**2.2 Prevention of HBV recurrence after LT**

238 Liver Transplantation – Basic Issues

discovered that ADV lacks cross-resistance with LAM and can be used as a rescue therapy in LAM-resistant patients. However, it was also reported that to avoid sequential resistance to ADV (resistance develops only if LAM is stopped), it is better to add ADV to LAM than to switch LAM on ADV (Villeneuve et al., 2003). In very sick patients who would not be able to tolerate hepatic flares related to the selection of resistant strains, the best option is to use *de novo* combination of LAM and ADV. In case of resistance to ADV (cumulative probability

**Preferred management** 

• add or switch to tenofovir or tenofovir + emtricitabine

• add or switch to tenofovir or tenofovir + emtricitabine

• add or switch to entecavir

• or tenofovir + emtricitabine

• add or switch to tenofovir • or tenofovir + emtricitabine

• add adefovir

• or tenofovir

appr. 2% in 2 years), the best option is to add LAM, telbivudine or entecavir.

telbivudine rtM204I • add adefovir

plus rtI169T and rtM250V or rtT184G and rtS202I

tenofovir none ?

Table 4. HBV mutations associated with drug resistance and rescue treatment options

Entecavir, launched in 2005, is a very potent and well tolerated nucleoside analogue with a high genetic barrier of resistance. Used as a first line therapy in a daily dose of 0.5mg dramatically reduces HBV DNA viremia within a few weeks irrespectively on HBeAg status, and currently is a drug of choice in the naïve patients with decompensated HBVrelated cirrhosis. Results obtained at 5 years of treatment showed practically negligible resistance rate (Colonno et al., 2006). However, in LAM-resistant patients the efficacy of entecavir is markedly reduced even at higher doses (1 mg daily), and resistance develops in more than one third of patients after 4-year treatment (Sherman et al., 2006). It can be explained by a selection of rtM204V/I mutants already being developed during LAM treatment and less susceptible to entecavir in comparison with wild-type HBV, and the emergence of another mutation at codons 184, 202 and 250 under entecavir pressure (Table 4). If at least three mutations develop together, a viral breakthrough occurs. Therefore, entecavir should not be used as a rescue therapy in LAM-resistant (or telbivudine-resistant) patients. Such sequence may select for multidrug resistant virus. In case of entecavir resistance the only possibility is to add (better than to switch on!) adefovir or tenofovir.

Tenofovir alone or in combination with emtricitabine is a nucleotide analogue successfully used in HIV-positive patients. In HIV/HBV coinfection it also showed high potency against HBV virus. To date resistant strains have not been discovered. In comparison with ADV it is far more potent and can be used as a rescue therapy in the majority of resistance situations.

**NUC Primary antiviral resistant mutation** 

rtA181T

rtN236T rtI233V\*

entecavir rtL180M and rtM204V

lamivudine rtM204V/I

adefovir rtA181V/T

\*primary non-response

Two-three decades ago HBV recurrence after liver transplantation was very frequent. Although HBV replicates almost exclusively in hepatocytes, reinfection can be caused by the circulating HBV particles or, less frequently, by HBV harvested from peripheral blood mononuclear cells. A good evidence for that was a close relation of reinfection risk with the pre-transplant viral load. Viremic patients developed reinfection almost inevitably. The course of recurrent HBV hepatitis was accelerated in comparison with HBV infection in nontransplant setting resulting in liver failure and premature death in the majority of patients. It could be explained by high doses of steroids, routinely included to the immunosuppression protocol in all transplanted patients (there is a glucocorticoid-susceptible element in HBV genome), loss of immune control over HBV replication together with a potent immunosuppression and sudden availability of new hepatocytes for viral replication. Due to the very poor results, retransplantation for recurrent HBV infection was performed reluctantly and in many transplant centers was contraindicated. There was a new histological finding in recurrent HBV reinfection characterized by cholestasis, marked inflammation and fibrosis, described as fibrosing cholestatic hepatitis (FCH). This particular form of reinfection, believed to be a direct cytopathic effect of HBV on hepatocytes, resulted in rapid development of hepatic decompensation and death, usually within one year post-LT (Lau et al., 1992). Before implementation of successful strategies to prevent reinfection, it was reasonable to withdraw steroids from immune suppression in HBV-positive patients or maintain them at a low dose, and to reduce immunosuppression strength to the lowest possible levels. There was no evidence that any of CNI inhibitors had an advantage or disadvantage in this particular group of recipients by stimulating or suppressing HBV replication (McMillan et al., 1995). Neither it was confirmed for mycophenolate mofetil (Maes et al., 2001). Rather the overall potency compromising immune system mattered. New approaches were essential to change these disappointing results and to make transplantation of HBV-related end-stage liver disease an acceptable procedure.

