Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: A review

Table 1 Seroprevalence of hepatitis A virus infection among human immunodeficiency virus-positive patients and at-risk populations

Ref.	Location	Study period	Study population	Age (yr)	HIV-positive population	Other populations	Associated factors1 and comments
HIV-positive population
Nandwani et al[26]	London, United Kingdom	1993	255 men attending genitourinary clinics	32	41.3%	MSM, 32.4%	No difference between homosexual and heterosexual men
						Heterosexuals, 30.0%
						Unknown HIV status, 26.4%
Fainboim et al[27]	Buenos Aires, Argentina	1994-1995	484 HIV-positive patients	29	84.0%	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, Brazil	1988-2004	581 HIV-positive patients	35	79.8%	NA	Older age and lower educational level
Lee et al[29]	Tainan, Taiwan	2000-2005	484 patients with recent diagnosed HIV infection	36	65.8%	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]	Taiwan	2004-2007	1580 HIV-positive patients	39	60.9%	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, Iran	2005-2006	247 HIV-positive patients	36	96.3%	NA
Hoover et al[32]	6 major cities2, United States	2004-2007	627 HIV-positive MSM	41	16.1%3	NA	Low HAV screening and vaccination rates (28.5%)
Linkins et al[33]	Bangkok, Thailand	2006-2008	1291 MSM	27	32.4%3	HIV-negative MSM, 25.5%	Older age and lower education level
Baek et al[34]	Seoul, South Korea	2008-2010	188 HIV-positive patients	39	62.8%	HIV-positive MSM, 57.1%	Older age
						HIV-positive heterosexuals, 65.8%
Tseng et al[35]	Taipei, Taiwan	2009-2010	1128 MSM	18-40	15.1%3	HIV-negative MSM, 7.4%	Older age
							No difference between HIV-positive and HIV-negative individuals
Kourkounti et al[36]	Athens, Greece	2007-2011	897 HIV-positive MSM	41	35.7%3	NA	Older age and being foreigners
At-risk populations (MSM and IDUs)
Corey et al[15]	Seattle, United States	1977-1979	159 patients from STD clinics	31	NA	MSM, 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, Canada	1977-1978	421 patients from STD clinics	25	NA	MSM, 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, Denmark	1979	269 men with previous syphilis	33	NA	MSM, 36.0%;	More episodes of syphilis in younger MSM
						Heterosexual, 20.0%
Coutinho et al[17]	Amsterdam, the Netherlands	1980-1982	689 MSM	31	NA	MSM, 42.0% (incidence, 14.0%)	Longer duration of homosexual activity
Crofts et al[22]	Victoria, Australia	1990-1992	2175 prison entrants	30	NA	IDU, 43.7%	History of incarceration
			293 IDUs			Prison entrants, 60.1%
						Blood donors, 30.0%
Katz et al[18]	San Francisco and Berkeley, United States	1992-1993	411 MSM	21	NA	MSM, 28.0%	Sexual and drug-using behaviors
Villano et al[13]	Baltimore, United States	1993-1994	294 MSM	NA	NA	MSM, 32.3%	Increased risk for HAV infection in MSM and IDUs
			292 IDUs			IDU, 66.4%
						Blood donors, 13.7%
Corona et al[19]	Rome, Italy	1997	432 male patients from STD clinics	NA	NA	MSM, 60.3%	Older age and more sexual partner
						Heterosexual, 62.2%
Ochnio et al[14]	Vancouver, Canada	1998	494 individuals from street outreach clinics	32	NA	MSM, 25.5%	Increased risk for HAV infection in MSM and IDUs
						IDU, 42.6%
						Street youth, 6.3%
Ross et al[21]	Birmingham, United Kingdom	2000	210 men attending genitourinary clinics	NA	NA	MSM, 23.0%; Heterosexual men, 32.0%	Ethnicity, older age, and history of sex in a sauna
Diamond et al[37]	Washington, United States	1997-2000	833 MSM	15-29	NA	MSM, 21.0%	Ethnicity, IDU, HBV and HIV infection
							Vaccination rate, 21%
Bialek et al[20]	7 major cities4, United States	1994-2000	2708 MSM	15-29	NA	MSM, 18.4%	More male sex partners and unprotected anal sex
O’Riordan et al[38]	London, United Kingdom	2004	395 MSM attending genitourinary clinics	NA	NA	MSM, 49.9%
Van Rijckevorsel et al[39]	Amsterdam, the Netherlands	1992-2006	1697 hepatitis A patients	NA	NA	Incidence, 0.97/1000 MSM	Clustered transmission in social MSM networks
Removille et al[23]	Luxembourg	2005	368 problem drug users	NA	NA	IDUs, 57.1%
						nIDUs, 65.9%
Bozicevic et al[40]	Zagreb, Croatia	2006	360 MSM	27	NA	MSM, 14.2%
Weerakoon et al[41]	Melbourne, Australia	2002-2011	3055 MSM	33	NA	MSM, 39.0%	Vaccination levels over 40%-50% to prevent outbreaks
Ali et al[42]	Sydney, Australia	1996-2012	14799 MSM	30	NA	MSM, 31.9% in 1996 to 63.8% in 2012	Vaccination rate, 9.8% in 1996 to 45.2% in 2012

