Comparable Serologic Responses to 2 Different Combinations of Inactivated Hepatitis A Virus Vaccines in HIV-Positive Patients During an Acute Hepatitis A Outbreak in Taiwan

Comparable Serologic Responses to 2 Different Combinations of Inactivated Hepatitis A Virus... Abstract We evaluated the serologic responses to different 2-dose combinations of the inactivated hepatitis A virus (HAV) vaccines Havrix and Vaqta among human immunodeficiency virus–positive individuals during an acute hepatitis A outbreak in Taiwan. In this 16-month retrospective study, one group received 1 dose of Havrix followed by 1 dose of Vaqta, and another group received 2 doses of Vaqta. The Havrix-Vaqta and Vaqta-Vaqta groups achieved similar seroconversion rates at weeks 28–36 (82.3% and 80.9%, respectively; absolute difference, 1.3% [95% confidence interval {CI}, −6.3%–3.7%]) and week 48 (94.7% and 94.4%, respectively; absolute difference, 0.3% [95% CI, −2.6%–3.2%]), suggesting the interchangeability of different combinations of HAV vaccines. The significantly higher seroconversion rate after the first dose of Vaqta, compared with the dose of Havrix (53.0% vs 32.4%) may provide potential benefits in preventing HAV infection during the outbreak. Viral hepatitis, vaccination, seroconversion, men who have sex with men Outbreaks of acute hepatitis A among men who have sex with men (MSM) have been occurring across Asia, Europe, and the United States since 2015 [1–3]. Hepatitis A virus (HAV) vaccination is the most effective strategy to prevent acute hepatitis A and has been recommended for at-risk populations, such as MSM and illicit drug users [4]. In the general population, HAV vaccines are highly immunogenic, with a high seroconversion rate of >95% following vaccination. Despite the suboptimal serologic response among human immunodeficiency virus (HIV)–positive individuals [5], the effectiveness of HAV vaccination could be as high as 96% in the outbreak setting [6]. During outbreaks of acute hepatitis A, the unexpected increases in the demand for HAV vaccines have constrained vaccine supplies in European countries and the United States [7]. The shortages of vaccine supplies have raised issues about implementing a single dose of HAV vaccine and concerns about the interchangeability between combinations of different vaccine types during the outbreaks [2]. The most commonly used formulations of inactivated HAV vaccines consist of 2 single-antigen vaccines (Havrix or Vaqta) [5]. Randomized, controlled trials have shown comparable seroconversion rates between Havrix and Vaqta in healthy subjects despite higher anti-HAV titers in subjects receiving Vaqta [8, 9]. However, the immunogenicity of different HAV vaccine combinations has rarely been evaluated among HIV-positive individuals. In this study, we aimed to compare the serologic responses to 2 different vaccine combinations and to identify the associated factors with serologic responses among HIV-positive individuals during an outbreak of acute hepatitis A. SUBJECTS AND METHODS Study Setting and Patients Between mid-2015 and late 2017, an outbreak of acute hepatitis A involving 1500 indigenous cases occurred in Taiwan [10]. More than half of case patients were MSM and/or HIV-positive individuals. At the start of the outbreak, all HIV-positive individuals at the National Taiwan University Hospital who tested negative for anti-HAV immunoglobulin G (IgG) were advised to receive 2 doses of HAV vaccine, administered 6 months apart [6]. In this retrospective study, we included HIV-positive, HAV-seronegative individuals aged ≥19 years who underwent HAV vaccination between 1 June 2015 and 30 September 2016. We excluded those who only received 1 dose of HAV vaccine or those who had undergone HAV vaccination before June 2015. As a public health response to the outbreak of acute hepatitis A, the provision of HAV vaccination and determination of HAV antibody titers were not considered of research interest only, and informed consent was waived by the Research Ethics Committee at National Taiwan University Hospital. Exposures and Outcomes Because of an early shortage of Havrix at the hospital, 1440 enzyme-linked immunosorbent assay (ELISA) U of Havrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) was substituted by 50 U of Vaqta (Merck, West Point, PA) on 19 May 2016. For this reason, HIV-positive individuals included in the study received either Havrix for both doses (the Havrix-Havrix group), Havrix as the first dose followed by Vaqta as the second dose (the Havrix-Vaqta group), or Vaqta for both doses (the Vaqta-Vaqta group). Because only 19 individuals were in the Havrix-Havrix group, this group was excluded from analyses. Havrix-Vaqta and Vaqta-Vaqta doses were administered during the peak of the outbreak (Supplementary Figure 1). After HAV vaccination, the anti-HAV IgG titer was determined between weeks 4 and 24 (before the second dose of vaccine), and at weeks 28–36 (after the second dose) and week 48. The included individuals were followed from the date of HAV vaccination until acute hepatitis A