Occult hepatitis B virus infection in Greek patients with chronic hepatitis C and in patients with diverse nonviral hepatic diseases

Occult hepatitis B virus (HBV) infection has been reported in patients with chronic hepatitis C who are negative for HBV surface antigen (HBsAg). However, the significance of 'silent' HBV in hepatitis C virus (HCV) infection is unknown. We investigated 540 subjects for the presence of occult HBV in Greek HCV patients, patients with nonviral liver diseases and healthy donors in an attempt to determine the frequency and importance of this phenomenon. One hundred and eighty-seven anti-HCV(+)/HBsAg(-) patients' sera were investigated for the presence of HBV-DNA by polymerase chain reaction. Two hundred and eighty-two selected blood donors (positive for antibodies to HBV core antigen) and 71 patients with various nonviral hepatic diseases consisted the control groups [both controls were anti-HCV(-)/HBsAg(-)]. HBV-DNA was detected in 26.2% of HCV-infected patients vs 8.5% of patients with nonviral diseases (P = 0.003) and 0/282 of donors (P = 0.0000). HBV-DNA was neither associated with HBV markers, nor with the clinical status of HCV and nonHCV patients. Neither epidemiological, histologic and virologic data nor the response to therapy were associated with the HBV-DNA detection. Hence one quarter of HCV-infected patients had occult HBV infection. Similar findings were not found in both control groups. Occult HBV infection in Greek patients with chronic hepatitis C does not seem to modify the progression of chronic liver disease. Further studies of longer duration are needed in order to clarify the role of 'silent' HBV infection in HCV-infected patients.     

Therapeutic effects of pegylated interferon plus ribavirin in chronic hepatitis C patients with occult hepatitis B virus dual infection

Background and Aim: Occult hepatitis B virus (HBV) infection is defined by the detectable serum HBV–DNA in HBV surface antigen‐negative patients. This retrospective study aims to evaluate the therapeutic effects of combined pegylated interferon (PEG–IFN) plus ribavirin (RBV) in patients with concurrent occult HBV/hepatitis C virus (HCV) dual infection. Methods: In total, 126 consecutive chronic hepatitis C (CHC) patients who received combined PEG–IFN and RBV therapy were included. Patients were divided into the occult HBV/HCV dual infection group or the HCV‐monoinfected group according to whether or not they had the detectable serum HBV–DNA. The biochemical and virological responses to combined therapy were compared between these two groups. Serum HCV‐RNA and HBV–DNA were checked before treatment, at the end of treatment as well as at 6‐ and 12‐months' follow up in the occult HBV/HCV group. Result: Six patients were seropositive for HBV–DNA and were included in the occult HBV/HCV dual infection group. There were no statistical differences in the biochemical and virological responses to combined therapy between these two groups. Undetectable serum HBV–DNA was noted at the end of the treatment and the 6‐ and 12‐months' follow up in patients with occult HBV/HCV dual infection. Conclusion: Occult HBV infection in CHC patients is rare. The biochemical and virological responses to combined PEG–IFN and RBV therapy might be similar in CHC patients with or without occult HBV infection. The serum HBV–DNA level was low in patients with occult HBV/HCV dual infection who responded to combined therapy.     

Occult hepatitis B virus infection and lamivudine-resistant mutations in isolates from renal patients undergoing hemodialysis

