**2.1 Pre-transplant HBV management**

There are a few therapeutic options in chronic hepatitis B including indirectly acting interferons and directly acting anti-HBV molecules such as nucleotide/nucleoside analogues. Interferons were the first drugs used for this indication, but limited efficacy and poor tolerability in cirrhotic patients hampered successful management of HBV-related liver decompensation and preparation for LT for many years. Chronic HBV infection in the replicative phase was considered by many transplant teams a contraindication for transplantation because of a great risk of recurrence under immunosuppression. A turning point was discovery of the first potent viral polymerase inhibitor that allowed effective HBV suppression and clinical improvement, and in consequence permitted LT. Without LT survival in HBV-related decompensated cirrhosis is very poor and does not exceed 14% at 5 years (Zoulim et al., 2008). Independent factors associated with survival are hepatitis B e antigen (HBeAg) positivity, bilirubin level, age, transaminase activity, presence of oesophageal varices and Child-Pugh score (Zoulim et al. 2008). In another study in addition to age, bilirubin and HBeAg status, platelet count, albumin level and splenomegaly were found to be significantly related to survival. In patients with signs and symptoms of decompensation (jaundice, increased bilirubin, low albumin level, low platelet count, prothrombin time prolongation), use of interferon alpha was associated with further deterioration and high risk of life-threatening flares in case of a minimal hepatic reserve. Its use was therefore restricted to experienced centers and was generally contraindicated. Notable improvement has been achieved in the recent years together with introduction of lamivudine (LAM), the first nucleoside analogue inhibiting HBV DNA polymerase, followed by the availability of new potent drugs with direct antiviral effect. In some patients excellent replication control and clinical stabilization allow removal from the waiting list. But these treatments do not eradicate HBV infection. HBV DNA polymerase can be suppressed and viremia effectively controlled only when patients take medications. As soon as treatment is stopped (or the patient is not compliant), the virus recurs in blood in most cases. That means the necessity for life-long treatment to maintain viral suppression and counteract decompensation.

The major concern connected with prolonged HBV therapy is a risk of drug resistance. Knowledge of the past antiviral treatment (if relevant), baseline parameters and patterns of mutations conferring resistance is essential in the management of candidates for LT. Patients require careful monitoring and prompt interventions as soon as resistance emerges. Determination of pretreatment HBV-DNA level is obligatory, because this value will be used for further comparisons and treatment efficacy evaluation. Quantitative HBV-DNA testing should be repeated in three to six month intervals, preferably using the same diagnostic assay. Primary non-response to treatment is defined by HBV-DNA decrease below 1 log after 24 weeks of a given therapy. Patients with primary failure require prompt switch to an alternative treatment. Increase in serum HBV-DNA level by at least 1 log above nadir is defined as virological resistance (or viral breakthrough). This can be related to genotypic resistance which means emergence of amino acid substitutions in the reverse transcriptase region of HBV polymerase gene during treatment. Suspicion of mutations conferring resistance require confirmation with genotypic testing, especially as the main reason for viral breakthrough is medication non-compliance and should be considered in the first instance to avoid unnecessary modification in therapy. If the patient denies medication negligence, one of the tests for the detection of resistant mutants should be ordered and if antiviral resistance confirmed, a rescue therapy has to be implemented (Table 4). If it is not done in time, clinical (or biochemical) resistance, defined as a significant liver enzymes elevation on treatment, can occur within months to years after development of polymerase gene mutations. It can be potentially life-threatening in patients with decompensated cirrhosis, and should be strictly avoided.

A question is when and with which drug to initiate antiviral treatment in patients awaiting LT to avoid prolonged administration and development of drug resistance. There is a consensus panel agreement that each patient with HBV DNA > 2000 IU/mL is in danger of disease progression and HCC development, therefore requires antiviral treatment (Chen et al., 2006; Iloeje et al., 2006). It is especially relevant in patients with liver cirrhosis, as viral suppression may lead to significant clinical improvement and withdrawal from transplant waiting list. It is also commonly accepted that in decompensated cirrhosis any HBV viremia preceding transplantation is harmful and should be treated. If a patient is HBV DNA repeatedly negative by one of commercially available sensitive PCR assays, they can be commenced on antiviral therapy at the time of transplantation.

Therapeutic decision should be based on drug potency and high genetic barrier to resistance. Several oral NUCs with different antiviral properties are currently available and can be considered for treatment (Table 3).


Table 3. Antivirals against hepatitis B virus

236 Liver Transplantation – Basic Issues

decompensation (jaundice, increased bilirubin, low albumin level, low platelet count, prothrombin time prolongation), use of interferon alpha was associated with further deterioration and high risk of life-threatening flares in case of a minimal hepatic reserve. Its use was therefore restricted to experienced centers and was generally contraindicated. Notable improvement has been achieved in the recent years together with introduction of lamivudine (LAM), the first nucleoside analogue inhibiting HBV DNA polymerase, followed by the availability of new potent drugs with direct antiviral effect. In some patients excellent replication control and clinical stabilization allow removal from the waiting list. But these treatments do not eradicate HBV infection. HBV DNA polymerase can be suppressed and viremia effectively controlled only when patients take medications. As soon as treatment is stopped (or the patient is not compliant), the virus recurs in blood in most cases. That means the necessity for life-long treatment to maintain viral suppression and

