Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs

Table 1 Four classes of immunotherapies licensed to treat rheumatoid arthritis

Class	Mode of action	Drug	Mechanism of action	Route of administration	Therapeutic regimen	Half-life	Major approved indications (FDA)
TNF inhibitors	TNF-α neutralization	Adalimumab (fully human monoclonal IgG1 antibody)	Binding to TNF	SC	40 mg every 2 wk	13 d	RA, JIA, PsA, AS, CD, UC, PP, non radiographic axial SpA
		Golimumab (fully human monoclonal IgG1 antibody)	Binding to soluble and membrane bound TNF	SC	50 mg every 4 wk	13 d	RA, PsA, AS, UC
		Certolizumab (pegilated FabI fragment of a human monoclonal antibody)	Binding to TNF	SC	200 mg every 2 wk or 400 mg monthly	14 d	RA, CD, PsA, AS, non-radiographic axial SpA
		Etanercept (p75 TNF receptor - IgG1 Fc fusion protein	Works as a decoy receptor. It binds to soluble TNF, blocking the binding to its receptor	SC	50 mg weekly or 25 mg twice a week	3-6 d	RA, PsA, AS, poliarticular JIA, PP
		Infliximab (chimeric mouse-human monoclonal IgG1 antibody)	Binding to soluble and membrane bound TNF	IV	3 mg/kg (up to 7.5 mg/kg if not effective) every 8 wk after loading at 0, 2 and 6 wk	9 d	RA, PsA, AS, CD, pediatric CD, UC, pediatric UC, PP
B-cell depletion	B-cell lysis	Rituximab (chimeric mouse-human monoclonal IgG1 antibody)	Binding to CD20 and depletion of CD20+ B cells	IV	Two infusions of 1000 mg 2 wk apart. This can be repeated every 6 mo if symptoms return. Infusions are preceded by IV methylprednisolone to reduce the incidence of infusion reactions	18 d (range 5-76)	BNHL, CLL, RA, GPA, MPA
T-cell inhibition	T-cell costimulation blockade	Abatacept (extracellular domain of CTLA4-IgG1 Fc recumbinant human fusion protein)	Binding to CD80/ CD86, blocking T-cell co-stimulation	IV	500-750-1000 mg infusions (for body weight < 60, between 60 and 100 or > 100 kg) every 4 wk following three loading infusions at 0, 2 and 4 wk	13 d (range 8-25)	RA, poliarticular JIA
				SC	125 mg weekly
IL-6 inhibition	IL-6 receptor blockade	Tocilizumab (humanized monoclonal IgG1 antibody)	Binding to soluble and membrane bound IL-6 receptor	IV	8 mg/kg every 4 wk	10-13 d	RA, poliarticular JIA, sistemic JIA

FDA: Food and Drug Administration; CTLA-4: Cytotoxic T-lymphocyte associated-antigen 4; IL-6: Interleukin 6; IV: Intraveneous injection; PEG: Polyethylene glycol; SC: Subcutaneous; TNF: Tumour necrosis factor; JIA: Juvenile Idiopathic Arthritis; PsA: Psoriatic arthritis; AS: Ankylosing spondylitis; SpA: Spondiloarthritis; CD: Chron’s disease; UC: Ulcerative colitis; PP: Plaque psoriasis; BNHL: B-cell non-Hodgkin lymphoma; CLL: Chronic lymphocytic leukemia; GPA: Granulomatosis with polyangiitis (Wegener’s disease); MPA: Microscopic polyangiitis.

Table 2 Nomenclatures and definitions used in hepatitis B virus infection

Markers	Chronic inactive carrier	HBeAg positive CHB	HBeAg negative CHB	“Resolved hepatitis B”
HBsAg	+	+	+	-
HBeAg	-	+	-	-
Anti-HBe	+	-	+/-	+/-
Anti-HBs	+	-	+/-	+/-
Anti-HBc	+	+/-	+	+/-
ALT	-	+/-	+	-
Serum HBV-DNA	Undetectable/< 2000 IU/mL	Persistent/intermittent ↑ (> 20000 IU/mL)	Persistent/intermittent ↑ (> 2000 UI/mL)	Detectable or undetectable
Liver injury	+/-	Moderate/severe CHB	Minimal to severe CHB	-
Necroinflammation	No (> 90%)	Yes (> 90%)	No (> 90%)	No

CHB: Chronic hepatitis B; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; anti-HBe: Antibodies to hepatitis B e antigen; anti-HBs: Antibodies to hepatitis B surface antigen; anti-HBc: Antibodies to hepatitis B core antigen; ALT: Alanine aminotransferase.