onset, death, loss to follow-up, or the end of the study (30 September 2017). The primary outcome was serologic response at weeks 28–36 after the first HAV vaccination. The secondary outcomes included the serologic response between 4 and 24 weeks after the first HAV vaccination, the serologic response at week 48 after the first HAV vaccination, and acquisition of acute hepatitis A. The serologic response was estimated by intention-to-treat (ITT) with last-observation-carried-forward (LOCF) analysis and per-protocol (PP) analysis. Laboratory Investigations The serum anti-HAV IgG titer was determined using a chemiluminescence immunoassay assay (Architect HAVAb-IgG; Abbott Diagnostics, Wiesbaden, Germany), which is a semiquantitative assay of the chemiluminescence reaction, measured in relative light units. A signal to cutoff (S/CO) value of ≥1.00 was reported as positivity for anti-HAV IgG. Owing to the direct relationship between the amount of anti-HAV IgG and the number of relative light units, the S/CO value was recorded as an indirect indicator of the geometric mean titer of anti-HAV IgG. Statistical Analysis Variables were compared across the 2 groups by 1-way analysis of variance, with Bonferroni tests for multiple pair-wise comparisons. A logistic regression model was used to assess factors associated with seroconversion. Variables considered for entry into multivariable models included variables with a P value of <.1 in univariable analyses. The generalized estimating equation (GEE) model was used to determine the associations between the predictor variables and repeated measurements. All tests were 2-tailed, and a P value of <.05 was considered statistically significant. All statistical analyses were performed using Stata, version 12.0 (Stata, College Station, TX). RESULTS During the 16-month study period, 946 HIV-positive individuals testing negative for anti-HAV antibodies were included; 395 (41.8%) were in the Havrix-Vaqta group, and 551 (58.2%) were in the Vaqta-Vaqta group (Supplementary Figure 2). The clinical characteristics of the 2 groups are shown in Table 1. Most (95.6%) were MSM, and the median age was 35 years. At vaccination, 97.1% of individuals had been receiving combination antiretroviral therapy, with a baseline median CD4+ T-cell count of 574 cells/µL, and 85.1% had a plasma HIV RNA load of <20 copies/mL. Table 1. Comparison of Clinical Characteristics and Outcomes Between the Havrix-Vaqta and Vaqta-Vaqta Groups Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Data are proportion (%) of patients or median value (interquartile range). Abbreviations: cART, combination antiretroviral therapy; CI, confidence interval; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ITT, intention to treat; LOCF, last observation carried forward. aIncluded concurrent use of chemotherapy and immunomodulation agents. bUndetectable (UD), defined as <20 copies/mL. cDifferences between the ITT with LOCF analyses and the per-protocol analyses were 1.3% (95% CI, −3.7%–6.3%) and −3.0% (95% CI, −6.7%–.7%), respectively. dDifferences between the ITT with LOCF analyses and the per-protocol analyses were 0.3% (95% CI, −2.6%–3.2%) and 1.1 (95% CI, −2.6%–4.8%), respectively. View Large Table 1. Comparison of Clinical Characteristics and Outcomes Between the Havrix-Vaqta and Vaqta-Vaqta Groups Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Data are proportion (%) of patients or median value (interquartile range). Abbreviations: cART, combination antiretroviral therapy; CI, confidence interval; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ITT, intention to treat; LOCF, last observation carried forward. aIncluded concurrent use of chemotherapy and immunomodulation agents. bUndetectable (UD), defined as <20 copies/mL. cDifferences between the ITT with LOCF analyses and the per-protocol analyses were 1.3% (95% CI, −3.7%–6.3%) and −3.0% (95% CI, −6.7%–.7%), respectively. dDifferences between the ITT with LOCF analyses and the per-protocol analyses were 0.3% (95% CI, −2.6%–3.2%) and 1.1 (95% CI, −2.6%–4.8%), respectively. View Large The comparisons of primary and secondary serologic outcomes following HAV vaccination between the Havrix-Vaqta and Vaqta-Vaqta groups are shown in Table 1 and Figure 1. At weeks 28–36, the seroconversion rate in the ITT with LOCF analysis was 82.3% for the Havrix-Vaqta group and 80.9% for the Vaqta-Vaqta group (absolute difference, 1.3%; 95% confidence interval [CI], −6.3%–3.7%). In the per-protocol analysis, the seroconversion rate was 92.1% (293 of 318 patients) for the Havrix-Vaqta group and 95.1% (331 of 348 patients) for the Vaqta-Vaqta group (absolute difference, −3.0%; 95% CI, −6.7%–.7%). At week 48, the seroconversion rate in the ITT with LOCF analysis was 94.7% for the Havrix-Vaqta group and 94.4% for the Vaqta-Vaqta group (absolute difference, 0.3%; 95% CI, −2.6%–3.2%). In the per-protocol analysis, the seroconversion rate was 95.3% (307 of 322 patients) and 94.2% (229 of 243 patients) for the Havrix-Vaqta group and Vaqta-Vaqta group, respectively (absolute difference, 1.1%; 95% CI, −2.6%–4.8%). No