Background and Aims:  Patients undergoing hemodialysis are at risk of infection with both hepatitis B virus (HBV) and hepatitis C virus (HCV). Occult HBV infection is usually associated with low levels of HBV and is frequently detected in HCV-infected patients. The aims of the present study were to compare the prevalence of occult HBV infection among anti-HCV-positive and anti-HCV-negative patients undergoing hemodialysis, and characterize the molecular patterns of HBV isolates from patients with occult infection.
Methods:  Serum samples from 100 patients negative for hepatitis B surface antigen undergoing hemodialysis, half of whom were positive for anti-HCV antibodies, were tested for the presence of HBV-DNA using semi-nested polymerase chain reaction (PCR). PCR products of the S gene were directly sequenced.
Results:  HBV-DNA was detected in 15 samples. There were no significant differences in HCV status, sex, age, time of dialysis, alanine aminotransferase levels or HBV serological markers between patients with or without occult HBV infection, with the exception of antibody to hepatitis B core antigen (anti-HBc)-only serological marker ( P  = 0.003). All six HBV isolates that could be sequenced were of genotype A/subgenotype A1. Four of these six HBV isolates contained mutations associated with lamivudine resistance in the DNA polymerase (two with L180M/M204V and two with rt173V/180M/204V) and a specific substitution (Y100C) in the HBV small surface protein.
Conclusions:  HBV isolates with the identified substitutions have the potential to spread silently by nosocomial transmission within the hemodialysis unit. These results have potential implications for the management of patients with occult HBV infection undergoing hemodialysis.     

Seroprevalence of occult hepatitis B among Egyptian paediatric hepatitis C cancer patients

Occult hepatitis B infection is characterized by the presence of hepatitis B virus (HBV) DNA in the serum in the absence of hepatitis B surface antigen (HBsAg). Prevalence of hepatitis C virus (HCV) infections in Egypt is among the highest in the world. In this study, we aim at analysing the rates of occult HBV infections among HCV paediatric cancer patients in Egypt. The prevalence of occult HBV was assessed in two groups of paediatric cancer patients (HCV positive and HCV negative), in addition to a third group of paediatric noncancer patients, which was used as a general control. All groups were negative for HBsAg and positive for HCV antibody. HBV DNA was detected by nested PCR and real‐time PCR. HCV was detected by real‐time PCR. Sequencing was carried out in order to determine HBV genotypes to all HBV patients as well as to detect any mutation that might be responsible for the occult phenotype. Occult hepatitis B infection was observed in neither the non‐HCV paediatric cancer patients nor the paediatric noncancer patients but was found in 31% of the HCV‐positive paediatric cancer patients. All the detected HBV patients belonged to HBV genotype D, and mutations were found in the surface genome of HBV leading to occult HBV. Occult HBV infection seems to be relatively frequent in HCV‐positive paediatric cancer patients, indicating that HBsAg negativity is not sufficient to completely exclude HBV infection. These findings emphasize the importance of considering occult HBV infection in HCV‐positive paediatric cancer patients especially in endemic areas as Egypt.     

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.     

Occult Hepatitis B Virus Infection in Hemodialysis Patients With Isolated Hepatitis B Core Antibody: A Multicenter Study

Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Occult HBV infection harbors potential risk of HBV transmission through hemodialysis (HD). The aim of this study was to assess the occult HBV infection in hemodialysis patients with isolated hepatitis B core antibody (anti-HBc). A total of 289 HD patients from five dialysis units in Tehran, Iran, were included in this study. Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (anti-HBs), anti-HBc, Hepatitis C antibody (anti-HCV), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were tested in all subjects. The presence of HBV-DNA was determined quantitatively in plasma samples of HD patients with isolated anti-HBc (HBsAg negative, anti-HBs negative and anti-HBc positive) by real-time PCR using the artus HBV RG PCR kit on the Rotor-Gene 3000 real-time thermal cycler. Of 289 patients enrolled in this study, 18 subjects (6.2%, 95% confidence interval (CI), 3.5%–8.9%) had isolated anti-HBc. HBV-DNA was detectable in 9 of 18 patients (50%, 95% CI, 27%–73%) who had isolated anti-HBc. Plasma HBV-DNA load was less than 50 IU/ml in all of these patients. Our study showed that detection of isolated anti-HBc could reflect unrecognized occult HBV infection in HD patients. The majority of these infections are associated with low viral loads.     

