Reactivation of hepatitis viruses following immunomodulating systemic chemotherapy

Reactivation of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection following anticancer chemotherapy and immunosuppressive therapy is a well‐known complication. HBV reactivation has been reported to be associated with anti‐CD20 monoclonal antibody rituximab‐containing chemotherapy and tumor necrosis factor‐α inhibitor‐containing immunosuppressive therapy in HBV resolved patients (hepatitis B surface antigen negative and antibodies against hepatitis B core antigen positive and/or antibodies against surface antigen positive). On the other hand, HCV reactivation has been reported to be associated with liver damage or hepatic dysfunction, but fulminant hepatitis due to HCV reactivation is a rare complication. In this review, we describe the pathophysiology of the reactivation of HBV and HCV infection, as well as the clinical evidence and management of HCV reactivation.     

Use of biological disease-modifying anti-rheumatic drugs in patients with concurrent rheumatic disease and hepatitis B

Background: Biological disease‐modifying anti‐rheumatic drugs (bDMARDs) are effective in the management of inflammatory arthritides. Reactivation of hepatitis B virus (HBV) is a potential adverse outcome in patients treated with bDMARDs. There is currently no consensus on the approach to identifying and treating these patients with underlying HBV infection. Aim: The aims of this study were to assess the risk of HBV reactivation in patients treated with bDMARDs, and to determine whether HBV screening should be carried out in all patients prior to commencing bDMARDs. Methods: A literature search was undertaken to identify all reports of patients with inflammatory arthritides and concurrent HBV infection being treated with bDMARDs. Results: Forty‐three patients with HBV infection were identified, of whom eight patients developed HBV reactivation after exposure to bDMARDs. Of the patients who experienced reactivation, two had unknown infection that surfaced during bDMARD therapy. Patients who experienced reactivation were promptly treated with antiviral therapy and saw clinical improvement. There are no long‐term data on these patients. Conclusions: HBV reactivation may result in serious consequences, including death. Tuberculosis screening prior to bDMARD treatment is already standard practice, as is HBV screening for patients undergoing cancer chemotherapy. Implementing HBV screening for all patients prior to bDMARD treatment can identify patients with chronic HBV who may require antiviral therapy.     

Comparing the risk of hepatitis B virus reactivation between direct‐acting antiviral therapies and interferon‐based therapies for hepatitis C

Hepatitis B virus (HBV) reactivation has been reported during antihepatitis C treatment in patients with hepatitis C virus (HCV) and HBV co‐infection. We aimed to evaluate the frequency and risk factors of HBV reactivation during anti‐HCV therapy and compared those between interferon (IFN)‐free direct‐acting antiviral (DAA) therapies and IFN‐based therapies. Three hundred and twenty‐two patients with HCV infection receiving anti‐HCV therapy were retrospectively screened. The baseline HBV infection statuses of all eligible patients and the HBV‐DNA level of all patients with current or previous HBV infection were examined at the end of treatment. In patients with baseline anti‐HBs positivity, changes in anti‐HBs titre were evaluated. Of 287 patients who met the inclusion criteria, 157 had current (n=4) or previous (n=153) HBV infection; 85 were treated with IFN‐free DAA therapies and 72 were treated with IFN‐based therapies. Six patients experienced HBV reactivation (n=2) or HBV reappearance (n=4) after IFN‐free DAA therapies, while no patient developed HBV reactivation after IFN‐based therapies. The risk factors of HBV reactivation or reappearance were DAA therapies and a reduction in anti‐HBs titre to <12 mIU mL^?1 by the end of treatment. The decline changes of anti‐HBs titre were significantly higher in patients treated with DAA therapies. Although HBV reactivation hepatitis was not observed, three of four patients with HBV reactivation or reappearance after achieving HCV eradication had viremia 8 weeks after completion of therapy. A significant proportion of patients develop HBV reactivation or reappearance without hepatitis after IFN‐free DAA therapies. Low levels of anti‐HBs and their decrease to <12 mIU mL^?1 after treatment are significant risk factors for HBV reactivation or reappearance.     

Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection

Dual hepatitis C virus(HCV)/hepatitis B virus(HBV)infection is found in HBV or HCV endemic areas,and in specific populations exhibiting a high risk of parenteral viral transmission.Clinical observations have revealed that HCV/HBV dually infected patients demonstrate a higher risk of liver disease progression compared with HBV or HCV monoinfected patients.The viral activity responsible for liver disease progression can be determined by examining the viral loads of HCV and HBV and by conducting liver biopsy examinations.Recent trials have confirmed that the combination therapy of peginterferon alpha-2a or 2b and ribavirin for dual hepatitis patients with HCV dominance appears to be as effective and safe as it is in patients with HCV monoinfections.Strikingly,approximately 60% of dually infected patients with inactive hepatitis B before treatment develop HBV reactivation after the clearance of the HCV.The clinical significance of this HBV reactivation and the strategy to prevent and treat this event should be determined.Furthermore,approximately 30%of dually infected patients lost hepatitis B surface antigen(HBsAg)within 5 years after the start of peginterferonbased therapy,and 40%of them harbored occult HBV infection.The underlying mechanisms of their accelerating HBsAg seroclearance and the development of occult HBV await further investigations.Moreover,the optimal treatment strategies for dually infected patients who are seropositive for the hepatitis B e antigen must be explored.Finally,the advent of new direct-acting antiviral-based anti-HCV therapy may change the optimal therapies for patients with dual hepatitis in the near future,which warrants further clinical trials.     

HBV再激活相关肝衰竭的研究进展

HBV感染是全球重大公共问题。当前的抗病毒治疗药物能够有效的控制病毒复制,但无法清除HBV,在停用了抗HBV药物之后病毒仍然有再激活的可能。实验研究及临床研究表明在感染HBV以后,虽然95%的成人能够自发达到临床痊愈,但病毒基因组仍在宿主的肝细胞内持续存在,当使用免疫抑制剂或肿瘤化疗等药物治疗实体和血液系统恶性肿瘤、风湿免疫疾病、HCV感染等基础疾病时,HBV复制可能重新激活。HBV再激活可能导致严重的临床结局,部分患者可出现肝衰竭,甚至死亡。我国的回顾性研究表明有9%~30%乙型肝炎相关慢加急性肝衰竭是由HBV再激活引起。因此,识别HBV再激活的风险人群并制订合理的预防措施对于减少乙型肝炎相关慢加急肝衰竭的发生有着非常重要的意义。简述了HBV再激活的定义、发生基础,同时论述了HBV再激活引起肝衰竭的诱因及机理,最后总结了需预防人群及措施。     

免疫抑制剂致乙肝病毒再激活的临床分析

目的 探讨需要使用免疫抑制剂的乙肝病毒（HBV）感染者使用免疫抑制剂后乙肝病毒再激活的发生及其抗病毒治疗的收益.方法 收集我院近3年收治的46例使用免疫抑制剂患者的临床资料,并分析其免疫抑制剂类型、肝脏损害程度及抗病毒治疗情况.结果 出现乙肝再激活17例（37.0%）,发生重症肝炎6例（13.0%）.接受拉米夫定预防性抗病毒治疗的患者有80%HBV DNA下降,乙肝再激活后再行抗病毒治疗的7例患者中,2例死于肝衰竭.未作抗病毒治疗的患者中有10例（47.6%）乙肝病毒再激活.结论 所有需要使用免疫抑制剂的患者在用药前需要进行常规的HBV筛查,对存在HBV感染的患者需要考虑到HBV再激活.使用强烈的免疫抑制剂、糖皮质激素以及低龄、男性患者容易发生乙肝再激活.对具有高危因素的患者需要及时使用抗病毒药物,抗病毒药物的使用可以降低病毒再激活的风险.     

