Understanding the Switchbacks: The Impact of Direct Antivirals on the Minimization of Hepatitis C Virus Recurrence After Transplantation

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1 LIVER TRANSPLANTATION 18:S47-S51, 2012 SUPPLEMENT Understanding the Switchbacks: The Impact of Direct Antivirals on the Minimization of Hepatitis C Virus Recurrence After Transplantation David Mutimer Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, United Kingdom Key Points 1. Interferon (IFN) and ribavirin can be used in select patients before or after liver transplantation, and they can reduce the risk of recurrence or effect a cure in these settings. 2. Currently licensed direct-acting antiviral drugs are used with IFN and ribavirin, so the safety and tolerability of triple therapy will be worse than those of double therapy in pretransplant and posttransplant settings. 3. Drug-drug interactions [exemplified by the interactions of protease inhibitors (PIs) with tacrolimus and cyclosporine] and the need for dose modifications (exemplified by the need to modify ribavirin doses in patients with renal dysfunction) challenge the safe use of antiviral drugs after transplantation. 4. Experience with the use of human immunodeficiency virus PIs and emerging data about hepatitis C virus (HCV) PIs show that this class of drugs can be used with care after transplantation. 5. Attempts to prevent HCV graft infections through the use of HCV immunoglobulin immediately after transplantation have been largely unsuccessful. 6. The blockade of cell surface HCV receptors with antibodies or small molecules appears to limit HCV cell entry in vivo and in a mouse model, and this may suggest a novel approach to limiting HCV recurrence at the time of transplantation. Liver Transpl 18:S47 S51, VC 2012 AASLD. Received May 1, 2012; accepted August 6, Until recently, interferon (IFN) and ribavirin were the only antiviral drugs licensed to treat hepatitis C virus (HCV). The first direct-acting antivirals (DAAs) to be licensed are telaprevir and boceprevir, which are specific inhibitors of the HCV-encoded protease. Although these protease inhibitors (PIs) may have some activity against other HCV genotypes, they are licensed only for the treatment of HCV genotype 1 (G1) infections. Published phase 3 studies have shown that the addition of a PI to IFN and ribavirin increases the rate of sustained virological response (SVR) for treatment-naive and treatment-experienced patients (including patients with established but well-compensated cirrhosis). 1 These studies also show that the inclusion of a PI in the treatment regimen is associated with an enhanced rate of early serum HCV RNA negativity, and early negativity is associated with high rates of SVR and with the opportunity to abbreviate the course of treatment. The phase 3 studies of telaprevir and boceprevir have included a minority of patients with established cirrhosis. At this year s annual meeting of the European Association for the Study of the Liver, an interim analysis was presented for a cohort of patients with cirrhosis who received either telaprevir- or boceprevir-containing triple therapy. 2 High Abbreviations: CNI, calcineurin inhibitor; DAA, direct-acting antiviral; DDI, drug-drug interaction; G1, genotype 1; G2, genotype 2; G3, genotype 3; G4, genotype 4; HBV, hepatitis B virus; HCIG, hepatitis C immunoglobulin; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; LT, liver transplantation; NA, not applicable; PCR, polymerase chain reaction; PEG-IFN, pegylated interferon; PI, protease inhibitor; SVR, sustained virological response. Potential conflict of interest: Nothing to report. Address reprint requests to David Mutimer, M.D., Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Nuffield House, 3rd Floor, Birmingham B15 2TH, United Kingdom. Telephone: ; Fax: ; david.mutimer@uhb.nhs.uk DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases Liver Transplantation, Vol 18, No 11, Suppl 2 (November), 2012: pp S47-S51 S47