Occult hepatitis B virus infection in HIV‐infected patients: Evaluation of biochemical,virological and molecular parameters

Aim: To determine the prevalence of occult hepatitis B virus (HBV) infection in a group of human immunodeficiency virus (HIV)‐infected Brazilian patients and to investigate its association with biochemical, virological and molecular features. Methods: Sera from 43 patients positive for HBV core antibody and negative for HBV surface antigen (HBsAg) were tested for HBV DNA positivity by semi‐nested PCR. HBV loads were assessed by real‐time PCR. S gene was cloned and sequenced for HBV isolates from 3 patients. HBsAg expression of these cases was performed in HuH7 cells. Results: HBV DNA was found in 6/43 (14%) samples, all except one associated with low viral loads. Occult HBV infection was further correlated with anti‐hepatitis C virus (anti‐HCV) antibodies positivity, but not with alanine aminotransferase (ALT) elevated levels. S gene sequences derived from three patients were determined. Two of them displayed mutations that may explain HBsAg negativity. In the first one, a stop codon mutation was found at position 216 in the C‐terminal end of HBsAg. In the second patient, E164D and I195M substitutions in HBsAg, associated with lamivudine‐resistance mutations in the polymerase were identified. As expected, all clones showing those mutations displayed undetectable or very low levels of HBsAg. Conclusion: Occult HBV infection was frequent in HIV‐infected patients, was not associated with ALT elevation but significantly correlated with HCV seropositivity. The low viremia and the detection of HBsAg mutants confirm that multifactorial mechanisms are involved in occult HBV infection. HBV molecular monitoring should be employed for an adequate management of HBV/HIV co‐infected patients.     

Occult hepatitis B in renal transplant patients

BACKGROUND: Occult hepatitis B (HB) is characterized by the presence of HBV-DNA in patients who do not have HB surface antigen (HBsAg) detectable in sera, and is frequently described in patients with hepatitis C virus (HCV) infection. These viral liver diseases are common and may have a negative impact on the survival of renal transplant patients, especially if they are both present. In this study we aimed to evaluate the prevalence of occult HB in renal transplant patients either with or without HCV infection. PATIENTS AND METHODS: In a cross-sectional survey 101 HbsAg-negative renal transplant patients were evaluated; 51 were anti-HCV positive. Sera were analyzed for the presence of the S and core genes of the HBV-DNA by a nested polymerase chain reaction technique. Markers of HBV infection and liver function tests were also analyzed. RESULTS: The core gene was identified in 1 HCV-infected patient and 1 anti-HCV-negative patient who also presented the S gene (prevalence: 2% and 1% for each gene, respectively). HCV-infected patients had longer pre-transplant dialysis time (50.8 +/- 34.6 vs. 32.0 +/- 20.9; P < 0.001). Liver function tests were also increased in the HCV-infected group: alanine aminotransferase (P < 0.001), aspartate aminotransferase (P < 0.05), gamma-glutamyl transpeptidase (P<0.02), and alkaline phosphatase (P < 0.04). Multivariate analysis revealed that HCV infection was the only determinant of the altered results of the liver function tests. CONCLUSION: We found that occult HB is a condition present in our population of renal transplant patients and that HCV infection does not seem to be associated with occult HB infection in this setting.     

Impact of occult hepatitis B virus infection on efficacy and prognosis of interferon-alpha therapy for patients with chronic hepatitis C.

BACKGROUND/AIMS: It is reported that some patients with undetectable hepatitis B surface antigen (HBsAg) have serum hepatitis B virus (HBV) DNA in patients with chronic hepatitis C (HCV). The aim of this study was to elucidate the impact of occult HBV infection on the efficacy and prognosis of interferon-alpha (IFN) therapy in HCV patients. METHODS: One hundred and forty HCV patients without HBsAg who received IFN therapy were studied. Serum HBV DNA was quantified by real-time detection polymerase chain reaction. RESULTS: Of 140 patients, 11 (7.9%) were HBV DNA-positive before IFN therapy. The serum HBV DNA levels ranged from 106 to 884 copies/ml. Four of these 11 patients showed a sustained virologic response by IFN, compared with 39 of 129 without HBV DNA (P = NS). Interestingly, two of the 11 patients developed hepatocellular carcinoma (HCC) after therapy, compared with 16 of 129 without HBV DNA (P = NS). In the serial study, serum HBV DNA was transiently undetectable during and after IFN; however, most became positive during follow-up. CONCLUSIONS: Occult HBV infection may not have a significant impact on response to IFN therapy for chronic HCV and development of HCC after therapy. Occult HBV may be sensitive to IFN although HBV is not completely eradicated.     

