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Peg-IFN and ribavirin treatment for recurrence of genotype 2 and 3 hepatitis C after liver transplantation a

b

c

d

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Malin Ackefors , Maria Castedal , Olav Dahlgard , Hans Verbaan , Henrik Gjertsen , Annika f

Wernerson & Ola Weiland

a

a

Department of Medicine, Division of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden b

Transplant Institute, Sahlgrenska University Hospital and the Sahlgrenska Academy, University of Gothenburg, Sweden c

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Division of Infectious Diseases Akers Rikshospital, Oslo, Norway

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Division of Gastroenterology, Skane University Hospital, Malmö, Sweden

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Division of Transplant Surgery Karolinska University Hospital, Stockholm, Sweden

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Department of Clinical Sciences, Intervention and Technology Karolinska Institutet and Clinical Pathology/Cytology, Stockholm, Sweden Published online: 04 Feb 2015.

To cite this article: Malin Ackefors, Maria Castedal, Olav Dahlgard, Hans Verbaan, Henrik Gjertsen, Annika Wernerson & Ola Weiland (2015) Peg-IFN and ribavirin treatment for recurrence of genotype 2 and 3 hepatitis C after liver transplantation, Infectious Diseases, 47:4, 209-217 To link to this article: http://dx.doi.org/10.3109/00365548.2014.984322

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Infectious Diseases, 2015; 47: 209–217

ORIGINAL ARTICLE

Peg-IFN and ribavirin treatment for recurrence of genotype 2 and 3 hepatitis C after liver transplantation

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MALIN ACKEFORS1, MARIA CASTEDAL2, OLAV DAHLGARD3, HANS VERBAAN4, HENRIK GJERTSEN5, ANNIKA WERNERSON6 & OLA WEILAND1 1Department

of Medicine, Division of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden, 2Transplant Institute, Sahlgrenska University Hospital and the Sahlgrenska Academy, University of Gothenburg, Sweden, 3Division of Infectious Diseases Akers Rikshospital, Oslo, Norway, 4Division of Gastroenterology, Skane University Hospital, Malmö, 5Division of Transplant Surgery Karolinska University Hospital, and 6Department of Clinical Sciences, Intervention and Technology Karolinska Institutet and Clinical Pathology/Cytology, Stockholm, Sweden

Abstract Background: Relapse of hepatitis C virus (HCV) infection after liver transplantation (LT) is universal. Tolerance for treatment with pegylated-interferon (peg-IFN) and ribavirin (RBV) is suboptimal and withdrawals due to adverse events frequent. We sought to improve tolerance for treatment to improve outcome. Methods: We used concentration-guided RBV dosing to achieve an intended 10 μmol/L concentration with darbepoetin support in combination with peg-IFN alfa-2a, 180 μg for genotype 1 and 135 μg for genotype 2/3 to improve tolerance. Results: A total of 51/54 patients (94%) completed a full treatment course. In the per-protocol analysis 43% of patients (22/51) achieved sustained virological response (SVR), 82% with HCV genotype 2/3 and 22% with genotype 1, p ⫽ 0.0001. Patients with IL28B CC achieved SVR in 73% (8/11) and patients with non-CC in 33% (14/43), p ⫽ 0.016. Patients with mild fibrosis (fibrosis stage 1–2) achieved SVR in 56% (15/27), and patients with advanced fibrosis (fibrosis stage 3–4) in only 26% (7/27), p ⫽ 0.0267. Conclusions: Concentrationguided RBV dosing with darbepoetin support substantially improves tolerance and offers high adherence to a full peg-IFN and RBV treatment course in patients with post-transplant HCV relapse. With this approach genotype 2 and 3 infections can be treated cost-effectively post-transplant. Genotype 1, IL28B non-CC genotype, and advanced fibrosis predicted a low SVR rate.

