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HCV Antiviral Therapy in Liver Transplant Candidates and Recipients With Renal Insufficiency

Verna, Elizabeth C. MD, MS1; Brown, Robert S. Jr MD, MPH1

doi: 10.1097/TP.0000000000001688
Reviews

Hepatitis C virus (HCV) remains the leading indication for liver transplant in much of the world and has traditionally been associated with diminished posttransplant survival due to recurrent HCV-related liver disease. This field has been dramatically changed by the advent of safe and effective direct-acting antiviral therapy, such that most patients can be cured in the pretransplant or posttransplant setting. In addition, there are now direct-acting antiviral regimens specifically approved for use in patients with severe renal insufficiency. However, patients with pre or posttransplant severe renal insufficiency remain more difficult to treat, due to mechanisms of drug metabolism in hepatic and renal failure, as well as posttransplant drug-drug interactions. Treatment options are even more restricted in non-1 HCV genotypes. Because renal insufficiency is common among patients with HCV, with decompensated cirrhosis, and in the posttransplant setting, this difficult scenario is relatively common. However, ongoing development of pangenotypic regimens with improved safety profiles, as well as additional data on dosing and safety among patients with severe renal insufficiency, will continue to expand options for cure even in these most difficult to treat patients.

The authors provide an update review on anti-HCV therapy in a group of patients that still have limited treatment options, those with renal failure in the peri-liver transplant setting.

1 Center for Liver Disease and Transplantation, New York Presbyterian Hospital, New York, NY.

Received 10 December 2016. Revision received 3 February 2017.

Accepted 8 February 2017.

E.C.V. Grant support form Salix Pharmaceuticals.

R.S.B. Consulting and grants Abbvie, Gilead, BMS, Merck.

E.C.V. and R.S.B. both contributed to the writing and editing of this review.

Correspondence: Robert S. Brown, Jr., MD, MPH, Division of Gastroenterology & Hepatology Weill Cornell Medicine Center for Liver Disease 1305 York Avenue, 4th Floor New York, NY 10021. (rsb2005@med.cornell.edu).

The rapid expansion of safe and effective direct-acting antiviral (DAA) agents has revolutionized the care of liver transplant (LT) candidates and recipients with hepatitis C virus (HCV) infection. Although HCV was previously rarely cured in LT recipients and led to high rates of recurrent cirrhosis, graft loss and death,1 the vast majority of patients can now be successfully treated either pre or post-LT2 to prevent this devastating outcome. Remarkably, many antiviral agents have even been studied in dedicated clinical trials in these traditionally most complex populations.

There are now 3 major classes of approved DAA agents: NS3/4A protease inhibitors, NS5B polymerase inhibitors and NS5A inhibitors. Medications from at least 2 classes are used in combination to minimize resistance and treatment failure. Although response rates in the general population currently exceed 90-95% with first-line regimens,3 there are important considerations when selecting the best regimen for individual patients. Genotype continues to have a significant impact on treatment selection, though pan-genotypic regimens are now coming to the market. In addition, there are important class-specific considerations that enter treatment decisions. Protease inhibitors, for example, may have more drug-drug interactions due to cytochrome P-450 metabolism and are hepatically metabolized and should thus be avoided in patients with moderate or severe hepatic impairment (Child Class B or C cirrhosis). The NS5B polymerase inhibitor sofosbuvir, conversely, is pangenotypic, has fewer drug-drug interactions and recommended for treatment in patients with decompensated cirrhosis. However, sofosbuvir is renally cleared and is not recommended in patients with advanced renal insufficiency (glomerular filtration rate [GFR] < 30 mL/min).

