In clinical practice, a variety of primary or secondary autoimmune kidney diseases, including nephrotic syndrome, IgA nephropathy, ANCA-associated glomerulonephritis or lupus nephritis, usually require high-dose corticosteroid monotherapy or corticosteroid in combination with csISs therapies. Combination therapy with corticosteroid and monthly cyclophosphamide pulse therapy is a commonly used treatment regimen. Other csISs, including mycophenolate, cyclosporine A, and tacrolimus are also used frequently.
In the past decade, a large number of studies have reported the occurrence of HBVr in patients receiving immunosuppressive therapy. The reactivation of hepatitis B in the context of immunosuppressive therapy may be severe and potentially fatal. HBVr mainly occurs in HBsAg- and anti-HBc-positive patients, but it also occurs in individuals with a prHBV infection . Among patients with a prHBV infection, HBVr mainly occurred in patients receiving rituximab-containing regimens with or without haematological diseases. In contrast, patients with non-haematological diseases or receiving rituximab-free regimens, including nonbiologic or biologic disease-modifying antirheumatic drugs (DMARDs), had a low risk of HBVr and may not require anti-HBV prophylaxis [12–14]. Some studies reported that in anti-HBc-positive patients with rheumatic diseases treated with conventional synthetic DMARDs, including methotrexate, tacrolimus, and azathiopurine, the risk of HBVr was also very low [15–16]. Risk factors for HBVr in these patients may include negative or low titres of HBsAb, advanced age, and a history of the use of ≥ 3 classes of immunosuppressants [14–16].
In 2015, according to patients’ HBsAg status and clinical treatment plans, the risk of HBVr was divided into 5 levels by the American Society for the Study of Liver Diseases . In patients with a prHBV infection who received high-dose corticosteroid therapy (e.g., ≥ 20 mg/day), the risk of HBVr was low (< 1%). For those treated with corticosteroid-free cytotoxic chemotherapy, anti-TNF therapy, methotrexate, or azathioprine, the risk was considered to be very low. For patients with a low and a very low risk for reactivation, it was recommended that regular monitoring should be carried out, and antiviral treatment should be started if HBVr occurred. However, the recommendations were considered to be weak and based on evidence of moderate quality. Our research is consistent with the literature. In this study, all the 258 patients received prednisone ≥ 20 mg/day for at least 3 months with a mean treatment time of 6.11 months (range: 3 ~ 24 months). Of these patients, 74.4% of them received corticosteroid in combination with csISs therapy, with cyclophosphamide as the most commonly used agent, followed by mycophenolate mofetil and calcineurin inhibitors. No hepatitis flare and reverse seroconversion to positive HBsAg status were observed during a mean follow-up time of 21.66 months.
The precise mechanism by which HBVr occurs is unclear, and the initial event is thought to be a disruption in the ability of the host immune system to control HBV replication . Among HBsAg-positive patients receiving corticosteroids, HBVr has occurred both with high-dose, rapidly tapered regimens and moderate-dose, prolonged regimens . The increased viral replication may be due, in part, to a corticosteroid responsive element in the HBV genome that stimulates viral replication and transcriptional activity .
HBVr refers to a sudden and significant increase in HBV replication (HBV DNA level), usually accompanied by an increase in serum transaminase levels. In patients with resolved infection, reactivation has been considered to occur upon the demonstration of reverse seroconversion to HBsAg-positive status . In our 258 patients, no hepatitis flare was observed in the course of regular and continuous monitoring of liver functions during and after the immunosuppressive therapy. 41.09% of them also reexamined HBV markers regularly and reverse seroconversion to positive HBsAg status was not observed. Meanwhile, there were no statistically significant differences in the clinical features and immunosuppressive therapies between patients with and without reexaminations for the serum HBV markers.
However, as our research was a retrospective study and some patients did not undergo regular monitoring of serum HBV markers, the actual incidence of HBVr may be underestimated. The actual rate of HBVr in this group of patients and whether the common preventive anti-HBV treatment is needed still needs prospective studies for confirmation.