Skip directly to site content Skip directly to page options Skip directly to A-Z link


Centers for Disease Control and Prevention. CDC twenty four seven. Saving Lives, Protecting People
															Search
		×
			Vaccines site
			Vaccines site
				All CDC
				Submit
			For a full list of topics:A-Z Index
			Advanced Search
		Advanced Search


Advisory Committee on Immunization Practices (ACIP)


Section Navigation
			
			CDC Home


Facebook
        Twitter
        LinkedIn
        Syndicate





Grading of Recommendations Assessment, Development and Evaluation (GRADE) for use of Hepatitis A Vaccine for Persons With HIV										Related Pages
										On This Page
			Evidence RetrievalBenefitsHarms
		
Printer friendly version of this page pdf icon[10 pages]
Evidence Retrieval
For evidence retrieval, we conducted a systematic review of data on hepatitis A vaccine and persons with HIV (PWHIV), including searches of Medline, EMBASE, CINAHL, Cochrane Library, and ClinicalTrials.gov through January 17, 2019.
Our search terms were as follows:
(((Hepatitis OR HAV OR hepatovirus) AND vaccin*) OR HepA OR VAQTA OR AVAXIM OR EPAXAL OR HAVPUR OR HAVRIX OR nothav) AND (HIV OR human immunodeficiency)
We did not restrict articles based on language or country of origin. We excluded articles based on the following criteria:
Articles focused solely on children or that did not have information on ages of included individuals
Articles with no data on HAVRIX or VAQTA, which are the two single-antigen hepatitis A vaccines currently licensed in the United States
Articles that did not provide new data, only included safety data among populations other than our target population of PWHIV, discussed vaccine introduction, made recommendations, or proposed guidelines
Articles that could not be obtained full-text or in English
Articles on animals other than humans
Clinical trials with no results available
Publication prior to 1996, when hepatitis A vaccine was introduced in the United States
We identified 927 unique abstracts; 584 abstracts met one or more of the exclusion criteria (above), leaving 343 articles for full-text review.
Based on review of the full publications, we eliminated another 319 articles per exclusion criteria. We also excluded 2 studies with populations that were a subset of other included studies.
We included a total of 22 studies in our GRADE analysis.Top of Page
GRADE of evidence for hepatitis A vaccination among persons living with HIV: Benefits*
Outcome #1: Hepatitis A infection
Study
Type
Site
Population
N = total
Age
Intervention
Comparison
CD4+ Count at Vaccination
HIV Viral Load at Vaccination
Immunogenicity*
Main Outcomes #1Lin, 2018
Obs
Taiwan
N = 1533
Median, vaccinated group: 35
At least 1 dose of HAV vaccine

Median, cells/lL:
550

Weeks 28–36: 63.8% (ITT) and 93.7% (PPA)
Vaccine effectiveness: 96.3%Cheng, 2017
Obs
Taiwan
N = 365
Mean:
30
HAVRIX, 2 doses at 0, 6 months; HAVRIX, 3 doses 0, 1, 6 months

Mean:
485 cells/mm3

Primary responders:
87.3% (2 dose)
88.9% (3 dose)
GMCs‡ of anti-HAV immunoglobulin G (IgG): significantly higher for 3-dose versus 2-doseTsachouridou, 2017
Obs
Greece
N = 1210
Mean: 34.51
HAVRIX, 2 doses at 0, 6–12 months;
ENGERIX, 3 doses at 0, 4, and 24 weeks;
PNEUMOVAX 23

Mean: 2.70 log10
Mean, log10 copies/ml:
4.18
80.7% seroconversion within 3 months of HepA series completion
Seroprotection not affected by nadir and current CD4+ cell count and plasma viral loadJablonowska, 2014
Obs
Poland
N = 234
Mean age, vaccinated: 30.7
HAVRIX, 2 doses,
6 months apart

