Immunosuppression in Patients with Chronic Hepatitis B

After hepatitis B virus (HBV) infection, HBV DNA persists in minute amounts in hepatocyte nuclei even in individuals with “resolved” infection. Viral replication and development of liver disease depend on the balance between viral mechanisms promoting persistence and host immune control. Patients with active or inactive disease or resolved HBV infection are at risk for reactivation with immunosuppressive therapy use. HBV reactivation varies from a clinically asymptomatic condition to one associated with acute liver failure and death. We review recent studies on HBV reactivation during immunomodulatory therapies for oncologic, gastroenterological, rheumatic, and dermatologic disorders. Risk calculation should be determined through HBV screening and assessment of immunosuppressive therapy potency. We also discuss monitoring for reactivation, prophylactic antiviral therapy, and treatment of reactivation. Prophylactic antiviral treatment is needed for all HBsAg carriers and selected patients who have anti-HBc without HBsAg and is critical for preventing viral reactivation and improving outcomes.     

Occult Hepatitis B Virus (HBV) Infections: Hepatitis B Surface Antigen (HBsAg) Negative and Primary Occult

Occult HBV infection (OBI) is defined as persistence of HBV genomes (with detectable or undetectable serum HBV DNA) in the liver of serum HBsAg negative individuals. It represents the HBsAg negative phase of the natural history of HBV infection in individuals with self-limited acute hepatitis B or in HBsAg carriers or chronic hepatitis B patients who lose HBsAg either naturally or after antiviral therapy and maintain lifelong anti-HBc in serum (with or without anti-HBs and\or anti-HBe). Rarely it may occur as primary “occult” infection when caused by minute viral amounts unable to induce humoral immune response. HBsAg negative infections stem from lifelong intrahepatic persistence of HBV-ccc-DNA under the host’s immune control and may lead to HBsAg positive reactivation after immunosuppressive therapies or epigenetic modifications. HBV reactivation can be avoided by pre-emptive antiviral therapy with nucleos(t)ide analogs. OBI in chronic liver disease of other etiologies may contribute to the development of hepatocellular-carcinoma.     

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.     

Hepatitis B virus reactivation during immunosuppressive therapy: Appropriate risk stratification

Our understanding of hepatitis B virus (HBV) reactivation during immunosuppresive therapy has increased remarkably during recent years. HBV reactivation in hepatitis B surface antigen (HBsAg)-positive individuals has been well-described in certain immunosuppressive regimens, including therapies containing corticosteroids, anthracyclines, rituximab, antibody to tumor necrosis factor (anti-TNF) and hematopoietic stem cell transplantation (HSCT). HBV reactivation could also occur in HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) positive individuals during therapies containing rituximab, anti-TNF or HSCT.For HBsAg-positive patients, prophylactic antiviral therapy is proven to the effective in preventing HBV reactivation. Recent evidence also demonstrated entecavir to be more effective than lamivudine in this aspect. For HBsAg-negative, anti-HBc positive individuals, the risk of reactivations differs with the type of immunosuppression. For rituximab, a prospective study demonstrated the 2-year cumulative risk of reactivation to be 41.5%, but prospective data is still lacking for other immunosupressive regimes. The optimal management in preventing HBV reactivation would involve appropriate risk stratification for different immunosuppressive regimes in both HBsAg-positive and HBsAg-negative, anti-HBc positive individuals.     

Hepatitis B virus reactivation after cytotoxic chemotherapy: the disease and its prevention.

Reactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy. In most cases, reactivations occur in patients who are carriers of HBV infection showing positive hepatitis B surface antigen (HBsAg). Reactivation also may occur in patients with resolved infection who are HBsAg negative, anti-HBs positive, and anti-hepatitis B core positive. HBV reactivations can lead to severe flares that may be life-threatening unless recognized and treated promptly. Physician awareness is essential because prophylactic antiviral treatment can diminish the occurrence and improve the outcome of such episodes. Patients undergoing cytotoxic therapy should be checked routinely for HBV serologic markers and serum HBV DNA levels. Patients who are HBV carriers or anti-hepatitis B core positive should be monitored closely during and after the administration of cytotoxic chemotherapy. Prophylactic treatment with a nucleoside or nucleotide analogue should be considered strongly to prevent HBV reactivation in these patients.     

