Reactivation Of Hepatitis B Virus Replication Research Articles

Management of Hepatitis B Virus in Allogeneic Hematopoietic Stem Cell Transplantation.

The high morbidity of HBV reactivation following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is partially due to the intense immunologic potency of complex therapeutic regimens, the use of antithymocyte globulin and calcineurin inhibitors to prevent graft versus-host disease (GVHD), prolonged immune reconstitution, and hematological malignancies infected with hepatitis B virus (HBV). Immunosuppression results in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, the role of viral mutations during HBV reactivation needs to be validated. All individuals scheduled to receive allo-HSCT or wish to donate stem cells should be screened for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core (anti-HBc), and HBV-DNA. HBsAg-positive recipients of allo-HSCT have a high risk of HBV reactivation; thus, they should receive prophylactic antiviral therapy. The high barrier to resistance nucleos(t)-ide analogs (NAs) seems to be superior to the low barrier agents. Resolved-HBV recipients have a lower risk of HBV reactivation than HBsAg-positive recipients. Although prophylactic antiviral therapy remains controversial, regular monitoring of alanine transaminase (ALT) and HBV-DNA combined with preemptive antiviral treatment may be an optimized strategy. However, optimal antiviral therapy duration and time intervals for monitoring remain to be established. Accepting stem cells from HBsAg-positive donors is associated with a risk of developing HBV-related hepatitis. The overall intervention strategy, including donors and recipients, may decrease the risk of HBV-related hepatitis following HSCT from HBsAg positive stem cells. In this review, we summarize the issues of HBV in allo-HSCT, including HBV reactivation mechanism, HBsAg-positive recipients, HBV-resolved infection recipients, and donor-related factors, and discuss their significance.

Hepatitis B Reactivation in Immunosupressed Patients, Prophylaxis and Management

Hepatitis B virus (HBV) reactivation is a clinical problem associated with high morbidity and mortality rates. Currently, this incidence seems to be increasing around the world. The reactivation commonly developes in immunosuppressed individuals, although it may also occur spontaneously. Individuals who develop malignancy with chronic hepatitis B virus infection are at high-risk for hepatitis B virus reactivation, since they are closely related to immunosuppression, especially when undergoing chemotherapy. The loss of immune control in these patients may results in the reactivation of HBV replication within hepatocytes. This review article will focus on HBV reactivation related to immunosuppressed patients, immunosuppressive drug classes and corresponding risk estimates of hepatitis B virus reactivation, screening test recommended before getting this drugs, choice of antiviral drugs for prophylaxis, and duration of prophylaxis treatment based on EASL, AASLD and APASL guidelines.

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage.

Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication.

Roles of Hepatitis B Virus Mutations in the Viral Reactivation after Immunosuppression Therapies.

Reactivation of hepatitis B virus (HBV) is a major problem in patients receiving chemotherapy for malignant diseases or immunosuppression therapies. It has been thought that a reduction in the immune responses might result in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, not only the host’s immune status, but also viral mutations have been reported to be associated with reactivation. Especially, several case reports about amino acid mutations in hepatitis B surface antigen (HBsAg) that escape from immune reactions have been reported, and recent reports showed that the frequencies of such mutations are higher than previously expected. In this review, we summarize the characteristics of viral mutations, including immune escape mutations in HBV-reactivated patients, and discuss their significance.

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.

New horizon for radical cure of chronic hepatitis B virus infection.

About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalently-closed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.

Prophylaxis and therapy of HBV infection in 20 patients treated with disease modifying antirheumatic drugs or with biological agents for rheumatic diseases

To evaluate the safety and tolerability of lamivudine in patients with HBV infection needing immunosuppressive treatment for rheumatic diseases. Twenty patients with rheumatic diseases planned to receive immunosuppressive DMARDs or biological agents were screened for HBV markers. In all active carriers antiviral treatment was recommended. Inactive carriers (HBsAg positive, aminotrasferase and viremia persistently normal) were divided into two risk categories according to the type and the degree of immunosuppression, and antiviral prophylaxis was started only in patients of the high risk category. Antiviral treatment was recommended also in potential occult carriers (HBsAg negative, HBcAb positive) treated with rituximab. In twenty patients antiviral treatment was started: 1 was a potential occult carrier planned to receive rituximab; 9 were inactive carriers, in which prophylactic therapy was needed for a high risk of HBV reactivation (in 3, for the use of TNF blocking agents); 10 were treated for active viral replication. Prophylaxis and therapy were performed with lamivudine. In three patients adefovir was associated. Antiviral drugs were well tolerated. In all cases, immunosuppressive treatment was given for the planned duration of therapy, with good results on the rheumatic diseases. Median duration of antiviral treatment was 19 months (for a total of 386 month/person). No cases of viral reactivation were observed. Our experience demonstrates the feasibility of a prophylaxis and therapy of HBV infection in patients with rheumatic diseases. This approach reduces the risk of viral reactivation and allows the choice of the optimal immunosuppressive treatment in rheumatic patients.

Clinical features and treatment efficacy of peginterferon alfa plus ribavirin in chronic hepatitis C patients coinfected with hepatitis B virus.

