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Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2017; 23(20): 3589-3606
Published online May 28, 2017. doi: 10.3748/wjg.v23.i20.3589
Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: A review
Kuan-Yin Lin, Guan-Jhou Chen, Yu-Lin Lee, Yi-Chia Huang, Aristine Cheng, Hsin-Yun Sun, Sui-Yuan Chang, Chun-Eng Liu, Chien-Ching Hung
Kuan-Yin Lin, Department of Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei 20844, Taiwan
Guan-Jhou Chen, Yi-Chia Huang, Aristine Cheng, Hsin-Yun Sun, Chien-Ching Hung, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan
Aristine Cheng, Hsin-Yun Sun, Chien-Ching Hung, National Taiwan University College of Medicine, Taipei 10002, Taiwan
Yu-Lin Lee, Chun-Eng Liu, Department of Internal Medicine, Changhua Christian Hospital, Changhua 50006, Taiwan
Sui-Yuan Chang, Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei 10048, Taiwan
Sui-Yuan Chang, Department of Laboratory Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan
Chien-Ching Hung, Department of Parasitology, National Taiwan University College of Medicine, Taipei 10048, Taiwan
Chien-Ching Hung, Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan
Chien-Ching Hung, China Medical University, Taichung 40402, Taiwan
Author contributions: Lin KY, Chen GJ, Lee YL, Huang YC, Cheng A, Sun HY and Chang SY performed the literature search and review, and wrote the paper; Liu CE and Hung CC edited and revised the manuscript.
Supported by Centers for Disease Control, Taiwan, No. JH105022.
Conflict-of-interest statement: Chien-Ching Hung has received research support from Janssen, Abbvie, Bristol-Myers Squibb, Merck, and ViiV and speaker honoraria from Gilead Sciences, and served on the advisory boards for Gilead Sciences, ViiV, Abbvie, and Janssen. Other authors report no potential conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Chien-Ching Hung, MD, PhD, Clinical Professor, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan. hcc0401@ntu.edu.tw
Telephone: +886-2-23123456-67552 Fax: +886-2-23707772
Received: February 12, 2017
Peer-review started: February 14, 2017
First decision: March 16, 2017
Revised: March 31, 2017
Accepted: May 4, 2017
Article in press: May 4, 2017
Published online: May 28, 2017

Abstract

Hepatitis A virus (HAV) is one of the most common infectious etiologies of acute hepatitis worldwide. The virus is known to be transmitted fecal-orally, resulting in symptoms ranging from asymptomatic infection to fulminant hepatitis. HAV can also be transmitted through oral-anal sex. Residents from regions of low endemicity for HAV infection often remain susceptible in their adulthood. Therefore, clustered HAV infections or outbreaks of acute hepatitis A among men who have sex with men and injecting drug users have been reported in countries of low endemicity for HAV infection. The duration of HAV viremia and stool shedding of HAV may be longer in human immunodeficiency virus (HIV)-positive individuals compared to HIV-negative individuals with acute hepatitis A. Current guidelines recommend HAV vaccination for individuals with increased risks of exposure to HAV (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant disease (such as those with chronic hepatitis). The seroconversion rates following the recommended standard adult dosing schedule (2 doses of HAVRIX 1440 U or VAQTA 50 U administered 6-12 mo apart) are lower among HIV-positive individuals compared to HIV-negative individuals. While the response rates may be augmented by adding a booster dose at week 4 sandwiched between the first dose and the 6-mo dose, the need of booster vaccination remain less clear among HIV-positive individuals who have lost anti-HAV antibodies.

Key Words: Epidemiology, Viral hepatitis, Acute hepatitis, Fecal-oral transmission, Oral-anal sex, Men who have sex with men, Injecting drug use, Immunosuppression, Immunization

Core tip: We provide an updated review of hepatitis A virus (HAV) coinfection among human immunodeficiency virus (HIV)-positive individuals, focusing on the epidemiology, clinical manifestations, and prevention for HAV infection. The reported outbreaks of acute hepatitis A among men who have sex with men and injecting drug users are summarized. Updated vaccination guidelines for prevention of HIV-positive individuals against HAV infection are presented. We also review the published data of effectiveness or efficacy of HAV vaccination studies and the different approaches to improvement of the serological responses to conventional HAV vaccines among HIV-positive individuals.



INTRODUCTION

Hepatitis A virus (HAV) is one of the most common infectious etiologies of acute hepatitis worldwide. According to the WHO estimates, HAV resulted in 13.7 million illnesses and 28000 deaths in 2010[1]. HAV is primarily transmitted fecal-orally via contaminated food or water, or through close contact with an infected person. With improved sanitation and provision of HAV vaccination, areas or populations with high HAV endemicity show patterns of declining endemicity, according to their socioeconomic backgrounds[2]. Based on the different age-specific HAV seroprevalence profiles, the world can be divided into countries of high, intermediate, low, and very low HAV endemicity[3]. In countries of high endemicity, most people acquire HAV in their early childhood and are immune to the virus. On the contrary, adults from low endemic areas are first exposed to HAV during travel to or residence in endemic areas, or being engaged in risky behaviors, such as contact with infected persons, being men who have sex with men (MSM), or using illicit drugs[2,4].

Several outbreaks of acute HAV infection among the MSM and injecting drug users’ (IDUs’) communities have been reported in several developed countries of low endemicity for HAV infection. The duration of HAV viremia and stool shedding of HAV may be longer in HIV-positive individuals, increasing the window of opportunity for wider transmission of HAV to those engaged in risk behaviors. HAV vaccination is the most efficient approach to prevention of acquiring HAV infection. However, the seroconversion rates following the recommended standard 2-dose HAV vaccination schedule are lower among HIV-positive individuals compared to HIV-negative individuals, and the vaccination effectiveness among HIV-positive individuals is rarely investigated in the outbreak setting[5]. In this article, we review the epidemiology and clinical manifestations of acute HAV infection and HAV vaccination among HIV-positive individuals in the era of combination antiretroviral therapy (cART).

HAV VIROLOGY

HAV, first identified by Feinstone et al[6] in 1973, belongs to the Hepatovirus genus of the family Picornaviridae. The genome of HAV is a positive-strand RNA (range, 7470 to 7478 nucleotides) and encodes only a single open reading frame, which is translated into a polyprotein. The polyprotein is then cleaved by the virus-encoded protease (3Cpro) to yield 8 viral proteins, including VP0, VP3, VP1-2A, 2B, 2C, 3AB, 3Cpro, and RNA-dependent RNA polymerase (RDRP, 3Dpol). The virus particle is composed of 3 proteins, VP0, VP1-2A, and VP3. During the assembly of the virus capsid, 2A will be removed from the VP1-2A by cellular protease or 3Cpro, and at the final stage of maturation, VP0 will be cleaved into VP2 and VP4. Five copies of each protein will be assembled to form a pentamer, and 12 copies of the pentamer will form a virus capsid. Despite that there are some amino acid variations between different HAV strains, the detection of anti-HAV antibody is not as complicated as other RNA viruses due to the fact that HAV exists as a single serotype. Due to the advances of molecular technology, 7 unique genotypes (I to VII) of HAV are defined by analysis of a 168-base region, located between the C terminus of VP1 and N terminus of P2A[7]. These 7 genotypes exhibit less than 85% of sequence identity between genotypes and no more than 15% of divergence within a genotype, a criterion used for polioviruses, another member of the family Picornaviridae. However, further detailed analyses of other viral regions reveal that the genotypes II and VII should be reclassified as subtypes A and B of genotype II[8], and genotypes I and III could also be divided into subgenotypes A and B[9]. Four genotypes (I, II, III, and VII) are of human origin, and 3 (IV, V, VI) are of simian origin. Genotypes I and III are the most prevalent genotypes identified in humans. Subgenotypes IA and IB are often found in North and South Americas, Europe, China, and Japan[7]. Clusters within genotypes predominant in certain geographic regions have been reported, such as a group of subgenotype IA strains from the United States[10], and genotype II in the Netherlands, France, and Sierra Leone[7,11]. However, in other regions, the presence of variant genotypes was reported in Europe and Japan, likely representing international spread from the endemic regions.

EPIDEMIOLOGY OF HAV INFECTION AMONG HIV-POSITIVE PATIENTS
HAV seroprevalence among HIV-positive patients

Previous studies have shown higher seroprevalence and incidence of HAV infection among MSM compared to the general population[12-14], which were associated with oral-anal sex and the number of sexual contacts and partners[12,15-20]. The HAV seroprevalence also increases with age, indicating the cohort effect[2,12,19,21]. Unlike MSM, heterosexual men with risky sexual behaviors has been inconsistently associated with higher HAV seroprevalence. While a few studies reported a lower seroprevalence and incidence among heterosexual men with sexually transmitted diseases (STDs) compared to MSM[15,16], others indicated that the risks for HAV infection among heterosexual men with STDs and MSM were similar[12,19,21]. IDUs also had a higher HAV seroprevalence than the general population[13,14,22,23]. However, the high seroprevalence might not be solely attributable to needle contamination, since some reported similar elevation of the HAV seroprevalence between IDUs and non-injecting illicit drug users[22,23].

Although the direct evidence on the correlation between contracting HIV and HAV was scarce, observational data suggested that HIV-positive individuals, especially MSM and IDUs, are at increased risk of acquiring HAV[24]. In addition, one small study including 15 HIV-positive individuals demonstrated that the duration of HAV viremia in HIV-positive individuals with acute hepatitis A was prolonged compared to that in HIV-negative individuals with acute hepatitis A, which may increase the probability of HAV transmission to others[25]. Several studies have reported the HAV seroprevalence among HIV-positive individuals and at-risk persons in areas of different HAV endemicities and vaccine coverage (Table 1)[12-23,26-42]. In these studies, the HAV seroprevalence among HIV-positive individuals ranged from 15.1% in Taiwan to 96.3% in Iran[31,35]. While studies conducted in countries of high HAV endemicity showed no differences in the HAV seroprevalence between HIV-positive and HIV-negative individuals[27], the seroprevalence in countries of low endemicity was higher among HIV-positive individuals compared to HIV-negative individuals[26,30]. Among HIV-positive individuals, older age and injecting drug use were identified as the independent factors associated with seropositivity for HAV; the HAV seroprevalence was lower in HIV-positive MSM despite the at-risk sexual behaviors[29,30,33-36].

