In recent years, there has been an increasing awareness of the risk for hepatitis B virus (HBV) reactivation associated with the use of direct-acting antivirals (DAAs) and immunosuppressive therapies. A serological pattern called “isolated anti-HBc” (IAHBc), characterized by the presence of hepatitis B core antibody (anti-HBc) and the absence of hepatitis B surface antigen and hepatitis B surface antibody, has been of particular interest in this context.1 Individuals who exhibit this pattern have been found to have higher rates of hepatitis C virus (HCV) coinfection compared with those with positive anti-HBs, and other findings showed a greater prevalence of IAHBc among patients who were HCV RNA-positive vs those who were HCV RNA-negative (22% vs 13%; P <.0001).2,3
This may be a result of “mechanisms of increased HCV replication in patients with IAHBc, including the cross-reactivity of immune response,” according to a 2017 review published in the American Journal of Gastroenterology.1 “For instance, the presence of anti-HBs and partial resolution of HBV may have implied a stronger immune response to both viruses, allowing for HCV suppression. Subsequent loss of anti-HBs may then allow for increased viremia and activity of HCV.”
Accumulating evidence points to IAHBc as a potential serological marker for occult HBV infection (OBI). “IAHBc has important clinical implications in the setting of co-infection with HCV, HBV reactivation risk with HCV DAA therapy and immunosuppression, as well as the progression of liver disease and HCC development,” wrote the authors of the review.
To explore the latest findings on the topic and relevant clinical implications, Infectious Disease Advisor interviewed Mindie H. Nguyen, MD, MAS, hepatologist and professor of medicine in the Division of Gastroenterology and Hepatology at Stanford University Medical Center, Palo Alto, California, and Yee Hui Yeo, MD, a postdoctoral research fellow at Stanford University Medical Center.
Infectious Disease Advisor: What is the clinical significance of IAHBc, and what are the reasons for the growing interest in this topic?
Dr Nguyen and Dr Yeo: In general, the vast majority of these patients are not at higher risk for liver failure or liver cancer. However, there are still some traces of the virus “hidden” in some of the liver cells or blood cells in some latent or “occult” state, which can be reactivated into active infection or even fulminant hepatitis and liver failure if the patient’s immune system becomes severely weakened, most commonly in the setting of medications that suppress the immune system.
This has become a topic of increasing importance because of the increasing availability of medications for cancer and noncancer treatments that can cause severe immunosuppression. Another unique situation is reactivation in the setting of DAA treatment for HCV. The high efficacy of DAA leads to rapid suppression of HCV that can allow for OBI to reactivate.
The observation that anti-HBc levels are most elevated during the immune active and immune reactivation phases implicates anti-HBc in the immune response to chronic HBV infection.1
Physicians need to keep in mind that it could be the result of an infection with variant viruses (S-escape mutants) undetectable by HBsAg commercial kits.
The clinical significance of IAHBc includes HBV transmission and HBV reactivation in the context of immunosuppressant therapy. The development of liver fibrosis and hepatocellular carcinoma [are additional concerns].
Infectious Disease Advisor: How are related issues, such as risk for HBV reactivation during DAA therapy for HCV, managed in clinical practice?
Dr Nguyen and Dr Yeo: The risk for reactivation in patients with isolated core antibody is very low, but not zero, so patients need to be monitored for HBsAg and/or HBV DNA PCR, and if either of these becomes positive, the patient should be treated with anti-HBV medications right away to avoid possible severe hepatitis B flare.
Previous research showed that HCV core protein may directly suppress transcription of HBV RNA and also limit HBsAg expression, resulting in lower levels of viremia, as well as enhanced clearance of HBsAg.4,5 Therefore, in patients with HBV and HCV dual infection, the administration of DAA may increase the chance of HBV relapse in patients with IAHBc.
After 29 cases of HBV reactivation occurred in patients with dual HBV and HCV infection who were being treated with DAA therapies, the US Food and Drug Administration issued a drug safety Boxed Warning regarding this risk.1
According to current guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, all patients being treated for HCV with DAA therapy should be tested for HBV coinfection via assessment of HBsAg, anti-HBs, and anti-HBc levels. However, findings from 3 recent reports (total N=168) revealed no HBV reactivation events patients with among IAHBc during DAA treatment.6-8
A report from Hong Kong showed that in 193 patients with HCV/IAHBc, DAA treatment did not result in HBV reactivation.9 Another report that included 765 patients with IAHBc with HCV co-infection showed that HBV reactivation occurred in 1 (0.1%) patient after initial resolution.10 However, the HBV DNA level spontaneously decreased after DAA therapy. Therefore, the overall risk for HBV reactivation among patients with IAHBc is low.
