the first study to report hepatitis A immunity and vaccination for CHB patients in a US cohort. Evidence of hepatitis B immunity and vaccination was more modest among CHC patients identified in the Department of Veterans Affairs (VA) Chronic Hepatitis C Clinical Case Registry (45.5% vs 59% in our study) [18]. Hepatitis A immunity was slightly higher (57.0%) in the VA CHC population. One major difference within the VA system was higher antibody testing rates: 82.2% for anti-hbs (vs 66.0% in our study) and 68.6% (vs 50.8% in our study) for anti-ha antibody. In the VA alo Alto Health Care System, 72% and 78% of 2968 hepatitis C positive patients were tested for hepatitis A and B, respectively, and 70.5% and 69.6% were immune or vaccinated for hepatitis A and B, respectively [19]. A 2005 study in the VA New York Harbor Healthcare System found that 53.7% of 1193 hepatitis C RNA positive patients were tested for hepatitis A and only 34.6% were immune or vaccinated, suggesting that there have been improvements over time in testing and vaccinating patients with chronic hepatitis [20]. The overall incidence of acute hepatitis A and acute hepatitis B is at an all-time low in the United States, with incidence rates Hepatitis A/B in Chronic Hepatitis B/C atients CID 2015:60 (15 February) 519

7 Table 4. Multivariable Analysis of Factors Associated With rotection Against Hepatitis A and B in Chronic Hepatitis B and C atients a HBV With HAV Immunity/Vaccination HCV With HAV Immunity/Vaccination HCV With HBV Immunity/Vaccination Characteristic OR 95% Wald Confidence Limits Characteristic OR 95% Wald Confidence Limits Characteristic OR 95% Wald Confidence Limits <30 y 1.00 Noncirrhotic 1.00 <30 y y Cirrhotic, y compensated y Cirrhotic, y decompensated y Health plan coverage, y y y FIB y y y y y White 1.00 White 1.00 Native American Native American Asian Asian Black Black Hawaiian/acific Islander Hawaiian/acific Islander Unknown Unknown Female 1.00 Noncirrhotic 1.00 Male Cirrhotic, compensated Health plan coverage, y Cirrhotic, decompensated Health plan coverage, y FIB Data are presented as No. (%) unless otherwise specified. Abbreviations: HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; OR, odds ratio. a All models adjusted for study site. of 0.5 acute hepatitis A cases per population and 1.1 cases of acute hepatitis B per population in 2010 [1]. Universal vaccination of children for both vaccines began in 1991 for hepatitis B vaccine and 2000 for hepatitis A vaccine. Foodborne hepatitis A outbreaks still occur, including a large outbreak in 2013 that was associated with at least 162 confirmed cases and 71 hospitalizations [21]. However, in our population, a large proportion of unvaccinated CHC patients tested for immunity were susceptible to hepatitis A infection (38%) or hepatitis B infection (44%). In addition, CHC patients may exhibit behaviors that put them at higher risk for hepatitis B infection such as injection drug use or unsafe sex practices. We excluded patients known to be coinfected with CHC and CHB. Because patients with chronic viral hepatitis or other chronic liver disease may be particularly susceptible to superinfection with other hepatotropic viruses, algorithms have been published to guide testing and vaccination of patients with chronic liver disease [9, 22, 23]. atients with chronic liver disease or CHB/CHC infection have lower initial response to hepatitis A vaccine but overall respond well to the 2 vaccine series [6]. Similarly, lower seroprotection after hepatitis B vaccination is observed in patients with CHC infection [24, 25]. It is likely that many or most patients receive their vaccine prior to progression to advanced liver disease, given that 65% of CHC and 78% of CHB patients in our study were categorized as noncirrhotic, so we expect their response to be similar to healthy controls. We observed a higher rate of hepatitis A and B immunity among our CHC patients with cirrhosis. Given the ambiguity around the definition of chronic liver disease in the published vaccination recommendations, and considering that the majority of both CHB and CHC patients are noncirrhotic and receive limited or late follow-up care, there may be missed opportunities to vaccinate before vaccine response rates drop [26]. We observed similar initiation of hepatitis A (34.4%) and hepatitis B vaccination (33.2%) in CHC patients. With the availability of a licensed combination hepatitis A/B vaccine, it should not be difficult to attain hepatitis B vaccine initiation at levels similar to hepatitis A vaccination. In addition, series completion 520 CID 2015:60 (15 February) Henkle et al