Background/AimsCross-sectional studies have documented that 2-10% of patients who are chronically infected with hepatitis C virus (HCV) are also positive for hepatitis B virus (HBV) surface antigen (HBsAg). Data related to HCV-HBV coinfection are lacking in Korea. This study evaluated the clinical characteristics, the treatment efficacy of peginterferon alfa plus ribavirin, and the changes induced by such treatment in HBV status in chronic hepatitis C (CHC) patients coinfected with HBV.MethodsEighteen (2.37%) HBsAg-positive CHC patients were selected from among the 758 subjects from the K(G)yeonggi-Incheon Peginterferon alfa and ribavirin in chronic hepatitis C Treatment (KIPECT) study, which evaluated the treatment efficacy and safety of peginterferon alfa plus ribavirin in CHC patients. Data on changes in the status of HBV infections were obtained.ResultsHCV genotype 1b was the most common (44%). The overall sustained virologic response rate was 72% in all patients, and 60% and 87.5% in genotypes 1 and 2, respectively. Two of the 18 patients were positive for HBeAg, and 15 had baseline HBV DNA level of less than 2,000 IU/mL. Two of the three whose levels exceeded this threshold showed no detectable DNA after treatment. After the completion of treatment, serum HBV DNA levels were increased in the two patients whose baseline HBV DNA levels were less than 2,000 IU/mL.ConclusionsThe prevalence of HBV coinfection in CHC patients was 2.37% and most of the patients were inactive carriers. The treatment efficacy was similar to that of HCV mono-infection. Reactivation of HBV replication was observed in some patients after CHC treatment.

Natural history and clinical management of chronic hepatitis B virus infection in children

Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.

Natural history of hepatitis B virus infection in renal transplant recipients--a fifteen-year follow-up.

Hepatitis B virus (HBV) markers were measured in 83 immunosuppressed renal transplant patients who were followed for periods of 2 to 15 years. Sixty-nine patients were negative for HBsAg before transplantation, of whom 14 were positive for anti-HBs. The remaining 14 patients were HBsAg positive prior to transplantation. Eighteen patients were identified as being HBsAg positive during the follow-up period. Four patients acquired primary type B hepatitis; one died of submassive hepatic necrosis and the remaining three became chronic HBV carriers with positive HBeAg, DNA polymerase, and HBV DNA. Several patterns of HBV expression were observed in HBsAg-positive patients. Four patients were HBsAg, HBeAg, DNA polymerase, and HBV DNA positive prior to transplantation, and these markers persisted. Reactivation of HBV replication occurred in eight patients, seven of whom were HBsAg positive and HBeAg and anti-HBe negative originally; one patient was anti-HBc positive. A single patient was HBsAg and anti-HBe positive and remained so for 22 months. The remaining previously HBsAg-positive patient is currently HBsAg negative. These serological data suggest that reactivation of HBV replication or continued hepatitis B virion replication occurs as commonly or more commonly than de novo infection in renal transplant recipients. The presence of HBeAg in serum predisposes to long-term Dane particle expression in immunosuppressed patients, whereas anti-HBe-positive carriers may not always be susceptible to reactivation of HBV replication despite immunosuppression.

Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection: Incidence, predisposing factors and etiology

Three hundred and eighty-six Chinese patients (262 men and 124 women), age 5–74 years, with chronic hepatitis B virus (HBV) infection were prospectively followed for 1–5 years to determine the incidence, predisposing factors and etiology of acute exacerbations that occurred during the course of chronic HBV infection. Group I consisted of 334 patients with serum alanine aminotransferase (ALT) levels below 200 IU/l at presentation. Of these, 29 (8.7%) patients developed 32 episodes of acute exacerbation during follow-up. The cumulative probabilities of developing exacerbations were 6.3% and 15% at the end of 1 and 4 years, respectively. Group II included 52 patients with ALT levels above 200 IU/l at presentation. Of these, 19 (37%) patients developed 26 episodes of exacerbation during follow-up. The cumulative probabilities of developing exacerbations were 24% and 47% at the end of 1 and 4 years, respectively. In both groups, the probability of developing exacerbations was slightly higher in men and significantly higher in those above the age of 20 and those who were HBeAg positive. Logistic regression analysis showed that HBeAg positivity ( p < 0.00001), elevated ALT levels (>200 IU/l) at presentation ( p < 0.0001) and male sex ( p = 0.03) were associated with a significantly higher probability of developing exacerbations. Twenty eight (48%) episodes of exacerbation were accompanied by symptoms of acute hepatitis. Thirty-three (57%) episodes of exacerbation were associated with inactivation and seven (12%) episodes with reactivation of HBV replication, one (2%) episode was due to superimposed acute hepatitis A, two episodes may be secondary to post-transfusion nor-A, non-B hepatitis. None of the exacerbations was related to superinfection with hepatitis D virus. An understanding of the factors that trigger these exacerbations will help to delineate the mechanism(s) of immune clearance of HBV and the pathogenesis of HBV-induced liver diseases.

Hepatitis B virus and hepatitis B-related viral infection in renal transplant recipients: A prospective study of 90 patients

Hepatitis B virus (HBV) infection may induce severe hepatitis and affect long-term survival of kidney transplant recipients. Persistent viral infection has been shown to occur despite the absence of usual serologic markers. The liver and serum HBV deoxyribonucleic acid (DNA) status of 90 patients were studied prospectively; recently transplanted patients, both hepatitis B virus surface antigen (HBsAg)-positive and negative, with and without liver disease, were investigated with HBV serology, serum HBV DNA, and liver histology. Thirty-four patients had detectable HBsAg, and 21 had viral multiplication at the time of transplantation. Serial HBV DNA determinations performed in 57 of 90 patients disclosed (a) reactivation of HBV replication in 11 of 12 HBsAg-positive patients, (b) increase of viral replication when positive on the initial sample in 6 of 11 patients, and (c) development of HBV replication in 7 of 35 of the HBsAg-negative patients. Moreover, liver HBV DNA studies showed a statistical correlation between the presence of integrated liver HBV DNA and chronic hepatitis in HBsAg-negative patients. This study demonstrates prospectively the significant association of HBsAg-positive as well as HBsAg-negative HBV infection with chronic hepatitis and suggests that immunosuppressive therapy may enhance the viral replication in both HBsAg-positive and negative subjects.