The first change came together with the use of human immune globulin containing high titers of anti-HBsAg antibodies (HBIG) to neutralize circulating virions and to prevent virus entry to the hepatocytes. Different schedules were used (Table 5), but it was soon proved that HBIG started at the anhepatic phase in a dose of 10 000 IU followed by high doses during the first days after transplantation (10 000 IU daily for a week) and administered long-term thereafter to maintain anti-HBs titer >100 IU/L was associated with a significant reduction risk of recurrence from 74 to 36% and far better prognosis (Samuel et al., 1993). The question arose why HBIG was not effective in all patients, but the answer is not entirely clear. Some centers tried to overcome this problem by administering larger and more frequent doses of HBIG in order to keep anti-HBs titer above 500 IU/L, but the costs of such approach were extremely high. Moreover, it was noticed that long-term use of HBIG results in selection of the escape mutants. Mutations occur in the coding region of 'a' determinant of the surface protein. In such cases vaccination failure is also present. Protective threshold of anti-HBs was not established. Some transplant teams preferred keeping anti-HBs at a level of 500 IU/L, whereas others accepted 300 IU/L or titers as low as 100 IU/L. A schedule of administration was either fixed (i.e. 2000 IU monthly or 5000 IU every second month) or individualized (on-demand) according to the anti-HBs titer. With HBIG monotherapy,


Table 5. Different HBIG protocols and recurrence rate

long-term thereafter to maintain anti-HBs titer >100 IU/L was associated with a significant reduction risk of recurrence from 74 to 36% and far better prognosis (Samuel et al., 1993). The question arose why HBIG was not effective in all patients, but the answer is not entirely clear. Some centers tried to overcome this problem by administering larger and more frequent doses of HBIG in order to keep anti-HBs titer above 500 IU/L, but the costs of such approach were extremely high. Moreover, it was noticed that long-term use of HBIG results in selection of the escape mutants. Mutations occur in the coding region of 'a' determinant of the surface protein. In such cases vaccination failure is also present. Protective threshold of anti-HBs was not established. Some transplant teams preferred keeping anti-HBs at a level of 500 IU/L, whereas others accepted 300 IU/L or titers as low as 100 IU/L. A schedule of administration was either fixed (i.e. 2000 IU monthly or 5000 IU every second month) or individualized (on-demand) according to the anti-HBs titer. With HBIG monotherapy,

**Type of HBIG Lead-in dose Maintenance dose Recurrence** 

10 000 IU monthly 0

5 000 IU monthly 4%

9.5%, only in LAMresistant patients

20%, only in LAMresistant patients

8%, mostly in LAMresistant patients

18%, only in LAMresistant patients

5.7%, only in LAMresistant patients

3.6%

To keep anti-HBs > 500 IU/L for the second week and > 100 IU/L thereafter

To keep anti-HBs >

To keep anti-HBs >

1 200 IU monthly to keep > 100 IU/L

To keep anti-HBs >

800 IU monthly 3.1%

800 IU monthly 14%

800 IU monthly 4%

2 000 IU to keep anti-HBs > 100 IU/L

100 IU/L

100 IU/L

100 IU/L

10 000 IU at LT followed by 10 000 IU daily for 7 days (80 000 IU in the first

46 500 IU in the first

40 000 IU in the first

10 000 IU daily until anti-HBs > 1000

10 000 IU daily until HBsAg is cleared

80 000 IU in the first

800 IU at LT and daily for one week

80 000 IU iv. in the first week post-LT

4 000 IU at LT and then 2 000 daily until anti-HBs > 200 IU/L

2 000 IU at LT and 800 IU daily for 6 days, weekly for 3

800 IU at LT and daily for 6 days

month)

High-dose (iv.)

Low- dose (im.)

