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Original Clinical Science—Liver

Treatment of Patients With Hepatitis C Virus Infection With Ledipasvir-Sofosbuvir in the Liver Transplant Setting

Abaalkhail, Faisal MD1,2; Elsiesy, Hussein MD1,2; Elbeshbeshy, Hany MD1; Shawkat, Mohamed MD1,3; Yousif, Sarra MD1; Ullah, Waheed MD1; Alabbad, Saleh MD1; Al-jedai, Ahmed Pharm. D1; Ajlan, Aziza PharmD1; Broering, Dieter MD, PhD1; Saab, Sammy MD4; Al Sebayel, Mohammed MD1; Al-Hamoudi, Waleed MD1,5

Author Information
doi: 10.1097/TP.0000000000001907
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Hepatitis C virus (HCV) infection is the leading indication for liver transplantation (LT) and is a major cause of liver-related mortality.1,2 It also has a negative impact on patient and graft survival, leading to an inferior transplant outcome compared with other indications.3,4 HCV eradication before LT will likely improve the patient’s outcome by eliminating the risk of posttransplant recurrence.5

HCV genotype 4 (HCV-G4) is the most prevalent genotype in the Middle East and in Northern Africa.6-8 Because of immigration, the frequency of infection with HCV-G4 is also increasing in European countries.9-11 The most common genotype in Europe and in the United States is genotype 1; therefore, HCV-G4 has not been adequately studied in prospective trials evaluating treatment outcomes and remains the least studied variant.

The percentage of liver transplant recipients with HCV-G4 varies according to geographic location. HCV-G4 represents more than 90% of indications for LT in Egypt.12 In Saudi Arabia, HCV represents approximately 29% of indications for LT, approximately 60% of which are secondary to HCV-G4.13 HCV-G4 is a relatively uncommon indication for LT in Europe and North America.14,15

Until recently, interferon-based therapy was the only treatment for HCV. However, this treatment has drawbacks including numerous side effects, low barrier to resistance, and reduced efficacy in prior null responders or cirrhotic patients. Direct-acting antiviral agents (DAAs) represent a breakthrough in the management of HCV.16 Multiple clinical studies have shown the superiority of sofosbuvir (SOF)-based therapy compared with the current standard of care in both treatment-naive and treatment-experienced patients and across all HCV genotypes. Because of its favorable pharmacologic profile and its reasonable drug-drug interactions, SOF has become the cornerstone in the management of HCV infection.17-21 Two open-label studies assessed treatment with ledipasvir (LDV), SOF, and RBV in patients infected with HCV-G1 or HCV-G4. Both studies included a cohort of patients with cirrhosis who had not undergone LT and another cohort of patients who had undergone LT. Sustain virological response (SVR)12 among the relatively small number of HCV-G4 patients ranged between 78% and 94%.22,23 More recently, ILTS convened a working group to develop a new guideline focused on the use DAA therapy in the liver transplant setting. They suggested treating most listed patients before LT. They also suggested that treatment should be deferred in patients with advanced decompensated cirrhosis (model for end-stage liver disease [MELD], ≥30) or those who are expected to undergo LT within 3 months.24 We conducted a prospective, single-arm, observational study that included a cohort of patients with HCV-G4-related cirrhosis who had not undergone LT and another cohort of patients who had undergone LT. Patients received LDV/SOF (90-400 mg single tablet) once daily for 12 to 24 weeks with or without RBV.

MATERIALS AND METHODS

This is a single-arm, prospective, observational study of HCV G4 patients in the preliver transplant (cohort A) and postliver transplant (cohort B) setting. Cohort A patients were further divided into 3 groups; group 1 child score A, group 2 child score B and group 3 child score C. The patients received LDV/SOF (90-400 mg) once daily for 12 weeks with or without ribavirin (RBV) (400-1200 mg). The inclusion criteria included all adult (18-75 years of age) patients infected with HCV G4 who were either referred for liver transplant assessment or had received a liver transplant in our center. We also included compensated and decompensated cirrhotic patients. The exclusion criteria consisted of creatinine clearance less than 30 mL/min per 1.73 m2, HCV/HIV coinfection, poor functional status (Eastern Cooperative Oncology Group performance status, >1) and patients infected with other genotypes.

