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In recent years our understanding and interest in occult hepatitis B infection has increased manifold. To render uniformity to this ever-changing field, occult Hepatitis B infection (OHBI) was defined at a recent consensus meeting as presence of Hepatitis B viral DNA (HBV DNA) in the liver in individuals tested negative for Hepatitis B surface antigen (HBsAg).[1] These patients can, however, test positive for other serological markers like IgG antibody against Hepatitis B core (IgG anti HBc) and/or against surface antigen (IgG anti HBs). On the other hand, up to 20% of patients with OHBI can be negative for both the antibodies.[2] HBV DNA levels in patients with OHBI, even if detectable, is usually very low (< 200 IU/mL). Host immunity plays an important part in induction and maintenance of this occult status of Hepatitis B infection.[3] Thus, immunosupression induced by cancer chemotherapy or immunosuppressant drugs in patients with OHBI have a potential to reactivate Hepatitis B infection. The intensity of immunosuppression and its duration may determine the magnitude of the risk for Hepatitis B re-activation in this scenario.

Viral reactivation has been shown to be much higher in patients with HBsAg positive state (20–50%) as compared to those with OHBI.[4-6] This remains true for tumor necrosis factor targeted therapy in Hepatitis B infected patients as well.[7] In the study reported by Zhang et al.[8] in this issue, patients were included from a previous multicentric randomised controlled trial of Infliximab in Rheumatoid arthritis (RA). Baseline/on-treatment data of patients with OHBI in this cohort have been presented. In this study, 41 patients with OHBI were treated with five doses of Infliximab (at 0, 2, 6, 14, 22 weeks). All patients had received Methotrexate for at least 3 months, prior to starting Infliximab. The patients were followed up for 26 weeks (i.e. 4 weeks after the last Infliximab infusion). There was no significant rise in serum aminotransferase or bilirubin during therapy and at 26 weeks. Thirty of the 41 patients maintained HBsAg negative status when retested. This study thus demonstrated an excellent short-term safety of Infliximab therapy in RA patients with OHBI.

In this study by Zhang et al.,[8] however, baseline or on-treatment serum HBV DNA were not reported. This is a limitation of this study in the light of multiple studies demonstrating, viral reactivation preceding biochemical flare of hepatitis,[9] albeit exact clinical significance of viral reactivation unaccompanied by hepatitis flares is unknown.

Male sex and absence of anti-HBs are implicated risk factors for viral reactivation.[10, 11] As expected in RA, 82% of patients in this cohort were females and majority were positive for anti-HBs antibody. This may, in part, explain the absence of hepatitis flares in the study. Moreover, flare of hepatitis is expected to occur weeks, rather than days after the cessation of immunosupressants.[9] Patients in this study had only a 4 week period of follow up after the last dose of Infliximab and therefore, time may tell more during the long term follow up of these patients.

American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines recommend Hepatitis B surface antigen (HBsAg) and anti-HBc testing of patients planned for cancer chemotherapy or immunosupressants.[12, 13] The adherence to these guidelines is incomplete,[14] and further studies in this field are necessary to enthuse and educate the treating physicians regarding the need of such a screening exercise before starting TNF blockers too.

Based on published evidence,[10, 15] both these guidelines strongly recommend pre-emptive therapy with nucleoside analogues in HBsAg positive patients planned for cancer chemotherapy or immunosupressants. The duration of anti-viral therapy depends on baseline HBV DNA load. AASLD does not, however, recommend pre-emptive treatment for patients with OHBI. Instead, it recommends periodic monitoring of HBV DNA and nucleoside analogues are reserved for patients with viral replication. EASL, on the other hand, recommends baseline HBV DNA in all anti HBc positive patients as well as pre-emptive therapy with nucleoside analogues in patients with any detectable HBV DNA level. If baseline HBV DNA is undetectable, EASL also recommends periodic monitoring of serum alanine aminotransferase and HBV DNA.

Finally, Zhang et al.[8] brought out useful evidence regarding short-term safety of Infliximab in patients with OHBI. This is of considerable importance, as 1/3rd of the world population harbours serological evidence of past or present Hepatitis B viral infection.[12] Further prospective studies are required to estimate the risk of viral reactivation and consequent flares of hepatitis accurately in patients on Infliximab and other TNF blockers which are not strictly classified as immunosuppressants.

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