1Pretransplant therapy, using a low-accelerating-dose regimen, is an option for patients with mildly decompensated liver disease and low laboratory Model for End-Stage Liver Disease scores. Achievement of an on-treatment virologic response is the goal of therapy. Preliminary data suggest that up to two-thirds of patients who become hepatitis C virus RNA–negative on treatment will be hepatitis C virus infection–free post-transplantation.
2Effective prophylactic therapies are not available. Hepatitis C antibody therapy has been ineffective in preventing hepatitis C virus infection in studies to date.
3Preemptive antiviral therapy started within weeks of transplantation is limited by tolerability, particularly in patients with high Model for End-Stage Liver Disease scores pre-transplantation. Rates of sustained virologic response vary from 8% to 39%. Histological benefits in virologic nonresponders have been demonstrated.
4Posttransplant antiviral therapy in those with evidence of recurrent disease is the mainstay of management. A combination of pegylated interferon and ribavirin is the treatment of choice, and sustained virologic response is achieved with 48 weeks of treatment in approximately 30% of treated patients. Attainment of early loss of hepatitis C virus RNA is highly predictive of sustained virologic response. Histologic improvements are seen in responders. Survival is prolonged among those achieving a sustained virologic response.
5Posttransplant antiviral therapy is limited by poor tolerability and the frequent need for dose reductions and/or discontinuation. Immunologic complications, including acute rejection, chronic rejection, and autoimmune-like hepatitis, occur in association with therapy, albeit at low rates.
6Hepatitis C virus–infected liver transplant recipients represent an important patient population in need of new therapeutics options to prevent patient and graft losses due to recurrent hepatitis C virus disease.
Current approaches to the management of hepatitis C virus (HCV)–infected patients undergoing transplantation fall into 2 broad categories: pretransplant antiviral therapy given with the goal of preventing reinfection and posttransplant antiviral therapy given with the goal of eradicating recurrent infection and preventing graft loss. Pretransplant therapy, using a low-accelerating-dose regimen (LADR), is an important treatment strategy but is applicable to selected patients only. Posttransplant antiviral therapy can be given early before any clinical evidence of recurrence (preemptive therapy), at the first clinical signs of recurrence (early posttransplant therapy), or only when progressive or severe histological disease develops (delayed posttransplant therapy; Table 1). The ideal time to intervene with antiviral therapy post-transplantation (early versus delayed) has not been systematically studied. Rates of viral clearance are not enhanced by early initiation of antiviral therapy, and tolerability is more limited. Thus, the primary point of intervention is post-transplantation, when recurrent disease is evident. Peg interferon and ribavirin (RBV) results in sustained virologic responses (SVR) in approximately 30% of treated patients. Tolerability is more limited than in nontransplant patients, and immunologic complications, including rejection and “autoimmune-like” hepatitis, occur in association with therapy. The substantial nonresponder pool of patients represents an important target group of HCV-infected patients with unmet needs in terms of therapeutics.
Table 1. Management Options for Liver Transplant Recipients at Risk for Recurrent HCV Disease
Timing/Type of Therapy
Abbreviations: HCV, hepatitis C virus; LADR, low-accelerating-dose regimen; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; SVR, sustained virologic response.
Initiated prior to transplantation with goal of achieving negative HCV RNA before surgery
LADR protocol with peginterferon and ribavirin is used; growth factor use is recommended to manage cytopenias.
Select use only. Target patients with low MELD, treatment-naïve patients, or relapsers.
Initiated at the time of transplantation and continued post-transplantation with the goal of preventing recurrent infection
Hepatitis C immune globulin and HCV E2 monoclonal antibodies had no virologic or biochemical benefits.
No effective agent.
Early posttransplant therapy
Preemptive: within first 8 weeks
Combination therapy using peginterferon and ribavirin is the treatment of choice. It is associated with low to modest SVR rates, but histological benefits are apparent.
Selective use only. Consider in patients predicted to be at high risk for progressive disease.
Early: typically 2–6 months post-LT
Combination therapy using peginterferon and ribavirin is the treatment of choice. SVR rates are not strikingly different from those with delayed therapy. Disease progression appears to be slower than in untreated controls.
Selective use only. Target those predicted to have progressive disease.
Delayed posttransplant therapy
Initiated for progressive or severe histologic or biochemical disease
Combination therapy with peginterferon and ribavirin is the treatment of choice. SVR is best predicted by early virologic responses and genotype. SVR is associated with stabilization of histology and improved survival.