¹Factors associated with HAV seropositivity were identified by bivariate or multivariable logistic regression analysis;

²The 6 major cities included Atlanta, Chicago, Los Angeles, Miami, New York City, and San Francisco;

³Only HIV-positive MSM were included;

⁴The 7 major cities included Baltimore, Dallas, Los Angeles, Miami, New York City, San Francisco, and Seattle. HAV: Hepatitis A virus; IDUs: Injecting drug users; MSM: Men who have sex with men; NA: Not available; nIDUs: Non-injecting drug users; STD: Sexually transmitted disease.

Table 2 Outbreaks of acute hepatitis A in the men who have sex with men population

Ref.	Location	Study period	Case number	Male	MSM	HIV-positive patients	Age (yr)	Risk factors1 and comments
	Europe
Høybye et al[43]	Copenhagen, Denmark	1977-1978	45	45	21	NA	29
Christenson et al[44]	Stockholm, Sweden	1979-1980	145	145	145	NA	NA	Multiple partners and oral-anal sexual contact
Mindel et al[45]	London, United Kingdom	1980	24	NA	23	NA	NA	HAV infection was associated with homosexual activity
Kani et al[46]	London, United Kingdom	1989-1990	7000	NA	41	NA	NA	Oral-anal sexual contact
Atkins et al[47]	London, United Kingdom	1989-1992	206	121	65	NA	NA	Oral-anal sexual contact and sexual promiscuity
Leentvaar-Kuijpers et al[48]	Amsterdam, the Netherlands	1992-1993	293	NA	39	NA	NA	Visiting saunas and darkrooms
Walsh et al[49]	Thames region, United Kingdom	1995	481	NA	58	NA	NA	Oral-anal and digital-rectal intercourse
Stene-Johansen et al[50]	Oslo, Norway	1995-1998	26	26	26	NA	NA
Bell et al[51]	London and East Sussex, United Kingdom	1997	48	NA	41	NA	NA	Eating shellfish and sex in gay saunas
Manfredi et al[52]	Bologna, Italy	1999-2004	122	104	81	11	28	Unprotected sexual contact
Mazick et al[53]	Copenhagen, Denmark	2004	18	18	18	NA	NA	Casual sex and sex in gay saunas
Girardi et al[54]	Rome, Italy	2002-2008	473	368	115	57	25-64	Same gender sex
								Routine HIV test in HAV-infected patients should be considered
Bordi et al[55]	Rome, Italy	2008-2010	162	143	34	14	36	Monophyletic HAV strain sustained the outbreak
Tortajada et al[56]	Barcelona, Spain	2002	48	47	NA	28%	31
		2003-2004	60	60	NA	24%	32
		2008-2009	189	185	NA	21%	33
Dabrowska et al[57]	Warsaw, Poland	2007-2008	860	NA	50	6	28	No difference in disease severity between HIV-positive and HIV-negative individuals
Tortajada et al[58]	Barcelona, Spain	2008-2009	150	126	87	NA	33
Sfetcu et al[59]	Northern Ireland, United Kingdom	2008-2009	38	36	26	NA	29	The outbreak strain was indistinguishable from that in Czech Republic
Taffon et al[60]	Tuscany, Italy	2008	240	NA	32%	NA	NA	A unique circulating HAV strain
	North America
Kosatsky et al[61]	Anchorage, Alaska	1982-1983	17	17	17	NA	19-31
Desenclos et al[62]	Florida, United States	1988-1989	311	69	26	NA	NA
Henning et al[63]	New York, United States	1991	180	180	62	NA	20-49	Anonymous sex partner, group sex, oral-anal and digital-rectal intercourse
Allard et al[64]	Montréal, Canada	1996-1997	376	376	376	NA	33	Vaccination campaign achieving 20%-41% coverage in MSM decreased incidence rapidly
Finton et al[65]	Atlanta, United States	1996	222	NA	75%	NA	NA	Vaccination campaign in MSM decreased reported cases
Cotter et al[66]	Ohio, United States	1998-1999	136	118	47	NA	33	Contact with hepatitis A cases
	Asia-Pacific region
Stewart et al[67]	Melbourne, Australia	1991	495	407	210	NA	NA	Sexual and social contact
Stokes et al[68]	Sydney, Australia	1991-1992	570	515	330	NA	31	Sexual contact was the most reported contact type
Ferson et al[69]	Sydney, Australia	1991-1996	1138	991	587	NA	30	Household or sexual contact
Delpech et al[70]	Sydney, Australia	1997-1999	354	265	139	NA	32
Chen et al[71]	Taiwan	2015-2016	> 1000	NA	> 70%	> 60%	NA	A total of 1296 cases reported as of February, 2017