Dual chronic hepatitis B virus and hepatitis C virus infection

Dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are common in HBV or HCV endemic areas. However, several clinical and pathogenetic issues remain unresolved. First, clinical and in vitro studies suggest the interactions between two viruses. The dynamics of the interaction in untreated setting versus treated setting and its influence on the long-term outcomes await further studies. A key issue regarding viral interactions is whether modulation of infection occurs in the same dually infected individual hepatocyte of the liver. Clarifying this issue may help to understand the reciprocal interference between HCV and HBV and provide clues for future immunopathogenetic studies. Second, the prevalence and clinical significance of coexisting occult HBV infection in patients with chronic HCV infection need further investigations. Third, combination therapy of peginterferon alfa-2a and ribavirin appears to be just as effective and safe for the treatment of hepatitis B surface antigen (HBsAg)-positive patients chronically infected with active chronic hepatitis C as it is in patients with HCV monoinfection. Nevertheless, one-third of dually infected patients with nondetectable serum HBV DNA-level pretreatment developed HBV reactivation posttreatment. How to prevent and treat this reactivation should be clarified. Furthermore, about 10% of the dually infected patients lost HBsAg. Underlying mechanisms await further investigations. Finally, the optimal treatment strategies for dually infected patients with hepatitis B e antigen-positive chronic hepatitis B should be identified in future clinical trials.     

Resolved hepatitis B infection in patients receiving immunosuppressive therapy: Monitor versus prophylaxis against viral reactivation

Risk of hepatitis B virus reactivation (HBVr) in patients with resolved HBV infection receiving immunosuppressive therapy has been a growing concern, particularly in the era of biological and targeted therapies. HBV monitoring versus antiviral prophylaxis against HBVr in those patients remains controversial. The aim of the study was to determine the incidence of HBVr and HBV-related hepatitis in resolved HBV patients who received immunosuppressive therapy with or without antiviral prophylaxis. This retrospective study included 64 patients with resolved HBV infection who received different regimens of immunosuppressive medications, with moderate risk of HBVr, for variable underlying diseases. Patients who had chronic HBV infection or other viral infections were excluded. Patients who received B-cell depleting therapies were ruled out. They were divided into 2 groups: group 1 included 31 patients who received immunosuppressive therapy without antiviral prophylaxis, and group 2 included 33 patients who received antiviral prophylaxis (entecavir) within 2 weeks of commencing the immunosuppressive therapy. HBVr, HBV-related hepatitis, and HBV-unrelated hepatitis were assessed along a 1-year duration. The overall HBVr incidence was 1.56% (1/64). This patient who had HBVr was seen in group 1. There were no significant differences between the 2 groups regarding the incidence of HBVr, HBV-related hepatitis, HBV-unrelated hepatitis, and immunosuppressive therapy interruption along a 1-year duration. Based on this retrospective study, close monitoring was equal to antiviral prophylaxis regarding the outcome of resolved HBV patients who received moderate risk immunosuppressive therapy. HBV treatment should commence once HBVr is confirmed.     

Reactivation of hepatitis B virus during interferon‐free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co‐infection

Direct‐acting antiviral agents (DAA) for hepatitis C virus (HCV) are not effective for hepatitis B virus (HBV), which may be suggestive of reactivation of anti‐HBe hepatitis during interferon (IFN)‐free DAA therapy in HBV/HCV co‐infected patients with inactive HBV. A 69‐year‐old male patient was diagnosed with chronic hepatitis due to HBV/HCV co‐infection with serum levels of alanine aminotransferase (ALT) of 94 U/L, HCV RNA of 4.2 log IU/mL and HBV DNA of 2.5 log copies/mL. HCV was thought to be responsible for the hepatitis activity because of low level of HBV core‐related antigen (3.1 log U/mL). He was treated with combination therapy of daclatasvir and asunaprevir. Serum ALT gradually increased, and reached 237 U/L on day 43 in spite of undetectable HCV RNA. Serum HBV DNA was increasing to 7.0 log copies/mL at that time. The treatment was stopped due to suspicion of drug‐induced liver injury and/or HBV reactivation. Administration of entecavir reduced HBV DNA levels, followed by improvement in ALT levels. This report proposes that close monitoring of HBV DNA during the anti‐HCV DAA therapy and the commencement of anti‐HBV therapy with nucleoside analogs after the increase of HBV DNA should be considered in patients with HBV/HCV co‐infection.     