Table 1 Seroprevalence of hepatitis A virus infection among human immunodeficiency virus-positive patients and at-risk populations.
Ref.LocationStudy periodStudy populationAge (yr)HIV-positive populationOther populationsAssociated factors1 and comments
HIV-positive population
Nandwani et al[26]London, United Kingdom1993255 men attending genitourinary clinics3241.3%MSM, 32.4%No difference between homosexual and heterosexual men
Heterosexuals, 30.0%
Unknown HIV status, 26.4%
Fainboim et al[27]Buenos Aires, Argentina1994-1995484 HIV-positive patients2984.0%HIV-positive MSM, 83.3%High seroprevalence without difference between HIV-positive and HIV-negative individuals
HIV-positive heterosexuals, 86.3%
HIV-positive IDUs, 85.7%
Blood donors, 82.4%
Aloise et al[28]Rio de Janeiro, Brazil1988-2004581 HIV-positive patients3579.8%NAOlder age and lower educational level
Lee et al[29]Tainan, Taiwan2000-2005484 patients with recent diagnosed HIV infection3665.8%HIV-positive MSM, 40.0%;Seroprevalence increased with age and among heterosexuals
HIV-positive heterosexuals, 85.2%
HIV-positive IDUs, 70.1%
Sun et al[30]Taiwan2004-20071580 HIV-positive patients3960.9%HIV-positive MSM, 50.5%Older age and injecting drug use
HIV-positive heterosexuals, 79.3%Higher seroprevalence in HIV-positive individuals
HIV-positive IDUs, 62.0%
HIV-negative individuals, 48.0%
Davoudi et al[31]Tehran, Iran2005-2006247 HIV-positive patients3696.3%NA
Hoover et al[32]6 major cities2, United States2004-2007627 HIV-positive MSM4116.1%3NALow HAV screening and vaccination rates (28.5%)
Linkins et al[33]Bangkok, Thailand2006-20081291 MSM2732.4%3HIV-negative MSM, 25.5%Older age and lower education level
Baek et al[34]Seoul, South Korea2008-2010188 HIV-positive patients3962.8%HIV-positive MSM, 57.1%Older age
HIV-positive heterosexuals, 65.8%
Tseng et al[35]Taipei, Taiwan2009-20101128 MSM18-4015.1%3HIV-negative MSM, 7.4%Older age
No difference between HIV-positive and HIV-negative individuals
Kourkounti et al[36]Athens, Greece2007-2011897 HIV-positive MSM4135.7%3NAOlder age and being foreigners
At-risk populations (MSM and IDUs)
Corey et al[15]Seattle, United States1977-1979159 patients from STD clinics31NAMSM, 30.4% (annual incidence, 22%)Oral-anal sexual contact
Heterosexuals, 12.3% (annual incidence, 0%)Higher seroprevalence and incidence in MSM
McFarlane et al[12]Nova Scotia, Canada1977-1978421 patients from STD clinics25NAMSM, 42.4%Higher number of sex partners and older age
Heterosexuals, 39.2%
Blood donors, 12.6%
Student nurses, 13.2%
Kryger et al[16]Copenhagen, Denmark1979269 men with previous syphilis33NAMSM, 36.0%;More episodes of syphilis in younger MSM
Heterosexual, 20.0%
Coutinho et al[17]Amsterdam, the Netherlands1980-1982689 MSM31NAMSM, 42.0% (incidence, 14.0%)Longer duration of homosexual activity
Crofts et al[22]Victoria, Australia1990-19922175 prison entrants30NAIDU, 43.7%History of incarceration
293 IDUsPrison entrants, 60.1%
Blood donors, 30.0%
Katz et al[18]San Francisco and Berkeley, United States1992-1993411 MSM21NAMSM, 28.0%Sexual and drug-using behaviors
Villano et al[13]Baltimore, United States1993-1994294 MSMNANAMSM, 32.3%Increased risk for HAV infection in MSM and IDUs
292 IDUsIDU, 66.4%
Blood donors, 13.7%
Corona et al[19]Rome, Italy1997432 male patients from STD clinicsNANAMSM, 60.3%Older age and more sexual partner
Heterosexual, 62.2%
Ochnio et al[14]Vancouver, Canada1998494 individuals from street outreach clinics32NAMSM, 25.5%Increased risk for HAV infection in MSM and IDUs
IDU, 42.6%
Street youth, 6.3%
Ross et al[21]Birmingham, United Kingdom2000210 men attending genitourinary clinicsNANAMSM, 23.0%; Heterosexual men, 32.0%Ethnicity, older age, and history of sex in a sauna
Diamond et al[37]Washington, United States1997-2000833 MSM15-29NAMSM, 21.0%Ethnicity, IDU, HBV and HIV infection
Vaccination rate, 21%
Bialek et al[20]7 major cities4, United States1994-20002708 MSM15-29NAMSM, 18.4%More male sex partners and unprotected anal sex
O’Riordan et al[38]London, United Kingdom2004395 MSM attending genitourinary clinicsNANAMSM, 49.9%
Van Rijckevorsel et al[39]Amsterdam, the Netherlands1992-20061697 hepatitis A patientsNANAIncidence, 0.97/1000 MSMClustered transmission in social MSM networks
Removille et al[23]Luxembourg2005368 problem drug usersNANAIDUs, 57.1%
nIDUs, 65.9%
Bozicevic et al[40]Zagreb, Croatia2006360 MSM27NAMSM, 14.2%
Weerakoon et al[41]Melbourne, Australia2002-20113055 MSM33NAMSM, 39.0%Vaccination levels over 40%-50% to prevent outbreaks
Ali et al[42]Sydney, Australia1996-201214799 MSM30NAMSM, 31.9% in 1996 to 63.8% in 2012Vaccination rate, 9.8% in 1996 to 45.2% in 2012
Hepatitis A outbreaks in the MSM population

In countries of low HAV endemicity, the majority of HAV-seronegative adults remain susceptible to acute HAV infection. Outbreaks of acute hepatitis A are often caused by introduction of HAV through contaminated foods and person-to-person transmission[2]. Numerous outbreaks of acute hepatitis A have been reported in the MSM population through sexual contacts, which are summarized in Table 2[43-70]. Since the early 1980s, outbreaks of acute hepatitis A among MSM have been described in Denmark[43], Sweden[44], the United Kingdom[45], and the United States[61,62]. The incidence of acute HAV infection among MSM peaked in the 1990s, and the affected countries included the United Kingdom[46,47,49,51], the Netherlands[48], Norway[50], the United States[63,65,66], Canada[64] and Australia[67-70]. One of the largest epidemics of acute hepatitis A occurred in Sydney, Australia, where 2 outbreaks affected 323 and 186 MSM during 1991-1992 and 1995-1996, respectively[69]. Since 2015, Taiwan reported a large outbreak involving more than 1000 indigenous cases, with more than 70% of the affected individuals being MSM[71]. While the HAV vaccine was licensed and recommended for MSM since the mid-1990s[47], the emergence of HAV infection continued to pose a health threat to MSM in several developed European countries during the 2000s, including Italy[52,54,55,60], Denmark[53], Spain[56,58], Poland[57], and the United Kingdom[59].

Table 2 Outbreaks of acute hepatitis A in the men who have sex with men population.
Ref.LocationStudy periodCase numberMaleMSMHIV-positive patientsAge (yr)Risk factors1 and comments
Europe
Høybye et al[43]Copenhagen, Denmark1977-1978454521NA29
Christenson et al[44]Stockholm, Sweden1979-1980145145145NANAMultiple partners and oral-anal sexual contact
Mindel et al[45]London, United Kingdom198024NA23NANAHAV infection was associated with homosexual activity
Kani et al[46]London, United Kingdom1989-19907000NA41NANAOral-anal sexual contact
Atkins et al[47]London, United Kingdom1989-199220612165NANAOral-anal sexual contact and sexual promiscuity
Leentvaar-Kuijpers et al[48]Amsterdam, the Netherlands1992-1993293NA39NANAVisiting saunas and darkrooms
Walsh et al[49]Thames region, United Kingdom1995481NA58NANAOral-anal and digital-rectal intercourse
Stene-Johansen et al[50]Oslo, Norway1995-1998262626NANA
Bell et al[51]London and East Sussex, United Kingdom199748NA41NANAEating shellfish and sex in gay saunas
Manfredi et al[52]Bologna, Italy1999-2004122104811128Unprotected sexual contact
Mazick et al[53]Copenhagen, Denmark2004181818NANACasual sex and sex in gay saunas
Girardi et al[54]Rome, Italy2002-20084733681155725-64Same gender sex
Routine HIV test in HAV-infected patients should be considered
Bordi et al[55]Rome, Italy2008-2010162143341436Monophyletic HAV strain sustained the outbreak
Tortajada et al[56]Barcelona, Spain20024847NA28%31
2003-20046060NA24%32
2008-2009189185NA21%33
Dabrowska et al[57]Warsaw, Poland2007-2008860NA50628No difference in disease severity between HIV-positive and HIV-negative individuals
Tortajada et al[58]Barcelona, Spain2008-200915012687NA33
Sfetcu et al[59]Northern Ireland, United Kingdom2008-2009383626NA29The outbreak strain was indistinguishable from that in Czech Republic
Taffon et al[60]Tuscany, Italy2008240NA32%NANAA unique circulating HAV strain
North America
Kosatsky et al[61]Anchorage, Alaska1982-1983171717NA19-31
Desenclos et al[62]Florida, United States1988-19893116926NANA
Henning et al[63]New York, United States199118018062NA20-49Anonymous sex partner, group sex, oral-anal and digital-rectal intercourse
Allard et al[64]Montréal, Canada1996-1997376376376NA33Vaccination campaign achieving 20%-41% coverage in MSM decreased incidence rapidly
Finton et al[65]Atlanta, United States1996222NA75%NANAVaccination campaign in MSM decreased reported cases
Cotter et al[66]Ohio, United States1998-199913611847NA33Contact with hepatitis A cases
Asia-Pacific region
Stewart et al[67]Melbourne, Australia1991495407210NANASexual and social contact
Stokes et al[68]Sydney, Australia1991-1992570515330NA31Sexual contact was the most reported contact type
Ferson et al[69]Sydney, Australia1991-19961138991587NA30Household or sexual contact
Delpech et al[70]Sydney, Australia1997-1999354265139NA32
Chen et al[71]Taiwan2015-2016> 1000NA> 70%> 60%NAA total of 1296 cases reported as of February, 2017

The duration of outbreaks of acute hepatitis A among MSM were mostly curtailed at 2 years; however, the outbreak in Canada extended from December 1994 to February 1998[64]. The cyclical outbreaks were noted in Australia during 1991-1996[69] and in Spain during 1989-2010[56], which might be facilitated by the continuous circulation of particular HAV strains in the MSM population[50,55,60]. The predominant circulating HAV strains among MSM belonged to genotype IA[50,55,59,60,72]. The patients contracting HAV during the outbreaks were mostly young adults with a mean or median age of 28-36 years[55,57]. HAV was recognized as being transmitted among MSM through sexual contacts[73], and case-control studies have identified several associated factors such as having anonymous sex partners, group sex, oral-anal and digital-rectal intercourse[63], contact with patients with acute hepatitis A[66], having sex in gay saunas[51,53], and visiting saunas and darkrooms[48]. In light of the risky sexual behavior, the largest HAV vaccination campaign for MSM was launched in Montréal, in which 9500-15000 first doses of HAV vaccine were administered to achieve a coverage rate between 20% and 41%. However, the decrease in the incidence of acute hepatitis A shortly after the vaccination campaign might indicate the relatively late implementation of HAV vaccination and the natural decline after herd immunity was established at the end of the outbreak[64]. The vaccination campaigns targeting MSM in Atlanta and Barcelona recruited 3,000 persons, which resulted in a 16% decrease of reported acute hepatitis A cases[56,65].

Coinfections with HAV and HIV were identified during the 2000s in Italy[52,54,55], Spain[56], and Poland[57]. Most HAV/HIV-coinfected individuals were males with known HIV status, while others were found to be HIV-positive concomitantly with acute HAV infections[52,54-57]. Among all male patients who received a diagnosis of acute hepatitis A during 2002-2008 in Italy, 15.2% (56/368) were HIV-positive[54]. After excluding those without available HIV serology, the HIV seroprevalence among was 27.6%[54]. The high proportion of HAV/HIV coinfection in the areas of low HAV endemicity highlights the importance of routine HIV testing in patients with acute hepatitis A[54].