¹Risk factors of acquiring HAV infection were identified by case-control studies. HAV: Hepatitis A virus; MSM: Men who have sex with men; NA: Not available.

Table 3 Outbreaks of acute hepatitis A in the injecting drug user population

Ref.	Location	Study period	Total patients	IDU	HIV-positive individuals	Age (yr)	Risk factors1 and comments
	Europe
Widell et al[74]	Malmo, Sweden	1970-1979	323	188	NA	NA
Sundkvist et al[75]	Helsingborg, Sweden	1983-1984	36	32	NA	18-35	The outbreak was associated with intrarectal transportation of illicit drugs
Leino et al[76]	Helsinki, Finland	1994-1995	238	131	NA	31	The outbreak was associated with intrarectal transportation of illicit drugs
Stene-Johansen et al[77]	Oslo, Norway	1995-1996	621	492	NA	NA	The outbreak was associated with needle sharing
O’Donovan et al[78]	United Kingdom	1998-1999	27	14	NA	25
Syed et al[79]	Bristol, United Kingdom	2000	123	69	NA	25	The outbreak was associated with parenteral transmission from contaminated illicit drugs; HAV vaccination of IDUs decreased the reported cases
Roy et al[80]	Aberdeen, Scotland	2000-2002	106	74	NA	NA	Not 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, Italy	2002-2003	47	35	2	34	Contact 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 States	1984-1987	79	42	NA	23-27
Jenkerson et al[83]	New York, United States	1986-1987	256	70	NA	NA
Jin et al[84]	Canada	1987-1989	65	59	NA	NA
Hutin et al[85]	Iowa, United States	1996-1997	158	9.7%	NA	NA	Methamphetamine injection, sharing methamphetamine use, using brown methamphetamine, and needle sharing
Vong et al[86]	Florida, United States	2001-2002	403	11%	NA	32	HAV vaccination in jail decreased the reported cases
	Asia-Pacific region
Shaw et al[87]	Queensland, Australia	1997	875	118	NA	NA	Sharing of instruments for smoking marijuana
Manor et al[88]	Tel-Aviv, Israel	2012-2013	75	9	NA	33

¹Risk factors of acquiring HAV infection were identified by case-control studies. HAV: Hepatitis A virus; HIV: Human immunodeficiency virus; IDU: Injecting drug user; NA: Not available.

