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Abstract Background:  Sporadic outbreaks of viral hepatitis and recent hepatitis A virus Abstract Background:  Sporadic outbreaks of viral hepatitis and recent hepatitis A virus

Abstract Background: Sporadic outbreaks of viral hepatitis and recent hepatitis A virus - PowerPoint Presentation

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Abstract Background: Sporadic outbreaks of viral hepatitis and recent hepatitis A virus - PPT Presentation

Methods We analyzed the data of patients who participated in this vaccination program from 2013 to 2019 Threedose vaccination of lyophilized inactivated aluminumfree hepatitis A vaccine Aimmugen ID: 927188

cd4 hepatitis antibody vaccination hepatitis cd4 vaccination antibody hiv ratio cd8 patients response hav 2013 median cell iqr serologic

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Slide1

Abstract

Background: Sporadic outbreaks of viral hepatitis and recent hepatitis A virus (HAV) outbreaks have caused severe epidemics worldwide. After the outbreak of hepatitis A among MSM in Tokyo from 1998 to 1999, we started a hepatitis A vaccination program for HIV-infected patients who are seronegative for protective antibodies. Methods: We analyzed the data of patients who participated in this vaccination program from 2013 to 2019. Three-dose vaccination of lyophilized inactivated aluminum-free hepatitis A vaccine (Aimmugen®) was administered to HAV-antibody-negative HIV-infected patients. Serology samples for hepatitis A virus antibody titers were taken 4–12 weeks later. Anti-hepatitis A virus antibody titers were measured by chemiluminescent immunoassay. The seroconversion rate was determined, and the influence of several factors including CD4 cell counts, CD4/CD8 ratio, plasma viral load, smoking status, HBc antibody, and HCV antibody were evaluated.Results: Four hundred and sixty-two patients were analyzed in this study: 99.2% were men and 98.9% were Japanese. Median age was 39 (IQR 32–45) years, 270 (58%) were HBc antibody positive, 15 (3.3%) were HCV antibody positive, and 178 (38.5%) were active smokers. The median CD4/CD8 ratio was 0.63 (0.46–0.87) and median CD4 cell count was 548.5 (417.2–715.3). Overall, 427 (92.4%) cases were positive for hepatitis A virus antibody after the initial series of vaccinations. Among those who did not develop serologic responses, one patient developed acute hepatitis A. The factor associated with seroconversion was higher CD4/CD8 ratio (per 0.50 increase, adjusted odds ratio, 3.12; 95% confidence interval, 1.25–7.79, p = 0.015).Conclusions: Hepatitis A vaccination was effective for HIV-infected patients. Higher CD4/CD8 ratio was associated with higher serologic response to hepatitis A vaccination. Therefore, we need to promote vaccination to prevent ongoing transmission and reduce the likelihood of future outbreaks.

BackgroundRecent sporadic outbreaks of HAV have caused severe global epidemics. HAV vaccination antibody seroconversion rates are lower than those in HIV-uninfected patients. After the outbreak of hepatitis A among MSM in Tokyo from 1998 to 1999, we started a hepatitis A and B vaccination program for HIV-infected patients in our clinic. In Japan, only one formulation of inactivated aluminum-free hepatitis A vaccine (Aimmugen®) is available.

Serologic response to hepatitis A vaccination among HIV-infected individuals

Takashi Muramatsu, Takeshi Hagiwara, Akito Ichiki, Yushi Chikasawa, Masato Bingo, Ryoko Sekiya, Kazuhisa Yokota, Mihoko Yotsumoto, Kagehiro Amano, and Ei KinaiDepartment of Laboratory Medicine, Tokyo Medical University Hospital, Tokyo, JAPAN

PRESENTED AT THE 23

RD

INTERNATIONAL AIDS CONFERENCE (AIDS 2020) | 6-10 JULY 2020

Acknowledgements

This vaccination program was originally started by Professor Katsuyuki Fukutake, Dr. Yasuharu Nishida, and the late Dr. Yasuyuki Yamamoto. We thank them for their efforts and respect their profound insight and tireless contribution to HIV care in Japan.

