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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Aliment Pharmacol Ther 2011; 34: 454–461

Summary

Background  In end-stage renal disease (ESRD) patients, hepatitis C virus (HCV) eradication improves patient and graft survival.

Aim  To determine optimal use of erythropoietin (EPO) and ribavirin, to compare ribavirin concentrations with those of HCV patients having normal renal function and to evaluate sustained virological response (SVR) in a prospective observatory of ESRD candidates for renal transplantation.

Methods  Thirty-two naïve patients were treated with Peg-IFN-α2a and ribavirin. Two different schedules of ribavirin and EPO administration were used: starting ribavirin at 600 mg per week and adapting EPO when haemoglobin (Hb) fell below 10 g/dL (adaptive strategy) or starting ribavirin at 1000 mg per week while increasing EPO from the start of treatment (preventive strategy).

Results  Patients treated with the adaptive strategy had lower median Hb levels (9.6 vs. 10.9 g/dL, = 0.02) and more frequent median Hb levels below 10 g/dL (58 vs. 5%, = 0.0007) despite lower median ribavirin doses (105 vs. 142 mg/day, < 0.0001) than patients treated with the preventive strategy. There was a trend for more frequent transfusion in patients treated with the adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, = 0.08). Compared to patients with normal renal function, ESRD patients had lower ribavirin concentrations during the first month (0.81 vs. 1.7 mg/L, = 0.007) and similar concentrations thereafter. SVR was reached in 50%.

Conclusions  Pegylated interferon (Peg-IFN) and an adapted schedule of ribavirin are effective in ESRD patients. Increasing EPO from the start of treatment provides better haematological tolerance. The optimal dosage of ribavirin remains unresolved, in light of frequent side effects.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

In patients with end-stage renal disease (ESRD), chronic hepatitis C virus (HCV) infection leads to enhanced morbidity and mortality, either before1, 2 or after3, 4 renal transplantation. This increased mortality is related to excessive liver-related death when compared to patients without HCV infection.1, 4 Moreover, patients undergoing renal transplantation may have an increased risk of HCV-mediated allograft nephropathy and diabetes mellitus.5–8 Therefore, viral eradication may improve the outcome of HCV patients after renal transplantation.

Combination therapy with pegylated interferon (Peg-IFN) and ribavirin is the standard therapy for chronic HCV infection. This regimen is usually contraindicated in renal transplant recipients because of an increased risk of graft rejection.9, 10 In haemodialysed patients, only markedly reduced doses of ribavirin may be used.11 However, the exact dose of ribavirin remains unknown and there is a high risk of drug-related toxicity, mainly haemolytic anaemia, due to the increase in ribavirin exposure.12, 13 This explains why most studies in ESRD patients tested ribavirin-free treatment schedules,14, 15 with approximately one-third of patients achieving a sustained virological response (SVR) regardless of genotype.16, 17 When considering the impact of ribavirin on the SVR rate in HCV patients with normal renal function, it is speculated that adding this molecule to the therapeutic regimen of ESRD-infected patients might increase the probability of viral eradication. Regimens of Peg-IFN with low doses of ribavirin have been tested in a prospective study18 and in small series of haemodialysed patients.19–21 Those studies yielded promising rates of SVR with acceptable haematological tolerance. Nevertheless, additional data are required to define the optimal schedule of treatment combining high efficacy and a good safety profile. In addition, comparison between ribavirin concentrations in ESRD patients and in patients with normal renal function treated with conventional doses of ribavirin may be helpful.

Erythropoietin (EPO) is the gold standard therapy for ESRD patients with anaemia, and leads to a drastic reduction in the red cell transfusion requirement.22 In the specific setting of HCV patients without renal failure, the use of recombinant EPO for anaemia during combination therapy enables maintenance of higher ribavirin doses.23, 24 Currently, for HCV patients with ESRD, no guidelines exist for treating anti-viral therapy-associated anaemia.

