Tocilizumab has demonstrated optimal efficacy and safety in patients with rheumatoid arthritis (RA) from clinical trials. However, the risk of hepatitis B virus reactivation (HBVr) in these patients remains uncertain because patients with underlying HBV have been excluded in phase III studies.
Systematical reviews were conducted on PubMed, Embase, and the Cochrane Central Register of Controlled Trials up to 21 February 2023. Random-effects meta-analysis was performed to calculate the pooled incidence of HBV reactivation.
We included 0 clinical trials and 11 observational studies with a total of 25 HBsAg+ and 322 HBsAg-/anti-HBc+ RA patients. Among the HBsAg+ patients without antiviral prophylaxis, the pooled rate was 69.4% (95% CI, 32.9-91.3), with a median time of 4 months (range, 1-8 months) from tocilizumab initiated. Half of these patients with HBVr experienced hepatitis flare-up but no deaths. HBVr was eliminated with prophylaxis in this population. Among HBsAg-/anti-HBc+ patients, the pooled incidence of reactivation was 3.3% (95% CI, 1.6-6.7), with a median time of 10 months (range, 2-43 months) from tocilizumab initiated. HBVr was not associated with hepatitis flare-up and death. HBsAg-/anti-HBc+ patients without anti-HBs antibodies had a significantly higher risk of HBVr (Odds ratio, 12.20; 95% CI, 1.16-128.06).
This systematic review indicated that the risk of HBVr in RA patients with anti-HBs-, HBsAg+, or HBsAg-/anti-HBc+ cannot be ignored but may be avoided. Clinicians should consider implementing appropriate antiviral prophylaxis and monitoring policies for RA patients to avoid unnecessary hepatic side effects from tocilizumab treatment.

The objective of this study was to assess the possibility of HBV reactivation (HBVr) in patients with RA under anti-IL-6 treatment.
Using PubMed, Scopus and EMBASE, we performed a systematic literature search for articles related to HBVr in RA patients under anti-IL-6 treatment. The search was performed with no date limits and was last updated 28 January 2023. The results from all the databases were combined and duplicates were excluded, as were non-English articles, case reports, position articles, comments, and paediatric studies.
Our initial search led to 427 articles; 28 were duplicates, 46 non-English, 169 reviews, 31 books/letters, 25 case reports, and 88 irrelevant to the meta-analysis aim; 21 were excluded due to inadequate information, leaving 19 articles, with a sum of 372 RA patients with chronic HBV (CHB) or resolved HBV infection, for further analysis. The overall risk for HBVr in RA patients with CHB was 6.7%, increasing to 37% when only RA patients with CHB and no antiviral prophylaxis were included. On the contrary, HBVr was close to 0% in RA patients with resolved HBV infection, irrespective of antiviral prophylaxis. All RA patients experiencing HBVr in these studies were successfully managed with antiviral treatment and/or drug withdrawal.
Overall, anti-IL-6 treatment comes with a significant risk of HBVr in RA patients with CHB; risk is diminished when antiviral prophylaxis is used. In contrast, in RA patients with resolved HBV infection, the risk of HBVr seems to be extremely low. Large, well-designed studies (either controlled trials or multicentre/international observational studies) are warranted to further validate these results.

