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      Early Seroreversion After 2 Doses of Hepatitis A Vaccination in Human Immunodeficiency Virus–Positive Patients: Incidence and Associated Factors

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          Abstract

          Serological responses (Seroresponse) and durability of hepatitis A virus (HAV) vaccination are reduced among human immunodeficiency virus (HIV)‐positive patients. Incidence of and associated factors with early seroreversion (loss of seroresponse) among HIV‐positive patients who have achieved seroresponses after two doses of HAV vaccination remain unclear. In this multicenter study, we followed HIV‐positive adults who had mounted seroresponses after completing two doses of HAV vaccination during a recent outbreak of acute hepatitis A between 2015 and 2017, a 1:4 case‐control study was conducted to identify factors associated with seroreversion. Case patients were those with seroreversion, and controls were those with similar follow‐up durations who were able to maintain seroresponses. During the study period, 49 of the 1,256 patients (3.9%) seroreverted after a median follow‐up of 611 days. In a case‐control study, seroreversion was more likely to occur in patients with a higher weight (adjusted odds ratio [aOR], 1.703; 95% confidence interval [CI], 1.292‐2.323, per 10‐kg increment) and HIV viremia at the time of vaccination (aOR, 2.922; 95% CI, 1.067‐7.924), whereas positive seroresponse at 6 months of HAV vaccination and higher CD4 lymphocyte counts at vaccination were inversely associated with early seroreversion with an aOR of 0.059 (95% CI, 0.020‐0.154) and 0.837 (95% CI, 0.704‐0.979, per 100‐cell/mm 3 increment), respectively, in multivariable analyses. Conclusion: During an outbreak setting, early seroreversion following two‐dose HAV vaccination occurred in 3.9% of HIV‐positive patients. Lower and delayed seroresponses to HAV vaccination, a higher weight, and HIV viremia and lower CD4 lymphocyte counts at the time of HAV vaccination were associated with early seroreversion. Regular monitoring of seroresponse and booster vaccination might be warranted, especially in HIV‐positive adults with predictors of early seroreversion.

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          Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).

          Routine vaccination of children is an effective way to reduce hepatitis A incidence in the United States. Since licensure of hepatitis A vaccine during 1995-1996, the hepatitis A childhood immunization strategy has been implemented incrementally, starting with the recommendation of the Advisory Committee on Immunization Practices (ACIP) in 1996 to vaccinate children living in communities with the highest disease rates and continuing in 1999 with ACIP's recommendations for vaccination of children living in states, counties, and communities with consistently elevated hepatitis A rates. These updated recommendations represent the final step in the childhood hepatitis A immunization strategy, routine hepatitis A vaccination of children nationwide. Implementation of these recommendations will reinforce existing vaccination programs, extend the benefits associated with hepatitis A vaccination to the rest of the country, and create the foundation for eventual consideration of elimination of indigenous hepatitis A virus transmission. This report updates ACIP's 1999 recommendations concerning the prevention of hepatitis A through immunization (CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1999:48[No. RR-12]:1-37) and includes 1) new data on the epidemiology of hepatitis A in the era of hepatitis A vaccination of children in selected U.S. areas, 2) results of analyses of the economics of nationwide routine vaccination of children, and 3) recommendations for the routine vaccination of children in the United States. Previous recommendations for vaccination of persons in groups at increased risk for hepatitis A or its adverse consequences and recommendations regarding the use of immune globulin for protection against hepatitis A are unchanged from the 1999 recommendations.
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            Long-term immune responses to vaccination in HIV-infected patients: a systematic review and meta-analysis.

            Vaccine-induced antibodies may wane more quickly in persons living with human immunodeficiency virus (HIV) than in healthy individuals. We reviewed the literature on vaccines routinely recommended in HIV-infected patients to estimate how seroprotection decreases over time in those who initially responded to immunization. For each study retrieved from the literature, the decrease of seroprotection was modeled with a log binomial generalized linear model, and data were pooled in a meta-analysis to provide estimates of seroprotection 2 and 5 years after the last vaccine administration. Our analyses confirmed that the duration of seroprotection was shorter in HIV-infected patients and that with current guidelines, a substantial proportion of patients would have lost protective antibodies before a booster was proposed. We therefore discuss the implications for the monitoring of antibody levels and timing of revaccination in these patients.
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              Hepatitis A Virus Outbreaks Associated with Drug Use and Homelessness — California, Kentucky, Michigan, and Utah, 2017

