Transplantation for Hepatitis A and B

Pretransplantation Antiviral Therapy

Until the end of the 1990s the presence of HBV replication was considered a contraindication to LT by most centers. The goals of treatment for patients with end-stage HBV liver disease are to improve liver function, thereby obviating the need for LT, and in patients who require a transplant to decrease the risk for HBV recurrence after transplant. The major factor in achieving these goals is obtaining sustained viral suppression and reduction in hepatic activity. LAM, adefovir (ADV), and telbivudine are no longer considered as an optimal first-line therapy related to a high rate of resistance development, and latest recommendations suggest using entecavir (ETV) or tenofovir (TDF) as primary antiviral agents.

LAM is well tolerated in decompensated cirrhosis. A rapid viral suppression within several weeks of therapy was observed in 73% to 100% of these patients ( Table 9-1 ). However, clinical improvement is slow, and a benefit may not be observed during the first 3 to 6 months of therapy. In a prospective study of 154 patients listed for transplantation and receiving LAM, 32 of the 154 patients (21%) died, with most of the deaths (25 of 32 [78%]) occurring within the first 6 months of therapy. The estimated actuarial 3-year survival of patients who survived at least 6 months was 88%. In multivariate analysis an elevated serum bilirubin level, elevated creatinine level, and serum HBV DNA level greater than 10 ⁵ copies/mL before treatment were independent predictors of 6-month mortality. Thus for patients with advanced liver failure, LT remains a critical component of management, irrespective of the antiviral response. The development of mutations in the HBV DNA polymerase gene is the main limitation of treatment with a reported incidence of 15% to 20% per year of therapy and a risk for fatal hepatitis flares. All patients receiving LAM therapy should have close monitoring of HBV DNA levels and prompt institution of additional antiviral therapy when breakthrough infection occurs, related to the risk for hepatitis flares or HBV recurrence after transplant.

ADV, a nucleotide analogue, is an effective therapy for patients with wild-type and LAM-resistant HBV infection. In a multicenter study on 226 LAM-resistant patients awaiting transplantation, 59% and 65% achieved an undetectable HBV DNA by PCR at weeks 48 and 96, respectively (see Table 9-1 ). However, 14% still died within the first year, and at least 33% required LT for long-term survival. As with LAM, the attainment of clinical benefits required survival of approximately 6 months, so for patients with advanced liver decompensation, concurrent consideration of transplantation is important. Dose reductions of ADV were required for 4% of patients with preexisting renal dysfunction (i.e., creatinine clearance < 50 mL/min). Virological resistance to ADV was less frequent (2% at 144 weeks). However, the longest follow-up studies showed a higher resistance rate: 11% at 3 years, 18% at 4 years, and 29% at 5 years. Although antiviral drug resistance is less common with ADV than with LAM, concerns remain regarding the slow rate of suppressing HBV replication with ADV, as well as the potential for dose-dependent nephrotoxicity in decompensated HBV patients.

New nucleos(t)ides analogues (i.e., ETV and TDF) exhibit stronger antiviral efficacy and a lower resistance rate. They are recommended for the treatment of HBV infection in patients with end-stage liver disease; however, experience with these drugs is more limited in this setting.