Occult hepatitis B virus infection: a covert operation

Summary. Detection of occult hepatitis B requires assays of the highest sensitivity and specificity with a lower limit of detection of less than 10 IU/mL for hepatitis B virus (HBV) DNA and <0.1 ng/mL for hepatitis B surface antigen (HBsAg). This covert condition is relatively common in patients with chronic hepatitis C virus (HCV) that seems to exert some influence on the replicative capacity and latency of HBV. Detection of virus‐specific nucleic acid does not always translate into infectivity, and the occurrence of primer‐generated HBV DNA that is of partial genomic length in immunocompetent individuals who have significant levels of hepatitis B surface antibody (anti‐HBs) may not be biologically relevant. Acute flares of alanine aminotransferase (ALT) that occur during the early phase of therapy for HCV or ALT levels that remain elevated at the end of therapy in biochemical nonresponders should prompt an assessment for occult hepatitis B. Similarly, the plasma from patients with chronic hepatitis C that is hepatitis B core antibody (anti‐HBc) positive (±anti‐HBs at levels of <100 mIU/mL) should be examined for HBV DNA with the most sensitive assay available. If a liver biopsy is available, immunostaining for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) should be contemplated and a portion of the sample tested for HBV DNA. This is another reason for optimal collection of a specimen (e.g. two passes with a 16‐guage needle under ultrasound guidance). Transmission of HBV to immunosuppressed orthotopic liver transplant recipients by donors with occult hepatitis B (OHB) will continue to occupy the interests of the transplant hepatologist. As patients with OHB may have detectable HBV DNA in serum, peripheral blood mononuclear cells (PBMC) and/or liver that can be reactivated following immunosuppression or intensive cytotoxic chemotherapy, the patient needs to be either monitored or treated depending on the pretreatment serological results such as an isolated anti‐HBc reaction or a detectable HBV DNA.     

Antibody to hepatitis B core antigen as a screening test for occult hepatitis B virus infection in Egyptian chronic hepatitis C patients

Purpose  The presence of hepatitis B virus (HBV) DNA in liver tissue and/or in serum in the absence of detectable hepatitis B surface antigen (HBsAg) is called occult HBV infection. This pattern was identified in patients with chronic hepatitis C virus (HCV) infection. The aim of this study was to determine the role of antibodies to hepatitis B core antigen (anti-HBc) as a screening test for occult HBV infection in Egyptian chronic HCV patients. Methods  One hundred chronic HCV patients negative for HBsAg were included and subdivided into two groups according to anti-HBc-IgG seroreactivity. Group A included 71 patients positive for anti-HBc (53 men and 18 women, mean age ± SD 48.8 ± 9.6 years), and group B included 29 patients negative for anti-HBc (18 men and 11 women, mean age ± SD 46.6 ± 11.7 years). All patients were subjected to full clinical assessment, routine laboratory investigations, abdominal ultrasonography and quantification of HBV-DNA by real-time PCR. Results  Chronic HCV patients positive for anti-HBc have more severe liver disease compared with anti-HBc negative patients. Although HBV-DNA in the serum was detected in 22.5% of anti-HBc-positive chronic HCV patients, it was not detected in any of anti-HBc-negative chronic HCV patients. There was no significant difference in any of the clinical and laboratory data tested between anti-HBc-positive patients with and without HBV-DNA in the serum. Conclusion  A significant number of patients with anti-HBc had detectable levels of HBV-DNA in the serum. Egyptian chronic HCV patients have a high prevalence of occult HBV infection.     