Routinely recommended as it offers the highest benefit for the lowest risk.
PRETRANSPLANT ANTIVIRAL THERAPY
Achievement of SVR prior to transplantation eliminates the risk of recurrent HCV infection.1, 2 Of potentially greater importance is the recognition that achievement of an “on-treatment” virologic response reduces significantly the risk of recurrent HCV infection.2 It is unknown whether a reduction in HCV viral load prior to transplant without achievement of undetectablity confers any posttransplant benefit. Thus, the primary goal of pretransplant antiviral therapy is the attainment of an undetectable HCV RNA level prior to transplantation to eliminate or reduce the risk of recurrent infection. A secondary goal, which may be possible in a lesser proportion of patients, is a reversal of liver decompensation and avoidance of transplantation.
The 2 landmark studies confirming that pretransplant HCV therapy can reduce the burden of posttransplant recurrent disease were published in 2004 and 2005.1, 2 Everson and his colleagues3 from the University of Colorado, who coined the term LADR, reported results for 124 patients with decompensated HCV-related cirrhosis treated with interferon (peginterferon and nonpegylated forms) and RBV. The mean Child-Pugh score was 7.4, and the mean Model for End-Stage Liver Disease (MELD) score was about 11.0. The on-treatment virologic response rate was 46%, and the SVR rate was 24%, with the SVR rate significantly higher in those with HCV genotype 2 or 3 (50%) than in those with genotype 1 (13%). Recurrent HCV infection was prevented in all patients achieving an SVR. Forns et al.2 from the University of Barcelona treated 30 patients (50% Child-Pugh class A) with antiviral therapy for a median of 12 weeks (range: 2-33 weeks); 9 patients achieved an undetectable HCV RNA on treatment prior to transplantation, and HCV recurrence was prevented in two-thirds of these patients (6 of 9).2 Dose reductions were required in 60%, and 20% discontinued therapy prematurely.
In all, approximately 250 patients with mostly mild to moderate liver decompensation were treated with interferon (nonpegylated and pegylated) with and without RBV (Table 2). Despite differences in therapy, the median on-treatment virologic response was 30% (range: 18%-56%) in genotype 1 and 83% (range: 82%-100%) in genotype 2/3 patients. However, because the majority of these patients were predominantly treatment-naïve or were previously treated with interferon monotherapy, on-treatment virologic responses may be lower in patients previously treated with peginterferon and RBV.
Table 2. Pretransplant Antiviral Therapy
On-Treatment Virologic Response
Abbreviations: CTP, Child-Turcotte-Pugh; IFN, interferon; MELD, Model for End-Stage Liver Disease; Peg-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response; tiw, three times in a week; G, genotype.
Antiviral Therapy Continued to Time of Transplantation
Peg-IFN alfa-2a, 135 μg/week, and RBV, 1-1.2 g/day
30% CTP-A 70% CTP-B
30% discontinued early.
Treatment duration: 48 weeks
There are potential risks associated with the use of antiviral therapy in HCV-infected patients with decompensated cirrhosis on the waiting list. Treatment discontinuation was required in up to 30%, and dose reductions due to adverse events were frequent; however, most studies were uncontrolled. In the study by Iacobellis and colleagues,4 an untreated control group of similar disease severity was found to have comparable rates of liver complications, with the exception of infections. Treated patients had higher odds of infection (2.43) than untreated controls, and the factors associated with infection were a higher Child-Turcotte-Pugh score and a neutrophil count < 900/mm3. Given the risks of liver-related complications with antiviral therapy, it is recommended that such treatment be undertaken only in experienced transplant centers.
This treatment strategy is limited to those with mild liver decompensation as patients with advanced decompensation (Child-Pugh class B+ or C; MELD ≥20) have an unacceptable risk of complications.5 Patients who are prior virologic nonresponders to peginterferon and RBV are not ideal candidates for this approach as the likelihood of achieving undetectable HCV RNA is very low (<10%). In contrast, prior relapsers to peginterferon and RBV would be well suited to this approach, as the likelihood of achieving an on-treatment response would be predicted to be high. Available data support the use of antiviral therapy in wait-listed patients with low MELD and Child-Turcotte-Pugh scores. The ideal target groups for such therapy are patients with living donors or those with compensated cirrhosis and HCC, as these patient groups typically have lower MELD scores than patients with decompensated cirrhosis awaiting deceased donor transplantation. A large multicenter study of pretransplant treatment of patients with living donors and those with HCC is currently underway (A2ALL LADR study), with results expected in 2009.
