Rheumatology meets hepatology in 2012: a clinician's guideline for TNF inhibitors in hepatitis B/C virus carriers

Abstract

Effective and less toxic biologics have revolutionized rheumatology as well as hepatology over the last decennia resulting in higher therapeutic goals. Traditional disease modifying anti-rheumatic drugs (tDMARDs) failing to achieve a quiescent chronic rheumatoid arthritis (RA) or spondylarthropathic arthritis (SA) inflammatory disease, nowadays are to be switched into a more potent strategy with ultimately a combination of tDMARD plus TNF inhibitors (TNFi) early in disease. Patients with previous microbiological infections however present a challenge for a modern rheumatologist aiming at complete remission, particularly in carriers of viral infections. Hepatologists nowadays, can treat chronic hepatitis B and C virus infections effectively with potent antivirals. In the current issue an overview is given regarding patients in whom TNFi may be indicated, but also have been infected with viral hepatitis.

Keywords::

• anti-TNF
• guideline
• HBV
• HCV
• rheumatoid arthritis
• spondylarthropathy
• TNF blockers
• TNF inhibitor (TNFi)

A biologic revolution occurred in rheumatology and hepatology over the last two decennia [1]. It is estimated that a total of two billion people have been in contact with HBV globally, and of these have around 400 million become chronic carriers with an increased risk of developing liver disease. The major cause of chronic HBV infections is vertical transmission, whereas drug use, sexual transmission and nosocomial transmission are the major reasons for resolving acute HBV infections. In immunocompetent adults, a strong cellular immune response to 'foreign' HBV proteins expressed by hepatocytes results in a clinically apparent acute hepatitis, which in 99% of infected people affects clearance of the infection. The progression of liver disease after HBV infection is fostered by active virus replication, indicated by a serum HBV DNA level > 2000 IU per ml [2]. In such cases THF inhibitors (TNFi), amongst other immune suppressants, are contraindicated without a preemptive antiviral regimen. A serum HBV DNA level < 2000 IU per ml and normal alanine aminotransferase (ALT) levels are considered to be indicators of inactivity in carriers with a low risk of clinical progression, but reactivation may occur following immune suppression or even spontaneously. As clinical and histological improvement accompanies reductions in HBV replication, interventions reducing HBV replication are indicated in such cases to limit progressive liver disease. Also, when the HBV infection has been overcome, immune suppression still cannot be considered to be fully safe.

Charpin et al. previously showed promising French data on the relative safety of TNFi in a small series of 21 hepatitis B carriers for up to 3 years [3]. Additional cohort studies found nil cases of HBV reactivation during TNFi therapy up to about 4 years in 216 patients with RA or SA [4-8]. Lan et al. recently added data on the risks in antiHBc^pos patients: safety of TNFi in 58 resolved HBV type of patients (HBsAg^neg/antiHBs^pos), versus a relative unsafety of TNFi in the occult carrier type of patients (HBsAg^neg/antiHBs^neg)HBV reactivation risk of 1 out of 12 patients (8%: 95% CI: 0 – 23%) in an endemic area [9]. Lan et al. also provided data on the safety of pre-emptive antivirals in 10 HBsAg^pos patients versus unsafety of antiviral abstinence in five out of eight HBsAg^pos patients when TNFi is started, that is 62% reactivation risk (95% CI 30 – 96%). These data implicate that during TNFi therapy HBV (re)activation may well occur in both active carriers (HBsAg^pos) and HBsAg^neg/antiHBc^pos patients with detectable HBV DNA, so-called occult HBV carriers. Antiviral prophylaxis appears to effectively reduce the HBV (re)activation risk in HBsAg^pos RA patients undergoing TNFi therapy [4,5].

Clearly, in HBsAg^pos patients hepatitis treatment should be prioritized for reasons of unacceptable risks for hepatitis reactivation (about 50%), fulminant hepatitis (about 10%), and death (about 4%) [10].

It took years to see TNFi and the viral hepatitis risks in the right perspective. Why?

Outcomes of HBV infection evolve only over decades, whereas clinical trials are limited to only several, rarely up to 5 years. Similarly, efficacy studies with TNFi are limited to the remission-induction phase in patients without a comorbid condition. One should realize that only little is known on the erosiveness of disease in patients with a HBV/HCV carriership. Literature also lacks data on cessation of TNFi after a 1 – 2 year period of successful TNFi in these patient groups. Over the past decades, more effective and less toxic biologics have revolutionized rheumatologic therapy in chronic autoimmune inflammation of rheumatoid arthritis (RA) and spondylarthropathic arthritis (SA). In upcoming years several unmet needs may present: adequate access of TNFi/antivirals, indicators for successful cessation of TNFi, management strategies for long-term safety, particularly how to deal with tumor and infection risk in ongoing treatment with TNFi.