individuals who received 2 doses of HAV vaccine acquired acute hepatitis A during the study period. However, 5 individuals receiving only a single dose of HAV vaccine acquired acute hepatitis A and were not included in the analysis; of them, 3 received Havrix and 2 received Vaqta. Figure 1. View largeDownload slide Seroconversion rates after hepatitis A virus (HAV) vaccination at different follow-up intervals in the Havrix-Vaqta and Vaqta-Vaqta groups. Data are from the intention-to-treat with last-observation-carried-forward analysis. IgG, immunoglobulin G. Figure 1. View largeDownload slide Seroconversion rates after hepatitis A virus (HAV) vaccination at different follow-up intervals in the Havrix-Vaqta and Vaqta-Vaqta groups. Data are from the intention-to-treat with last-observation-carried-forward analysis. IgG, immunoglobulin G. The rates of serologic response at different follow-up intervals in the ITT with LOCF analysis are depicted in Figure 1. Four weeks after the first dose of vaccine, the seroconversion rate was only 3.5% for individuals receiving Havrix and 2.7% for those receiving Vaqta. Between weeks 4 and 24, before the second dose of vaccine, the seroconversion rate increased; the highest serologic response rate, observed during weeks 21–24, was 32.4% in individuals receiving Havrix and 53.0% for those receiving Vaqta (absolute difference, −20.6%; 95% CI, −14.4%–26.8%). The seroconversion rates at different follow-up intervals, based on per-protocol analysis, are depicted in Supplementary Figure 3. After the second dose of HAV vaccine, seroconversion rates could further increase to >90% without statistically significant differences between the 2 groups. The S/CO values of anti-HAV IgG demonstrated significantly higher titers of anti-HAV IgG for the Vaqta-Vaqta group, compared with the Havrix-Vaqta group (Supplementary Figure 4). At weeks 21–24, the S/CO value for the Vaqta-Vaqta group was higher than that for the Havrix-Vaqta group (median, 2.8 vs 0.8; P < .001). Despite the similar seroconversion rates between the 2 groups at weeks 28–36 and 48, the S/CO values remained significantly higher for the Vaqta-Vaqta group, compared with those for the Havrix-Vaqta group, at weeks 28–36 (median, 10.8 vs 9.2; P < .001) and week 48 (median, 9.7 vs 8.4; P < .001). In multivariable analysis, the factors associated with seroconversion at weeks 28–36 included a younger age (adjusted odds ratio [AOR], 1.06 per 1-year decrease; 95% CI, 1.02–1.11), a higher CD4+ T-cell count (AOR, 1.04 per 10-cells/µL increase; 95% CI, 1.02–1.05), and an undetectable plasma HIV RNA load at vaccination (AOR, 2.92; 95% CI, 1.38–6.18). The factors associated with seroconversion between 4 and 24 weeks included a younger age (AOR, 1.02 per 1-year decrease; 95% CI, 1.01–1.04), a higher CD4+ T-cell count at vaccination (AOR, 1.01 per 10-cells/µL increase; 95% CI, 1.00–1.01), receipt of Vaqta as the first dose of HAV vaccine (AOR, 4.56; 95% CI, 3.26–6.39), and the interval from vaccination to anti-HAV IgG testing (AOR, 1.14 per 1-week increase; 95% CI, 1.12–1.16; Supplementary Table 1). Discussion In this study of HAV vaccination during an acute hepatitis A outbreak, we found that different 2-dose combinations of HAV vaccines achieved similar seroconversion rates at weeks 28–36 and 48 among HIV-positive individuals, suggesting that the 2 vaccine combinations are interchangeable. However, a single dose of Vaqta induced faster and better serologic responses than that of Havrix. A younger age and improved surrogate markers of immune status enhanced the immunogenicity to HAV vaccination. While 50 U of Vaqta are equivalent to approximately 50 ng of viral protein, the viral antigen activity of Havrix is expressed in ELISA U. In addition to the intrinsic difficulties in comparing their amounts of viral protein, the immunoassays used to evaluate anti-HAV titers in pivotal studies were also different [11, 12]. The comparison of serologic responses to the 2 vaccine types was studied in 2 clinical trials in the healthy population. Both trials demonstrated the similarly high seroconversion rates (>95%) across the study groups with significantly higher geometric mean titers in subjects receiving Vaqta, compared with those receiving Havrix, at weeks 24 and 28 [8, 9]. Another clinical trial investigated the boosting effect of Havrix and Vaqta in healthy adults who had received a single dose of Havrix. Although Vaqta tended to achieve numerically higher serologic responses, the study concluded noninferiority and indicated that the 2 vaccines were interchangeable [13]. HIV-positive individuals have poorer serologic responses to HAV vaccination than the general population [14]. Our data demonstrating similar seroconversion rates between Havrix-Vaqta and Vaqta-Vaqta also support the interchangeability of the 2 different vaccines among HIV-positive individuals. Because HIV-positive patients receiving 1 dose of HAV vaccine without achieving seroprotective antibody levels are still at risk for acquiring acute hepatitis A, the strategies to facilitate serologic