Keywords: HCV, peg-IFN, ribavirin, liver transplantation, chronic HCV

Introduction Currently hepatitis C cirrhosis with end-stage liver disease is the main cause for liver transplantation (LT) in the USA and Europe [1,2]. The number of transplants for chronic hepatitis C infection is also increasing in Scandinavia [3]. Since recurrence of hepatitis C virus (HCV) in the graft is universal, and the development of fibrosis more rapid, about 30% of transplant patients have developed advanced fibrosis/cirrhosis within 5 years [4,5]. Furthermore, HCV recurrence is a major cause of graft loss and reduced survival [6,7]. In non-transplanted patients, 50–80% will achieve sustained virological response (SVR) with pegylated interferon (peg-IFN) and ribavirin

(RBV) treatment [8–10], but in transplanted patients only 20–45%, and patients with genotype 1 only 15–30% will achieve SVR [1,11]. These SVR rates will improve dramatically when new direct antiviral agents (DAAs), particularly sofosbuvir, become available, but at high economic cost [12,13]. The low SVR rate, seen earlier with RBV and peg-IFN in transplant patients, is in part due to impaired tolerance causing frequent premature withdrawals from treatment [1,14]. Better results, however, are achieved when peg-IFN and RBV treatment has been given before advanced fibrosis/cirrhosis has developed [15,16]. The most common adverse event caused by RBV and peg-IFN treatment has been anemia

Correspondence: Ola Weiland, Karolinska Institutet, I73 Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. Tel: ⫹ 46 8 585 800 00, ext. 82273. Fax: ⫹ 46 8 585 81916. E-mail: [email protected] (Received 10 September 2014 ; accepted 22 October 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.984322

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induced by RBV [17] but reinforced by peg-IFNinduced bone marrow suppression [18]. Erythropoeitin has been used to reduce the impact of anemia [19]. In the near future, treatment for recurrent HCV with sofosbuvir in combination with RBV will be available. This combination offers promising results, as presented at the AASLD meeting in 2013 [13]. Since RBV seems to be needed in combination with sofosbuvir for treatment of post-transplant HCV recurrence, optimal dosing of RBV will continue to be of importance to reduce adverse events and improve tolerance. We here show that high SVR rates can be achieved when RBV is used in combination with low-dose peg-IFN and darbepoetin support for genotypes 2 and 3 and also offers high adherence in transplant patients. This study was based on a pilot study using the same RBV treatment regimen in patients with hepatitis C recurrence after LT [20]. All patients were given darbepoetin with start 2 weeks before commencement of the RBV and peg-IFN therapy, to increase tolerance to treatment. The primary aim was to see if tolerance and adherence to treatment could be improved, and if SVR could be kept at an adequate level. Furthermore, rapid viral response (RVR), early viral response (EVR), end-of-treatment (EOT), and factors influencing treatment outcome were studied.

Materials and methods Protocol biopsies were performed 12 months after transplantation, and thereafter on a yearly basis. Additional biopsies were performed when clinically indicated. Patients with histological recurrence of hepatitis C after LT were offered antiviral treatment. The local ethics committees granted approval, and all patients gave informed written consent. Patients At Karolinska University Hospital in Stockholm, liver transplant patients, with or without hepatocellular carcinoma (HCC), with documented recurrence of HCV, received darbepoetin with start 2 weeks before commencement of RBV and peg-IFN treatment, as reported earlier in a pilot study [20]. Darbepoetin support was continued throughout treatment, and the RBV dose was calculated with the intention to reach a target plasma concentration of 10 μmol/L, which has offered favorable response rates in previous studies [21–23]. Hepatitis C recurrence was confirmed in a liver biopsy with findings consistent with a histological relapse with fibrosis stage 1 or more, according to