Hepatitis A outbreak in the IDU population

Outbreaks of acute hepatitis A in the IDU population have been reported since 1970s as the numbers of IDUs increased[74]. The studies of outbreaks of acute hepatitis A among IDUs are summarized in Table 3[74-88]. During 1970-1979, the cyclic occurrence of outbreaks of acute hepatitis A in Sweden suggested a continuously increasing pool of susceptible young IDUs in the closed communities[74]. The outbreaks were mostly described in Europe[75-78] and the United States[82,83,85] in the 1980s and 1990s, but were seldom described after the early 2000s[79-81,86]. Up to 492 IDUs were infected with HAV in Norway between 1995 and 1996[77]. In Terni, Italy; 47 cases of acute hepatitis A were reported during 2002-2003, among which included 35 IDUs and 2 HIV-positive individuals. The most recent outbreak of acute HAV infection among IDUs was described in Israel during 2012-2013, which occurred in IDUs and homeless adults with subsequent spread to the general population in Tel Aviv, despite the nation-wide implementation of universal toddler’s vaccination in 1999[88].

Table 3 Outbreaks of acute hepatitis A in the injecting drug user population.
Ref.LocationStudy periodTotal patientsIDUHIV-positive individualsAge (yr)Risk factors1 and comments
Europe
Widell et al[74]Malmo, Sweden1970-1979323188NANA
Sundkvist et al[75]Helsingborg, Sweden1983-19843632NA18-35The outbreak was associated with intrarectal transportation of illicit drugs
Leino et al[76]Helsinki, Finland1994-1995238131NA31The outbreak was associated with intrarectal transportation of illicit drugs
Stene-Johansen et al[77]Oslo, Norway1995-1996621492NANAThe outbreak was associated with needle sharing
O’Donovan et al[78]United Kingdom1998-19992714NA25
Syed et al[79]Bristol, United Kingdom200012369NA25The outbreak was associated with parenteral transmission from contaminated illicit drugs; HAV vaccination of IDUs decreased the reported cases
Roy et al[80]Aberdeen, Scotland2000-200210674NANANot washing hands after using the toilet, or before preparing food or drugs, sharing needles/syringes, and injecting contact with jaundiced persons
Spada et al[81]Terni, Italy2002-20034735234Contact with jaundiced persons, but not related to injecting practices; HAV vaccination of IDUs decreased the reported cases
North America
Harkess et al[82]Oklahoma, United States1984-19877942NA23-27
Jenkerson et al[83]New York, United States1986-198725670NANA
Jin et al[84]Canada1987-19896559NANA
Hutin et al[85]Iowa, United States1996-19971589.7%NANAMethamphetamine injection, sharing methamphetamine use, using brown methamphetamine, and needle sharing
Vong et al[86]Florida, United States2001-200240311%NA32HAV vaccination in jail decreased the reported cases
Asia-Pacific region
Shaw et al[87]Queensland, Australia1997875118NANASharing of instruments for smoking marijuana
Manor et al[88]Tel-Aviv, Israel2012-2013759NA33

The outbreaks of acute hepatitis A among IDUs mainly lasted between 1 and 2 years, and young patients with a mean or median age of 20-34 years were predominantly affected[74,81]. HAV could be transmitted fecal-orally through poor personal hygiene and living conditions, or percutaneously through contamination of illicit drugs or injecting equipment by fecal materials or blood[81]. Three case-control studies identified not washing hands after using the toilet or before preparing food, not washing hands prior to preparing drugs, sharing of needles or syringes, use of contaminated illicit drugs, and contact with jaundiced persons to be factors associated with acute hepatitis A in IDUs[80,81,85]. To curb the epidemic of acute hepatitis A, HAV vaccination programs were implemented in the United Kigndom[79], Norway[89] and Italy[81], and harm reduction program by providing clean injecting equipment was implemented in Switzerland[90].

CLINICAL MANIFESTATIONS OF ACUTE HAV INFECTION

The incubation period of acute HAV infection is 2.5 to 5 wk[91]. The typical symptoms of acute hepatitis A include fatigue, malaise, nausea, vomiting, anorexia, fever, and right upper quadrant pain. The frequencies of symptoms or signs of acute hepatitis A are listed in Table 4[92-96]. While most of acute HAV infections are self-limited, the severity of the symptoms may vary with age and concurrent comorbidities, particularly chronic viral hepatitis. Acute HAV infection is usually silent or subclinical in children, but approximately 30% of the infected patients older than 6 years have symptoms including hepatitis, jaundice, and abdominal pain[97]. Less than 25% of the patients have diarrhea though HAV is transmitted through fecal-oral route[98]. The data on the symptoms of acute hepatitis A among HIV-positive individuals are limited, and the study by Ida et al[25] of 15 HIV-positive and 15 HIV-negative individuals with acute hepatitis A suggested no differences in the frequency and severity of clinical symptoms of acute hepatitis A between the two groups.

Table 4 Clinical symptoms and signs of patients with acute hepatitis A infection[92-96].
SymptomsFrequency
Asymptomatic14%
Fever48%-87%
Nausea/vomiting56%-88%
Anorexia66%-96%
Fatigue/malaise49%-80%
Upper abdominal pain42.5%-82%
Diarrhea8%-23%
Signs
Jaundice24%-99%
Hepatomegaly7%-78%
Splenomegaly18%-30%

Patients with acute hepatitis A usually have significantly elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. In previous studies, the average peak levels of total bilirubin were 7-8 mg/dl and the levels of AST and ALT were higher than 1000 IU/L[25,92,93,98-100]. Alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GT) are also elevated in patients with acute hepatitis A. Resolution of the abnormal biochemical tests generally occurs within 1 to 6 wk after the onset of the illness[99]. Approximately 85% of the patients who are infected with HAV have full clinical and biochemical recovery within 3 mo and nearly all have a complete recovery by 6 mo[92]. The study by Ida et al[25] reported lower elevations in total bilirubin, AST, and ALT in HIV-positive individuals during acute hepatitis A than HIV-negative individuals, which were considered to be related to the weaker immune responses in HIV-positive patients or clonal spreading of a specific HAV strain that was able to escape from immunity in the study. Regulatory T cells (Tregs) normally suppress the T-cell responses directed against hepatitis viruses and down-regulate the immune reaction that is responsible for liver damage in viral hepatitis[101]. The study by Choi et al[102] suggested a decrease in Tregs leading to a severe liver injury during acute hepatitis A. HIV-positive individuals however are known to have high Tregs, compared to their HIV-negative counterparts, hence they may experience less severe injury during acute hepatitis A[103]. On the other hand, Ida et al[25] reported higher levels of ALP and γ-GT during acute hepatitis A in HIV-positive individuals than HIV-negative patients. Biliary tract is not the primary target of HAV infection. Lymphocytic cholangitis is rarely seen with acute HAV infection[104]. However, HIV-related cholangitis or cholangiography is a well-recognized late complication of acquired immunodeficiency syndrome (AIDS). Opportunistic infections such as cytomegalovirus infection or cryptosporidiosis may also cause cholangitis. HIV is also able to cause direct cytopathic effects on the biliary tract mucosa. Hence, the higher levels of ALP and γ-GT observed in HIV-positive patients with acute hepatitis A may be explained by multiple factors other than the liver injury caused by HAV itself.

In the general population, stool shedding of HAV antigen can be detected 19 d before the peak elevation of ALT levels and continue for at least 25 d[105] and even up to 80 d[106]. The duration of viremia is estimated to last around 20 to 40 d[25,106,107] and even longer than 3 mo[108]. In the study by Ida et al[25], the median duration of HAV viremia in HIV-positive individuals with acute hepatitis A was 53 d, which was longer than that of HIV-negative individuals. A longer duration of HAV viremia may be related to impaired host immunity[100]. Besides, the relationship between duration of viremia and specific HAV genotypes is still inconclusive[106,107]. The comparisons of clinical manifestations of acute hepatitis A between HIV-positive and HIV-negative individuals are summarized in Table 5[25,57,91-93,95,98-100,105-109].

Table 5 Comparison of clinical manifestations of hepatitis A virus between human immunodeficiency virus-positive patients or human immunodeficiency virus-negative patients with acute hepatitis A.
HIV-positive patientsHIV-negative patients
Natural course of acute HAV infection
Incubation period (wk)NA2.5-5[91]
Duration of stool shedding (d)NA25 (HAV antigen)[105]
81 (HAV RNA)[106]
Duration of viremia (d)53 (10-89)[25]22-95[25,106-108]
Laboratory findings
Peak T-bilirubin (mg/dL)5.1-5.9[25]5.7-8.7[25,92,93,95,98,99]
Peak AST (IU/L)929-1339[25,57]1231-2271[25,92,93,99]
Peak ALT (IU/L)1995-2368[25,57]1079-3442[25,92,93,99,100]
Duration of elevated AST/ALT (d)63 ± 38[109]51[92]
Peak ALP (IU/L)807[25,57]228-396[25,92]

Other atypical presentations of acute hepatitis A include renal insufficiency and relapsing hepatitis[93], which are usually present in children. Some individuals experienced a prolonged hepatitis (5.8%)[93] or cholestasis (6.8%), especially in the presence of hepatitis B virus[94]. Severe hepatic failure is rare and occurs more commonly in patients with underlying diseases or advanced age. Reported case fatality rates were 0.1% in infants and children, 0.45% in those aged 15 to 39 years, and 1.1% in those aged > 40 years. Patients with chronic hepatitis C virus (HCV) infection have a substantial risk of fulminant hepatitis and death associated with HAV superinfection[110]. HIV-positive individuals acquire HAV infection mostly in their adulthood and often have other underlying liver disease[25,57], which may increase the risk of hepatic failure and fatality caused by HAV. Therefore, prevention by HAV vaccination is important, especially for the HIV/HCV-coinfected individuals.

HAV VACCINATION AND FACTORS ASSOCIATED WITH IMMUNOGENICITY AND PERSISTENT PROTECTION
Vaccine immunogenicity and factors associated with immunogenicity

HAV vaccination is not universally recommended for HIV-positive individuals but specifically for those with increased risks of exposure (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant disease (such as those with chronic hepatitis) (Table 6)[111-114]. Of the two types of HAV vaccines that are currently available internationally, the live attenuated vaccine (based on H2 or LA-1 HAV strains and manufactured as well as mainly used in China or India) and the inactivated HAV vaccine (based on clinical trials since 1991 and licensed in the United States since 1995), only the latter is recommended for HIV-positive individuals. There are 3 formulations of inactivated HAV vaccines that have been assessed in HIV-positive individuals with varying degrees of immunodeficiency as shown in Table 7[115-129]. Although different specific anti-HAV IgG titers have been used to define seroconversion (10, 18, 20, or 33 mIU/mL), the majority of these studies have adopted 20 mIU/ml as the surrogate titer for seroprotection.

