Dig Dis Sci (2011) 56:1848–1852 DOI 10.1007/s10620-010-1526-5
ORIGINAL ARTICLE
Treatment of Genotype 4 Hepatitis C Recurring After Liver Transplantation Using a Combination of Pegylated Interferon Alfa-2a and Ribavirin Waleed Al-hamoudi • Hazem Mohamed • Faisal Abaalkhail • Yaser Kamel • Nasser Al-Masri • Naglaa Allam • Saleh Alqahtani • Mohammed Al-Sofayan Hatem Khalaf • Mohammed Al-Sebayel • Ahmed Al-jedai • Ayman Abdo
•
Received: 7 August 2010 / Accepted: 9 December 2010 / Published online: 8 January 2011 Ó Springer Science+Business Media, LLC 2011
Abstract Background Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and tends to be more aggressive. Data on post-transplant HCV genotype 4 treatment is scarce. The aim of this study is to assess the safety and efficacy of pegylated interferon alpha-2a (PEGIFN) in combination with ribavirin in the treatment of recurrent HCV genotype 4 after LT. Methods Twenty-five patients infected with HCV genotype 4 were treated with PEG-IFN alpha-2a at a dose of 180 lg/week in addition to 800 mg/day of ribavirin (the dose was adjusted within the tolerated range of 400–1,200 mg). Pretreatment liver biopsies were obtained from all patients. Biochemical and virological markers were assessed before, during, and after treatment. Results Twenty-two patients (88%) achieved an early virological response (EVR) (12 patients tested negative for
HCV-RNA). Fifteen (60%) and 14 patients (56%) achieved an end of treatment virological response (ETVR) and a sustained virological response (SVR), respectively. Five patients had advanced pretreatment liver fibrosis. Pretreatment ALT was elevated in 24 patients (96%). The most common adverse effects were flu-like symptoms and cytopenia. Eighteen patients (72%) required erythropoietin alpha and/or granulocyte-colony stimulating factor as a supportive measure. One patient developed severe rejection complicated by sepsis, renal failure, and death. Other adverse effects included depression, mild rejection, impotence, itching, and vitiligo. Conclusions Post-transplant treatment with pegylated interferon alpha-2a and ribavirin achieved SVR in 56% of liver transplant recipients with chronic HCV genotype 4 infection. The combination was relatively safe and exhibited a low rate of treatment withdrawal.
W. Al-hamoudi (&) A. Abdo Gastroenterology Unit (59), Department of Medicine, College of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia e-mail:
[email protected]
N. Al-Masri e-mail:
[email protected]
A. Abdo e-mail:
[email protected] W. Al-hamoudi H. Mohamed F. Abaalkhail Y. Kamel N. Al-Masri N. Allam S. Alqahtani M. Al-Sofayan H. Khalaf M. Al-Sebayel A. Al-jedai A. Abdo Department of Liver Transplantation and Hepatobiliary Surgery, King Faisal Specialist Hospital and Research Center, MBC 72, PO Box 3354, Riyadh 11211, Saudi Arabia e-mail:
[email protected] F. Abaalkhail e-mail:
[email protected] Y. Kamel e-mail:
[email protected]
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N. Allam e-mail:
[email protected] S. Alqahtani e-mail:
[email protected] M. Al-Sofayan e-mail:
[email protected] H. Khalaf e-mail:
[email protected] M. Al-Sebayel e-mail:
[email protected] A. Al-jedai e-mail:
[email protected]
Dig Dis Sci (2011) 56:1848–1852
Keywords HCV Genotype 4 Liver transplantation Sustained virological response
Introduction Hepatitis C virus (HCV) recurrence following liver transplantation (LT) is universal and tends to be associated with a more severe course and worse outcome [1, 2]. Approximately 30% of patients progress to cirrhosis within the first 5 years following transplantation [3]. This aggressive course may result in loss of graft function, retransplantation, or death. The use of standard interferon alone or in combination with ribavirin to treat HCV recurrence following LT has been associated with poor results [4–6]. Treatment regimens have been hindered by a high incidence of adverse effects leading to treatment withdrawal [4–6]. Data on the use of pegylated interferon and ribavirin to treat HCV recurrence after LT are limited. Furthermore, most of the data come from studies combining pegylated interferon a2b and ribavirin, while data on the use of pegylated interferon a-2a after liver transplantation are scarce. Reported SVR rates using pegylated interferon combination therapy following liver transplantation have been lower than those reported in the non-transplant population. However, most of these studies were performed in genotype 1 HCV infected patients. Data on treating genotype 4 HCV recurrence following LT are lacking. The aim of this study was to assess the efficacy and safety of pegylated interferon alfa-2a and ribavirin in the treatment of genotype 4 HCV recurrence after liver transplantation.