8 rates were similar for hepatitis B vaccine (68%), which requires 3 injections, and hepatitis A vaccine (70%), which requires 2 injections. We chose to consider the 38% of unvaccinated patients with anti-hbc alone as immune, based on prior studies that show that high-risk patients with isolated anti-hbc are protected from reinfection with hepatitis B virus [27]. This assumption may underestimate the number of patients who are susceptible to hepatitis B infection. The presence of at least 10 miu/ml of anti-hbs is the standard correlate of immunity, but the response to a hepatitis B vaccine challenge dose implies immunity even at low or undetectable anti-hbs [28]. The presence of anti- HBc indicates prior exposure, and immunologic memory likely provides immunity if the patient is reexposed [29]. Nevertheless, AASLD practice guidelines recommend a full hepatitis B vaccine series in patients who are anti-hbc positive and anti- HBs negative [30]. At a minimum, a booster dose may be needed in these patients [23, 31]. Among those tested for anti-ha, 60% of unvaccinated CHC and 81% of unvaccinated CHB patients tested positive. For comparison, based on National Health and Nutrition Examination Survey data, an estimated 40% of the US population aged 30 years is anti-ha positive (unpublished data, Centers for Disease Control and revention). The higher rates of protection observed in this study may represent selective testing in anticipation of vaccine series initiation or missed documentation of vaccination. Among unvaccinated CHC patients tested for anti-hbs or anti-hbc, 55% tested positive to 1 or both. As an indicator of prior hepatitis B exposure, 75% of those testing positive for anti-hbs also tested positive for anti-hbc. The cost effectiveness of testing prior to vaccination is largely dependent on the prevalence of prior vaccination and lifetime risk of infection. The high levels of coinfection observed in our CHB and CHC patients suggest that many of the untested patients are actually protected and that prescreening followed by vaccination of antibody-negative patients would be cost effective for both hepatitis A and hepatitis B vaccines [32, 33]. Our study has several strengths, including the mean followup of >5.5 years since hepatitis B or hepatitis C diagnosis and 8 years of plan membership. Because patients were plan members, laboratory tests and results and vaccination administration records should be captured in the electronic health record. The previous VA studies nearly exclusively included men (97%), whereas our population-based study is geographically and ethnically diverse and includes women. As we previously discussed, many of the untested patients will be protected due to past exposure to infection or prior vaccination. One limitation of our vaccine history assessment is that some patients with positive anti-ha will have had prior vaccinations not captured in the electronic health record. This would have been more likely at Geisinger and Henry Ford, where we relied on billing and claims data for documentation of vaccine administration. Because the 2 Kaiser ermanente sites include data from immunization registries as well as information capture during encounter, we would expect better capture of vaccinations. In contrast, we considered a single vaccine as immunity inducing, which could overestimate the number protected by an estimated 27% for hepatitis A vaccine, although we observed high completion rates (70%) in our CHC population, which confers immunity in >90% of CHC patients [6]. There is less evidence that a single hepatitis B