A previous HBV infection clearly presents a challenge for clinicians [8]. If HBV serology suggests a resolved HBV state, then TNFi appears to be relatively safe during a limited follow-up period of 3 years. Studies are needed with longer follow-up, particularly in patients with decreasing antibody titres (anti-HBc). Therefore we think the following clinical rules can be used (Table 1): If really complete remission of the rheumatic condition is to be aimed at and a biologic is to be considered, a series of screening tests should be performed according to national guidelines weighing regional endemic and personal behavioural or professional risks. In cases with active HBV/HCV a hepatologist should be consulted for preemptive potent antivirals [2,8,11]. In patients with anti-core antibodies the safety of TNFi cannot be guaranteed, unless adequate surface and core antibodies have developed. In endemic areas and/or high-risk groups TNFi treatment is associated with hepatitis risks in seronegative patients: HBsAg^neg/antiHBs^neg/antiHBc^neg; this explains why liver function test should be performed at predefined time intervals during follow-up according to national guidelines. After a 3-year period a re-evaluation of TNFi indication, for example, cessation of TNFi should be considered, possibly even advised in order to re-evaluate an individual's chance of a biologic-free remission. As we currently know that in the maintenance phase of chronic arthritides, TNFi can be stopped in about 60% of cases if initiated early in disease [12]. Rules reflecting stopping or continuing TNFi should become part of national guidelines nowadays focussing at expedient use of biologics. Much of the additional risks of biologics are not fully clear yet, but similarly, HBV reactivation has been seen following immune suppression by rituximab as well (> 9%). Further studies are warranted as these hepatitis risks should be kept in mind before aiming at complete remission in all subsets of patients with a chronic rheumatoid inflammation. For now, the following rules may give guidance to the rheumatologist.

Table 1. Clinician's rules for appropriate use of TNFi.

Before starting TNFi: patients should be offered screening for transaminase plus HBV/HCV, that is HBsAg, antiHBs and antiHBc, antiHCV	Level III*
Monitoring schedule during TNFi treatment in patients with normal transaminases:  intensive (every 1 – 3 months) follow-up of transaminase/HBsAg in high risk groups/endemic countries  low-frequency follow-up of transaminase (every 6 – 12 months or only after travelling to a higher risk country)  in low endemic areas/non-risk groups; HBsAg to be considered in endemic regions or for increased individual risk  (from behaviour or profession)	Level III
Active HBV that is HBsAg^pos: consultation of a hepatologist for pre-emptive potent antivirals such as tenofovir/entecavir – Caveat: emergence of a lamivudine-resistant mutant strain in chronic HBV-infected patients	Level II-1
HBV carrier/partial protection: without full serological HBV protection that is HBsAg^neg/antiHBs^neg/antiHBc^pos TNFi is not fully safe – Advice: transaminase/HBsAg (every 1 – 3 months in an endemic region or higher individualized risk)	Level II-1
HBV carrier/full serological protection: transaminase may be considered but a regular monitoring scheme not needed in low risk patients/regions as TNFi is safe if HBsAg^neg/antiHBs^pos/antiHBc^pos	Level II-1
HCV patient: consultation of a hepatologist for the combined treatment, if non-cirrhotic. Caveat: drug-induced liver insufficiency (DILI) can be caused by TNFi-induced autoimmune hepatitis (predominantly described after infliximab)	Level II-1 Level II-3

Level I: Evidence obtained from at least one properly designed randomized controlled trial.

Level II-1: Evidence obtained from well-designed controlled trials without randomization.

Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one centre or research group.

Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials could also be regarded as this type of evidence.

Level III: Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.

*Graded levels of evidence-based medicine.

• (1) Screening for hepatitis status via transaminases should be obtained in anyone with an indication for biologics at the start and should be considered during follow-up every 3 – 6 months thereafter depending on risk factors.

• (2) Screening for HBV and HCV should be done at the initiation of biologic therapy, and regularly thereafter with a frequency based on an individualized risk profile (endemic region plus individual risk due to behaviour/profession) to be addressed by national guidelines.

• (3) After having reached a low disease activity score (LDAS)/complete remission of the chronic rheumatic condition during a 1 – 3-year-period of time a biologic (TNFi)-free remission should be aimed at in HBV/HCV patients, particularly since successful cessation of biologics may be achievable.

Declaration of interest

No funding was received in preparation of this manuscript. TL Jansen has received advisory board and speakers fees from Abbott, BMS, Pfizer, Roche, UCB and Menarini/Ipsen. CJJ Mulder has nothing to disclose.