responses during the acute hepatitis A outbreak need to be evaluated [6]. In our study, Vaqta achieved higher seroconversion rates and anti-HAV IgG titers than Havrix before the second dose of HAV vaccine was administered, which may have potential benefit in preventing HAV infection in the outbreak setting. However, a shortage of Havrix, which permitted 2 doses to be administered to only 19 patients, precluded us from investigating whether 2 doses of Vaqta could achieve higher immunogenicity than 2 doses of Havrix among HIV-positive individuals (Supplementary Figure 2). Our study has several limitations. First, the administration of HAV vaccines and determination of anti-HAV IgG titers were conducted at regular intervals instead of fixed time points, owing to the nature of this observational study. Second, we used a convenient sample, and an a priori sample size calculation was not performed. However, our study was sufficiently powered to demonstrate the noninferiority between the study groups [15]. Third, decreased awareness of the importance of measuring anti-HAV IgG titers after the outbreak was contained might have led to a greater number of missing data points in the Vaqta-Vaqta group during the later period of study. Finally, the serologic responses observed could be attributed to vaccination or natural infection. However, the impact of natural infection on serologic responses would be expected to be similar since most HAV vaccination was conducted during the peak of the outbreak and because the incidence of syphilis, a surrogate of risky sexual behavior, was similar across the study groups. In conclusion, while Vaqta elicited more-rapid and better serologic responses than Havrix before administration of the second dose of HAV vaccine, the serologic responses to 2-dose combinations of Havrix-Vaqta as compared to Vaqta-Vaqta were similar among HIV-positive individuals during an outbreak of acute hepatitis A. Supplementary Data Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Notes Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. 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– 40. Google Scholar CrossRef Search ADS PubMed  2. European Centre for Disease Prevention and Control. Hepatitis A outbreaks in the EU/EEA mostly affecting men who have sex with men—third update, 2017. https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-hepatitis-outbreak-eueea-mostly-affecting-men-who-have-sex. Accessed 1 January 2018. 3. Latash J, Dorsinville M, Del Rosso P, et al.   Notes from the field: increase in reported hepatitis A infections among men who have sex with men—New York City, January–August 2017. MMWR Morb Mortal Wkly Rep  2017; 66: 999– 1000. Google Scholar CrossRef Search ADS PubMed  4. Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2012. Ann Intern Med  2012; 156: 211– 7. CrossRef Search ADS PubMed  5. Lin KY, Chen GJ, Lee YL, et al.   Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: a review. World J Gastroenterol  2017; 23: 3589– 606. Google Scholar CrossRef Search ADS PubMed  6. Lin KY, Hsieh SM, Sun HY, et al.   Serologic responses and effectiveness of hepatitis A vaccination among HIV-positive individuals during the outbreak of acute hepatitis A. Hepatology  2018; doi: 10.1002/hep.29780. 7. Barreiro P, Soriano V. Hepatitis A outbreaks in European homosexual men. AIDS Rev  2017; 19: 113– 4. Google Scholar PubMed  8. Braconier JH, Wennerholm S, Norrby SR. Comparative immunogenicity and tolerance of Vaqta and Havrix. Vaccine  1999; 17: 2181– 4. Google Scholar CrossRef Search ADS PubMed  9. Ashur Y, Adler R, Rowe M, Shouval D. Comparison of immunogenicity of two hepatitis A vaccines–VAQTA and HAVRIX–in young adults. Vaccine  1999; 17: 2290– 6. Google Scholar CrossRef Search ADS PubMed  10. Taiwan National Infectious Disease Surveillance System. https://nidss.cdc.gov.tw/en/. Accessed 1 January 2018. 11. Havrix: full prescription information [package insert]. Rixensart, Belgium: GlaxoSmithKline Biologicals, 2017. 12. VAQTA: Full Prescription Information (Package Insert). MERCK&Co, 2017. 13. Connor BA, Phair J, Sack D, et al.   Randomized, double-blind study in healthy adults to assess the boosting effect of Vaqta or Havrix after a single dose of Havrix. Clin Infect Dis  2001; 32: 396– 401. Google Scholar CrossRef Search ADS PubMed  14. 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– 9. Google Scholar CrossRef Search ADS PubMed  15. Tseng YT, Chang SY, Liu WC, et al.   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– 41. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. 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Comparable Serologic Responses to 2 Different Combinations of Inactivated Hepatitis A Virus Vaccines in HIV-Positive Patients During an Acute Hepatitis A Outbreak in Taiwan

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© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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0022-1899
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Abstract