Thus, despite significant advances, there remain small subgroups of patients that still have limited treatment options and suboptimal outcomes, including those with renal failure in the peri-LT setting. Mechanisms of drug metabolism and observed toxicities have significantly impeded the utility of specific medications in specific patient populations. Patients with a combination of both moderate or severe hepatic impairment (Childs-Turcotte-Pugh [CTP] class B and C) and advanced renal insufficiency have contraindications to both protease inhibitor and nucleotide NS5B polymerase inhibitor-based therapy, respectively. Posttransplant patients with renal failure are further impacted by drug-drug interactions, especially with calcineurin inhibitors. As renal insufficiency is very common among patients with HCV, with decompensated cirrhosis, and in the posttransplant setting, difficulty in finding the right regimen for these patients with the greatest need is unfortunately common. However, ongoing development of pangenotypic regimens with improved safety profiles will continue to expand options for cure even in these most difficult to treat patients.

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PRETRANSPLANT TREATMENT

HCV is implicated in the pathogenesis of several forms of kidney injury, including most commonly mixed cryoglobulinemia, membranoproliferative glomerulonephritis, membranous nephropathy, polyarteritis nodosa. As a result of HCV-specific forms of renal disease as well as the high prevalence of HCV risk factors among patients with end-stage renal disease (ESRD), including transfusion and dialysis, 1% to 8% of patients on dialysis in Western countries and up to 70% in other parts of the world have chronic HCV infection.4,5

Renal insufficiency is also very common among patients awaiting liver transplantation and is present in up to 54% of hospitalized patients with cirrhosis.6 In addition, creatinine is the main driver of the Model for End-stage Liver Disease score used to prioritize patients for LT due to the profound impact of renal failure on mortality in this population,7-9 and criteria for judicious use of simultaneous liver-kidney transplantation continues to be debated.10 Therefore, the possibility of stabilization or improvement in chronic kidney disease (CKD) in patients on the LT waitlist with viral clearance, as well as prevention of post-LT HCV recurrence, is highly desirable. HCV antiviral regimens that are safe and effective against all HCV genotypes in patients with both decompensated cirrhosis and renal failure would be ideal. However, due to the impact of renal impairment on DAA clearance, treatment options remain limited in these patients, especially for non-1 HCV genotypes (Table 1).

TABLE 1

TABLE 1

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Compensated Cirrhosis

The current recommendations for patients on the LT waitlist with renal insufficiency and compensated (or CTP class A) liver disease and are similar to those for patients without advanced fibrosis.3 For patients with GFR > 30 mL/min per 1.73 m2, currently approved DAA regimens do not require significant dose adjustment and treatment recommendations are identical to patients with normal renal function. Thus, this section will focus on the complexities of treatment patients with severe renal insufficiency (GFR < 30 mL/min per 1.73 m2) or ESRD. The recommendations in this population are based on a limited number of clinical trials, which have generally included small numbers of patients overall and minimal numbers with cirrhosis (Table 2).

TABLE 2

TABLE 2

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Elbasvir/Grazoprevir

The regimens that have been best studied in patients with severe renal insufficiency are those with phase 1 data showing minimal renal excretion and no required dose adjustments in patients with ESRD.11,12 The largest trial to date evaluated the NS3/4A protease inhibitor grazoprevir (100 mg once daily) and an NS5A inhibitor elbasvir (50 mg once daily) versus placebo (delayed treatment) for 12 weeks in patients with HCV genotype 1 and stages 4 or 5 CKD (GFR < 30 mL/min per 1.73 m2 or dialysis).13 This trial included small numbers of treatment experienced (20%) or cirrhotic (6%) patients, and patients with decompensated liver disease or peritoneal dialysis were excluded. However, response rates were excellent. Among the 116 patients in the early treatment arm reported, the sustained virologic response (SVR) 12 weeks after completing therapy (SVR12) was 99%, with 1 patient experiencing virologic relapse at posttreatment week 12. All 6 (100%) patients with cirrhosis achieved SVR 12. In addition, the treatment was well tolerated with similar adverse events reported between treatment and placebo groups, including no difference in progression of renal failure. Interestingly, NS5A resistance associated variants (RAVs) were not associated with treatment failure in genotype 1a patients in this study despite the lack of ribavirin use.