Occult hepatitis B virus infection as a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C in whom viral eradication fails.

Aim: Recent studies have suggested that an occult hepatitis B virus (HBV) infection negative for HBsAg but positive for HBV-DNA contributes to hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Some follow-up studies have suggested the clinical importance of occult HBV infections in HCC development even after interferon (IFN) therapy, but a recent study denies the significance of the impact of occult HBV infection. Focusing on HCC development in patients in whom hepatitis C virus (HCV) eradication by interferon (IFN) therapy had failed, we conducted this study in order to assess the impact of occult HBV infections on HCC development in these patients. Methods: We enrolled 141 patients with chronic hepatitis C (histological stage F2 or F3) who were seropositive for HCV-RNA even after IFN therapy. Serum HBV-DNA was assayed using the real-time polymerase chain reaction. During follow-up, ultrasonography and/or computed tomography (CT) were performed at least every 6 months to monitor HCC development. Results: The cumulative incidence rates of HCC were 8.9%, 25.7% and 53.7% at 5 years, 10 years and 15 years, respectively, after IFN therapy. Multivariate analysis indicated that low platelet counts (<12 x 10(4)/mm(3)), occult HBV infection, high ALT levels (>/=80 IU/L) after IFN therapy and the staging of liver fibrosis were important independent factors affecting the appearance of HCC. Conclusions: Occult HBV was a risk factor for HCC development in patients with chronic hepatitis C in whom HCV eradication had failed. Therefore, patients with chronic hepatitis C with occult HBV should be monitored carefully for HCC after IFN therapy.     

Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes

Background

Occult HBV infection is defined by detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg. The prevalence of occult HBV is higher in hepatitis C virus (HCV) positive patients than HCV negative patients and may have an impact on their clinical outcome. In this study, we evaluated the role of occult hepatitis B virus infection in chronic hepatitis C patients with ALT flare.

Methods

Sixty HBsAg negative patients with chronic hepatitis C virus infection were included. Patients were divided into 2 groups according to their ALT level: 30 patients with normal or slightly high ALT and 30 patients with ALT flare (≥ 5 times normal values). Patients in both groups were examined for the detection of anti-HBs, anti-HBc IgM, and anti-HBc IgG. HBV DNA was detected using semi-nested PCR technique.

Results

In patients with normal or slightly high ALT, HBV DNA was detected in 4 (13.3%) patients, while in those with ALT flare, HBV DNA was detected in 19 (63.3%) patients (p < 0.001). No association was found between the presence of HBV DNA and various serology markers of HBV infection.

Conclusion

Presence of occult hepatitis B, with its added deleterious effect, must always be considered in chronic hepatitis C patients especially those with flare in liver enzymes; HBsAg should not be used alone for the diagnosis of HBV infection.     

Occult hepatitis B virus infection in Southern African blacks with hepatocellular carcinoma

Background and Aim:  To ascertain the prevalence of occult hepatitis B virus (HBV) infection in southern African blacks with hepatocellular carcinoma.
Methods:  Sera from 118 patients negative for HBV surface antigen but positive for HBV antibodies were studied. HBV-DNA was detected using a nested polymerase chain reaction (PCR) assay and confirmed by nucleotide sequencing of the surface and precore/core genes.
Results:  Surface gene HBV-DNA was detected in a single PCR assay in 48.4% of the patients. Positive results increased to 57.7% after two PCR assays (not significant) and 75.7% after four assays ( P  < 0.001). No false positive results were obtained in these assays or in the 15 control samples for which PCR assays were performed four times. Significant differences in positivity rates were not observed between patients positive for HBV core antibody alone and those positive for core and surface antibodies. The sensitivity of the PCR amplification of the precore/core gene was significantly less than that of the surface open reading frame: the yield of positive results was 23.7% after one assay, 32.2% after two assays (not significant), and 52% after four assays ( P  < 0.001). Combining the results of the assays of the two genes increased the yield of positive results for the first assay (by 11.9%, P  = 0.015), but not the second (6.1%) or fourth assays (4.6%).
Conclusion:  Occult HBV infection is present in the serum of the majority of hepatocellular carcinomas in southern African blacks whose serum is negative for hepatitis B surface antigen but positive for anti-HBV core antigen. The yield of positive results increases if more than one PCR assay is performed.     