              During 2017, CDC received 1,521 reports of acute hepatitis A virus (HAV) infections from California, Kentucky, Michigan, and Utah; the majority of infections were among persons reporting injection or noninjection drug use or homelessness. Investigations conducted by local and state health departments indicated that direct person-to-person transmission of HAV infections was occurring, differing from other recent, large HAV outbreaks attributed to consumption of contaminated commercial food products. Outbreaks with direct HAV transmission among persons reporting drug use or homelessness signals a shift in HAV infection epidemiology in the United States, and vaccination of these populations at high risk can prevent future outbreaks. Epidemiologic Investigation Outbreak cases were defined as those meeting the 2012 CDC-Council of State and Territorial Epidemiologists’ (CSTE) definition of acute hepatitis A infection,* having a specimen matching an outbreak strain, or an epidemiologic link to a previously identified case. Local and state health department personnel reviewed clinical charts and interviewed patients using standard questionnaires that evaluated risk factors associated with infection, including recent drug use, sexual history, housing status, recent international travel, and contact with another person with HAV infection. Among states reporting increases in HAV infections to CDC outside or inside the National Notifiable Disease Surveillance System, only California, Kentucky, Michigan, and Utah reported sustained within-state transmission. This report includes outbreaks that occurred during 2017 in these four states. Additional cases reported from other states were excluded because they were attributed to HAV exposure during travel to one of the four outbreak states, and because prolonged, ongoing transmission did not occur in the other states. During 2017, a total of 1,521 outbreak-associated HAV cases were reported from California, Kentucky, Michigan, and Utah, with 1,073 (71%) hospitalizations and 41 (3%) deaths (Table 1). Among patients for whom clinical or laboratory records were available for review, 42 (3%) had confirmed or probable hepatitis B virus coinfection, and 341 (22%) had confirmed or probable hepatitis C virus coinfection. Overall, 866 (57%) patients reported drug use, homelessness, or both (Table 2). Among all cases, 818 (54%) had an indication for hepatitis A vaccination before becoming infected (i.e., using drugs or being men who had sex with men [MSM]) as recommended by the Advisory Committee on Immunization Practices (ACIP) ( 1 ). TABLE 1 Demographic and clinical characteristics of hepatitis A outbreak–associated cases, by state — four states, 2017 Characteristic California Kentucky Michigan Utah Total Total cases, no. 682 59 632 148 1,521 Male, no. (%) 471 (69) 39 (66) 412 (65) 97 (66) 1,019 (67) Median age, yrs (range) 42 (5–87) 36 (1–84) 41 ( 100 because of men who had sex with men being included independently and as part of “homelessness,” “drug use,” and “neither homeless nor drug use” categories. Laboratory Investigation When available, serum specimens from patients who met the CSTE case definition were sent to CDC’s Division of Viral Hepatitis laboratory for HAV RNA isolation, genotyping, and genetic characterization. HAV RNA was extracted from immunoglobulin M antibody-positive serum samples and used to amplify and Sanger-sequence a 315–base-pair fragment of the VP1/P2B region ( 2 ). During 2017, 1,169 specimens from outbreak-associated cases from the four affected states were sent to CDC for additional testing. A total of 1,054 (90%) specimens had HAV confirmed by polymerase chain reaction, 1,014 (96%) of which tested positive for a genotype 1b viral strain. The strains circulating in California, Kentucky, and Utah were genetically different from those circulating in Michigan. Public Health Response CDC worked with affected local and state health departments to apply control measures through health advisories, public education, and vaccination clinics that provided outreach and vaccination to the targeted populations. Vaccine was administered in jails, emergency departments, syringe exchange programs, drug treatment facilities, and homeless shelters. In certain jurisdictions, investigation teams also visited homeless encampments to educate and vaccinate unsheltered homeless groups. Although reporting of new outbreak cases in California has ended, new case investigations continue in Kentucky, Michigan, and Utah. Vaccination campaigns also continue for MSM and persons who use drugs or report homelessness in the affected states. Discussion After the introduction of hepatitis A vaccine in 1996, the incidence of reported HAV infection steadily decreased in the United States until 2011 and then stabilized at an annual average of approximately 1,600 reported cases, mostly among international travelers returning from countries with endemic HAV or as part of foodborne outbreaks ( 1 , 3 ). HAV outbreaks among illicit drug users were common in the prevaccine era; during the mid-1980s, drug users accounted for >20% of all HAV cases reported to CDC ( 3 , 4 ). However, large community outbreaks within this population rarely occurred after 1996, when hepatitis A vaccine was first recommended for persons who use illicit drugs ( 3 , 4 ). Person-to-person transmission of HAV between those who report drug use or homelessness can result from unsafe sanitary conditions or specific sexual contact or practices, or it can be parenterally transmitted through contaminated needles or other injection paraphernalia ( 4 – 6 ). Transient housing, economic instability, limited access to health care, and distrust of government services make outbreaks among affected populations more difficult to control, requiring tailored comprehensive public health interventions that address their specific circumstances and needs ( 5 – 7 ). During 2016, U.S. hospitalization and mortality rates associated with HAV infections were 42% and 0.7%, respectively ( 3 ). Increased hospitalization and mortality rates observed in the 2017 HAV outbreaks might be attributable to preexisting illnesses, including chronic hepatitis B and hepatitis C infections, other comorbidities, age, and risk behaviors common among persons reporting drug use and homelessness (e.g., heavy alcohol use) ( 8 ). Increasingly, investigations of HAV infections are using molecular epidemiology to confirm outbreaks ( 2 ). Laboratory data, when combined with reliable epidemiologic data, can be effective in understanding transmission networks, particularly among populations distrustful of investigators. The majority of surveillance specimens tested by CDC’s laboratory before 2017 were genotype 1a, the most common genotype in North and South America, but expansion of genotype 1b attributed to the current outbreaks is leading to increased detection of this previously uncommon genotype ( 2 , 9 ). Vaccination rates among existing ACIP-identified risk groups are unknown but are believed to be low ( 10 ). On October 24, 2018, ACIP voted unanimously to add “homelessness” as an indication for ACIP-recommended HAV vaccination ( 1 ). † Although the outbreak has ended in California, hepatitis A outbreaks among persons reporting drug use or homelessness continue in Kentucky, Michigan, and Utah, and, as of October 12, 2018, >7,000 outbreak associated cases have been reported from 12 states. § Increasing vaccination coverage among all at-risk groups recommended by ACIP to receive hepatitis A vaccine might halt ongoing outbreaks and prevent future large community outbreaks ( 1 ). CDC has recommended that local health jurisdictions experiencing HAV outbreaks among persons who report drug use or homelessness ensure procedures are in place for identifying these risk factors and that these groups are vaccinated against HAV infection. ¶ State and local health departments and CDC should be notified of any new suspected clusters of acute HAV infections. Summary What is already known about this topic? Hepatitis A is a vaccine-preventable viral infection of the liver that is commonly transmitted through consumption of microscopic amounts of feces. Outbreaks of hepatitis A infections are infrequent in the United States and are typically associated with contaminated food items. What is added by this report? During 2017, California, Kentucky, Michigan, and Utah reported 1,521 hepatitis A infections, mostly among persons who reported drug use or homelessness, signaling a shift in hepatitis A epidemiology from point-source outbreaks associated with contaminated food to large community outbreaks with person-to-person transmission. What are the implications for public health practice? Increasing vaccination among groups at risk for hepatitis A infection might halt ongoing outbreaks and prevent future outbreaks.
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                Author and article information