Although this regimen is the best studied among patients with advanced renal insufficiency to date, the number of patients with cirrhosis and other possibly negative predictors of treatment response included in this study were too small to draw firm conclusions about whether baseline RAV testing or the addition of ribavirin may be of benefit in specific circumstances. In addition, this regimen has some significant limitations in the pre-LT setting. As detailed below, it has not been studied in patients with decompensated liver disease (CTP B and C) and carries a warning in its label against the use in decompensated cirrhosis, and is only approved for HCV genotypes 1 and 4.

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Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir

Fixed-dose paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) (PrOD), with (genotype 1a) or without (genotype 1b) ribavirin, has also been studied in limited numbers of patients with advanced renal insufficiency.11 In an open-label phase 2B study, 20 patients with HCV genotype 1 infection and stage 4 or 5 CKD were treated with this regimen for 12 weeks. However, patients with cirrhosis or prior treatment experience were excluded. The overall SVR12 rate was 90% with 1 relapse and 1 patient death 14 days after completion of treatment during an inpatient admission for heart failure. Ribavirin was interrupted in 9 of the 13 patients with genotype 1a, but no transfusions were required. The treatment was otherwise well tolerated.

The use of ribavirin for genotype 1a patients in this trial was problematic given the frequent dose interruption and use of growth factors. As a result, treatment with fixed-dose paritaprevir, ritonavir, and ombitasvir with dasabuvir (PrOD) without ribavirin in patients with HCV genotype 1a (n = 13) and fixed-dose paritaprevir, ritonavir, and ombitasvir without dasabuvir (PrO) without ribavirin for HCV genotype 4 (n = 5) were preliminarily reported in a small open-label study of patients with stage 4 or 5 CKD.14 The overall SVR12 rate was 94% with 1 patient discontinuing treatment early to undergo elective kidney transplantation. There were no virologic failures though 1 patient discontinued treatment early due to ALT elevation.

There is also a preliminary report from a combination of 9 clinical trials with the PrOD regimen, excluding those on dialysis, which found a mean increase in estimated GFR after treatment in patients with a baseline GFR 60 to 90 (1.3 mL) or 60 mL/min per 1.73 m2 or less (6.0 mL).15 In multivariable analysis, baseline proteinuria, the presence of diabetes, body mass index, and black race were independently associated with an increased in GFR greater than 10 mL/min per 1.73 m2. Thus, there is evidence that treatment with some DAA regimens may in fact lead to improved renal function in patients with moderate renal insufficiency.

Although it is encouraging to have a second regimen with some clinical data reported in patients with advanced renal insufficiency, the very small number of patients included, the exclusion of patients with cirrhosis or prior treatment experience, and the limitation to HCV genotypes 1 and 4 may significantly limit the use of this regimen in LT candidates. Like grazoprevir/elbasvir, this protease inhibitor based regimen carries a warning in the label against use in decompensated cirrhosis, due to higher levels of paritaprevir and potential hepatotoxicity.

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Sofosbuvir-Based Regimens

Unlike most DAAs, the nucleotide analogue NS5B polymerase inhibitor sofosbuvir is primarily renally excreted. In patients with ESRD on dialysis compared with those with normal renal function, the AUCs for sofosbuvir and its metabolite GS-331007 were 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis and 60% and 2070% when dose 1 hour after dialysis, respectively.16 Thus, there are no current dosing recommendations for patients with GFR < 30 mL/min per 1.73 m2 and no formal clinical trial data have been published in this population. In small open-label studies reported in abstract form, high rates of treatment failure were seen in patients receiving reduced dose sofosbuvir (200 mg daily) with ribavirin (SVR12 in 4/10, 40%)17 or full dose sofosbuvir (400 mg daily) with ribavirin (SVR12 in 6/10, 60%),18 and there is a small group being treated with sofosbuvir and ledipasvir yet to be reported.