HBIG

HBIG

month

week

IU/L

month

weeks

Table 5. Different HBIG protocols and recurrence rate

however the recurrence rate was high when HBV DNA was detectable in blood at the time of transplantation. Lower recurrence was observed in negative HBV DNA patients, in the concomitant delta virus infection and in fulminant B hepatitis.

High costs of HBIG, the necessity of frequent testing and inconvenient immune globulin administration led transplant centers to study some other options. Early results with lamivudine showing recurrence rate of 10% at the first year post-LT were very promising and gave hope to abandon costly immunoprophylaxis, but further observations were less enthusiastic, as 43-50% of patients developed recurrence within 3 years after LT largely due to cumulative LAM-resistance and high pre-transplant viral load [Mutimer et al., 1999; Perillo et al., 2001)]. Because monotherapy either with HBIG or with LAM was not satisfactory, a combination of these two agents was soon proposed. As both drugs have different mode of action and exert additive prophylactic effect, it was quickly proved that such strategy is very effective and prevents HBV recurrence in more than 90% of recipients. Combination of LAM with intravenous high dose anti-HBV immune globulin (IV HBIG) is currently a standard of care in terms of anti-HBV prophylaxis. LAM can be replaced with another NUC (or combination of NUCs), usually the one that was started before transplantation. Some centers try to reduce IV HBIG use by switching on the intramuscular formula or by administering HBIG only when anti-HBs titer falls below 10 IU/L. The latter approach turned out to be safe and no recurrence was noted despite low cumulative dose of HBIG. The authors suggested that in the concomitant use of NUC it is not necessary to keep anti-HBs at higher levels (Takaki et al., 2007). Recent publication from Australia and New Zealand on the efficacy of low-dose IM HBIG in combination with LAM is very promising and supports efforts to reduce high costs of anti-HBV prophylaxis. IM HBIG is given at a dose of 800 IU daily for 7 days post-transplant and in a dose of 400–800 IU monthly thereafter. With this strategy the rate of recurrence was only 4% at 5 years (Gane et al., 2007). The authors suggest that in case of low risk of recurrence (HBV-DNA < 2 000–20 000 IU/mL at baseline, HDV coinfection, fulminant hepatitis) HBIG can be withdrawn within one-two years post-LT with NUC to be continued life-long. In high recurrence risk (HBV-DNA > 2 000–20 000 IU/mL before treatment commence, history of drug resistance) IM HBIG in combination with NUC should be administered indefinitely. According to Gane et al. IM HBIG can be possibly replaced by the combination of two potent analogues. Further studies on this issue are warranted.

Another strategy to provide an effective anti-HBV prophylaxis without immunoglobulin administration is a vaccination program. The idea was to start active immunization at an anti-HBs titer around 100 IU/mL hoping to maintain this level after indefinite HBIG withdrawal. First generation vaccines did not prove to be useful. Some success has been achieved with the pre-S vaccines in lamivudine treated recipients. In one series anti-HBs response was obtained in 50% of vaccinated, two third of whom managed to maintain titers (Lo et al., 2007). Spontaneous antibody production was also noted in a small number of patients and development of a novel vaccine that is able to sustain that production would be of great importance.

#### **2.3 Management of** *de novo* **or recurrent HBV hepatitis**

As it was already mentioned, in the absence of an effective prevention, recurrent B hepatitis, defined as detectable HBsAg in blood after LT, occurs in a substantial proportion of patients preoperatively positive for HBsAg. In the nineties of the last century recurrence rate was reported to be as high as 70 to 90% among HBsAg-positive recipients (Lake & Wright, 1991). Nowadays these proportions are notably better and vary between 26 and 53%, possibly due to more accurate selection of HBV DNA negative candidates (Yeo et al., 2004). To a lesser extent HBsAg may reappear in circulation as a result of reactivation in patients with previously resolved infection, that is in HBsAg-negative but anti-HBc positive individuals. Berger et al. found reactivation in 0.9% of anti-HBc positive liver recipients, whereas other authors reported a bit higher risk of HBsAg reappearance reaching approximately 3% of transplant patients (Barclay et al., 2008). In addition to reactivation, *de novo* HBV infection following LT has been reported in HBsAg-negative individuals who received livers from anti-HBc-positive donors (Dickson et al., 1997; Prieto et al., 2001). Currently, livers from anti-HBc-positive donors can only be transplanted to the HBsAg-positive recipients or to the anti-HBc-positive recipients with high anti-HBs titers. The same applies to kidney donors and recipients. Anti-HBc-positive heart and lung donors do not pose a significant risk of HBV transmission. In most transplant centers there is a policy to administer pre-emptively one of the NUCs (usually lamivudine for at least one year post-LT) to the anti-HBc-positive recipient to prevent reactivation of an occult HBV infection. It is needless to say that harvesting organs from HBsAg-positive donors is not allowed.

