Hepatitis B virus reactivation associated with antirheumatic therapy: Risk and prophylaxis recommendations

Table 1 Definition of resolved hepatitis B virus infection, inactive carrier state, chronic hepatitis B, and immunization due to vaccination

	HBsAg	Anti-HBs	HBeAg	Anti-HBe	Anti-HBc	ALT	HBV-DNA in serum (copies/mL)	HBV-DNA in the liver	Liver injury
Resolved infection	-	+/-	-	+/-	+/-	Normal	Negative	+	No
Inactive carriers	+	-	-	+	+	Normal	Negative to 104	+	No
Chronic hepatitis B	+	-	+	-	+	Elevated	> 105	+	Yes
(HBeAg-positive)
Chronic hepatitis B	+	-	-	+	+	Elevated	> 104	+	Yes
(HBeAg-negative)
Immunized	-	+	-	-	-	Normal	Negative	-	No

HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; anti-HBs: Anti-hepatitis B surface antibody; HBeAg: Hepatitis B e antigen; anti-HBe: Anti-hepatitis B e antibody; anti-HBc: Anti-hepatitis B core antibody; ALT: Alanine aminotransferase.

Table 2 Studies evaluating the prevalence of resolved hepatitis B virus infection and hepatitis B surface antigen carriers in patients with rheumatic diseases

Study	Author	Country	Publication (year)	Disease	Total numbers	Resolved infection1n (%)	HBsAg carriers n (%)	Vaccination n (%)	Ref.
1	Charpin	France	2009	RA, PsA, AS	504	58 (11.5)	2 (0.4)	ND	[46]
2	Vassilopoulos	Greece	2010	RA, SpA, others	131	19 (14.5)	14 (10.7)	19 (14.5)	[47]
3	Caporali	Italy	2010	RA, AS, PsA	732	67 (9.2)	5 (0.7)	ND	[48]
4	Giardina	Italy	2013	RA, AS, PsA	57	15 (26.3)2	3 (5.3)	ND	[55]
5	Biondo	Italy	2014	RA, AS, PsA	169 (HBsAg-negative)	20 (11.8)	-	24 (14.2)	[57]
6	Ballanti	Italy	2014	RA	344	25 (7.3)	1 (0.2)	ND	[58]
7	Barone	Italy	2015	RA, PsA, SpA, AS, others	1138	179 (15.7)	0	ND	[60]
8	Kim	South Korea	2010	RA, AS, PsA, JRA	266	88 (33.1)	8 (3.0)	ND	[29]
9	Urata	Japan	2011	RA	428	135 (31.5)2	6 (1.4)	ND	[49]
10	Tamori	Japan	2011	RA	50 (anti-HBc-positive)	45	5 (10)	-	[50]
11	Mori	Japan	2011	RA	239	60 (25.1)	2 (0.8)	ND	[51]
12	Kato	Japan	2011	RA, SLE, Vasculitis, others	414	35 (8.5)	ND	ND	[52]
13	Nakamura	Japan	2014	RA	251	57 (22.7)2	1 (0.4)	6 (2.4)	[59]
14	Lan	Taiwan	2011	RA	106	70 (66.0)	18 (17.0)	ND	[53]
15	Tan	China	2012	RA	390	188 (48.2)	27 (6.9)	ND	[54]
16	Ye	China	2014	RA, AS, PsA	98	50 (51.0)	37 (37.8)	ND	[56]

¹Resolved HBV infection was defined as HBsAg-negative/anti-HBc-positive serology;

²In these studies, HBsAg-negative/anti-HBs-positive/anti-HBc-negative serology was also considered to indicate resolved infection if patients had no previous HBV vaccination. HBsAg: Hepatitis B surface antigen; anti-HBc: Anti-hepatitis B core antibody; RA: Rheumatoid arthritis; SpA: Spondyloarthropathy; AS: Ankylosing spondylitis; PsA: Psoriatic arthritis; JRA: Juvenile rheumatoid arthritis; SLE: Systemic lupus erythematosus; ND: Not described.