ETV, a nucleoside analogue, is more potent in suppressing serum HBV DNA levels than LAM in both HBeAg-positive and HBeAg-negative patients. Related to a high genetic barrier of resistance, this drug exhibits a very low resistance rate (i.e., near 1%) in LAM-naive patients, even after 5 years of therapy. In contrast, ETV resistance occurred in more than 35% of patients after 4 years of therapy in LAM-resistant patients. In a recent study Shim et al evaluated clinical outcome and virological responses of 70 decompensated patients compared with 144 compensated patients treated with ETV (0.5 mg/day) as first-line therapy during 1 year (see Table 9-1 ). At month 12 of therapy the mean reduction in serum HBV DNA levels (-6.8 versus -6.7 log ₁₀ copies/mL), the proportion of patients achieving undetectable viremia (89% versus 78%) and the rate of HBeAg seroconversion (22% versus 24%) did not differ significantly between the decompensated and compensated groups. In the decompensated group, as reported with LAM, the majority of adverse outcomes occurred within the first 6 months of therapy: 6 patients died as a result of liver failure, and 3 patients underwent transplantation. These 9 patients had more severe liver failure at entry compared with the other decompensated patients (Child-Turcotte-Pugh [CTP] score 10.1 versus 8.1, P = .001); however, the baseline HBV DNA levels, the presence of HBeAg, and the early response to antiviral therapy were similar. Five patients developed HCC during the follow-up period. In a second study, 191 patients with decompensated HBV cirrhosis (positive or negative for HBeAg and experienced or naive for treatment with nucleos[t]ide analogues) were randomized to ETV (1 mg/day) or ADV (10 mg/day) (see Table 9-1 ). The ETV group showed a greater change from baseline in HBV DNA at all time points through week 48 and a higher proportion of subjects who achieved an HBV DNA level of less than 300 copies/mL at week 48 (ETV, 57%; ADV, 20%; P < .0001). Adverse events were comparable between groups. Safety of ETV in severely decompensated patients is poorly evaluated. A recent study showed that 5 of 16 patients with decompensated HBV-related disease (Model for End-Stage Liver Disease [MELD] score > 20) developed symptomatic lactic acidosis, leading to death in a patient with fulminant hepatitis B, after receiving ETV for 4 to 240 days. The mechanisms of toxicity are unclear; however, concomitant drugs, comorbidities, and other host factors may alter drug pharmacokinetics.

TDF is a nucleotide analogue and is very potent against the wild-type and nucleoside analogue–resistant HBV strains. Phase III studies have shown that TDF has higher antiviral efficacy than ADV. It has been shown that TDF can control HBV replication in the majority of patients and can rescue LAM resistance or nonresponse to ADV. No drug-resistant variants have been reported with 3 years of continuous treatment. TDF could be prescribed in combination with emtricitabine, a nucleoside analogue with an antiviral activity profile similar to that of LAM (Truvada).

A recent study compared the safety and efficacy of TDF versus TDF plus emtricitabine versus ETV in 112 decompensated HBV patients (see Table 9-1 ). The frequency of undetectable HBV DNA at weeks 12, 24, and 48 was comparable in the three treatment groups. However, among the subjects with LAM-resistant HBV, 71% of the 18 patients in the TDF-containing arms had undetectable HBV DNA at week 48 compared with 33% in the 3 ETV-treated patients. Improvements in CTP and MELD scores at week 48, rates of nephrotoxicity, and patient mortality were similar in the three treatment arms. There are growing concerns regarding the long-term safety of TDF in some patients, including nephrotoxicity and metabolic bone disease.

In summary, patients with decompensated cirrhosis should be treated in specialized liver units, because the application of antiviral therapy is complex. All studies emphasized the need for early treatment in patients with decompensated cirrhosis. Most studies have shown a biphasic survival pattern with most deaths occurring within the first 6 months of treatment. Patients with higher pretreatment bilirubin levels, creatinine levels, and HBV DNA levels were at greatest risk for early death, whereas early suppression of HBV replication was not associated with more favorable outcomes. Transplantation should not be delayed in patients with CTP class C or a MELD score greater than or equal to 15 at baseline or should be urgently considered in patients displaying suboptimal improvement in hepatic reserves after 3 months of antiviral treatment, because of our inability to identify those patients with a poor short-term prognosis ( Fig. 9-1 ). Conversely, long-term antiviral treatment could be done in patients who can be stabilized with antiviral therapy.

The oral agents that most effectively suppress HBV replication with the lowest rate of drug resistance during prolonged use (i.e., ETV, TDF) have emerged as preferred first-line agents over the other available drugs (LAM, ADV, telbivudine). Combination therapy using LAM and ADV could be used according to local health policies. Decompensated HBV patients receiving oral nucleos(t)ide analogues must undergo frequent clinical and laboratory assessment to ensure medication compliance and surveillance for virological and clinical response, as well as drug side effects, drug resistance, and HCC. Patients who fail to achieve primary response, as evidenced by less than a 2 log ₁₀ decrease in serum HBV DNA levels after 6 months of therapy, should be switched to an alternative treatment or receive additional treatment. Patients who develop breakthrough infection, defined by an increase of HBV DNA levels by more than 1 log ₁₀ from nadir, should be assessed for compliance with therapy, and a test for antiviral-resistant mutation should be performed.