Reactivation of hepatitis B: Pathogenesis and clinical implications

Chronic hepatitis B virus (HBV) is estimated to be present in 350 million people worldwide. One of its major complications is reactivation of dormant HBV, which is associated with significant morbidity and mortality. Although reactivation can occur spontaneously, the most common risk factor is initiation of immunosuppression. As the use of immunosuppressive therapy increases, the incidence of HBV reactivation is expected to rise. Screening with serologic markers for hepatitis B is recommended before initiating immunosuppressive therapy. In patients with no evidence of HBV infection, immunization is recommended. In chronic carriers, prophylactic antiviral treatment has been shown to decrease overall morbidity and mortality. Patients with inactive HBV should be monitored closely during immunosuppressive treatment with alanine transaminase and serum HBV-DNA levels and treated promptly if they develop HBV reactivation. Although HBV reactivation is a serious complication, it can be prevented with screening and prophylactic treatment.     

Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases

The emergence of tumor necrosis factor-α (TNF-α)-targeted therapies as a key therapeutic option for patients with rheumatic, digestive, and dermatologic autoimmune diseases has been associated with increasing reports of liver damage in patients with hepatitis B virus (HBV) infection. We studied the current evidence on the use of anti-TNF agents in patients with HBV through a systematic analysis of cases reported in the MEDLINE and EMBASE databases using the MeSH term "hepatitis B virus" combined with the terms "infliximab," "etanercept," "adalimumab," "certolizumab," "golimumab," and "anti-TNF agents," and summarize the results here. We analyzed 257 patients with positive HBV markers who received anti-TNF therapy (255 identified in the search strategy and 2 new cases), 89 HBsAg+ carriers, and 168 anti-HBc+ persons. HBV reactivation was reported in 35 (39%) HBsAg+ carriers. The percentage of reactivation was higher in patients previously treated with immunosuppressive agents (96% vs. 70%, p=0.033) and lower in those who received antiviral prophylaxis (23% vs. 62%, p=0.003). Acute liver failure was reported in 5 patients, 4 of whom died. Infliximab was associated with a higher rate of induced liver disease (raised transaminase levels, clinical signs, viral reactivation, and acute liver failure) compared with etanercept. In anti-HBc+ persons, reactivation was reported in 9 (5%) cases, including 1 patient who died due to fulminant liver failure.In summary, our search of the current evidence identified 257 reported HBV+ patients treated with anti-TNF agents, with a significant percentage of liver damage in HBsAg+ carriers, including raised transaminase levels (42%), signs and symptoms of liver disease (16%), reappearance of serum HBV-DNA (39%), and death related to liver failure (5%). The rate of reactivation in anti-HBc+ persons was 7-fold lower than in HBsAg+ carriers. The increasing number of reported cases of HBV reactivation following TNF-targeted therapies and the associated morbidity and mortality demand specific preventive strategies.     

Prophylaxis and treatment of hepatitis B in immunocompromised patients.

The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and referred mainly to the pre-antivirals era. Today a rational approach to the problem of hepatitis B in these patients provides for: (a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), (b) the treatment with antivirals (therapy) of active carriers, (c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if they are undergoing immunosuppressive therapies judged to be at high risk, (d) the biochemical and hepatitis B surface antigen (HBsAg) monitoring (or universal prophylaxis, in case of high risk immunosuppression) in subjects with markers of previous contact with HBV (HBsAg negative and anti-HBc positive), in order to prevent reverse seroconversion. Moreover it is suggested a strict adherence to criteria of allocation based on the virological characteristics of both recipients and donors in the general setting of transplants and in liver transplantation the universal prophylaxis with nucleos(t)ides analogues (frequently combined with specific anti-HBV immunoglobulins) in HBsAg positive candidates and in HBsAg negative recipients of anti-HBc positive grafts.     

