Reactivation of overt and occult hepatitis B infection in various immunosuppressive settings

Abstract

The aim of the study was to evaluate clinical and virological differences in HBV reactivation between patients with overt and occult HBV infection. Twenty-three consecutive patients with symptomatic HBV reactivation occurring during or after immunosuppressive therapy were enrolled in a retrospective study: 10 with reactivation of overt HBV infection (overt group) and 13 of occult HBV infection (occult group). Twenty-one patients were treated with nucleot(s)ide analogues after HBV reactivation. Regimens including rituximab or fludarabine were administered more frequently in the occult group (61% vs. 31%, respectively). HBV reactivation was severe frequently in the overt (40%) and occult groups (38.4%). Patients in the overt group showed higher HBV-DNA titers (1.1 × 10(8) ± 1.4 × 10(8) vs. 5.1 × 10(5) ± 6.8 × 10(5) IU; P < 0.005). Seven patients died during HBV reactivation, two in the overt and five in the occult group. Of these seven patients, two remained untreated and five had been treated with Lamivudine; of the 16 patients showing remission of HBV reactivation, four had been treated with Lamivudine, four with Entecavir, two with Telbivudine, and six with Lamivudine plus Adefovir. It is concluded that HBV reactivation is life-threatening in patients with diseases inhibiting the immune response and/or receiving immunosuppressive drugs. Supportive therapy without antiviral drugs or Lamivudine monotherapy may not be effective for treating patients with HBV reactivation.

Clinical impact of occult hepatitis B virus infection in immunosuppressed patients

“…Reactivation of HBV infection in patients under immunosuppressive treatment is a well-known, life-threatening event described in HBsAg-positive patients (overt HBV infection) and in subjects with OBI [20,21,[42][43][44][45][46][47][48][49][50] . The reactivation of HBV infection, overt or occult, is characterized by a marked enhancement of viral replication during immunosuppressive therapy, with a wide spread of HBV to uninfected hepatocytes and a substantial increase in the HBV DNA serum level followed by the restoration of the immune function after treatment withdrawal and consequent cytotoxic-T-cell-mediated necrosis of HBVinfected hepatocytes usually responsible for a hepatic flare and in some instances for liver failure and even death [42] .…”

“…Both in overt and occult infection the risk of HBV reactivation is estimated as high when immunosuppression is marked, particularly in onco-hematological patients (21%-67%), in those receiving hematopoietic stem cell transplantation and in those treated with the anti-CD20 monoclonal antibody rituximab or with the monoclonal anti-CD52 antibody alemtuzumab, both responsible for profound, long-lasting immunosuppression [20,21,43,[51][52][53][54][55][56][57][58][59] . Under these conditions HBV reactivation has a mortality rate close to 20%, due to a hepatic failure or to the progression of the underlying disease due to the discontinuation of specific treatment [51,60,61] .…”

“…A precore stop mutation (A1896) was detected in one patient with genotype Bj who developed fulminant liver failure [63] . Also sub-genotype D1 has been described as possibly associated with HBV reactivation in two studies, one from Egypt and one from Italy [21,64] . There is general agreement for the use of nucleos(t)ide analogues to prevent HBV reactivation in HBsAgpositive immunosuppressed patients, whereas it is still a matter of debate whether subjects with occult HBV infection should be treated or closely monitored for early treatment once HBsAg positivity has developed.…”

“…The drugs commonly responsible for HBV reactivation are those used in hematological malignancy, such as fludarabine, anthracyclines, high dose corticosteroids [51,52] and, more recently, rituximab (anti-CD20) and alemtuzumab (anti-CD52) [53] . Evidence has become available in hematological malignancy that the reactivation of occult HBV infection is frequent in patients treated with rituximab or fludarabine in the absence of lamivudine prophylaxis [21,60,61] . However, due to the retrospective nature of most studies published, the geographical differences in HBV epidemiology and the genetic differences in HBV and the host have not been investigated, and the prevalence of HBV reactivation varies widely (from 3% to 45%) [21,48,52,[65][66][67][68][69] .…”

“…OBI has also been described as a serological condition characterized by the presence of hepatitis B core antigen (anti-HBc) in the absence of HBsAg and anti-HBs (isolated anti-HBc) [7,[11][12][13][14][15] . OBI may be observed in the window period of acute HBV infection [16] in blood donors and in recipients of blood and blood products [9,17,18] , in patients with HCV chronic infection [7,19] , in cryptogenic chronic hepatitis, in patients under pharmacological suppression of the immune system [20,21] and in those with immunodepression due to HIV infection; it has also been associated to the development of hepatocellular carcinoma [22][23][24][25][26][27][28][29][30] . It has been shown that the hepatitis B virus maintains its pro-oncogenic properties in OBI [31] and that its presence in patients with chronic hepatitis C is associated with a higher risk of disease progression and HCC development [32][33][34][35][36] and with a reduced response to alfa interferon treatment [37][38][39] .…”