Table 6 Hepatitis A virus vaccination recommendations by the British human immunodeficiency virus Association, the European AIDS Clinical Society, the US Advisory Committee for Immunization Practices and the World Health Organization.
Health AuthorityTarget candidatesDosing ScheduleComments
BHIVA[111]Household and sexual contacts of infected personsMonovalent HAV vaccine recommendedWe support the BHIVA’s recommendations of targeted vaccination during outbreaks and of stratifying dosing schedule by CD4 counts, particularly administering a 3-dose schedule for those with lower CD4 counts. Despite waning antibody levels, we could not find evidence to justify routine boosters every 10 yr for those at risk. It may be preferable to follow antibody titers and revaccinate seroreverters
TravellersPatients with CD4 counts > 350 cells/mm3 should be offered 2 vaccine doses at 0 and 6 mo
MSM
Injecting and non-injecting drug usersPatients with CD4 counts < 350 cells/mm3 should receive 3 vaccine doses at 0, 1, and 6 mo
Individuals at risk of infection during outbreaks
Those with occupational exposure to HAV (e.g., laboratory workers, sewage workers)Patients at continued risk of exposure receive a boosting vaccine dose every 10 yr
HemophiliacsFollowing a significant exposure, HIV-positive contacts who are HAV-seronegative receive post-exposure prophylaxis with the HAV vaccine, with the first dose given as soon as possible and within 14 d of exposure; if the CD4 count is < 200 cells/mm3, they should also receive human normal immunoglobulin
Residents of care institutions, and their care givers
EACS[112]TravellersVaccinate if seronegative. Did not specify howShorter list of at risk candidates for vaccination. Our review supports their recommendation to check antibody titers in individuals with risk profile to guide the need for primary or booster vaccinations
MSM
IDUs
Active hepatitis B or C infection
ACIP[113]MSMMonovalent vaccine formulations should be administered in a 2-dose schedule at either 0 and 6-12 mo (Havrix), or 0 and 6-18 mo (Vaqta)Unlike BHIVA, in addition to the monovalent vaccine formulations, ACIP also recommends the combined hepatitis A and B vaccine
Injection or non-injection illicit drugs users
Persons working with HAV-infected primates or
with HAV in a research laboratory setting
Persons with chronic liver diseaseIf the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 mo; alternatively, a 4-dose schedule may be used, administered on days 0, 7, and 21-30 followed by a booster dose at 12 moNo mention of the need to follow antibody titers or booster vaccines or the application of immunization during outbreaks
Persons who receive clotting factor concentrates
Travellers
Close personal contact (e.g., household or regular babysitting) with an international adoptee during the first 60 d after arrival in the United States from a country with high or intermediate endemicity
WHO[114]TravellersInactivated vaccine: 2 doses, the second dose normally 6 mo after the first. If needed, this interval may be extended to 18-36 moDoes not specify whether all HIV-positive persons should be considered as immunosuppressed patients although evidence from Table 5 suggests that except for the duration of viremia acute HAV is not more severe in HIV-positive compared to HIV-negative patients
Immunosuppressed patients
Patients with chronic liver disease
Table 7 Primary response rates and predictors of seroconversion after hepatitis A virus vaccination in human immunodeficiency virus-positive patients.
Ref.DatesDesign/CountryNo. of patient1HAV/dosing schedules (mo)CD4, cells/mm3PVL, log10, copies/mLARTTiming of response2, mo/cut-off3, mIU/mL/assayResponse rate (%): ITT/PPPredictors and comments4
Tseng et al[115]2009-2010Prospective, TaiwanStandard 2-doseHAVRIX 1440 U/Mean, 538Mean, 2.567.1%12, 18/20, a. CIA (ARCHITECT HAVAb-IgG) b. ELISA (ETIAB- HAVK PLUS)12 m (CIA): 75.7/81.7MSM only study; Higher baseline CD4 and suppressed PVL; 3 doses over 2 doses
All 126;2 doses (0, 6)12 m (ELISA): NA/88.6
CD4 matched, 11418 m (ELISA): NA/86.6
3-doseHAVRIX 1440/Mean, 452Mean, 358.2%12 m (CIA): 77.8/81.8
All, 213;3 doses (0, 1, 6)12 m (ELISA): NA/89.2
CD4 matched, 11418 m (ELISA): NA/86.9
Standard 2-doseHAVRIX 1440/NANANA12 m (CIA): 88.5/97.9
HIV-negative, 1932 doses (0, 6)12 m (ELISA): NA/100
18 m (ELISA): NA/100
Mena et al[116]1997-2009Retrospective, SpainStandard 2-dose, 241HAVRIX 1440/Median, 53155.3%561.4%10-16/20, CIA (Advia Centaur)NA/80.7Higher CD4/CD8 ratio; 2 or more doses compared to 1 dose only; female; no HCV infection
(0, 6-12)
Accelerated, 41TWINRIX 720/Median, 54373.2%80.5%5/20, CIA (Advia Centaur)NA/70.7
(0, 7, 21 d, 6-12)
Jimenez et al[117]2002-2008Retrospective, United StatesStandard 2-dose, 125HAVRIX 1440/ (0, 6-12)Median, 410Median, 3.170.0%Variable/< 0.8 signal relative to cut-off, CIA (Vitros ECi)NA/54Higher baseline CD4 count and suppressed PVL
101TWINRIX 720/NA/53
(0, 1, 6-12)
Kourkounti et al[118]Retrospective, GreececART-experienced, 63HAVRIX 1440 or Vaqta 50/ (0, 6-12)628< 1.7100.0%7-13/20, ELFA (VIDAS)NA/78Higher baseline CD4 count
cART-naïve, 504723.90.0%NA/76
Weinberg et al[119]1994-2010Prospective observational, United StatesHormone oral contraceptive, 132 doses (0, 6) or 3 doses (0, 2, 6)47847%578.0%NA/20, ELISA (Mediagnost)NA/62Women only study; Higher baseline CD4 count and suppressed PVL
No contraceptive, 149NA/51
Launay et al[120]2003-2005Randomized controlled trial, FranceStandard 2-dose, 49HAVRIX 1440/ (0, 6)Median, 355Median, < 1.778.0%6-18/20, ELISA (ETIAB- HAVK PLUS)6 m: 44.9/46.8Absence of tobacco smoking
7 m: 69.4/72.3
18 m: 61.2/69.8
3-dose, 46HAVRIX 1440/ (0, 1, 6)Median, 351Median, < 1.783.0%6 m: 69.6/74.4
7 m: 82.6/88.4
18 m: 78.3/85.7
Overton et al[121]1997-2004Retrospective, United States1 or 2-dose, 268HAVRIX 1440/Mean, 447Mean, 2.967.5%NA/NANA/49.6Male; PVL < 1000 copies/mL
NA (1 or 2 doses)ELISA (Not specified)
Weissman et al[122]2001-2003Retrospective, United StatesStandard 2-dose, 138HAVRIX 1440/Mean, 424NA81.9%6-13/18, EIA (Abbot IMx HAV Ab)48.6 (67/138)Female; CD4 count at vaccination > 200 cells/mm3
(0, 6-12)
Wallace et al[123]1997-1998Randomized controlled trial, United StatesStandard 2-dose, HIV-positive, 55Vaqta 50/ (0, 6)Mean, 457.54.5276.0%1, 6, 7, 12/10, Quantitative modified HAVAb assay (NA)1 m: NA/61,100% of subjects with CD4 counts ≥ 300 cells/mm3 seroconverted
CD4 < 300/ 300+, 48/74
7 m: NA/94,
CD4 < 300/ 300+, 87/100
12 m: NA/90,
CD4 < 300/ 300+, 80/100
Standard 2-dose, HIV-negative, 72Vaqta 50/ (0, 6)NANANA1 m: NA/90
7 m: NA/100
13 m: NA/90
Kemper et al[124]1995-1997Double-blind, placebo-controlled trial, United StatesStandard 2-dose, HIV-positive, 48HAVRIX 1440/ (0, 6)3763.2991.0%1, 6, 7, 9/33, ELISA (Enzymun; Boehringer Mannheim)1 m: NA/11Subjects with higher baseline CD4 counts were more likely to seroconvert and to have higher antibody titers
CD4 < 200/ 200+, 0/16
6 m: NA/9
CD4 < 200/ 200+, 0/13
7 m: NA/49,
CD4 < 200/ 200+, 11/62
9 m: NA/52,
CD4 < 200/ 200+, 9/67
Neilsen et al[125]Pre-1996Randomized controlled trial, AustraliaAccelerated 2-dose, HIV-positive, 48HAVRIX 1440/ (0, 1)Mean 569NANA1, 3/20, ELISA (Enzymun; Boehringer Mannheim)1 m: NA/80.0MSM only study; subjects with higher baseline CD4 counts were more likely to seroconvert and to have higher antibody titers; Vaccine schedule did not affect response; HIV-negative subjects had higher seroconversion rates and GMTs
7 m: NA/93.2
CD4 ≤ 200, 64
Standard 2-dose, HIV-positive, 42HAVRIX 1440/ (0, 6)Mean 454NANA1, 7/20, ELISA (Enzymun; Boehringer Mannheim)1 m: NA/75.6
7 m: NA/81.3
CD4 ≤ 200, 64
Standard 2-dose, HIV-negative, 46HAVRIX 1440/ (0, 6)NANANA1, 7/20, ELISA (Enzymun; Boehringer Mannheim)1 m: NA/90.2
7 m: NA/100
Wilde et al[126]Pre-1995Prospective, United KingdomThree mini-dose, HIV-positive hemophiliacs, 31HAVRIX 720/ (0, 1, 6)Median 450 (IgG positive after 2 doses)NA01, 2, 7/20, EIA (SORIN Biomedica INCstar, Italy)2 m: NA/29Hemophiliacs only (all anti-HCV positive); no patients with CD4 counts < 170 cells/mm3 seroconverted
Median 335 (IgG positive after 3 doses)7 m: NA/55
Tilzey et al[127]Pre-1995Prospective, United KingdomThree mini-dose, HIV-positive hemophiliacs, 25HAVRIX 720/ (0, 1, 6)NANANA1, 2, 6, 7/20, ELISA (Boehringer-Mannheim)1 m: NA/26Men only study; After 3 doses, all HIV-positive hemophiliacs with anti-HAV titers of < 50 mIU/mL had CD4 counts < 100 cells/mm3. HAVRIX 1440 was given as a 4th booster dose to the 4 HIV vaccinees with anti-HAV < 50 mIU/mL after 3 doses; only 1 subsequently developed anti-HAV > 50 mIU/mL
2 m: NA/50
6 m: NA/47
7 m: NA/76
Three mini-dose, HIV-negative hemophiliacs, 8HAVRIX 720/ (0, 1, 6)NANANA1 m: NA/57
2 m: NA/86
6 m: NA/100
7 m: NA/100
Three mini-dose, HIV-negative healthy controls, 25HAVRIX 720/ (0, 1, 6)NANANA1 m: NA/100
2 m: NA/100
6 m: NA/100
7 m: NA/100
Hess et al[128]Pre-1994Prospective, controlled, GermanyThree mini-dose, HIV-positive MSM, 26HAVRIX 720/ (0, 1, 6)495NANA1, 2, 6, 7/20, ELISA (SB Biologicals)2 m: NA/78.6MSM only study; Seroconversion rates were independent of CD4 counts
7 m: NA/76.9
Three mini-dose, HIV-negative MSM, 20HAVRIX 720/ (0, 1, 6)NANANA2 m: NA/100
7 m: NA/100
Santagostino et al[129]Pre-1994NA, ItalyThree mini-dose, HIV-positive hemophiliacs, 47HAVRIX 720 (0, 1, 6)NANANA1, 2, 7, 12/2012 m: NA/76.6Hemophiliacs; Seroconversion rates were dependent on stage of HIV disease
Three mini-dose, HIV-negative hemophiliacs, 66HAVRIX 720 (0, 1, 6)NANANANA12 m: NA/100

The earliest studies of HAV vaccination in moderately to severely immunodeficient HIV-positive individuals preceded the licensure of the adult formulation of HAVRIX 1440 U wherein a triple-mini dosing scheme (3 pediatric doses of HAVRIX 720 U administered at 0, 1, and 6 mo) was applied to hemophiliac patients and MSM with or without HIV[127-129]. The seroconversion rates among such HIV-positive hemophiliacs and MSM at month 7 were consistently between 76.0%-76.9% and lower than their HIV-negative counterparts at 100%[127-129]. Later studies of HIV-positive individuals without hemophilia but with other risk factors such as MSM confirmed that the seroconversion rates following the recommended standard adult dosing schedule (2 doses of HAVRIX 1440 U or VAQTA 50 U administered 6-12 mo apart) were lower among HIV-positive adults compared to HIV-negative healthy adults, ranging from 48.6%-94.0%[122-125]. In a meta-analysis including 8 studies, combining a total of 458 HIV-positive patients, the overall rate of serological response to HAV vaccination was 64%[130]. In addition, the geometric mean titers (GMTs) of specific antibodies were also lower among HIV-positive individuals compared to the healthy population[115,123,127].