We began a prospective follow-up observatory in ESRD patients who were candidates for renal transplant, and treated them with Peg-IFN-α2a and an individual schedule of ribavirin. In the present study, we only considered naïve patients treated with Peg-IFN-α2a and an adapted schedule of ribavirin. Our aims were: (i) to define optimal use of EPO and adequate doses of ribavirin tailored by the haemoglobin level; (ii) to compare ribavirin concentrations in ESRD patients and in HCV patients with normal renal function treated with conventional doses of ribavirin and (iii) to evaluate SVR rates.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Patients

Prospective follow-up of ESRD candidates for renal transplant treated with Peg-IFN and an individual schedule of ribavirin were started. Anti-viral therapy was not begun in cases of decompensated liver disease and if any of the following haematological criteria were present: 1/haemoglobin (Hb) <8.5 g/dL; 2/white blood cells <2000/mm3 (neutrophil count <1000/mm3); 3/platelet count <80 000/mm3.

Treatment strategy

Prospective follow-up was first initiated at Lille Hospital and was approved by the Ethical Committee of Lille Hospital (CP number 06/38). Patients were treated with a combination of Peg-IFN-α2a (PEGASYS; Roche, Hertfordshire, UK) 135–180 μg once a week and an adapted schedule of ribavirin (COPEGUS; Roche). In the present study, only naïve patients were considered.

All patients were treated with intravenous recombinant human EPO (NeoRecormon, Roche, Epoetin-alfa, Eprex, Janssen Cilag S.p.A, Turnhout, Belgium or darbepoietin α, Aranesp, Amgen, Neuilly sur Seine, France). To use the same units for EPO dosage, we multiplied the dose of darbepoietin-α in microgram by 200 to obtain the equivalence in terms of units of Eprex or NeoRecormon as previously done.25

Two different schedules of administration of ribavirin and EPO were used. In a first step, ribavirin was started at 600 mg per week (200 mg thrice weekly). EPO was used according to Hb levels, with a stepwise increase only when Hb fell below 10 g/dL (adaptive strategy of EPO administration). As analysis of the results of the first patients revealed that blood transfusions were frequent, we modified the schedule of treatment thereafter. Ribavirin was started at 1000 mg per week (200 mg five times a week), while EPO was increased from the start of the treatment according to Hb levels before the start of treatment and then adapted to Hb levels during treatment with a stepwise increase so as to reach 11 g/dL (preventive strategy of EPO administration).

After preliminary presentation of our experiment, three other centres (Hôpital Erasme, Brussels, CHU Nice and CHU Caen) decided to treat their HCV patient candidates for renal transplantation using the second treatment strategy. All data were prospectively collected and sent to the Lille centre.

A stepwise reduction in the Peg-IFN-α2a dose was allowed so as to manage adverse events or laboratory abnormalities. A stepwise reduction in ribavirin doses was planned when Hb fell to 8.5 g/dL despite an increase in EPO to a maximum dose of 90 000 IU/week. A stepwise reduction in EPO doses was planned when Hb levels increased to above 12 g/dL.

At the Lille and Nice Hospitals, ribavirin concentrations were measured monthly up until the sixth month, and at 9 and 12 months of treatment in patients treated with the second strategy.

Patients were assigned to receive treatment for 48 weeks if they were infected with HCV-1 or -4, while 24-week treatment duration was used in HCV-2 or -3 patients. Those showing a slow virological response were evaluated for 6-month prolonged therapy. Anti-viral therapy was discontinued in HCV-1 or -4 patients with detectable HCV RNA 6 months after the start of treatment.

Virological tests

Anti-HCV antibodies were determined using a chemiluminescence immunoassay (Architect anti-HCV assay; Abbott Diagnostics, Abbott Park, IL, USA). HCV genotyping was performed using a direct sequencing assay, Trugene HCV 5′NC Genotyping Kit (Siemens Healthcare Diagnostics, Tarrytown, NY, USA). Levels of serum HCV RNA were quantified by real-time PCR (Cobas AmpliPrep/Cobas TaqMan HCV Test, Roche Diagnostic Systems, Basel, Switzerland). The range of linear quantification was from 43 to 69 millions IU/mL. The lower limit of detection was 15 IU/mL. SVR was defined as an undetectable HCV RNA 6 months after the end of anti-viral therapy.

Statistical analysis

Ribavirin doses were assessed monthly. EPO doses were measured prior to the beginning of treatment, as well as monthly during treatment and during the 3 months following treatment. Viral load was determined before starting the treatment, during treatment: at 1 month; at 3 months; at 6 months and at the end of treatment. It was also evaluated 6 months after stopping treatment. Hb levels were monitored every week during the first month, and then every month thereafter both during and after treatment.

