Features of occult hepatitis B diagnostics in cancer patients

Purpose of the study. Analysis of the frequency of detection of HBsAg-negative hepatitis B  serological and molecular biological markers in cancer patients.

Materials and methods. The blood serum samples of patients hospitalized at the National Medical Research Centre for Oncology in 2016–2023 were studied. 41,523 samples were tested for HBsAg, 2,035 for anti-HBcore, of which 958 were tested simultaneously for both markers using the enzyme-linked immunosorbent assay (ELISA) or chemiluminescent immunoassay (CLIA). 1,380 samples were tested for the presence of hepatitis B virus (HBV) DNA in blood plasma using real time polymerase chain reaction (qPCR).

Results. The HBsAg prevalence in cancer patients accounted for 2.5 % (1051/41523), 23.7 % (483/2035) for anti-HBcore. Simultaneous examination for HBsAg and anti-HBcore revealed various combinations of markers. Among HBV-positive variants, the most common was the combination anti-HBcore+HBsAg-. The average number of such patients was 20.6 % (197/958). The simultaneous presence of both markers was noted in 4.6 % of patients (44/958). There were no isolated HBsAg detection cases. The total number of HBV+ individuals was 25.2 % (241/958). 81.7 % out of these (197/241) were HBsAg-negative.

219 samples with the HBV DNA presence in the blood plasma were identified. 19 of these were examined simultaneously for HBsAg, anti-HBcore. The majority (78.9 %) had all three markers. 21.1 % were HBsAg-negative but DNA-positive (latent form of infection), 15.8 % of which were anti-HBcore-positive, and 5.3 % did not have a single serological marker.

Conclusion. The detection of anti-HBcore in the absence of HBsAg can indicate the presence of occult forms of hepatitis B, which under conditions of drug immunosuppression can be reactivated. The identified significant percentage of cancer patients with occult hepatitis B variants highlights the necessity to expand the number of diagnostic markers for screening. Additional testing for anti-HBcore can significantly increase the likelihood of detecting HBV during prehospital testing.

1. Lampertico P., Agarwal K., Berg T. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2017;67(2):370–98. https://doi.org/10.1016/j.jhep.2017.03.021

2. Fazylov V.KH., Yeremeyeva ZH.G., Turayev R.G. Puti optimizatsii diagnostiki latentnoy formy gepatita B u donorov krovi. Infektsionnyye bolezni: novosti, mneniya, obucheniye. 2023;12(1):54–61. (In Russ.). https://doi.org/10.33029/2305-3496-2023-12-1-54-61

3. Zaytsev I.A. Occult HBV infection. Aktual'naâ Infektologiâ. 2018;6(3):132-140. (In Russ.). https://doi.org/10.22141/2312-413x.6.3.2018.136646

4. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-398. https://doi.org/10.1016/j.jhep.2017.03.021

5. You H., Wang F., Li T., Xu X., Sun Y., Nan Y., Wang G., Hou J., Duan Z., Wei L., Jia J., Zhuang H.; Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2022). J Clin Transl Hepatol. 2023 Nov 28;11(6):1425-1442. https://doi.org/10.14218%2FJCTH.2023.00320

6. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO. Available at: https://iris.who.int/bitstream/handle/10665/376353/9789240090903-eng.pdf?sequence=1

7. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. https://doi.org/10.1002/hep.29800

8. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxì A, Donato F, Ferrari C, Gaeta GB, Gerlich WH, Levrero M, Locarnini S, Michalak T, Mondelli MU, Pawlotsky JM, Pollicino T, Prati D, Puoti M, Samuel D, Shouval D, Smedile A, Squadrito G, Trépo C, Villa E, Will H, Zanetti AR, Zoulim F. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008 Oct;49(4):652-7. https://doi.org/10.1016/j.jhep.2008.07.014

9. Raimondo G, Locarnini S, Pollicino T, Levrero M, Zoulim F, Lok AS; Taormina Workshop on Occult HBV Infection Faculty Members. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J Hepatol. 2019 Aug;71(2):397-408. https://doi.org/10.1016/j.jhep.2019.03.034

10. Semenenko T.A., Yarosh L.V., Bazhenov A.I., Nikitina G.Yu., Kleimenov D.A., Elgort D.A., Cozhushny A.P., Feldsherova A.A., Hatc Yu S., Godkov M.A., Suslov A.P. Epidemiological Evaluation of the Prevalence of «Occult» Forms and Epidemiological Estimation of the «Occult» Hepatitis B Infection and HBsAg-mutations Prevalence at Patients with Hematological Disease. Epidemiology and Vaccinal Prevention. 2012;6(67). (In Russ.).