Overall, factors that correlated best with the poor response to HAV vaccination among HIV-positive individuals were surrogates of immune status such as low CD4 cell counts and high plasma HIV RNA loads at the time of vaccination as shown in Table 7[115-129]. Other factors identified with low rates of seroconversion were HCV coinfection and tobacco smoking[116,120]. Both male and female genders have been associated with seroconversion[121,122].

While the vaccination effectiveness among HIV-positive individuals was mostly evaluated by seroconversion rates in the countries of low endemicities, the serological and clinical responses to HAV vaccination were rarely investigated in the outbreak setting. In a recent prospective observational study during the outbreak of acute hepatitis A among MSM in Taiwan, the overall seroconversion rate among HIV-positive MSM was 39.7% and 93.4% after receiving 1 dose and completing 2-dose series of HAV vaccination, respectively. Despite the delayed serological response, HAV vaccination had led to a 93% reduction in the risk of acute HAV infection among HIV-positive MSM during the outbreak setting. Higher CD4 cell counts were consistently correlated with higher seroconversion rates[131].

Studies published after the meta-analysis in 2006 made various attempts to augment the immune response to the inactivated HAV vaccine despite the aforementioned non-modifiable adverse factors. One attempt was by using a virosome-formulated HAV vaccine (Epaxal1, Berna Biotech Ltd.) to enhance the immune responses of 14 HIV-positive individuals compared to 64 healthy adults[132]. After a primary dose at day 1 and a booster dose 12 mo later, the seroconversion rates (anti-HAV IgG > 20 mIU/mL) at month 13 were 91.7% and 100% in HIV-positive adults and in healthy adults, respectively. The GMTs of anti-HAV increased from 25.5 mIU/mL after the primary immunization to 659.2 mIU/mL after the booster dose in HIV-positive adults[132].

Other attempts were by increasing the number of doses of vaccine administered[115,120,121]. Two doses over 1 dose of HIV vaccine increased seroconversion rates in HIV-positive individuals[121,123,124]. There is less convincing evidence to show that 3 doses over 2 doses further increased seroconversion rates, possibly due to the smaller margin of benefit and the relatively larger sample size of adequate power needed to demonstrate the benefit. However, 2 studies showed trends of augmented responses in terms of seroconversion rates and GMTs by adding a booster dose at week 4 sandwiched between the first dose and the second dose at week 24[115,120]. In the intention-to-treat (ITT) analysis, seroconversion at week 28 was observed in 82.6% vs 69.4% (p = 0.13) and at week 48 in 84.2% vs 78.1% (p = 0.23) in the 3-dose vs the 2-dose group for the French and Taiwanese studies, respectively.

When multiple doses have been used, the timing of the second and third dose did not affect immunogenicity in persons with limited immunodeficiency[125]. Hence, in the outbreak settings, an accelerated schedule, i.e., delivering the second or third booster dose at an interval of less than 3 mo from the first dose may be preferable although more studies are needed[131]. However, in HIV-positive individuals with more advanced immunodeficiency (CD4 < 300 cells/mm3 or AIDS status), it may be preferable to wait for the CD4 count to recover before delivering the booster doses[123,127]. In the most primitive example, of the 2 HIV-positive hemophiliacs with CD4 counts below 100 cells/mm3 who, after the third dose of HAVRIX 720 U, went on to receive a fourth booster dose of HAVRIX 1440 U, neither seroconverted[127].

To our knowledge, there is limited experience with using HAV vaccination as post-exposure prophylaxis in HIV-positive individuals. Although in healthy individuals, HAV vaccine has been demonstrated to be capable of protecting susceptible contacts with benefits of long-term protection when compared to passive immunization by immunoglobulins[133].

Durability of seroprotection and factors associated with persistent seroprotection

In healthy adults following a primary 2-dose schedule, mathematical models indicate that anti-HAV antibodies may persist in > 90% of vaccinees for 40 years or more[134]. In HIV-positive individuals, a slight decrease was observed over time; 88.6%-100% of responders were still seroprotected after 1 year[115,120], 86.8%-90% after 3 years[135,136], 85%-85.4% after 4 years[136,137], and 75.5%-88.4% after 5 years[135,136,138]. Percentages of seroprotection at the end of 5 years of follow-up were 78.9% vs 76.4% by ITT analysis (p = 0.61) (Table 8)[135-138]. GMTs were significantly higher throughout each consecutive year with the 3-dose schedule as compared to the standard 2-dose schedule[136]. Factors associated with persistent seroprotection include virologic suppression at vaccination and maintained lower levels of HIV viremia as denoted by time-updated plasma HIV RNA load[135,137], 3-dose compared to 2-dose schedule (adjusted odds ratio 3.36; 95%CI: 1.14-9.93), acute syphilis and absence of acute hepatitis C[136,138].

Table 8 Long-term response rates and predictors of sustained seroprotection after hepatitis A virus vaccination in human immunodeficiency virus-positive patients.
Ref.DatesDesign/CountryNo. of patient1HAV/dosing schedules (mo)CD4, cells/mm3PVL, log10, copies/mLART (%)Timing of assay2, yr/cut-off3, mIU/mL/AssayResponse rate (%): ITT/PPPredictors of persistent response and comments4
Cheng et al[136]2010-2015Prospective, TaiwanPrimary responders:HAVRIX 1440 U/560/4152.5/2.870/562, 3, 4, 5/20At 1.5 yr:MSM only study; 3-doses over 2-dose, syphilis, lack of acute HCV
2 doses, 1102 doses (0, 6)ELISA (ETIAB- HAVK PLUS)2 doses: 90.0/93.4
3 doses, 1853 doses (0, 1, 6)3 doses: 87.0/94.7
Non-470/3152.9/3.359/63At 5 yr:
responders:2 doses: 76.4/88.4
2 doses, 163 doses: 78.9/94.2
3 doses, 23
Kernéis et al[137]2006-2009Prospective, FrancePrimary responders:HAVRIX 1440/36262%5NA7, 43/20At 3.7 yr:PVL < 50 copies/mL at time of last vaccine dose and a short duration of HIV infection
71 (52)2 doses (0, 6)ELISA (ETIAB-Overall: 61.9/84.6
3 doses (0, 1, 6)HAVK PLUS)
Jablonowska et al[138]2004Prospective, PolandPrimary responders:HAVRIX 1440450NA371.5, 5/20At 1.5 yr:Lack of co-infection with HCV
66(0, 6)CIA (Cobas, Roche)75.8/81.9
At 5 yr:
56.1/75.5
Crum-Cianflone et al[135]1996-2003Retrospective, United States116Vaqta 50 or HAVRIX 1440 (0, 6-18)Median, 46750%5623, 6-10/10At 3 yr:Lower PVL; PVL < 400 copies/mL
90
At 6-10 yr:
85

Given the lower initial antibody levels, the apparent waning of antibody levels and the increasing life expectancy of HIV-positive individuals, post-vaccination booster doses may be necessary to maintain anti-HAV levels after 10 years in HIV-positive individuals in the absence of virologic suppression[111]. Currently, only the British HIV Association (BHIVA) recommends delivering booster vaccination every 10 years whilst other health authorities recommend regular monitoring of anti-HAV IgG and booster vaccinations only if at continued risk after seroconversion (Table 6)[111-114]. However, among immunocompetent hosts, memory responses to HAV may exist even in the absence of detectable antibodies[139], and in the era of cART, the same may apply to HIV-positive patients with immune reconstitution[131]. Nevertheless, the strategies of booster HAV vaccination to those with waning immunity or non-responders need more studies to confirm the effectiveness.

Vaccine safety

Serious adverse events following HAV vaccination in HIV-positive individuals are rare and not more common among HIV-positive individuals compared to HIV-negative vaccinees. HAV vaccination does not have a significant impact on plasma HIV RNA load, progression to AIDS, or CD4 cell count[123,124,130].

CONCLUSION

In this review, we have found that, in developed countries of low HAV endemicity, HIV-positive individuals remain susceptible to HAV infection because of low adherence to recommended HAV vaccination, at-risk sexual behaviors, and injecting drug use, as demonstrated by the recent outbreaks of acute HAV infections among MSM and IDUs in Taiwan and Israel, respectively[71,88], despite the implementation of HAV vaccination programs in children. Serological response rates to the recommended 2-dose HAV vaccination are lower in HIV-positive individuals than HIV-negative individuals; an additional dose of HAV vaccine may improve serological responses and durability of seroprotection in HIV-positive individuals with initial low CD4 cell counts. While clinical trials are warranted to confirm the HAV vaccine efficacy in the outbreak setting of acute HAV infection, the recent observational study suggested that implementation of the 2-dose HAV vaccination was effective in preventing acute HAV infection among MSM. With ongoing improvements in survival and quality of life with modern cART, the importance of awareness of and adherence to HAV vaccination recommendations cannot be overemphasized among health care providers as well as at-risk populations.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Saudi Arabia

Peer-review report classification

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P- Reviewer: Castiella A, Otsuka M S- Editor: Ma YJ L- Editor: A E- Editor: Wang CH