Median:
450 cells/mm3

79.5%, one month after second dose
75.5%, 5 years after vaccination
Most HIV-infected adults with high CD4+ counts had a durable response up to 5 years post vaccinationKourkounti, 2014
Obs
Greece
N = 897
Mean, vaccinated group: 40.2
HAVRIX or VAQTA, 2 doses, 6-12 months apart



Response rate: 76%
GMT‡: 305 mIU/ml (95% CI 255-361 mIU/ml)Jimenez, 2013
Obs
USA
N = 226
Mean: 41.8
At least 1 dose:
a) HAVRIX
b) TWINRIX (720 EU)

Median:
410 cells/mm3
Median: 1287 copies/mL
53.5% overall
54% (HAVRIX)
53% (TWINRIX)
Patients with CD4+ counts >350 cell/mm3 (60%) were more likely to respond than those with CD4+ counts <200 cell/mm3 (35%) (*P* = 0.0498).
Responders were also more likely to be virologically suppressed (48% versus 32%; *P* = 0.0024).Kourkounti, 2013
Obs
Greece
N = 113
Median: 40
HAVRIX or VAQTA, 2 doses, 6–12 months apart

Median, cells/mm3:
570
Median, copies/mL:
<50
After the second dose: 77.0%
GMT‡: Highly active antiretroviral therapy (HAART) patients, 237 mIU/mL [95% CI, 201–321 mIU/mL]; no HAART, 158 mIU/mL [95% CI, 130–221 mIU/mL]), *P* = 0.068Mena, 2013
Obs
Spain
N = 499
Median: 36.3
(a) HAVRIX, 1 dose
(b) HAVRIX, 2 doses, 6 months apart
(c) TWINRIX (720 EIU), 3 doses at 0,7,14–21 days

Median, cells/mm3:
– 531, standard schedule
– 543, rapidly accelerated
Median, log10 copies/ml:
2.3
Overall rate: 73.4%
(a) 60.0%
(b) 80.7%
(c) 70.7%
Protective antibody response to vaccination was associated with a higher CD4+/CD8 ratio
Higher response was associated with reception of 2 doses of standard schedule (in comparison with those receiving only one of those of the same schedule)Tseng, 2013
Obs
Taiwan
N = 582 (365 HIV+)
age range: 18–40
(a) HAVRIX, 2 doses at 6 months apart
(b) HAVRIX, 3 doses at 0, 1, and 6 months
(c) HAVRIX, 2 doses at 6 months apart
(HIV- group)
Mean, cells/mm3:
(a) 538
(b) 452
(a) 2.5 log10 copies/mL
(b) 3.0 log10 copies/mL
Week 48 (ITT**):
(a) 75.7% for 2-dose HIV+
(b) 77.8% for 3-dose HIV+
(c) 88.5% for 2-dose HIV-
GMC‡ at week 48 (*P* <0.01):
(a) 2-dose, 1.94 log10 mIU/mL
(b) 3-dose, 2.29 log10 mIU/mLProtective antibody response associated with higher CD4+ counts and undetectable plasma HIV RNA loadKourkounti, 2012
Obs
Greece
N = 351
Median: 40 (range 34–45)
HAVRIX or VAQTA, 2 doses, 6–12 months apart

Median:
564 cells/mm3
60% had <50 copies/mL at or prior to dose 1 HAV
1 month after the second dose: 74.4%
GMTs: 315, 203, 153, and 126 mIU/ml at months 1, 6, 12, and 18
A higher response rate and higher GMTs were observed in patients with CD4+ counts ≥500 cells/mm3 (76.6%) than in patients with CD4+ counts 200–499 cells/mm3.-
Protective antibody response to vaccination was associated with higher baseline median CD4+ count at vaccination.Weinberg, 2012
Obs
USA
N = 373
Mean:
responders: 41.7
non-responders: 41.6
HepA (unspecified 2 dose vaccine 6 months apart or 3 dose vaccine every 2 months)

