Risk of Hepatitis Flare in Patients With Previous Hepatitis B Virus Exposure Amongst Patients

Immunosuppression Clinical Trial

Official title:

Risk of Hepatitis Flare in Patients With Previous Hepatitis B Virus Exposure Amongst Patients on Immunosuppressive and Biological Modifier Therapies Exposure

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04356404
• Other study ID #: HEP-FLARE_Protocol_20210604_V5
• Status: Terminated
• Start date: May 1, 2020
• Est. completion date: January 12, 2022

Study information

• Verified date: January 2022
• Source: Chinese University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to study the risk of hepatitis flare in patients with previous hepatitis B virus exposure amongst patients on immunosuppressive and biological modifier therapies

Description:

Chronic hepatitis B infection remains a global health threat despite vaccination program.[1] Nearly 3 billion population are infected with chronic hepatitis B infection globally. In China, the pooled prevalence of chronic hepatitis B infection was around 7% in year 2018, making an estimated 84 millions of population living with chronic hepatitis B infection. Hepatitis B virus infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, leading to significant morbidity and mortality. Patients with hepatitis B infection can present with a wide range of clinical presentation, ranging from inactive carrier to fulminant hepatitis, cirrhosis or development of hepatocellular carcinoma. Besides, a significant proportion of patients are suffering from occult hepatitis B infection (OBI), which is defined as a state of undetectable serum HBsAg yet detectable serum and/ or intrahepatic HBV DNA. Report from the European Association for the Study of the Liver (EASL) in 2008 has revealed that around one-third of the global population has serological evidence of past or present HBV infection. Disappearance of HBsAg, also known as HBsAg seroclearance, can occur either spontaneously or after anti-viral treatment. However, patients with past or resolved HBV infection are still at risk of development of hepatocellular carcinoma, liver cirrhosis and liver-related mortality.The reported prevalence of OBI amongst patients with non-alcoholic fatty liver disease in Hong Kong was 35% (submitted to American Journal of Gastroenterology, under review). It is well known that there is risk of HBV reactivation after chemotherapy or immunosuppressive therapy which can lead to fulminant liver failure or even death. Short course of high dose corticosteroid could increase the risk of hepatitis flare in patients with chronic hepatitis B infection. Even in patients with OBI, a high daily dose of corticosteroid (>40mg prednisolone equivalents) increased risks of hepatitis flare. It is thus important to know the hepatitis B virus status before start of chemotherapy, immunosuppressive therapy or corticosteroid.

Biologics is one of the mainstay treatments for many autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), psoriasis etc. The incidence of IBD has increased rapidly in Hong Kong over the past 30 years. The age-adjusted incidence of IBD in Hong Kong has rose from 0.10 per 100,000 individuals in 1985 to 3.12 per 100,000 individuals in 2014. The reported prevalence of RA in Hong Kong was 0.35% while the reported prevalence of SLE in Hong Kong was 0.1% with annual incidence of 6.7 per 100,000 individuals. It is well known that treatment with biological agent like anti-CD20 monoclonal antibody (rituximab) in patients with OBI can lead to fulminant hepatitis B flare. Recently, anti-tumor necrosis factor alpha (TNF α) has been widely used in patients with inflammatory bowel disease and various rheumatological diseases. Risk of hepatitis B reactivation after anti-TNF α has been reported, but actual risk remains controversial. In a report from Japan including 135 rheumatoid arthritis patients with previous HBV infections, 17/135 (12.6%) had HBV reactivation after receiving immunosuppressants and patients who were treated with biologics were more frequent to develop HBV reactivation compared to those who were not on biologics. In another study, 9/168 (5%) anti-HBc positive patients developed HBV reactivation after receiving anti-TNF α and one patient died due to fulminant liver failure.However, another three studies revealed low rates of HBV reactivation (0-2%) amongst rheumatology patients with previous HBV infections receiving anti-TNF α. The European Crohn's and Colitis Organisation (ECCO) suggested routine antiviral prophylaxis for patients with previous HBV infection starting biologics is not recommended. Instead, regular monitoring of ALT/ AST, change in HBV serology and HBV DNA every 1 to 3 months should be performed. In 2015, the American Gastroenterology Association (AGA) has developed guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive therapy. It classifies patients receiving anti-TNF α as moderate risk of developing HBV reactivation and antiviral prophylaxis is preferred over monitoring alone, but it is a weak recommendation. Therefore, it is now still uncertain whether prophylactic anti-viral should be given for patients with previous HBV exposure before starting anti-TNF α.

With the advancement of technology, there are now more biological agents and small molecules for the treatment of IBD and various rheumatological conditions. These include anti-integrin, cytokine inhibitors, and small molecules e.g. JAK inhibitors. Cytokine inhibitor, ustekinumab (anti-IL12/23), has been reported to be leading to hepatitis reactivation in a psoriasis patient who has past HBV infection.[26] Whether these agents can lead to hepatitis flare in patients with past HBV exposure remains largely unknown.

