Reactivation of occult hepatitis B virus infection in patients with rheumatic diseases: pathogenesis,risk assessment and prevention

Over the past decade, reactivation of occult hepatitis B virus (HBV) infection has garnered much attention from rheumatologists owing to a number of reports which have indicated the potential risk of biologics in causing this previously ignored infectious complication. Hepatitis due to reactivation of occult HBV infection occurs only occasionally but with high mortality upon occurrence, placing us in a clinical dilemma “to address or not to address?” In this review, we discuss how biological and other immunosuppressive therapies increase the risk of developing reactivation of occult HBV infection and attempt to solve this clinical quandary.     

Hepatitis B reactivation after chemotherapy: two decades of clinical research

Hepatitis due to hepatitis B virus reactivation after cytotoxic or immunosuppressive therapy is a serious cause of liver-related morbidity and mortality. With the characterization of the underlying pathogenesis, much progress in the management of this important clinical problem has been made in the past 2 decades. By year 2008, it is mandatory to screen for hepatitis B surface antigen status before initiating intensive chemotherapy or immunosuppressive therapy. All those who are hepatitis B surface antigen positive should be started on preemptive nucleos(t)ide analogues. However, there remains important issues, such as the type and duration of nucleos(t)ide analogue therapy, which need to be understood. As not all hepatitis B surface antigen-positive patients will suffer from HBV reactivation, it is therefore useful to identify risk factors related to HBV reactivation so that patients will not be treated unnecessarily with nucleos(t)ide analogues. To date, a high baseline level of viral replication, as reflected by high serum HBV DNA level, positive serum hepatitis B e antigen, and a high intrahepatic covalently closed circular DNA level, is the most important predictor for HBV reactivation. Recently, there has been an increased awareness of reactivation of occult hepatitis B virus, especially in hepatitis B virus endemic area, such as the Asia-Pacific region. Careful epidemiological study will be needed to clarify the impact of occult hepatitis B infection in patients treated with cytotoxic or immunosuppressive therapy.     

Effect of Antiviral Prophylaxis Strategy for Chemotherapy-Associated Hepatitis B Reactivation in Non-Hodgkin’s Lymphoma Patients with Hepatitis B Virus Infection: A Retrospective Cohort Study

Recent data indicates that nucleoside/nucleotide analogue (NUC) is effective in preventing and controlling hepatitis B virus (HBV) reactivation in HBV-carrying cancer patients who undergo chemotherapy, but the ideal antiviral agent and optimal application protocol still needs to be determined. Meanwhile, it is uncertain whether those with past HBV infection require antiviral prophylaxis during chemotherapy. This report retrospectively analyzed non-Hodgkin’s lymphoma (NHL) patients seen from January, 2004 to June, 2009 in West China Hospital. We found that the prevalence of chronic HBV infection in our NHL patients was 20.7 % while that of past HBV infection was 21.05 %. Compared with the high rate (25.6 %) of HBV reactivation in patients with chronic HBV infection, none of those with past HBV infection in fact had occult HBV infection thus none experienced reactivation. Of the 82 patients with chronic HBV infection who received chemotherapy, antiviral prophylaxis could significantly reduce the incidence of HBV reactivation (5.0 vs. 45.2 % in the control group) and the incidence of liver function damage (32.5 vs. 73.8 % in the control group). The results of the current study confirmed previous reports that prophylactic NUCs administration can effectively prevent HBV reactivation and significantly reduce the incidence of HBV reactivation especially for patients receiving rituximab-containing regimens. Due to the fact that none of individuals who had past HBV infection developed HBV reactivation reported in our study, antiviral prophylaxis may not be required for patients with past HBV infection. Close observation of alanine aminotransferase and HBV–DNA contributes to early diagnosis and timely treatment of HBV reactivation.     

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.     

Occult Hepatitis B: Clinical Implications and Treatment Decisions

First reported in 1978, occult hepatitis B is a term used to describe the presence of hepatitis B virus (HBV) DNA without hepatitis B surface antigenemia. The prevalence of occult HBV is unclear and depends in part on the sensitivity of the hepatitis B surface antigen (HBsAg) and DNA assays used as well as the prevalence of HBV infection in the study population. The origin of occult HBV also remains in question. Several mechanisms have been hypothesized including mutations in the regulatory regions of the HBV genome, persistence of Ig-bound HBV immune complexes, viral interference, and blockage of free HBsAg secretion. Occult HBV has important clinical implications such as transmission through blood transfusion, reactivation in the setting of immunosuppression, and interference with hepatitis C treatment. To date, there is little data pertaining to the treatment of occult HBV outside of the setting of chemotherapy-induced HBV reactivation.     

