To the editor
The reactivation of resolved hepatitis B virus (HBV) infection termed reverse seroconversion (RS). HBV-RS is a complication after allogeneic stem cell transplantation (SCT) in patients exposed to hepatitis B virus. 1-4 Recently, Onozawa et al reported that HBV vaccination is effective in the prevention of HBV-RS after SCT 1, but there are limited data about RS of hepatitis B in long term SCT survivors. At our institute 15 of 103 patients with hematological disorders (14 leukemia or myelodysplastic syndrome, 1 severe apalstic anemia) receiving SCT from an HLA identical sibling and surviving 3 or more years, had a pre-transplant resolved HBV infection (negative HBsAg, positive anti-HBs and anti-HBc antibodies). Twelve (median age 39.5 years) had received total body irradiation (TBI)-based myeloablative SCT followed by a T-cell depleted peripheral blood stem cell transplantation (PBSCT) and three (median age 13 years) received a reduced-intensity regimen of fludarabine and cyclophosphamide, followed by PBSCT. All received cyclosporine as graft-verse-host disease (GVHD) prophylaxis. Eight developed acute GVHD, and 12 developed chronic GVHD, 8 of whom continued immunosuppressive therapy (IST) 3 years or more after SCT. Serologic HBV markers were followed serially (median follow-up 59 months, range 40-113).
The probability of developing HBV-RS post transplant in recipients with resolved pre-transplant HBV infection was 30%. Five patients, 3 of whom had received lamivudine, developed RS with reappearance of HBsAg, 21-101 (median 31) months after SCT. Three developed clinical hepatitis, which was successfully treated with lamivudine with decrease of HBV viral load after additional antiviral drugs in one. Of the 10 patients who did not have RS, 6 were vaccinated with HBV around 1 year post-transplant and 5 also received lamivudine prophylaxis starting 3 months post-transplant and continuing until anti-HBs antibody became positive. The median length of lamivudine prophylaxis time was 16.6 month. Six donors had been vaccinated for HBV or had resolved HBV infection pre-transplant. Two recipients of these donors developed RS (Table 1). Fourteen (93%) patients are alive (median follow-up 59 months). One patient with RS died with relapsed MDS, 59 months after SCT. There was no significant difference in the age, conditioning regimen, incidence of acute or chronic GVHD, nor duration of IST between RS and non RS patients.
Table 1.
Comparison of patients with and without HBV-RS.
| Variable | With HBV-RS | Without HBV-RS | P Value |
|---|---|---|---|
| Cases | 5 (33%) | 10 (67%) | |
|
| |||
| Age in years (median, range) | 45 (10-46) | 32(13-56) | 0.83 |
| Conditioning regimen | |||
| Myeloablative | 4/5 (80%) | 8/10 (80%) | 1.0 |
| Reduced intensity | 1/5 (20%) | 2/10 (20%) | 1.0 |
| aGVHD | 1/5 (20%) | 7/10 (70%) | 0.12 |
| Grade II-IV aGVHD | 1/5 (20%) | 1/10 (10%) | 1.0 |
| cGVHD | 4/5 (80%) | 8/10 (80%) | 1.0 |
| Extensive cGVHD | 1/5 (20%) | 1/10 (10%) | 1.0 |
| IST for cGVHD >3 years | 3/5 (60%) | 5/10 (50%) | 1.0 |
| Lamivudine Treatment | 3/5 (60%) | - | |
| Lamivudine Prophylaxis | 0 | 5/10 (50%) | |
| HBV Vaccine after SCT | 0 | 6/10 (60%) | |
| Donors with vaccination of HBV | 1/5 (20%) | 1/10 (10%) | 1.0 |
| Donors with resolved HBV infection | 1/5(20%) | 3/10 (30%) | 1.0 |
| RS of HBV in months (median, range) | 31 (21-101) | - | |
| Follow-up in months (median, range) | 59(55-105) | 57.5 (40-113) | 0.37 |
RS: reverse seroconversion; HBV: hepatitis B virus; aGVHD: acute GVHD; cGVHD: chronic GVHD; IST: immunosuppressive therapy; *also received HBV vaccination.
The frequency of RS in our series was within the range of 14-50% reported1-3, 6. However the median time to RS was longer (29 months vs19 months (range 6-72 months)2, 4. Variations may be attributable to different immunosuppressive regimens or different incidence and severity of chronic GVHD. The presence of chronic GVHD may result in earlier onset of RS 3, 7, but this was not a significant factor in our small series. These results emphasize the need for continued monitoring for HBV RS in patients at risk, especially those receiving prolonged IST 2. Prophylactic vaccination with hepatitis B vaccine for patients with pre-transplant resolved HBV infection is recommended beginning 1year post-transplant or after withdrawal of IST 1, and hepatitis B vaccination of the donor may help to prevent RS by passive transfer of immunity against HBV to the SCT recipients 8, although neither prior HBV infection nor vaccination is completely protective as we also found 6. Therefore, the recipient should also receive early post-transplant vaccination following donor Hepatitis B vaccination. Although lamivudine prophylaxis can prevent RS of HBV, it is unknown at what stage prophylaxis can be discontinued9 and fatal fulminant hepatitis B has occurred after withdrawal of lamivudine in SCT patients 9.
Since 2004, our policy for patients with positive anti-HBc antibody before SCT, is to give lamivudine 100mg/day, within 3 months post-transplant, vaccinate around 1 year post SCT and continue lamivudine until the anti-HBs antibody becomes positive. HBV reactivation is monitored at regular intervals by testing HBsAg, HBV-DNA, anti-HBs and anti-HBc antibodies. Anti-viral therapy e.g. lamivudine therapy should be considered early in patients positive for HBV-DNA, additionally newer anti-HBV agents like adefovir, entecavir, telbivudine and tenofovir, could be used if lamivudine resistance occurs.
In conclusion RS of HBV post SCT is a significant long-term complication in patients with pre-transplant resolved HBV infection. Our study emphasizes the importance of post-transplant prophylaxis with lamivudine, hepatitis B vaccine, long-term hepatitis B serologic monitoring, and prompt initiation of lamivudine treatment if HBV-RS occurs.
Footnotes
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References
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