Table 4 Clinical symptoms and signs of patients with acute hepatitis A infection[92-96]

Symptoms	Frequency
Asymptomatic	14%
Fever	48%-87%
Nausea/vomiting	56%-88%
Anorexia	66%-96%
Fatigue/malaise	49%-80%
Upper abdominal pain	42.5%-82%
Diarrhea	8%-23%
Signs
Jaundice	24%-99%
Hepatomegaly	7%-78%
Splenomegaly	18%-30%

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 patients	HIV-negative patients
Natural course of acute HAV infection
Incubation period (wk)	NA	2.5-5[91]
Duration of stool shedding (d)	NA	25 (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]

HIV: Human immunodeficiency virus; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HAV: Hepatitis A virus; NA: Not available.

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 Authority	Target candidates	Dosing Schedule	Comments
BHIVA[111]	Household and sexual contacts of infected persons	Monovalent HAV vaccine recommended	We 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
	Travellers	Patients with CD4 counts > 350 cells/mm3 should be offered 2 vaccine doses at 0 and 6 mo
	MSM
	Injecting and non-injecting drug users	Patients 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
	Hemophiliacs	Following 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]	Travellers	Vaccinate if seronegative. Did not specify how	Shorter 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]	MSM	Monovalent 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 disease	If 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 mo	No 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]	Travellers	Inactivated vaccine: 2 doses, the second dose normally 6 mo after the first. If needed, this interval may be extended to 18-36 mo	Does 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

HAV: Hepatitis A virus; HIV: Human immunodeficiency virus; IDUs: Injecting drug users.

Table 7 Primary response rates and predictors of seroconversion after hepatitis A virus vaccination in human immunodeficiency virus-positive patients