HCV detection and quantification were performed using the Abbott Real-Time M2000 RT-PCR assay. This assay detects and quantifies HCV genotypes (1-6) with a detection limit that ranges from 30 to 100 000 000 IU/mL. Before treatment, the HCV genotype was assayed in all patients using INNO-LiPAHCV II (Innogenetics NV, Ghent, Belgium). All patients provided their informed consent and received a direct contact number in the event of serious adverse effects. The following data were collected within a month before starting treatment: age, HCV genotype, quantitative PCR, transient elastography score (fibroscan), baseline laboratory results, and history of previous treatment experience. For cohort B, the additional data included immunosuppressive regimen, immunosuppressive medication levels, and any episode of rejection. Posttransplant HCV recurrence was diagnosed based on the presence of HCV PCR without the need of liver biopsy. The patients who failed a previous DAA or PEGylated interferon therapy were treated for 24 weeks; all other patients were treated for 12 weeks. RBV was added to all treatment experienced patients in both cohorts including those treated with PEGylated interferon. Additionally, cohort B patients with a baseline hemoglobin exceeding 12 g/L also received RBV.

All patients were included in the intention to treat analysis. To ensure compliance, all patients were scheduled for regular office visits at weeks 2, 4, 8, 12, and 3 months after treatment had ceased. During these visits, the patients were interviewed by both a research nurse and a primary investigator. The HCV PCR was repeated at weeks 4 and 12 and at month 3 posttreatment completion. During each visit, the following investigations were repeated: alanine aminotransferase, aspartate aminotransferase, total bilirubin, international normalized ratio (INR), creatinine, estimated glomerular filtration rate, albumin, immunosuppressive medication levels, and complete blood count. After transplantation, the patients were maintained on their immunosuppressive medications without any modification. During the patients’ visits, all data were registered electronically by a research coordinator.

The primary endpoint was to achieve SVR 12, as well as medication safety and tolerability.

Statistical Methods

The statistical analysis was performed using the latest version of SPSS software (SPSS, Inc., Chicago, IL). The baseline parametric data are expressed as the mean and standard deviation values; any differences in the groups were analyzed using the paired Student t test, the χ2 test, or the Mann-Whitney U test as appropriate. A P value less than 0.05 was statistically significant.

Ethical Consideration and Patient Confidentiality

This study was conducted in accordance with the latest version of the Declaration of Helsinki and Good Clinical Practice (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South Africa), the policies and procedures of the Research and Ethic Committee of Research Office Affairs of the King Faisal Specialist Hospital and Research Center, Riyadh, and the laws of Saudi Arabia. The investigators assured that the subjects’ anonymity would be maintained and that their identities would be protected from unauthorized parties. The subjects’ names would not be supplied to parties other than the study investigators. The study data and findings would be stored on a computer and would be handled in strictest confidence in accordance with the local data protection laws. The study records would be maintained by the principal investigator in a secure location. The protocol used was approved by the local institutional review board.

RESULTS

A total of 111 patients (53 males and 58 females) were treated from January 2015 to September 2016. Cohort A patients were subdivided per the Child-Pugh classification; group 1 included 37 Child-Pugh class A patients; group 2 included 19 Child-Pugh class B patients; and group C included 5 Child-Pugh class C patients. Cohort B included all postliver transplant recipients irrespective of the fibrosis stage.

Nine and 8 patients in cohorts A and B had an additional genotype coinfection. All DAA treatment experienced patients in both cohorts received SOF-RBV only. None of the patients had exposure to NS5A inhibitors. Thirty-one (50%) of cohort A patients had a high viral load (>800 000 IU/mL), and 24 (39%) patients were treatment experienced. Eighteen patients received prior pegylated interferon and RBV combination, whereas 6 patients received SOF-based therapy. In cohort B, 39 (78%) patients had a high viral load, and 6 (12%) patients were treatment experienced. Renal function was normal in patients of both cohorts. Liver function was preserved in Child-Pugh class A patients (group 1), whereas Child-Pugh class B and C patients had impaired synthetic liver function (Table 1).

