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Boortalary et al. Hepatoma Res 2020;6:48 I http://dx.doi.org/10.20517/2394-5079.2020.38 Page 5 of 7

With our patient, the etiology of the HCC was unclear given her negative HBsAg and undetectable serum
viral load. Suspicion for HBV as the possible cause for her HCC was prompted by HBV positivity in
her daughters. It is likely that she was infected with HBV during her reproductive period and vertically
transmitted the virus to her daughters. Additionally, the presence of HBV DNA in the liver tumor and
the more sensitive HBV serum DNA assay suggested a case of OBI. Indeed, the failure of commercial
HBV assays to detect HBV DNA has been reported, particularly in patients harboring treatment-resistant
[20]
mutations . This highlights the need for a more rigorous HBV DNA assay test and reinforces the need
[2]
to target at least three different locations in the HBV genome . Furthermore, HBV DNA assays used in
diagnosing OBI should be able to distinguish between the detection of integrated HBV DNA and replication
competent HBV DNA, which encompasses both cccDNA and/or relaxed circular DNA (rcDNA), the direct
product of transcriptionally active cccDNA.

The presence of integrated HBV in OBI-associated HCC has recently been reported at a high frequency
[22]
[21]
(76%) and in cccDNA-negative patients (88%) . The presence of integrated HBV DNA in OBI-HCC can
further complicate disease management and antiviral regimens. However, its detection can play a critical role
in patients’ HCC management as new HBV-directed T cell immunotherapies emerge. Recently, the potential
application of HBV-specific T cells in targeting HBV antigens derived from integrated HBV DNA has been
[23]
shown to have antiviral and anti-tumor effects .

In this report, we present a rare case of a patient with OBI with HCC who survived multiple resections,
including resection of a pulmonary metastasis, and had no recurrence of disease or tumor burden after
beginning antiviral therapy. This case is interesting for many reasons and offers several educational points.
HBV DNA was negative in the commercial assay suggesting that the patient had reached a “functional cure”
in the setting of negative HBsAg and positive anti-HBs. Numerous studies have shown that seroconversion
of HBsAg is associated with improved clinical outcomes [24,25] . Unfortunately, the association between her
HCC and HBV profile was unclear at presentation. It was not clarified until later in her clinical course when
a more sensitive assay found a viral load of 3,271 copies/mL in her serum. Therefore, it is important to realize
that the diagnosis of OBI can be challenging given different serological presentations and the limitations
of routine assays. Further, it has been reported that spontaneous HBsAg seroconversion does not mean
[26]
complete elimination of HBV and patients can still have risk of developing HBV associated HCC .

Even if the diagnosis of OBI is made, management of such patients can be difficult as there are no guidelines
regarding the initiation of antivirals or screening for HCC. Additionally, the prognosis of OBI-associated
HCC is unclear and outcome studies are limited. A prior study investigated surgical outcomes in patients
with OBI and HCC. They found that patients with OBI were younger at the time of surgery but did not differ
in disease free survival or overall survival compared to those with HCC attributed to other carcinogenetic
[27]
factors such as alcohol abuse, NASH, and diabetes . Regarding the management of OBI related HCC,
studies have shown that after the development of HCC, anti-HBV therapy can prevent recurrence or new
HCC in the majority of cases [28-30] .

In summary, this case suggests a strong role for OBI in HCC development and indicates that OBI can be
cured with anti-HBV treatment and complete surgical removal of HBV infected hepatocytes and other
cells. Further studies are required to better define the role of OBI in carcinogenesis, and to determine the
mechanisms by which it exerts pro-oncogenic activity.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception, design of the study and writing of the paper: Boortalary T,
Hann HW