However, the clinical impact of the accumulation of sofosbuvir and GS-331007 is not well understood. In addition, while ribavirin requires dose reduction with progressive decline in GFR, other agents frequently given with sofosbuvir are primarily hepatically metabolized, including simeprevir, daclatasvir, ledipasvir, and velpatasvir. Thus, many patients have been treatment off-label with multiple sofosbuvir-based regimens in this setting. In the largest “real world” experience of patients treated with sofosbuvir with advanced renal insufficiency, 73 patients with GFR of 45 mL/min per 1.73 m2 or less were reported from the HCV-TARGET multicenter cohort, of which 64% had cirrhosis.19 This cohort included patients treated with sofosbuvir in combination with pegylated-interferon and ribavirin, ribavirin alone or simeprevir with or without ribavirin. SVR12 rates were 88% and 81% in patients with GFR ≤ 30 mL/min per 1.73 m2 and 31 to 45 mL/min per 1.73 m2, respectively. However, the presence of cirrhosis was independently predictive of treatment failure. In addition, worsening of renal function and serious adverse events were at least 3.5 times more common among patients with GFR ≤ 45 mL/min per 1.73 m2, compared to controls with GFR greater than 45 mL/min per 1.73 m2 in the HCV-TARGET cohort, raising concern that accumulation of sofosbuvir and its metabolites may in fact have toxicities.

More recently, a prospective multicenter cohort from France enrolled 50 patients with GFR < 35 mL/min per 1.73 m2.20 All genotypes were included, 54% of patients had cirrhosis, and again multiple sofosbuvir-based regimens were used (ribavirin, pegylated-interferon with ribavirin, daclatasvir with or without ribavirin, or simeprevir with or without ribavirin) at the discretion of the investigator. The overall SVR12 rate was 86% due to 4 relapses, 2 deaths and 1 patient who received a liver-kidney transplant. There was no significant change in GFR for patients who were not on dialysis. Thus, while there are conflicting data on whether high levels of metabolites are injurious and concerns about dose adjustment, sofosbuvir-based therapy may be effective in patients with severe renal insufficiency. However, additional data are needed to assess safety, including the impact of treatment on renal function, especially in the high-risk pre-LT cirrhotic population.

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On the Horizon

Small trials are now ongoing with the use of more potent sofosbuvir-based regimens in patients with severe renal insufficiency, including the fixed-dose combination of sofosbuvir/ledipasvir (NCT01958281). Although response rates are likely to be higher than seen with reduced dose sofosbuvir or sofosbuvir with ribavirin alone, it is not clear that a sufficiency number of patients will be enrolled to demonstrate the safety of this regimen, especially as it pertains to progression of renal disease among patients not yet on dialysis.

Among the numerous limitations to our ability to treat patients with cirrhosis and severe renal insufficiency is the lack of effective and safe treatment for patients with HCV genotypes 2, 3, 5, and 6. These are among the only patients for whom pegylated-interferon and reduced dose ribavirin are remain the first-line treatments in current guidelines.3 Although the addition of sofosbuvir/velpatasvir to the treatment armamentarium was a significant step toward an effective pan-genotypic regimen, there are no data to date on the use of this combination in patients with severe renal impairment. However, there are other next-generation regimens with trials specifically in this population.

The preliminarily results of a single-arm trial of the pangenotypic NS3/4A protease inhibitor glecaprevir coformulated with the NS5A inhibitor pibrentasvir were recently reported in 104 patients with genotypes 1 to 6 HCV and stage 4 or 5 CKD.21 Compensated cirrhosis was present in 19% of patients, and 42% were treatment experienced. The overall SVR12 was 98% with no virologic failures. The 2 treatment failures were due to 1 early discontinuation and 1 patient who was lost to follow up. This regimen may represent a significant advance for patients with compensated cirrhosis and severe renal impairment, especially for patients with non-1 genotype HCV, as both drugs are hepatically metabolized with no renal elimination, but likely will carry the same warning regarding hepatic decompensation.

