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Volume: 15 Issue: 1 February 2017 - Supplement - 1

FULL TEXT

Pre- Versus Posttransplant Treatment of Hepatitis C Virus With Direct-Acting Antivirals in Liver Transplant Recipients: More Issues to be Solved

Objectives: Our goal was to investigate wait times related to hepatitis C virus treatment with direct-acting antivirals before versus after liver transplant at a single center as well as wait times for insurance approval for preemptive treatment with these agents after liver transplant.

Material and Methods: We retrospectively evaluated hepatitis C virus infections in transplant recipients of deceased liver donations in 2014 and 2015. Demo­graphics, hepatocellular carcinoma incidence, Model for End-Stage Liver Disease scores, and transplant wait times were compared between patients treated before or after liver transplant. Wait times to approval of direct-acting antiviral treatment were evaluated in those untreated before transplant.

Results: During our study period, of 67 deceased-donor liver transplants, 21 patients received hepatitis C virus treatment pretransplant (treated group) and 46 patients were not treated pretransplant (untreated group). Twenty-five patients in the untreated group received hepatitis C virus-positive donations, with all in this group treated with direct-acting antivirals. We found no statistically significant differences regarding age, sex, race, donation after cardiac death, or incidence of hepatocellular carcinoma between groups. The treated group had a longer median wait time (287 vs 172 days; P = .02). Twelve of the 46 untreated patients (26.1%) developed biopsy-proven hepatitis C virus-related relapse (median 87 days; range, 55-383 days). Preemptive direct-acting antiviral therapy was initiated at a median of 81 days in the untreated group.

Conclusions: Although treatment of hepatitis C virus before liver transplant is an attractive option to eliminate the risk of complications, it can limit the donor pool for recipients to uninfected donors, significantly increasing wait times in regions with large hepatitis C virus-positive donor pools. Allocation of Model for End-Stage Liver Disease score was not different between the treated and untreated groups. Insurance companies should revise their policies for rapid approval of preemptive direct-acting antiviral treatment after liver transplant.


Key words : Therapy, Transplant wait time, Waiting list

Introduction

Hepatitis C virus (HCV) infection accounts for the most common cause of chronic liver disease. Recent data have shown that HCV affects an estimated 185 million individuals worldwide and 3 to 4 million people in the United States.1,2 Hepatitis C virus-associated liver disease has become the most common indication for orthotopic liver transplant (LT) in North America.3,4

In the past, treatment of HCV both before and after transplant was difficult because of the adverse effects of interferon-based therapy and also because sustained virologic response (SVR) rates were low.5 In December 2013, the US Food and Drug Admin­is­tration approved use of direct-acting antivirals (DAA) such as sofosbuvir and simeprevir; later, in October 2014, it approved the sofosbuvir plus ledipasvir combination, which have allowed SVR rates of > 90%.5-9 Therapy with these new drugs are associated with significantly low adverse effects. Interferon-free regimens soon were adapted for the treatment of HCV among candidates on LT wait lists, in an effort to clear the virus before the anticipated LT, thus potentially eliminating the risk of posttransplant graft reinfection.5 However, the effects of HCV clearance before LT still remain largely unknown.5

In 2014, deceased liver donations were 6449 in the United States.10 Organ shortage has brought into question the suitability of HCV-positive grafts, especially in centers that are located in areas that have a relatively large pool of HCV-positive donors. The use of HCV antibody-positive livers in trans­plants does not influence overall or graft survival; however, it may increase the risk of advanced hepatic fibrosis.11,12

On the other hand, the risks of graft rejection or accelerated graft fibrosis and cirrhosis increase dramatically with high viral load. Studies have shown that achieving SVR before LT reduces liver-related morbidity, mortality, and risk for retransplant.13 With a pan-genotypic sofosbuvir-velpatasvir regimen, overall SVR rates among decompensated HCV cirrhosis cases from 6 genotypes were 83% with 12-week and 86% with 24-week treatment. Serious adverse events occurred in 16% to 19% of cases.14 Comparatively, recent data on achieving SVR with DAA after LT are encouraging.15-17 The SVR rates among those with genotype 1 and 4 disease and Child-Pugh A, B, and C cirrhosis were found to be 87%, 96%, and 85% after 12 weeks of ledipasvir-sofosbuvir-ribavirin treatment. On the other hand, among LT recipients without cirrhosis, the SVR rate was 93% with 12 weeks and 100% with 24 weeks of treatment. Moreover, SVR rates among those with posttransplant cirrhosis were 100% with Child-Pugh A score (12 weeks of treatment), 95% with Child-Pugh B score (12 weeks of treatment), and 80% with Child-Pugh C score (24 weeks of treatment). Even with involvement of severe fibrosing cholestatic hepatitis, SVR was 100% according to a recent study.18

Pretransplant viral clearance has been shown to be a major advantage. On the other hand, a potential consequence of HCV RNA elimination before LT is that the recipient becomes restricted to HCV-negative donor offers. This subsequently may limit access to LT in areas that frequently use HCV-positive de­ceased donations.