Data were expressed as percentage or median (95% CI). Analyses were conducted using variance analysis, the chi-square test, two-sided Fisher exact test, Mann–Whitney test, Wilcoxon test and two-sample Student’s t-test when appropriate. All statistical testing was two-tailed at the 5% level. All statistical analyses were performed using NCSS 2005 software (NCSS, Kaysville, UT, USA). The analysed endpoints were: A/safety profile, including detailed evolution of Hb levels and EPO doses during treatment; B/evolution of ribavirin dosage and concentrations and C/rates of SVR.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Characteristics of patients

Starting in 1 January 2004, 32 haemodialysed naïve HCV patients who were candidates for renal transplant were prospectively followed up (Table 1). All patients were treated with Peg-IFN-α2a (median doses of 180 μg once a week, 95% CI: 135–180). Twelve patients were treated with the first strategy in which ribavirin was started at 600 mg per week (corresponding to an average of 86 mg/day, 95% CI: 57–86, adaptive strategy) and 20 patients with the second strategy in which ribavirin was started at 1000 mg per week (corresponding to an average of 142 mg/day, 95% CI: 142–142, preventive strategy) (see Patients and methods).

Table 1.   Baseline demographic and clinical characteristics of the study population according to the strategy used
 Adaptive strategy (= 12)Preventive strategy (= 20)P value
  1. Values in bold denote variables reaching a significant level in statistical analysis.

  2. * Data expressed as median (95% CI).

  3. † According to the METAVIR scoring system.

Gender ratio (men/women)4/815/200.02
Genotype 1/2/3/49/1/2/010/2/2/60.2
Age (years)*46 (36–55)52 (49–55)0.2
Body mass index (kg/m²)*20.6 (18.4–25.4)24.0 (20.9–26.0)0.06
Viral load (IU/mL)*1 900 000 (228 204–4 940 000)274 500 (123 000–1 104 445)0.1
Duration of haemodialysis (years)*18.1 (1.1–27.2)1.8 (1.0–8.9)0.08
Duration of infection (years)*25.6 (15.9–30.4)21.1 (19.9–23.2)0.3
ALT (ULN)*0.75 (0.40–1.05)0.70 (0.50–0.95)0.9
Fibrosis stage†,*1 (0–2)1 (1–2)0.4
Fibrosis ≥3† (n, %)1 (8%)4 (20%)0.4

A/Safety profile

A1/Evolution of haemoglobin levels during treatment and need for transfusion according to adaptive vs. preventive strategy.  The median decrease in Hb levels between the start of treatment and the third month was 2.6 g/dL (95% CI: 1.6–3.6). No patient had an Hb level higher than 16 g/dL. When compared to patients treated with preventive strategy, those treated with adaptive strategy had lower median Hb levels from the start to the end of anti-viral therapy (9.6 vs. 10.9 g/dL, = 0.02), and more frequently median Hb levels below 10 g/dL (58 vs. 5%, = 0.0007). There was a trend for more frequent transfusion in patients treated with adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, = 0.08) (Table 2). The starting dose of Peg-IFN-α2a did not influence haematological tolerance.

Table 2.   Haematological tolerance, side effects and treatment discontinuation
 Adaptive strategy for EPO administration (= 12)Preventive strategy for EPO administration (= 20)P value
  1. Values in bold denote variables reaching a significant level in statistical analysis.

  2. * Discontinuation of treatment due to severe asthenia in one case and due to sepsis in the other.

  3. † Discontinuation of treatment due to severe asthenia in three cases and due to febrile neutropenia in the fourth case.

Haematological tolerance
 Median Hb levels at the start of the treatment (g/dL, 95% CI)12.1 (10.5–13.1)12.6 (11.9–13.6)0.13
 Median Hb levels under treatment (g/dL, 95% CI)9.6 (9.3–11.0)10.9 (10.6–11.4)0.02
 Median Hb levels under treatment <10 g/dL –n (%)7 (58)1 (5)0.0007
 Median nadir Hb levels (g/dL, 95% CI)7.7 (6.5–8.9)9.0 (8.4–9.5)0.006
 Patients transfused –n (%)6 (50)4 (20)0.08
Severe side effects –n (%)6 (50)8 (40)0.6
 Severe asthenia –n (%)2 (17)5 (25) 
 Infection –n (%)1 (8)1 (5) 
 Depression –n (%)1 (8)0 (0) 
 Death –n (%)0 (0)2 (10) 
 Other side effect –n (%)2 (17)0 (0) 
Discontinuation of treatment due to side effects –n (%)2 (17)*4 (20)†0.8