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Decompensated Cirrhosis

The currently recommended antiviral regimens for patients with moderate or severe hepatic impairment (CTP class B and C) include sofosbuvir with ledipasvir, velpatasvir or daclatasvir, with or without ribavirin (for HCV genotypes 1 or 4), or sofosbuvir with velpatasvir or daclatasvir, with or without ribavirin (for HCV genotypes 2 or 3).3,22-27 In general, patients who are ineligible for ribavirin (often including those with renal impairment) are treated with an extended course of therapy.3 For patients with renal impairment but GFR > 30 mL/min per 1.73 m2, these regimens can be used without dose adjustment per current guidelines. However, sofosbuvir is not approved for treatment in the setting of GFR < 30 mL/min per 1.73 m2. Although there are some data on the use of sofosbuvir in patients with advanced renal impairment as detailed above, few patients included in these reports had decompensated cirrhosis. Thus treatment with sofosbuvir-based regimens cannot be recommended in this setting.

Unfortunately, due to hepatic metabolism and reports of hepatotoxicity, currently available NS3/4A protease inhibitors often used in patients with renal insufficiency are not recommended in patients with moderate to severe hepatic impairment (CTP class B and C). The fixed-dose combination of elbasvir/grazoprevir has not been studied in patients with decompensated cirrhosis. A small phase 2 open-label study included 30 patients with HCV genotype 1 and CTP B cirrhosis treated with reduced dose grazoprevir (50 mg daily) and elbasvir 50 mg daily.28 The SVR12 rate was 90% and 1 patient died at week 4 posttreatment. However, there are no data on the currently approved dosage, and this regimen cannot be recommended in patients with decompensated disease.

The PrOD regimen is also contraindicated in patients with CTP class B and C cirrhosis. Due to the predominantly hepatic clearance, the AUC of paritaprevir increases by 62% in subjects with moderate hepatic impairment and 945% in patients with severe hepatic impairment.29 PrOD has been used with high response rates in a small number of patients with CTP B cirrhosis reported in real-world efficacy reports. For example, in a multicenter European cohort of 209 patients treated with this regimen, the SVR12 rate was 100% among the 14 patients with CTP B disease reported. However, in this cohort, there were 7 patients with cirrhosis who experienced hepatic decompensation, 2 of which were felt by the treating physicians to be possibly related to treatment. Pre-treatment measures of liver function including CTP score and MELD were predictive of decompensation. There are now additional reports of hepatic decompensation in patients with compensated CTP A cirrhosis at the start of therapy. These reports include an FDA Drug Safety Communication reporting 26 cases of liver injury considered possibly or probably due to medications, occurring 1 to 4 weeks after starting treatment.30 In addition, a multicenter cohort from Israel reported 7 patients who received PrOD and decompensated within 1 to 8 weeks of starting treatment, including a patient who died.31 It remains uncertain whether the PrOD regimen is truly more likely to cause liver injury and decompensation in patients mild or moderate hepatic impairment than other approved regimens (including simeprevir used with sofosbuvir, for example).32 However, PrOD remains contraindicated in patients with CTP B or C cirrhosis and should be used with caution even in patients with compensated cirrhosis, with more frequent monitoring of liver function in the early treatment period.

Therefore, patients with both advanced renal insufficiency and decompensated cirrhosis remain one of the only groups with no currently recommended antiviral treatment options. Given these safety concerns and the prognosis of these patients in advanced multiorgan failure, the benefits of attempting treatment in this setting are uncertain. Response rates and safety profiles likely favor post-LT treatment in LT candidates, especially given the poor nontransplant survival of patients with decompensated liver disease and severe renal impairment. For non-LT candidates, prolonged survival may be uncommon even with SVR. Though there is a growing literature on stabilization and perhaps improvement in liver function in patients treated with decompensated cirrhosis, patients with advanced renal insufficiency were generally excluded from these studies with sofosbuvir-based regimens,22,26 and those with the highest MELD scores (which is often the case with significant creatinine elevation) are less likely to recompensate, perhaps indicating there is a “point of no return.”33 Thus, the risks and benefits of treatment in this setting must be individualized.