BACKGROUND: More and more novel anticancer drugs have been approved for patients with hematological malignancies in recent years, but HBV reactivation (HBV-R) data in this population is very scarce. This study aimed to evaluated HBV-R risk in patients with hematological malignancies receiving novel anticancer drugs.
METHODS: HBV markers and serum HBV DNA levels of patients with hematological malignancies receiving novel anticancer drugs in a tertiary cancer hospital were retrospectively collected. HBV-R risk in the whole cohort and subgroups was described. The relevant literature was reviewed to make a pooled analysis.
RESULTS: Of 845 patients receiving novel anticancer drugs, 258 (30.5%) were considered at risk for HBV-R. The median duration of exposure to novel drugs was 5.6 (0.1-67.6) months. The incidence of HBV-R was 2.1% in patients with past HBV infection without prophylactic antiviral treatment (PAT) and 1.2% in all patients at risk of HBV-R. In a pooled analysis of 11 studies with 464 patients, the incidence of HBV-R was 2.4% (95% CI: 1.3-4.2) in all at-risk patients receiving novel anticancer drugs and 0.6% (95% CI: 0.03-3.5) in patients with anticancer drugs plus PAT. The incidence of death due to HBV-R was 0.4% (95% CI: 0.1-1.6) in all at-risk patients and 18.2% (95% CI: 3.2-47.7) in patients with HBV-R.
CONCLUSIONS: Most episodes of HBV-R are preventable, and most cases with HBV-R are manageable. We recommend that novel anticancer drugs should not be intentionally avoided when treating cancer patients with HBV infection.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have been explored as first-line treatment in various types of previously untreatable malignancies, while limited evidence is available on the management of hepatitis B virus (HBV) in patients undergoing immunotherapy. We systematically reviewed data concerning challenges of hepatic adverse events including HBV reactivation and hepatitis in patients with chronic HBV infection undergoing immunotherapy.
METHODS: A systematic search was conducted in Medline, web of science, Embase and Cochrane library up to May 31, 2022. Studies reporting the safety profile of ICIs in patients with HBV infection were eligible. Meta-analyses were conducted to generate odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS: A total of 13 studies including 2561 patients were included for meta-analysis. The overall incidence rates of HBV reactivation in patients with chronic HBV infection and past HBV infection were 1.0% (95% CI 0-3%) and 0% (95% CI 0-0%), respectively. Among patients with chronic HBV infection, the incidence rates of HBV reactivation were 1.0% (95% CI 0-2%) and 10.0% (95% CI 4-18%) for patients with and without antiviral prophylaxis, respectively. Patients with chronic HBV infection were at a higher risk of HBV reactivation compared with those with past HBV infection [OR = 8.69, 95% CI (2.16-34.99)]. Antiviral prophylaxis significantly reduced the risk of HBV reactivation [OR = 0.12, 95% CI (0.02-0.67)] and HBV-associated hepatitis [OR = 0.05, 95% CI (0.01-0.28)] in patients with chronic HBV infection.
CONCLUSIONS: Prophylactic antiviral therapy should be administered to patients with chronic HBV infection undergoing anticancer immunotherapy. Patients with past HBV infection are at lower risk of HBV reactivation compared with those with chronic HBV infection, they could be initiated with antiviral prophylaxis or monitored with the intent of on-demand antiviral therapy.

The cytokine storm from the evolution of severe cases of COVID-19, requiring strong immunosuppressive therapies, has raised the issue of reactivation of hepatitis B virus (HBV) infections in these patients. An analysis of the first observational studies in patients with COVID-19 and immunosuppressive therapy and HBV infection along with special clinical cases was presented, as well as personal experience on a series of cases (a group of 958 patients with COVID-19), compared with the analysis of studies performed on patients with HBV infection that underwent biological therapies for psoriasis and personal experience (a group of 81 psoriasis patients treated with biological therapies). Clinical studies have revealed that HBV reactivation in patients undergoing biological therapies for psoriasis, can be prevented with monitoring and treatment protocols and thus, these therapies have been demonstrated to be safe and effective. In COVID-19, immunosuppressive therapies are short-lived but in high doses, and the conclusions of clinical trials are contradictory, but there are published cases of HBV reactivation, which requires a unitary attitude in the prevention of HBV reactivation in these patients. An algorithm was presented for monitoring and treatment of HBV infection for patients with psoriasis treated with biological therapy and the conditions when this protocol can be used for patients with COVID-19 and immunosuppressive therapy.

Occult hepatitis B infection (OBI) is characterized by the detection of hepatitis B virus (HBV) DNA in serum or liver but negativity for hepatitis B surface antigen. OBI, which is thought to be maintained by host, immunological, viral and/or epigenetic factors, is one of the most challenging clinical features in the study of viral hepatitis. Currently, there is no validated detection test for OBI. It is believed that OBI is widely distributed throughout the world, with a higher prevalence in populations at high-risk HBV, but the detailed worldwide prevalence patterns are unknown. We conducted a survey of recently published studies on OBI rates across all continents. High prevalence rates of OBI are observed in some specific groups, including patients with hepatitis C virus, human immunodeficiency virus co-infection or hepatocellular carcinoma. In 2016, the World Health Organization adopted strategies to eliminate viral hepatitis by 2030, but the difficulties in detecting and treating OBI currently challenge this goal. Subjects with OBI can transmit HBV, and episodes of reactivation can occur. Further studies to understanding the mechanisms that drive the development of OBI are needed and can contribute to efforts at eliminating viral hepatitis.

HBV reactivation (HBVr) can occur due to the ability of HBV to remain latent in the liver as covalently closed circular DNA and by the capacity of HBV to alter the immune system of the infected individuals. HBVr can occur in patients undergoing hematopoietic stem cell transplantation (HSCT) with a clinical spectrum that ranges from asymptomatic infection to fulminant hepatic failure. The risk of HBVr is determined by a complex interplay between host immunity, virus factors, and immunosuppression related to HSCT. All individuals who undergo HSCT should be screened for HBV. HSCT patients positive for HBsAg and also those HBcAb-positive/HBsAg-negative are at high risk of HBV reactivation (HBVr) due to profound and prolonged immunosuppression. Antiviral prophylaxis prevents HBVr, decreases HBVr-related morbidity and mortality in patients with chronic or previous HBV. The optimal duration of antiviral prophylaxis remains to be elucidated. The vaccination of HBV-naïve recipients and their donors against HBV prior to HSCT has an important role in the prevention of acquired HBV infection. This narrative review provides a comprehensive update on the current concepts, risk factors, molecular mechanisms, prevention, and management of HBVr in HSCT.