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.     

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.     

Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients

AIM: To investigate the frequency of occult hepatitis B, the clinical course of hepatitis B virus (HBV) reactivation and reverse seroconversion and associated risk factors in autologous hematopoietic stem cell transplantation (HSCT) recipients. METHODS: This study was conducted in 90 patients undergoing autologous HSCT. Occult HBV infection was investigated by HBV-DNA analysis prior to transplantation, while HBV serology and liver function tests were screened prior to and serially after transplantation. HBV...     

Reactivation of hepatitis B virus in cancer patients treated with chemotherapy for solid tumors. Is the prophylaxis really required?

BackgroundReactivation of hepatitis B virus during cancer chemotherapy for non-hematological tumors is not fully clear.AimTo evaluate the risk of hepatitis B virus reactivation in carriers of hepatitis B virus cancer patients treated with chemotherapy for solid tumors.MethodsTwo hundred sixty-seven patients with solid tumors were consecutively enrolled: 13 (4.8%) were hepatitis B s-antigen positive, of whom 6 were documented inactive carriers and 7 had chronic liver disease. Thirty-two patients (12%) were hepatitis B s-antigen negative/hepatitis B c-antibody positive. Hepatitis B virus inactive carriers were followed every 3 months by alanine aminotransferases, hepatitis B virus-DNA; whereas hepatitis B virus occult carriers were followed every 3 months by alanine aminotransferases and hepatitis B s-antigen.ResultsNone of the 38 total patients with inactive or occult B infection who did not receive prophylaxis presented hepatitis B virus reactivation during the follow-up period.ConclusionThis study suggests that, in hepatitis B s-antigen negative patients who undergo chemotherapy for solid tumors, hepatitis B and c-antibody screening results are not relevant to clinical decision and can be avoided. Larger studies are needed to establish whether the risk of reactivation of HBV during chemotherapy is negligible in this subset of patients and they could not be monitored for HBV reactivation.     

Hepatitis B and human immunodeficiency virus co-infection

Hepatitis B and human immunodeficiency virus (HBV and HIV) infection share transmission patterns and risk factors, which explains high prevalence of chronic HBV infection in HIV infected patients. The natural course of HBV disease is altered by the HIV infection with less chance to clear acute HBV infection, faster progression to cirrhosis and higher risk of liver-related death in HIV-HBV co-infected patients than in HBV mono-infected ones. HIV infected patients with chronic hepatitis B should be counseled for liver damage and surveillance of chronic hepatitis B should be performed to screen early hepatocellular carcinoma. Noninvasive tools are now available to evaluate liver fibrosis. Isolated hepatitis B core antibodies (anti-HBc) are a good predictive marker of occult HBV infection. Still the prevalence and significance of occult HBV infection is controversial, but its screening may be important in the management of antiretroviral therapy. Vaccination against HBV infection is recommended in non-immune HIV patients. The optimal treatment for almost all HIV-HBV co-infected patients should contain tenofovir plus lamivudine or emtricitabine and treatment should not be stopped to avoid HBV reactivation. Long term tenofovir therapy may lead to significant decline in hepatitis B surface Antigen. The emergence of resistant HBV strains may compromise the HBV therapy and vaccine therapy.     

Pitfall of hepatitis B surface antigen testing in a kidney transplant recipient presenting hepatitis B reactivation

Diagnosis of hepatitis B virus (HBV) infection based on hepatitis B surface antigen (HBsAg) detection can be hampered in the setting of HBV reactivation in immunocompromized patients with prior serology indicating past cured infection, and can be associated with severe or fulminant and fatal hepatitis. We present a case of HBV reactivation in a renal transplant patient in whom HBsAg failed to be confirmed as a true positive result. One year after transplantation, systematic testing showed HBsAg positivity with a titer at 244 pg/mL, anti-hepatitis B core antibody and concurrent anti-hepatitis B surface antibody positivity. Confirmation of HBsAg detection by seroneutralization did not confirm HBsAg positivity, indicating that HBsAg detection was a false positive result. Notwithstanding, HBV DNA titer in serum was concurrently 8.6 Log IU/mL. HBV DNA sequencing showed a genotype D and several amino acid substitutions within HBsAg, including some previously involved in impaired diagnosis and altered immunogenicity. Although no perturbation of liver biochemical markers was observed, treatment with tenofovir was introduced. One month later, HBV DNA level had decreased by 2.6 Log IU/mL and no clinical and biochemical symptoms of hepatitis had occurred. The present case underlines that serologic diagnosis of HBV reactivation can be tricky in transplant recipients with a prior serology indicating past HBV infection. This prompts to perform HBV DNA testing in case of positive HBsAg testing, regardless of the result of neutralization by anti-HBs antibodies.     