References
1.  Havelaar AH, Kirk MD, Torgerson PR, Gibb HJ, Hald T, Lake RJ, Praet N, Bellinger DC, de Silva NR, Gargouri N. World Health Organization global estimates and regional comparisons of the burden of foodborne disease in 2010. PLoS Med. 2015;12:e1001923.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 641]  [Cited by in F6Publishing: 277]  [Article Influence: 106.8]  [Reference Citation Analysis (0)]
2.  Aggarwal R, Goel A. Hepatitis A: epidemiology in resource-poor countries. Curr Opin Infect Dis. 2015;28:488-496.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 10]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
3.  Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine. 2010;28:6653-6657.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 315]  [Cited by in F6Publishing: 179]  [Article Influence: 28.6]  [Reference Citation Analysis (0)]
4.  Nelson NP, Murphy TV. Hepatitis A: The changing epidemiology of hepatitis A. Clin Liver Dis (Hoboken). 2013;2:227-230.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 5]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
5.  Mena G, García-Basteiro AL, Bayas JM. Hepatitis B and A vaccination in HIV-infected adults: A review. Hum Vaccin Immunother. 2015;11:2582-2598.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 28]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
6.  Feinstone SM, Kapikian AZ, Purceli RH. Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science. 1973;182:1026-1028.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Robertson BH, Jansen RW, Khanna B, Totsuka A, Nainan OV, Siegl G, Widell A, Margolis HS, Isomura S, Ito K. Genetic relatedness of hepatitis A virus strains recovered from different geographical regions. J Gen Virol. 1992;73:1365-1377.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 332]  [Cited by in F6Publishing: 218]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
8.  Costa-Mattioli M, Cristina J, Romero H, Perez-Bercof R, Casane D, Colina R, Garcia L, Vega I, Glikman G, Romanowsky V. Molecular evolution of hepatitis A virus: a new classification based on the complete VP1 protein. J Virol. 2002;76:9516-9525.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Lu L, Ching KZ, de Paula VS, Nakano T, Siegl G, Weitz M, Robertson BH. Characterization of the complete genomic sequence of genotype II hepatitis A virus (CF53/Berne isolate). J Gen Virol. 2004;85:2943-2952.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 56]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
10.  Nainan OV, Armstrong GL, Han XH, Williams I, Bell BP, Margolis HS. Hepatitis a molecular epidemiology in the United States, 1996-1997: sources of infection and implications of vaccination policy. J Infect Dis. 2005;191:957-963.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 38]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
11.  Tjon GM, Wijkmans CJ, Coutinho RA, Koek AG, van den Hoek JA, Leenders AC, Schneeberger PM, Bruisten SM. Molecular epidemiology of hepatitis A in Noord-Brabant, The Netherlands. J Clin Virol. 2005;32:128-136.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 22]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
12.  McFarlane ES, Embil JA, Manuel FR, Thiébaux HJ. Antibodies to hepatitis A antigen in relation to the number of lifetime sexual partners in patients attending an STD clinic. Br J Vener Dis. 1981;57:58-61.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Villano SA, Nelson KE, Vlahov D, Purcell RH, Saah AJ, Thomas DL. Hepatitis A among homosexual men and injection drug users: more evidence for vaccination. Clin Infect Dis. 1997;25:726-728.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Ochnio JJ, Patrick D, Ho M, Talling DN, Dobson SR. Past infection with hepatitis A virus among Vancouver street youth, injection drug users and men who have sex with men: implications for vaccination programs. CMAJ. 2001;165:293-297.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Corey L, Holmes KK. Sexual transmission of hepatitis A in homosexual men: incidence and mechanism. N Engl J Med. 1980;302:435-438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 148]  [Cited by in F6Publishing: 23]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
16.  Kryger P, Pedersen NS, Mathiesen L, Nielsen JO. Increased risk of infection with hepatitis A and B viruses in men with a history of syphilis: relation to sexual contacts. J Infect Dis. 1982;145:23-26.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Coutinho RA, Albrecht-van Lent P, Lelie N, Nagelkerke N, Kuipers H, Rijsdijk T. Prevalence and incidence of hepatitis A among male homosexuals. Br Med J (Clin Res Ed). 1983;287:1743-1745.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Katz MH, Hsu L, Wong E, Liska S, Anderson L, Janssen RS. Seroprevalence of and risk factors for hepatitis A infection among young homosexual and bisexual men. J Infect Dis. 1997;175:1225-1229.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Corona R, Stroffolini T, Giglio A, Cotichini R, Tosti ME, Prignano G, Di Carlo A, Maini A, Mele A. Lack of evidence for increased risk of hepatitis A infection in homosexual men. Epidemiol Infect. 1999;123:89-93.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Bialek SR, Barry V, Bell BP, Valleroy LA, Behel S, Mackellar DA, Secura G, Thiede H, McFarland W, Ford WL. Seroprevalence and correlates of hepatitis a among HIV-negative American men who have sex with men. Sex Health. 2011;8:343-348.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 6]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
21.  Ross JD, Ghanem M, Tariq A, Gilleran G, Winter AJ. Seroprevalence of hepatitis A immunity in male genitourinary medicine clinic attenders: a case control study of heterosexual and homosexual men. Sex Transm Infect. 2002;78:174-179.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Crofts N, Cooper G, Stewart T, Kiely P, Coghlan P, Hearne P, Hocking J. Exposure to hepatitis A virus among blood donors, injecting drug users and prison entrants in Victoria. J Viral Hepat. 1997;4:333-338.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Removille N, Origer A, Couffignal S, Vaillant M, Schmit JC, Lair ML. A hepatitis A, B, C and HIV prevalence and risk factor study in ever injecting and non-injecting drug users in Luxembourg associated with HAV and HBV immunisations. BMC Public Health. 2011;11:351.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 16]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
24.  Franco E, Giambi C, Ialacci R, Coppola RC, Zanetti AR. Risk groups for hepatitis A virus infection. Vaccine. 2003;21:2224-2233.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Ida S, Tachikawa N, Nakajima A, Daikoku M, Yano M, Kikuchi Y, Yasuoka A, Kimura S, Oka S. Influence of human immunodeficiency virus type 1 infection on acute hepatitis A virus infection. Clin Infect Dis. 2002;34:379-385.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 48]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
26.  Nandwani R, Caswell S, Boag F, Lawrence AG, Coleman JC. Hepatitis A seroprevalence in homosexual and heterosexual men. Genitourin Med. 1994;70:325-328.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Fainboim H, González J, Fassio E, Martínez A, Otegui L, Eposto M, Cahn P, Marino R, Landeira G, Suaya G. Prevalence of hepatitis viruses in an anti-human immunodeficiency virus-positive population from Argentina. A multicentre study. J Viral Hepat. 1999;6:53-57.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Aloise R, de Almeida AJ, Sion FS, Morais-de-Sá CA, Gaspar AM, de Paula VS. Changes in hepatitis A virus seroepidemiology in HIV-infected Brazilian patients. Int J STD AIDS. 2008;19:321-326.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 2]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
29.  Lee HC, Ko NY, Lee NY, Chang CM, Ko WC. Seroprevalence of viral hepatitis and sexually transmitted disease among adults with recently diagnosed HIV infection in Southern Taiwan, 2000-2005: upsurge in hepatitis C virus infections among injection drug users. J Formos Med Assoc. 2008;107:404-411.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 17]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
30.  Sun HY, Kung HC, Ho YC, Chien YF, Chen MY, Sheng WH, Hsieh SM, Wu CH, Liu WC, Hung CC. Seroprevalence of hepatitis A virus infection in persons with HIV infection in Taiwan: implications for hepatitis A vaccination. Int J Infect Dis. 2009;13:e199-e205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 10]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
31.  Davoudi S, Rasoolinejad M, Jafari S, Erfanzadeh M, Foroughi M, Hajiabdolbaghi M, Mohraz M. Prevalence of hepatitis A virus infection in a HIV positive community. Acta Med Iran. 2010;48:192-195.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Hoover KW, Butler M, Workowski KA, Follansbee S, Gratzer B, Hare CB, Johnston B, Theodore JL, Tao G, Smith BD. Low rates of hepatitis screening and vaccination of HIV-infected MSM in HIV clinics. Sex Transm Dis. 2012;39:349-353.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 14]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
33.  Linkins RW, Chonwattana W, Holtz TH, Wasinrapee P, Chaikummao S, Varangrat A, Tongtoyai J, Mock PA, Curlin ME, Sirivongrangson P. Hepatitis A and hepatitis B infection prevalence and associated risk factors in men who have sex with men, Bangkok, 2006-2008. J Med Virol. 2013;85:1499-1505.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 11]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
34.  Baek JH, Kim CO, Park JY, Jeong SJ, Koo NS, Kim HW, Han SH, Choi JY, Song YG, Kim JM. Clinical factors associated with hepatitis A virus seropositivity in HIV-infected adults living in a country with an epidemiologic shift for hepatitis A virus infection. J Korean Med Sci. 2012;27:969-971.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 3]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
35.  Tseng YT, Sun HY, Chang SY, Wu CH, Liu WC, Wu PY, Lu CL, Hsieh CY, Hung CC. Seroprevalence of hepatitis virus infection in men who have sex with men aged 18-40 years in Taiwan. J Formos Med Assoc. 2012;111:431-438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 28]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
36.  Kourkounti S, Paparizos V, Leuow K, Kyriakis K, Antoniou C. Prevalence and titre of antibodies against Hepatitis A virus in HIV-infected men having sex with men in Greece. Infez Med. 2014;22:206-212.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Diamond C, Thiede H, Perdue T, Secura GM, Valleroy L, Mackellar D, Corey L. Viral hepatitis among young men who have sex with men: prevalence of infection, risk behaviors, and vaccination. Sex Transm Dis. 2003;30:425-432.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  O’Riordan M, Goh L, Lamba H. Increasing hepatitis A IgG prevalence rate in men who have sex with men attending a sexual health clinic in London: implications for immunization policy. Int J STD AIDS. 2007;18:707-710.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 8]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
39.  Van Rijckevorsel GG, Sonder GJ, Bovée LP, Thiesbrummel HF, Geskus RB, Van Den Hoek A. Trends in hepatitis A, B, and shigellosis compared with gonorrhea and syphilis in men who have sex with men in Amsterdam, 1992-2006. Sex Transm Dis. 2008;35:930-934.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 1]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
40.  Bozicevic I, Rode OD, Lepej SZ, Johnston LG, Stulhofer A, Dominkovic Z, Bacak V, Lukas D, Begovac J. Prevalence of sexually transmitted infections among men who have sex with men in Zagreb, Croatia. AIDS Behav. 2009;13:303-309.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 10]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
41.  Weerakoon AP, Chen MY, Read TR, Bradshaw C, Fairley CK. Immunity to hepatitis A when outbreaks of infection in men who have sex with men (MSM) are rare. Vaccine. 2012;30:3430-3434.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 9]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
42.  Ali H, Regan DG, Guy RJ, Robertson P, Watchirs-Smith L, McNulty AM, Donovan B. Increasing hepatitis A immunity in men who have sex with men in Sydney, 1996-2012. Vaccine. 2015;33:4745-4747.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 4]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