Abstract We evaluated the serologic responses to different 2-dose combinations of the inactivated hepatitis A virus (HAV) vaccines Havrix and Vaqta among human immunodeficiency virus–positive individuals during an acute hepatitis A outbreak in Taiwan. In this 16-month retrospective study, one group received 1 dose of Havrix followed by 1 dose of Vaqta, and another group received 2 doses of Vaqta. The Havrix-Vaqta and Vaqta-Vaqta groups achieved similar seroconversion rates at weeks 28–36 (82.3% and 80.9%, respectively; absolute difference, 1.3% [95% confidence interval {CI}, −6.3%–3.7%]) and week 48 (94.7% and 94.4%, respectively; absolute difference, 0.3% [95% CI, −2.6%–3.2%]), suggesting the interchangeability of different combinations of HAV vaccines. The significantly higher seroconversion rate after the first dose of Vaqta, compared with the dose of Havrix (53.0% vs 32.4%) may provide potential benefits in preventing HAV infection during the outbreak. Viral hepatitis, vaccination, seroconversion, men who have sex with men Outbreaks of acute hepatitis A among men who have sex with men (MSM) have been occurring across Asia, Europe, and the United States since 2015 [1–3]. Hepatitis A virus (HAV) vaccination is the most effective strategy to prevent acute hepatitis A and has been recommended for at-risk populations, such as MSM and illicit drug users [4]. In the general population, HAV vaccines are highly immunogenic, with a high seroconversion rate of >95% following vaccination. Despite the suboptimal serologic response among human immunodeficiency virus (HIV)–positive individuals [5], the effectiveness of HAV vaccination could be as high as 96% in the outbreak setting [6]. During outbreaks of acute hepatitis A, the unexpected increases in the demand for HAV vaccines have constrained vaccine supplies in European countries and the United States [7]. The shortages of vaccine supplies have raised issues about implementing a single dose of HAV vaccine and concerns about the interchangeability between combinations of different vaccine types during the outbreaks [2]. The most commonly used formulations of inactivated HAV vaccines consist of 2 single-antigen vaccines (Havrix or Vaqta) [5]. Randomized, controlled trials have shown comparable seroconversion rates between Havrix and Vaqta in healthy subjects despite higher anti-HAV titers in subjects receiving Vaqta [8, 9]. However, the immunogenicity of different HAV vaccine combinations has rarely been evaluated among HIV-positive individuals. In this study, we aimed to compare the serologic responses to 2 different vaccine combinations and to identify the associated factors with serologic responses among HIV-positive individuals during an outbreak of acute hepatitis A. SUBJECTS AND METHODS Study Setting and Patients Between mid-2015 and late 2017, an outbreak of acute hepatitis A involving 1500 indigenous cases occurred in Taiwan [10]. More than half of case patients were MSM and/or HIV-positive individuals. At the start of the outbreak, all HIV-positive individuals at the National Taiwan University Hospital who tested negative for anti-HAV immunoglobulin G (IgG) were advised to receive 2 doses of HAV vaccine, administered 6 months apart [6]. In this retrospective study, we included HIV-positive, HAV-seronegative individuals aged ≥19 years who underwent HAV vaccination between 1 June 2015 and 30 September 2016. We excluded those who only received 1 dose of HAV vaccine or those who had undergone HAV vaccination before June 2015. As a public health response to the outbreak of acute hepatitis A, the provision of HAV vaccination and determination of HAV antibody titers were not considered of research interest only, and informed consent was waived by the Research Ethics Committee at National Taiwan University Hospital. Exposures and Outcomes Because of an early shortage of Havrix at the hospital, 1440 enzyme-linked immunosorbent assay (ELISA) U of Havrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) was substituted by 50 U of Vaqta (Merck, West Point, PA) on 19 May 2016. For this reason, HIV-positive individuals included in the study received either Havrix for both doses (the Havrix-Havrix group), Havrix as the first dose followed by Vaqta as the second dose (the Havrix-Vaqta group), or Vaqta for both doses (the Vaqta-Vaqta group). Because only 19 individuals were in the Havrix-Havrix group, this group was excluded from analyses. Havrix-Vaqta and Vaqta-Vaqta doses were administered during the peak of the outbreak (Supplementary Figure 1). After HAV vaccination, the anti-HAV IgG titer was determined between weeks 4 and 24 (before the second dose of vaccine), and at weeks 28–36 (after the second dose) and week 48. The included individuals were followed from the date of HAV vaccination until acute hepatitis A onset, death, loss to follow-up, or the end of the study (30 September 2017). The primary outcome was serologic response at weeks 28–36 after the first HAV vaccination. The secondary outcomes included the serologic response between 4 and 24 weeks after the first HAV vaccination, the serologic response at week 48 after the first