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Occult Hepatitis B InfectionEdit

Occult hepatitis B infection (OBI) is a form of hepatitis B virus (HBV) persistence that challenges conventional serology. In individuals with OBI, the usual marker of infection, the surface antigen HBsAg, is not detectable in the blood using standard tests, yet HBV genetic material can be found in the liver and, in some cases, at very low levels in the blood. This means that HBV is present and potentially infectious, even when routine screening suggests there is no active HBV infection. OBI can occur after a resolved HBV infection, or it can represent a low-level, ongoing replication that escapes standard surveillance. The condition is clinically important because it can reactivate under certain circumstances and can complicate decisions around blood transfusion, organ transplantation, and immunosuppressive therapy. For context, HBV is a major human pathogen with a genome that can persist in hepatocytes in various forms, including integrated DNA, which contributes to the occult state HBV.

The term “occult” reflects diagnostic challenges rather than a fully benign natural history. OBI may be detected in people who previously had hepatitis B infection or in persons who never had overt disease, depending on geography, exposure, and the sensitivity of testing. Because standard panels do not routinely test for HBV DNA, many cases go undiagnosed unless specific molecular testing is performed. The clinical significance of OBI ranges from transfusion and transplantation safety to the risk of reactivation during immune system perturbations, as discussed in the sections that follow.

Pathophysiology

In occult HBV infection, the virus persists in the liver at very low levels. The biology that underlies this pattern includes:

  • HBV DNA in hepatocytes without detectable HBsAg in serum, and often with very low or intermittent HBV DNA in blood
  • The possibility of HBV DNA integration into the host genome, a trait that can sustain viral persistence even when surface antigen levels are undetectable
  • Immune control that suppresses viral replication to subclinical levels, which can be disrupted by immunosuppression or liver injury
  • Diverse mechanisms for the apparent loss of HBsAg, including mutations in the S gene (pre-S/S) or limitations of assay sensitivity

Detection depends on highly sensitive molecular testing for HBV DNA, either in serum or liver tissue, and is more likely to be identified in people with risk factors or in scenarios where HBV DNA testing is performed as part of pre-transplant evaluation or research screening HBV.

Epidemiology and clinical associations

OBI is not restricted to a single population; it has been described worldwide, with prevalence influenced by historical exposure to HBV, vaccination programs, and the sensitivity of routine testing. In HBsAg-negative individuals, the proportion who harbor HBV DNA can vary from undetectable to a minority who carry low-level replication. Among people with anti-HBc positivity (indicating prior exposure to HBV), the likelihood of detecting HBV DNA in serum or liver is higher than in those who lack anti-HBc, but it still depends on regional epidemiology and testing methods. In settings such as blood donation and organ transplantation, the concern is not only whether HBV DNA is present but whether it can be transmitted or reactivated under immunosuppressive therapy HBV.

Transmission, reactivation, and clinical consequences

  • Transmission: OBIs can be transmitted via blood products and organ/tissue transplantation when controls rely on HBsAg screening alone. Donor-derived HBV transmission has been reported in liver and other organ transplants from donors with OBI, underscoring the need for careful donor assessment in high-sturity programs liver transplantation.
  • Reactivation risk: The most clinically important aspect of OBI is the potential for HBV reactivation when the immune system is suppressed. Immunosuppressive regimens, especially those including rituximab, high-dose steroids, or certain chemotherapy agents, markedly raise the risk of HBV reactivation in individuals with OBI, potentially leading to hepatitis flares or liver injury immunosuppression.
  • Long-term risk: There is ongoing study of whether OBI contributes to long-term liver disease, including cirrhosis or hepatocellular carcinoma, particularly in the context of other liver insults or chronic viral coinfections. The data are not uniformly definitive, but vigilance is warranted in at-risk patients hepatocellular carcinoma.

Diagnosis

Diagnosing occult HBV infection requires targeted testing beyond routine serology. Key elements include:

  • HBsAg-negative serology: The absence of detectable surface antigen in standard assays does not rule out infection
  • HBV DNA testing: Detection of HBV DNA in serum or liver tissue confirms occult infection, and the level of DNA tends to be low
  • Serologic profile: Many OBIs occur in individuals with anti-HBc (and often anti-HBs) indicating prior exposure; however, OBIs can occur with variable serologic patterns
  • Liver biopsy or liver-directed testing: In some clinical situations, especially with unexplained liver injury or in transplant workups, HBV DNA may be sought in liver tissue
  • Testing context: Screening for OBIs is usually targeted (e.g., before immunosuppressive therapy or organ transplantation, or in research settings) rather than universal

Clinical management depends on the context of testing, with decisions driven by reactivation risk, current liver function, and the feasibility of antiviral prophylaxis or close monitoring HBsAg.

Management and prevention

  • Antiviral prophylaxis for immunosuppressed patients: For individuals with OBI who are about to receive immunosuppressive therapy, particularly regimens known to promote HBV reactivation, clinicians may use prophylactic antiviral therapy with nucleos(t)ide analogs such as entecavir or tenofovir to reduce the risk of reactivation. This is especially common in patients who are anti-HBc positive or who have detectable HBV DNA at low levels, even if HBsAg is negative nucleos(t)ide analogs.
  • Donor and transplant considerations: In liver and other organ transplantation, OBIs in donors raise concerns about recipient safety. Some centers implement antiviral prophylaxis for recipients or additional donor screening to mitigate transmission risk. The approach balances potential benefits with medication costs and potential side effects over the long term liver transplantation.
  • Monitoring strategies: In patients with known OBI who will not receive antiviral prophylaxis, a strategy of regular monitoring for HBV DNA and liver function tests during immunosuppressive therapy may be employed, with a low threshold to initiate antiviral therapy if reactivation is detected
  • Vaccination and prior exposure: Vaccination against HBV is the standard strategy for preventing primary infection, but in the context of occult infection, vaccination does not eradicate existing HBV reservoirs. Vaccination remains important for susceptible individuals but does not directly treat OBI
  • Guidelines and practice points: Several major liver disease and transplant guidelines discuss HBV reactivation risk and prophylaxis strategies, noting the importance of risk stratification based on serologic status and planned therapy HBV.

Controversies and debates

  • Scope of screening: A major policy question is whether universal HBV DNA screening should be performed in all donors or patients prior to immunosuppression or transplantation, or whether a risk-based, targeted approach is sufficient. Proponents of targeted screening argue that resources should be focused on high-risk populations and settings with higher HBV prevalence, arguing that this approach reduces unnecessary costs while maintaining patient safety. Opponents warn that even low-level viral persistence can pose a reactivation risk in vulnerable patients, and that gaps in screening could lead to preventable hepatitis or transmission.
  • Definition and detection: There is ongoing discussion about how best to define and detect OBI, including the sensitivity of assays and the interpretation of very low HBV DNA levels. Different laboratories and guidelines may use varying thresholds, which can affect prevalence estimates and management decisions.
  • Long-term outcomes: The extent to which OBIs contribute to chronic liver disease or hepatocellular carcinoma, independent of other risk factors, remains an area of active research. Critics of overinterpretation caution against assuming high risk in all OBIs, while others emphasize monitoring and proactive management for high-risk individuals.
  • Resource allocation and public health messaging: In systems with limited resources, policymakers must weigh the benefits of detecting and treating occult infections against other public health priorities. The conservative stance emphasizes practicality and cost-effectiveness, while others advocate for broader safety nets for transfusion and transplant safety.

See also