Until 2014, before the availability of the new direct-acting antiviral drugs (DAA), the HCV treatment in patients with ESRD was based on INF±Rib60 (Table 1).

As said, HCV infection in RT is associated with worse patient and graft survival as compared to patients without infection.24 Given the risk of INF to induce renal graft dysfunction,61,62 international guidelines had recommended treating HCV infection before RT. This was the treatment before direct-acting antiviral drugs became available.1,63

Despite the recommendations to treat HCV infection before RT, only 1% of patients HCV RNA+ hemodialysis received treatment with IFN as reported in the study DOPPS. This is, a very low percentage probably due to the poor tolerance and poor efficacy of this antiviral regime.64

International guidelines have recommended that patients with active HCV infection should be evaluated for the degree of liver fibrosis, and until a few years ago only liver biopsy was available for such evaluation. Likewise in patients with cirrhosis, it is necessary to determine the presence of portal hypertension; if a gradient of hepatic venous pressure is ≥10mmHg and/or esophageal varices are observed, the consensus of guidelines have considered that isolated RT should not be performed and the possibility of combined Liver and renal transplant should be considered65 (Fig. 1).

Fig. 1.

Approach to the treatment of HCV in patients with terminal end stage renal disease patients candidates for renal transplantation.

(0.63MB).

Antiviral treatment of dialysis patients with HCV infection in the interferon era included INF-pegylated for 48 weeks for genotypes 1, 4 and for 24 weeks for genotypes 2 and 3. During the treatment, patients were excluded from the waiting list, and once virus was removed after completion of therapy it was recommended to wait at least 28 days before receiving a RT.1,66

A meta-analysis of 287 patients treated with INF and Rib showed a sustained viral response (SVR) in 60% of the patients with 18% abandonment due to side effects, especially anemia and infections.67 With these results it was assumed that in the pre-DAA era, the INF-pegylated and Rib were the standard treatment of HCV in dialysis patients.

Patients who were unable to clear up the RNA virus with antiviral treatment could be included in the waiting list for TR, given the fact that the life expectancy of patients with HCV replication is higher if they are transplanted than if they remain on dialysis.41–44,68

A meta-analysis of 16 clinical studies showed that the sustained viral response was 34% and the abandonment of treatment was 32%.67

The most frequent and serious side effect of treatment with INF in RT patients was graft dysfunction, usually as steroid-resistant acute rejection, which required discontinuation of the treatment.1,56,69

During the INF era KDIGO guidelines advised treatment with IFN only in cases of RT in which the benefits of antiviral therapy were greater than the risks, such as cholestatic fibrosing hepatitis, rapidly evolving cirrhosis or de novo or recurrent cryoglobulinemic MPGN.1

The great advance in the knowledge of the HCV life cycle and the characteristics of the proteins of this virus has facilitated the development of new DAA that act specifically on the HCV life cycle70 (Fig. 2).

Fig. 2.

Treatments directed against HCV life cycle.

(0.3MB).

According to the phase of the life cycle in which the DAA acts to prevent HCV replication, they DAA are classified as protease inhibitors (PI), inhibitors of NS5A replication complex and NS5Bpolymerase inhibitors.71

Since 2014, new DAA have been commercialized60 (Table 1), achieving a SVR greater than 95% in the general population.

The first DAAs used in the treatment of HCV were the IP NS3/4A telaprevir72 and boceprevir,73 that were approved for the treatment of HCV 1 genotype in 2011 in combination with INF-pegylated and Rib.8 Although the SVR rate obtained was a 75% of cases, the cost, side effects and complexity of its administration was limitation in the use of these antivirals.

The launch of the first generation of IP NS3/4A served as a springboard for the development of new DAAs, such as NS5B polymerase inhibitors, inhibitors of NS5A viral replication complex and second generation PIs with a great improvement in efficacy and security.7,8,74

In United States, year 2013 and in Europe, February 2014, were approved three new DAA simeprevir (IP-NS3/NS4A), daclatasvir (Inhibitor-NS5A) and sofosbuvir (polymerase-NS5B inhibitor). Having these new DAAs available allowed the development of different therapeutic strategies against HCV that were safe and efficient and without the need of INF. This has been a great advance in the treatment of HCV, and especially for the patients such as RT in which the use of INF is contraindicated.