DiscussionThe hepatitis A vaccination response rate is favorable but not perfect. Compared with previous studies (Table 4), three vaccination doses had a better effect than two doses (except rapidly-accelerated schedules), and our group showed relatively higher CD4 cell counts compared with other studies, resulting in a better response. We observed no serious adverse events among vaccinated individuals. Only one patient who showed primary failure after the complete series of vaccinations developed acute hepatitis A during the outbreak.Nadir CD4, CD4 cell count, and CD4/CD8 ratio were significantly associated with a high rate of serological response. Reported factors related to better serological response included high CD4 cell counts, high CD4/CD8 ratio, controlled HIV viremia, female, non-smoker, and no HCV coinfection. We did not evaluate the impact of female or HCV coinfection because of small percentages of these in our study.

Results

Table 2. Characteristics of all

participants, responders, and non-responders

CharacteristicsAll patients (n=462)Responders (n=427)Non-responders (n=35)P-valueAge, median [IQR], years39 [32-45]39 [32-46]41 [35-47]0.249Sex (male:female)457:5422:535:01.000Body mass index, median [IQR], kg/m223.3 [21.2-26.3]23.4 [21.2-26.3]22.6 [20.5-25.7]0.386NationalityJapanese or East Asian 98.8%―――Active smoker, n (%)192 (41.6)176 (41.2)16 (45.7)0.598Alcohol (> 10 units/week), n (%) 121 (26.2)110 (25.8)11 (31.4)0.548Hypertension, n (%)57 (12)52 (12.0)5 (14)0.404Diabetes mellitus, n (%)16 (3.5)13 (3.0)3 (8.6)0.080Chronic kidney disease, n (%)14 (3)11 (2.6)3 (8.6)0.057Steroid use, n (%)2 (0.4)2 (0.5)0―Hepatitis B core antibody, n (%) 270 (58)252 (59.0)18 (51.4)0.380Hepatitis C antibody, n (%)15 (3.3)13 (3.0)2 (5.7)0.316AIDS 48 (10.4)39 (9.1)9 (25.7)0.006Nadir CD4, median [IQR], cells/μL251 [118-374]264 [131-386]155 [49-243]0.001CD4 cell count, median [IQR], cells/μL549 [417-715]555 [430-725]381 [290-560]<0.001CD4 cell count > 200 cells/μL, n (%)455 (98.5)424 (99.3)31 (88.6)0.001CD4/CD8 ratio, median [IQR]0.63 [0.46-0.87]0.64 [0.48-0.88]0.42 [0.25-0.61]<0.001ART, n (%)395 (85.5)364 (85.2)31 (88.6)0.601ART duration, median [IQR], years2.7 [0.7-5.8]2.8 [0.7-5.9]1.6 [0.9-4.0]0.210HIV viral load  HIV-RNA < 400 copies/mL, n (%)396 (85.7)364 (85.2)32 (91.4)0.452  HIV-RNA < 50 copies/mL, n (%)382 (82.7)353 (82.7)29 (82.9)1.000HAV serological response, n (%)427 (92.4)427 (100)0―Serious adverse effects, n000―Acute hepatitis A, n101―

Table 3. Factors Associated With Serologic Response

Univariate analysisMultivariate analysisCharacteristicsOdds ratio (95%CI)P-valueOdds ratio (95%CI)P-valueAge (per 1-year increase)0.985 (0.953-1.018)0.3610.978 (0.945-1.012)0.208Body mass index1.025 (0.941-1.116)0.578Active smoker0.833 (0.417-1.664)0.6041.021 (0.469-2.222)0.959Alcohol (> 10 units/week)0.757 (0.359-1.596)0.465Hypertension0.693 (0.254-1.890)0.474Diabetes mellitus0.283 (0.076-1.052)0.060Chronic kidney disease0.238 (0.063-0.904)0.035Anti HBc antibody1.360 (03682-2.712)0.383Anti HCV antibody0.518 (0.112-2.394)0.400AIDS0.290 (0.127-0.664)0.003Nadir CD4 (per 50 cells/μL increase)1.211 (1.071-1.369)0.002CD4 (per 50 cells/μL increase)1.143 (1.042-1.252)0.0041.095 (0.980-1.224)0.111CD4/CD8 ratio (per 0.50 increase)4.440 (2.039-9.667)<0.0013.12 (1.25-7.79)0.015HIV viral load  VL <4000.393 (0.092-1.683)0.208  VL <500.684 (0.234-2.004)0.4890.435 (0.141-1.338)0.278ART implementation0.620 (0.183-2.094)0.441