HAV vaccination, and acquisition of acute hepatitis A. The serologic response was estimated by intention-to-treat (ITT) with last-observation-carried-forward (LOCF) analysis and per-protocol (PP) analysis. Laboratory Investigations The serum anti-HAV IgG titer was determined using a chemiluminescence immunoassay assay (Architect HAVAb-IgG; Abbott Diagnostics, Wiesbaden, Germany), which is a semiquantitative assay of the chemiluminescence reaction, measured in relative light units. A signal to cutoff (S/CO) value of ≥1.00 was reported as positivity for anti-HAV IgG. Owing to the direct relationship between the amount of anti-HAV IgG and the number of relative light units, the S/CO value was recorded as an indirect indicator of the geometric mean titer of anti-HAV IgG. Statistical Analysis Variables were compared across the 2 groups by 1-way analysis of variance, with Bonferroni tests for multiple pair-wise comparisons. A logistic regression model was used to assess factors associated with seroconversion. Variables considered for entry into multivariable models included variables with a P value of <.1 in univariable analyses. The generalized estimating equation (GEE) model was used to determine the associations between the predictor variables and repeated measurements. All tests were 2-tailed, and a P value of <.05 was considered statistically significant. All statistical analyses were performed using Stata, version 12.0 (Stata, College Station, TX). RESULTS During the 16-month study period, 946 HIV-positive individuals testing negative for anti-HAV antibodies were included; 395 (41.8%) were in the Havrix-Vaqta group, and 551 (58.2%) were in the Vaqta-Vaqta group (Supplementary Figure 2). The clinical characteristics of the 2 groups are shown in Table 1. Most (95.6%) were MSM, and the median age was 35 years. At vaccination, 97.1% of individuals had been receiving combination antiretroviral therapy, with a baseline median CD4+ T-cell count of 574 cells/µL, and 85.1% had a plasma HIV RNA load of <20 copies/mL. Table 1. Comparison of Clinical Characteristics and Outcomes Between the Havrix-Vaqta and Vaqta-Vaqta Groups Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Data are proportion (%) of patients or median value (interquartile range). Abbreviations: cART, combination antiretroviral therapy; CI, confidence interval; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ITT, intention to treat; LOCF, last observation carried forward. aIncluded concurrent use of chemotherapy and immunomodulation agents. bUndetectable (UD), defined as <20 copies/mL. cDifferences between the ITT with LOCF analyses and the per-protocol analyses were 1.3% (95% CI, −3.7%–6.3%) and −3.0% (95% CI, −6.7%–.7%), respectively. dDifferences between the ITT with LOCF analyses and the per-protocol analyses were 0.3% (95% CI, −2.6%–3.2%) and 1.1 (95% CI, −2.6%–4.8%), respectively. View Large Table 1. Comparison of Clinical Characteristics and Outcomes Between the Havrix-Vaqta and Vaqta-Vaqta Groups Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Characteristic  Havrix-Vaqta  Vaqta-Vaqta  P  Age, y  35 (30–41)  34 (29–42)  .265  Men who have sex with men  373/395 (94.4)  531/551 (96.4)  .153  Current smoker  109/395 (27.6)  141/551 (25.6)  .837  HBsAg positive  44/395 (11.1)  53/551 (9.6)  .447  Anti-HCV positive  17/395 (4.3)  37/551 (6.7)  .115  Receiving immunosuppressanta  4/395 (1.0)  2/551 (0.4)  .214  Receiving cART at vaccination  385/395 (97.5)  534/551 (96.9)  .614  CD4+ T-cell count at vaccination         Overall, cells/µL  571 (437–748)  577 (441–743)  .779   >350 cells/µL  349/395 (88.4)  487/551 (88.4)  .989  Plasma HIV RNA load at vaccination         Overall, copies/mL  UDb  UDb  .859   <20 copies/mL  337/395 (85.3)  468/551 (84.9)  .871  Receiving cART at wk 28–36  389/395 (98.5)  539/551 (97.8)  .464  CD4+ T-cell count at wk 28–36, cells/µL  585 (460–781)  617 (480–781)  .355  Plasma HIV RNA load at wk 28–36         Overall, copies/mL  UDb  UDb  .336   <20 copies/mL  355/395 (89.9)  501/551 (90.9)  .197  Syphilis during follow-up  115/395 (29.1)  140/551 (25.4)  .205  Serologic response at wk 28–36c   ITT with LOCF analysis  325/395 (82.3)  446/551 (80.9)  .301   Per-protocol analysis  293/318 (92.1)  331/348 (95.1)  .056  Serologic response at wk 48d   ITT with LOCF analysis  374/395 (94.7)  520/551 (94.4)  .418   Per-protocol analysis  307/322 (95.3)  229/243 (94.2)  .278  Acquisition of acute hepatitis A  0/395 (0)  0/551 (0)    Data are proportion (%) of patients or median value (interquartile range). Abbreviations: cART, combination antiretroviral therapy; CI, confidence interval; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ITT, intention to treat; LOCF, last observation carried forward. aIncluded concurrent use of chemotherapy and immunomodulation agents. bUndetectable (UD), defined as <20 copies/mL. cDifferences between the ITT with LOCF analyses and the per-protocol analyses were 1.3% (95% CI, −3.7%–6.3%) and −3.0% (95% CI, −6.7%–.7%), respectively. dDifferences between the ITT with LOCF analyses and the per-protocol