Table 3 Studies evaluating reactivation rates in rheumatic disease patients with resolved hepatitis B virus infection¹

Study2	Patient number	Age (yr)	Biological DMARDs (number)	Non-biological DMARDs and PSL (%)	Follow-up (mo)	Prophylaxis (number)	Reactivation number (%)	Ref.
1	21	58 (mean)	ETN (14), ADM (3), IFX (4)	MTX (48)	27 (mean)	No	0	[46]
2	19	52 (mean)5	ETN, ADM, IFX	ND	24	No	0	[47]
3	67	57 (mean)	ETN (23), IFX (25), ADM (19)	MTX (76), PSL (64)	43 (mean)	No	0	[48]
4	153	49 (mean)5	ETN, IFX	MTX(42)5, PSL(60)5	24	No	0	[55]
5	20	63 (mean)	ETN (10), ADM (7), IFX (2), GOL (1)	MTX (80), others (35), PSL (65)	45 (mean)	No	0	[57]
6	25	63 (mean)5	ETN (15), ADM (10)	DMARDs (72)5	27 (mean)5	2	0	[58]
7	179	57 (mean)	ETN (74), IFX (43), ADM (29), RTX (14), TCZ (7), ABT (9), ANK (3)	DMARDs (75), PSL (46), High-dose PSL (4)	55, 32, 17 (median)	No	010	[60]
8	88	51 (mean)	ETN (60), IFX (12), ADM (16)	ND	25 (mean)	No	144	[29]
9	523	ND	ETN (38), IFX (15), ADM (7), TCZ (4), RTX (1)8	MTX (48)6, others (59)6, PSL (39)6	12	No	6 (11.5)	[49]
9	833	ND	Not used	MTX (48)6, others (59)6, PSL (39)6	12	No	1 (1.2)	[49]
10	42	59 (mean)6	ETN (19), IFX (21), ADM (2)	DMARDs (93)6,	23 (mean)6	No	0	[50]
				PSL (76)6
10	3	59 (mean)6	Not used	DMARDs (93)6,	23 (mean)6	No	1 (33)	[50]
				PSL (76)6
11	36	73 (median)6	ETN (18), IFX (19), ADM (2), TCZ (5)8	MTX (90)6, others (50)6, PSL (63)6	ND	No	1 (2.8)	[51]
11	24	73 (median)6	Not used	MTX (90)6, others (50)6, PSL (63)6	ND	No	1 (4.2)	[51]
12	6	62 (mean)6	ETN (1), IFX (1), TCZ (1), RTX (3)	DMARDs (60)6,	6	No	1 (16.7)	[52]
				PSL pulse (60)6
12	29	62 (mean)6	Not used	DMARDs (60)6,	6	No	5 (17.2)	[52]
				PSL pulse (60)6
13	57	64 (median)	ETN (22), IFX (20), ADM (22), TCZ (18), ABT (2)8	MTX (74), others (18), PSL (74)	18 (median)	No	3 (5.3)	[59]
14	70	51 (mean)	ETN (31), ADM (39)	MTX (91), PSL (100)	ND	No	1 (1.4)	[53]
15	188	ND	Not used	DMARDs (123), PSL (65)	20 (mean)	No	2 (1.1)	[54]
16	50	46 (mean)	ETN (9), IFX (41)	MTX (780), others (16)	12 (mean)	No	0	[56]
177	7	51 (mean)	ADM (7)	ND	ND	No	0	[114]
187	34	54 (mean)9	ETN (20), ADM (10), IFX (4)	ND	19, 28, 29 (mean)	No	0	[113]
19	12	60 (mean)5	RTX (12)	DMARDs (80)5,	19 (mean)5	No	0	[115]
				MTX (41)5, PSL (85)5

¹Resolved HBV infection was defined as HBsAg-negative/anti-HBc-positive serology;

²Study numbers 1-16 correspond to those used in Table 2;

³In these studies, HBsAg-negative/anti-HBs-positive/anti-HBc-negative serology was also considered to indicate resolved infection if patients had no history of HBV vaccination;

⁴In this study, 14 patients showed an abnormality in a liver function test (a twofold or greater increase of aminotransferases on two consecutive tests), but HBV reactivation could not be confirmed (no data on viral load);

⁵Data reported for all patients included in this study, not just for those with resolved infection;

⁶Data reported for all patients included in this study, not separately reported according to the use or nonuse of biological DMARDs;

⁷This study was performed on psoriatic arthritis patients in Italy;

⁸Some patients in these studies received two or three different biological DMARDs;

⁹Data reported for all psoriasis patients included in this study, not just for those with psoriatic arthritis;

¹⁰In this study, seven patients showed an abnormality in a liver function test (among those, three had a twofold or greater increase of aminotransferases), but no HBV DNA was detected. DMARDs: Disease-modifying antirheumatic drugs; PSL: Prednisolone; MTX: Methotrexate; RTX: Rituximab; TCZ: Tocilizumab; ANK: Anakinra; ABT: Abatacept; ADM: Adalimumab; IFX: Infliximab; ETN: Etanercept; GOL: Golimumab; ND: Not described.

