This case highlights several observations, both in the therapeutic approach and in the virological setting.
In particular, there are some clinical and virological points which deserve consideration: 1) a non-protective HBsAb titer in high-viremic HBV infection; 2) a difficult-to-treat infection, both with IFN therapy and with NAs (ADV and ADV plus ETV); 3) a strong response to second-generation NAs combination (ETV plus TDV), finally with seroconversion to anti-HBe and HBsAg loss.
First, the clinical significance of the co-existence of HBsAg and HBsAb is not well understood, since clinical data are lacking in most studies. A screening of 411 patients with CHB from China revealed a relatively high percentage (4.9%) of detectable serum HBsAb levels, while in a French study a lower prevalence (3.1%) was observed
[11, 12]. The exposure of patients to HBV infection of different subtypes could not be excluded as a possible explanation of coexistence of HBsAg and HBsAb. The epidemiological importance of such HBV mutants is supported by reports from Taiwan, where the HBV vaccination program was associated with an increased prevalence of HBsAg mutants
. Later reports suggested that the presence of HBsAb can drive the selection of HBsAg escape mutants, even if HBV isolates are often without relevant mutations in the coding region of HBsAg, such as in our case
Second, only one case of CHB with a population of HBsAg mutants was described to have seroconversion to anti-HBe and HBsAg clearance after therapy with peg-IFN
. Nowadays, it is unknown if these cases are more difficult to cure with standard therapies.
Third, the oral antiviral therapy is able to achieve and maintain virological suppression during long-term use. The most powerful combination of NAs, ETV and TDV, could provide additive or synergistic antiviral activity. Nevertheless, in a study of 379 NAs naïve patients with HBeAg positive and HBeAg negative CHB, the efficacy of ETV was comparable to that of ETV plus TDF combination, in term of HBsAg loss and rate of anti-HBe seroconversion
. However, specific data concerning the response to treatment (both with IFN and NAs) of CHB with concurrent HBsAg/HBsAb are lacking, and, from most of clinical studies, results can not even be extrapolated.
Moreover, our patient experienced a seroreversion from HBeAg-negativity/anti-HBe positivity to HBeAg positivity. The appearance and disappearance of HBeAg may be related to the alternating balance of the host immune control over the viral replication, and it could not be excluded that subtle changes in the composition of HBV quasispecies were responsible for the processes of HBeAg seroconversion and seroreversion, as well as for the HBsAg/HBsAb coexistence
The virological findings associated with this case remain so far unexplained. It is possible that genome alterations were present in regions different from those analysed in the study. For this reason, the sequencing of the whole genome would have been probably more informative. Furthermore it is possible that host-associated factors (i.e. immunological competence, innate immunity response, gene polymorphisms associated with poor control of chronic viral infections) may be responsible for the anomalous response pattern observed in this patient.
Finally, we cannot exclude the coexistence of minor mutant strains, not detected by UDPS in serum, that could have been found in the liver or leukocytes.
This is, to our knowledge, the first case described of a CHB with HBsAg/HBsAb positivity, wild type for mutations clinically relevant in HBsAg and rt ORFs, successfully treated with a combination of NAs.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.