Prospective study of HBV reactivation risk in rheumatoid arthritis patients who received conventional disease-modifying antirheumatic drugs

Studies that reported hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients have caused attention of disease-modifying antirheumatic drug (DMARD)-related HBV reactivation. Most of the studies were focused on HBV reactivation risk of biologic DMARDs; insufficient data are available to identify the exact risk of conventional DMARD (c-DMARD)-related HBV reactivation. This prospective study aimed to investigate the risk of HBV reactivation in HBV-infected RA patients who received c-DMARDs. A total of 476 RA patients were screened in this prospective non-randomized, non-controlled study. HBV-infected patients characterized by hepatitis B surface antigen (HBsAg) positive or HBsAg negative/anti-hepatitis B core antigen (anti-HBc) positive were analyzed for HBV DNA, followed with HBV DNA monitoring scheduled every 3 months, serum alanine aminotransferase test at 2-month intervals, or more frequently. Prevalence of HBsAg positive and HBsAg negative/anti-HBc positive was 6.51 and 51.1 %, respectively, among the 476 RA patients. Among 211 patients (23 patients were HBsAg positive and 188 patients were HBsAg negative/anti-HBc positive) who received c-DMARDs without antiviral prophylactic treatment, 4 patients developed HBV reactivation. Both HBsAg positive and HBsAg negative/anti-HBc positive patients have the possibility of developing HBV reactivation. There was no correlation between HBV reactivation and any specific c-DMARD. Glucocorticoid coadministration and negative anti-hepatitis B surface antigen (anti-HBs) at baseline showed correlation with reactivation. In conclusion, it would be rational to initiate antiviral prophylaxis according to risk stratification rather than universal prophylaxis for HBV-infected RA patients. Conventional DMARDs are relatively safe to HBV-infected patients with low reactivation risk (low HBV DNA level, no GCs administration, and anti-HB positive).     

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level( 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable( 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.     

Management of psoriasis patients with hepatitis B or hepatitis C virus infection

The systemic therapies available for the management of Psoriasis(PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can worsen or reactivate a chronic infection. Therefore, before administering immunosuppressive therapies with either conventional disease-modifying drugs(c DMARDs) or biological ones(b DMARDs) it is mandatory to screen patients for some infections, including hepatitis B virus(HBV) and hepatitis C virus(HCV). In particular, the patients eligible to receive an immunosuppressive drug must be screened for the following markers: antibody to hepatitis B core, antibody to hepatitis B surface antigen(anti-HBs Ag), HBs Ag, and antibody to HCV(anti-HCV). In case HBV or HCV infection is diagnosed, a close collaboration with a consultant hepatologist is needed before and during an immunosuppressive therapy. Concerning therapy with immunosuppressive drugs in PsO patients with HBV or HCV infection, data exist mainly for cyclosporine a(Cy A) or b DMARDs(etanercept, adalimumab, infliximab, ustekinumab). The natural history of HBV and HCV infection differs significantly as well as the effect of immunosuppression on the aforementioned infectious diseases. As a rule, in the case of active HBV infection, systemic immunosuppressive antipsoriatic therapies must be deferred until the infection is controlled with an adequate antiviral treatment. Inactive carriers need to receive antiviral prophylaxis 2-4 wk before starting immunosuppressive therapy, to be continued after 6-12 mo from its suspension. Due to the risk of HBV reactivation, these patients should be monitored monthly for the first 3 mo and then every 3 mo for HBV DNA load together with transaminases levels. Concerning the patients who are occult HBV carriers, the risk of HBV reactivation is very low. Therefore, these patients generally do not need antiviral prophylaxis and the sera HBs Ag and transaminases dosing can be monitored every 3 mo. Concerning PsO patients with chronic HCV infection their management with immunosuppressive drugs is less problematic as compared to those infected by HBV.In fact, HCV reactivation is an extremely rare event after administration of drugs such as CyA or tumor necrosis factor-α inhibitors. As a rule, these patients can be monitored measuring HCV RNA load, and ALT, aspartate transaminase, gamma-glutamyl-transferase, bilirubin, alkaline phosphatase, albumin and platelet every 3-6 mo. The present article provides an updated overview based on more recently reported data on monitoring and managing PsO patients who need systemic antipsoriatic treatment and have HBV or HCV infection as comorbidity.     

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.     

Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy

Reactivation of hepatitis B virus (HBV) has been reported as a fatal complication following systemic chemotherapy or other immunosuppressive therapy. The risk of HBV reactivation differs according to both the patient’s HBV infection status prior to systemic chemotherapy and the degree of immunosuppression due to chemotherapy. For establishing an optimal strategy for hepatitis prevention and treatment, it is necessary to understand the characteristics, the clinical course and the risk factors for HBV reactivation and to recognize the difference between hepatitis B surface antigen (HBsAg)-positive and -negative patients with HBV reactivation. Among the important viral risk factors, HBV-DNA level and HBV-related serum markers have been reported to be associated with HBV reactivation in addition to cccDNA, genotypes and gene mutations. Rituximab-plus-steroid combination chemotherapy has recently been identified as a host risk factor for HBV reactivation in hepatitis B core antibody (anti-HBc)-positive and/or hepatitis B surface antibody (anti-HBs) positive—but nonetheless HBsAg-negative—lymphoma patients. For these patients with resolved hepatitis B, preemptive therapy guided by serial HBV-DNA monitoring is a reasonable strategy to enable early diagnosis of HBV reactivation and initiation of antiviral therapy. In this review, we summarize the characteristics of HBV reactivation following rituximab-plus-steroid combination chemotherapy, mainly in HBsAg-negative lymphoma patients, and propose a strategy for managing HBV reactivation.     

Clinical Implications of HBsAg Quantification in Patients with Chronic Hepatitis B

Quantification of serum hepatitis B surface antigen (HBsAg) helps the management of patients with chronic hepatitis B virus (HBV) infection. Median HBsAg levels differ significantly during the natural history of HBV infection, progressively declining from immune tolerance to inactive phase. The combination of an HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL at a single time point accurately identifies true inactive carriers. During antiviral treatment, HBsAg levels decline more rapidly in patients under peg-interferon (Peg-IFN) than in those under nucleos(t)ide analogues (NUC), and in responders to peg-IFN compared to non responders suggesting that a response-guided therapy in both HBeAg-positive and -negative patients treated with Peg-IFN could improve to cost-effectiveness of this therapeutic approach. Given the low rates of HBsAg clearance on NUC therapy, new studies to test whether Peg-IFN and NUC combination fosters HBsAg decline in long-term responders to NUC, are being explored.     

Prevalence and time course of hepatitis B virus infection in patients with systemic lupus erythematosus under immunosuppressive therapy

Objective

To clarify the prevalence and time course of hepatitis B virus (HBV) infection in patients with systemic lupus erythematosus under immunosuppressive therapy.

Methods

We performed serological examination of 248 lupus patients to determine the presence of HBV, including hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). Serum HBV DNA levels were measured in HBsAg-positive patients or resolved HBV carriers (HBsAg-negative, anti-HBs-positive, and/or anti-HBc-positive). If possible, we repeatedly performed examination of markers of HBV infection in resolved carriers.

Results

Two (0.8 %) patients were positive for HBsAg. Among 41 (16.5 %) patients who were considered as resolved HBV carriers, 1 (2.4 %) showed serum HBV DNA, which indicated occult HBV infection. The mean age and positive rate of anti-double stranded DNA antibody were significantly higher in resolved carriers than in anti-HBs- and anti-HBc-negative patients. Repeated examination showed that the anti-HBs and anti-HBc titer decreased below the threshold in 4 resolved carriers.

Conclusions

The prevalence of resolved HBV carriers in Japanese lupus patients was 16.5 %. Among them, occult HBV infection and decrease in anti-HBs and anti-HBc titer were observed. These findings indicated that all lupus patients should undergo serological examination for HBV before treatment. If patients have already been treated, we must carefully monitor their liver function, even when all HBV markers are negative.     

Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy

With the increasing use of potent immunosuppressive therapy, reactivation of hepatitis B virus (HBV) in endemic regions is becoming a clinical problem requiring special attention. A recent annual nationwide survey clarified that HBV reactivation related to immunosuppressive therapy has been increasing in patients with malignant lymphoma, other hematological malignancies, oncological or rheumatological disease. In the survey, rituximab plus steroid‐containing chemotherapy was identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg) negative patients with malignant lymphoma. In this setting, HBV reactivation resulted in fatal fulminant hepatitis regardless of the treatment of nucleoside analog. The Intractable Hepatobiliary Disease Study Group and the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis jointly developed guidelines for preventing HBV reactivation. The essential features of the guideline are as follows. All patients should be screened for HBsAg by a sensitive method before the start of immunosuppressive therapy. Second, hepatitis B core antigen (HBcAb) and hepatitis B surface antibody (HBsAb) testing should be performed in HBsAg negative patients, especially those receiving intensive immunosuppressive therapy. Prophylaxis with nucleoside analogs is essential for preventing HBV reactivation in HBsAg positive patients. In contrast, HBsAg negative with HBcAb and/or HBsAb positive patients should be monitored monthly for an increase in serum HBV DNA during and 12 months after completion of chemotherapy. Nucleoside analogs should be administrated immediately when HBV DNA becomes positive during this period. This strategy facilitates commencement of nucleoside analogs at an early stage of HBV reactivation and results in prevention of severe hepatitis.     

Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers

Viral reactivation in hepatitis B surface antigen (HBsAg) carriers undergoing immunosuppressive therapy is well documented. To evaluate the role of lamivudine prophylaxis in Hepatitis B virus (HBV) carriers treated with immunosuppression for nonhepatic disorders, we reviewed our experience between 1997 and 2000 at Hadassah University Hospital (Jerusalem, Israel). Controls were patients who were HBV carriers and who, between 1990 and 1995, were treated for hematological malignancies but were not treated with lamivudine. Eighteen HBsAg-positive patients were treated with immunosuppression. Fourteen were males, with a mean age of 48 years. Eleven patients had lymphoma; 2 had colonic adenocarcinoma; and 5 had cryoglobulinemia, enophthalmitis, vasculitis, malignant histocytosis, or ulcerative colitis. Fourteen patients were treated with chemotherapy, and 4 with prolonged high-dose corticosteroids. All patients were HBsAg-positive; 4 had hepatitis B e antigen, and 10 had HBV DNA by polymerase chain reaction. Lamivudine was administered to 13 patients in the treatment group 1 to 60 days (mean, 15 days) before immunosuppressive treatment and continued 0.5 to 24 months (mean, 7 months) following initiation of immunosuppression. Mean follow-up after lamivudine administration was 21 months. Three patients died of lymphoma complications and 10 (77%) survived. None of the patients had clinical or serological evidence of HBV reactivation during or after lamivudine prophylaxis. Of 6 patients who presented with liver function test disturbances, 5 improved during combined lamivudine and immunosuppression treatment. At the end of follow-up, HBV DNA became undetectable in 2 of 10 patients. In 2 patients, seroconversion from HBsAg to anti-HBs was observed. In contrast, 2 of 5 control patients had HBV reactivation. Lamivudine prophylaxis in HBsAg carriers receiving immunosuppressive therapy may prevent HBV reactivation and hepatic failure.     

Replication of hepatitis B virus in adult carriers in an endemic area

We have examined serological markers of replicative and nonreplicative infection in 124 adult, black South African carriers of hepatitis B virus (HBV), in whom this infection is predominantly acquired in early childhood. The mean age of the group was 36 years. Antibody to hepatitis B e antigen (anti-HBe) was present in the serum of 93.5% of these carriers. Only 25.8% of the carriers were positive for HBV DNA in serum, and in the majority of these only trace amounts were detectable. IgM antibody to hepatitis B core antigen (IgM anti-HBc) was negative in 54% of the carriers, and only 26% had IgM anti-HBc in high titer. A significantly greater proportion of carriers who were positive for anti-HBe were positive for IgM anti-HBc (43.1%) than were positive for HBV DNA (24.5%). Serum aminotransferases were less than twofold elevated in 90.3% of the carriers. Only one carrier has thus far developed hepatocellular carcinoma. These results suggest that there is an inexorable progression to predominantly nonreplicative infection in the majority of southern African adult, black carriers, an occurrence that may take several decades. In areas endemic for HBV infection, antiviral agents effective against replicative HBV will have to be administered in childhood.     

Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management

Chronic hepatitis B virus (HBV) infection is endemic in the Asian-Pacific region, and reactivation of HBV post-cancer chemotherapy has become an emerging clinical challenge. Patients with detectable serum HBV DNA before chemotherapy and those receiving intensive chemotherapy are particularly at a risk of HBV reactivation. Most patients with HBV reactivation are positive for hepatitis B surface antigen (HBsAg) and are, therefore, easily identified by recommended serological screening before chemotherapy. However, a small, but significant proportion of subjects who have apparently recovered from HBV infection as reflected by HBsAg negativity and hepatitis B core antibody positivity in HBV endemic areas may also experience reactivation when host immunity is severely compromised by cancer chemotherapy. Serum alanine aminotransferase, HBsAg, and/or HBV DNA should be monitored closely in these subjects and antiviral therapy should be administered immediately when any evidence of HBV reactivation is detected during chemotherapy. The prophylactic use of nucleos(t)ide analogs before chemotherapy and its continuation until reconstitution of host immunity remain the mainstay of effective prevention of hepatitis B reactivation in this special clinical entity.