A2/Side effects.  Six patients discontinued treatment prematurely due to serious side effects, without significant differences between adaptive and preventive strategies (Table 2). There were no differences in the frequency of side effects regarding the starting dose of Peg-IFN-α2a. Two patients treated with preventive strategy died during anti-viral therapy. Those two deaths did not appear to be directly related to anti-viral treatment. The first 39-year-old patient died of cerebral haemorrhage after 4 months of treatment. He had cirrhosis and chronically suffered from hypertension. He was receiving 80 μg/week of Aranesp. His highest Hb level under treatment was 10.6 g/dL. The last Hb level was 8.3 g/dL and the last platelet count was 92 000/mm3. The second patient died after 6 months of treatment. He was 73 years old. He developed extradural haematoma after an accidental fall; he was receiving Eprex 80 000 U/week. His highest Hb level under treatment was 11.7 g/dL. The last Hb level was 8.8 g/dL and the last platelet count was 44 000/mm3. For the latter patient, we cannot exclude the possibility that treatment-induced thrombopenia aggravated the course of extradural haematoma.

A3/Evolution of EPO doses during treatment.  Overall, the median dose of EPO was increased by 141% (95% CI: 75–250%, < 0.0001) when compared to doses before starting anti-viral therapy. Median total dose of EPO was similar in patients treated with adaptive or preventive strategy (12 833 vs. 20 250 IU/mL, respectively, = 0.1). Conversely, there was a difference in the timing of the EPO increase: EPO doses increased within the first month in 17 vs. 60% (= 0.02) of patients treated with adaptive and preventive strategies, respectively (Figure 1).

image

Figure 1.  Evolution of EPO doses during treatment. EPO doses (U/week). Full line: adaptive strategy for EPO administration. Dotted line: preventive strategy for EPO administration.

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B/Ribavirin doses and concentrations

When compared to patients given preventive treatment, patients who were given the adaptive strategy had lower median ribavirin doses during treatment: 105 vs. 142 mg/day (< 0.0001). These differences were sustained until the end of anti-viral therapy.

Ribavirin concentrations were measured in 11 patients using preventive strategy and in 34 patients with normal renal function treated with subcutaneous Peg-IFN and at standard doses of ribavirin (800–1200 mg per day according to genotype and body weight). Haemodialysed patients had lower ribavirin concentrations than patients with normal renal function during the first month of treatment, at 2 weeks (0.49 vs. 1.3 mg/L, = 0.002) and at 1 month (0.81 vs. 1.7 mg/L, = 0.004). There were no significant differences thereafter.

C/Virological results

All patients reached the 6 months follow-up period. Sixteen patients (50%) attained SVR (40% for HCV-1, 4 patients; 86% for HCV-2, 3 patients, = 0.02) (Table 3). There was no difference in SVR rates between patients treated with the adaptive or preventive strategy (58 vs. 45%, N.S.) neither in those infected with genotype 1 (44 vs. 40%, N.S.) nor in those infected with genotype 2 or 3 (100 vs. 75%, N.S.). Ribavirin and EPO dosages were no different between responders and non-responders (data not shown). However, ribavirin concentration at 1 month was higher in responders than in non-responders (2.96 vs. 0.76 mg/dL, = 0.04). Other predictive factors in SVR were baseline HCV RNA, fibrosis stage and undetectable HCV RNA at 1 month and at 3 months (data not shown).

Table 3.   Virological results according to genotype
 RVREVRUndetectable HCV RNA at month 3End-of-treatment VRRelapseSVR
  1. RVR, rapid virological response; EVR, early virological response; SVR, sustained virological response; VR, virological response.

  2. = 0.008 between genotype 1–4 patients and genotype 2–3 patients.

  3. † = 0.03 between genotype 1–4 patients and genotype 2–3 patients.