Ref.	Dates	Design/Country	No. of patient1	HAV/dosing schedules (mo)	CD4, cells/mm3	PVL, log10, copies/mL	ART	Timing of response2, mo/cut-off3, mIU/mL/assay	Response rate (%): ITT/PP	Predictors and comments4
Tseng et al[115]	2009-2010	Prospective, Taiwan	Standard 2-dose	HAVRIX 1440 U/	Mean, 538	Mean, 2.5	67.1%	12, 18/20, a. CIA (ARCHITECT HAVAb-IgG) b. ELISA (ETIAB- HAVK PLUS)	12 m (CIA): 75.7/81.7	MSM 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, 114						18 m (ELISA): NA/86.6
			3-dose	HAVRIX 1440/	Mean, 452	Mean, 3	58.2%		12 m (CIA): 77.8/81.8
			All, 213;	3 doses (0, 1, 6)					12 m (ELISA): NA/89.2
			CD4 matched, 114						18 m (ELISA): NA/86.9
			Standard 2-dose	HAVRIX 1440/	NA	NA	NA		12 m (CIA): 88.5/97.9
			HIV-negative, 193	2 doses (0, 6)					12 m (ELISA): NA/100
									18 m (ELISA): NA/100
Mena et al[116]	1997-2009	Retrospective, Spain	Standard 2-dose, 241	HAVRIX 1440/	Median, 531	55.3%5	61.4%	10-16/20, CIA (Advia Centaur)	NA/80.7	Higher CD4/CD8 ratio; 2 or more doses compared to 1 dose only; female; no HCV infection
				(0, 6-12)
			Accelerated, 41	TWINRIX 720/	Median, 543	73.2%	80.5%	5/20, CIA (Advia Centaur)	NA/70.7
				(0, 7, 21 d, 6-12)
Jimenez et al[117]	2002-2008	Retrospective, United States	Standard 2-dose, 125	HAVRIX 1440/ (0, 6-12)	Median, 410	Median, 3.1	70.0%	Variable/< 0.8 signal relative to cut-off, CIA (Vitros ECi)	NA/54	Higher baseline CD4 count and suppressed PVL
			101	TWINRIX 720/					NA/53
				(0, 1, 6-12)
Kourkounti et al[118]		Retrospective, Greece	cART-experienced, 63	HAVRIX 1440 or Vaqta 50/ (0, 6-12)	628	< 1.7	100.0%	7-13/20, ELFA (VIDAS)	NA/78	Higher baseline CD4 count
			cART-naïve, 50		472	3.9	0.0%		NA/76
Weinberg et al[119]	1994-2010	Prospective observational, United States	Hormone oral contraceptive, 13	2 doses (0, 6) or 3 doses (0, 2, 6)	478	47%5	78.0%	NA/20, ELISA (Mediagnost)	NA/62	Women only study; Higher baseline CD4 count and suppressed PVL
			No contraceptive, 149						NA/51
Launay et al[120]	2003-2005	Randomized controlled trial, France	Standard 2-dose, 49	HAVRIX 1440/ (0, 6)	Median, 355	Median, < 1.7	78.0%	6-18/20, ELISA (ETIAB- HAVK PLUS)	6 m: 44.9/46.8	Absence of tobacco smoking
									7 m: 69.4/72.3
									18 m: 61.2/69.8
			3-dose, 46	HAVRIX 1440/ (0, 1, 6)	Median, 351	Median, < 1.7	83.0%		6 m: 69.6/74.4
									7 m: 82.6/88.4
									18 m: 78.3/85.7
Overton et al[121]	1997-2004	Retrospective, United States	1 or 2-dose, 268	HAVRIX 1440/	Mean, 447	Mean, 2.9	67.5%	NA/NA	NA/49.6	Male; PVL < 1000 copies/mL
				NA (1 or 2 doses)				ELISA (Not specified)
Weissman et al[122]	2001-2003	Retrospective, United States	Standard 2-dose, 138	HAVRIX 1440/	Mean, 424	NA	81.9%	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]	1997-1998	Randomized controlled trial, United States	Standard 2-dose, HIV-positive, 55	Vaqta 50/ (0, 6)	Mean, 457.5	4.52	76.0%	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, 72	Vaqta 50/ (0, 6)	NA	NA	NA		1 m: NA/90
									7 m: NA/100
									13 m: NA/90
Kemper et al[124]	1995-1997	Double-blind, placebo-controlled trial, United States	Standard 2-dose, HIV-positive, 48	HAVRIX 1440/ (0, 6)	376	3.29	91.0%	1, 6, 7, 9/33, ELISA (Enzymun; Boehringer Mannheim)	1 m: NA/11	Subjects 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-1996	Randomized controlled trial, Australia	Accelerated 2-dose, HIV-positive, 48	HAVRIX 1440/ (0, 1)	Mean 569	NA	NA	1, 3/20, ELISA (Enzymun; Boehringer Mannheim)	1 m: NA/80.0	MSM 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, 42	HAVRIX 1440/ (0, 6)	Mean 454	NA	NA	1, 7/20, ELISA (Enzymun; Boehringer Mannheim)	1 m: NA/75.6
									7 m: NA/81.3
									CD4 ≤ 200, 64
			Standard 2-dose, HIV-negative, 46	HAVRIX 1440/ (0, 6)	NA	NA	NA	1, 7/20, ELISA (Enzymun; Boehringer Mannheim)	1 m: NA/90.2
									7 m: NA/100
Wilde et al[126]	Pre-1995	Prospective, United Kingdom	Three mini-dose, HIV-positive hemophiliacs, 31	HAVRIX 720/ (0, 1, 6)	Median 450 (IgG positive after 2 doses)	NA	0	1, 2, 7/20, EIA (SORIN Biomedica INCstar, Italy)	2 m: NA/29	Hemophiliacs 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-1995	Prospective, United Kingdom	Three mini-dose, HIV-positive hemophiliacs, 25	HAVRIX 720/ (0, 1, 6)	NA	NA	NA	1, 2, 6, 7/20, ELISA (Boehringer-Mannheim)	1 m: NA/26	Men 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, 8	HAVRIX 720/ (0, 1, 6)	NA	NA	NA		1 m: NA/57
									2 m: NA/86
									6 m: NA/100
									7 m: NA/100
			Three mini-dose, HIV-negative healthy controls, 25	HAVRIX 720/ (0, 1, 6)	NA	NA	NA		1 m: NA/100
									2 m: NA/100
									6 m: NA/100
									7 m: NA/100
Hess et al[128]	Pre-1994	Prospective, controlled, Germany	Three mini-dose, HIV-positive MSM, 26	HAVRIX 720/ (0, 1, 6)	495	NA	NA	1, 2, 6, 7/20, ELISA (SB Biologicals)	2 m: NA/78.6	MSM only study; Seroconversion rates were independent of CD4 counts
									7 m: NA/76.9
			Three mini-dose, HIV-negative MSM, 20	HAVRIX 720/ (0, 1, 6)	NA	NA	NA		2 m: NA/100
									7 m: NA/100
Santagostino et al[129]	Pre-1994	NA, Italy	Three mini-dose, HIV-positive hemophiliacs, 47	HAVRIX 720 (0, 1, 6)	NA	NA	NA	1, 2, 7, 12/20	12 m: NA/76.6	Hemophiliacs; Seroconversion rates were dependent on stage of HIV disease
			Three mini-dose, HIV-negative hemophiliacs, 66	HAVRIX 720 (0, 1, 6)	NA	NA	NA	NA	12 m: NA/100