T1-20
TABLE 1:
Baseline demographic characteristics

Pretransplant Group (Cohort A)

The overall SVR12 in this cohort was 91.8%. The standard duration of therapy was 12 weeks with or without RBV. RBV was used in treatment-experienced patients in both cohorts. Thirty-six of 37 patients in group 1 (Child-Pugh class A) achieved SVR12, and only 1 patient relapsed after discontinuing treatment. There was no breakthrough during treatment. Four (10%) of 37 patients in this group were treated for 24 weeks, and all 4 achieved SVR12. Six (16%) were on the transplant list; 3 had severe encephalopathy, 2 had ascites and 1 had hepatocellular carcinoma (HCC). One patient was transplanted for HCC after achieving SVR.

Eighteen (95%) of 19 of patients in group 2 (Child-Pugh class B) achieved SVR12. Two patients in this group were treated for 24 weeks because of prior treatment history. Only 1 patient from this group relapsed (5%). One patient died because of severe infection and spontaneous bacterial peritonitis (Figure 1).

F1-20
FIGURE 1:
SVR 12 in cohort A and B patients.

There was an average 2-point reduction in the MELD score in groups 1 and 2 (pretreatment, 13.82 vs posttreatment, 11.05); 49 (80%) patients in these 2 groups had a posttreatment MELD score less than 15. This resulted in a clinical improvement in the majority of treated patients; however, none of these patients were delisted and remained as low priority for transplantation on our cadaveric list. Living donor liver transplantation was cancelled in 8 patients because of significant biochemical and clinical improvement. Five other patients had a reduction in the MELD score with persistent features of portal hypertension. Three patients from this group were transplanted after achieving SVR. This positive response was not observed in group 3 patients (Figure 2). Two (40%) of 5 patients in group 3 (Child-Pugh class C) achieved SVR12. All patients in this group received 12 weeks of therapy. Three (60%) patients developed virological failure, and 1 patient died secondary to urosepsis (Table 2). One of the nonresponders in this group underwent LT and achieved SVR12 post-LT. All other patients in groups 2 and 3 remained on our transplant list.

F2-20
FIGURE 2:
MELD score before and after treatment in cohort A patients.
T2-20
TABLE 2:
Treatment outcome (cohort A)

Posttransplant Group (Cohort B)

Forty-three (86%) of 50 patients in this cohort achieved SVR12. Three (6%) patients in this group received 24 weeks of therapy. There was no adverse event (AE) or any serious AE or death in this cohort. The average time from transplantation to starting antiviral treatment was 42 months (range, 1-84 months). All patients had a transient elastography (fibroscan) before treatment to determine the stage of fibrosis. None of the patients in this cohort were cirrhotic before starting treatment.

All patients in cohort B who had a mix of genotypes 4 and 1 achieved SVR (7 patients). The only patient who had both genotypes 4 and 2 also achieved SVR12 (Table 3).

T3-20
TABLE 3:
Treatment outcome (cohort B)

Impact of Pretreatment Viral Load and RBV Use

SVR rates in cohort A for patients with a viral load below 800 000 were significantly higher than SVR rates in patients with a viral load exceeding 800 000 (100% vs 83.9%, P = 0.022). The viral load did not impact SVR rates in cohort B patients.

The use of RBV in cohort A was as follows: 43%, 31%, and 40% in groups 1, 2, and 3, respectively. In cohort B, 24 (48%) patients received RBV. The SVR rates with or without RBV were similar in cohorts A (89% vs 93%, P = NS) and B (80% vs 92%, P = NS).

Immunosuppression

The standard immunosuppression protocol in our institution includes calcineurin inhibitors, mycophenolate mofetil during the first 6 to 12 months, and oral prednisone for the first 3 months after transplantation. No major medication interaction requiring a change in immunosuppression dose occurred during the study period.