Batts and Ludwig when HCV RNA was detected in serum [24]. Treatment All patients received 50 μg darbepoetin subcutaneously once weekly, starting 2 weeks before antiviral treatment. Peg-IFN alfa-2a (Pegasys) 180 μg weekly was used for patients with HCV genotypes 1 and 4, and 135 μg weekly for patients with HCV genotypes 2 and 3, according to Swedish consensus (http:// www.lakemedelsverket.se/malgrupp/Halso---sjukvard/ Behandlings--rekommendationer/Behandlingsrek ommendation---listan/Hepatit-C/) [25]. The RBV dose was calculated according to the formula: (RBV dose ⫽ 0.244 ⫻ Ctarget ⫻ T ⫻ (0.12 2 ⫻ Clcreat ⫹ 0.0414 ⫻ body weight) [22]. Creatinine clearance (Clcreat) was calculated according to serum creatinine, body weight, gender, and age (www.fass.se) [26], and the target concentration of RBV was set to 10 μmol/L. The dosing interval (T) was set to 12 h. Treatment duration was 24 weeks for HCV genotypes 2 and 3, and 48 weeks for HCV genotypes 1 and 4, with an option to give an additional 24 weeks for ‘slow viral responders,’ who had reached EVR, but had not become HCV RNA negative at treatment week 12. Dose adjustment of darbopoetin was done when necessary, if indicated by a fall in hemoglobin levels, or by a suboptimal RBV concentration in serum, and/or due to treatment-induced side effects.

Methods HCV RNA levels were measured at baseline, after 4 and 12 weeks, at the end of treatment, and during follow-up 6 months after treatment cessation. Analyses were performed with the TaqMan Roche test, with a sensitivity of 15 IU/ml. Rapid viral response (RVR) was defined as a negative HCV RNA test at week 4, early viral response (EVR) as a 2 log10 drop in HCV RNA levels 12 weeks after start of treatment. Patients who did not achieve EVR stopped treatment at week 12. End of treatment viral response (EOT) was defined as negative HCV RNA when treatment was stopped, and sustained viral response (SVR) as negative HCV RNA at treatment cessation and after 24 weeks of follow-up. Compliance was defined as complete if treatment in patients with HCV genotypes 2 and 3 was carried on throughout 24 weeks, and for HCV genotypes 1 and 4 throughout 48 weeks. The compliance was also defined as complete if the treatment was withdrawn

Treatment for recurrent HCV after liver transplantation at week 12 due to non-response, and at week 24 if HCV RNA had not become negative. RBV concentrations were analyzed at weeks 4 and 12. Hematological parameters, including hemoglobin levels and biochemical response to treatment, were analyzed at baseline, at weeks 2 and 4, and thereafter every fourth week or at closer intervals if needed. Additional testing was performed when clinically indicated.

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Histological evaluation of liver biopsies All protocol liver biopsies were fixed in 4% paraformaldehyde, dehydrated, and embedded in paraffin according to standard procedures. Then 2–3 μm thick sections were cut on a microtome and stained with hematoxylin/eosin (HE) and Sirius staining, eight and four section levels, respectively. The biopsy material was estimated as representative if the number of portal zones was more than eight. Inflammation was graded 1–4 (A1–4) in HE staining and the fibrosis was staged 1–4 (F1–4) according to Batts and Ludwig [24]. Liver stiffness measurement with FibroScan All patients included at the Department of Infectious Diseases at Karolinska University Hospital, with confirmed histological recurrence of hepatitis C, were evaluated with FibroScan and the mean kPa value was converted into fibrosis stage F1–F4 according to Casteras et al. [27]. When the liver biopsy was performed earlier than 3 months before treatment start, the result from liver elasticity evaluation was used as fibrosis assessment in the study. Statistical analysis The primary end point was to see if tolerance and adherence to treatment could be improved and if SVR could be kept at an adequate level. Secondary end points were RVR, EVR, EOT, biochemical, and virological responses. The statistical evaluation was based on per-protocol analysis. Baseline demographic data are presented as proportions, mean or median levels with ranges. HCV RNA levels of ⬍ 15 IU/ml were set to 14 IU/ml for the statistical analyses. The chi-squared test or Fisher’s exact twotailed test was used to test categorical variables and the Wilcoxon rank sum test for continuous values. A p value ⬍ 0.05 was considered statistically significant. Multivariate Cox regression analysis was applied to assess factors associated with SVR. Factors significantly associated with SVR in the univariate

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analysis were subsequently used in the multivariate analysis. These were HCV genotype, IL28B genotype, and pretreatment fibrosis.

