The hepatitis A virus (HAV) is an important cause

Transcription

1 Susceptibility to Hepatitis A in Patients With Chronic Liver Disease Due to Hepatitis C Virus Infection: Missed Opportunities for Vaccination Michael Shim, Inessa Khaykis, James Park, and Edmund J. Bini Hepatitis A virus (HAV) superinfection is associated with a high risk of liver failure and death in patients with underlying chronic liver disease. Although HAV vaccination is recommended for all patients with chronic hepatitis C virus (HCV) infection, little is known about adherence to these recommendations in clinical practice. The aims of this study were to determine the frequency of HAV testing and vaccination among patients with chronic HCV infection. We conducted a retrospective cohort study of 1,193 patients diagnosed with chronic HCV infection over a 1-year period. During 1,646 person-years of follow-up, patients were seen by their primary care provider a median of 10.0 times (interquartile range, ). HAV antibody testing was performed in 640 subjects (53.6%), and 317 (49.5%) of those tested were susceptible (HAV antibody negative). Only 94 of the 1,193 patients (7.9%) received the HAV vaccine, including 26.8% of the 317 susceptible patients, 0.9% of the 323 patients who were already immune to HAV, and 1.1% of the 553 subjects who were never tested. Among the 94 vaccinated patients, 45 received only one dose of the vaccine. Three of the unvaccinated patients developed acute HAV infection during follow-up, and 1 of them died of acute liver failure. In conclusion, despite published recommendations to vaccinate against HAV in patients with chronic HCV infection, we found that HAV testing and vaccination rates were low in clinical practice. Public health programs to increase awareness about HAV vaccination in patients with chronic liver disease are needed. (HEPATOLOGY 2005;42: ) The hepatitis A virus (HAV) is an important cause of acute hepatitis worldwide, and this virus has been responsible for numerous disease outbreaks from close personal or sexual contact, 1-3 contaminated food or water, 1,4-7 injection drug use, 8,9 and other modes of transmission. 8,10 Despite the availability of the HAV vaccine since 1995, HAV infection continues to be one of the most common vaccine-preventable illnesses in the United States. 11 After adjusting for asymptomatic illness and disease underreporting, the Centers for Disease Control and Prevention estimated that 180,000 cases of HAV Abbreviations: HAV, hepatitis A virus; HCV, hepatitis C virus; VA, Veterans Affairs. From the Department of Medicine and Division of Gastroenterology, VA New York Harbor Healthcare System and NYU School of Medicine, New York, NY. Received March 9, 2005; accepted June 20, 2005 Address reprint requests to Edmund J. Bini, M.D., M.P.H., Division of Gastroenterology, VA New York Harbor Healthcare System, 423 East 23rd Street, New York, NY Edmund.Bini@med.va.gov; fax: Copyright 2005 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience ( DOI /hep Potential conflict of interest: Nothing to report. infection occurred in the United States in In addition, the economic burden of acute HAV infection in the United States has been estimated at more than $300 million annually. 12 Although the overall case-fatality rate of acute HAV among persons of all ages is only 0.01% to 0.3%, 11,13,14 it is higher (1.8%) among adults 50 years of age and older. 11 More importantly, acute HAV superinfection causes severe liver disease, acute liver failure, and even higher mortality rates in patients with underlying chronic liver disease. In a prospective cohort study of adults with chronic hepatitis C virus (HCV) infection, Vento et al. 15 reported that 41.2% of patients with acute HAV superinfection developed acute liver failure, and 35.3% died. Numerous other studies have also identified chronic liver disease as a risk factor for fulminant hepatitis and death from acute HAV infection. 4,16-22 Based on the potential risk for fulminant hepatic failure and death from acute HAV superinfection, the 1996 Advisory Committee on Immunization Practices recommended HAV vaccination for all patients with chronic liver disease, including those with chronic HCV infec- 688