Mean, cells/μl:
responders: 519
non-responders: 450
Plasma HIV RNA <400 copies/ml:
responders: 46%
non-responders: 35%
52% in HAV-seronaïve
Plasma HIV RNA <400 copies/ml, higher CD4+ cells/μl, and baseline antibody titers <20 mIU/ml (HAV seronaïve) were significantly associated with an antibody response to the vaccineCrum-Cianflone, 2011
Obs
USA
N = 130
Median: 35
VAQTA or HAVRIX, 2 doses, 6–18 months apart
Controls: HIV-negative, VAQTA, 2 doses
Median:
461 cells/mm3
Plasma HIV RNA level, <1000 copies/mL: 49%
89% overall
78%, CD4+ <350 cells/mm3
94%, CD4+ ≥350 cells/mm3
GMCs‡ among HIV+ adults: 154, 111, and 64 mIU/mL at 1, 3, and 6–10 years
Higher GMCs over time among HIV-infected adults were associated with lower log10 HIV RNA levels (*P* = 0.04)Armstrong, 2010
Obs
USA
N = 451
Mean:
40
HepA (standard dose) or HepB (standard dose) or TWINRIX

64%, CD4+ >400 cells/mm3
36%, CD4+ ≤400 cells/mm3

HepA:
60%, overall
62.5%, CD4+ >400
55.56%, CD4+ ≤400
Immune development to HepA increased as CD4+ counts increasedHorster, 2010
Obs
Germany
N = 131
Mean:
40
HAVRIX, 2 doses at months 1 and 6 or TWINRIX (720 EU), 3 doses at months 1, 3, 6; plus additional vaccines***

Median: 423.0 CD4+/μl
Median: below limit of detection
63.6%
Seroconversion was 63.6% among those receiving hepatitis A vaccineLaunay, 2008
RCT
France
N = 99
Mean:
38.8 years
HAVRIX, 2 doses, 24 weeks apart
HAVRIX, 3 doses at weeks 0, 4, 24
Median, cells/mm3: 355
Median, copies/mL (IQR): <50 (<50–1300)
Week 28, ITT**:
69.4%, 2-dose group
82.6%, 3-dose group
(*P* = 0.13)
GMT‡, mIU/mL: 138.2, 2-dose vs. 323.5, 3-dose group at 28 weeksOverton, 2007
Obs
USA
N = 906
Mean, vaccinated group: 38.1
HAVRIX, at least 1 dose

Mean, cells/mm3: 447

49.6% overall
Protective antibody response to vaccination with HIV viral RNA load <1000 copies/mlWeissman, 2006
Obs
USA
N = 503
Mean:
responders, 43.5
non-responders, 45.0
HAVRIX, 2 doses,
6–12 months apart

Mean, cells/mm3:
overall: 424
responder: 508.6
non-responder: 344.3

After the 2nd dose (mean of 187 days post series completion): 48.5%
Protective antibody response to vaccination was associated with higher CD4+ countRimland, 2005
Obs
USA
N = 659
Age not published
HAVRIX, 2 doses



After the 2nd dose: 60.7%
Protective antibody response to vaccination was associated with higher CD4+ count, especially if >200 cells/mm3Wallace, 2004
RCT
USA
N = 180 (90 HIV+)
Mean:
32.6 years
VAQTA, 2 doses, week 0 and week 24
Placebo
Mean, cells/mm3:
457.5, VAQTA
493.6, placebo
Mean, copies/mL:
0.33 x 105, VAQTA
0.16 x 105, placebo
Week 28: 94% among HIV-infected subjects
87%, CD4+ <300 cells/mm3
100%, CD4+ ≥300 cells/mm3
GMT‡, mIU/mL: 517 subjects with CD4+ <300 cells/mm3; 1959 subjects with ≥300 cells/mm3Kemper, 2003
RCT
USA
N = 133
Mean:
38 years
HAVRIX, 2 doses, 6 months apart
Placebo, 2 doses, 6 months apart
Mean, cells/mm3:
376, vaccine
327, placebo
(*P*, not significant)
Mean, log10 copies/mL:
3.2, vaccine
3.39, placebo
Month 9:
68%, CD4+ ≥200 cells/mm3
9%, CD4+ <200 cells/mm3
(*P* = 0.004)
Protective antibody response to vaccination was significantly associated with CD4+ cell counts ≥200 cells/mm3Lederman, 2003
Obs
USA
N = 643
Median: 40
HAVRIX, 2 doses, weeks 16 and 40 + multiple antigens****