Results In total, 54 patients (42 males and 12 females), with a mean age of 54 years were recruited from February 2010 to May 2012 from the four centers in Stockholm, Gothenburg, Malmö, and Oslo. In all, 36/54 (67%) patients had HCV genotype 1 and 18/54 (33%) had genotype 2 or 3 (n ⫽ 2 for genotype 2, n ⫽ 16 for genotype 3 cases). The mean time from LT to start of antiviral treatment was 29 months (range 5–78 months). Baseline demographics and immunosuppressive treatment according to HCV genotypes 1 and 2 or 3 are shown in Table I. Duration of treatment, adherence, and rejection episodes In total, 13/36 (36%) of HCV genotype 1 patients received treatment for 48 weeks; 11/36 (31%) stopped at week 12, 8/36 (22%) stopped between weeks 13 and 24 due to non-response, and 2/36 (6%) received a prolonged treatment. Only 2/36 (6%) with HCV genotype 1 withdrew from treatment prematurely, one at week 1 due to rash and pruritus, and one at week 4 due to myocardial infarction. Also, 11/18 (61%) patients with HCV genotypes 2 or 3 received treatment for 24 weeks, and 6/18 (33%) prolonged treatment to 48 weeks. One patient (6%) stopped treatment at week 6 due to cholangitis. Thus, only 3/54 (6%) patients were withdrawn from treatment prematurely due to adverse events or other complications. These three patients were classified as non-responders (NRs) in the intention-to-treat analysis, but were excluded from the per-protocol analysis of virological response. Consequently, 51/54 (94%) patients completed a full treatment course (Figure 1). Serious adverse events One patient stopped treatment at week 1 due to rash and pruritus, one had a myocardial infarction at week 4, and one developed a severe cholangitis at week 6. At week 12, one patient with HCV genotype 1a stopped treatment due to NR. He developed an acute cellular rejection after treatment cessation, due to low serum Ciklosporin concentrations. Only two patients needed blood transfusions due to anemia, but were able to complete a full treatment course.

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M. Ackefors et al. Table I. Baseline demographics at start of antiviral treatment in 54 patients with recurrent hepatitis C after liver transplantation according to HCV genotype 1 and HCV genotype non-1.

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Characteristic

Genotype 1 (n ⫽ 36)

Male/female 30/6 Age at LT (years), mean (range) 55 (40–67) Donor age (years), mean (range) 58 (23–74) Donor cause: ICH/FAP/trauma/other 24/4/4/4 IL28B genotype CC/CC/TT 7/27/3 HCC, n (%) 19 (53) Age at AVT (years), mean (range) 52 (44–69) Time from LT to AVT (months), mean (range) 31 (6–69) HCV RNA level (kop ⫻ 10*5/ml), mean (range) 147 (0.95–695) AVT before transplantation, n (%) 19 (53) Fibrosis stage: F1/F2/F3/F4 7/10/11/8 ALT level (ukat/ml), mean (range) 2.24 (0.36–10) Hb (g/L), mean (range) 149 (114–180) 4.7 (1.4–8.3) Leucocyte count (⫻ 10*9/L), mean (range) 146 (66–290) Platelet count (⫻ 10*9/L), mean (range) Basic immunosuppressant Tacrolimus n (%) 24 (67) Ciklosporin n (%) 8 (22) 20 (56) Other* n (%) Prednisolone, n (%) 20 (56) Prednisolone (mg), mean (range) 4.9 (2.5-5)

Genotype non-1 (n ⫽ 18)

All (n ⫽ 54)

13/5 52 (40–59) 47 (19–72) 12/0/4/2 3/13/1 8 (44) 55 (49–63) 25 (8–78) 193 (3.7–711) 11 (61) 7/7/0/4 3.86 (0.69–23) 149 (132–164) 5.0 (2.3–8.9) 167 (71–444)

42/12 54 (40–67) 53 (19–74) 36/4/8/6 10/40/4 22 (41) 56 (30–67) 29 (5–78) 163 (0.95–710) 30 (56) 14/17/11/12 2.79 (0.36–23) 149 (114–180) 4.83 (1.4–8.9) 153 (66–444)

11 4 12 12 4.6

(61) (22) (67) (67) (2.5–5)

35 12 32 32 3

(65) (24) (63) (63) (2.5–5)

AVT, antiretroviral treatment; FAP, familial amyloid polyneuropathy: Hb, hemoglobin; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICH, intracranial hemorrhage; LT, liver transplantation. *Sirolimus, everolimus, or combination.