Hepatitis B virus reactivation in hepatitis B virus surface antigen negative patients receiving immunosuppression: A hidden threat

AIM: To present the characteristics and the course of a series of anti- hepatitis B virus core antibody (HBc) antibody positive patients, who experienced hepatitis B virus (HBV) reactivation after immunosuppression. METHODS: We retrospectively evaluated in our tertiary centers the medical records of hepatitis B virus surface antigen (HBsAg) negative patients who suffered from HBV reactivation after chemotherapy or immunosuppression during a 3-year period (2009-2011). Accordingly, the clinical, laboratory and virological characteristics of 10 anti-HBc (+) anti-HBs (-)/HBsAg (-) and 4 anti-HBc (+)/antiHBs (+)/HBsAg (-) patients, who developed HBV reactivation after the initiation of chemotherapy or immunosuppressive treatment were analyzed. Quantitative determination of HBV DNA during reactivation was performed in all cases by a quantitative real time polymerase chain reaction kit (COBAS Taqman HBV Test; cut-off of detection: 6 IU/mL). RESULTS: Twelve out of 14 patients were males; median age 74.5 years. In 71.4% of them the primary diagnosis was hematologic malignancy; 78.6% had received rituximab (R) as part of the immunosuppressive regimen. The median time from last chemotherapy schedule till HBV reactivation for 10 out of 11 patients who received R was 3 (range 2-17) mo. Three patients (21.4%) deteriorated, manifesting ascites and hepatic encephalopathy and 2 (14.3%) of them died due to liver failure. CONCLUSION: HBsAg-negative anti-HBc antibody positive patients can develop HBV reactivation even 2 years after stopping immunosuppression, whereas prompt antiviral treatment on diagnosis of reactivation can be lifesaving.     

Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

Hepatitis due to hepatitis B virus(HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximabcontaining therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen(HBs Ag) and antibody to hepatitis B core antigen(antiHBc). Patients found to be positive for HBs Ag should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving highrisk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBs Ag-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.     

Current therapy for hepatitis C or D or immunodeficiency virus concurrent infection with chronic hepatitis B

Concurrent hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) infection with chronic hepatitis B virus (HBV) appears to increase the risk of progressive liver disease including liver cirrhosis and hepatocellular carcinoma. There is a 10% prevalence of HCV infection in chronic HBV or HDV infection. Serological evidence of previous exposure to HBV is found in more than 80% of HIV-positive patients in the high risk group. Notably, the most recently acquired virus tends to suppress the pre-existing virus. In chronic HBV infection acquired perinatally or in early childhood, usually HCV is dominant and may suppress or even displace HBV and HDV. Less frequently, HBV or HDV suppresses HCV. It is generally agreed that the dominant virus should be identified in order to make appropriate treatment decisions. Studies with standard interferon (IFN) to treat patients with HCV dominantly dual HBV/HCV infection have showed only limited virological response. But high dose of IFN has been demonstrated with better response rate. Combined ribavirin with standard or pegylated IFN therapy could achieve a sustained HCV clearance rate comparable with those infected with HCV alone. On the contrary, patients with HBV dominantly dual viral infection might indicate more appropriate addition of lamivudine to IFN than ribavirin. Additionally, patients with concurrent infection of HBV and HDV, IFN seems to be the only effective agent. However, the efficacy of IFN is related to the dose. High dose of IFN [9 MU tiw (thrice per week)] and longer treatment duration (at least 2 years) have been shown to achieve adequate virological response. In patients with concurrently infected HBV and HIV, anti-HBV therapy should be considered for all patients with evidence of liver disease, irrespective of the CD4 cell count. In patients not requiring antiretroviral therapy, HBV therapy should be preferentially based on IFN, adefovir, or telbivudine. In contrast, in patients with CD4 cell counts <350 cells/μl or those already on antiretroviral therapy, agents with double anti-HBV and anti-HIV activity are preferred. At present, the evidence of therapeutic efficacy is not sufficient to make a recommendation in treating patients with dual HBV/HCV or HBV/HDV or HBV/HIV infection. Further studies of the well-designed, larger scale are needed to elucidate the role of different regimens or combination in the treatment of dual viral infection.     