Table 4. Comparison of recent studies of HAV vaccine for PLWH

AuthorsnvaccinerouteMedian CD4Serologic response rate (%)CommentsTseng et al. 1Taiwan (2013)582Havrix®IM452-53875.7-89.22 or 3 doses58%-67% on ARTJimenez et al. 2USA (2013)226Havrix® vs Twinrix®IM44653-542 doses85% on ARTKourkounti et al. 3Greece (2013)113Havrix®/VAQTA®IM57071-802 doses56% on ART Jablonowska et al. 4Poland (2014)234Havrix®IM45077.02 doses40% on ARTLin et al. 5Taiwan (2018)1,001Havrix®/VAQTA®IM55488.4-94.52 dosesFritzsche et al.6Germany (2019)131Havrix®/Twinrix®IM49080.22 or 3 dosesOur study502Aimmugen®SC54992.43 doses85.5% on ART

ReferencesHepatology 2013;57:1734-41, Vaccine 2013;31:1328-33, Viral Immunol 2013;26:357-63Int J STD AIDS 2014;25:745-50, Hepatology. 2018;68:22-31, Vaccine 2019;27:2278–2283

Contact informationTakashi MuramatsuNishi-Shinjuku 6-7-1, Shinjuku-ku, Tokyo, JapanE-mail: tk4mrmz@tokyo-med.ac.jp

MethodsWe investigated demographic data and laboratory results of participants who had completed this vaccination program between 2013 and 2019. Anti-hepatitis A virus antibody titers were measured by chemiluminescent immunoassay 4–12 weeks after the last dose (serologic response was defined as an anti-hepatitis A virus antibody signal-to-cutoff > 1.0). Statistical analysis Chi-square test was used for comparisons of categorical variables between two groups. A non-parametric Mann-Whitney U-test was performed for comparisons of continuous variables. Logistic regression was used to determine factors associated with serologic responses. Statistical analysis was performed by SPSS software, version 22.0 (SPSS).

Patients who visited the clinic with a negative anti-HAV IgG testn = 1,132Patients who agreed to participate in the vaccination programn = 642

Excluded patients (n = 160)

Declined 1 Failed to complete series 26 Lost during follow-up 133

Patients included in the analysisn = 482

Figure 1. Study enrollment overview

Figure 2. Case study: 49-year-old man (acute hepatitis A case after vaccination)

CD4/CD8

2013 2014 2015 2016 2017 2018

CD4 (/μL)

HIV-RNA (copies/mL)

CD4 (/

μL

)HIV-RNA (copies/mL)

CD4/CD8

Year

Acute

hepatitis A

HAV ab titer <0.50 <0.50 7.24

HAV

vaccine

IM: intramuscular, SC: subcutaneous

ConclusionWe confirmed hepatitis A vaccination was effective for HIV-infected patientsHigher CD4/CD8 ratio was associated with higher serologic responses to hepatitis A vaccinationWe need to promote further vaccination to prevent ongoing transmission and reduce the likelihood of future outbreaks

Diagnosed in 1999 (Pneumocystis pneumonia, CMV retinitis, MAC lymphadenitis, nadir CD4 2/μL)Medical history: hyperthyroidism Social history: active smokerStarted ART in 1999 (d4T+3TC+EFV→TAF/FTC+EFV)Low CD4 cell counts (150–200) and CD4/CD8 ratio (0.2) despite good viral suppressionJoined vaccination program in 2015 → primary failureDeveloped acute hepatitis A in 2018Seroconversion was confirmed after acute hepatitis

IQR: interquartile range

AgentAluminumRegular scheduleRecommended routeContents (antigen)Aimmugen®--3 dosesSC or IMHighly purified inactivated HAV 0.5 μgHavrix®Adsorbed2 dosesIM1,440 ELISA unitsVAQTA®Adsorbed2 dosesIM50 units

Table 1. Comparison of HAV vaccination agents

IM: intramuscular, SC: subcutaneous