RBV dose and serum concentration

Tolerance

The mean RBV dose at treatment start was 800 mg, median 800 mg (range 400–1400 mg). At week 12, the mean RBV dose was 890 mg, median 800 mg (range 200–1600 mg). The mean RBV dose in patients with HCV genotype 1 was 870 mg (range 200–1400 mg), median 800 mg, and the mean was 940 mg (range 600–1600 mg), median 1000 mg for genotypes 2 and 3. During treatment the baseline RBV dose was changed in 38/49 (78%) patients when week 12 was reached. In 28/38 (74%) the RBV dose was raised due to low RBV concentration, and in 10/38 (26%) patients the RBV dose was tapered due to anemia. The mean serum RBV concentration at week 4 was 7.7 μmol/L (range 3.1–15.9). In HCV genotype 1 it was 8.1 (3.1–15.9) versus 7.0 (3.4–10.7) in HCV genotype 2 and 3, p ⫽ 0.17. At week 12 the mean RBV concentration was 11.2 μmol/L (5.3–21.6), in HCV genotype 1 it was 11.5 (5.3–21.6) versus 10.7 (5.8–17.1) in HCV genotype 2 and 3, p ⫽ 0.68. Five patients (9%) had an RBV concentration below 5 μmol/L at week 4. Due to violation of protocol, two of these received suboptimal dosing of RBV. Three patients discontinued early as described above, and one stopped treatment just before week 12 due to NR.

Here we consider hemoglobin levels, dose of darbepoetin, and blood transfusions. The hemoglobin level at treatment start was 149 g/L (range 114–180). The nadir hemoglobin level was 111 g/L (range 77–154), and the mean drop in hemoglobin level was 37 g/L (range 0–87). The nadir hemoglobin level occurred at week 22 (range 4–56). The start dose of darbepoetin was 50 μg per week in 50 patients. One patient did not receive darbepoetin due to high hemoglobin levels (180 g/L), one received 40 μg/week, and two received 60 μg/week. At week 12, the darbepoetin dose had been adjusted in 26/50 (52%) patients. In 23/26 (88%), it was raised due to anemia, and in 3/26 (12%) it was tapered due to high hemoglobin levels. The mean darbepoetin dose at week 12 was 70 μg (range 0–150). Two (4%) patients received blood transfusions on one occasion each, but neither of these patients stopped treatment prematurely. Virological response according to HCV genotype In total, 9/54 (17%) patients achieved RVR, 4/36 (11%) with genotype 1 and 5/18 (28%) with genotypes 2 and 3, p ⫽ 0.13. EVR was achieved in 31/54 (57%), in 15/36 (42%) with genotype 1 and in 16/18

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Treatment for recurrent HCV after liver transplantation

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Figure 1. Flow chart showing 54 patients meeting the inclusion criteria and the final distribution regarding sustained virological response (SVR) and non-responders (NRs). EOT, end of treatment; EVR, early viral response; MI, myocardial infarction; RVR, rapid viral response; w1, week 1; w4, week 4.