11. Available at: https://cyberleninka.ru/article/n/epidemiologicheskaya-otsenka-rasprostranennosti-skrytyh-form-i-hbsag-mutantov-virusa-gepatita-v-u-gematologicheskih-bolnyh

12. Semenov А.V., Ostankova Yu.V. Occult (latent) hepatitis B virus: problems of laboratory diagnostics. Infektsionnye bolezni: novosti, mneniya, obuchenie [Infectious Diseases: News, Opinions, Training]. 2019; 8 (3): 60–9. doi: 10.24411/2305-3496-2019-13010 (In Russ.). https://doi.org/10.24411/2305-3496-2019-13010

13. Feoktistova P.S., Vinnitskaya Ye.V., Nurmukhametova Ye.A., Tikhonov I.N. Prakticheskiye rekomendatsii po profilaktike i lecheniyu reaktivatsii/obostreniya khronicheskikh virusnykh gepatitov u patsiyentov, poluchayushchikh protivoopukholevuyu terapiyu. Prakticheskiye rekomendatsii RUSSCO, chast' 2. Zlokachestvennyye opukholi. 2023;13(#3s2):292–299. (In Russ.). doi: 10.18027/2224-5057-2023-13-3s2-2-296-303. Available at: https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-55.pdf

14. Tseng TC, Wu JW, Kao JH. Looking Into the Crystal Ball: A Novel Biomarker for Outcomes of Patients With Chronic Hepatitis B Virus Infection. Hepatol Commun. 2022 Jan;6(1):5-7. https://doi.org/10.1002/hep4.1856

15. Sandmann L, Bremer B, Ohlendorf V, Jaroszewicz J, Wedemeyer H, Cornberg M, Maasoumy B. Kinetics and Value of Hepatitis B Core-Related Antigen in Patients with Chronic Hepatitis B Virus Infection during Antiviral Treatment. Viruses. 2024; 16(2):255. https://doi.org/10.3390/v16020255

16. Carey I, Gersch J, Wang B, Moigboi C, Kuhns M, Cloherty G, et al. Pregenomic HBV RNA and Hepatitis B Core-Related Antigen Predict Outcomes in Hepatitis B e Antigen-Negative Chronic Hepatitis B Patients Suppressed on Nucleos(T)ide Analogue Therapy. Hepatology 2020;72(1):42-57. https://doi.org/10.1002/hep.31026

17. Dahari H, Shlomai A, Cotler SJ. Early HBV RNA kinetics under NA treatment may reveal new insights into HBV RNA dynamics and NA mode of action-more detailed kinetic studies are needed. J Viral Hepat 2021;28(4):687-688. https://doi.org/10.1111%2Fjvh.13463

18. Shi Y, Wang Z, Ge S, Xia N, Yuan Q. Hepatitis B Core Antibody Level: A Surrogate Marker for Host Antiviral Immunity in Chronic Hepatitis B Virus Infections. Viruses. 2023; 15(5):1111. https://doi.org/10.3390/v15051111

19. Bochkova G.D., Ishchenkova I.V., Palukhin S.I., Kudinova E.Ye., Ryabikina E.V., Gerasimova O.V., Alaverdyan A.I. Frequency of detection of markers of hemotransmissive infections in donors of the Rostov region. Glavnyy vrach Yuga Rossii. 2019;66(2):4-6. (In Russ.). Available at: https://cyberleninka.ru/article/n/chastota-vyyavleniya-markerov-gemotransmissivnyh-infektsiy-u-donorov-rostovskoy-oblasti

20. Zykova T.A., Nikolaeva N.V., Kapuza E.A., Pushkareva T.F., Shatokhina O.I., Velikorodnaya L.A., Shevyakova E.A., Lysenko I.B. The effect of chemotherapy on the reactivation of chronic viral hepatitis B in patients with lymphomas. In the book: Materials of the IV St. Petersburg Oncology Forum “White Nights 2018” Abstracts. Autonomous non-profit scientific and medical organization “Oncology Issues”. 2018. P. 223. (In Russ.). Available at: https://www.elibrary.ru/download/elibrary_35290827_55119149.pdf

21. Hwang JP, Feld JJ, Hammond SP, Wang SH, Alston-Johnson DE, Cryer DR, Hershman DL, Loehrer AP, Sabichi AL, Symington BE, Terrault N, Wong ML, Somerfield MR, Artz AS. Hepatitis B Virus Screening and Management for Patients With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update. J Clin Oncol. 2020 Nov 1;38(31):3698-3715. https://doi.org/10.1200/jco.20.01757

22. Prevention and Treatment of Cancer-Related Infections. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Version 1.2024 — April 30, 2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf

23.