                Contributors
                yangcj1206@gmail.com
                Journal
                Hepatology
                Hepatology
                10.1002/(ISSN)1527-3350
                HEP
                Hepatology (Baltimore, Md.)
                John Wiley and Sons Inc. (Hoboken )
                0270-9139
                1527-3350
                14 February 2019
                August 2019
                : 70
                : 2 ( doiID: 10.1002/hep.v70.2 )
                : 465-475
                Affiliations
                [ 1 ] Department of Internal Medicine National Taiwan University Hospital Hsin‐Chu Branch Hsin‐Chu Taiwan
                [ 2 ] Department of Tropical Medicine and Parasitology National Taiwan University College of Medicine Taipei Taiwan
                [ 3 ] Department of Internal Medicine Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University Kaohsiung Taiwan
                [ 4 ] Department of Internal Medicine, Tri‐Service General Hospital National Defense Medical Center Taipei Taiwan
                [ 5 ] Department of Internal Medicine Kaohsiung Municipal Ta‐Tung Hospital Kaohsiung Taiwan
                [ 6 ] School of Medicine Chung Shan Medical University Taichung Taiwan
                [ 7 ] Department of Internal Medicine Chung Shan Medical University Hospital Taichung Taiwan
                [ 8 ] Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan
                [ 9 ] Department of Internal Medicine National Taiwan University Hospital Yun‐Lin Branch Yun‐Lin Taiwan
                [ 10 ] Department of Internal Medicine Changhua Christian Hospital Changhua Taiwan
                [ 11 ] Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung Taiwan
                [ 12 ] Department of Internal Medicine Taoyuan General Hospital, Ministry of Health and Welfare Taoyuan Taiwan
                [ 13 ] Department of Medicine National Taiwan University Hospital Jin‐Shan Branch New Taipei City Taiwan
                [ 14 ] School of Public Health Taipei Medical University Taipei Taiwan
                [ 15 ] Department of Internal Medicine Far Eastern Memorial Hospital New Taipei City Taiwan
                [ 16 ] School of Medicine National Yang‐Ming University Taipei Taiwan
                [ 17 ] Department of Internal Medicine National Taiwan University Hospital and National Taiwan University College of Medicine Taipei Taiwan
                Author notes
                [*] [* ] Address Correspondence and Reprints Request to:

                Chia‐Jui Yang, M.D.

                Department of Internal Medicine, Far Eastern Memorial Hospital

                No. 21, Section 2, Nanya South Road

                Banciao District

                New Taipei City 220, Taiwan

                E‐mail: yangcj1206@ 123456gmail.com

                Tel: +886‐2‐77281321

                Author information
                https://orcid.org/0000-0001-6877-5345
                Article
                HEP30495
                10.1002/hep.30495
                6767446
                30614542
                7fca2df3-70a1-422f-b660-504ae0145038
                © 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 11 October 2018
                : 04 January 2019
                Page count
                Figures: 2, Tables: 3, Pages: 11, Words: 15183
                Categories
                Original Article
                Original Articles
                Viral Hepatitis
                Custom metadata
                2.0
                hep30495
                August 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:30.09.2019

                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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