Safety

Despite including advanced liver disease patients and liver transplant patients who received multiple medications, the therapy was generally well tolerated with no serious side effects.

Cohort A

Two patients in cohort A died during the study period. The first patient (group 2) died secondary to spontaneous bacterial peritonitis and multiorgan failure after achieving a negative viral load. The second patient (group 3) was a treatment failure and died secondary to urosepsis. Treatment was not disrupted or discontinued in any other patient in this cohort. Six (10%) patients developed worsening liver decompensation while on treatment and manifested increasing ascites or encephalopathy. Two patients developed newly diagnosed HCC after completing therapy, and 1 patient had HCC recurrence posttherapy. Ten (16%) patients developed significant anemia (<10 g/dl), 2 patients required blood transfusion, and 1 patient received erythropoietin. No significant renal or biochemical derangement occurred during therapy. Anemia, in most cases, was thought to be related to RBV, resulting in a dose reduction. The most common adverse effect was headache (30%). Other reported side effects included fatigue (15%), hair loss (2 patients), and blurred vision (1 patient).

Cohort B

No mortality was reported in this cohort. Additionally, the treatment was not interrupted or discontinued in any postliver transplant patient. Seven patients developed anemia (hb < 10) requiring RBV dose adjustment, and 1 patient required blood transfusion. We did not observe any rejection or significant biochemical derangements. The most common side effect was headache (30%); other side effects included fatigue, hair loss, and abdominal pain.

DISCUSSION

This is the largest study evaluating the outcome of genotype 4 HCV treatment in the liver transplant setting. Reinfection of the graft is universal after LT regardless of genotype, leading to an accelerated course of liver injury in many cases.25 Most studies on disease recurrence worldwide have investigated HCV-G1, HCV-G2, and HCV-G3, and there are few reports on post-LT recurrence of HCV-G4.

Viral eradication or suppression before LT reduces the posttransplant recurrence rates.26 Until recently, the only available treatment regimens were interferon-based and were therefore contraindicated in patients with advanced cirrhosis.27,28 However, the treatment of patients with HCV is rapidly evolving. New oral DAAs have emerged with better safety and efficacy profiles, leading to dramatic changes in the practice of HCV management. These choices include SOF-based therapy with or without RBV.

This study included a cohort of patients with advanced liver disease who were referred for LT. Overall, the SVR in cohort A was 91.8% and was highest among patients with Child A cirrhosis (36/37, 97%), whereas Child B and C patients achieved an SVR of 95% (18/19) and 40% (2/5), respectively. Six patients with Child B and C cirrhosis were treatment experienced and received 24 weeks of therapy; all other patients were treated with a 12-week therapy. Liver function and MELD scores improved, especially in Child A and B patients after therapy. In the current study, SVR12 rates in cohort A were significantly higher in patients with a viral load below 800 000 this observation needs to be confirmed in a larger study.

These results are superior to SOF and RBV combination. In a recent study, 61 patients with HCV of any genotype awaiting LT for HCC were included. These patients received up to 48 weeks of SOF/RBV before LT. Of 46 patients who were transplanted, 43 had HCV-RNA levels of less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) exhibited a posttransplantation virological response at 12 weeks.29 In another study from Egypt, the SVR rates in cirrhotic patients treated with the same combination were 63% and 78% for patients treated for 12 and 24 weeks, respectively.30