CI, confidence interval; CMV, cytomegalovirus; CTP, Child-Turcotte-Pugh; EVR, early virologic response; HBIG, hepatitis B immune globulin; HCIG, hepatitis C immune globulin; HCV, hepatitis C virus; IFN, interferon; LADR, low-accelerating-dose regimen; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; Peg-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response; tiw, three times in a week.
In acute hepatitis C, a strong neutralizing antibody response correlates with declining HCV RNA levels and spontaneous resolution of infection.6 Immune globulin products obtained from HCV-positive donors have broadly reactive neutralizing antibodies.7 Two lines of evidence suggest that hepatitis C immune globulin (HCIG) might have a role to play in the prevention of recurrent HCV infection after liver transplantation. First, a retrospective study of 205 patients with hepatitis B virus and HCV who were transplanted with (n = 34) or without hepatitis B immune globulin (HBIG; n = 171) found that the 3-year actuarial rate of HCV-related hepatitis was lower in patients receiving HBIG than in those not receiving HBIG (27% versus 70%, P < 0.001), and among HBIG-treated recipients, recurrent hepatitis C was less frequent in patients transplanted before March 1990 (10%), prior to screening of donors for HCV, than in patients transplanted after this date (61%), when HCV-positive donors were excluded.8 These results suggested that HCV antibodies (in HBIG) had an ameliorating effect on HCV recurrence. Second, in a chimpanzee model of acute infection, HCIG was shown to delay or prevent the development of acute infection.7, 9
Unfortunately, clinical studies of hepatitis C antibody therapy in the form of HCIG10 or monoclonal antibodies directed against the E2 region11 have not proven it to be effective. In 18 patients with HCV infection undergoing liver transplantation treated with 17 infusions of HCIG at doses of 75 or 200 mg/kg beginning in the anhepatic phase and continued for 14 weeks, no discernable antiviral or immunological effects were identified, and no patient was prevented from developing recurrent HCV infection.10 In 24 patients undergoing liver transplantation treated with the monoclonal antibody HCV-AbXTL68 (at doses ranging from 20 to 240 mg) or placebo repeatedly administered for a total of 12 weeks, all patients developed recurrent HCV infection.11 Only the higher doses of HCV-AbXTL68 achieved a reduction in HCV RNA levels (−1.8 for the 120-mg dose and −2.4 log for the 240-mg dose versus −1.5 log with placebo), but all patients became viremic post transplantation.11 Further development of HCV-AbXTL68 has been halted. HCIG (Civacir, Biotest Pharmaceuticals, Boca Raton, FL) has orphan drug status in Europe.
Whether higher doses or alternative schedules of drug administration of HCIG in combination with antiviral therapy will produce more favorable results is unknown. At present, there is no established role for HCV antibody therapy in the management of liver transplant recipients with HCV.
EARLY POSTTRANSPLANT ANTIVIRAL THERAPY
Following transplantation, there is an initial decline in HCV RNA levels with a variable rate of increase over the first 2 weeks12 to peak values at 3 to 4 months post-transplantation. Biochemical and histological evidence of hepatitis is typically seen within the first 6 months. A preemptive antiviral strategy initiates treatment within the first few weeks post-transplantation when HCV RNA values are lower than at later timepoints posttransplantation and histologic injury is absent. Treatment during the early phase of infection may be more easily treated than established chronic disease, as occurs with the treatment of acute hepatitis in nontransplant patients. Additionally, exposure to interferon in the early posttransplant phase of reinfection may modulate HCV-specific CD4+ T helper 1 cell and CD8+ T cell responses in a manner that would favor less progressive disease or modulate fibrogenesis pathways to reduce the likelihood of fibrosis.
These theoretical benefits have only partially been borne out in clinical studies. Rates of SVR are variable, ranging from 8% to 39% (median: 16%), with overall response rates lower in US studies than in studies from Japan and Italy (Table 3).13–17 In studies reporting genotype-specific results, 5% to 33% of genotype 1 patients and 14% to 100% of genotype 2/3 patients achieved SVR.15–17 Most studies used combination interferon and RBV; studies using interferon monotherapy (pegylated and nonpegylated) had the lowest SVR rates.13, 17 Dose reductions were required, more frequently for RBV than interferon, and treatment discontinuations were highly variable across the studies, ranging from 0% to 57%.