(89%) with genotypes 2 and 3, p ⫽ 0.0005. EOT response was achieved in 31/54 (58%) patients, 16 (44%) with genotype 1 and 15 (88%) with genotypes 2 and 3, p ⫽ 0.0014. Finally, SVR was achieved in 22/54 (41%), 7 (22%) with genotype 1 and 14 (78%) with genotypes 2 and 3, p ⫽ 0.0001. In the per-protocol analysis, including 51 patients, the corresponding values for genotype 1 versus genotypes 2 and 3 patients for RVR were 4/34 (12%) versus 5/17 (29%) patients, p ⫽ 0.13; for EVR 15/34 (44%) versus 15/17 (88%), p ⫽ 0.0015; and for EOT response 16/34 (47%) versus 16/17 (94%), p ⫽ 0.0004. SVR was achieved in 8/34 (24%) genotype 1 patients versus 14/17 (82%) patients with genotypes 2 and 3, p ⬍ 0.0001. Three patients with recently completed treatment had SVR12 (Figure 2a).

Virological response according to IL28B SVR was achieved in 8/11 (73%) patients with IL28B CC versus 14/43 (33%) with IL28B non-CC, p ⫽ 0.016. The corresponding figures in the perprotocol analysis were 8/11 (73%) versus 14/40 (35%), p ⫽ 0.025. SVR according to IL28B and HCV genotype is depicted in Figure 2a. Virological response according to baseline histology SVR was achieved in 15/27 (56%) patients with mild fibrosis (fibrosis stage 1–2), and in 7/27 (26%) patients with advanced fibrosis (fibrosis stage 3–4), p ⫽ 0.025. The corresponding figures in the perprotocol analysis were 15/26 (58%) in patients with

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M. Ackefors et al. protocol analysis, were 6/20 (30%) versus 16/31 (52%), p ⫽ 0.12.

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Univariate and multivariate analyses of factors associated with SVR

Figure 2. (a) Sustained virological response (SVR) according to IL28B genotype (gt) CC or non-CC and HCV genotype 1 or non-1 (genotype 2 or 3). SVR rates were 73% and 35% in IL28B genotype CC versus non-CC, p ⫽ 0.025, and 24% and 82% in recipients with HCV genotype 1 versus non-1, p ⬍ 0.0001, respectively. (b) Rapid viral response (RVR), early viral response (EVR), end of treatment response (EOT), and SVR according to mild (F1–2) or severe (F3–4) fibrosis. RVR was seen in 27% of patients with mild fibrosis and 8% of patients with advanced fibrosis, p ⫽ 0.069. The corresponding figures for EVR were 70% versus 48%, p ⫽ 0.12; for EOT 69% versus 56%, p ⫽ 0.33; and for SVR 58% versus 28%, p ⫽ 0.027.

mild versus 7/25 (28%), in patients with advanced fibrosis, p ⫽ 0.027. Treatment response according to mild (F1–2) versus advanced fibrosis (F3–4) is depicted in Figure 2b. When divided into cirrhosis (F4) and non-cirrhosis (F1–F3), 3/12 (25%) versus 19/42 (45%) patients achieved SVR, p ⫽ 0.20. In the per-protocol analysis, the corresponding figures were, 3/11 (27%) patients versus 19/40 (48%), p ⫽ 0.22. Virological response according to HCC at time of liver transplantation SVR was achieved in 6/22 (27%) patients with HCC versus 16/32 (50%) in those without HCC, p ⫽ 0.09. The corresponding figures in the per-

Factors analyzed were age, gender, HCV genotype, IL28B gene polymorphism, fibrosis stage before treatment, and mean RBV concentration at week 4 and 12. Factors found to be significantly associated with SVR in the univariate analysis were HCV genotype (p ⫽ 0.0001), IL28B gene polymorphism (p ⫽ 0.025), and fibrosis pretreatment (p ⫽ 0.031), as depicted in Table II. When analyzed for association with SVR in the univariate model, RVR was found to be significantly associated (p ⫽ 0.0016) but not when analyzed by multivariate analysis. Since RVR is not an independent baseline factor it was not included in the final multivariate analysis on the influence of baseline factors. The final multivariate analysis was performed on HCV genotype, IL28B gene polymorphism, and fibrosis pretreatment, all factors significantly associated with SVR in the univariate analysis. HCV genotype (p ⫽ 0.0003) and IL28B gene polymorphism (p ⫽ 0.0068) were found to be strongly associated with SVR, whereas mild versus advanced pretreatment fibrosis stage (p ⫽ 0.0583) did not reach full significance (Table III). Biochemical response The mean alanine aminotransferase (ALT) level at baseline was 2.79 μkat/ml (range 0.36–23), and was 0.98 μkat/ml (range 0.2–3.11) at EOT. The mean ALT at EOT in patients who achieved SVR versus those who did not achieve SVR was 0.74 μkat/ml (range 0.2–2.1) versus 1.14 (0.22–3.11), p ⫽ 0.028.