This initial antiviral therapeutic scheme against HCV entails the combination of two or three of these new drugs given orally, with or without Rib, but without INF, during a period of 12–24 weeks depending on factors such as the virus genotype, the degree of hepatic fibrosis, the previous history of anti-HCV treatment and renal function. These therapies have achieved a SVR of 90–100%, with a good safety profile.75,76

The next stage in the development of new strategies against HCV started in 2015 with the use of combinations of DAA after the approval of new formulations without INF or Rib60 (Table 1). The fixed combination of sofosbuvir (SOF) with ledipasvir (LDV) was approved by the FDA in October 2014 and in Spain in March 2015. In the last 3 years there has been a continuous incorporation of new DAAs, such as elbasvir (EBR) glecaprevir (GLE), asunaprevir, paritaprevir (PTV), grazoprevir (GRA), pibrentasvir (PIB), velpatasvir (VEL), ritonavir (r), ombistavir (OBV), dasabuvir (DSV) and voxilaprevir (VOX)60,75 (Table 1).

The fast research progress in this field has allowed to outspread the therapeutic coverage to all HCV genotypes (pangenotype), reducing the duration of treatment, improving the safety profile and minimizing pharmacological interactions77 (Table 2).

In general, the tolerance to the new DAAs is acceptable and with only a few side effects (Table 2). Antivirals, alone or in combination, such as SOF, SOF/LDV, SOF/VEL, GRA/LDV and GLE/PIB, are associated with fatigue and headache.76 Headache, diarrhea and nausea have been the most frequent side effects with SOF/VEL/VOX, these gastrointestinal manifestations are superior to those observed with the double combination SOF/VEL.78

Using the new DAA, without INF, the cure of HCV is achievable in all genotypes, regardless of the presence of cirrhosis. However, one of the main problems is the risk of interactions with other drugs, which may decreased efficacy or increased toxicity.

The most relevant interactions are through the cytochrome P450 enzyme (CYP450). Interactions with glycoprotein P (P-gp) and with breast cancer resistance protein (BCRP) also have the potential to affect the bioavailability of the drug.79,80 Ritonavir, a potent CYP3A4 inhibitor, if co-administered with drugs metabolized by this enzyme may result in a marked increase in plasma concentrations. Therefore, before planning the antiviral treatment, it is advisable to evaluate the specific data sheet of the drug to have a detailed description of the interactions with other medications.

The use of some inducers of CYP450 and P-gp is contraindicated in all regimes because of the risk of significantly decreasing DAA concentrations. On the other hand, regimes that include an NS3-4A IP, such as PTV-r, GRA, GLE or VOX, should not be used in patients with decompensated cirrhosis Child-Pig B or C, because the increased risk of high IP concentration with the consequent toxicity.78

In relation with renal function, there are only recommendations for the use of NS5B SOF polymerase inhibitor, since its elimination is mainly through the kidneys, so it is not recommended if the estimated glomerular filtration rate (eGFR) is <30ml/min/1.73m2, unless there are no other therapeutic options, and if used it should be under close monitoring.78

According to the RUBY-1 study the combination OMB/PTVr/DSV for the treatment of genotype1 in patients with advanced CKD without cirrhosis produced a SVR of 90%.95

The clinical trial phase III, C-Surfer, included 122 patients with CKD stage 4 and 5 (6% cirrhotic and 20% not naïve) with genotype 1HCV treated with oral combination GRA/EBR for 12 weeks. The response achieved excluding 6 patients with non-viral failure was 99.1%, and 94.2% in the complete analysis96 (Table 4).

The GLE/GDP combination was evaluated in the Expedition-IV trial, a 12week treatment of patients with genotypes 1 to 6, naïve or with a previous treatment with INF, and in patients with CKD stages 4 or 5. This combination obtained an SVR of 98%97 (Table 4).

Based on these results, these combinations have been regularly recommended to treat HCV in patients with advanced CKD and on maintenance dialysis.78,81

Pioneering studies have shown excellent results in the treatment of HCV in RT patients with SOF regimens with,92,93,98,99 achieving a SVR of 100% after 12 weeks.

Based on data from the Spanish renal transplant registry, in 103 patients treated with DAAs in different regimens without INF, the SVR12 was 98%.98 The most commonly used combinations were SOF/LDV (57%) and SOF/daclatasvir (17%), and 41% of patients received Rib. Immunosuppressive adjustment was required in 55% of patients. No significant changes were detected in proteinuria and renal function before and after treatment; although 3 patients had acute humoral rejection likely in the context of a reduced exposure to immunosuppressive treatment.98

A multicenter randomized phase II including 114 TR patients with HCV genotype with 1 and 4 with the combination SOF/LDV for 12 or 24 weeks achieved a SVR of 98%86; 18% of patients required adjustment in the immunosuppressive dose without episodes of rejection. Accordingly, in patients with good renal function, the SOF-based regimen has been efficient and safe (Table 4).

