Use of Hepatitis A Vaccine for Persons With HIV – GRADE and Evidence Tables

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. 

https://www.cdc.gov/vaccines/acip/recs/grade/hep-a-hiv-h.pdf 7/17/2020
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 HIVGMC‡ at week 48 (P <0.01): 

(a) 2-dose, 1.94 log10 

mIU/mL

(b) 3-dose, 2.29 log10 

mIU/mL

Protective 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

- nonresponders: 

41.6

HepA

(unspecified 2 

dose vaccine 6 

months apart or 3 

dose vaccine 

every 2 months)

Mean, cells/μl:

responders: 

519

nonresponders: 

450

Plasma HIV 

RNA <400 

copies/ml:

responders: 

46%

nonresponders: 

35%

52% in HAVseronaïve

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

CrumCianflone, 

2011 Obs USA N = 130 Median: 35

VAQTA or 

HAVRIX, 2 doses, 

6–18 months 

apart

Controls: HIVnegative, 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

- nonresponders, 

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 HIVinfected 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/IL2 recipients

Seroconversion was 88% 

among HAART-only and 36% 

among HAART/IL-2 groups

‡

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.
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 nonsignificant. 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 selflimited 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 HIV51.6%, 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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