analyses were 0.3% (95% CI, −2.6%–3.2%) and 1.1 (95% CI, −2.6%–4.8%), respectively. View Large The comparisons of primary and secondary serologic outcomes following HAV vaccination between the Havrix-Vaqta and Vaqta-Vaqta groups are shown in Table 1 and Figure 1. At weeks 28–36, the seroconversion rate in the ITT with LOCF analysis was 82.3% for the Havrix-Vaqta group and 80.9% for the Vaqta-Vaqta group (absolute difference, 1.3%; 95% confidence interval [CI], −6.3%–3.7%). In the per-protocol analysis, the seroconversion rate was 92.1% (293 of 318 patients) for the Havrix-Vaqta group and 95.1% (331 of 348 patients) for the Vaqta-Vaqta group (absolute difference, −3.0%; 95% CI, −6.7%–.7%). At week 48, the seroconversion rate in the ITT with LOCF analysis was 94.7% for the Havrix-Vaqta group and 94.4% for the Vaqta-Vaqta group (absolute difference, 0.3%; 95% CI, −2.6%–3.2%). In the per-protocol analysis, the seroconversion rate was 95.3% (307 of 322 patients) and 94.2% (229 of 243 patients) for the Havrix-Vaqta group and Vaqta-Vaqta group, respectively (absolute difference, 1.1%; 95% CI, −2.6%–4.8%). No individuals who received 2 doses of HAV vaccine acquired acute hepatitis A during the study period. However, 5 individuals receiving only a single dose of HAV vaccine acquired acute hepatitis A and were not included in the analysis; of them, 3 received Havrix and 2 received Vaqta. Figure 1. View largeDownload slide Seroconversion rates after hepatitis A virus (HAV) vaccination at different follow-up intervals in the Havrix-Vaqta and Vaqta-Vaqta groups. Data are from the intention-to-treat with last-observation-carried-forward analysis. IgG, immunoglobulin G. Figure 1. View largeDownload slide Seroconversion rates after hepatitis A virus (HAV) vaccination at different follow-up intervals in the Havrix-Vaqta and Vaqta-Vaqta groups. Data are from the intention-to-treat with last-observation-carried-forward analysis. IgG, immunoglobulin G. The rates of serologic response at different follow-up intervals in the ITT with LOCF analysis are depicted in Figure 1. Four weeks after the first dose of vaccine, the seroconversion rate was only 3.5% for individuals receiving Havrix and 2.7% for those receiving Vaqta. Between weeks 4 and 24, before the second dose of vaccine, the seroconversion rate increased; the highest serologic response rate, observed during weeks 21–24, was 32.4% in individuals receiving Havrix and 53.0% for those receiving Vaqta (absolute difference, −20.6%; 95% CI, −14.4%–26.8%). The seroconversion rates at different follow-up intervals, based on per-protocol analysis, are depicted in Supplementary Figure 3. After the second dose of HAV vaccine, seroconversion rates could further increase to >90% without statistically significant differences between the 2 groups. The S/CO values of anti-HAV IgG demonstrated significantly higher titers of anti-HAV IgG for the Vaqta-Vaqta group, compared with the Havrix-Vaqta group (Supplementary Figure 4). At weeks 21–24, the S/CO value for the Vaqta-Vaqta group was higher than that for the Havrix-Vaqta group (median, 2.8 vs 0.8; P < .001). Despite the similar seroconversion rates between the 2 groups at weeks 28–36 and 48, the S/CO values remained significantly higher for the Vaqta-Vaqta group, compared with those for the Havrix-Vaqta group, at weeks 28–36 (median, 10.8 vs 9.2; P < .001) and week 48 (median, 9.7 vs 8.4; P < .001). In multivariable analysis, the factors associated with seroconversion at weeks 28–36 included a younger age (adjusted odds ratio [AOR], 1.06 per 1-year decrease; 95% CI, 1.02–1.11), a higher CD4+ T-cell count (AOR, 1.04 per 10-cells/µL increase; 95% CI, 1.02–1.05), and an undetectable plasma HIV RNA load at vaccination (AOR, 2.92; 95% CI, 1.38–6.18). The factors associated with seroconversion between 4 and 24 weeks included a younger age (AOR, 1.02 per 1-year decrease; 95% CI, 1.01–1.04), a higher CD4+ T-cell count at vaccination (AOR, 1.01 per 10-cells/µL increase; 95% CI, 1.00–1.01), receipt of Vaqta as the first dose of HAV vaccine (AOR, 4.56; 95% CI, 3.26–6.39), and the interval from vaccination to anti-HAV IgG testing (AOR, 1.14 per 1-week increase; 95% CI, 1.12–1.16; Supplementary Table 1). Discussion In this study of HAV vaccination during an acute hepatitis A outbreak, we found that different 2-dose combinations of HAV vaccines achieved similar seroconversion rates at weeks 28–36 and 48 among HIV-positive individuals, suggesting that the 2 vaccine combinations are interchangeable. However, a single dose of Vaqta induced faster and better serologic responses than that of Havrix. A younger age and improved surrogate markers of immune status enhanced the immunogenicity to HAV vaccination. While 50 U of Vaqta are equivalent to approximately 50 ng of viral protein, the viral antigen activity of Havrix is expressed in ELISA U. In addition to the intrinsic difficulties in comparing their amounts of viral protein, the immunoassays used to evaluate anti-HAV titers in pivotal studies were also different [11, 12]. The comparison of serologic responses to the 2 