In the present case anti-HBc was the only detectable HBV marker (“anti-HBc only status” [15, 16]) between October 2003 and October 2007. The HBV DNA fluctuated between 10 to 357 IU/ml, indicating an occult chronic HBV infection. Several explanations have been declared for ‘anti-HBc only’ status, including false positive detection of anti-HBc, low replication level of HBV, HBV mutations, coinfection with other viruses and formation of HBsAg-anti-HBs immune complexes . Anti-HBc only serostatus has been described frequently among individuals coinfected with HIV or hepatitis C virus (HCV) infection [18, 19]. It is advised to monitor such patients at regular intervals by HBV serology [15, 20] and the HBV DNA should be investigated in case of elevated transaminases .
Although about 17-42% of patients coinfected with HIV/HBV have anti-HBc only, there are few reports on the reactivation of HBV in these patients [20, 21]. Previously, Chamorro et al. reported on a reactivation of HBV after the removal of lamivudine in an HIV-infected patient with anti-HBc as the only serological marker . In the present case, the reactivation of HBV occurred spontaneously in a patient with a stable CD4+ T cell count who had not received antiretroviral drugs for years before the hepatic flare. An interesting finding is that the K to R mutation at s122 occurred during the flare-up phase and led to the change of the HBV serotype from adw to ayw. Most of the other aa substitution in the HBsAg found during the flare-up phase described here have been reported before and in combination with the K122R mutation, possibly causing HBV escape from anti-HBs. Amino acid substitutions, which change the hydrophilicity, the electrical charge or the acidity could change the conformation of the a-determinant . M133I and D144E mutation were reported to cause a reduced HBsAg affinity to anti-HBs [24, 25]. F134V mutation was supposed to be a vaccine induced escape mutant  and L175S mutation was found in patients with HBsAg-anti-HBs coexistence . The replication competence of HBV strains from different time points need to be compared.
The question was raised whether the hepatitis flare in this patient could be interpreted as a superinfection. However, this patient was constantly positive for HBV DNA for many years. The sequence analysis revealed that the HBV preC/C region was strictly conserved during the course of infection, an evidence preferably for reactivation. Another point for dispute is the fact that there was no obvious pressure by anti-HBs responses for the selection of escape mutations. However, Weinberger et al.  indicated that the variability of the major hydrophilic loop of HBsAg was raised significantly in individuals with anti-HBc only compared with HBsAg positive individuals. The patient in this study was positive for anti-HBc only for a long period and represents a typical case of such status. The anti-HBc only status during the chronic phase might be due to the control of HBV replication by the immune surveillance and/or due to the detection escape mutation that may occurred early in the chronic phase. The mutations may have accumulated under these pressures and became the dominant strain. In addition, it is possible that the patient had a low anti-HBs response which remained under the detection limit due to HIV infection. We also detected anti-HBc IgM in the patient during chronic HBV infection and in the flare-up phase. Although normally the appearance of anti-HBc IgM indicates a new infection, it may also be detected during HBV reactivation [29, 30]. Therefore, we could not completely rule out the possibility of superinfection but do not have evidence favoring this hypothesis.
Before the hepatitis flare, the patient did not receive any antiviral treatment, immunosuppressive therapy, or radiation treatment, which may be related to HBV reactivation [31, 32]. It seems that the reactivation happened spontaneously. The accumulation and selection of HBV escape mutants might be one important factor. On the other hand, the immune suppression caused by HIV infection probably also played a role in HBV reactivation. Previously, interleukin-6 (IL-6) was proven to serve as the main bystander mediator of radiotherapy induced HBV replication and IL-6 and radiotherapy have synergistic effect . However, it is not clear whether the cytokine profile was changed in this patient and related to the reactivation.
In conclusion, we reported on a case of spontaneous HBV reactivation in an HIV coinfected patient with isolated anti-HBc, in which the escape mutants in s gene might be responsible for the flare-up. Continued monitoring of the patient with respect to HIV and HBV is necessary for recognizing a possible re-flare of the HBV infection. Retrospectively, the reactivation of HBV might already have been diagnosed in August 2007 when HBsAg and HBV DNA tested positive as indicated from Table 1.