Occult hepatitis C virus infection is more common than hepatitis B infection in maintenance hemodialysis patients

Patients of end stage renal disease on maintenance hemodialysis were enrolled to study the prevalence of occult and dual hepatitis B virus （HBV） and hepatitis C virus （HCV） infection and non-occult hepatitis B and C virus infection. One hundred and two patients were enrolled. Thirty patients had HCV infection, three of them were positive in anti-HCV. So, 27 （90%） of HCV-positive patients had occult HCV infection. Eleven （11%） patients had HBV infection. Five patients were positive in anti-HBc or HBV-DNA, but negative in HBsAg （occult HBV infection）. Three （3%） patients had dual HBV and HCV infection. None of the patients showed changes in viral markers during the follow-up of 8 mo on average （1-12 mo）.     

Analysis of occult hepatitis B virus infection in liver tissue of HIV patients with chronic hepatitis C

OBJECTIVE: Current data on the prevalence of occult hepatitis B virus (HBV) infection in HIV-positive individuals conflict. As occult HBV infection could have an impact on the outcome of liver disease in HIV-positive patients, we investigated a large number of HIV-positive/HBV-surface-antigen (HBsAg) negative subjects with hepatitis C virus (HCV) infection by using the 'gold standard' approach for occult HBV detection--analysis of liver DNA extracts. METHODS: The presence or absence of HBV DNA was determined by PCR testing of four different viral genomic regions in DNA extracts of needle liver biopsy specimens of 101 HBsAg negative individuals with HIV/HCV co-infection. HBV genotyping was performed by sequencing analysis of the preS-S gene in occult HBV isolates from 18 cases. RESULTS: Occult HBV infection was diagnosed in 42 of the 101 cases (41%). No clinically relevant difference was found between occult HBV-positive and -negative patients. HBV genotype D and A were detected, respectively, in 11 (61%) and 7 (39%) of 18 cases analysed. CONCLUSIONS: Occult HBV infection frequently occurs in HIV/HCV co-infected patients indicating the importance of performing prospective studies able to clarify its clinical impact in these patients. HBV genotype A is highly prevalent in HIV-infected subjects with occult HBV infection in a similar way to HBsAg/HIV-positive individuals.     

Acute hepatitis A and acquired immunity to hepatitis A virus in hepatitis B virus (HBV) carriers and in HBV- or hepatitis C virus-related chronic liver diseases in Thailand

A number of studies have suggested that the clinical course of hepatitis A virus (HAV) infection is more severe in patients with chronic liver disease (CLD). A study was undertaken to determine the impact of acute HAV in asymptomatic hepatitis B surface antigen (HBsAg) carriers (n = 20) and patients with hepatitis B virus (HBV)-(n = 8) or hepatitis C virus (HCV)-related (n = 4) CLD. Disease progression was compared with that in 100 patients with isolated HAV infection. No patient with HAV infection alone developed complications, and all recovered fully. Fulminant or submassive hepatitis occurred in 55% of HBsAg carriers and 33% of patients with HBV- or HCV-related CLD. The mortality rate in HBsAg carriers (25%) was not significantly different from that in the patients with CLD (33%). The seroprevalence of anti-HAV immunoglobulin G in 820 individuals was also determined. Approximately 50% of the individuals had acquired HAV infection between the ages of 21 and 30 years. It was demonstrated that HAV infection may have a more severe clinical course in patients with underlying CLD, particularly among older individuals. Vaccination for such patients should be considered.     

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.