The major concern connected with prolonged HBV therapy is a risk of drug resistance. Knowledge of the past antiviral treatment (if relevant), baseline parameters and patterns of mutations conferring resistance is essential in the management of candidates for LT. Patients require careful monitoring and prompt interventions as soon as resistance emerges. Determination of pretreatment HBV-DNA level is obligatory, because this value will be used for further comparisons and treatment efficacy evaluation. Quantitative HBV-DNA testing should be repeated in three to six month intervals, preferably using the same diagnostic assay. Primary non-response to treatment is defined by HBV-DNA decrease below 1 log after 24 weeks of a given therapy. Patients with primary failure require prompt switch to an alternative treatment. Increase in serum HBV-DNA level by at least 1 log above nadir is defined as virological resistance (or viral breakthrough). This can be related to genotypic resistance which means emergence of amino acid substitutions in the reverse transcriptase region of HBV polymerase gene during treatment. Suspicion of mutations conferring resistance require confirmation with genotypic testing, especially as the main reason for viral breakthrough is medication non-compliance and should be considered in the first instance to avoid unnecessary modification in therapy. If the patient denies medication negligence, one of the tests for the detection of resistant mutants should be ordered and if antiviral resistance confirmed, a rescue therapy has to be implemented (Table 4). If it is not done in time, clinical (or biochemical) resistance, defined as a significant liver enzymes elevation on treatment, can occur within months to years after development of polymerase gene mutations. It can be potentially life-threatening in patients with

A question is when and with which drug to initiate antiviral treatment in patients awaiting LT to avoid prolonged administration and development of drug resistance. There is a consensus panel agreement that each patient with HBV DNA > 2000 IU/mL is in danger of disease progression and HCC development, therefore requires antiviral treatment (Chen et al., 2006; Iloeje et al., 2006). It is especially relevant in patients with liver cirrhosis, as viral suppression may lead to significant clinical improvement and withdrawal from transplant waiting list. It is also commonly accepted that in decompensated cirrhosis any HBV viremia preceding transplantation is harmful and should be treated. If a patient is HBV DNA repeatedly negative by one of commercially available sensitive PCR assays, they can be

counteract decompensation.

decompensated cirrhosis, and should be strictly avoided.

commenced on antiviral therapy at the time of transplantation.

Careful consideration of the past medical history, resistance pattern (if detected) and crossresistance data is mandatory (Table 4). Lamivudine was the first NUC used in patients with decompensated cirrhosis, initially with a great success. It is a relatively cheap, very well tolerated and potent drug showing effective suppression of HBV viremia within a few weeks of treatment. It improves hepatic function in more than a half of patients with decompensated cirrhosis within the first year of treatment and is associated with better survival. Usual daily dose is 100–150 mg. A significant disadvantage is a low genetic barrier of resistance making long-term treatment with LAM impossible in a considerable number of patients. It was shown that drug-resistant mutants emerge in 20% of patients treated with LAM per year. Therapy with LAM requires frequent determinations of HBV viremia, preferably every three months, and prompt initiation of rescue therapy in case of genetic breakthrough (Table 4). LT performed in patients on lamivudine with LAM resistance mutations can give inferior results and should be avoided (Perillo et al., 2001).

Another disadvantage is cross-resistance with other NUCs, considerably limiting rescue treatment options. Albeit LAM provided an important progress in LT for hepatitis B, now it is not indicated as a first line therapy in decompensated cirrhosis type B. The same concerns telbivudine, another L-nucleoside, which is even more potent than LAM, but relatively quickly selects for mutations at the same sites as LAM and entecavir. For these reasons it is neither recommended as a first line therapy in cirrhotic patients nor as a rescue therapy in LAM or entecavir resistance.

Adefovir (ADV), a nucleotide analogue of adenosine monophosphate, is effective as a first line treatment of wild type HBV infection as well as a rescue therapy in LAM-resistant patients. It is a slowly acting molecule, and in some patients delayed decrease in viremia can be mistaken with a primary non response to treatment or with a breakthrough if the baseline HBV DNA level was not determined. Its use as a drug of choice in decompensated cirrhosis is limited due to a relatively weak inhibition of HBV DNA polymerase and slow viral suppression at the approved dose (10 mg daily). A potential nephrotoxicity also limits indication for ADV in patients with cirrhosis and concomitant renal insufficiency. Dose adjustment in case of renal impairment is necessary. Despite a few disadvantages, it was 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 appr. 2% in 2 years), the best option is to add LAM, telbivudine or entecavir.


\*primary non-response

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. The daily dose is 300 mg. The drug is potentially nephrotoxic and should be used with caution in renal insufficiency. Tenofovir has been only recently registered in Europe to treat patients with chronic hepatitis B, therefore the experience in decompensated cirrhosis is very limited. Because of its excellent antiviral activity and lack of mutations associated with drug resistance it is reasonable to restrict its use to the patients who require rescue therapy and failed previous treatments.

In conclusion, the best option in treatment-naïve patients with decompensated HBV-related cirrhosis, especially if they await LT and will continue antiviral treatment after transplantation, is entecavir in a standard dose. In case of LAM-experienced patients, either with or without LAM-resistance, the best option is to add adefovir and to keep patients on the combination therapy until transplantation. To ensure ongoing viral susceptibility frequent, preferably in 3 month intervals, testing for HBV-DNA level is mandatory.