2 HEPATOLOGY, Vol. 42, No. 3, 2005 SHIM ET AL. 689 tion. 23 These recommendations have also been endorsed by the World Health Organization, 24 the National Institutes of Health, 25 the United States Veterans Health Administration, 26 the American Association for the Study of Liver Diseases, 27 the American Liver Foundation, 28 the American College of Gastroenterology, 29 and others However, little is known about adherence to these recommendations in clinical practice. The aims of the current study were to determine the frequency of HAV antibody testing in patients with chronic HCV infection, to evaluate the proportion of those tested who were susceptible to HAV, and to investigate whether susceptible patients were vaccinated against HAV infection according to published guidelines. Patients and Methods Study Population. We identified all patients who had HCV antibody testing performed over a 1-year period from January through December 2000 at the Veterans Affairs (VA) New York Harbor Healthcare System in New York. The VA New York Harbor Healthcare System consists of 2 main VA medical centers located in New York, NY and Brooklyn, NY. Patients were identified using our computerized patient record system and were included in this study if they were newly diagnosed as being HCV antibody and HCV RNA positive. Patients were excluded from this study if they had undetectable HCV RNA by polymerase chain reaction testing, if HCV RNA testing was not performed, or if they were co-infected with HIV. The study protocol was reviewed and approved by the Institutional Review Board at our medical center. Study Design. Demographic and clinical information were collected by reviewing the electronic medical record of all HCV-positive patients. Data collected on each patient included age, sex, race/ethnicity, current or prior injection drug use, current use of alcohol ( 3 drinks per day), active psychiatric disease, whether they were homeless, whether they had sex with a same-sex partner, history of sexually transmitted diseases, and the presence of cirrhosis. Patients were considered to have active psychiatric disease if so diagnosed by a psychiatrist and if they were receiving treatment for the condition. The diagnosis of cirrhosis was made by liver biopsy or by compatible findings on physical examination or abdominal imaging. Although our computerized record system and pharmacy database are very comprehensive, certain data (such as history of sexually transmitted diseases) were not as well documented. However, the other demographic and clinical data were complete for all patients. Follow-up data were collected through June 30, 2002 by reviewing the electronic medical record for each patient to determine the number of HCV-infected patients who had HAV antibody testing performed and the number who actually received HAV vaccination. To ensure that all patients who received the HAV vaccine were identified, we also reviewed our computerized pharmacy database. The duration of follow-up was calculated from the time of diagnosis of HCV infection until the date that the patient was last seen in the hospital or outpatient clinic. Study Outcomes. The primary outcome measure of this study was the proportion of patients with chronic HCV infection who were vaccinated against HAV. Patients were considered vaccinated if they had received at least 1 dose of any of the commercially available HAV vaccines. The secondary outcome measures included the number of doses of HAV vaccine received, whether HAV antibody testing was performed, the proportion of patients who were susceptible to HAV among those who were tested, factors associated with HAV antibody testing and HAV vaccination, and the incidence of acute HAV infection during follow-up. Susceptibility was defined as a negative total HAV antibody. Statistical Analysis. Continuous variables were compared using an unpaired t test or the Mann-Whitney U test as appropriate. Data are expressed as means SD for those variables that were normally distributed, and medians and interquartile range (25 th -75th percentile) for those with a non-normal distribution. Categorical variables are expressed as proportions and were compared using the chi-square test or Fisher s exact test. All outcomes analyses used time-to-event methods with Cox proportional-hazards models. 34 Univariate Cox regression analysis was used to identify factors associated with HAV antibody testing and HAV vaccination. Subsequently, separate multivariable Cox regression models for HAV antibody testing and HAV vaccination were created involving all variables evaluated in the univariate analyses. The multivariable analyses could then assess the independent effect of each variable in the model adjusted for the effects of each of the other variables. The strength of the association between covariates and HAV testing as well as HAV vaccination are expressed as hazard ratios (HR)with 95% confidence intervals (CI). Statistical analysis was performed using SPSS software version 13.0 for Windows (SPSS Inc., Chicago, IL), and a two-tailed P value of less than.05 was considered statistically significant. Results Demographic and Clinical Characteristics. During the 1-year study period, a total of 8,203 patients had