Table 3 Hepatitis virus B reactivation in rheumatoid arthritis patients receiving tumor necrosis factor-α inhibitors: studies in patients with markers of chronic or remote hepatitis virus B infection

Ref.	Study design	Target population	No. of patients	Treatment	Antiviral Prophylaxis	HBsAg+	Anti-HBc+ and anti-HBs-	Anti-HBc+ and anti-HBs+	HBV-DNA+	Anti-HBs+/anti-HBc-	Reactivation
Carroll et al[69]	Case series	Rheumatic pts or pts with IBD with CHB	13	11 treated with IFX, 2 treated with ETN	Lamivudine	13 pts (100%)	-	-	-	-	7 cases with IFX, 2 cases with ETN
Charpin et al[70]	Prospective	RA (12)/SpA (9) pts with resolved HBV infection	21	4 treated with IFX, 14 with ETN, 3 with ADA	0 pts	0 pts	0 pts 100% (with 3 pts < 100 UI/mL)		0 pts	-	Mean decrease in anti-HBs titre 8%; no cases of HBV reactivation
Chung et al[71]	Retrospective	RA (41), SpA (60), JIA (2) pts	103	TNFα inhibitors	0 pts	8 pts	-	-	0 pts	-	1/8 HBsAg+ (12.5%) after 6 wk of IFX
Caporali et al[72]	Prospective	RA (59), SpA (8) pts with resolved HBV infection	67	25 treated with IFX, 23 with ETN, 19 with ADA	0 pts	0 pts	46 pts	28 pts	0 pts	-	No cases of HBV reactivation
Vassillopoulos et al[73]	Prospective	RA (66), SpA (64), other (1) patients with actual/remote HBV infection or vaccinated for HBV	131	43 treated with IFX, 64 with ETN, 62 with ADA	14 pts (100% of CHB group): 11 with lamivudine, 2 with entecavir, 1 with telbivudine	14 pts	19 pts		0 pts among CHB group	19 pts (vaccinated)	No cases of HBV reactivation in pts with resolved HBV infection. In vaccinated pts, slight decrease in anti-HBs titres (median 163 > 105 IU/mL,P= 0.01). Among CHB pts, 1 (7%) treated withLamivudine + ETN developed HBV reactivation due to a resistant mutant strain
Mori et al[74]	Prospective	RA pts with actual/remote HBV infection	239	9 treated with IFX, 18 with ETN, 2 with ADA, 5 with TCZ, 28 with csDMARDs	2 (100% of HBsAg+ pts) with entecavir	2 pts	60 pts		0 pts	-	2 cases of HBV reactivation in anti-HBc+ pts (3.3%), 1 with csDMARDs and 1 with ADA
Tamori et al[75]	Prospective	RA pts with positive anti-HBc	50	22 treated with IFX, 20 with ETN, 2 with ADA	Entecavir	5 pts	45 pts		-	-	2/5 (40%) cases of HBV reactivation among HBsAg+ pts; 1/45 (2%) cases of HBV reactivation among HBcAb+/HBsAg- pts, not under TNFI
Pérez-Alvarez et al[76]	Systematic review	TNFI-treated pts	257	Anti-TNF (not specified)	Not specified	89 pts	168 pts		-	-	HBV reactivation in 35 (39%) pts among HBsAg+ group, fatal in 4 cases. Lower risk if pre-emptive NAs (23%vs62%,P= 0.003). Higher risk with IFXvsETN. Nine cases (5%) of HBV reactivation in HBcAb+/HBsAg- pts, fatal in 1 pt