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POSTTRANSPLANT TREATMENT

For patients who remain with HCV viremia at the time of LT, recurrent HCV-associated liver disease is virtually universal. Recurrent HCV has traditionally been associated with an accelerated course post-LT, leading to excess graft loss and mortality among LT recipients with HCV.34,35 As a result, transplant recipients are among the highest priority for treatment.3

CKD after LT is unfortunately very common impacting between 20-80% of LT recipients.36-38 Risk factors for the development of CKD include preexisting CKD, perioperative acute kidney injury, advanced age and chronic HCV infection. Post-LT CKD not only leads to increased risk of ESRD, but also to increased cardiovascular events and mortality. Thus, post-LT renal insufficiency is both common and morbid. While there are many factors that likely contribute to this high burden of CKD in transplant recipients, including high rates of diabetes and hypertension as well as chronic calcineurin inhibitor use, there is evidence that HCV treatment may have a favorable impact on renal function in patients with baseline mild renal insufficiency.15,39 Thus, HCV treatment is a priority in all LT recipients, but perhaps especially those with renal insufficiency. However, there have been no trials specifically assessing safety and efficacy in patients with posttransplant severe renal insufficiency, thus recommendations must be extrapolated from other patient populations.

An increasing proportion of post-LT treatment will be performed among patients with early stage recurrent liver disease. In fact many centers now treat HCV 3 months post-LT or earlier in stable patients, and data are even emerging on peritransplant treatment regimens.40 Thus, deterioration in hepatic function is no longer the main obstacle when choosing a regimen post-LT in most cases. However, the additional consideration in this population is the potential for significant drug-drug interactions, most prominently with the calcineurin inhibitors cyclosporine and tacrolimus, which continue to be the backbone of the immunosuppressive regimen at most centers. Data on the impact of each DAA on the AUC for cyclosporine and tacrolimus are summarized in Table 3. Although there are several regimens that do not require significant a priori dose adjustment in calcineurin dosing, there are agents including the available NS3/4A protease inhibitors (especially those which are coformulated with ritonavir), which lead to significant interactions and the need for both dose adjustment and intensive monitoring. Unfortunately, data on drug-drug interactions are generally not available for some other classes immunosuppressive drugs often used in calcineurin inhibitor-sparing renally protective regimens, including the mammalian target of rapamycin inhibitors everolimus and sirolimus.41

TABLE 3

TABLE 3

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Sofosbuvir-Based Regimens

For post-LT patients with renal insufficiency but GFR > 30 mL/min per 1.73 m2, treatment recommendations are the same as for patient with normal renal function. The first-line recommended regimens in these patients include fixed dose sofosbuvir/ledipasvir with weight-based ribavirin for 12 weeks or sofosbuvir and daclatasvir with low dose ribavirin (600 mg daily initially and increased as tolerated) for 12 weeks genotypes 1 or 4, with alternative regimens including extension of these therapies to 24 weeks for ribavirin intolerant patients.3 Additional alternatives for genotype 1 include sofosbuvir and simeprevir with weight-based ribavirin for 12 weeks, or PrOD and weight-based ribavirin for 24 weeks. For genotypes 2 and 3, sofosbuvir and daclatasvir with low dose ribavirin (600 mg daily initially and increased as tolerated) for 12 weeks is the current first-line regimen. Some providers may also be treating patients with genotype 2 or 3 HCV with the recently approved combination of velpatasvir/sofosbuvir with ribavirin, though clinical trials of this regimen in posttransplant patients are not yet complete.