Infectious Disease Advisor: In addition to the points noted here, what would be the additional clinical implications if IAHBc is confirmed as a serological marker for OBI?
Dr Nguyen and Dr Yeo: A cohort study showed that in cirrhotic patients with negative hepatitis B surface antigen and negative anti-hepatitis C virus, OBI increased hepatocellular carcinogenesis by 8 times.11
Before initiating immunosuppressive medications, physicians need to consider the types of immunosuppression and the risk for HBV reactivation. Previous studies suggested that B-cell-depleting agents such as rituximab and tumor necrosis factor-α inhibitors are associated with HBV reactivation in patients with IAHBc.12,13
In 1 meta-analysis, HBV reactivation (ALT >3× normal and either an increase in HBV DNA from baseline or HBsAg seroreversion) was estimated at 6.3% in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma.14 Wang et al reported that in 124 patients who were diagnosed with HCV and OBI, DAA treatment did not result in HBV reactivation.9
In addition, OBI can be transmitted, for example, through blood transfusion and liver transplantation, causing classic forms of hepatitis B in newly infected individuals. Therefore, the implementation of progressively more sensitive and specific diagnostic tests is important to lower the risk for posttransfusion hepatitis B infection.
Infectious Disease Advisor: What should be the focus of future research in this area?
Dr Nguyen and Dr Yeo: As increasingly more biologic and immunotherapies become available, additional research is needed to investigate the risk for reactivation for specific agents or classes of agents in the population the treatment is being used for.
More important, patients with IAHBc should be counseled for possible risk for reactivation should they receive any immune-altering medications or DAA for HCV. They should also be monitored for HBsAg and/or HBV DNA PCR during treatment, as well as after treatment until immune control of hepatitis B can recover. In addition, all patients contemplating DAA treatment for HCV, or chemotherapy or other immunotherapies for cancer or noncancer diseases, should be tested for HBsAg, anti-HBc, and anti-HBs.
With the emergence of new immunosuppressant and targeted therapy, the risk for HBV reactivation remains poorly known and will be the focus of future research. Previous evidence regarding the risk for cirrhosis and HCC in patients with IAHBc is also limited by small sample size; thus, more studies with large sample sizes and long follow-up are needed.
- Wu T, Kwok RM, Tran TT. Isolated anti-HBc: The relevance of hepatitis B core antibody – a review of new issues. Am J Gastroenterol. 2017;112(12):1780-1788.
- Jilg W, Sieger E, Zachoval R, Schätzl H. Individuals with antibodies against hepatitis B core antigen as the only serological marker for hepatitis B infection: high percentage of carriers of hepatitis B and C virus. J Hepatol. 1995;23(1):14-20.
- Wedemeyer H, Cornberg M, Tegtmeyer B, Frank H, Tillmann HL, Manns MP. Isolated anti-HBV core phenotype in anti-HCV-positive patients is associated with hepatitis C virus replication. Clin Microbiol Infect. 2004;10(1):70-72.
- Schuttler CG, Fiedler N, Schmidt K, Repp R, Gerlich WH, Schaefer S. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol. 2002; 37(6):855-862.
- Chu CM, Yeh CT, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection. J Clin Microbiol. 1998;36(7):2084-2086.
- Loggi E, Gitto S, Galli S, et al. Hepatitis B virus reactivation among hepatitis C patients treated with direct-acting antiviral therapies in routine clinical practice. J Clin Virol. 2017; 93:66-70.
- Yeh ML, Huang CF, Hsieh MH, et al. Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis B virus infection treated with direct acting antivirals. J Gastroenterol Hepatol. 2017;32(10):1754-1762.
- Tang L, Tolaymat M, Stonesifer E, Kottilil S, Wilson E. Absence of hepatitis B reactivation among veterans with serological evidence of previous hepatitis B infection receiving anti-hepatitis C direct acting antivirals. J Hepatol. 2017;66(1):S251-S252.
- Wang C, Ji D, Chen J, et al. Hepatitis due to reactivation of Hepatitis B Virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2017;15(1):132-136.
- Tamori A, Abiru S, Enomoto H, et al. Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy. J Viral Hepat. 2018;2(5):608-611.
- Ikeda K, Kobayashi M, Someya T, et al. Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: a cohort study. J Viral Hepat. 2009;16(6):437-443.
- Matsue K, Kimura S, Takanashi Y, et al. Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer. 2010;116(20):4769-4776.
- Pei SN, Chen CH, Lee CM, et al. Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol. 2010;89(3):255-862.
- Mozessohn L, Chan KK, Feld JJ, Hicks LK. Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis. J Viral Hepat. 2015;22(10):842-849.