2 S48 MUTIMER LIVER TRANSPLANTATION, November 2012 rates of serious adverse events and treatment discontinuation were observed. Patients with cirrhosis have much to gain from viral eradication, but physicians must be alert to the risks of antiviral treatment (either dual or triple therapy) given to patients with advanced liver disease. Indeed, there are no published data describing the efficacy and safety of triple therapy in patients with very advanced disease, such as those with liver failure on the transplant waiting list. It seems inevitable that these PIs and other DAAs in the development pipeline will transform the outcomes of patients with advanced liver disease and patients with HCV infections after transplantation. These expectations are based on the evidence of the benefits of successful antiviral treatment with IFN and ribavirin without PIs in the pretransplant and posttransplant settings. The successful antiviral treatment of the patient with well-compensated cirrhosis dramatically reduces the future risk of hepatic decompensation and also reduces the risk of the development of primary liver cancer. 3 The patient with more advanced cirrhosis at the baseline poses a greater challenge, and IFN-based treatment regimens are poorly tolerated. However, the successful treatment of decompensated cirrhosis may also improve clinical outcomes and reduce the need for transplantation. 4 In most published studies, the aims of antiviral treatment for advanced disease have been the achievement of serum HCV negativity and the reduction of the risk of posttransplant HCV recurrence 4-9 (see Mutimer and Lok 10 for a review; see also Table 1). These studies suggest that serum polymerase chain reaction (PCR) negativity during antiviral therapy at the time of transplantation decreases the risk of posttransplant HCV recurrence, and this should in turn be associated with superior graft and patient outcomes. This leads to the proposal of a potentially important role for DAA-containing antiviral regimens in the peritransplant management of HCV patients. For G1- infected patients with well-compensated disease and with primary liver cancer as the indication for transplantation, triple therapy with IFN, ribavirin, and either boceprevir or telaprevir can achieve serum PCR negativity at an earlier stage of treatment and in a higher proportion of treated patients. Such protocols may be easier to implement for patients who have a living donor because the timing of the transplant operation can be reconciled with the course of the antiviral treatment and with the results of serum HCV testing. In the future, IFN-free regimens for all HCV genotypes may transform the management of patients with advanced disease, including those on our transplant waiting lists. HCV recurrence in the transplanted liver is associated with impaired graft and patient survival after transplantation. There is an abundance of published series describing the outcomes of dual therapy with IFN and ribavirin for HCV after liver transplantation (LT; see Roche and Samuel 11 for a review). In highly select cohorts, investigators have reported that SVR can be achieved in 30% of treated patients. Obstacles TABLE 1. Studies of HCV Antiviral Therapy in Patients With Decompensated Cirrhosis SVR After LT (n/n) PCR-Negative Before LT (n/n) PCR-Negative at the End of Treatment (n/n) SVR (n/n) Patients Study Treatment Regimen Duration (n) 20 NA NA 12/20 4/20 Thomas et al. 8 5 MU of IFNa2b daily 14 months ( months)* NA NA Iacobellis et al. 4 PEG-IFNa2b/ribavirin 24 weeks (43% for G2/G3 and 7% for G1/G4) NA NA Iacobellis et al. 9 PEG-IFNa2b/ribavirin weeks (57% for G2/G3 and 16% for G1/G4) 12 weeks 30 NA NA 9/30 6/30 (2-30 weeks) weeks /47 12/47 Forns et al. 5 3 MU of IFNa2b daily/ribavirin Everson et al. 7 IFNa2b/ribavirin (low accelerating dose regimen) Carrion et al. 6 PEG-IFNa2a/ribavirin 15 weeks 51 NA NA 15/43 # 10/43 # (1-57 weeks) NOTE: Some studies were specifically designed to treat patients until the time of transplantation, so the duration of treatment was quite variable. *The data are presented as the mean and the range. The data are presented as the median and the range. In this study, 47 of the original 124 patients underwent LT. # In this study 43 patients underwent LT.