43.  Høybye G, Skinhøj P, Hentzer B, Faber V, Mathiesen L. An epidemic of acute viral hepatitis in male homosexuals. Etiology and clinical characteristics. Scand J Infect Dis. 1980;12:241-244.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Christenson B, Broström C, Böttiger M, Hermanson J, Weiland O, Ryd G, Berg JV, Sjöblom R. An epidemic outbreak of hepatitis A among homosexual men in Stockholm. Hepatitis A, a special hazard for the male homosexual subpopulation in Sweden. Am J Epidemiol. 1982;116:599-607.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Mindel A, Tedder R. Hepatitis A in homosexuals. Br Med J (Clin Res Ed). 1981;282:1666.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Kani J, Nandwani R, Gilson RJ, Johnson AM, Maguire HC, Tedder RS. Hepatitis A virus infection among homosexual men. BMJ. 1991;302:1399.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Atkins M, Zambon M, Watkins P. Hepatitis A virus infection. Should susceptible homosexual men be offered immunization. BMJ. 1993;307:562.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Leentvaar-Kuijpers A, Kool JL, Veugelers PJ, Coutinho RA, van Griensven GJ. An outbreak of hepatitis A among homosexual men in Amsterdam, 1991-1993. Int J Epidemiol. 1995;24:218-222.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Walsh B, Sundkvist T, Maguire H, Young Y, Heathcock R, Iverson A. Rise in hepatitis A among gay men in the Thames regions 1995 and 1996. Genitourin Med. 1996;72:449-450.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Stene-Johansen K, Jenum PA, Hoel T, Blystad H, Sunde H, Skaug K. An outbreak of hepatitis A among homosexuals linked to a family outbreak. Epidemiol Infect. 2002;129:113-117.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Bell A, Ncube F, Hansell A, Davison KL, Young Y, Gilson R, Macdonald N, Heathcock R, Warburton F, Maguire H. An outbreak of hepatitis A among young men associated with having sex in public venues. Commun Dis Public Health. 2001;4:163-170.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Manfredi R, Calza L, Chiodo F. Changing epidemiology of hepatitis A in the Bologna metropolitan area, northern Italy: importance of counselling and prophylactic measures for the male homo/bisexual population. Clin Microbiol Infect. 2005;11:845-848.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 7]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
53.  Mazick A, Howitz M, Rex S, Jensen IP, Weis N, Katzenstein TL, Haff J, Molbak K. Hepatitis A outbreak among MSM linked to casual sex and gay saunas in Copenhagen, Denmark. Euro Surveill. 2005;10:111-114.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Girardi E, Scognamiglio P, Sciarrone MR, Loffredo M, Gnesivo C, Noto P, Antonucci G, Capobianchi MR, Ippolito G. High HIV prevalence in male patients with acute hepatitis A in the Rome metropolitan area, Italy 2002-2008. J Hepatol. 2011;54:1102-1106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 6]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
55.  Bordi L, Rozera G, Scognamiglio P, Minosse C, Loffredo M, Antinori A, Narciso P, Ippolito G, Girardi E, Capobianchi MR. Monophyletic outbreak of Hepatitis A involving HIV-infected men who have sex with men, Rome, Italy 2008-2009. J Clin Virol. 2012;54:26-29.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 25]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
56.  Tortajada C, de Olalla PG, Diez E, Pinto RM, Bosch A, Perez U, Sanz M, Caylà JA. Hepatitis A among men who have sex with men in Barcelona, 1989-2010: insufficient control and need for new approaches. BMC Infect Dis. 2012;12:11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 12]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
57.  Dabrowska MM, Nazzal K, Wiercinska-Drapalo A. Hepatitis A and hepatitis A virus/HIV coinfection in men who have sex with men, Warsaw, Poland, September 2008 to September 2009. Euro Surveill. 2011;16.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Tortajada C, de Olalla PG, Pinto RM, Bosch A, Caylà J. Outbreak of hepatitis A among men who have sex with men in Barcelona, Spain, September 2008-March 2009. Euro Surveill. 2009;14.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Sfetcu O, Irvine N, Ngui SL, Emerson C, McCaughey C, Donaghy P. Hepatitis A outbreak predominantly affecting men who have sex with men in Northern Ireland, October 2008 to July 2009. Euro Surveill. 2011;16.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Taffon S, Bidini G, Vichi F, Corti G, Genovese D, Kondili LA, Bindi R, Armellini F, Leoncini F, Bartoloni A. A unique HAV strain circulated in patients with acute HAV infection with different risk exposures in Tuscany, Italy. J Clin Virol. 2011;50:142-147.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 14]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
61.  Kosatsky T, Middaugh JP. Linked outbreaks of hepatitis A in homosexual men and in food service patrons and employees. West J Med. 1986;144:307-310.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Desenclos JC, MacLafferty L. Community wide outbreak of hepatitis A linked to children in day care centres and with increased transmission in young adult men in Florida 1988-9. J Epidemiol Community Health. 1993;47:269-273.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Henning KJ, Bell E, Braun J, Barker ND. A community-wide outbreak of hepatitis A: risk factors for infection among homosexual and bisexual men. Am J Med. 1995;99:132-136.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Allard R, Beauchemin J, Bédard L, Dion R, Tremblay M, Carsley J. Hepatitis A vaccination during an outbreak among gay men in Montréal, Canada, 1995-1997. J Epidemiol Community Health. 2001;55:251-256.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Centers for Disease Control and Prevention (CDC). Hepatitis A vaccination of men who have sex with men--Atlanta, Georgia, 1996-1997. MMWR Morb Mortal Wkly Rep. 1998;47:708-711.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Cotter SM, Sansom S, Long T, Koch E, Kellerman S, Smith F, Averhoff F, Bell BP. Outbreak of hepatitis A among men who have sex with men: implications for hepatitis A vaccination strategies. J Infect Dis. 2003;187:1235-1240.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 33]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
67.  Stewart T, Crofts N. An outbreak of hepatitis A among homosexual men in Melbourne. Med J Aust. 1993;158:519-521.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Stokes ML, Ferson MJ, Young LC. Outbreak of hepatitis A among homosexual men in Sydney. Am J Public Health. 1997;87:2039-2041.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Ferson MJ, Young LC, Stokes ML. Changing epidemiology of hepatitis A in the 1990s in Sydney, Australia. Epidemiol Infect. 1998;121:631-636.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Delpech VC, Thackway SV, Young L, Pontivivo G, Smedley E, Morgan K, Ferson MJ. Hepatitis A in south-eastern Sydney 1997-1999: continuing concerns for gay men and an outbreak among illicit drug users. Commun Dis Intell. 2000;24:203-206.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Chen GJ, Lin KY, Hung CC, Chang SC. Hepatitis A outbreak among men who have sex with men in a country of low endemicity of hepatitis A infection. J Infect Dis. 2017;215:1339-1340.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 16]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
72.  Stene-Johansen K, Tjon G, Schreier E, Bremer V, Bruisten S, Ngui SL, King M, Pinto RM, Aragonès L, Mazick A. Molecular epidemiological studies show that hepatitis A virus is endemic among active homosexual men in Europe. J Med Virol. 2007;79:356-365.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 36]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
73.  Urbanus AT, van Houdt R, van de Laar TJ, Coutinho RA. Viral hepatitis among men who have sex with men, epidemiology and public health consequences. Euro Surveill. 2009;14.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Widell A, Hansson BG, Moestrup T, Serléus Z, Mathiesen LR, Johnsson T. Acute hepatitis A, B and non-A, non-B in a Swedish community studied over a ten-year period. Scand J Infect Dis. 1982;14:253-259.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Sundkvist T, Johansson B, Widell A. Rectum carried drugs may spread hepatitis A among drug addicts. Scand J Infect Dis. 1985;17:1-4.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Leino T, Leinikki P, Hyypiä T, Ristola M, Suni J, Sutinen J, Holopainen A, Haikala O, Valle M, Rostila T. Hepatitis A outbreak amongst intravenous amphetamine abusers in Finland. Scand J Infect Dis. 1997;29:213-216.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Stene-Johansen K, Skaug K, Blystad H, Grinde B. A unique hepatitis A virus strain caused an epidemic in Norway associated with intravenous drug abuse. The Hepatitis A Study Group. Scand J Infect Dis. 1998;30:35-38.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  O’Donovan D, Cooke RP, Joce R, Eastbury A, Waite J, Stene-Johansen K. An outbreak of hepatitis A amongst injecting drug users. Epidemiol Infect. 2001;127:469-473.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Syed NA, Hearing SD, Shaw IS, Probert CS, Brooklyn TN, Caul EO, Barry RE, Sarangi J. Outbreak of hepatitis A in the injecting drug user and homeless populations in Bristol: control by a targeted vaccination programme and possible parenteral transmission. Eur J Gastroenterol Hepatol. 2003;15:901-906.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Roy K, Howie H, Sweeney C, Parry J, Molyneaux P, Goldberg D, Taylor A. Hepatitis A virus and injecting drug misuse in Aberdeen, Scotland: a case-control study. J Viral Hepat. 2004;11:277-282.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 10]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
81.  Spada E, Genovese D, Tosti ME, Mariano A, Cuccuini M, Proietti L, Giuli CD, Lavagna A, Crapa GE, Morace G. An outbreak of hepatitis A virus infection with a high case-fatality rate among injecting drug users. J Hepatol. 2005;43:958-964.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 31]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
82.  Harkess J, Gildon B, Istre GR. Outbreaks of hepatitis A among illicit drug users, Oklahoma, 1984-87. Am J Public Health. 1989;79:463-466.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Centers for Disease Control (CDC). Hepatitis A among drug abusers. MMWR Morb Mortal Wkly Rep. 1988;37:297-300, 305.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Jin A, Bardsley J. Intravenous drug use and hepatitis A: an investigation of an outbreak. Can J Public Health. 1990;81:79-81.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Hutin YJ, Sabin KM, Hutwagner LC, Schaben L, Shipp GM, Lord DM, Conner JS, Quinlisk MP, Shapiro CN, Bell BP. Multiple modes of hepatitis A virus transmission among methamphetamine users. Am J Epidemiol. 2000;152:186-192.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Vong S, Fiore AE, Haight DO, Li J, Borgsmiller N, Kuhnert W, Pinero F, Boaz K, Badsgard T, Mancini C. Vaccination in the county jail as a strategy to reach high risk adults during a community-based hepatitis A outbreak among methamphetamine drug users. Vaccine. 2005;23:1021-1028.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 11]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
87.  Shaw DD, Whiteman DC, Merritt AD, el-Saadi DM, Stafford RJ, Heel K, Smith GA. Hepatitis A outbreaks among illicit drug users and their contacts in Queensland, 1997. Med J Aust. 1999;170:584-587.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Manor Y, Lewis M, Ram D, Daudi N, Mor O, Savion M, Kra-Oz Z, Shemer Avni Y, Sheffer R, Shouval D. Evidence for Hepatitis A virus endemic circulation in Israel despite universal toddlers’ vaccination since 1999 and low clinical incidence in all age groups. J Infect Dis. 2016; Epub ahead of print.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
89.  Grinde B, Stene-Johansen K, Sharma B, Hoel T, Jensenius M, Skaug K. Characterisation of an epidemic of hepatitis A virus involving intravenous drug abusers--infection by needle sharing? J Med Virol. 1997;53:69-75.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Naef MR, Bucher HC, Erb P, Gyr N, Bassetti S, Battegay M. Reduced infections with HIV and hepatitis A during a Swiss intravenous opiate maintenance program. J Acquir Immune Defic Syndr. 1999;21:349-351.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Istre GR, Hopkins RS. An outbreak of foodborne hepatitis A showing a relationship between dose and incubation period. Am J Public Health. 1985;75:280-281.  [PubMed]  [DOI]  [Cited in This Article: ]
92.  Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. J Infect Dis. 1995;171 Suppl 1:S15-S18.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Lee EJ, Kwon SY, Seo TH, Yun HS, Cho HS, Kim BK, Choe WH, Lee CH, Kim JN, Yim HJ. [Clinical features of acute hepatitis A in recent two years]. Korean J Gastroenterol. 2008;52:298-303.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Tekin R, Yolbas I, Dal T, Demirpençe Ö, Kaya S, Bozkurt F, Deveci Ö, Çelen MK, Tekin A. Evaluation of adults with acute viral hepatitis a and review of the literature. Clin Ter. 2013;164:537-541.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