Table 3. Virologic Efficacy and Safety of Preemptive Antiviral Therapy
Several early studies reported a trend toward reduced severity of recurrent hepatitis C at the end of treatment in patients receiving preemptive therapy compared to untreated controls.16–19 A recent study identified significant long-term histological benefits among patients treated with preemptive antiviral therapy who were virological nonresponders, with only 22% in a group receiving preemptive therapy progressing to a Batts-Ludwig fibrosis score ≥ 2 at 48 months post–liver transplantation versus 49% of patients not receiving preemptive therapy (P = 0.08).20 These histologic benefits may be a relevant consideration in patient groups with a high likelihood of virological nonresponse to antiviral therapy, such as patients who have failed peginterferon and RBV treatment pre-transplantation.
In general, the preemptive treatment strategy is applicable only to patients without significant posttransplant complications and whose clinical status is sufficiently stable to allow initiation of antiviral treatment within the first few weeks post-transplantation. In a US study from a single center with a median laboratory MELD score at transplant of 18 (range: 7-49), only 41% of 124 consecutive patients were candidates to start antiviral therapy within the first 6 weeks post-transplantation, with cytopenias, renal dysfunction, and infectious complications the most common reasons for exclusion.13 Thus, preemptive therapy is applicable to selected transplant recipients only.
Other studies have evaluated antiviral therapy initiated within the first 6 months after transplantation rather than the first few weeks.21, 22 In 1 study that initiated antiviral therapy at the first clinical manifestation of “acute” recurrent HCV (elevated liver enzymes and lobular hepatitis on biopsy), 63% of patients achieved an end-of-treatment virologic response, and 35% achieved SVR.21 In a second study of 23 patients, 35% achieved an end-of-treatment response, and the SVR rate was 19%.22 In both studies, the mean time to treatment was 3 to 4 months post-transplantation. Tolerability of therapy appeared to be better than that seen in studies of therapy started within the first few weeks of transplantation, with fewer patients requiring treatment discontinuation (Table 3). A multicenter US study of peginterferon alfa-2a and RBV (the PHOENIX study), started 10 to 24 weeks post-transplantation and continued for 48 weeks, will provide additional data on the safety and efficacy of early antiviral therapy.23 Final results of this study are anticipated in 2008.
POSTTRANSPLANT ANTIVIRAL THERAPY FOR RECURRENT DISEASE
The primary strategy used to manage HCV infection in transplant recipients is to initiate antiviral treatment if significant (defined variably) or progressive histologic disease develops. The consensus of an expert panel convened in 2003 was to treat patients with moderate to severe necroinflammatory activity (grade 3 or 4) or fibrosis stage 2 or greater (scale of 4) fibrosis.24 Published studies suggest that treatment is frequently initiated with milder disease.25, 26 The goals of therapy are to achieve viral eradication. There is a survival benefit in patients treated with interferon-based therapy who achieve SVR compared to nonresponders.27, 28 This survival benefit is seen in those with advanced fibrosis (bridging fibrosis and cirrhosis) and those with milder disease.
The majority of the published studies are uncontrolled and retrospective and have a relatively small sample size. Two systematic reviews of the efficacy of interferon/peginterferon and RBV for 6 to 12 months have been published (Table 4). The first from Wang and colleagues29 included studies of both nonpegylated and pegylated interferons in combination with RBV. A total of 38 studies published between 1980 and 2005 met the inclusion criteria and included SVR results (22 with interferon and RBV; 16 with peginterferon and RBV). The weighted average of individual studies was used to summarize response rates. The pooled estimate of SVR was 20% for interferon and RBV and 24% for pegylated interferon and RBV. End-of-treatment virologic responses were 34% and 42%, respectively, indicating that relapse was a major factor in the low SVR rates. End-of-treatment biochemical and histological responses were more frequent, occurring in ≥50% of treated patients. A second systematic review from Berenguer26 focused on studies of peginterferon and RBV only. A total of 19 studies published between 2002 and 2007 with a total of 611 patients were included. Peginterferon alfa-2b was used in 16 studies, peginterferon alfa-2a was used in 6 studies, and both were used in 3 studies. Most studies used RBV doses of 600 to 800 mg daily, and growth factors were used in 13 of 19 studies. The mean (nonweighted) overall end-of-treatment virologic response and SVR rates were 42.2% (range: 17%-68%) and 30.2% (range: 0%-50%), respectively. The mean SVR rate for genotype 1 patients was 28.7% (range: 12.5%-40%). Biochemical responses were seen in 54.8%, and histological endpoints were judged to be too heterogeneous in definition and assessment to provide a summary estimate. However, it was noted that histological improvements were generally confined to treated patients who achieve SVR.
