The appearance of antibodies to hepatitis B surface antigen (HBsAb) and core antigen (HBsAb) has been considered as serological evidence of resolved infection with the clearance of hepatitis B virus (HBV). HBV serology is dynamic, however, and loss of immunity with the reappearance of HBV surface antigen (HBsAg) has been documented. This phenomenon has been termed reverse seroconversion; its significance in HIV-positive patients is unknown.
We describe the largest case series in the literature of six patients with hepatitis B virus reverse seroconversion from our HIV Atlanta Veterans' Affairs Cohort Study. We found 1957 patients from the cohort study in whom HBV serologies were available; 696 (36%) were exposed and immune. It is not clear why 229 patients had repeat serologies determined despite being exposed and immune to HBV; six underwent reverse seroconversion, accounting for 0.019 cases per 100 person-years.
Using the Medline search engine with the following search words ‘hepatitis B’ and ‘HIV’ combined with either ‘reverse seroconversion’, ‘reactivation’, ‘reinfection’ or ‘markers’, we found 18 case reports published in 13 articles [1–13]. We analysed the data on all 24 patients and describe the clinical features related to reverse seroconversion in HIV patients (Table 1). We included all these cases even though some of them lacked complete clinical data. When available, the following parameters before and after reverse seroconversion were collected: CD4 cell count, CD4 cell percentage, HIV viral load, HIV therapy, liver transaminases (aspartate transaminase, normal range 8–40 IU/l; alanine transaminase, normal range 3–36 IU/l), HBsAg, HBsAb, HBcAb, hepatitis B e antigen, antibody to hepatitis B e antigen, HBV viral load (HBV DNA) and hepatitis A, C and D serologies. A change in the CD4 cell count was defined as a change by 30% in the total CD4 cell count or more than a 3% change in the CD4 cell percentage.
All but four patients had a positive confirmatory HBV DNA. All patients were men. The median age was 43 years (19–80). Death occurred in two cases (8%) as a result of HBV flare. Three out of 14 (21%) had a positive serology for hepatitis C and only one out of 16 (6%) had hepatitis D. Elevated transaminases were observed in 13 out of 21 patients (62%). Nine out of 20 patients (45%) had a decline in the CD4 cell count, six out of 20 (30%) had no change and five out of 20 (25%) had increasing CD4 cell counts at the time of reverse seroconversion when compared with previous CD4 cell numbers and percentages obtained when the HBsAg was last negative. In our case series, the HIV viral load varied between 184 and 482 000 copies/ml. We found one report of reverse seroconversion after lamivudine withdrawal  and another similar case in our series. Only one patient from our series had reverse seroconversion 2 months after tenofovir withdrawal. None of the patients were on emtricitabine. Reverse seroconversion occurred in one patient while on lamivudine for more than 2 years, suggesting possible HBV resistance to lamivudine. Among the patients who underwent reverse seroconversion, three were on hemodialysis, one patient was on steroids and no patient was on chemotherapy or other immunosuppressants.
Our rate of HBV reverse seroconversion (0.019 cases/100 person-years) is lower than observed in other studies (0.2 cases/100 patient-years) [9,11]. Not all of our HBV naturally immune patients underwent repeated serology and the repeated serologies were not performed at a standard interval. More frequent serological testing may have resulted in our detecting a higher rate of reverse seroconversion.
Several mechanisms have been postulated to explain the phenomenon of reverse seroconversion: reinfection, low levels of HBV replication and the failure of immune surveillance.
The most intuitive theory is reinfection . This could not be excluded in any of our patients but was ruled out by others . Immunity to HBV is, however, against various epitopes and therefore should protect from other subsequent HBV subtype infections.
HBV reactivation is another explanation for reverse seroconversion. Low levels of HBV replication in the serum or liver with negative HBsAg  is a well-described entity. Studies have shown [16,17] a detectable HBV DNA in 20% of HIV patients naturally immune to HBV. Despite being low, this level of replication (< 10 000 copies/ml) has a clinical significance in the settings of blood transfusion , organ donation  and the development of hepatocellular carcinoma .
It is also thought that resolution of acute HBV infection does not necessarily indicate eradication of infection but rather the control of residual virus particles by an efficient and persistent immune response . Both T and B-cell functions are altered in HIV infection. In the overall series, reverse seroconversion occurred in the setting of worsening CD4 cell counts in nine out of 20 patients and another three patients with a CD4 cell count of less than 100 cells/μl. HIV viral load was not suppressed in any of the six patients in our case series. The phenomenon of reverse seroconversion has also been described in transplant patients , another group with T-cell abnormalities. Waning humoral immunity to HBV in HIV patients has also been documented in studies [23,24].
A further complication of serological interpretation could be the decreased sensitivity of HBsAg in patients with mutations in the ‘a’ determinant, the main target of HBsAb. This could result from a virus selection process causing an escape from the host's immune system  and a reduction in the sensitivity of the HBsAg assays because of the S protein becoming less immunoreactive with the commercial assays . It is also possible that the inability to detect HBsAg is caused by the binding of all HBsAg to HBsAb in the form of circulating immune complexes .
The control of HBV replication relies not only on an intact immune system but also on anti-HBV therapy. The appearance of reverse seroconversion after failure or interruption of lamivudine, emtricitabine or tenofovir needs to be considered. Lamivudine-resistant mutations develop commonly after lamivudine use in HIV-positive patients , and could explain reverse seroconversion in patient no. 5.
The diagnosis of reverse seroconversion should be considered in any HIV patient who has immunity to HBV. Serial testing may be needed in HIV patients with unexplained elevated transaminases, HIV virological failure, hemodialysis, immunosuppressive drugs or with the prolonged use or discontinuation of anti-HBV-specific therapy. Prospective studies are needed to assess the magnitude of HBV reverse seroconversion in HIV.
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