¹Number of HIV-positive individuals with baseline negative anti-HAV and data available;

²Duration specified after the first dose when primary serological response was assayed;

³Cut-off value of specific anti-HAV IgG used to define serological response;

⁴Factors identified by multivariate analysis in HIV-positive individuals unless specified;

⁵Percentage of patients with undetectable plasma HIV RNA load. cART: Combination of antiretroviral therapy; CIA: Chemiluminescence immunoassay; EIA: Enzyme immunoassay; ELISA: Enzyme linked immunosorbent assay; HAV: Hepatitis A virus; HCV: Hepatitis C virus; ITT: Intention-to-treat; NA: Not available; PVL: Plasma HIV RNA load; PP: Per-protocol.

Table 8 Long-term response rates and predictors of sustained seroprotection after hepatitis A virus vaccination in human immunodeficiency virus-positive patients

Ref.	Dates	Design/Country	No. of patient1	HAV/dosing schedules (mo)	CD4, cells/mm3	PVL, log10, copies/mL	ART (%)	Timing of assay2, yr/cut-off3, mIU/mL/Assay	Response rate (%): ITT/PP	Predictors of persistent response and comments4
Cheng et al[136]	2010-2015	Prospective, Taiwan	Primary responders:	HAVRIX 1440 U/	560/415	2.5/2.8	70/56	2, 3, 4, 5/20	At 1.5 yr:	MSM only study; 3-doses over 2-dose, syphilis, lack of acute HCV
			2 doses, 110	2 doses (0, 6)				ELISA (ETIAB- HAVK PLUS)	2 doses: 90.0/93.4
			3 doses, 185	3 doses (0, 1, 6)					3 doses: 87.0/94.7
			Non-		470/315	2.9/3.3	59/63		At 5 yr:
			responders:						2 doses: 76.4/88.4
			2 doses, 16						3 doses: 78.9/94.2
			3 doses, 23
Kernéis et al[137]	2006-2009	Prospective, France	Primary responders:	HAVRIX 1440/	362	62%5	NA	7, 43/20	At 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]	2004	Prospective, Poland	Primary responders:	HAVRIX 1440	450	NA	37	1.5, 5/20	At 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]	1996-2003	Retrospective, United States	116	Vaqta 50 or HAVRIX 1440 (0, 6-18)	Median, 467	50%5	62	3, 6-10/10	At 3 yr:	Lower PVL; PVL < 400 copies/mL
									90
									At 6-10 yr:
									85

¹Number of vaccinees with primary seroconversion after the last dose of vaccine; (figure in parentheses is the number of vaccinees with primary conversion and subsequent sera for follow-up of antibody persistence);

²Duration specified after the first dose when primary serological response was assayed;

³Cut-off value of specific anti-HAV IgG used to define serological response;

⁴Factors identified by multivariate analysis in HIV-positive individuals unless specified;

⁵Percentage of patients with undetectable plasma HIV RNA load. ART: Antiretroviral therapy; CIA: Chemiluminescence immunoassay; ELISA: Enzyme linked immunosorbent assay; HAV: Hepatitis A virus; HCV: Hepatitis C virus; ITT: Intention-to-treat; MSM: Men who have sex with men; NA: Not available; PVL: Plasma HIV RNA load; PP: Per-protocol.