Methods A retrospective chart review of all patients treated at our center for post-transplant treatment of hepatitis C virus recurrence was conducted. Between January 2000 and December 2008, 80 patients were transplanted for HCVrelated cirrhosis in our center. Of those 39 patients (12 nongenotype four patients and two treatment experienced genotype 4 patients) were treated using pegylated interferon alpha-2a and ribavirin combination therapy. For this study, we included all genotype 4 HCV treatment-naive patients (25 patients). The indications for treatment were as follows: an increase in alanine aminotransferase (ALT) of at least 1.59 upper limit of normal (normal B 45 IU/l) or the presence of advanced fibrosis (Metavir C 3) on liver biopsy in patients with normal liver enzymes, the presence of HCV RNA determined by polymerase chain reaction
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(PCR), the absence of other causes of liver disease, and a normal serum creatinine level (normal \ 110 lmol/l). HCV detection and quantification were performed using the Abbot 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. Prior to treatment, the HCV genotype was assayed in all patients using INNO-LiPAHCV II (Innogenetics NV, Ghent, Belgium). All patients underwent a liver biopsy to confirm the diagnosis and to rule out rejection or the existence of other diseases. All liver biopsies were performed within a period of 3 months prior to initiating antiviral treatment. Histological recurrence of HCV was based on the presence of lobular and portal inflammation in the absence of features suggestive of rejection. The Banff rejection-activity index was used to grade and stage the histological features of cellular rejection. Exclusion criteria were as follows: renal impairment (creatinine levels [ the upper normal limit), histological rejection on liver biopsy, prior exposure to pegylated interferon, the presence of other viral diseases, decompensated liver disease, and the presence of cytopenias (hemoglobin \ 10 g/dl, neutrophilic count \ 1,500/ll, and platelet count \ 75/ll) prior to treatment. During treatment, patients were followed every 2–4 weeks or more frequently if required. Complete blood count (CBC) and liver enzymes were checked on each visit. To maintain the starting dose of pegylated interferon and ribavirin, erythropoietin and granulocyte-colony stimulating factor (G-CSF) were given for treatment-induced anemia or neutropenia. Four thousand units of erythropoietin alpha were administrated subcutaneously 2–3 times per week if hemoglobin dropped below 10 g/dl. If no improvement was observed, the ribavirin dose was reduced temporarily. G-CSF was given if the neutrophil count decreased to \1,000/ll. All patients were treated for 48 weeks. Viral-load measurements were repeated at 12 and 48 weeks to assess those who achieved an early virological response (EVR) and an end of treatment virological response (ETVR), respectively. These measurements were repeated 6 months after completing interferon therapy to confirm a sustained virological response (SVR). This study was approved by the Research Ethics Committee at our hospital. Immunosuppression Nineteen patients were on tacrolimus and six patients were treated with cyclosporine. The standard immunosuppression protocol in our institution includes calcineurin inhibitors, mycophenolate mofetil (MMF) during the first
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6–12 months, and oral prednisone for the first 3 months following transplantation. Statistical Analysis All variables were checked for normality. Descriptive statistics were summarized as mean ± SD for normally distributed data and median (range) for skewed data. Fisher’s exact or Chi-square test was used to assess group differences for categorical variables and Student’s t test was used to assess difference between continuous variables. Pearson’s correlation test was used to study the correlation between ALT and possible predictors of antiviral treatment response. All tests were two-sided with an alpha level of 5%. All analyses were performed using Stata version 10 (Stata Corp, Texas, USA).