With these details in mind, we investigated whether, in our center the allocation Model for End-Stage Liver Disease (MELD) score and the transplant wait time differ between those treated for HCV before LT (treated group) and those with HCV who are not treated (untreated group). We also looked at wait times to insurance approval of the DAAs during the post-LT period, since preemptive treatment is considered as an option to minimize recurrence of HCV after LT.

Materials and Methods

After obtaining approval from the Institutional Review Board, we retrospectively reviewed the medical records of recipients who had undergone deceased-donor LT with primary indication of HCV infection at The Johns Hopkins Liver Transplant program from January 1, 2014, to December 31, 2015. Demographics, laboratory data, and wait times to LT and to initiation of DAA after LT were collected. Coexistence of hepatocellular carcinoma (HCC) was also recorded.

Serum HCV RNA results were obtained from all HCV-positive recipients on post-LT day 5 with genotyping. The DAA treatment modality was based on this newly obtained genotype according to the American Association for the Study of Liver Diseases guidelines. The insurance company approval process initiates thereafter for preemptive HCV treatment. The time elapsed until the medication is actually dispensed by the pharmacy was recorded (DAA wait time). No HCV RNA and genotyping results were obtained for recipients who were treated for HCV before LT and who were negative at the time of LT.

Recipients with unexplained elevations of liver transaminase levels during the DAA approval wait time underwent liver biopsy. The presence or absence of viral hepatitis features on the histo­pathologic examination was recorded.

Patients were categorized into 2 groups: (1) patients who received HCV treatment before LT with achievement of SVR with 12-week treatment and transplanted with HCV-negative donor grafts (treated group); and (2) patients with HCV who were not treated for HCV and who were transplanted with either HCV-positive or HCV-negative donor grafts (untreated group).

Pre-LT HCV treatment is defined as SVR at 12 weeks at time of LT. Patients who had living-donor transplants or retransplants were excluded from the study.

Statistical analyses
Statistical analyses were performed using Stata (Stata Corp., Lakeway Drive, TX, USA). Comparisons between categorical variables were done using Fishers exact test. Because of nonparametric dis­tribution and insufficient patient numbers, comparisons between continuous variables were done with the Mann-Whitney U test. P values ≤ .05 were considered statistically significant.

Results

During our study period, 67 deceased-donor LTs were performed with primary indication of HCV infection. Living-donor LTs, second LTs, and reci­pients with evidence of previous spontaneous HCV recovery were excluded. Sustained virologic res­ponse was achieved among 21 recipients; these patients had undetectable viral load at the time of LT (Table 1). All except 1 patient in this treated group were matched to HCV-nonexposed grafts. That recipient was matched to an HCV antibody-negative but RNA-positive graft. In this specific case, the donor was a young intravenous drug user who died of drug overdose. The recipient had severe hepatopulmonary syndrome; due to the urgency of the clinical situation, the graft was used with her consent.

Our untreated group (detectable viral load at the time of LT) included 46 patients. Of these, 25 received HCV-positive grafts, with 11 receiving HCV antibody-positive/RNA-negative, 11 receiving HCV antibody-positive/RNA-positive, and 3 receiving HCV antibody-negative/RNA-positive donor grafts. As anticipated, HCV-positive grafts were more commonly used in untreated cases (P ≤ .001).

We found no statistically significant differences in age, sex, race, donation after cardiac death, and HCC between the 2 groups (Table 1). Among 46 untreated patients, 12 patients (26%) developed post-LT biopsy-proven HCV recurrence at mild to moderate stages. Median time to biopsy-proven recurrence was 87 days (range, 55-383 d). Of these 46 untreated patients, 41 were preemptively treated with DAA after LT. The prescribed DAA regimens were based on the American Association for the Study of Liver Diseases guidelines, according to the genotype and comorbidities of the patient (ie, renal disease).

Direct-acting antiviral therapy was initiated, as per the approval of the insurance company, at a median of 81 days (range, 11-508 d) after LT. The mean was 127 days (standard deviation = 116.2; n = 41 patients). In 2 patients, treatment was initiated just before LT (4 and 9 days), by their referring gastro­enterologists. One patient had consented to late treatment (day 639) despite recommendations to initiate DAA earlier. In addition, 2 patients, who died after prolonged intensive care unit stay, were excluded from the treatment initiation time analysis. Among the untreated group of 46 patients, there were 3 deaths within our 1-year study period, occurring on post-LT days 57, 139, and 254. During the same period, there was only 1 mortality in the treated group (on day 232).

Table 2 shows recipient characteristics related to HCV status at time of LT. Median days on wait list was 287 (range, 11-1066 d) in the treated group and 172 (range, 3-923 d) in the untreated group (P = .02). The median allocation MELD score at the time of LT was 28 in both the treated and untreated groups, with no statistically significant difference (P = .43).