3 690 SHIM ET AL. HEPATOLOGY, September 2005 Fig. 1. Flow of patients through the study. Table 1. Demographic and Clinical Characteristics of the 1,193 Patients With Chronic HCV Infection Age, yr* 53.0 ( ) Male 1,164 (97.6%) Race/ethnicity Non-Hispanic white 381 (31.9%) Non-Hispanic black 576 (48.3%) Hispanic or Latino 221 (18.5%) Other 15 (1.3%) Injection drug use 699 (58.6%) Alcohol use 388 (32.5%) Homeless 192 (16.1%) Active psychiatric disease 449 (37.6%) Sex with same-sex partner 44 (3.7%) Prior sexually transmitted disease 104 (8.7%) Cirrhosis 110 (9.2%) *Data are expressed as median (25th-75th percentile). HCV antibody testing performed, of whom 1,363 (16.6%) were HCV antibody and HCV RNA positive. The flow of patients through the study is shown in Fig. 1. Of the 1,363 patients, 1,193 had chronic HCV infection and met our study eligibility criteria. The baseline demographic and clinical characteristics of these 1,193 patients are shown in Table 1. Most patients were male, and the population was ethnically diverse. Histories of injection drug use, alcohol abuse, and psychiatric disease were highly prevalent in our subjects. HAV Antibody Testing. During a total of 1,646 person-years of follow-up, the median number of times that patients were seen by their primary care provider for any reason was 10.0 (IQR, ). A total of 469 (39.3%) of the 1,193 patients were seen in the Gastroenterology clinic at least once during follow-up. Despite the high frequency of follow-up visits, HAV antibody testing was only performed in 640 (53.6%; 95% CI, 50.8%-56.5%) of the 1,193 patients with chronic HCV infection. To better characterize HAV testing among patients with chronic HCV infection, we determined the proportion of patients who had HAV antibody testing performed according to select demographic and clinical characteristics (Table 2). In the unadjusted Cox proportional hazards analysis, older patients were less likely to have HAV antibody testing performed, whereas patients with a prior sexually transmitted disease and individuals seen in our gastroenterology clinic were more likely to be tested. After adjusting for potential confounding variables, multivariable Cox regression analysis found that older patients and those with active psychiatric disease were less likely to have HAV antibody testing performed, whereas patients with a prior sexually transmitted disease and individuals seen in our gastroenterology clinic were more likely to be tested (Table 2). Susceptibility to HAV Infection. Among the 640 patients who had HAV antibody testing performed, 323 (50.5%; 95% CI, 46.5%-54.4%) were immune to HAV, and 317 (49.5%; 95% CI, 45.6%-53.5%) were susceptible. Susceptibility to HAV declined with age, was higher in women than in men, and differed according to race/ ethnicity (Table 3). In addition, susceptibility to HAV was significantly greater in those who used injection drugs, whereas it was lower in persons who had sex with a same-sex partner and those with a prior sexually transmitted disease. HAV Vaccination. During follow-up, only 94 of the 1,193 patients (7.9%; 95% CI, 6.4%-9.6%) with chronic HCV infection received 1 or more doses of the HAV vaccine; none of the patients was vaccinated against HAV before the diagnosis of HCV infection. The vaccine was administered to 85 of the 317 patients (26.8%) who were susceptible to HAV, 3 of the 323 patients (0.9%) who were already immune to HAV, and 6 of the 553 subjects (1.1%) who never had HAV testing. Among the 94 vaccinated patients, 45 received only 1 dose of the vaccine, 41 received 2 doses, and 8 received 3 or more doses. All 8 patients who received 3 or more doses of the vaccine received more than the recommended number of doses of the commercially available HAV vaccine; none received the combined HAV and hepatitis B vaccine. Of the 94 patients who received the HAV vaccine, 88 (93.6%) had HAV antibody testing before vaccination. Patients who had HAV antibody testing performed were significantly more likely to receive the HAV vaccine as compared with those who never had