Table 4. Systematic Reviews of Antiviral Therapy for Recurrent Hepatitis C Virus
The baseline factors associated with SVR included non-1 genotype, low pretreatment HCV viral load, and absence of prior antiviral therapy. However, early virologic responses emerged as the most important predictors of response and nonresponse. Failure to achieve a decline in HCV RNA during the first 3 months of treatment was highly predictive of non-SVR.30–33 Achievement of a rapid virologic response (undetectable HCV RNA at week 4 of treatment) was highly predictive of SVR in patients receiving peginterferon and RBV for 48 weeks.32
Virologic relapse occurs in a substantial proportion of transplant recipients achieving an end-of-treatment response (Fig. 1). Studies in nontransplant HCV-infected patients suggest that prolongation of treatment duration can reduce the rate of relapse. In particular, patients who achieve a significant decline in HCV RNA during the first 12 weeks of treatment but who are still viremic may benefit from an extension of treatment to 72 weeks. There are no published studies evaluating extended therapy in liver transplant recipients who are “slow responders.”
Safety and Tolerability
Dose reductions are frequent and drug discontinuation rates are higher than in nontransplant patients, with only one-third of transplant recipients achieving target doses and duration of therapy.26, 29 In the systematic review of studies of peginterferon and RBV therapy in transplant recipients, dose reductions of RBV and peginterferon were seen in 54% and 39% of patients, respectively,26 and the pooled weighed rate of treatment discontinuation was 26%. Cytopenias, mood disturbances, and acute rejection are the most common reasons for dose reduction or discontinuation. Growth factor use is advocated by experts to manage cytopenias, and although tolerability may be improved, there is little evidence that SVR rates are improved.26, 29 Persistent hypersplenism, concurrent immunosuppressive therapy, and abnormal renal function are the key factors contributing to the higher rate of dose-limiting cytopenias.
Because interferon has immune modulatory properties, there is a potential risk of acute or chronic rejection occurring with antiviral therapy. In uncontrolled studies, the reported rates of acute rejection ranged from 0% to 33%, but in controlled studies, no significant difference in the rate of acute or chronic rejection between treated patients and untreated controls was found.17, 34 In the systematic review by Wang et al., the pooled weighted estimate of the risk of acute rejection was 2% (95% CI: 1%-3%) for interferon and RBV and 5% (95% CI: 3%-7%) for peginterferon and RBV.29 Chronic rejection was more frequently associated with graft loss.35 Factors of potential importance in triggering rejection during treatment include the use of peginterferon (versus nonpegylated interferon), prior episodes of treated acute rejection, and declining levels of calcineurin inhibitors during therapy.
Another immunologic phenomenon linked to antiviral therapy is the development of autoimmune-like hepatitis.33, 36–38 The histological hallmarks include a plasma cell–predominant portal-based infiltrate with interface hepatitis and, in some cases, moderate to severe necrosis with cell dropout and parenchymal collapse. Two clinical profiles have been described. In some cases, an increase in aspartate aminotransferase and alanine aminotransferase from baseline is seen during or after antiviral therapy in patients experiencing a virologic response (ie, undetectable HCV RNA). Autoimmune markers are usually absent, and most cases respond to increased immunosuppression.37 In other cases, the increase in aspartate aminotransferase and alanine aminotransferase is accompanied by de novo detection of autoimmune markers (antinuclear antibody and others) and the presence of other autoimmune conditions. HCV RNA levels may be detectable or undetectable, and most cases respond to discontinuation of antiviral therapy and increased immunosuppression.36, 38 The underlying factors contributing to expression of this “autoimmune-like” hepatitis are unknown.
The mainstay of management of liver transplant recipients with HCV is posttransplant treatment of recurrent disease. Although the optimal timing of treatment initiation is unknown, early preemptive therapy is not recommended except in patients at high risk for progressive disease, and most studies have initiated treatment when recurrent and progressive histologic disease is present. Overall, SVR rates are highest with combination peginterferon and RBV, but only about one-third of treated patients achieve this endpoint. The genotype, baseline viral load, and prior treatment history are the best baseline predictors of response. However, early viral responses are best at identifying responder and nonresponders. Survival benefits are evident in those achieving SVR. Pretransplant antiviral treatment is an option for selected patients awaiting transplantation, namely those with favorable virologic characteristics (a non-1 genotype or low viral load) and mild to moderate decompensation. However, because complications can be serious, treatment of these patients should be confined to experienced centers. Better tolerated and more efficacious therapies are obviously needed.