Diagnostic Utility of Pre-Genomic Hepatitis B RNA in the Evaluation of HBV/HIV Coinfection
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Abstract
Background: Newer biomarkers of Hepatitis B virus (HBV) infection and treatment response have not been well-characterized in individuals with HBV/HIV coinfection.
Methods: Pre-genomic RNA (pgRNA) and quantitative HBsAg (qHBsAg) were used to evaluate the associations with baseline characteristics. Participants included two separate groups – 236 with HBV/HIV coinfection enrolled in a cross-sectional cohort in Ghana and 47 from an HBV nucleoside/nucleotide treatment trial comparing tenofovir to adefovir in the United States.
Results: In both cohorts, HBe antigenemia was highly associated with pgRNA and HBV DNA levels. In the treatment cohort, pre-treatment pgRNA serum concentration was 7.0 log10 U/mL, and mean qHBsAg was 201,297 IU/mL. The observed treatment-associated decrease in pgRNA was consistent with a biphasic decline curve that reached second-phase kinetics following treatment week 12. Changes from baseline were significantly correlated with changes in serum ALT (r = - 0.518; P = 0.023) but not with changes in HBV DNA (r = 0.132, P = NS). qHBsAg also correlated with ALT change (r = - 0.488, P = 0.034).
Conclusion: pgRNA and qHBsAg represent newer biomarkers of HBV replication that may help monitor response and treatment outcomes. HBV pgRNA is highly associated with both HBeAg and ALT and may predict both active replication from the closed circular DNA (cccDNA) template as well as hepatic injury.
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References
1. Shire NJ, Sherman KE. Management of HBV/HIV-Coinfected Patients. Semin Liver Dis. 2005;25 Suppl 1:48-57. PubMed PMID: 16103981.
2. Patel EU, Thio CL, Boon D, Thomas DL, Tobian AAR. Prevalence of Hepatitis B and Hepatitis D Virus Infections in the United States, 2011-2016. Clin Infect Dis. 2019;69(4):709-12. doi: 10.1093/cid/ciz001. PubMed PMID: 30605508; PMCID: PMC6669285.
3. Sherman KE. Management of the Hepatitis B Virus/HIV-Coinfected Patient. Top Antivir Med. 2015;23(3):111-4. PubMed PMID: 26518394; PMCID: PMC6148934.
4. Jeng WJ, Papatheodoridis GV, Lok ASF. Hepatitis B. Lancet. 2023;401(10381):1039-52. doi: 10.1016/s0140-6736(22)01468-4. PubMed PMID: 36774930.
5. Jeng WJ, Lok ASF. What will it take to cure hepatitis B? Hepatol Commun. 2023;7(4). doi: 10.1097/hc9.0000000000000084. PubMed PMID: 36972391; PMCID: PMC10043561.
6. Wang ZL, Zheng JR, Yang RF, Huang LX, Chen HS, Feng B. An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients: High-sensitivity Quantitative HBsAg Loss. J Clin Transl Hepatol. 2023;11(1):197-206. doi: 10.14218/jcth.2022.00289. PubMed PMID: 36406318; PMCID: PMC9647097.
7. Yip TC, Lok AS. How Do We Determine Whether a Functional Cure for HBV Infection Has Been Achieved? Clin Gastroenterol Hepatol. 2020;18(3):548-50. doi: 10.1016/j.cgh.2019.08.033. PubMed PMID: 31446185.
8. Lin N, Ye A, Lin J, Liu C, Huang J, Fu Y, Wu S, Xu S, Wang L, Ou Q. Diagnostic Value of Detection of Pregenomic RNA in Sera of Hepatitis B Virus-Infected Patients with Different Clinical Outcomes. J Clin Microbiol. 2020;58(2). doi: 10.1128/jcm.01275-19. PubMed PMID: 31723011; PMCID: PMC6989074.
9. Xu L, Li X, Lu L, Liu X, Song X, Li Y, Han Y, Zhu T, Cao W, Li T. HBV pgRNA profiles in Chinese HIV/HBV coinfected patients under pre- and posttreatment: a multicentre observational cohort study. J Viral Hepat. 2022;29(8):616-26. doi: 10.1111/jvh.13704. PubMed PMID: 35582838; PMCID: PMC9541493.
10. Jakharia N, Kottilil S, Chua JV. Quantification of Hepatitis B Surface Antigen: Is there a Role in HIV-Hepatitis B Virus Coinfection? AIDS Rev. 2019;21(4):175-83. doi: 10.24875/AIDSRev.19000077. PubMed PMID: 31834330.