Occult hepatitis B in Mexican patients with HIV, an analysis using nested polymerase chain reaction

Hepatitis B virus infection (HBV) with undetectable levels of HBsAg, has been named occult HBV infection and observed in immunosuppressed patients. The aim of this study was to determine the frequency of occult HBV infection in patients with HIV from the West of México, using a combination of serological markers and nPCR. Thirty eight HIV/AIDS patients, 32 men (84.2%) and 6 (5.8%) women, without liver damage related symptoms were studied. HBV coinfection was observed in 10 (26.3%) patients; while only 3 (7.9%) of them were positive to HBsAg. Thus, 7 (18.4%) occult HBV infected patients could be assessed in this population. One (10%) patient with occult HBV infection was positive to anti-HBs, in spite of the reinfection protection attributed to this serological marker. Anti-HBc was detected only in 2 (20%) patients with occult HBV infection. No significant association could be established between occult HBV infection and CD+4 cell count, biochemical, clinical parameters, AIDS stage, or any other risk factor. This study suggest that determination of HBV DNA utilizing highly sensitive techniques, as nPCR, should be performed to detect occult HBV infection, even in the absence of anti-HBc in HIV/ AIDS patients, in order to have a reliable diagnosis, prevent HBV dissemination and acute exacerbation of chronic hepatitis B or even fulminant hepatitis. To our knowledge this is the first study of occult HBV infection in Mexican patients with HIV. However, further studies are necessary in order to determine HBV genotypes and its relationship with evolution and clinical manifestation of the disease.     

Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies

The prevalence of hepatitis B virus (HBV) infection in patients with haematological malignancies is increased compared with the general population worldwide. HBV reactivation is common following chemotherapy and is associated with a high mortality despite prompt anti‐viral treatment. HBV reactivation may necessitate interruption of chemotherapy with adverse prognostic consequences for the haematological disease. Chemotherapy‐induced immune suppression may lead to increased HBV replication. Immune reconstitution within the weeks and months following recovery from chemotherapy may be associated with a flare of hepatitis B manifested by hepatocellular injury. Risk factors associated with HBV reactivation include detectable hepatitis B surface antigen (HBsAg), HBV DNA, Hepatitis B e (HBeAg) antigen, antibodies to hepatitis B core antigen (anti‐HBc), treatment with corticosteroids, young age and male gender. Lamivudine is effective during HBV reactivation due to immune suppression. Clinical trials have demonstrated that pre‐emptive antiviral treatment with lamivudine is superior to deferred treatment. Current recommendations emphasise screening for HBV infection in all haematology patients, particularly prior to chemotherapy. Patients who are HBsAg positive or HBV DNA positive should receive pre‐emptive treatment with lamivudine before chemotherapy. The duration of lamivudine treatment may be prolonged commensurate with the degree of immunosuppression. HBV naïve patients should be immunised against hepatitis B, as should haematopoietic stem cell donors. In summary, overt and occult HBV pose a serious, but preventable, threat. Pre‐treatment screening of patients at risk should be practiced diligently by all clinicians that treat patients with malignancies.     

＂Anti-HBc alone＂ in human immunodeficiency virus-positive and immuno-suppressed lymphoma patients

Hepatitis B virus （HBV） infection is endemic in various parts of the world. A proportion of patients have resolved prior exposure to HBV, as evidenced by the clearance of circulating hepatitis B surface antigen and the appearance of antibody to hepatitis B core antigen （anti-HBc）, which could produce protective antibody to hepatitis B surface antigen （anti-HBs）. With time, anti-HBs in some patients may become negative. Such patients are described as having occult HBV infection or ＂anti-HBc alone＂. In the context of immunodeficient patients, such as HIV patients or lymphoma patients undergoing immunosuppressive immunotherapy, the lack of protective anti-HBs may increase the risk of hepatitis B reactivation. Serum HBV DNA testing may be necessary in ＂anti-HBc alone＂ patients, to detect patients at a high risk of developing HBV infection allowing appropriate prophylactic management.     