Median, cells/mm3:
226
Median copies/mL: ≤500
8 weeks after second dose: 46%
46% of subjects seroconverted after 2 doses of hepatitis A vaccineValdez, 2003
Obs
USA
N = 38
Median: 38
HAART and IL-2 vaccinated with:
HAVRIX + tetanus toxoid + REMUNE + ENGERIX
HAART-only vaccinated with:
HAVRIX + tetanus toxoid + REMUNE + ENGERIX
Median, cells/μL:
HAART/IL-2: 865
HAART: 445
Median, log10 copies/mL (IQR):
HAART/IL-2: 1.7 (1.7 – 2.6)
HAART: 1.7 (1.7 – 1.7)
88% of
HAART-only recipients
36% of HAART/IL-2 recipients
Seroconversion was 88% among HAART-only and 36% among HAART/IL-2 groupsShow More
Table 1 Footnotes
‡GMT/ GMC: geometric mean titer/geometric mean concentration
* Seroconversion defined as anti-HAV antibody concentrations:
• ≥10 mIU/ mL: Horster; Wallace
• ≥10 mIU/ mL at 12 (±6) months after second dose: Crum-Cianflone
• ≥20 mIU/mL: Kourkounti, 2012; Kourkounti, 2013; Kourkounti, 2014; Mena; Tsachouriou; Weinberg; Tseng; Launay; Jablonowska
• Primary responders: ≥20 mIU/mL at month 12: Cheng
• ≥33 mIU/mL: Kemper
** ITT: Intention to treat analysis.
*** Additional vaccines administered: trivalent influenza split-vaccine (INFLUSPLIT), pneumococcal vaccine (PNEUMOVAX 23), hepatitis B (ENGERIX; administered at months 1, 3, if HAVRIX given for hepatitis A).
**** Antigens included Candida albicans, mumps skin test, and TT US Pharmacopeia fluid; tetanus toxoid vaccine was also administered unless previously received in past 12 months.
Top of Page
GRADE of evidence for hepatitis A vaccination among persons living with HIV: Harms
Outcome #2: Mild adverse events
Study
Type
Site
Population
N = total
Age, years
Intervention
Comparison
Main Outcomes #2Kemper, 2003
RCT
USA
N = 133
Mean: 38
HAVRIX, 2 doses, 6 months apart
Placebo, 2 doses, 6 months apart
Minor injection site soreness: 35% of vaccine doses administered versus 8% of placebo doses (*P* <0.01).
Reported bacterial, viral, or fungal infections post-vaccination similar for patients receiving vaccine or placebo (24% vs. 26%, respectively; *P* >0.20).
Within 4 days of vaccination, 1 subject (1.6%) in each group experienced severe headache; 1 subject (1.6%) in vaccine group experienced severe fatigue. This difference was non-significant. We consider these to be relatively mild adverse events. The authors concluded that the vaccine was well tolerated in this population.Wallace, 2004
RCT
USA
N = 180 (90 HIV+)
Mean: 32.6
VAQTA, 2 doses, week 0 and week 24
Placebo
Local reaction at injection site in 57% of VAQTA group and 60% of placebo group.
Systemic adverse events (predominantly self-limited headache and fever) were more common among PWHIV who received VAQTA (37%) than among PWHIV who received placebo (23%).
Only 3 subjects experienced clinically significant adverse events within 2 weeks after receipt of either vaccine dose. Only 1 of these 3 events (a severe headache) was thought to be vaccine-associated. There were no significant changes in complete blood counts or the results of liver function tests in any group at any point in this study.Tseng, 2013
Obs
Taiwan
N = 582 (365 HIV+)
range: 18–40
HAVRIX, 2 doses, 6 months apart
HAVRIX, 3 doses at 0,1 and 6 months
51.6% of all subjects (HIV+ 51.7% vs HIV- 51.6%, *P*= 0.98) experienced mild tenderness at local injection site within 24 hours of vaccination.Outcome #3: Serious adverse events
Study
Type
Site
Population
N = total
Age
Intervention
Comparison
Main Outcomes #2Launay, 2008
RCT
France
N = 99
Mean:
38.8
HAVRIX, 2 doses, 24 weeks apart
HAVRIX, 3 doses at weeks 0, 4, 24
There were no serious adverse events associated with the vaccine.
No significant changes in CD4+ T-cell counts or plasma HIV-1 RNA levels during 28-week follow-up.Bodsworth, 1997
Obs
Australia
N = 180
Mean:
– case: 33.2
– control: 36.6
HAVRIX, 2 doses at 1 or 6 months apart
No vaccine for controls
No significant differences (*P* >0.2) between case and control groups after 1 year for:
– AIDS progression, 10.1% versus 10.7%
– Death, 7.3% versus 7.6%
– Mean CD4+ decline, 125 x106/l versus 123 x106/l
No serious adverse events attributable to vaccination.Wallace, 2004
RCT
USA
N = 180 (90 HIV+)
Mean:
32.6
VAQTA, 2 doses, week 0 and week 24
Placebo
No adverse effect on either HIV viral load or CD4+ cell count found.*RCT – randomized control trial
Obs – observational study
GMT – geometric mean titer
GMC – geometric mean concentration
ITT- intention to treat
Top of Page
					View Page In:pdf icon Print version		
					