These recommendations are based largely upon clinical trials that excluded patients with advanced renal insufficiency. In the SOLAR-1 and 2 multiarm trials of sofosbuvir/ledipasvir, the creatinine clearance required for study entry was > 40 ml/min per 1.72 m2.22,24 Although response rates were excellent in these trials, even in patients with recurrent decompensated cirrhosis, the efficacy and safety among patients with severe renal insufficiency remains unknown. In the real world data presented from the HCV-TARGET cohort, 49 of the patients included in the analysis the impact of GFR ≤ 45 mL/min per 1.73 m2 were LT recipients.19 Although being a transplant recipient was not independently associated with a decline in SVR or worsening of renal function in this cohort, the numbers were very small and additional study is necessary once the safety of sofosbuvir is demonstrated in nontransplant patients with severe renal insufficiency.

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Elbasvir/Grazoprevir

While the fixed-dose combination of elbasvir/grazoprevir is the regimen with the most data available for use in patients with stages 4 or 5 CKD, it has never been studied in solid organ transplant recipients. There is a small pilot study that is not yet enrolling among LT recipients (NCT02890719), as well as a kidney transplant trial for treating HCV seronegative recipients transplant with HCV positive kidney grafts (NCT02743897). From preliminary pharmacokinetic studies, there is likely no need for a priori dose adjustment in tacrolimus, however there is a significant increase in the AUC for elbasvir and grazoprevir when given in the presence of cyclosporine, and thus this combination is not recommended. These trials along with perhaps real-world effectiveness studies will provide essential information about the safety and actual pharmacokinetics needed to treat transplant recipients with severe renal insufficiency.

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Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir

The PrOD regimen, which also does not require dose adjustment in patients with GFR < 30 ml/min, has undergone clinical trials in transplant recipients, though with very few patients reported to date. In the initial trial, 34 LT recipients with early stage fibrosis (stage F0-F2) and HCV genotype 1 were treated with PrOD and weight-based ribavirin for 24 weeks.42 The overall SVR12 rate was 97%, and although 15% of patients required erythropoietin, none were transfused. There were no episodes of allograft rejection, though the calcineurin inhibitor dose adjustments required due to the drug-drug interactions with ritonavir and paretaprevir were significant. For most patients, 0.5- and 0.2-mg doses of tacrolimus were administered with a median frequency of 10 and 5 days, respectively. It is important to note that the mean creatinine at treatment initiation was 1.1 mg/dL, thus this patient population had normal baseline renal function. Although the PrOD regimen is attractive in patients with advanced renal insufficiency due to the lack of dose adjustment that is needed, for posttransplant patients on calcineurin inhibitors, the severity of this drug-drug interaction may be of more significant concern in patients with renal failure. It is likely that further reduction in tacrolimus dosing frequency will be required, and the risk of tacrolimus-related progression of renal disease in this setting is unknown. A larger group of liver as well as kidney transplant recipients have now been treated with this regimen, with analysis ongoing.

Real-world data on the use of PrOD in transplant recipients are also emerging. In a multicenter European series, the efficacy of PrOD with or without ribavirin was reported in 209 patients with genotypes 1 or 4 HCV, 21 of whom were post-LT and SVR12 was 100% in this subgroup.43 This study included patients with recurrent cirrhosis after LT, and 3 of these patients experienced decompensation of liver function on treatment. While the report notes that changes in immunosuppression dosing was frequent in this population, further details were not provided.

A trial of the pan-genotyic glecaprevir/pibrentasvir coformulation in liver and kidney transplant recipients is also now ongoing (NCT02692703) and may provide additional options for these patients. Glecaprevir which is not co-formulated with ritonavir is expected to have far fewer interaction with tacrolimus (likely similar to grazoprevir) and less interaction with cyclosporine than other PI-based regimens.

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Posttransplant Recurrent Decompensated Cirrhosis

LT recipients with recurrent decompensated cirrhosis are among the most difficult patients to treat. As in the nontransplant setting, for patients with GFR > 30 ml/min per 1.72 m2, treatment recommendations are the same as for patients with normal renal function. Based on data from the SOLAR trials,22,24 the current recommendations are for fixed-dose sofosbuvir/ledipasvir with initial low dose ribavirin for 12 weeks for HCV genotypes 1 and 4.3 Sofosbuvir and initial low dose ribavirin for 24 weeks is recommended for genotype 2, though given the real world experience to date, many centers would consider the use of daclatasvir with sofosbuvir for all genotypes. However, for patients with recurrent decompensated cirrhosis and severe renal insufficiency, there are no current recommendations due to the limitations of each regimen discussed above. As posttransplant patients with advanced multiorgan failure may have few options to attempt to prolong survival, the risks and benefits of antiviral therapy in this scenario should considered for each individual.

