Grading of Recommendations Assessment, Development and Evaluation (GRADE) for use of Hepatitis A Vaccine for Persons With HIV

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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.
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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 #1
Lin, 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-dose
Tsachouridou, 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 load
Jablonowska, 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 vaccination
Kourkounti, 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 = 0.068
Mena, 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 load
Kourkounti, 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 vaccine
Crum-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 increased
Horster, 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 vaccine
Launay, 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 weeks
Overton, 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/ml
Weissman, 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+ count
Rimland, 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/mm3
Wallace, 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/mm3
Kemper, 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/mm3
Lederman, 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 vaccine
Valdez, 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 groups


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.

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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 #2
Kemper, 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 #2
Launay, 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
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Page last reviewed: July 2, 2020
Content source: National Center for Immunization and Respiratory Diseases