11. Boyd A, Gozlan J, Miailhes P, Lascoux-Combe C, Cam MS, Rougier H, Zoulim F, Girard PM, Lacombe K. Rates and determinants of hepatitis B ‘e’ antigen and hepatitis B surface antigen seroclearance during long-term follow-up of patients coinfected with HIV and hepatitis B virus. Aids. 2015;29(15):1963-73. doi: 10.1097/qad.0000000000000795. PubMed PMID: 26153669.
12. Matthews GV, Ali RJ, Avihingsanon A, Amin J, Hammond R, Bowden S, Lewin SR, Sasadeusz J, Littlejohn M, Locarnini SL, Ruxrungtham K, Dore GJ. Quantitative HBsAg and HBeAg predict hepatitis B seroconversion after initiation of HAART in HIV-HBV coinfected individuals. PLoS One. 2013;8(4):e61297. doi: 10.1371/journal.pone.0061297. PubMed PMID: 23593455; PMCID: PMC3622017.
13. Chung RT, King WC, Ghany MG, Lisker-Melman M, Hinerman AS, Khalili M, Sulkowski M, Jain MK, Choi EK, Nalesnik MA, Bhan AK, Cloherty G, Wong DK, Sterling RK, Network H-HCSotHBR. A Prospective Cohort Study of Novel Markers of Hepatitis B Virus Replication in Human Immunodeficiency Virus Coinfection. Clin Gastroenterol Hepatol. 2023;21(1):125-35 e8. doi: 10.1016/j.cgh.2021.12.038. PubMed PMID: 34973459; PMCID: PMC9240105.
14. Zoutendijk R, Zaaijer HL, de Vries-Sluijs TE, Reijnders JG, Mulder JW, Kroon FP, Richter C, van der Eijk AA, Sonneveld MJ, Hansen BE, de Man RA, van der Ende ME, Janssen HL. Hepatitis B surface antigen declines and clearance during long-term tenofovir therapy in patients coinfected with HBV and HIV. J Infect Dis. 2012;206(6):974-80. doi: 10.1093/infdis/jis439. PubMed PMID: 22782950.
15. Butler EK, Luk KC, Gersch J, McNamara A, Holzmayer V, Kuhns M, De Medina MD, Schiff ER, Cloherty GA. Performance of an automated prototype assay for the detection and quantification of Hepatitis B pregenomic RNA in chronic HBV patients receiving nucleo(t)side analogue therapy. Hepatology. 2017;66:1016a-a. PubMed PMID: WOS:000412089802271.
16. Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S, Polsky B. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006;44(5):1110-6. PubMed PMID: 17058225.
17. Archampong TN, Lartey M, Sagoe KW, Obo-Akwa A, Kenu E, Gillani FS, Yang H, Boamah I, Flanigan T, Kwara A. Proportion and factors associated with Hepatitis B viremia in antiretroviral treatment naïve and experienced HIV co-infected Ghanaian patients. BMC Infect Dis. 2016;16:14. doi: 10.1186/s12879-016-1342-4. PubMed PMID: 26759172; PMCID: PMC4710995.
18. Archampong TN, Boyce CL, Lartey M, Sagoe KW, Obo-Akwa A, Kenu E, Blackard JT, Kwara A. HBV genotypes and drug resistance mutations in antiretroviral treatment-naive and treatment-experienced HBV-HIV-coinfected patients. Antivir Ther. 2017;22(1):13-20. doi: 10.3851/imp3055. PubMed PMID: 27167598; PMCID: PMC5106338.
19. Gao M, Feng C, Ying R, Nie Y, Deng X, Zhu Y, Tang X, Guan Y, Hu F, Li F. A novel one-step quantitative reverse transcription PCR assay for selective amplification of hepatitis B virus pregenomic RNA from a mixture of HBV DNA and RNA in serum. Arch Virol. 2019;164(11):2683-90. doi: 10.1007/s00705-019-04372-0. PubMed PMID: 31428915.
20. Anderson M, Stec M, Thi EP, Picchio G, Mbanya D, Cloherty G. Measuring hepatitis B pgRNA stability using an updated automated HBV pgRNA assay with increased sensitivity. Hepatol Commun. 2023;7(4). doi: 10.1097/hc9.0000000000000099. PubMed PMID: 36930867; PMCID: PMC10027030.