Lan et al[77]	Prospective	RA anti-HBc+ pts	88	40 pts treated with ETN, 48 with ADA	10 HBsAg+ pts treated with lamivudine	18 pts	12 pts	58 pts	0 pts	22 pts (vaccinated)	Among HBsAg+ pts, no cases of HBV reactivation if pre-emptive NAs; mean decrease in HBV-DNA = 153 IU/mL (P < 0.001); 5/8 cases of reactivation without antivirals. 1 case of HBV reactivation in the HBsAg-/anti-HBs- group
Lee et al[78]	Systematic review	HBsAg+ rheumatic disease-positive pts	122	14 pts treated with IFX, 56 with ETN and 25 with ADA	48 pts (drug not specified)	122 pts	-	-	Not specified	-	15 cases (12.3%) of HBV reactivation, including 1 SpA patient treated with pre-emptive lamivudine
Lee et al[79]	Systematic Review	HBsAg-/anti-HBc+ rheumatic disease-positive (RA 327, SpA 121) pts	468	100 pts treated with IFX, 269 with ETN and 95 with ADA	Not specified	0 pts	Not specified	Not specified	Not specified	-	8 cases (1.7%) of HBV reactivation, 7 with ETN and 1 with ADA; satisfactory clinical outcomes with antiviral therapy
Droz et al[38]	Retrospective	Pts with immune-mediated inflammatory diseases (RA 14, CTD 7, vasculitis 5, other 9) developing HBV reactivation	35	7 pts treated with TNF-α inhibitors (not specified), 4 with RTX, 1 with ABA, 1 with TCZ, the others with steroids and/or other immunosuppressants	5 pts (drug not specified)	23 pts	12 pts		Not specified	-	Reactivation occurred a median of 35 wk after therapy start. 88.6% were asymptomatic; 25.7% had severe hepatitis. Management were NAs in 91.4% cases and decrease/withdrawal of immunosuppressants in 45.7%. Pooling these data with literature, earlier reactivation for RTX and HBsAg/HBV-DNA+ pts
Ye et al[80]	Prospective	Inflammatory arthritis pts (50 RA, 37 SpA)	87	TNFα inhibitors: 56 treated with IFX, 31 with ETN)	4 pts among CHB group , 9 pts among inactive carriers (not specified)	37 (6 HBV-DNA+, 31 HBV-DNA-) pts	50 pts		Not specified	-	2 cases of HBV reactivation among CHB pts not receiving pre-emptive NAs, none in those receiving it. Among inactive HBsAg carriers, 6 cases of reactivation in pts who didn’t receive NAs, none in those who did. No cases in HBsAg- pts
Nakamura et al[81]	Retrospective	RA	57	48 treated with TNFα inhibitors (including 9 receiving also TCZ); 7 with TCZ alone and 2 with TCZ and ABA	0 pts	0 pts	11 pts	38 pts	0 pts	8 pts (not vaccinated)	HBV-DNA detected in 3 pts (5.3%), 2 receiving TCZ and 1 receiving ETN, with serum HBV-DNA < 2,1 log copies/mL, and subsequent undetectable HBV-DNA within months