3 LIVER TRANSPLANTATION, Vol. 18, No. 11, 2012 MUTIMER S49 to successful treatment in this setting include low baseline hemoglobin, white cell, and platelet counts and chronic impairment of renal function. In addition, some patients have already demonstrated poor sensitivity to IFN-containing regimens administered before transplantation. Thus, published series have included a minority of transplant patients with HCV, and the results of treatment have been inferior to the results achieved in the nontransplant setting. Nevertheless, a significant number of patients have been cured by dual therapy, and the response rates for patients with more favorable HCV genotypes are acceptable. In addition, it has been shown that successful treatment is associated with improved graft and patient survival in the posttransplant setting. 12 The availability of telaprevir and boceprevir may improve the chance of a cure for select transplant patients. However, the tolerability of triple therapy is worse than that of dual therapy. The addition of a PI is associated with additional side effects, including anemia and bone marrow suppression. Also, PIs have significant potential drug-drug interactions (DDIs), particularly with drugs that are substrates of cytochrome p450, such as tacrolimus and cyclosporine [calcineurin inhibitors (CNIs)]. The potentially troublesome interactions of PI treatments with these immunosuppressive drugs have previously been described for human immunodeficiency virus (HIV) PIs in the transplant setting. 13 Many transplant units have experience with the transplantation of HIV-positive patients and with the adjustments of tacrolimus and cyclosporine administration in that context. The impact of telaprevir on the metabolism of tacrolimus and cyclosporine has been demonstrated in healthy volunteers, and appropriate experience and caution will be prerequisites for the safe and effective use of HCV PIs in transplant patients. 14,15 The coadministration of PIs with tacrolimus or cyclosporine dramatically reduces the metabolism of those drugs and demands immediate reductions of the doses and frequencies of the immunosuppressive drugs. Despite the challenge, appropriate dose adjustments can be made, and patients can be treated without the development of drug toxicity (usually reflected by renal dysfunction) or suboptimal immunosuppression (causing rejection). The reduction of CNI exposure can be achieved by the reduction of the daily dose and/or the dosing frequency. It is my preference to reduce the dosing frequency and to administer small doses (0.5 or 1 mg of tacrolimus) according to frequently measured CNI blood levels. For instance, the patient described in Fig. 1 required only eight 1-mg doses of tacrolimus during a 12-week period of telaprevir therapy, with the interval between consecutive doses ranging from 6 to 14 days (median ¼ 9 days). The figure shows that levels can be maintained within the desired range and without the development of significant renal dysfunction. For the PI-taking HIV patient, however, the challenges are largely confined to the time of the PI s introduction after transplantation. Thereafter, both Figure 1. This patient received telaprevir-containing triple therapy for recurrent HCV after transplantation. The graph shows his blood tacrolimus and serum creatinine levels during the 12 weeks of triple therapy. Before the treatment (not shown on the graph), he required tacrolimus at 1 mg/day to maintain a trough level of 5 to 10. During the treatment, he required only eight 1-mg doses to maintain that blood level. After the telaprevir component of the antiviral treatment was stopped, the patient s tacrolimus levels fell promptly (not shown on the graph), and he required a prompt increase in the tacrolimus dose to 3 mg/day to maintain blood levels. the CNI and the PI are taken indefinitely, so substantial adjustments of the CNI dose should not be required. For the HCV PI-containing regimen, the duration of the PI administration is finite. As a result, additional significant changes to the CNI dose will be required at the time of the conclusion of the PI treatment. PI withdrawal restores p450 function, and this demands an immediate increase in the CNI dose in order to maintain therapeutic drug levels. 16 Thus, for DAAs that affect p450 metabolism, the HCV patient can be exposed to the risk of DDIs at both the commencement and conclusion of therapy. Frequent monitoring of CNI levels is essential. Despite concerns about the risks of these DDIs, there is emerging experience with the use of triple therapy in the posttransplant setting. Indeed, Coilly et al. 17 presented an interim analysis of a cohort of transplant patients who received triple therapy (including either telaprevir or boceprevir) for recurrent HCV infections. The key observations were that (1) a high proportion (approximately 70%) of treated patients achieved serum HCV RNA negativity during the first 4 to 8 weeks of treatment, (2) erythropoietin and transfusion were frequently required, and (3) the interaction of the PI with cyclosporine and tacrolimus was manageable (without the development of drug toxicity). It is inevitable that the emerging and as yet unlicensed DAAs will be used with enthusiasm in the posttransplant patient. 18 Some of these drugs will be metabolized, and others will rely principally on renal elimination. When these drugs are used in appropriately selected patients with caution, it is likely that SVR rates will be enhanced. Safe administration will demand informative data and familiarity with DDIs