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TIMING OF TREATMENT

There is significant interest in determining the optimal timing of treatment on the LT waitlist, both in terms of patient outcomes as well as cost-effectiveness.44-46 Treatment before transplant may have the potential benefit of improvement or stabilization of liver function with SVR, treatment of extrahepatic manifestations perhaps including renal failure, and prevention of recurrent disease in the allograft post-LT. However, there is concern that pretransplant treatment may inadvertently lead to diminished access to transplant and thus prolong the time on the waitlist. This may be due to both a decline but not normalization in MELD score (so-called “MELD purgatory”) as well as subsequent reluctance to accept a graft from an HCV positive donor. In addition, overall SVR rates may be higher in the early post-LT period as compared to when awaiting LT with CTP class C cirrhosis. Thus posttransplant treatment could theoretically decrease the risk of treatment failure-related resistance, and could be a better option for patients with limited access to medications and have “one shot” at treatment.

Modeling to inform an approach to treatment timing for a population is complex, and requires taking into account multiple variables including the patient’s prognosis on the list with and without treatment, as well as the dynamics of allograft allocation including the availability of HCV positive donors. This was recently simulated using a Markov-based microsimulation model that incorporated both information from HCV treatment trials pre- and post-LT, as well as United Network for Organ Sharing data.46 The authors conclude that the optimal MELD threshold below which patients awaiting LT should receive HCV treatment may be between 23-27, depending on the transplant region.

However, given the limited data upon which many essential assumptions are made in modeling analyses, treatment decisions must remain individualized, and the complexity of this decisionmaking is likely the highest in patients with pre-LT severe renal insufficiency. This is particularly true for patients with high MELD scores (>20) who have been categorically excluded from treatment trials. However, how to reliably identify which of these patients will benefit is not known.33 In addition, treatment may be increasingly complex for patients with prior DAA exposures and thus resistance to various agents. For these patients, testing to identify specific resistance associated substitutions will be needed, and treatment posttransplant with additional treatment options is likely warranted as the patient will be more stable and next-generation therapies with increased potency against resistant variants should be available.

Our strategy for treatment of patients listed for LT alone is presented in Figure 1, but many of these patients will be candidates for dual organ transplant. In the recently proposed simultaneous liver-kidney allocation policy, patients with either ESRD or advanced medical renal disease (defined as GFR of <60 mL/min for >90 days before listing and a GFR of <35 mL/min at the time of listing) will be eligible for dual organ listing, as will patients with sustained acute kidney injury (defined as requiring dialysis for 6 consecutive weeks).10 Given the lack of data on the clinical impact of HCV treatment pretransplant in this setting, and the complexities of dual organ allocation, how to select patients for pre-LT treatment is uncertain. For patients who require dual organ transplant, the difficulties in selecting a pretransplant regimen and the advantages of being able to accept HCV positive organs likely favor posttransplant therapy in the majority of these cases.

FIGURE 1

FIGURE 1

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CONCLUSIONS

LT candidates and recipients with renal insufficiency remain among the highest priority for HCV treatment given the significant morbidity and mortality attributed to HCV-related liver and kidney disease. However, with the regimens currently available, the combination of renal insufficiency along with either hepatic dysfunction (pre-LT) or significant medications interactions (post-LT) leave these patients with limited treatment options, especially those with non-1 HCV genotype. Despite these difficulties, data are now emerging on the currently available agents, as well as next-generation regimens that may significantly improve the safety and efficacy of treatment in these small groups of patients yet to be well served by the regimens available.

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REFERENCES

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