Table 4 Characteristics and outcomes of rheumatic disease patients with resolved hepatitis B virus infection who experienced viral reactivation during treatment with biological disease-modifying antirheumatic drugs

Case	Age/sex	Disease	Anti-HBs/anti-HBe	DMARDs	Duration	HBV-DNA1 (copies/mL)	ALT2 (IU/L)	Antiviral therapy	Outcomes	Ref
1	71/F	RA	Pos./Pos.	IFX, MTX, PSL	16 mo	ND	NR	-	-	[119]
				ADM, MTX, PSL	11 mo	1 × 109	674	Yes	Died5
2	80/F	RA	ND	IFX, MTX, PSL	48 mo	Neg.	NR	-	-	[51]
				ETN, MTX, PSL	4 mo	Neg.	NR	-	-
				ADM, MTX, PSL	15 mo	Pos.3	NR	No	Recovered
3	73/M	AS	Pos./Pos.	ETN, PSL	14 mo	8.8 × 103	65	Yes	Recovered	[118]
4	54/F	RA	Neg./Pos.4	ETN, MTX, PSL	5 mo	1.6 × 106	199	Yes	Recovered	[53]
5	75/ND	RA	ND	ETN, MTX, PSL	ND	2.5 × 102	NR	Yes	Recovered	[49]
6	60/ND	RA	ND	ETN, LEF	ND	1.0 × 102	NR	No	Recovered	[49]
7	49/ND	RA	ND	ETN, BUC, PSL	ND	2.5 × 107	NR	Yes	Recovered	[49]
8	46/ND	RA	ND	ETN, MTX, TAC	ND	5.0 × 103	NR	Yes	Recovered	[49]
9	65/ND	RA	ND	ETN, PSL	ND	1.0 × 105	NR	Yes	Recovered	[49]
10	77/ND	RA	ND	TCZ, MTX	ND	1.0 × 102	NR	No	Recovered	[49]
11	75/M	RA	ND	TCZ, PSL6	2 mo	Pos.3	NR	No	Recovered	[59]
12	55/F	RA	ND	IFX	25 mo	Neg.	NR	-	-	[59]
				ETN	35 mo	Neg.	NR	-	-
				TCZ, MTX PSL6	2 mo	Pos.3	NR	No	Recovered
13	60/F	RA	ND	ETN, MTX, PSL6	65 mo	Pos.3	NR	No	Recovered	[59]
14	64/F	RA	Pos./ND	RTX, MTX	24 mo	> 1.0 × 108	72	Yes	Recovered	[123]
15	71/F	RA	Neg./ND	RTX, PSL	4 wk	Pos.	NR	No	Recovered	[52]
16	64/F	RA	Pos./Neg.	RTX, MTX	2 yr	1.1 × 108	605	Yes	Recovered	[124]
17	78/M	RA	Pos./ND	IFX, MTX, PSL	ND	ND	NR	-	-	[122]
				RTX, PSL	27 mo	107	421	Yes	Recovered
18	68/F	RA	Neg./Pos.	ABT, MTX	10 mo	1.1 × 108	NR	Yes	Recovered	[125]
19	72/F	RA	Pos./Pos.	ADA, PSL	2 yr	Neg.	NR	-	-	[120]
			Pos./Pos.	ABT, LEF, PSL	13 mo	7.0 × 104	2 × ULN	Yes	Recovered

No patients had received preemptive therapy against HBV infection. Underlined entries represent biological agents.

¹HBV-DNA levels were determined at diagnosis of HBV reactivation;

²ALT values were determined at diagnosis of HBV reactivation or were the highest values measured after HBV reactivation;

³HBV-DNA tested positive on real-time PCR, but DNA levels were below 2.1 log copies/mL;

⁴An HBV-DNA level was 3.5 log copies/mL;

⁵The patient died of hepatic failure;

⁶The patient continued biological therapy after HBV reactivation. RA: Rheumatoid arthritis; AS: Ankylosing spondylitis; DMARDs: Disease-modifying antirheumatic drugs; PSL: Prednisolone; MTX: Methotrexate; BUC: Bucillamine; LEF: Leflunomide; TAC: Tacrolimus; RTX: Rituximab; ADM: Adalimumab; IFX: Infliximab; ETN: Etanercept; TCZ: Tocilizumab; ABT: Abatacept; HBV: Hepatitis B virus; anti-HBs: Anti-hepatitis B surface antibody; anti-HBe: Anti-hepatitis B e antibody; ALT: Alanine aminotransferase; Neg.: Negative; Pos.: Positive; ULN: Upper limits of normal; NR: Normal range; ND: Not determined or not described.