4 HEPATOLOGY, Vol. 42, No. 3, 2005 SHIM ET AL. 691 Table 2. Factors Associated With HAV Antibody Testing According to Select Demographic and Clinical Characteristics (N 1,193) Characteristic Number of Subjects Proportion Tested for HAV (%) Unadjusted Adjusted HR (95% CI) P Value* HR (95% CI) P Value* Age, yr (reference) 1.00 (reference) ( ) ( ) ( ) ( ) and older ( ) ( ).12 Sex Female (reference) 1.00 (reference) Male 1, ( ) ( ).61 Race/ethnicity Non-Hispanic white (reference) 1.00 (reference) Non-Hispanic black ( ) ( ).92 Hispanic or Latino ( ) ( ).78 Other ( ) ( ).35 Injection drug use No (reference) 1.00 (reference) Yes ( ) ( ).41 Alcohol use No (reference) 1.00 (reference) Yes ( ) ( ).11 Homeless No 1, (reference) 1.00 (reference) Yes ( ) ( ).82 Active psychiatric disease No (reference) 1.00 (reference) Yes ( ) ( ).009 Sex with same-sex partner No 1, (reference) 1.00 (reference) Yes ( ) ( ).58 Prior sexually transmitted disease No 1, (reference) 1.00 (reference) Yes ( ) ( ).001 Cirrhosis No 1, (reference) 1.00 (reference) Yes ( ) ( ).94 Seen in gastroenterology clinic No (reference) 1.00 (reference) Yes ( ) ( ).008 *The P values were derived from Cox regression analysis. HAV testing (HR, 9.12; 95% CI, ). Among the 1,099 patients who did not receive the HAV vaccine, documentation that they refused the vaccine was only noted for 2 patients. To further evaluate HAV vaccination among patients with chronic HCV infection, we determined the proportion of patients who received at least 1 dose of the HAV vaccine according to select demographic and clinical characteristics (Table 4). In the unadjusted Cox proportional hazards analysis, older patients and Hispanics were less likely to be vaccinated, whereas patients with cirrhosis and those seen in the gastroenterology clinic were more likely to receive the HAV vaccine. After adjusting for potential confounding variables, multivariable Cox regression analysis found that older patients and Hispanics were significantly less likely to be vaccinated, whereas being seen in our gastroenterology clinic was strongly associated with an increased likelihood of receiving the HAV vaccine (Table 4). Incidence of Acute HAV Infection. A total of 3 of the 1,193 patients with chronic HCV infection developed acute HAV infection during 1,646 person-years of follow-up, an incidence rate of 1.82 per 1,000 person-years. The 3 patients were men, and all had elevations of alanine aminotransferase levels greater than 25 times the upper limit of normal and were IgM HAV antibody positive at the time of diagnosis of acute HAV-associated hepatitis. The potential risk factors for acute HAV infection in these 3 men included injection drug use, unprotected anal intercourse with another man, and travel to an endemic area. Among these 3 patients, 1 died of acute liver failure, corresponding to a case-fatality rate of 33.3%. All 3 of

5 692 SHIM ET AL. HEPATOLOGY, September 2005 Table 3. Proportion of Patients Susceptible to HAV Infection According to Select Demographic and Clinical Characteristics (N 640) Characteristic these patients were known to be HAV antibody negative in the past, and none of them received the HAV vaccine. Discussion Number of Subjects Proportion Susceptible to HAV (%) P Value* Age, yr and older Sex.08 Female Male Race/ethnicity.03 Non-Hispanic white Non-Hispanic black Hispanic or Latino Other Injection drug use.001 No Yes Alcohol use.28 No Yes Homeless.28 No Yes Active psychiatric disease.66 No Yes Sex with same-sex partner.005 No Yes Prior sexually transmitted disease.001 No Yes Cirrhosis.74 No Yes NOTE: Susceptible was defined as a negative total HAV antibody. *The P values were calculated using the chi square test. In a large retrospective cohort study, we showed that a substantial proportion of patients with chronic HCV infection did not have HAV antibody testing performed, and most of the susceptible patients were never vaccinated against HAV. The low rates of HAV testing and vaccination are striking given the presence of recommendations to vaccinate these individuals against HAV since 1996, the long duration of follow-up, and the high number of visits with their primary care provider. These findings have substantial public health implications and represent missed opportunities for prevention. Among our 1,193 patients with chronic HCV infection, only 53.6% had HAV antibody testing performed. These findings were similar to a retrospective study by Siddiqui et al., 35 which showed that HAV testing was performed in 61.4% of patients with chronic HCV infection. The reasons for these low rates of HAV testing