Results The characteristics of the 25 patients included in this study are shown in Table 1. Treatment was started 1–72 months (mean 14.3 months) following LT. Treatment was initiated within the first 2 years following transplantation in the majority of patients. The only patient treated 1 month after transplantation had an increase in his ALT that peaked at 325 IU/l. A liver biopsy revealed a Metavir inflammation score of 2 and a fibrosis score of 1 and no evidence of rejection. Two patients were treated at 60 and 72 months
Table 1 Patients pre-treatment characteristics Median and mean ± SD or frequency (%) Gender (M/F)
17 (68%)/8 (32%)
Age
55.2 ± 11
Completed treatment Type of donor (CAD/LR)
24 (96%) 17 (68%)/8 (32%)
Abnormal pretreatment ALTb
24 (96%)
Pretreatment ALT
228 (32–1,000)a
BMI
25.9 ± 4.1
post-transplantation, and in both cases there were both an increase in the ALT level of at least 1.59 upper limit of normal and a Metavir score of at least grade 2 inflammation and stage 2 fibrosis. Twenty-four patients (96%) completed the treatment duration. An EVR was achieved in 22 (88%) patients. Of those, 12 patients had a complete EVR, defined as being aviremic, at 12 weeks. Fifteen (60%) and 14 (56%) patients achieved ETVR and SVR, respectively (Table 2). The probability of achieving SVR was related to achieving a negative HCV RNA at week 12 (p = 0.002). Other factors, including age, pretreatment HCV RNA, body mass index, the type of transplantation (living related vs. deceased donor), and the presence of diabetes did not predict treatment outcome (Table 3). All the patients experienced treatment-related sideeffects. The most common side-effects were flu-like illness and cytopenias. Adjuvant therapies, such as administration of erythropoietin, granulocyte-colony stimulating factors, or both, were used in 72% of the patients. Two patients (8%) had a drop in hemoglobin below 7 g/dl and were given a blood transfusion with a reduction in the ribavirin dose to 400 mg/day. The pegylated interferon dose was not reduced in either case. The ribavirin dose was reduced temporarily to 600 mg/day in five other patients (28%) who had a drop in hemoglobin below 9 g/dl, despite the use of erythropoietin. Two patients developed mild acute rejection, which was treated with a dose escalation of tacrolimus. One patient developed vitiligo 22 weeks into treatment. Other reported side-effects included the following: depression, diarrhea, impotence, itching, and hair loss. None of these side-effects resulted in treatment withdrawal. One patient developed severe acute cellular rejection after achieving a complete EVR, and the treatment was discontinued after 14 weeks of therapy. His pretreatment liver biopsy revealed stage 3 fibrosis. His acute cellular rejection was treated with intravenous methylprednisolone; subsequently, he developed sepsis, ascites, and renal failure, and then died after a prolonged ICU admission. During his initial presentation, his white blood cell count was 11.5/ ll and his hemoglobin and platelet counts were normal.
Post-transplant/treatment interval (months) 14.3 ± 18.8 Diabetic patients
12 (48%)
HCV RNA (million IU/ml)
5.7 (0.3–63.9)a
Table 2 Virological response
Metavir inflammatory score B 2
18 (72%)
Treatment outcome
Frequency
Percentage
Metavir fibrosis score B 1
11 (44%)
Metavir fibrosis score = 2
9 (36%)
SVR
14
56
Metavir fibrosis score = 3
4 (16%)
Relapse
1
4
1 (4%)
Non-responders
9
36
Treatment discontinued
1
4
Total
25
100
Metavir fibrosis score = 4 a b
Median (range) [1.59 upper limit of normal
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Dig Dis Sci (2011) 56:1848–1852 Table 3 Parameters associated with SVR
DM diabetes mellitus, CAD cadaveric, LR living related, BMI body mass index
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Factor
Responders
Non-responders
p value
Negative HCV-PCR at week 12
11/14 (79%)
1/11 (1%)
0.002
Age (mean)
56 ± 12.1
53.7 ± 9.6
0.55
DM
7
6
0.82
Pretreatment PCR
10 9 106 ±16.3
7 9 106 ± 5.8
0.45
Type of donor (CAD/LR)
11/3
6/5
0.20
Mean post-transplant/treatment interval
13.5 ± 18.1
15.3 ± 20.3
0.81
BMI
24.7
27.3
0.11
Metavir fibrosis score C 2
6
8
0.135
In the 24 patients completing a full course of therapy, pegylated interferon and ribavirin therapy resulted in a significant biochemical improvement with normalization of ALT in 92% of those who achieved SVR (p = 0.0006) and 64% of the non-responders (p = 0.02). During treatment, all patients discontinued steroid treatment, and MMF was discontinued in patients with pretreatment cytopenias and was reduced to a maximum of 1 g/day in patients with normal blood counts.