						Page last reviewed:  July 2, 2020					Content source: 	National Center for Immunization and Respiratory Diseases homeACIP Home
Meeting Information
Committee Informationplus icon
Role of the ACIP in CDC’s Vaccine Recommendations
Charter
Economics Studies
Committee Membersplus icon
ACIP Membership Roster
Apply for ACIP Membership
Work Groupsplus icon
VaST Reportsplus icon
June 28, 2021
May 24, 2021
May 17, 2021
March 29, 2021
Recommendationsplus icon
Shared Clinical Decision-Making Recommendations
Evidence Based Recommendationsplus icon
About GRADE
Grade Evidence Tables
Evidence to Recommendations Frameworks Vaccines & ImmunizationsImmunization SchedulesVFC ResolutionsVaccine Information Statements (VISs)
  1600 Clifton Road, N.E., Mailstop A27
Atlanta, GA 30329-4027acip@cdc.gov


About CDC
					Contact Us
					800-232-4636
 Facebook Twitter Instagram LinkedIn Youtube Pinterest Snapchat
 CONTACT CDC
				Contact Us
							Call 800-232-4636
							Email Us
			ABOUT CDC
				About CDC
							Jobs
							Funding
			POLICIES
				Accessibility
							External Links
							Privacy
							Policies
							No Fear Act
							FOIA
							OIG
							Nondiscrimination
							Vulnerability Disclosure Policy
			CONNECT WITH US
				Facebook
								Twitter
								Instagram
								LinkedIn
							Youtube
								Pinterest
								Snapchat
								Email
			LANGUAGES
				Español
							繁體中文
							Tiếng Việt
							한국어
							Tagalog
							Русский
							العربية
							Kreyòl Ayisyen
							Français
							Polski
							Português
							Italiano
							Deutsch
							日本語
							فارسی
							English


U.S. Department of Health & Human Services
			Accessibility
			External Links
			Privacy
			Policies
			No Fear Act
			FOIA
			Nondiscrimination
			OIG
			Vulnerability Disclosure Policy
			USA.gov


Exit Notification / Disclaimer Policy Close
 Links with this icon  indicate that you are leaving the CDC website. The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website.
				Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
				You will be subject to the destination website's privacy policy when you follow the link.
				CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website. Website Disclaimers
 Cancel Continue