Table II. Variables associated with SVR in univariate analysis, in 51 patients with HCV relapse, treated with peg-IFN and RBV after liver transplantation. Variable

p value

Age over (n ⫽ 28)/under (n ⫽ 23) mean 56 Sex: M (n ⫽ 40)/F (n ⫽ 11) HCV genotype 1 (n ⫽ 34)/non-genotype 1 (n ⫽ 17) IL28B CC (n ⫽ 11)/non-CC (n ⫽ 40) F1–2 (n ⫽ 26)/F3–4 (n ⫽ 25) F1–3 (n ⫽ 40)/cirrhosis (n ⫽ 11) RBV under (n ⫽ 27)/over (n ⫽ 24) mean 7.7 μmol/L RBV under (n ⫽ 27)/over (n ⫽ 22) mean 11.2 μmol/L

0.079 0.61 ⬍ 0.0001* 0.025* 0.031* 0.22 0.056 0.28

F, female; F1–F4, fibrosis stage; HCV, hepatitis C; M, male; peg-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virological response. *Significantly associated with SVR.

Treatment for recurrent HCV after liver transplantation Table III. Multivariate Cox regression analysis of variables associated with SVR in the univariate analysis, in 51 patients with HCV relapse treated with peg-IFN and RBV after liver transplantation. Variable HCV genotype 1 (n ⫽ 34)/non-genotype 1 (n ⫽ 17) IL28B CC (n ⫽ 11)/non-CC (n ⫽ 40) F1–2 (n ⫽ 26)/F3–4 (n ⫽ 25)

p value 0.0003* 0.0068* 0.0583

F1–F4, fibrosis stage; HCV, hepatitis C; peg-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virological response. *Significantly associated with SVR.

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Discussion Treatment of hepatitis C recurrence after LT has been a major problem and the efficacy has been suboptimal. Antiviral therapy with peg-IFN and RBV post-transplant often fails, particularly in patients with HCV genotype 1 infection. Furthermore, since treatment is compromised with frequent withdrawals due to adverse events, improvements are needed [11]. Soon new DAAs, particularly sofosbuvir, will become available for treatment of HCV relapse in liver transplant patients in regimens where RBV still will be used. Sofosbuvir in combination with RBV has thus offered very promising results, when used both before and after LT, but carries a high cost [13,28]. However, an optimized RBV dose will continue to be of major importance. In this uncontrolled study, we used RBV concentration-guided dosing with darbepoetin support and a low peg-IFN alpha-2a dose for HCV genotypes 2 and 3 to improve tolerance and adherence for treatment post-transplant. We found that tolerability was good in the majority of our patients, who achieved the intended 10 μmol/L RBV serum concentration at weeks 4 and 12 during treatment. The formula used to calculate the RBV dose thus performed reasonably well. Furthermore, the darbepoetin support with start 2 weeks before initiation of peg-IFN plus RBV treatment, and maintained during the full treatment course, offered high adherence rates to a full treatment course. When darbepoetin is introduced when anemia already has occurred, we have noticed that it fails to correct the anemia within a short time period (O. Weiland, personal communication). Therefore, we did not include a control group commencing darbepoetin when anemia already had occurred. Our model can possibly be utilized also when RBV is combined with sofosbuvir to improve tolerance in anemia-prone patients and to optimize RBV dosing. As compared with treatment including sofosbuvir, peg-IFN plus concentration-guided RBV treatment is less costly. The intended RBV concentration of 10 μmol/L has been shown to correlate with favorable response