are likely multifactorial, including patient barriers, provider barriers, and other system-based factors. Patient-related barriers potentially include refusal and poor compliance, whereas provider-related barriers may include lack of knowledge regarding HAV antibody testing, lack of time or resources, or other unidentified reasons. It is also possible that providers did not order HAV antibody testing because they did not believe that it was necessary. The need for pre-vaccination antibody testing in these patients remains controversial. It may be costeffective to offer pre-vaccination testing in populations with a high prevalence of natural immunity to HAV, whereas universal vaccination (vaccination of all patients without pre-testing) may be more appropriate in populations with a low prevalence of immunity. 11,36 However, a universal vaccination strategy is an unlikely explanation for the low testing rates in our population, given that only 6 of the 553 patients who were not tested for HAV were vaccinated. Among the 640 patients who had HAV antibody testing in our study, 49.5% were HAV antibody negative and were susceptible to HAV infection. The proportion of susceptible patients in our study was similar to that of other studies but lower than the 62.4% percent reported by Siddiqui at al. 35 or the 67% susceptibility to HAV found in the general population of the United States. 11 These differences may be explained by differences in the patient populations studied. Our patients were older than the subjects included in the United States seroprevalence study and included a high proportion of men and Hispanics, subgroups that have a high prevalence of natural immunity to HAV. 11 In addition to the low rates of HAV antibody testing in our patients, we also found that an even lower proportion (94/1,193; 7.9%) was vaccinated against HAV. More importantly, only 26.8% of patients who were known to be susceptible to HAV received at least 1 dose of the HAV vaccine. To date, we are only aware of 1 other study that has addressed HAV vaccination rates among patients with chronic liver disease in clinical practice. In a random sample of 105 patients with cirrhosis who were referred for liver transplantation, 26.3% of the 76 susceptible patients had been vaccinated against HAV. 40 These findings underscore the need to implement educational programs and other interventions to improve vaccination rates in this population. The reasons for the low vaccination rates in our study are unknown. In addition to the patient-related barriers

6 HEPATOLOGY, Vol. 42, No. 3, 2005 SHIM ET AL. 693 Table 4. Factors Associated With Receiving At Least One Dose of the HAV Vaccine According to Select Demographic and Clinical Characteristics (N 1,193) Characteristic Number of Subjects Proportion Vaccinated (%) Unadjusted Adjusted HR (95% CI) P Value* HR (95% CI) P Value* Age, yr (reference) 1.00 (reference) ( ) ( ) ( ) ( ) and older ( ) ( ).006 Sex Female (reference) 1.00 (reference) Male 1, ( ) ( ).76 Race/ethnicity Non-Hispanic white (reference) 1.00 (reference) Non-Hispanic black ( ) ( ).35 Hispanic or Latino ( ) ( ).002 Other ( ) ( ).96 Injection drug use No (reference) 1.00 (reference) Yes ( ) ( ).68 Alcohol use No (reference) 1.00 (reference) Yes ( ) ( ).10 Homeless No 1, (reference) 1.00 (reference) Yes ( ) ( ).52 Active psychiatric disease No (reference) 1.00 (reference) Yes ( ) ( ).48 Sex with same-sex partner No 1, (reference) 1.00 (reference) Yes ( ) ( ).31 Prior sexually transmitted disease No 1, (reference) 1.00 (reference) Yes ( ) ( ).63 Cirrhosis No 1, (reference) 1.00 (reference) Yes ( ) ( ).20 Seen in Gastroenterology clinic No (reference) 1.00 (reference) Yes ( ) ( ).001 *The P values were derived from Cox regression analysis. for HAV testing discussed above, patients may not have received the HAV vaccine because of a lack of awareness that the vaccine was necessary, belief that they were not at risk for HAV infection, doubts about vaccine efficacy, misperceptions about vaccine side effects, fear of needles, or other reasons. Alternatively, it is possible that HAV vaccination was not offered by providers because of the need to address other more important issues during clinic visits, inadequate reimbursement, lack of knowledge about whom to vaccinate, or the belief that vaccination is not safe, effective, or cost-effective in this population. However, several studies have shown that vaccination against HAV is safe and effective in patients with chronic liver disease, especially in those with well-compensated liver disease. 