BACKGROUND: Until recently, the role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation during immunosuppressive therapy or chemotherapy in patients with resolved HBV infection was unclear. The aim of the study reported here was to compare the efficacy of antiviral prophylaxis versus that of non-prophylaxis in resolved HBV-infected patients undergoing chemotherapy or immunosuppressive therapy.
METHODS: PubMed, the Cochrane library, and the ClinicalTrials.gov website were searched from inception until December 2017. Studies comparing reactivation in prophylaxis versus non-prophylaxis in patients undergoing immunosuppressive therapy or chemotherapy were included. The meta-analysis was performed to calculate the relative risk (RR) and the pooled estimates.
RESULTS: A meta-analysis was conducted of 13 studies (2 randomized controlled trials [RCTs] and 11 cohort studies). The summary RR for HBV reactivation was 0.47 (95% confidence interval [CI] 0.13-1.69) for antiviral prophylaxis versus non-prophylaxis. Both of the RCTs included in the meta-analysis enrolled patients treated with rituximab. Subgroup analyses showed that the two RCTs ± high-quality cohort studies showed a decreased risk of HBV reactivation among the antiviral prophylaxis groups (RCT 1: RR 0.13, 95% CI 0.02-0.70; P = 0.02; RCT 2: 0.28, 95% CI 0.08-0.98; P = 0.05). Subgroup analyses further showed that the cohort studies did not support an association between the antiviral prophylaxis groups and HBV reactivation (RR 0.62, 95% CI 0.14-2.83; P = 0.54); adjusting for confounding factors, such as detectable anti-HBs antibodies, failed to produce a significant association (RR,0.29, 95% CI 0.07-1.28; P = 0.10).
CONCLUSIONS: Our meta-analyses did not show an association between antiviral prophylaxis use and risk of HBV reactivation. As using only the RCTs ± high-quality cohort studies data rendered this association significant, clinicians can consider providing antiviral prophylaxis to patients with resolved HBV infection who are undergoing rituximab-based therapy.

It is estimated that more than two billion people around the world have been infected by Hepatitis B virus (HBV). Reactivation of HBV (rHBV) is a potentially fatal complication after biological therapy. With the increasing use of biologics and targeted therapy in rheumatoid arthritis (RA) patients who are refractory to conventional synthetic disease-modifying anti-rheumatic drugs, rHBV in those with past infection has become increasingly problematic, especially in HBV-endemic regions. Among those receiving biological therapy, the risk of rHBV varies according to the status of HBV infection and the degree of biologic-related immunosuppression. As rHBV is largely preventable, it is imperative that the risk status of rHBV in RA patients receiving biological and targeted therapy be stratified. Therefore, the aim of this review was to summarize the reported data on rHBV, and propose management strategies for RA patients with different risks of rHBV based on evidence presented in the current literature.

BACKGROUND: The growth of new therapeutic options and practices increases the risk of hepatitis B virus (HBV) reactivation in patients with haematologic malignancies and/or patients undergoing haematologic stem cell transplantation (HSCT).
OBJECTIVE: To provide a systematic review supporting recommendations for prevention, monitoring, prophylaxis and therapy of HBV reactivation in patients with haematologic malignancies and HSCT.
METHODS: The systematic review was based on a strategy using PubMed and the Cochrane Library searching literature published from 1991 to December 31, 2016. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were followed.
METHODS: Randomized control trials, prospective and retrospective cohort studies.
UNASSIGNED: Cochrane Risk of Bias Tool and Newcastle Ottawa Quality Assessment Scale.
RESULTS: Forty-two studies of fair or good quality were included in this systematic review. The following main results were obtained: haematologic patients should be screened for HBV before chemotherapy; HBV DNA levels should be monthly monitored in all HBV-positive patients not receiving prophylaxis; hepatitis B surface antigen (HBsAg)-positive haematologic patients and patients undergoing HSCT should receive prophylaxis and third-generation HBV drugs should be provided; and anti-hepatitis B core protein-positive lymphoma patients and patients who underwent HSCT should receive antiviral prophylaxis.
CONCLUSIONS: A higher quality of evidence is needed. However, the level of evidence was sufficient to support the recommendations published in this issue of the journal.