Based on the compelling data, the investigators hypothesize that use of biologic modifier therapies in patients with occult hepatitis B infection will lead to hepatitis flare. The investigators aim to assess the rate of hepatitis flare while on biological modifier therapies in both retrospective population-based database and prospectively in patients who are on biological modifier therapies.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 68
• Est. completion date: January 12, 2022
• Est. primary completion date: January 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years old at the time of starting biological modifier therapies or at the time of recruitment

• Positive for anti-HBc OR

• Positive for anti-HBs and born before year 1988

Exclusion Criteria:

• Known HBV carrier with HBsAg positive

• Concomitant HCV and/ or HIV infection

• Already on HBV anti-viral

• Refuse to consent

• Baseline ALT > 80 IU/ml

Related Conditions & MeSH terms

• Biological Substance; Adverse Effect
• Hepatitis
• Hepatitis A
• Hepatitis B
• Immunosuppression
• Occult Hepatitis B

Locations

Country	Name	City	State
Hong Kong	The Chinese University of Hong Kong	Hong Kong

Sponsors (2)

Lead Sponsor	Collaborator
Chinese University of Hong Kong	University of Malaya

Country where clinical trial is conducted

Hong Kong, 

References & Publications (26)

Caporali R, Bobbio-Pallavicini F, Atzeni F, Sakellariou G, Caprioli M, Montecucco C, Sarzi-Puttini P. Safety of tumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases. Arthritis Care Res (Hoboken). 2010 Jun;62(6):749-54. doi: 10.1002/acr.20130. — View Citation

Chung SM, Sohn JH, Kim TY, Yoo KD, Ahn YW, Bae JH, Jeon YC, Choi JH. [Fulminant hepatic failure with hepatitis B virus reactivation after rituximab treatment in a patient with resolved hepatitis B]. Korean J Gastroenterol. 2010 Apr;55(4):266-9. Korean. — View Citation

Ho CTK, Mok CC, Cheung TT, Kwok KY, Yip RML; Hong Kong Society of Rheumatology. Management of rheumatoid arthritis: 2019 updated consensus recommendations from the Hong Kong Society of Rheumatology. Clin Rheumatol. 2019 Dec;38(12):3331-3350. doi: 10.1007/s10067-019-04761-5. Epub 2019 Sep 4. Review. — View Citation

Khan ZH, Ilyas K, Ghazanfar H, Khan HH, Hussain Q, Hammad S, Munir A, Asim R. Fatal Fulminant Hepatitis from Rituximab-induced Hepatitis B Reactivation in a Patient with Follicular Lymphoma: A Case Report and a Brief Review of Literature. Cureus. 2018 Mar 2;10(3):e2257. doi: 10.7759/cureus.2257. — View Citation

Koo YX, Tay M, Teh YE, Teng D, Tan DS, Tan IB, Tai DW, Quek R, Tao M, Lim ST. Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis. Ann Hematol. 2011 Oct;90(10):1219-23. doi: 10.1007/s00277-011-1241-0. Epub 2011 Apr 26. — View Citation

Koskinas J, Tampaki M, Doumba PP, Rallis E. Hepatitis B virus reactivation during therapy with ustekinumab for psoriasis in a hepatitis B surface-antigen-negative anti-HBs-positive patient. Br J Dermatol. 2013 Mar;168(3):679-80. doi: 10.1111/bjd.12120. Epub 2013 Jan 31. — View Citation

Lee YH, Bae SC, Song GG. Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HBV occult carriers) undergoing anti-tumor necrosis factor therapy. Clin Exp Rheumatol. 2013 Jan-Feb;31(1):118-21. Epub 2012 Oct 30. Review. — View Citation

Maynard JE. Hepatitis B: global importance and need for control. Vaccine. 1990 Mar;8 Suppl:S18-20; discussion S21-3. Review. — View Citation

Mok CC. Epidemiology and survival of systemic lupus erythematosus in Hong Kong Chinese. Lupus. 2011 Jun;20(7):767-71. doi: 10.1177/0961203310388447. Epub 2010 Dec 10. — View Citation

Ng SC, Leung WK, Shi HY, Li MK, Leung CM, Ng CK, Lo FH, Hui YT, Tsang SW, Chan YK, Loo CK, Chan KH, Hui AJ, Chow WH, Harbord M, Ching JY, Lee M, Chan V, Tang W, Hung IF, Ho J, Lao WC, Wong MT, Sze SF, Shan EH, Lam BC, Tong RW, Mak LY, Wong SH, Wu JC, Chan FK, Sung JJ. Epidemiology of Inflammatory Bowel Disease from 1981 to 2014: Results from a Territory-Wide Population-Based Registry in Hong Kong. Inflamm Bowel Dis. 2016 Aug;22(8):1954-60. doi: 10.1097/MIB.0000000000000846. — View Citation

Pérez-Alvarez R, Díaz-Lagares C, García-Hernández F, Lopez-Roses L, Brito-Zerón P, Pérez-de-Lis M, Retamozo S, Bové A, Bosch X, Sanchez-Tapias JM, Forns X, Ramos-Casals M; BIOGEAS Study Group. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore). 2011 Nov;90(6):359-371. doi: 10.1097/MD.0b013e3182380a76. — View Citation

Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018 Jun;3(6):383-403. doi: 10.1016/S2468-1253(18)30056-6. Epub 2018 Mar 27. Review. — View Citation

Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y, Cottone M, de Ridder L, Doherty G, Ehehalt R, Esteve M, Katsanos K, Lees CW, Macmahon E, Moreels T, Reinisch W, Tilg H, Tremblay L, Veereman-Wauters G, Viget N, Yazdanpanah Y, Eliakim R, Colombel JF; European Crohn's and Colitis Organisation (ECCO). Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014 Jun;8(6):443-68. doi: 10.1016/j.crohns.2013.12.013. Epub 2014 Mar 6. — View Citation

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. doi: 10.1016/j.jhep.2008.07.014. Epub 2008 Jul 31. — View Citation

Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter YT; American Gastroenterological Association Institute. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015 Jan;148(1):215-9; quiz e16-7. doi: 10.1053/j.gastro.2014.10.039. Epub 2014 Oct 31. Review. Erratum in: Gastroenterology. 2015 Feb;148(2):455. multiple investigator names added. — View Citation

Sera T, Hiasa Y, Michitaka K, Konishi I, Matsuura K, Tokumoto Y, Matsuura B, Kajiwara T, Masumoto T, Horiike N, Onji M. Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab. Intern Med. 2006;45(11):721-4. Epub 2006 Jul 3. — View Citation

Tamori A, Koike T, Goto H, Wakitani S, Tada M, Morikawa H, Enomoto M, Inaba M, Nakatani T, Hino M, Kawada N. Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts. J Gastroenterol. 2011 Apr;46(4):556-64. doi: 10.1007/s00535-010-0367-5. Epub 2011 Jan 19. — View Citation

Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis. 2002 Aug;2(8):479-86. Review. — View Citation

Urata Y, Uesato R, Tanaka D, Kowatari K, Nitobe T, Nakamura Y, Motomura S. Prevalence of reactivation of hepatitis B virus replication in rheumatoid arthritis patients. Mod Rheumatol. 2011 Feb;21(1):16-23. doi: 10.1007/s10165-010-0337-z. Epub 2010 Jul 29. — View Citation

Wang H, Men P, Xiao Y, Gao P, Lv M, Yuan Q, Chen W, Bai S, Wu J. Hepatitis B infection in the general population of China: a systematic review and meta-analysis. BMC Infect Dis. 2019 Sep 18;19(1):811. doi: 10.1186/s12879-019-4428-y. — View Citation

Wong GL, Wong VW, Yuen BW, Tse YK, Yip TC, Luk HW, Lui GC, Chan HL. Risk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure. J Hepatol. 2020 Jan;72(1):57-66. doi: 10.1016/j.jhep.2019.08.023. Epub 2019 Sep 6. — View Citation

Wong GL, Yuen BW, Chan HL, Tse YK, Yip TC, Lam KL, Lui GC, Wong VW. Impact of dose and duration of corticosteroid on the risk of hepatitis flare in patients with chronic hepatitis B. Liver Int. 2019 Feb;39(2):271-279. doi: 10.1111/liv.13953. Epub 2018 Sep 25. — View Citation

Yip TC, Chan HL, Wong VW, Tse YK, Lam KL, Wong GL. Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Hepatol. 2017 Nov;67(5):902-908. doi: 10.1016/j.jhep.2017.06.019. Epub 2017 Jun 24. — View Citation

Yip TC, Wong GL, Chan HL, Tse YK, Lam KL, Lui GC, Wong VW. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues. J Hepatol. 2019 Mar;70(3):361-370. doi: 10.1016/j.jhep.2018.10.014. Epub 2018 Oct 25. — View Citation

Yip TC, Wong GL, Wong VW, Tse YK, Lui GC, Lam KL, Chan HL. Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients. J Hepatol. 2017 Oct 6. pii: S0168-8278(17)32332-2. doi: 10.1016/j.jhep.2017.09.018. [Epub ahead of print] — View Citation

Yip TC, Wong GL. Current Knowledge of Occult Hepatitis B Infection and Clinical Implications. Semin Liver Dis. 2019 May;39(2):249-260. doi: 10.1055/s-0039-1678728. Epub 2019 Mar 25. Review. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of hepatitis flare	Hepatitis flare, defined as ALT >2xULN IU/L, according to the Asia Pacific Association for the Study of the Liver (APASL) definition while on biological modifier therapy. The upper limit of normal (ULN) was defined as 40 IU/L by APASL.	24 months
Secondary	Rate of severe hepatitis flare	Severe hepatitis flare, defined as ALT > 5xULN or > 10xULN, as defined by the APASL definition, while on biological modifier therapy	24 months
Secondary	Rate of icteric flare	Icteric flare, defined as ALT raised >3xULN together with serum total bilirubin >2xULN (i.e. >38 µmol/L), while on biological modifier therapy	24 months
Secondary	Rate of HBsAg seroreversion	HBsAg seroreversion, defined as reappearance of HBsAg	24 months
Secondary	Risk factors associated with development of hepatitis flare	Risk factors associated with development of hepatitis flare, Including concomitant use of steroid and immunosuppressants	24 months