41,42 In addition, HAV vaccination has been shown to be cost-effective in patients with chronic liver disease. 43,44 Although the HAV vaccine is also safe in patients with decompensated disease and in liver transplant recipients, the immunogenicity of the vaccine is substantially lower than in those with compensated liver disease. 42,45,46 Therefore, early vaccination against HAV is important in patients with chronic liver disease. Another important finding in our study was that only half of the patients who were vaccinated received the full vaccination course. Although the HAV vaccine is effective in patients with chronic liver disease, the geometric mean titer of HAV antibody induced by the vaccine in these patients is lower than in those without chronic liver disease, and, therefore, high rates of protection against HAV are only achieved after the administration of both doses of the vaccine. 41,42,47 Although some of our patients who received only one dose of the vaccine completed the full

7 694 SHIM ET AL. HEPATOLOGY, September 2005 course after our study ended, it does raise some concerns that these individuals may not be adequately protected against HAV infection. Additional studies are needed to determine whether an accelerated vaccination schedule 48 or the use of the combination HAV and hepatitis B virus vaccine 49 improves physician and patient compliance with vaccination. In addition to demonstrating that HAV testing and vaccination rates were low in patients with chronic HCV infection, we determined that the incidence rate of acute HAV infection in our subjects was 1.82 per 1,000 personyears. More importantly, 1 of the 3 patients who developed acute HAV infection died of acute liver failure, and this case-fatality rate was similar to what has been reported by other investigators. 15 Unfortunately, all 3 of these patients had been tested for HAV antibodies before the development of acute HAV infection, but none of them was vaccinated despite documentation that they were susceptible. Although the number of patients with acute HAV infection in our study was small, this finding highlights the risk of morbidity and mortality from acute HAV infection in patients with underlying chronic liver disease and underscores the importance of HAV vaccination in these individuals. The strengths of the current study include the large number of HCV-infected patients, the availability of long-term follow-up data, and the use of the computerized patient record system and pharmacy database to obtain detailed demographic and clinical data. However, there are some limitations of this study that should be considered when interpreting our findings. Although the most obvious limitation of this investigation was the retrospective study design, we believe that it would be difficult to conduct this study prospectively because it would likely influence patient and provider behaviors and bias the results. Another limitation of this study is that it was performed at a single VA healthcare system, and most of our patients were men. Therefore, our findings may not be generalizable to other VA medical centers, non-va settings, or women. Finally, the reasons for the low HAV testing and vaccination rates in patients with chronic HCV infection could not be determined in our study. It is likely that the low testing and vaccination rates were due to a combination of factors, including patient barriers, provider barriers, and other unidentified variables. Alternatively, we may have underestimated HAV testing and vaccination rates because some patients received these outside of the VA health care system. However, this is not likely to have been a common event because the patients were followed up closely and had a median of 10 visits with their primary care provider. Furthermore, even if they did receive testing and vaccination at another facility, these issues should have been addressed by our primary care providers and documented in the electronic medical record. In conclusion, despite published recommendations to vaccinate against HAV in patients with chronic HCV infection, we found that HAV testing and vaccination rates were low in clinical practice. These findings are particularly important given the high risk of acute liver failure from HAV superinfection in patients with underlying chronic liver disease, as well as data demonstrating that HAV vaccination is safe, effective, and cost-effective in this population. 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