vaccine is adequate, considering that 31% of CHC patients in a German vaccine trial and 44% of CHC patients in an Italian vaccine trial did not respond to a full hepatitis B series [24, 25]. Due to the observational nature of the study, we do not have a full set of preand postvaccine tests to fully assess immunity. In summary, the presently reported US population based estimates demonstrate that a substantial proportion of patients with chronic viral hepatitis remain susceptible to vaccinepreventable hepatitis A and hepatitis B infections. These data reinforce the observation that efforts are needed to improve both antibody testing and subsequent vaccination for vulnerable populations of chronic viral hepatitis patients. Given that CHB and CHC patients often do not receive optimal followup care, it may be appropriate to consider recommendations that target vaccination at diagnosis or before the development of more advanced fibrosis or cirrhosis. Notes CHeCS Investigators. Scott D. Holmberg, Eyasu H. Teshale, hilip R. Spradling, and Anne C. Moorman (Division of Viral Hepatitis, National Centers for Human Immunodeficiency Virus, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis revention, Centers for Disease Control and revention [CDC], Atlanta, Georgia); Stuart C. Gordon, David R. Nerenz, Mei Lu, Lois Lamerato, Loralee B. Rupp, Nonna Akkerman, Nancy Oja-Tebbe, Chad M. Cogan, and Dana Larkin (Henry Ford Health System, Detroit, Michigan); Joseph A. Boscarino, Zahra S. Daar, Joe B. Leader, and Robert E. Smith (Geisinger Health System, Danville, ennsylvania); Cynthia C. Nakasato, Vinutha Vijayadeva, Kelly E. Sylva, John V. arker, and Mark M. Schmidt (Kaiser ermanente Hawaii, Honolulu, Hawaii); Emily M. Henkle, Mark A. Schmidt, Tracy L. Dodge, and Erin M. Keast (Kaiser ermanente Northwest, ortland, Oregon). Acknowledgments. WethankAnneMoorman,EyasuTeshale,Scott D. Holmberg, hil Spradling, and Allison Naleway for reviewing the manuscript. Author contributions. E. H.: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; M. L.: study concept and design; statistical analysis; critical revision of the manuscriptforimportantintellectualcontent;l.b.r.,j.a.b.,v.v., M. A. S., S. C. G.: study concept and design; acquisition of data; critical revision of the manuscript for important intellectual content. Financial support. Chronic Hepatitis Cohort Study was funded by the CDC Foundation, which received grants from Abbott Laboratories; Genentech, a member of the Roche Group; Janssen harmaceutical Companies of Johnson & Johnson; and Vertex harmaceuticals. otential conflicts of interest. S. C. G. receives grant/research support from AbbVie harmaceuticals, Bristol-Myers Squibb, Gilead harmaceuticals, GlaxoSmithKline, Intercept harmaceuticals, Merck, and Vertex Hepatitis A/B in Chronic Hepatitis B/C atients CID 2015:60 (15 February) 521

9 harmaceuticals; is a consultant/advisor for Amgen, Bristol-Myers Squibb, CVS Caremark, Gilead harmaceuticals, Merck, Novartis, and Vertex armaceuticals; and is on the data monitoring board for Tibotec/Janssen harmaceuticals. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of otential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Centers for Disease Control and revention. Viral hepatitis surveillance United States, Available at: Surveillance/. Accessed 18 October Oh JK, Shin HR, Lim MK, et al. Multiplicative synergistic risk of hepatocellular carcinoma development among hepatitis B and C co-infected subjects in HBV endemic area: a community-based cohort study. BMC Cancer 2012; 12: Bell B. Hepatitis A and hepatitis B vaccination of patients with chronic liver disease. Acta Gastroenterol Belg 2000; 63: Fiore AE, Wasley A, Bell B. revention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization ractices (ACI). MMWR Recomm Rep 2006; 55: Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998; 338: Keeffe EB, Iwarson S, McMahon BJ, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology 1998; 27: Armstrong GL, Wasley A, Simard E, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through Ann Intern Med 2006; 144: Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep 2008; 57: Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization ractices (ACI) part II: immunization of adults. MMWR Recomm Rep 2006; 55:1 33; quiz CE The Hepatitis C Task Force; Boldt MD, Brill JV, Davis GL, et al. Hepatitis C screening: summary of recommendations from the clinical decision tool. Gastroenterology 2013; 145: Moorman AC, Gordon SC, Rupp LB, et al. Baseline characteristics and mortality among people in care for chronic viral hepatitis: the Chronic Hepatitis Cohort Study. Clin Infect Dis 2012; 56: Gordon SC, ockros J, Terrault NA, et al. Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection. Hepatology 2012; 56: Holmberg SD, Lu M, Rupp LB, et al. Noninvasive serum fibrosis markers for screening and staging chronic hepatitis C virus patients in a large US cohort. Clin Infect Dis 2013; 57: Teshale E, Lu M, Rupp LB, et al. ARI and FIB-4 are good predictors of the stage of liver fibrosis in chronic hepatitis B: the Chronic Hepatitis Cohort Study (CHeCS). J Viral Hepat 2014; 21: European Association For The Study Of The Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012; 57: Center for Medicare and Medicaid Services hysician Quality Reporting System (QRS) measures list. Available at: Medicare/Quality-Initiatives-atient-Assessment-Instruments/QRS/ MeasuresCodes.html. Accessed 18 October Kramer JR, Hachem CY, Kanwal F, Mei M, El-Serag HB. Meeting vaccination quality measures for hepatitis A and B virus in patients with chronic hepatitis C infection. Hepatology 2011; 53: Hernandez B, Hasson NK, Cheung R. Hepatitis C performance measure on hepatitis A and B vaccination: missed opportunities? Am J Gastroenterol 2009; 104: Shim M, Khaykis I, ark J, Bini EJ. Susceptibility to hepatitis A in patients with chronic liver disease due to hepatitis C virus infection: missed opportunities for vaccination. Hepatology 2005; 42: Centers for Disease Control and revention. Multistate outbreak of hepatitis A virus infections linked to pomegranate seeds from Turkey (final update). Available at: /index.html. Accessed 6 May Lau DT, Hewlett AT. Screening for hepatitis A and B antibodies in patients with chronic liver disease. Am J Med 2005; 118(suppl 10A):28S Kumar M, Herrera JL. Importance of hepatitis vaccination in patients with chronic liver disease. South Med J 2010; 103: Mattos AA, Gomes EB, Tovo CV, Alexandre CO, Remiao JO. Hepatitis B vaccine efficacy in patients with chronic liver disease by hepatitis C virus. Arq Gastroenterol 2004; 41: Wiedmann M, Liebert UG, Oesen U, et al. Decreased immunogenicity of recombinant hepatitis B vaccine in chronic hepatitis C. Hepatology 2000; 31: Spradling R, Rupp L, Moorman AC, et al. Hepatitis B and C virus infection among 1.2 million persons with access to care: factors associated with testing and infection prevalence. Clin Infect Dis 2012; 55: Quaglio G, Lugoboni F, Vento S, et al. Isolated presence of antibody to hepatitis B core antigen in injection drug users: do they need to be vaccinated? Clin Infect Dis 2001; 32:E Spradling R, Xing J, Williams R, et al. Immunity to hepatitis B virus (HBV) infection two decades after implementation of universal infant HBV vaccination: association of detectable residual antibodies and response to a single HBV challenge dose. Clin Vaccine Immunol 2013; 20: West DJ, Calandra GB. Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination. Vaccine 1996; 14: Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45: Keeffe EB. Hepatitis A and B superimposed on chronic liver disease: vaccine-preventable diseases. Trans Am Clin Climatol Assoc 2006; 117:227 37; discussion Duncan M, Hirota WK, Tsuchida A. rescreening versus empirical immunization for hepatitis A in patients with chronic liver disease: a prospective cost analysis. Am J Gastroenterol 2002; 97: Siddiqui F, Mutchnick M, Kinzie J, eleman R, Naylor, Ehrinpreis M. revalence of hepatitis A virus and hepatitis B virus immunity in patients with polymerase chain reaction-confirmed hepatitis C: implications for vaccination strategy. Am J Gastroenterol 2001; 96: CID 2015:60 (15 February) Henkle et al