Overall population –n (%)9/31 (29)27/32 (84)18/32 (56)25/32 (78)9/25 (36)16/32 (50)
Patients with genotype 1–4 –n (%)6/25 (24)20/25 (80)11/25 (44)*18/25 (72)8/18 (44)10/25 (40)†
Patients with genotype 2–3 –n (%)3/6 (50)7/7 (100)7/7 (100)*7/7 (100)1/7 (14)6/7 (86)†

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

In ESRD candidates for renal transplantation, viral eradication is an attractive option when considering the deleterious effect of HCV infection on patient and graft survival.1–4 However, this group of patients is usually considered difficult to treat because of the high risk of drug-related toxicity, mainly haemolytic anaemia, due to the increase in ribavirin exposure.12, 13 The present study reporting only results on naïve patients observed that pegylated bitherapy induced SVR of 40% in HCV-1 and 4 patients and 86% in HCV-2 and 3 patients. In addition, it provides data on the safety profile of anti-viral therapy and suggests a means of using EPO, or so-called preventive strategy, which permits maintaining the ribavirin dose without inducing significant anaemia. However, as there were no differences between patients treated with the two strategies in terms of SVR, median EPO doses or treatment discontinuation rates, we cannot firmly conclude that preventive strategy is more effective than adaptive strategy. Finally, as they were sequentially administered, comparison of the two therapeutic strategies was suboptimal.

Despite the use of higher ribavirin doses, preventive strategy involving increased EPO from the start of anti-viral therapy led to better haematological tolerance than adaptive strategy which involves increasing EPO on demand. This preventive strategy integrates the pharmacokinetics of EPO, as it requires approximately 3 weeks before EPO induces an increase in Hb levels.26 However, it must be pointed out that intensive monitoring, as was done in this study, is mandatory so as to minimise the risk related to EPO-induced polycythaemia. With this close follow-up of Hb levels, no patient had Hb levels equal to or higher than 16 g/dL under treatment in the present study.

At first glance, the two deaths observed (6% of the overall population) might be considered to preclude evaluation of pegylated bitherapy in ESRD patients under dialysis. However, several studies in untreated haemodialysed HCV patients showed an approximate 5–10% and 15–20% death rate at 1 and 4 years, respectively.1, 27 This poor prognosis is no doubt related to the fact that these patients frequently have rapid progression of arteriosclerosis and suffered from multiple comorbidities such as hypertension and diabetes mellitus, in addition to those related to HCV infection. The two patients who died in the present study suffered from such comorbidities: one patient had cirrhosis and the other was 73 years old. Although we cannot formally exclude the possibility that these drugs were partly responsible for the two deaths, this seems unlikely, as the last measurements of Hb levels were 8.3 and 8.8 g/dL in these two cases, and we did not observe any significant increase in blood pressure, psychiatric disorders or infection. Nevertheless, patients must be carefully selected when anti-viral treatment is considered. As this study only included candidates for renal transplantation, our recommendations for treating ESRD patients only apply to this highly select group of patients.

This study also confirms that combination therapy with Peg-IFN and an adapted schedule of ribavirin is effective in ESRD patients. These results seem more positive than those reported when Peg-IFN is used alone,28–31 and are similar to or even more favourable than those reported in other small series of patients treated with Peg-IFN and ribavirin;19–21 they are also close to those observed in HCV patients with normal renal function.32–34 However, they differ from results of another recent study reporting a high rate of SVR (97%).18 As a complement to other studies, our report provides data which enable narrowing the range of adequate ribavirin doses in haemodialysed patients, leading to sufficient exposure. In previous studies,18–21, 35–37 haemodialysed patients were not treated with ribavirin doses higher than 400 mg per day. The observed 1-month delay before reaching steady-state ribavirin concentrations suggests that 1000 mg per week is not yet optimal, and provides additional evidence that 1400 mg per week may be better adapted. This seems important when considering the impact of early ribavirin exposure on SVR rates in HCV-1 patients with normal renal function.38 Regarding Peg-IFN-α2a, 135 μg/week is currently considered the standard dose in ERSD patients.

In conclusion, candidates for renal transplantation, when treated with Peg-IFN and adapted doses of ribavirin, attained SVR in nearly the same proportions as patients with normal renal function. However, they require a specific strategy for EPO use and close monitoring of clinical and biological parameters. The optimal daily dose of ribavirin still remains unsettled.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References