Treatment of patients with dual hepatitis C virus and hepatitis B virus infection: Resolved and unresolved issues

Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is not uncommon in HCV or HBV endemic areas and among subjects at risk of parenteral transmission. In patients dually infected with hepatitis C and B, the disease manifestations are usually more severe than those with either virus infection. In the past decade, the following issues have been resolved. In dually infected patients with active hepatitis C, combined pegylated interferon alfa plus ribavirin was effective, the treatment outcomes being similar to patients with HCV monoinfection. During long‐term follow‐up, the HCV response was sustained in around 97% of patients; and the long‐term outcomes including the development of hepatocellular carcinoma and liver‐related mortality were improved. However, several clinical issues remain to be resolved. First, host and viral factors influencing the long‐term outcomes and treatment options in patients with dual HCV/HBV infection await further studies. Second, about 60% of dually infected patients with baseline undetectable serum HBV DNA levels develop HBV reactivation after the start of treatment. How to prevent and treat HBV reactivation should be clarified. Third, about 30% of dually infected patients lose hepatitis B surface antigen at 5 years after the end of combination therapy; the mechanisms need further investigations. Fourth, the optimal treatment strategies for dually infected patients with active hepatitis B or established cirrhosis should be explored in future clinical trials. Finally, the role of new direct‐acting antiviral‐based therapy for the treatment of patients with dual HCV/HBV infection also remains to be evaluated.     

Risk of hepatitis B reactivation in patients treated with direct-acting antivirals for hepatitis C

The recent introduction of direct-acting antiviral drugs(DAAs) for treatment of the hepatitis C virus(HCV) has greatly improved the management of HCV for infected patients. These viral protein inhibitors act rapidly, allowing HCV clearance and increasing the sustained virological response rates. However, hepatitis B virus(HBV) reactivation has been reported in HCV/HBV co-infected patients. Hepatitis B reactivation refers to an abrupt increase in the HBV and is welldocumented in patients with previously undetected HBV DNA due to inactive or resolved HBV infection. Reactivation can occur spontaneously, but in most cases, it is triggered by various factors. Reactivation can be transient, without clinical symptoms; however, it usually causes a hepatitis flare. HBV reactivation may occur regardless of HCV genotype and type of DAA regimen. HBV screening is strongly recommended for co-infected HCV/HBV patients before initiation and during DAA therapy regardless of HBV status, HCV genotype and class of DAAs used. HBV reactivation can be prevented with pretreatment screening and prophylactic treatment when necessary. Additional data are required to evaluate the underlying mechanisms of HBV reactivation in this setting.     

Management of hepatitis B reactivation in immunosuppressed patients: An update on current recommendations

The proportion of hepatitis B virus(HBV) previously exposed patients who receive immunosuppressive treatment is usually very small. However, if these individuals are exposed to potent immunosuppressive compounds, the risk of HBV reactivation(HBVr) increases with the presence of hepatitis B surface antigen(HBsAg) in the serum. Chronic HBsAg carriers have a higher risk than those who have a total IgG anticore as the only marker of resolved/occult HBV disease. The loss of immune control in these patients may results in the reactivation of HBV replication within hepatocytes. Upon reconstitution of the immune system, infected hepatocytes are once again targeted and damaged by immune surveillance in an effort to clear the virus. There are different virological scenarios, and a wide spectrum of associated drugs with specific and stratified risk for the development of HBVr. Some of this agents can trigger a severe degree of hepatocellular damage, including hepatitis, acute liver failure, and even death despite employment of effective antiviral therapies. Currently, HBVr incidence seems to be increasing around the world; a fact mainly related to the incessant appearance of more powerful immunosuppressive drugs launched to the market. Moreover, there is no consensus on the length of prophylactic treatment before the patients are treated with immunosuppressive therapy, and for how long this therapy should be extended once treatment is completed. Therefore, this review article will focus on when to treat, when to monitor, what patients should receive HBV therapy, and what drugs should be selected for each scenario. Lastly, we will update the definition, risk factors, screening, and treatment recommendations based on both current and different HBV management guidelines.     

