Acta Dermatovenerol APA
Acta Dermatovenerologica
Alpina, Pannonica et Adriatica
2019;28:143-147
doi: 10.15570/actaapa.2019.35
Asymptomatic reactivation of hepatitis B virus after prolonged treatment with etanercept
Nuno Gomes1 Beatriz Leao2, Candida Abreu2, Filomena Azevedo1, Sofia Magina1,3
Abstract
Etanercept is an anti-tumor necrosis factor a (anti-TNFa) drug used for treating immunomediated inflammatory diseases. It is least associated with hepatitis B virus (HBV) reactivation. We present a 71-year-old man with psoriasis refractory to phototherapy and acitretin, which led to etanercept monotherapy. Before anti-TNFa treatment, past contact with HBV was elicited; antibodies to HBc and HBs were positive whereas HBsAg was negative. Seven years after treatment initiation, while the patient was completely asymptomatic, a transaminase elevation was found and a reactivation of HBV was documented, with a high viral load of the virus. He started entecavir therapy and, after a 14-month follow-up, the viral load is still detectable at a low level, as well as HBsAg. We emphasize the late and asymptomatic reactivation of HBV associated with soluble anti-TNFa monotherapy. This case reinforces the importance of current recommendations for periodic monitoring of viral load and HBV markers in all patients that have had prior contact with HBV (positive anti-HBc), with or without indication for treatment of HBV (HBsAg and HBV-DNA negative).
Keywords: hepatitis B virus, hepatitis B virus reactivation, etanercept, anti-TNFa, psoriasis
Received: 5 August 2019 | Returned for modification: 13 September 2019 | Accepted: 28 October 2019
Introduction
Hepatitis B virus (HBV) reactivation associated with anti-tumor necrosis factor a (anti-TNFa) drugs for the treatment of immunomediated inflammatory diseases is rarely reported in the absence of surface hepatitis B antigen (HBsAg) (1). Etanercept, a soluble anti-TNFa, is the least associated with HBV reactivation (2). Clinical hepatitis reactivation has a wide spectrum, ranging from asymptomatic cases to potentially fatal fulminant hepatic failure (3, 4). In 2015, the European Centre for Disease Prevention and Control (ECDC) estimated the prevalence of HBV infection as 0.9%; in Portugal, it is estimated that 0.4 to 1.0% of the population is positive for HBsAg (5). The highest published reported incidence of HBV reactivation in patients with past HBV infection is 5%, including one fatal case due to liver failure (6). Therefore it is considered safe, and the European Association for the Study of the Liver (EASL) (7) recommends that patients with past HBV infection (anti-HBc positive and anti-HBs positive) in the absence of HBsAg (and negative for HBV-DNA) should start anti-TNFa therapy with clinical and analytical monitoring and serial HBV-DNA testing (3, 8).
Case report
We present the case of a 71-year-old man followed at the Derma-Table 1 | Evolution of hepatitis B virus (HBV) serological status.
tology Outpatient Clinic since 2002 due to plaque psoriasis. He started on phototherapy and acitretin with insufficient response (Psoriasis Area and Severity Index [PASI] 11.4), and so etanercept 50 mg per week was prescribed in 2010, with PASI 0 at 20 weeks' follow-up. Before anti-TNFa treatment, past contact with HBV was elicited: antibodies to HBc and HBs (quantified titer: 29.30 IU/l) were positive with HBsAg being negative; anti-HIV and anti-HCV were both negative (Table 1). He has been on etanercept continuously since 2010, treatment was interrupted for 2 months in 2015, with recurrence of psoriatic lesions, and he resumed treatment again with efficacy. In October 2015, HBV screening elicited the same serological markers.
In September 2017, asymptomatic transaminase elevation was found (alanine aminotransferase [ALT] 99 IU/l, aspartate ami-notransferase [AST] 66 IU/l), and etanercept was immediately stopped (PASI 0 at this date) on suspicion of toxicity. On reevaluation in November 2017, transaminases were still on the rise (ALT 431 IU/l, AST 220 IU/l), HBsAg became positive, and a high viral load of HBV was found (16,000,000 IU/ml). He was sent to the Infectious Diseases Clinic in December 2017 and on the same day started entecavir. The patient remained completely asymptomatic, without hyperbilirubinemia or coagulopathy. The HBV was genotype A, without detected resistances.
After 1 month of entecavir therapy, the viral load was 11,871 IU/ml (a decrease of three logarithms) and transaminases were
	Mar	Oct	Nov	Jan	Mar	Jun	Oct	Nov	Mar
	2010	2015	2017	2018	2018	2018	2018	2018	2019
HBsAg (NR < 0.9 - R > 1.1)	0.37	0.20	217.40	-	-	-	-	-	-
Anti-HBc (NR < 0.9 - R > 1.1)	7.27	9.40	8.70	-	-	-	-	-	-
Anti-HBs (IU/l)	29.30	2.29	79.99	-	-	-	4.44	-	-
Anti-HBe (NR < 0.9 - R > 1.1)	-	-	0.00	-	-	-	-	-	-
HBeAg (NR < 0.9 - R > 1.1)	-	-	982.5	-	-	-	-	-	-
HBV-DNA			16,000,000 UI/ml	11,871 UI/ml	626 UI/ml	262 UI/ml	315 UI/ml	157 UI/ml	258 UI/ml
			7.20 log10	4.07 log10	2.80 log10	2.42 log10	2.50 log10	2.20 log10	2.41 log10
NR = non-reactive, R = reactive, IU = international units.
•Department of Dermatovenereology, Centro Hospitalar Universitario de Sao Joao, Porto, Portugal. 'Department of Infectious Diseases, Centro Hospi-talar Universitario de Sao Joao, Porto, Portugal. 3Faculty of Medicine, Porto University, Porto, Portugal. h Corresponding author: nunompretogomes@ gmail.com
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within normal values. At 3 months of therapy, he had HBV-DNA of 626 IU/ml and abdominal ultrasonography was irrelevant except for steatosis. At 14 months of therapy, viral load is still detectable at a low level as well as HBsAg. Consequently, the patient will maintain entecavir even without immunosuppression. He remained asymptomatic during the entire follow-up period. At 17 months' follow-up since etanercept was stopped, he is only being treated with topical medications for psoriasis and has a PASI score of 2.
Discussion
We emphasize the late and asymptomatic reactivation of HBV associated with soluble anti-TNFa monotherapy in a 71-year-old patient suffering from psoriasis. In our specific case, unfortunately, the HBV viral load prior to the start of etanercept was not measured.
The majority of publications in this field are in the scope of rheumatological diseases. Tamori et al., for example, designed a prospective study to clarify the prevalence of HBV reactivation in rheumatoid arthritis patients receiving long-term immunosup-
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