21. Rattanachaisit P, Suksawatamnuay S, Sriphoosanaphan S, Thanapirom K, Thaimai P, Siripon N, Sittisomwong S, Poovorawan Y, Komolmit P. Stability of hepatitis B virus pregenomic RNA in plasma specimens under various temperatures and storage conditions. PeerJ. 2021;9:e11207. doi: 10.7717/peerj.11207. PubMed PMID: 33954043; PMCID: PMC8052958.
22. Chudy M, Scheiblauer H, Hanschmann KM, Kress J, Nick S, Wend U, Schüttler C, Nübling CM, Gerlich WH. Performance of hepatitis B surface antigen tests with the first WHO international hepatitis B virus genotype reference panel. J Clin Virol. 2013;58(1):47-53. doi: 10.1016/j.jcv.2013.06.011. PubMed PMID: 23829967.
23. Kim SW, Yoon JS, Lee M, Cho Y. Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus. Clin Mol Hepatol. 2022;28(1):17-30. doi: 10.3350/cmh.2021.0093. PubMed PMID: 34281294; PMCID: PMC8755466.
24. Bassit L, Ono SK, Schinazi RF. Moving Fast Toward Hepatitis B Virus Elimination. Adv Exp Med Biol. 2021;1322:115-38. doi: 10.1007/978-981-16-0267-2_5. PubMed PMID: 34258739; PMCID: PMC8988908.
25. Ligat G, Verrier ER, Nassal M, Baumert TF. Hepatitis B virus-host interactions and novel targets for viral cure. Curr Opin Virol. 2021;49:41-51. doi: 10.1016/j.coviro.2021.04.009. PubMed PMID: 34029994; PMCID: PMC7613419.
26. Strassl R, Reiberger T, Honsig C, Payer BA, Mandorfer M, Grabmeier-Pfistershammer K, Rieger A, Kundi M, Grundtner P, Peck-Radosavljevic M, Popow-Kraupp T. Viral determinants predicting hepatitis B surface antigen (HBsAg) seroclearance in HIV-/HBV-coinfected patients. J Viral Hepat. 2014;21(7):508-16. doi: 10.1111/jvh.12175. PubMed PMID: 24112778.
27. Lisker-Melman M, Wahed AS, Ghany MG, Chung RT, King WC, Kleiner DE, Bhan AK, Khalili M, Jain MK, Sulkowski M, Wong DK, Cloherty G, Sterling RK. HBV transcription and translation persist despite viral suppression in HBV-HIV co-infected patients on antiretroviral therapy. Hepatology. 2023;77(2):594-605. doi: 10.1002/hep.32634. PubMed PMID: 35770681; PMCID: PMC9800637.
28. Grudda T, Hwang HS, Taddese M, Quinn J, Sulkowski MS, Sterling RK, Balagopal A, Thio CL. Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment. J Clin Invest. 2022;132(18). doi: 10.1172/jci161818. PubMed PMID: 35797115; PMCID: PMC9473722.
29. Balagopal A, Hwang HS, Grudda T, Quinn J, Sterling RK, Sulkowski MS, Thio CL. Single Hepatocyte Hepatitis B Virus Transcriptional Landscape in HIV Coinfection. J Infect Dis. 2020;221(9):1462-9. doi: 10.1093/infdis/jiz607. PubMed PMID: 31740931; PMCID: PMC7137881.
30. Pan J, Tian Y, Xu J, Luo H, Tan N, Han Y, Kang Q, Chen H, Yang Y, Xu X. Dynamics of Hepatitis B Virus Pregenomic RNA in Chronic Hepatitis B Patients With Antiviral Therapy Over 9 Years. Front Med (Lausanne). 2022;9:851717. doi: 10.3389/fmed.2022.851717. PubMed PMID: 35572978; PMCID: PMC9099358.
31. Sherman KE, Shire NJ, Rouster SD, Peters MG, James Koziel M, Chung RT, Horn PS. Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virus-infected patients. Gastroenterology. 2005;128(2):313-27. doi: 10.1053/j.gastro.2004.11.059. PubMed PMID: 15685543; PMCID: PMC4036101.
32. Gu F ZK, Lan X, He Y, Li F, Tang X, Hu F, Li L. . Measuring HBV pregenomic RNA may be a potential biomarker to determine HBV functional cure in HIV/HBV-co-infected patients with HBsAg loss. J Med Virol. 2024;96(6).