History and prevention of de novo hepatitis B virus-related hepatitis in Japan and the world

Hepatitis B virus (HBV) replication has been shown to persist at low levels in the liver for decades, even in patients with resolved HBV infection. In these cases, reactivation of HBV and ensuing hepatitis during or after cytotoxic or immunosuppressive therapy is now recognized as de novo HBV-related hepatitis. The occurrence of de novo HBV-related hepatitis has become more frequent after the introduction of rituximab for the treatment of hematological disorders, such as malignant lymphomas. More alarmingly, reactivation can lead to fatal fulminant hepatic failure, indicating a need to establish guidelines to prevent the occurrence of de novo HBV-related hepatitis. It is possible that lamivudine prophylaxis and close surveillance of serum HBV DNA are effective in this regard. However, such measures are currently not available to hepatitis B surface antigen (HBsAg)-negative patients in Japan. A preliminary guideline for preventing HBV reactivation during and after cytotoxic or immunosuppressive therapies was made in 2008 by two collaborative study groups from the Japanese Ministry of Health, Labour, and Welfare, including measures not only for HBV carriers, but also for patients with resolved HBV infection. Since this recommendation is a tentative one, further testing and improvements are being planned.     

Entecavir as treatment for reactivation of hepatitis B in immunosuppressed patients

AIM: To study the efficacy and safety of entecavir (ETV) as first-line therapy for hepatitis B virus (HBV) reactivation due to immunosuppression. METHODS: Four patients that were treated with different immunosuppressive regimens for hematological malignancies, who presented with HBV reactivation were treated with ETV. Clinical outcome, biochemical and virological factors, including quantitative hepatitis B surface antigen (HBsAg) were studied. RESULTS: In all patients, ETV induced suppression of HBV, and rapid clinical improvement without side effects. In one patient with an alanine aminotransferase (ALT) flare, tenofovir was added after 3 mo of treatment. Until death from disease progression at 6 mo after treatment initiation, this patient did not clear HBV infection. Retrospectively, it is highly probable that thepatient had been non-adherent. In the other three patients, the virological responses were associated with an expeditious decrease in quantitative HBsAg titers with negativity after 2 mo, and all three had HBsAg seroconversion. In one patient, HBV DNA reached a plateau after 3 mo, before becoming undetectable after 1 year, despite early ALT normalization and undetectable quantitative HBsAg. CONCLUSION: ETV seems to be effective and safe treatment for HBV reactivation. Monitoring of quantitative HBsAg might be an additional useful tool to monitor treatment response.     

Prophylaxis of hepatitis B reactivation with immunosuppressive therapy in rheumatic diseases. Orientations for clinical practice

Reactivation of infection with hepatitis B virus (HBV) is a potentially serious complication of immunosuppression, which can be identified and efficiently prevented. There have been an increasing number of cases of HBV reactivation in patients receiving immunosuppression in the context of rheumatic diseases such as rheumatoid arthritis or systemic lupus erythematosus. The recommendations in this area should be individualized taking into account two aspects: immunosuppressive regimens used (high or low risk of reactivation) and the different stages of HBV infection: chronic hepatitis B, inactive HBV carrier, occult hepatitis B infection defined by HB surface antigen (HBsAg) negative and antibody anti-HB core (anti-HBc) positive. In patients with rheumatic diseases that will start high-risk immunosuppressive drugs, we propose a universal screening with serological tests for hepatitis B (HBsAg, anti-HBs and anti-HBc). Patients with chronic hepatitis B (HBsAg positive, HBV DNA ≥ 2000 IU/ml, elevated ALT) should initiate antiviral therapy. Inactive HBV carriers (HBsAg positive, HBV DNA <2000 IU / ml, normal aminotransferases) exposed to high risk immunosuppressive therapy should undergo prophylaxis of HBV reactivation. Prophylaxis should be started 2 to 4 weeks before the beginning of immunosuppressive therapy and maintained for at least 6 to 12 months after its suspension. It is recommended to use entecavir or tenofovir as first line antiviral agents. In inactive HBsAg carriers under low-risk immunosuppressive therapy and patients with HBsAg negative/anti-HBc positive (HBV infection in the past), the strategy should be monitoring of viral reactivation with aminotransferases and HBV DNA determination in every 6 months.     