"Anti-HBc alone" in human immunodeficiency virus-positive and immuno-suppressed lymphoma patients

Hepatitis B virus (HBV) infection is endemic in various parts of the world. A proportion of patients have resolved prior exposure to HBV, as evidenced by the clearance of circulating hepatitis B surface antigen and the appearance of antibody to hepatitis B core antigen (anti-HBc), which could produce protective antibody to hepatitis B surface antigen (anti-HBs). With time, anti-HBs in some patients may become negative. Such patients are described as having occult HBV infection or "anti-HBc alone". In the context of immunodeficient patients, such as HIV patients or lymphoma patients undergoing immunosuppressive immunotherapy, the lack of protective anti-HBs may increase the risk of hepatitis B reactivation. Serum HBV DNA testing may be necessary in "anti-HBc alone" patients, to detect patients at a high risk of developing HBV infection allowing appropriate prophylactic management.     

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.     

Quantification of intrahepatic hepatitis B virus (HBV) DNA in patients with chronic HBV infection

No data are available about the amount of hepatitis B virus (HBV) genomes in liver of patients with chronic HBV infection. The aim of this study was to quantify the intrahepatic HBV DNA in hepatitis B surface antigen (HBsAg)-positive patients with either active or suppressed viral replication and in HBsAg-negative subjects with occult HBV infection. We optimized the Roche "Amplicor HBV Monitor" kit for quantifying liver HBV DNA and analyzed hepatic DNA extracts and serum samples from 19 HBs-Ag-positive and 43 HBsAg-negative individuals. Eight of the HBsAg carriers had active HBV replication, and for 3 of them we analyzed samples obtained before and at the end of 1 year of lamivudine treatment. Five hepatitis Delta virus (HDV) coinfected patients and 6 healthy HBsAg carriers had inhibited HBV activity. Among the HBsAg-negative subjects 21 had occult HBV infection and 22 had no evidence of HBV infection. The median of HBV genomes per microgram of liver DNA milliliter of serum was 34,500 to 2,620,000 in patients with active viral replication, 20,000 to 3,900, 000 before and 10,000 to 2,800 at the end of therapy in lamivudine-treated individuals, 9,800 to 600 in HDV-infected individuals, and 7,450 to 17,400 in healthy HBsAg carriers. These data indicate that cases with suppressed HBV activity, despite the very low levels of viremia, maintain a relatively high amount of intrahepatic viral genomes. This virus reservoir is likely involved in HBV reactivation, which is usually observed after stopping lamivudine treatment. Finally, the analysis of cases with occult HBV infection showed that the assay we used was able to specifically detect and quantify as few as 100 copies of viral genomes per microgram of liver DNA.     

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.     

Occult hepatitis B virus infection and its clinical implications

Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 10⁴ copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV-DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV-DNA sequence; (ii) integration of HBV-DNA into host's chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV-containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well-designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.     

A case of acute hepatitis B in a chronic hepatitis C patient after daclatasvir and asunaprevir combination therapy: hepatitis B virus reactivation or acute self-limited hepatitis?

Reactivation of hepatitis B virus (HBV) in HBV surface antigen (HBsAg)-positive patients treated with cytotoxic chemotherapy is well known. HBV reactivation in patients with HBV and hepatitis C virus (HCV) coinfection caused by direct-acting antiviral (DAA) therapy has also recently been reported. We report a case of acute hepatitis B in a patient with HCV infection after DAA therapy. An 83-year-old woman was referred for chronic hepatitis C. She was infected with HCV genotype 1b and negative for HBsAg at baseline. She received daclatasvir and asunaprevir therapy, and HCV became negative at 4 weeks and remained negative until 6 months after the end of DAA therapy. Acute hepatitis B developed 5 months after ending DAA therapy. Genome sequencing revealed the subgenotype as B1, and the serological subtype as adr. T118 K mutation at the S region as an immune escape mutant was identified. These virologic features led to HBV reactivation. The presence of hepatitis B core antibody or HBs antibody was not determined before DAA therapy, so prior HBV infection status was unclear. This case is speculated to represent HBV reactivation in a patient with previously resolved HBV induced by DAA therapy, based on virologic analysis and clinical status. The risk might be very low, but DAA therapy can cause HBV reactivation in chronic hepatitis C patients with prior HBV infection. When acute hepatitis emerges in patients who have received DAA therapy for HCV, HBV reactivation should be considered to allow early initiation of anti-HBV therapy.