Discussion

Hepatitis C virus-related cirrhosis remains the leading cause for LT among candidates.19,20 In January 2015, there were about 17 000 patients registered for LT in the United States. The number of patients dying or too ill for LT has risen from 11.1 per 100 in 2009 to 12.3 per 100 in 2014.10 To help improve the shortage of liver donors, HCV-positive donors are considered. The proportion of HCV-positive recipients who have received HCV-positive livers has increased from 6.9% in 2010 to 16.9% in 2015.21 An attempt is made to match HCV-positive donors to HCV-positive recipients. When an HCV-positive recipient receives an HCV-negative or HCV-positive graft, infection of the graft occurs almost instantly, with viral titers often reaching pretransplant levels as early as a few days, sometimes with changing of genotype of the disease in favor of the donor’s HCV genotype.22

In our cohort, the time for developing biopsy-proven HCV recurrence was detected at a median of 87 days (range, 55-383 d, n = 12). There were no protocol liver biopsies obtained, as the indication for the liver biopsy is made on a clinical basis. In contrast to that shown pretransplant, HCV infection can demon­strate accelerated fibrosis progression after LT. In fewer than 10% of the cases, a clinical picture can be seen as severe progressive fibrosing cholestatic hepatitis. It has also been shown that, in post­transplant patients with untreated HCV, the clinical course of the disease is rapid, with 15% to 30% developing cirrhosis within 5 years after transplant.23

Preemptive treatment was initiated at a median of 81 days (range, 11-508 d) after LT (mean of 127 days; standard deviation = 116.2). The main reason for this relative delay is mostly due to the wait time until insurance approval is secured. It has been shown that mortality can be reduced with earlier initiation of HCV treatment after liver transplant, with effectiveness decreasing if given late.14 However, the time to initiate treatment remains poorly described and is influenced by several factors.23-25 Until recently, due to theoretical risks of drug interactions with immunosuppressives and renal impairment, treatment was suggested to be delayed for the first 3 months after LT.25 However, according to well-designed studies with DAAs as well as real-life experiences, these theoretical risks seem far from real, except for dose adjustments for ribavirin.6,9,14-18 Insurance companies commonly follow a policy of using the relatively old argument to delay the treatment for 3 months. In our opinion, this should be revised, keeping in mind we saw histopathologic changes start as early as 55 days after LT.

In our study of 67 deceased-donor LTs performed for HCV-related liver disease, 46 recipients (67%) were HCV RNA positive at time of LT. Of these patients, 25 (54%) received HCV-positive donor allografts. Of the 46 untreated patients, 44 received DAA treatment after LT. Fourteen patients in this group (30.4%) received HCV RNA-positive grafts. Our analyses showed no statistically significant differences in age, sex, race, donor after cardiac death status, and HCC between the untreated and treated groups. This latter finding is particularly important since presence of HCC has a large effect on allocation MELD score with earlier donor availability.

Some transplant centers may have a relatively higher pool of HCV-positive donors. Patients may be better served at these centers by waiting until after LT to consider the antiviral treatment, in an effort to recover organs from the HCV-positive donor pool.26 In our institution, over a 2-year period, 39% (26 of 67 recipients) of HCV-related cirrhosis patients received an LT from HCV-positive donors (Table 1). This fact must have played a role in decreasing the median wait time from 287 days in the treated group to 172 days in the untreated group (Table 2; P = .02). The median MELD score was not significantly different between the 2 groups (28 vs 28) (Table 2). This means that patients with the same severity of disease can be transplanted after a shorter wait period if they remain untreated during the pre-LT period.

Our study has several limitations. It is a single center experience with retrospective data. We do not have the HCV treatment results yet, and we do not have morbidity and long-term survival data.

In conclusion, although HCV treatment before LT is an attractive option to eliminate the risk of post-LT complications, it can limit the donor pool for the recipient to HCV-uninfected donors and therefore significantly increase the wait time to transplant, especially in regions with larger HCV-positive donor pools. Therefore, regarding the pre-LT HCV treatment decision, we recommend this perspective to be discussed with LT candidates on deceased-donor wait lists. On the other hand, in communities where living-donor LT is considered as the main access to transplant, it is imperative to treat the recipient before LT to be able to achieve the best post-LT success. Insurance policies governing approval of DAAs after LT should be revised with the current data in mind, as a more rapid approval process for initiation of HCV treatment soon after LT is likely to improve the HCV-related outcomes.


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Volume : 15
Issue : 1
Pages : 1 - 5
DOI : 10.6002/ect.mesot2016.L19


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From the 1Division of Internal Medicine, Medstar Franklin Square Hospital, Baltimore, Maryland, USA; the 2Transplant Hepatology Section, Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and the 3Division of Transplant Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Acknowledgements: The authors have no conflicts of interest to declare. We acknowledge support for the statistical analysis from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health through Grant Number 1UL1TR001079.
Corresponding author: Ahmet Gurakar, Johns Hopkins University School of Medicine, Transplant Hepatology, Division of Gastroenterology and Hepatology, 720 Rutland Avenue, Ross Research Building #918, Baltimore, Maryland USA
Phone: +1 410 614 3369
E-mail: aguraka1@jhmi.edu