Effect of immunosuppressive therapy on patients with inflammatory bowel diseases and hepatitis B or C virus infection

Viral hepatitis reactivation has been widely reported in patients undergoing immunosuppressive therapy; however, few data are available about the risk of HBV and HCV reactivation in patients with inflammatory bowel disease, receiving immunosuppressive drugs. The aim of our study was to assess the prevalence of HBV and HCV infection in a consecutive series of patients with inflammatory bowel disease and to value the effects of immunosuppressive therapy during the course of the infection. Retrospective observational multicenter study included all consecutive patients with inflammatory bowel disease who have attended seven Italian tertiary referral hospitals in the last decade. A total of 5096 patients were consecutively included: 2485 Crohn's disease and 2611 Ulcerative Colitis. 30.5% and 29.7% of the patients were investigated for HBV and HCV infection. A total of 30 HBsAg positive, 17 isolated anti‐HBc and 60 anti‐HCV‐positive patients were identified. In all, 20 patients with HBV or HCV infection received immunosuppressive therapy (six HBsAg+; four isolated anti‐HBc+ and 10 anti‐HCV+). One of six patients showed HBsAg+ and one of four isolated anti‐HBc+ experienced reactivation of hepatitis. Two of six HBsAg patients received prophylactic therapy with lamivudine. Only one of 10 anti‐HCV+ patients showed mild increase in viral load and ALT elevation. Screening procedures for HBV and HCV infection at diagnosis have been underused in patients with inflammatory bowel disease. We confirm the role of immunosuppressive therapy in HBV reactivation, but the impact on clinical course seems to be less relevant than previous reported.     

Previous hepatitis B virus infection is associated with worse disease stage and occult hepatitis B virus infection has low prevalence and pathogenicity in hepatitis C virus‐positive patients

Abstract: Background: Anti‐hepatitis C virus (anti‐HCV) patients with chronic liver disease (CLD) frequently show markers of previous hepatitis B virus (HBV) infection. Moreover, they may carry occult HBV infection. These features might influence clinical and biochemical features as well as stage of disease. Aim: To assess the prevalence and clinical associations of previous (positivity for anti‐HBs and/or anti‐HBc antibodies) and occult HBV infection (positivity for HBV‐DNA by nested‐PCR) in the serum of anti‐HCV‐positive, HCV‐RNA‐positive, HBsAg‐negative patients with various degrees of CLD seen at a tertiary referral centre. Patients: A total of 119 patients fulfilled the inclusion criteria (84 chronic hepatitis and 35 liver cirrhosis). Results: Forty‐eight patients (40.3%) showed markers of previous HBV infection. This feature was more frequent (P = 0.02) among cirrhotics (57%) as compared to chronic hepatitis patients (33%). Chronic hepatitis patients positive for markers of previous HBV infection had worse histology as compared to negative ones (grading: 6.4 ± 2.7 versus 4.6 ± 3.0, P = 0.004; staging: 1.6 ± 1.2 versus 1.0 ± 1.0, P = 0.01). Eight patients were positive for HBV‐DNA in serum (6.7%). No difference in the presence of occult HBV infection was seen between various degrees of liver disease (7.1% of chronic hepatitis, 5.7% of cirrhosis) and among patients who were positive (10.4%) or negative (4.2%) for markers of previous HBV infection. No significant biochemical, virological, or histological difference was observed between age, age at infection, duration of infection, marker patterns of previous HBV infection‐matched HBV‐DNA‐positive and negative chronic hepatitis patients. Conclusions: Our findings suggest that previous HBV infection among anti‐HCV patients is associated with worse disease stage. In these patients, the prevalence of occult HBV infection is low and there is no difference in distribution among patients with or without markers of previous HBV infection. Furthermore, it does not seem to be associated with disease stage. Lastly, at least among patients with chronic hepatitis, it does not seem to affect the severity of disease.