Pts: Patients; CHB: Chronic hepatitis B; IFX: Infliximab; ETN: Etanercept; IBD: Inflammatory bowel disease; SpA: Spondyloenthesoarthropaties (psoriatic arthritis included); csDMARDs: Conventiona Synthetic disease-modifying antirheumatic drugs; JIA: Juvenile idiopathic arthritis; TCZ: Tocilizumab; NAs: Nuclet(s)ide analogues; CTD: Connettive tissue disease; RTX: Rituximab; ABA: Abatacept. Adapted from Lunel-Fabiani et al[82] Joint Bone Spine 2014.

Table 4 Case reports and studies of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing rituximab

Ref.	Study design	Patients charachteristics	Therapy	Baseline virological status	Timing of HBV reactivation	Antiviral Therapy	Results	Comments
Pyrpasopoulou et al[88]	Case Report	56-year-old female RA pt starting RTX after 3 anti-TNF (ETN, IFX, ADA) and ABA. Previous diagnosis of CHB	RTX Antiviral prophylaxis with lamivudine	HBsAg+, anti-HBe+	1 mo after first RTX administration	Tenofovir + lamivudine RTX withdrawal	Good clinical, serological and virological response	-
Ghrénassia et al[89]	Case Report	78-year-old with RA test+ and erosive RA starting RTX after IFX because of a concomitant diagnosis of lymphoma	RTX monotherapy	HBsAg-/anti-HBc+	9 mo after RTX starts	Entecavir RTX withdrawal	Good clinical, serological and virological response	-
Gigi et al[90]	Case Report	64-year-old female RA pt starting RTX as a first-line bDMARD	RTX + methotrexate	HBsAg-/anti-HBc+	2 yr after RTX start	Entecavir RTX withdrawal	Good clinical, serological and virological response	-
Mitroulis et al[91]	Prospective study	41 rheumatic pts (34 RA; 7 others) who had received ≥ 1 cicle of RTX and had ≥ 6 mo of follow-up	17 pts treated with concomitant methotrexate, 35 with concomitant steroids. 2 pts treated with NAs without HBV reactivation	23 pts not HBV exposed; 4 vaccinated pts; 12 HBsAg-/anti-HBc+ (9 anti-HBs+); 2 pts HBsAg+ anti-HBc+. HBV-DNA undetectable in all pts	No cases of viral reactivation observed	-	-	Slight decrease in anti-HBs titres in vaccinated pts (P = 0.29), never under protective levels
Droz et al[38]	Retrospective (subgroup analysis)	4 pts affected with immune-mediated inflammatory disease treated with RTX	Not specified	Not specified	4 cases of HBV reactivation a median of 35 wk after therapy start (global data)	Not specified	No cases of fulminant hepatitis	Early reactivation with RTX and in HBsAg+/HBV-DNA+ pts (global data)

Pts: Patients; ETN: Etanercept; IFX: Infliximab; ADA: Adalimumab; ABA: Abatacept; CHB: Chronic hepatitis B; bDMARD: Biological disease-modifying antirheumatic drug; NAs: Nucleot(s)ide analogues; RTX: Rituximab; HBsAg: Hepatitis B surface antigen.

Table 5 Case reports of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing tocilizumab

Ref.	Study design	Patient charachteristics	Therapy	Basal virological Status	Timing of HBV reactivation	Antiviral Therapy	Results	Comments
Nagashima et al[92]	Case Report	60-year-old female RA pt, RA test and ACPA positive with erosive disease, starting TCZ after IFX and methotrexate	TCZ + steroids	HBsAg-10 yr before TCZ start, basal serological screening not performed	6, 5 years after TCZ start	Entecavir Ongoing TCZ	Subclinical, good serological and virological responses	Diagnosis made by detection of persistently high serological markers in an asymptomatic pt without liver function tests’ alterations
Tsuboi et al[93]	Case Report	59-year-old female RA pt initially treated with IFX thus withdrawn for HBV reactivation	IFX and then TCZ (after HBV reactivation)	Serological screening not performed before IFX. At 5th IFX infusion HBsAg+/HBV-DNA+/HBeAg+	32 wk after IFX start	Lamivudine Ongoing TCZ	Good clinical, serological and virological response until 2 years after TCZ start	-
Kishida et al[94]	Case Report	Adult-onset Still’s disease pt affected with CHB	TCZ + ongoing entecavir	HBsAg+	No reactivation observed	-	Good clinical, serological and virological response until end of follow-up	-
Nakamura et al[81]	Retrospective	Among 9 RA pts treated with TCZ (7 with TCZ alone and 2 with TCZ and ABA in sequence), 2 cases of HBV reactivation were detected: (a) 75-year old male pt starting TCZ as a first line therapy	TCZ monotherapy	HBcAb+ Undetectable HBV-DNA	4 mo after TCZ start	-	Subclinical, subserological, good virological response	HBV-DNA fluctuated always < 2, 1 log copies/mL throughout 4 mo until it became persistently undetectable, even after switch to ETN (due to lack of efficacy)
		(b) 55-year-old female pt starting TCZ after IFX and ETN	TCZ + methotrexate	HBcAb+ Undetectable HBV-DNA	2 mo after TCZ start	-	Subclinical, subserological, good virological response	HBV-DNA fluctuated always < 2, 1 log copies/mL throughout 5 mo until it became persistently undetectable, even after switch to ADA (due to lack of efficacy)
Droz et al[38]	Retrospective (subgroup analysis)	1 pt affected with immune-mediated inflammatory disease treated with TCZ	Not specified	Not specified	median of 35 wk after therapy start (global data)	Not specified	No cases of fulminant hepatitis	Early reactivation in HBsAg+/HBV-DNA+ pts (global data)