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rates in non-transplanted and hemodialysis patients [22,23]. This concentration was achieved in the majority of our patients. The darbepoetin dose used in the present study had to be increased in 43% of the patients due to anemia, as seen also in our pilot study [20]. However, blood transfusions were only necessary in two patients, who were both able to finish a full treatment course. The overall 43% SVR rate with peg-IFN and RBV seen in the per-protocol analysis was not impressive. However, in patients with HCV genotypes 2 and 3, 82% achieved SVR as compared with only 24% of patients with genotype 1, p ⬍ 0.0001. Furthermore, the SVR rate reached in our patients infected with genotypes 2 and 3 is comparable to that in nontransplant patients with genotype 2 or 3 infections, and in liver transplant patients treated with sofosbuvir and RBV [9,29,30]. For genotype 1-infected patients, however, our treatment is suboptimal and should be replaced by combinations including sofosbuvir, possibly in combination with daclatasvir [12]. SVR in recipients with IL28B genotype CC was 73% but in recipients with non-CC it was only 35%, p ⫽ 0.025. This highlights that HCV genotype and IL28B gene polymorphism in the recipient are the most important predictors of treatment response in patients with HCV relapse after transplantation, when treatment is given with peg-IFN and RBV. When HCV genotype and IL28B gene polymorphism are combined for prediction of response, the highest SVR rate was found in recipients with HCV genotypes 2 and 3 and IL28B CC. Hence, all our three patients with this combination achieved SVR, consistent with earlier findings by us and others [31,32]. This confirms that recipients with such favorable baseline factors can also achieve high SVR rates with the current peg-IFN and RBV treatment. Fibrosis stage before treatment has been shown to be a very important predictor of response. Hence, poor response is achieved in patients with advanced fibrosis/cirrhosis [16,30]. We found that 58% of our patients with mild fibrosis (F1–F2) achieved SVR versus only 28% with advanced fibrosis (F3–F4), p ⫽ 0.027. These results indicate that treating patients with HCV recurrence at earlier stages, before advanced fibrosis has developed, will increase the possibility of achieving SVR. We found that by utilizing our proposed RBV dosing scheme and starting treatment before advanced fibrosis has developed, favorable SVR rates could be achieved, at least for patients infected with HCV genotypes 2 and 3. In the near future, combination treatment with sofosbuvir and RBV seems to offer great improvements for patients with HCV relapse after transplantation, particularly in patients with genotype 1, as presented

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at AASLD 2013 by Charlton et al. [13]. Treatment including two new DAAs, sofosbuvir and daclatasvir, has also given promising results. In the near future, however, RBV in combination with sofosbuvir seems to offer great improvement and fewer adverse events but at a higher cost. We performed a multivariate analysis on the factors associated with SVR in the univariate analysis, such as HCV genotype, IL28B gene polymorphism, and fibrosis stage before treatment. Only HCV genotype (p ⫽ 0.0003) and IL28B gene polymorphism (p ⫽ 0.0068) were found to be statistically associated with SVR, whereas fibrosis stage pretreatment (p ⫽ 0.058) did not reach full statistical significance. However, our univariate analysis and earlier findings have shown that less advanced baseline fibrosis stage predicts a better treatment response [16,20]. We conclude that a treatment algorithm utilizing concentration-guided RBV dosing with early introduction of darbepoetin support improves tolerance and results in a high adherence rate to RBV and pegIFN treatment. Furthermore, for HCV genotypes 2 and 3, it offers a less expensive and effective alternative to the new treatments including sofosbuvir. Genotype 1, recipient IL28B non-CC gene polymorphism, and an advanced fibrosis stage are all unfavorable baseline factors, predicting a low chance of reaching SVR. Declaration of interest: This study was supported by grants from Roche and with financial support from the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet.The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Peg-IFN and ribavirin treatment for recurrence of genotype 2 and 3 hepatitis C after liver transplantation.

Relapse of hepatitis C virus (HCV) infection after liver transplantation (LT) is universal. Tolerance for treatment with pegylated-interferon (peg-IFN...
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