The Solar 1 trial was an open-label study that assessed treatment using (LDV/SOF), and RBV in patients infected with HCV-G1 or HCV-G4. This study included a cohort of patients with cirrhosis who had not undergone LT and another cohort of patients who had undergone LT. In the nontransplant cirrhotic group, SVR12 was achieved in 86% to 89% of patients. There was no difference in response rates in the 12- and 24-week groups. Consistent with the outcomes in the current study, the patients with Child C cirrhosis had a lower response rate. However, despite being a large study, the Solar 1 trial did not adequately address the response noted in G4 patients as it only included 4 patients in both cohorts.22 An open-label study at 34 sites in Europe, Canada, Australia, and New Zealand recruited 2 groups of patients; cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone LT. Cohort B included posttransplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients received 12 or 24 weeks of LDV (90 mg) and SOF (400 mg) once daily, plus RBV (600–1200 mg daily). Of 333 patients who received treatment, 296 had genotype 1 HCV, and 37 had genotype 4 HCV. Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%) of 18 patients and 16 (94%) of 17 patients treated for 12 weeks and 24 weeks, respectively. Of the 5 patients who did not achieve SVR12, 3—all receiving 12 weeks of treatment—had virological relapse, and 2 died (1 posttransplantation CTP-A at 12 weeks of treatment, and 1 untransplanted CTP-C at 24 weeks of treatment).23 In another recent study, 20 of 21 patients infected with HCV-4 completed 12 weeks of LDV and SOF and achieved SVR12 including 7 patients with cirrhosis.31

In cohort B of our study population, 43 (86%) of 50 achieved SVR. The majority of patients in this cohort had a low fibrosis score, and none had established cirrhosis. Treatment was well tolerated with no interactions with other medications, particularly immunosuppressive agents. Forty-seven (94%) patients were treated for 12 weeks, and only 3 patients received 24 weeks of treatment. Seventy-eight percent of cohort B patients had a negative viral load at week 4 and subsequently achieved SVR12. HCV-G4 SVR rates in the present study were better than the SOF/RBV combination therapy in the posttransplant setting in which the SVR rates ranged between 59% and 91%.32-35 Our results, however, were comparable to the previously mentioned multicenter study involving 34 centers from different parts of the world in which 25 of 27 HCV-G4 in the posttransplant setting achieved SVR; the only 2 relapsers were cirrhotic patients23

Forty-six and 48% of the patients in cohorts A and B, respectively, received RBV. Adding RBV to LDV/SOF did not improve the outcome in both cohorts. In cohort B, 5 of the 7 relapsers received RBV; furthermore, RBV use was associated with significant anemia in both cohorts with no added benefits. The side effect profile of RBV, especially in the posttransplant setting, limits its role. This result is consistent with studies that questioned the use of RBV combined with LDV/SOF in the postliver transplant setting.36,37 In a recent study, a total of 51 patients received SOF/LDV with or without RBV. Twenty-nine HCV genotype 1 or 4 patients with histologically proven stage 0 to 2 fibrosis were treated with SOF/LDV for 12 weeks; another 22 patients with advanced fibrosis (stage 3-4) received either SOF/LDV plus weight-adjusted RBV or prolonged treatment for 24 weeks. The group that received RBV developed significantly more AEs compared with the SOF/LDV group. Anemia was the most common side effect (43%), leading to dose reduction or discontinuation in 55% and 40% of the affected patients, respectively.37

No serious AEs were reported in our study. Two mortalities involving patients from cohort A were reported. The first patient had decompensated liver disease before treatment and died because of sepsis; the second patient presented 3 months later with an infiltrative HCC after achieving SVR and subsequently died. The safety profile of LVD/SOF with RBV was also evaluated in a pooled analysis of 2 large multicenter studies (Solar-1 and -2). The patients involved were either cirrhotic or post-LT patients (616G1 and 42G4) and were randomized to 12 or 24 weeks of treatment. Of 134 severe AEs, only 20 were related to treatment. The RBV-associated anemia was the most common adverse effect, representing 11 (55%) of 20 reported drug-related AEs.38 In conclusion, SOF/LDV combination is a reliable therapy for managing recurrent HCV G4 infection in the liver transplant setting. Therapy was well tolerated in the pretransplant and posttransplant setting with no significant adverse effects or drug-drug interactions. Child-Pugh class C patients were less likely to achieve SVR; therefore, it may be better to defer treatment after LT. The small number of treatment failures in this study makes it difficult to assess factors that may negatively impact the outcome. We should emphasize that adding RBV to treatment experienced patients did not increase SVR and was associated with anemia.

ACKNOWLEDGMENTS

The authors would like to thank their Liver Transplant/HCV coordinator Ms. Rania Alarieh and Ms. Zohoor Mubaraki for their help and contribution to this study.

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