95.  Dahanayaka NJ, Kiyohara T, Agampodi SB, Samaraweera PK, Kulasooriya GK, Ranasinghe JC, Semage SN, Yoshizaki S, Wakita T, Ishii K. Clinical features and transmission pattern of hepatitis A: An experience from a hepatitis A outbreak caused by two cocirculating genotypes in Sri Lanka. Am J Trop Med Hyg. 2016;95:908-914.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 2]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
96.  Routenberg JA, Dienstag JL, Harrison WO, Kilpatrick ME, Hooper RR, Chisari FV, Purcell RH, Fornes MF. Foodborne outbreak of hepatitis A: clinical and laboratory features of acute and protracted illness. Am J Med Sci. 1979;278:123-137.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Ford JC. Infective Hepatitis. 300 Cases in an Outer London Borough. Lancet. 1943;241:675-678.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Hyun JJ, Seo YS, An H, Yim SY, Seo MH, Kim HS, Kim CH, Kim JH, Keum B, Kim YS. Optimal time for repeating the IgM anti-hepatitis A virus antibody test in acute hepatitis A patients with a negative initial test. Korean J Hepatol. 2012;18:56-62.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 4]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
99.  Su CW, Wu JC, Huang YS, Huo TI, Huang YH, Lin CC, Chang FY, Lee SD. Comparison of clinical manifestations and epidemiology between acute hepatitis A and acute hepatitis E in Taiwan. J Gastroenterol Hepatol. 2002;17:1187-1191.  [PubMed]  [DOI]  [Cited in This Article: ]
100.  Hussain Z, Das BC, Husain SA, Polipalli SK, Ahmed T, Begum N, Medhi S, Verghese A, Raish M, Theamboonlers A. Virological course of hepatitis A virus as determined by real time RT-PCR: Correlation with biochemical, immunological and genotypic profiles. World J Gastroenterol. 2006;12:4683-4688.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 12]  [Cited by in F6Publishing: 6]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
101.  Alatrakchi N, Koziel M. Regulatory T cells and viral liver disease. J Viral Hepat. 2009;16:223-229.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 62]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
102.  Choi YS, Lee J, Lee HW, Chang DY, Sung PS, Jung MK, Park JY, Kim JK, Lee JI, Park H. Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis. Gut. 2015;64:1303-1313.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 23]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
103.  Chevalier MF, Weiss L. The split personality of regulatory T cells in HIV infection. Blood. 2013;121:29-37.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 136]  [Cited by in F6Publishing: 107]  [Article Influence: 15.1]  [Reference Citation Analysis (0)]
104.  Gupta E, Chakravarti A. Viral infections of the biliary tract. Saudi J Gastroenterol. 2008;14:158-160.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 5]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
105.  Mao JS, Yu PH, Ding ZS, Chen NL, Huang BZ, Xie RY, Chai SA. Patterns of shedding of hepatitis A virus antigen in feces and of antibody responses in patients with naturally acquired type A hepatitis. J Infect Dis. 1980;142:654-659.  [PubMed]  [DOI]  [Cited in This Article: ]
106.  Tjon GM, Coutinho RA, van den Hoek A, Esman S, Wijkmans CJ, Hoebe CJ, Wolters B, Swaan C, Geskus RB, Dukers N. High and persistent excretion of hepatitis A virus in immunocompetent patients. J Med Virol. 2006;78:1398-1405.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 16]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
107.  Kwon OS, Byun KS, Yeon JE, Park SH, Kim JS, Kim JH, Bak YT, Kim JH, Lee CH. Detection of hepatitis A viral RNA in sera of patients with acute hepatitis A. J Gastroenterol Hepatol. 2000;15:1043-1047.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Bower WA, Nainan OV, Han X, Margolis HS. Duration of viremia in hepatitis A virus infection. J Infect Dis. 2000;182:12-17.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 68]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
109.  Arteaga-Rodríguez A, Carrasco-Garrido P, de Andrés AL, de Miguel AG, Santos J, Jiménez-García R. Changes in the epidemiology of hepatitis A in Spain (2005-2008): trends of acute hepatitis A hospitalizations, comorbidities, and costs associated with the hospitalization. Eur J Gastroenterol Hepatol. 2010;22:1284-1289.  [PubMed]  [DOI]  [Cited in This Article: ]
110.  Vento S, Garofano T, Renzini C, Cainelli F, Casali F, Ghironzi G, Ferraro T, Concia E. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338:286-290.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 517]  [Cited by in F6Publishing: 74]  [Article Influence: 22.5]  [Reference Citation Analysis (0)]
111.  British HIV Association. BHIVA guidelines on the use of vaccines in HIV-positive adults. 2015.  Available from: http://www.bhiva.org/documents/Guidelines/Vaccination/2015-Vaccination-Guidelines.pdf.  [PubMed]  [DOI]  [Cited in This Article: ]
112.  European AIDS Clinical Society. EACS Treatment Guidelines updated. 2016.  Available from: http://www.eacsociety.org/files/guidelines_8.2-english.pdf.  [PubMed]  [DOI]  [Cited in This Article: ]
113.  Advisory Committee for Immunization Practices. Hepatitis A ACIP Vaccine Recommendations. 2017.  Available from: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5507a1.htm.  [PubMed]  [DOI]  [Cited in This Article: ]
114.  World Health Organization. Hepatitis A. 2017.  Available from: http://www.who.int/ith/vaccines/hepatitisA/en/.  [PubMed]  [DOI]  [Cited in This Article: ]
115.  Tseng YT, Chang SY, Liu WC, Sun HY, Wu CH, Wu PY, Lu CL, Hung CC, Chang SC. Comparative effectiveness of two doses versus three doses of hepatitis A vaccine in human immunodeficiency virus-infected and -uninfected men who have sex with men. Hepatology. 2013;57:1734-1741.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 24]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
116.  Mena G, García-Basteiro AL, Llupià A, Díez C, Costa J, Gatell JM, García F, Bayas JM. Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy. Vaccine. 2013;31:3668-3674.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 11]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
117.  Jimenez HR, Hallit RR, Debari VA, Slim J. Hepatitis A vaccine response in HIV-infected patients: are TWINRIX and HAVRIX interchangeable? Vaccine. 2013;31:1328-1333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 14]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
118.  Kourkounti S, Mavrianou N, Paparizos VA, Kyriakis K, Hatzivassiliou M, Kordosis T, Katsambas A. Immune response to hepatitis A vaccination in HIV-infected men in Greece. Int J STD AIDS. 2012;23:464-467.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 11]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
119.  Weinberg A, Allshouse AA, Mawhinney S, Canniff J, Benning L, Wentz EL, Minkoff H, Young M, Nowicki M, Greenblatt R. Responses to hepatitis A virus vaccine in HIV-infected women: effect of hormonal contraceptives and HIV disease characteristics. J Acquir Immune Defic Syndr. 2012;60:e15-e18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 2]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
120.  Launay O, Grabar S, Gordien E, Desaint C, Jegou D, Abad S, Girard PM, Bélarbi L, Guérin C, Dimet J. Immunological efficacy of a three-dose schedule of hepatitis A vaccine in HIV-infected adults: HEPAVAC study. J Acquir Immune Defic Syndr. 2008;49:272-275.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 14]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
121.  Overton ET, Nurutdinova D, Sungkanuparph S, Seyfried W, Groger RK, Powderly WG. Predictors of immunity after hepatitis A vaccination in HIV-infected persons. J Viral Hepat. 2007;14:189-193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 29]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
122.  Weissman S, Feucht C, Moore BA. Response to hepatitis A vaccine in HIV-positive patients. J Viral Hepat. 2006;13:81-86.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 33]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
123.  Wallace MR, Brandt CJ, Earhart KC, Kuter BJ, Grosso AD, Lakkis H, Tasker SA. Safety and immunogenicity of an inactivated hepatitis A vaccine among HIV-infected subjects. Clin Infect Dis. 2004;39:1207-1213.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 40]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
124.  Kemper CA, Haubrich R, Frank I, Dubin G, Buscarino C, McCutchan JA, Deresinski SC. Safety and immunogenicity of hepatitis A vaccine in human immunodeficiency virus-infected patients: a double-blind, randomized, placebo-controlled trial. J Infect Dis. 2003;187:1327-1331.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 46]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
125.  Neilsen GA, Bodsworth NJ, Watts N. Response to hepatitis A vaccination in human immunodeficiency virus-infected and -uninfected homosexual men. J Infect Dis. 1997;176:1064-1067.  [PubMed]  [DOI]  [Cited in This Article: ]
126.  Wilde JT, Rymes N, Skidmoe S, Swann M, Linin J. Hepatitis A immunization in HIV-infected haemophilic patients. Haemophilia. 1995;1:196-199.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
127.  Tilzey AJ, Palmer SJ, Harrington C, O’Doherty MJ. Hepatitis A vaccine responses in HIV-positive persons with haemophilia. Vaccine. 1996;14:1039-1041.  [PubMed]  [DOI]  [Cited in This Article: ]
128.  Hess G, Clemens R, Bienzle U, Schönfeld C, Schunck B, Bock HL. Immunogenicity and safety of an inactivated hepatitis A vaccine in anti-HIV positive and negative homosexual men. J Med Virol. 1995;46:40-42.  [PubMed]  [DOI]  [Cited in This Article: ]
129.  Santagostino E, Gringeri A, Rocino A, Zanetti A, de Biasi R, Mannucci PM. Patterns of immunogenicity of an inactivated hepatitis A vaccine in anti-HIV positive and negative hemophilic patients. Thromb Haemost. 1994;72:508-510.  [PubMed]  [DOI]  [Cited in This Article: ]
130.  Shire NJ, Welge JA, Sherman KE. Efficacy of inactivated hepatitis A vaccine in HIV-infected patients: a hierarchical bayesian meta-analysis. Vaccine. 2006;24:272-279.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 32]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
131.  Lin KY, Hsieh SM, Sun HY, Lo YC, Sheng WH, Chuang YC, Pan SC, Hung CC, Chang SC.  Effectiveness of HAV vaccination among HIV-positive patients during an acute hepatitis A outbreak. the 22th Conference of Retroviruses and Opportunistic Infections Abstract no 582. 2017;.  [PubMed]  [DOI]  [Cited in This Article: ]
132.  Loutan L, Bovier P, Herzog C. Immunogenicity and safety of a virosomal hepatitis A vaccine in HIV-positive patients. Vaccine. 2007;25:6310-6312.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 3]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
133.  Victor JC, Monto AS, Surdina TY, Suleimenova SZ, Vaughan G, Nainan OV, Favorov MO, Margolis HS, Bell BP. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med. 2007;357:1685-1694.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 184]  [Cited by in F6Publishing: 27]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
134.  Theeten H, Van Herck K, Van Der Meeren O, Crasta P, Van Damme P, Hens N. Long-term antibody persistence after vaccination with a 2-dose Havrix (inactivated hepatitis A vaccine): 20 years of observed data, and long-term model-based predictions. Vaccine. 2015;33:5723-5727.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 35]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
135.  Crum-Cianflone NF, Wilkins K, Lee AW, Grosso A, Landrum ML, Weintrob A, Ganesan A, Maguire J, Klopfer S, Brandt C. Long-term durability of immune responses after hepatitis A vaccination among HIV-infected adults. J Infect Dis. 2011;203:1815-1823.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 29]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
136.  Cheng A, Chang SY, Sun HY, Tsai MS, Liu WC, Su YC, Wu PY, Hung CC, Chang SC. Long-term durability of responses to 2 or 3 doses of hepatitis A vaccination in human immunodeficiency virus-positive adults on antiretroviral therapy. J Infect Dis. 2017;215:606-613.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 4]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
137.  Kernéis S, Desaint C, Brichler S, Rey D, Belarbi L, Gordien E, Pacanowski J, Lortholary O, Abgrall S, Boëlle PY. Long-term persistence of humoral immunity after hepatitis A vaccination in HIV-infected adults. J Acquir Immune Defic Syndr. 2011;57:e63-e66.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 7]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
138.  Jabłonowska E, Kuydowicz J. Durability of response to vaccination against viral hepatitis A in HIV-infected patients: a 5-year observation. Int J STD AIDS. 2014;25:745-750.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 9]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
139.  Iwarson S. Are we giving too many doses of hepatitis A and B vaccines? Vaccine. 2002;20:2017-2018.  [PubMed]  [DOI]  [Cited in This Article: ]