Pts: Patients; ACPA: Anti-citrullinated peptide antibodies; IFX: Infliximab; CHB: Chronic hepatitis B; ABA: Abatacept; ETN: Etanercept; HBsAg: Hepatitis B surface antigen; TCZ: Tocilizumab; HCV: HCV: Hepatitis B virus.

Table 6 Case reports of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing abatacept

Ref.	Study design	Patientscharacteristics	Therapy	Basal virological status	Timing of HBV reactivation	Antiviral therapy	Results	Comments
Kim et al[95]	Retrospective	8 RA pts affected with CHB	ABA + pre-emptive NAs (4 pts: 3 with entecavir and 1 with tenofovir) ABA without antiviral prophylaxis (4 pts)	HBsAg+ Detectable HBV-DNA in 3/8 pts	Not specified	Not specified	Among pts receiving NAs, no cases of HBv reactivation. Among pts without antiviral prophylaxis, all pts experienced HBV reactivation	Among pts receiving NAs, a statistically significant improve in DAS28-ERS was detected; which was not noted in the control group
Germanidis et al[96]	Case Report	72-year-old female RA pt starting ABA after ADA	ABA + leflunomide	Anti-HBc+/HBsAg-/anti-HBs+/anti-HBe+	6 mo after ABA start	ABA and leflunomide withdrawal Consequent anviral treatment with tenofovir (12 about 1 yr later)	Good clinical, serological and virological response to tenofovir	2 mo time lag between ABA withdrawal and liver tests flare, suggesting that HBV reactivation evolved in parallel with T cell immune reconstitution
Fanouriakis et al[97]	Case report	68-year-old female RA pt with erosive disease	ABA + methotrexate	HBsAg-/anti-HBc+ Basal HBV-DNA unknown	10 mo after ABA start	Tenofovir ABA withdrawal	Good clinical, serological and virological response	-
De Nard et al[98]	Case series	9 RA pts treated with ABA	ABA 8/9 pts treated with concomitant methotrexate Lamivudine in 2 pts (1 HBsAg+ and 1 HBsAg-) from baseline, and in 1 pt with comorbid HCV infection after ABA start	8 HBsAg-/anti-HBc+ 1 HBsAg+/HBV-DNA-	1 pt with comorbid HCV infection experienced aminotransferases elevation (< 2 x ULN) 2 mo after ABA start	Lamivudine Ongoing ABA	Subclinical, gradual amelioration of liver function tests, persistently undetectable HBV-DNA	No cases of HBV reactivation among pts receiving pre-emptive NAs
					1 pt with resolved HBV infection not receiving NAs developed HBV-DNA positivation 12 mo after ABA start	Ongoing ABA No prophylaxis	ConsecutiveHBV-DNA fluctuations; no flares in liver function tests even after entecavir initiation at 24 mo while switching to ADA (unpublished data)
Droz et al[38]	Retrospective (subgroup analysis)	1 pt affected with immune-mediated inflammatory disease treated with ABA	Not specified	Not specified	median of 35 wk after therapy start (global data)	Not specified	No cases of fulminant hepatitis (global data)	Early reactivation in HBsAg+/HBV-DNA+ pts (global data)

Pts: Patients; CHB: Chronic hepatitis B; NAs: Nucleot(s)ide analogues; ADA: Adalimumab; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis B virus.