However, post-LT HBV infection still occurs either as recurrent hepatitis B due to the unsuccessful prophylaxis or as *de novo* community acquired infection, but most frequently because of use of an organ from anti-HBc-positive/HBsAg-negative donor. In case of recurrent B hepatitis or newly acquired HBV infection recipients have to be treated promptly with one of the potent NUCs, preferably the one with high genetic barrier of resistance, i.e. entecavir or tenofovir (in LAM-experienced patients). Adefovir should be considered with caution as the potency of the drug is moderate and there are reports on nephrotoxicity. Antiviral therapy should be continued until the end-point is reached (preferably HBsAg loss and seroconversion to anti-HBs) or life-long. HBV-DNA level and aminotransferase activity should be monitored every 12 to 24 weeks to seek for primary non-response, partial virological response (HBV-DNA decrease >1 log but <2 logs without resistance) and virological breakthrough. In primary and partial non-response a rapid switch to another NUC is recommended. In case of genotypic resistance-related virological breakthrough (after excluding non-compliance) adding-on a second drug is the optimal strategy. Knowledge of cross-resistance patterns is obligatory (European Association for the Study of the Liver, 2009). Clinical experience with interferons in the recurrent or *de novo* hepatitis B in liver transplant recipients is scarce.

#### **3. References**


preoperatively positive for HBsAg. In the nineties of the last century recurrence rate was reported to be as high as 70 to 90% among HBsAg-positive recipients (Lake & Wright, 1991). Nowadays these proportions are notably better and vary between 26 and 53%, possibly due to more accurate selection of HBV DNA negative candidates (Yeo et al., 2004). To a lesser extent HBsAg may reappear in circulation as a result of reactivation in patients with previously resolved infection, that is in HBsAg-negative but anti-HBc positive individuals. Berger et al. found reactivation in 0.9% of anti-HBc positive liver recipients, whereas other authors reported a bit higher risk of HBsAg reappearance reaching approximately 3% of transplant patients (Barclay et al., 2008). In addition to reactivation, *de novo* HBV infection following LT has been reported in HBsAg-negative individuals who received livers from anti-HBc-positive donors (Dickson et al., 1997; Prieto et al., 2001). Currently, livers from anti-HBc-positive donors can only be transplanted to the HBsAg-positive recipients or to the anti-HBc-positive recipients with high anti-HBs titers. The same applies to kidney donors and recipients. Anti-HBc-positive heart and lung donors do not pose a significant risk of HBV transmission. In most transplant centers there is a policy to administer pre-emptively one of the NUCs (usually lamivudine for at least one year post-LT) to the anti-HBc-positive recipient to prevent reactivation of an occult HBV infection. It is needless to say that

However, post-LT HBV infection still occurs either as recurrent hepatitis B due to the unsuccessful prophylaxis or as *de novo* community acquired infection, but most frequently because of use of an organ from anti-HBc-positive/HBsAg-negative donor. In case of recurrent B hepatitis or newly acquired HBV infection recipients have to be treated promptly with one of the potent NUCs, preferably the one with high genetic barrier of resistance, i.e. entecavir or tenofovir (in LAM-experienced patients). Adefovir should be considered with caution as the potency of the drug is moderate and there are reports on nephrotoxicity. Antiviral therapy should be continued until the end-point is reached (preferably HBsAg loss and seroconversion to anti-HBs) or life-long. HBV-DNA level and aminotransferase activity should be monitored every 12 to 24 weeks to seek for primary non-response, partial virological response (HBV-DNA decrease >1 log but <2 logs without resistance) and virological breakthrough. In primary and partial non-response a rapid switch to another NUC is recommended. In case of genotypic resistance-related virological breakthrough (after excluding non-compliance) adding-on a second drug is the optimal strategy. Knowledge of cross-resistance patterns is obligatory (European Association for the Study of the Liver, 2009). Clinical experience with interferons in the recurrent or *de novo*

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