Discussion Our study is the first to report on the safety and efficacy of pegylated interferon a-2a and ribavirin in the management of recurrent genotype 4 HCV infection following LT and among only a few to report on the results of using pegylated IFN alpha- 2a post-liver transplantation. In this study, treatment of HCV genotype 4 patients was associated with an SVR rate of 56%. The results of this study suggest that the post-transplant treatment outcome in genotype 4 is probably better than genotype 1 and is less favorable than genotypes 2 and 3. This response pattern among the different genotypes parallels the response pattern in the immunocompetent population [7]. Genotype 4 is the most prevalent genotype in the Middle East and in most North African countries [7–12]. Recently, an increasing rate of genotype 4 infection has been reported in European countries, particularly among intravenous drug users [13, 14]. However, to date, most of the studies on HCV treatment outcomes were conducted in Western populations in which genotypes 1, 2, and 3 predominates, while genotype 4 is the least-studied HCV variant. The initial results of the treatment of HCV genotype 4 in the non-transplant population were disappointing. Earlier studies using conventional interferon and ribavirin resulted in low SVR rates, thus indicating that genotype 4 is difficult to treat [15]. One of the first trials evaluating the use of pegylated interferon and ribavirin in treating genotype 4 infected patients was conducted by Al-faleh et al. [16]. They demonstrated that 48 weeks of a combination of pegylated
interferon a-2b and ribavirin resulted in an SVR in 43% of patients. However, the potential limitations of this study included the use of a lower fixed ribavirin dose, a fixed dose of pegylated interferon, a lack of adjuvant supporting therapy, and higher dose-reduction rates. More-recent studies, including large, controlled, randomized clinical trials using pegylated interferon-based treatments, revealed higher SVR rates ranging between 50 and 70% [7, 17]. The expanding liver transplant programs in the Middle East resulted in the emergence of new data on the natural history of HCV genotype 4 and its response to treatment. We have previously compared the recurrence and outcome between HCV genotype 4 and other genotypes following liver transplantation [18]. In that study, there was no significant difference in the 3-year survival, histological disease staging, and graft loss when comparing patients with genotype 4 to other genotypes. Gane et al. [1] compared the severity of recurrence among different genotypes following liver transplantation. In their study, 14 patients were infected with genotype 4; half of them developed severe hepatitis or cirrhosis. They reported that patients infected with genotypes 1b and 4 had the worst outcomes, while genotype 2 and 3 patients had less-severe disease recurrence. Sugo et al. [19] reported a higher recurrence rate in patients infected with genotype 1b compared to other genotypes, including genotype 4. Others have suggested a worse outcome in genotype 4-infected patients; however, these studies are limited by their small number of genotype 4-infected patients [20]. In the present study, all the involved patients were infected with HCV genotype 4 and were treatment-naive. As part of the treatment protocol, these patients were monitored every 2 weeks during the first month of treatment and then monthly thereafter. Despite the high frequency of side-effects necessitating dose reduction or treatment withdrawal in the various published studies, treatment was discontinued in only one patient in our study. This patient developed acute cellular rejection that required intravenous steroids and subsequently resulted in disease progression and death. Two other patients in our study developed mild rejection
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requiring a dose adjustment of tacrolimus. None of the other reported side-effects in our study resulted in treatment withdrawal. The ribavirin dosage was reduced temporarily in seven patients. The following are potential explanations for the relatively high response rate in our study: (1) all included patients were treatment-naive, (2) the use of growth factors that allowed patients to complete their course of therapy, (3) the low treatment-withdrawal rate, and (4) the reduction of immunosuppression doses during treatment. Additionally, difficult-to-treat patients, including patients who failed previous pre- or post-transplant treatment, renal failure patients, and patients with pretreatment cytopenia, were excluded from this study. The early introduction of erythropoietin and granulocyte-colony stimulating factor (G-CSF) allowed the maintenance of a higher ribavirin dose and subsequently reduced treatment withdrawal rates. Furthermore, treatment was started relatively early; the Metavir inflammatory and fibrosis scores were below 3 in 72 and 80% of the patients, respectively. Predictors of virological response in chronic HCV infection include genotypes other than 1 and the ability to tolerate the full treatment dose and duration [21]. This probably holds true for the transplant population; the SVR rates were higher in studies where the percentage of genotype 1 infection was lower. Dinges et al. [22] reported a post-transplant SVR of 71% in patients who were treated with pegylated interferon a-2a and ribavirin and completed treatment. They also demonstrated significantly higher SVR rates in the non-genotype 1 patients. Other studies confirmed the same finding of a better response in patients infected with genotypes 2 and 3 [23]. In conclusion, based on this study, the sustained virological response rates to pegylated interferon and ribavirin in HCV genotype 4 patients are intermediate between the relatively difficult-to-treat HCV genotype 1 and the more responsive genotypes 2 and 3. Conflict of interest
None.
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