To choose the right combination of DAA in RT patients, it is necessary to take into account the renal function, and the HCV genotype77,78 (Tables 5 and 6).

The phase II study, MAGELLAN-II included 100 patients with genotype 1, 2, 3, 4, 5 or 6 without cirrhosis with liver transplant (80%) or renal transplant (20%) treated for 12 weeks with GLE/GDP. Except for the genotype 3 (only naïve), naïve and non-naïve (prior treatment with regimens including INF, peg-INF, RBV±SOF) were included, achieving an SVR at 12 weeks in 98% of patients (Table 4).

Recommendations for the treatment of HCV in patients with RT are detailed in Table 6. During and after completion of DAA treatment patients should be monitored for calcineurin inhibitor levels,77,92,93 renal function88 and proteinuria. It should be noted that glomerular segmental and focal hyalinosis has been reported after treatment with DAA.89

The recommended treatment before or after RT will depend on the type of donor, the time on waiting list for a given type of donor, the possibility of using organs from HCV+ donor, the HCV genotype and the degree of liver fibrosis77 (Fig. 1).

As previously mentioned, all HCV patients who are candidates for RT cirrhosis should be evaluated using liver biopsy or a non-invasive method to stratify the degree of liver fibrosis.77,78 In patients with compensated cirrhosis without portal hypertension, isolated RT may be considered, while combined liver -renal transplant is recommended in decompensated cirrhosis and/or severe portal hypertension.

It is important to consider what is the optimal time to perform the antiviral treatment while on the waiting list for transplantation. Except in cases of decompensated cirrhosis or significant portal hypertension, if the RT is expected to be performed soon (within 6 months approximately) from living donor the AAD treatment may be programmed post-RT. Conversely, if the RT is planned beyond 24 weeks, it must be assessed the risk-benefit of deferring treatment after transplantation.77

Likewise, in patients on the waiting list for RT from a cadaveric donor, antiviral treatment may be deferred after RT to allow for the possibility of receiving a donor kidney HCV+ and reduce waiting time,66 especially if the immunological risk is low and the possibility of receiving soon a compatible donor is high. However, patients without the possibility of being transplanted as an HCV+ donor, or in those with low chances of being offered a compatible graft soon, antiviral treatment should be offered before the RT.

It is important to consider that in patients who remain HCV+ while on the waiting list, an annual evaluation of the degree of liver fibrosis should be performed, and if there is evidence of progression of liver damage, antiviral treatment should be initiated.

The type of genotype may also influence the decision on what is the optimal time to perform antiviral treatment. Until now, in patients on the waiting list for RT infected by genotype 1 or 4, antiviral treatment is indicated before RT using GRA/EBR or OMB/PTVr/DSV in the case genotype 1b. However for genotype no-1 or no-4 the treatment is postponed after the TR, since the regimes approved to date have been based on SOF. With the recent FDA approval of the GLE/PIB pangenotype combination, without the need for adjustment in renal insufficiency, treatment can be planned in all cases before RT78 (Table 5).

Patients on the waiting list with cirrhosis despite becoming HCV- should be assessed every 6 months with ultrasound to rule out the occurrence of hepatocellular carcinoma.96

In HCV and HBV co-infection, the serum level of HBV-DNA is often undetectable, with HCV being the main causative agent of hepatic inflammatory activity, so with the clearance of HCV there is a risk of HBV reactivation.

It is essential to determine the serological status for HBV before starting treatment against HCV and in patients with HCV-HBV coinfection, concomitantly with anti-HCV therapy, it should be started treatment against HBV with nucleoside/nucleotide analogs.78 If the HBsAg if positive, specific treatment against HBV should be performed for 12 weeks after completing treatment with AAD. If HBsAg is negative but anti-core HBV is positive, the HBV-DNA and HBsAg should be monitored in case of increasing or not normalizing transaminases (monthly determinations) during or after HCV treatment, and initiate anti-HBV therapy if HBsAg and/or HBV-DNA are detected.78

After demonstrating that organ transplantation can transmit HCV,100 there was general consensus that the kidneys of HCV+ donors should not be transplanted in HCV− patients.101 However, due to organ shortage, it was raised the possibility of transplanting kidneys from HCV+ donors into HCV+ recipients.102,103

The first experiences in RT using HCV+ donor kidneys in HCV+ receptors, in which our country was a pioneer, demonstrated that in short term this strategy was feasible and safe.103–106 As a consequence, national and international guidelines recommended this practice to avoid loss of organs.