Table 5 Characteristics and outcomes of rheumatic disease patients with resolved infection who experienced viral reactivation during treatment with non-biological disease-modifying antirheumatic drugs

Case	Age/sex	Disease	Anti-HBs/anti-HBe	DMARDs	Duration	HBV-DNA1 (copies/mL)	ALT2 (IU/L)	Antiviral therapy	Outcomes	Ref
1	74/F	DM	ND /Pos.	AZA, PSL	12 mo	1.7 × 107	146	Yes	Died7	[75]
2	43/F	RA	ND/Pos.	LEF, SSZ, PSL	1 mo	3.5 × 103	79	Yes	Recovered	[54]
3	73/F	RA	Pos./Pos.3	MTX	10 mo	5.0 × 104	480	Yes	Recovered	[50]
4	72/M	TA	Neg./ND	MTX, PSL	6 mo	> 1.0 × 108	308	Yes	Recovered	[123]
5	57/F	RA	ND4	MTX, PSL	5 mo5	> 1.0 × 109	2012	Yes	Recovered	[121]
6	59/F	RA	ND	MTX, PSL	7 yr	1.6 × 107	378	Yes	Died7	[117]
7	47/F	RA	ND/Pos.	MTX, SSZ, PSL	15 mo	6.5 × 103	31	No	Recovered	[54]
8	75/M	DM	Neg./ND	MTX, AZA, CYA, PSL	15 mo	7.4 × 105	657	Yes	Recovered	[123]
9	67/F	RA, MCD	ND	MTX	37 mo	Neg.	NR	-	-	[51]
				MTX, TAC, PSL6	5 mo	Pos.3	NR	Yes	Recovered
10	74/ND	RA	ND	MTX, PSL	ND	1.0 × 103	NR	Yes	Recovered	[49]
11	77/F	RA, IP	Pos./ND	TAC, PSL6	4 wk	4.2 log	NR	Yes	Recovered	[52]
12	78/F	MPA	Neg./ND	CPA, PSL	8 wk	1.8 log	NR	No	Recovered	[52]
13	58/F	SLE	Neg./ND	CPA, TAC, PSL6	4 wk	7.5 log	NR	Yes	Died7	[52]
14	30/F	SLE	Neg./ND	CPA, PSL6	8 wk	Pos.	Elevated	ND	Died7	[52]
15	59/F	SLE	Pos./ND	CPA, PSL6	4 wk	Pos.	NR	ND	Died7	[52]

No case had received preemptive therapy against HBV infection.

¹HBV-DNA levels were determined at diagnosis of HBV reactivation;

²ALT values were determined at diagnosis of HBV reactivation or were the highest values measured after HBV reactivation;

³HBV-DNA level was below 2.1 log copies/mL but HBV-DNA tested positive on real-time PCR;

⁴Anti-HBc was also not searched;

⁵The patient had received PSL and MTX (10 mg/wk) for 15 and 5 years prior to viral reactivation, respectively. Five months previously, the MTX dose had been increased to 12 mg/wk;

⁶The patient received steroid pulse therapy;

⁷The patients died of cerebral infarction (case 1), liver failure (case 6), sepsis (cases 13 and 14), and hemolytic anemia (case 15). DM: Dermatomyositis; RA: Rheumatoid arthritis; MCD: Minimal change disease; IP: Interstitial pneumonia; MPA: Microscopic polyangiitis; SLE: Systemic lupus erythematosus; DMARDs: Disease-modifying antirheumatic drugs; PSL: Prednisolone; MTX: Methotrexate; AZA: Azathioprine; CYA: Cyclosporine A; LEF: Leflunomide; SSZ: Sulfasalazine; TAC: Tacrolimus; CPA: Cyclophosphamide; HBV: Hepatitis B virus; anti-HBs: Anti-hepatitis B surface antibody; anti-HBe: Anti-hepatitis B e antibody; ALT: Alanine aminotransferase; Neg.: Negative; Pos.: Positive; ULN: Upper limits of normal; NR: Normal range; ND: Not determined or not described.