vaccine types was studied in 2 clinical trials in the healthy population. Both trials demonstrated the similarly high seroconversion rates (>95%) across the study groups with significantly higher geometric mean titers in subjects receiving Vaqta, compared with those receiving Havrix, at weeks 24 and 28 [8, 9]. Another clinical trial investigated the boosting effect of Havrix and Vaqta in healthy adults who had received a single dose of Havrix. Although Vaqta tended to achieve numerically higher serologic responses, the study concluded noninferiority and indicated that the 2 vaccines were interchangeable [13]. HIV-positive individuals have poorer serologic responses to HAV vaccination than the general population [14]. Our data demonstrating similar seroconversion rates between Havrix-Vaqta and Vaqta-Vaqta also support the interchangeability of the 2 different vaccines among HIV-positive individuals. Because HIV-positive patients receiving 1 dose of HAV vaccine without achieving seroprotective antibody levels are still at risk for acquiring acute hepatitis A, the strategies to facilitate serologic responses during the acute hepatitis A outbreak need to be evaluated [6]. In our study, Vaqta achieved higher seroconversion rates and anti-HAV IgG titers than Havrix before the second dose of HAV vaccine was administered, which may have potential benefit in preventing HAV infection in the outbreak setting. However, a shortage of Havrix, which permitted 2 doses to be administered to only 19 patients, precluded us from investigating whether 2 doses of Vaqta could achieve higher immunogenicity than 2 doses of Havrix among HIV-positive individuals (Supplementary Figure 2). Our study has several limitations. First, the administration of HAV vaccines and determination of anti-HAV IgG titers were conducted at regular intervals instead of fixed time points, owing to the nature of this observational study. Second, we used a convenient sample, and an a priori sample size calculation was not performed. However, our study was sufficiently powered to demonstrate the noninferiority between the study groups [15]. Third, decreased awareness of the importance of measuring anti-HAV IgG titers after the outbreak was contained might have led to a greater number of missing data points in the Vaqta-Vaqta group during the later period of study. Finally, the serologic responses observed could be attributed to vaccination or natural infection. However, the impact of natural infection on serologic responses would be expected to be similar since most HAV vaccination was conducted during the peak of the outbreak and because the incidence of syphilis, a surrogate of risky sexual behavior, was similar across the study groups. In conclusion, while Vaqta elicited more-rapid and better serologic responses than Havrix before administration of the second dose of HAV vaccine, the serologic responses to 2-dose combinations of Havrix-Vaqta as compared to Vaqta-Vaqta were similar among HIV-positive individuals during an outbreak of acute hepatitis A. Supplementary Data Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Notes Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. 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– 40. Google Scholar CrossRef Search ADS PubMed  2. European Centre for Disease Prevention and Control. 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Lin KY, Hsieh SM, Sun HY, et al.   Serologic responses and effectiveness of hepatitis A vaccination among HIV-positive individuals during the outbreak of acute hepatitis A. Hepatology  2018; doi: 10.1002/hep.29780. 7. Barreiro P, Soriano V. Hepatitis A outbreaks in European homosexual men. AIDS Rev  2017; 19: 113– 4. Google Scholar PubMed  8. Braconier JH, Wennerholm S, Norrby SR. Comparative immunogenicity and tolerance of Vaqta and Havrix. Vaccine  1999; 17: 2181– 4. Google Scholar CrossRef Search ADS PubMed  9. Ashur Y, Adler R, Rowe M, Shouval D. Comparison of immunogenicity of two hepatitis A vaccines–VAQTA and HAVRIX–in young adults. Vaccine  1999; 17: 2290– 6. Google Scholar CrossRef Search ADS PubMed  10. Taiwan National Infectious Disease Surveillance System. https://nidss.cdc.gov.tw/en/. Accessed 1 January 2018. 11. Havrix: full prescription information [package insert]. Rixensart, Belgium: GlaxoSmithKline Biologicals, 2017. 12. VAQTA: Full Prescription Information (Package Insert). MERCK&Co, 2017. 13. Connor BA, Phair J, Sack D, et al.   Randomized, double-blind study in healthy adults to assess the boosting effect of Vaqta or Havrix after a single dose of Havrix. Clin Infect Dis  2001; 32: 396– 401. Google Scholar CrossRef Search ADS PubMed  14. 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– 9. Google Scholar CrossRef Search ADS PubMed  15. Tseng YT, Chang SY, Liu WC, et al.   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– 41. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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The Journal of Infectious DiseasesOxford University Press

Published: Apr 16, 2018

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