Despite these recommendations, RT using HCV+ donor kidneys in HCV+ receptors has continued but remains controversial.104–107 American studies, mostly based on analysis of registries, show a shorter waiting time for RT but it was associated with a small increase in the risk of death, graft loss and severe liver disease, compared to those receiving kidneys from HCV− donors.108–111 These authors suggest that the high incidence of new onset diabetes after transplant (NODAT) in HCV+ receptors may explain the decrease in patient survival. However, the survival of patients receiving kidneys from HCV+ donors is higher than HCV+ patients maintained on the waiting list.77,104–107

The cooperative study between the hospitals October 12 of Madrid and Clínic of Barcelona, in RT patients from HCV+ donors in HCV RNA+ receptors, reported that at a long term a positive donor serology is not an independent risk factor for liver disease or grafts and patient survival.21 These results have been reproduced in recent studies, also pointing out that the shorter waiting list time contributes to improved graft survival (censored death) compared to HCV+ recipients transplanted with kidneys from HCV−112 donors. Therefore, the KDIGO guidelines continue to recommend transplantation with HCV+ donors into HCV+ RNA receptors.77

In recent years there has been a decrease in the incidence and prevalence of HCV infection on dialysis, so that the offer of a donor kidney HCV+ may sometimes not be used due to lack of an adequate recipient,110 suggesting that organizational measures should be taken, including the offer of these kidneys for early RT.109

As recently suggested, the success of DAAs therapy will help to increase the use of the HCV+ donor kidneys (Fig. 1). It is being proposed to transplant HCV+ patients with mild fibrosis with an HCV+ donor kidney and treat them after RT with the new DAA,4 so that the period of time waiting for transplant would be shortened. In addition, there are already experiences of HCV+ receptors of a HCV+ kidney that were treated with DAA and achieved the eradication of the virus after transplantation.113

In short, the use of HCV+ donor kidneys in HCV+ RNA receptors is a long-term safe strategy that provides a patient survival which is longer than that of HCV+ patients who remain on the waiting list for RT. The availability of DAAs therapy after TR, will help to increase the pool of donors by using the HCV kidneys in HCV+ receptors throughout the world. However, antiviral treatment in advanced CKD or on dialysis patients, in countries with universal or almost universal access to antiviral treatment will reduce or may even make to disappear the number of possible HCV+ receptors; actually this is happening in Spain (data not published).

The waiting list for RT is increasing every year in most countries, and the waiting time for transplantation is too long. In this context, the question that has emerged in the transplant community is: “In the new era of antivirals, RT with HCV+ donor kidneys in HCV receptors; is it feasible and ethically acceptable?”.113,114

Two North American trials using kidneys from HCV+ donors in HCV receptors− have been the pioneers in assessing the possibility and safety of this therapeutic option.115,116 The THINKER trial included 10 patients HCV− receiving a kidney donor HCV RNA+ with genotipe 1. Antiviral treatment with grazoprevir/elbasvir was administered when viremia was evidenced which occurred around the third day posttransplant. All patients became infected, and after 12weeks of treatment all showed SVR.115 Likewise the EXPANDER trial included 8 patients on, grazoprevir/elbasvir, preoperatively and after transplant, and again all patients became infected and they all had SVR after 12 weeks of treatment.116 The data published by Goldberg et al.,115 is being completed and expanded with the recent work by Reese et al.,117 showing the results of 20 HCV− patients after receiving a HCV RNA+ kidney transplant obtaining a 100% eradication of the virus at 12 month treatment. A recent study also confers economic advantages in favor of using HCV RNA+ kidneys for RT to HCV− receptors compared to HCV− patients on regular dialysis on the waiting list for a HCV− donor.118

The strategy of using HCV RNA+ donors in HCV receptors− offers the possibility of increasing the pool of donors for RT and thus reducing the waiting list119; however, although the protocols have been already established in some national and international centers, the experience is still scarce.

Although these experiences are promising, caution should be maintained until more complete information is available. In fact, the HCV Consensus Conference of the American Transplant Society recommends that the transplantation of HCV+ donor organs into HCV recipients− should be performed only as a research protocol with a thorough and rigorous informed consent that must be authorized by the ethical committee of each center.101