4 S50 MUTIMER LIVER TRANSPLANTATION, November 2012 and/or dose modifications in the setting of renal dysfunction. In summary, a conventional approach to the use of DAA drugs for HCV will involve the application of treatment regimens in waiting-list patients and in patients with established chronic infections after transplantation. As an alternative or possibly as a complement to the early introduction of DAA treatment, attempts to limit graft reinfection in the early posttransplant period might also be made. Similarly to hepatitis B immunoglobulin, which has been successfully used for transplant patients with hepatitis B virus (HBV), hepatitis C immunoglobulin (HCIG) has been used for HCV patients. Two informative studies, one using a human plasma derived product 19 and the other using a human monoclonal antibody, 20 have been published. In both studies, the immunoglobulin treatment was given according to algorithms similar to those used for hepatitis B immunoglobulin. Each study monitored the impact of the HCIG treatment on the evolution of HCV antibodies and HCV RNA measurements. The administration of the plasma product at a high dose seemed to have a measurable though short-lived effect on serum HCV antibody levels, but there was no discernable impact on posttransplant HCV RNA titers. The administration of monoclonal HCIG at a high dose was also associated with a measurable rise in serum antibody titers and with a measurable reduction of serum viral titers. The impact of HCIG on serum viral titers was observed only with high doses and during the early posttransplant period with more intensive administration. Central to the assessment of the impact of HCIG treatment on HCV recurrence is an understanding of the observed kinetics of serum HCV RNA in the early posttransplant period. For instance, in the study by Davis et al., 19 a single treated patient was serum PCR negative on days 7 and 14 after transplantation, but the titer rose rapidly thereafter. It is recognized that this pattern with very low titers during the first posttransplant week can be observed for a proportion of transplant patients in the absence of any treatment to ameliorate the recurrence of infection. 21 Studies of viral kinetics after transplantation have demonstrated significant variations The following pattern has been established. The HCV titer usually declines rapidly during the reperfusion phase of the transplant operation, and this possibly reflects the immediate uptake of the circulating virus by the newly implanted liver mass. Viral titers continue to decline for the majority of patients and achieve nadir values 24 to 48 hours after transplantation. Thereafter, the rate of the rise of serum viral titers varies greatly. For a proportion of patients, titers rise rapidly to reach or exceed pretransplant values within a week of transplantation. For others, titers persist at relatively low levels during the first posttransplant week or longer and then rise to reach or exceed pretransplant levels before 4 weeks have elapsed. Thus, attempts to prevent or modify the process of graft reinfection need to incorporate careful and frequent measurements of HCV titers, and their interpretation needs to consider the heterogeneity of the kinetic patterns of serum HCV titers in this setting. Attempts to prevent HCV graft reinfection need to consider the biology of HCV entry into hepatocytes. There have been significant developments in our understanding of this process (as reviewed by Timpe and McKeating 24 ). The process is complex and involves the interaction of the virus (and lipoviral particles) with cell surface molecules, including low-density lipoprotein receptor, heparan sulfate proteoglycans, CD81, scavenger receptor B1, claudin 1, and occludin. In addition to an attempted blockade of virus-cell interactions through the use of putative neutralizing antibodies (ie, HCIG), some of these molecules might present therapeutic targets for preventing or reducing the infection of the graft in the early posttransplant period. For instance, Meuleman et al. 25,26 used the urokinase plasminogen activator/severe combined immunodeficient mouse to evaluate the effects of receptor blockade on HCV infection. Administered to the mouse before HCV inoculation, anti-cd81 or anti scavenger receptor B1 monoclonal antibodies could prevent HCV infection. Thus, in addition to targeting HCV and its components, potential approaches to the prevention and treatment of graft infections might explore the potential of specific antibodies or small molecules that target human cellular receptors for the virus. Such studies in humans are underway. In conclusion, we are just entering the era of DAAs for the treatment of HCV patients. The use of DAAs in the noncirrhotic population should eventually diminish the number of patients who develop complications requiring LT. This will be an important step in reducing the overall demand for donor organs and in bridging the gap between the organ supply and demand. In addition, the development of DAA protocols to prevent graft reinfection will represent a major advance in our management of patients who cannot avoid transplantation. In the same way that protocols for the prevention of HBV graft infections transformed the outcomes of HBV patients, the prevention of HCV graft reinfection will improve graft and patient survival. For select patients with established HCV G1 graft infections, the availability of boceprevir and telaprevir represents an opportunity. Drugs in the development pipeline will soon provide opportunities for a higher proportion of patients, including those with non-1 genotypes. The major challenge will be to use the drugs safely in this setting, and particular attention to drug interactions and dosing will be essential. REFERENCES 1. Rowe IA, Mutimer DJ. Protease inhibitors for treatment of genotype 1 hepatitis C virus infection. BMJ 2011;343: d Hezode C, Dorival C, Zoulim F, Poynard T, Mathurin P, Pol S, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non responders. 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