1 Division of Renal Medicine, Department of Clinical Science, 2 Division of Infectious Diseases, Department of Medicine, 3 Division of Clinical Pharmacology, Department of Medical Laboratory Sciences and Technology and 4 Division of Pathology, Department of Immunology, Microbiology and Pathology, Karolinska Institute and Huddinge University Hospital, S-141 86 Stockholm, Sweden
Correspondence and offprint requests to: Annette Bruchfeld, MD, K 56, Division of Renal Medicine, Department of Clinical Science, Karolinska Institute and Huddinge University Hospital, S-141 86 Stockholm, Sweden. Email: annette.bruchfeld{at}klinvet.ki.se
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Abstract |
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Methods. Seven patients, two with cryoglobulinaemia, vasculitic manifestations and glomerulonephritis (GN), four with MPGN and one with FSGS were treated with a combination of interferon and ribavirin. Two patients were given pegylated interferon and ribavirin. All patients had at presentation renal insufficiency, with a glomerular filtration rate (GFR) between 10 and 65 ml/min. One patient had HCV genotype 1, the remainder 2 and 3. Duration of therapy was according to genotype (612 months). Ribavirin in plasma was monitored by high-performance liquid chromatography (HPLC) to avoid over-dosing, aiming at a target concentration of 1015 µmol/l. The main side effect of ribavirin, haemolytic anaemia, was monitored closely with haemoglobin controls.
Results. Six of seven patients became HCV-RNA-PCR negative and four of seven have maintained both virological and renal remission. One of seven has maintained virological and partial renal remission. One patient did not tolerate interferon, but is in renal remission with low-dose ribavirin. One vasculitis patient responded with complete remission, but relapsed virologically and had a minor vasculitic flare after 9 months. Only one patient with vasculitis had low-dose immunosuppression in addition to anti-viral therapy. Average daily ribavirin dose was 200800 mg. Ribavirin-induced anaemia was managed in five of seven patients with low-dose iron and erythropoietin between 4000 and 20 000 IU/week.
Conclusions. Interferon and ribavirin can with reasonable safety be used in HCV-related vasculitis and GN irrespective of renal function.
Keywords: cryoglobulinaemia; interferon; HCV; pegylated interferon; renal manifestations; ribavirin; vasculitis
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Introduction |
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Treatment for renal disease has mostly consisted of interferon therapy, with in some cases a favourable outcome, but often with recurrence of disease after cessation of therapy [4,5]. With the addition of the nucleoside analogue ribavirin treatment successes for HCV have improved significantly, but only a few case reports deal with treatment outcomes for extrahepatic manifestations and renal disease [6,7]. However, ribavirin has been contraindicated in renal insufficiency due to its main side effect, anaemia, and because of insufficient knowledge regarding dosing. We have recently shown that ribavirin can be used in combination with interferon-alfa-2b in dialysis patients, the corner-stones being reduced ribavirin doses, ribavirin plasma monitoring and high-dose erythropoietin treatment, as well as ensuring adequate iron stores for erythropoiesis [8]. The high-performance liquid chromatography (HPLC) method developed by us to monitor ribavirin [9] has also been used in patients treated for HCV with moderate to severe renal insufficiency. Pegylated interferon, currently available as pegylated interferon-alfa-2a (Pegasys® 40 kDa, Roche) and pegylated interferon-alfa-2b (PegIntron® 12 kDa, Schering-Plough), are polyethylene glycol modified forms of interferon-alfa with an increased plasma half-life given as weekly injections, being promising new additions and are believed to replace interferon-alfa, given thrice weekly, for treatment of HCV [10]. The use of pegylated interferon has not been reported previously in glomerular disease caused by HCV. However, neither are well studied in renal insufficiency or end-stage renal disease, although pegylated interferon-alfa-2a (Pegasys, Summary of Product Characteristics, Roche) is reported to have a large metabolic clearance compared with a higher degree of renal clearance for pegylated interferon-alfa-2b (PegIntron, Summary of Product Characteristics, Schering-Plough).
Seven patients with renal insufficiency at presentation were treated with interferon-alfa-2b or pegylated interferon-alfa-2b in combination with ribavirin for HCV-related renal disease with or without cryo-globulinaemia between 1998 and 2002 at Huddinge University Hospital.
The aim of this study was to retrospectively analyse the outcome of these patients, regarding viral and renal response, as well as their tolerability to treatment.
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Subjects and methods |
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The renal biopsies showed varying glomerular pathology (Table 2). Five of the seven patients demonstrated a picture suggestive of MPGN. The biopsy from case 3 showed ANCA-associated GN as the likely primary renal disease, while case 4 displayed the features of an FSGS. In cases 1, 2 and 3 active crescentic components were found. In cases 2, 3, 4, 6 and 7 sclerotic lesions were prominent, suggestive of long-standing renal disease.
The study was approved by the local ethics committee.
Treatment schedule and monitoring
Patients 1 through to 5 received interferon-alfa-2b (Intron®, Schering-Plough) 3 MU thrice weekly, except for patient 2 who started with 1.5 MU thrice weekly. Patients 6 and 7 were given pegylated interferon-alfa-2b (PegIntron®, Schering-Plough), which was the pegylated interferon approved at the time. Patient 6 was given a dose of 1 µg/kg, equivalent to 50 µg subcutaneously once a week due to a near-normal renal function and patient 7 also received 50 µg subcutaneously once a week, which was a reduction by 25% from the dose of 1 µg/kg due to a low GFR. Ribavirin (Rebetol®, Schering-Plough) was introduced at a dose varying between 200 and 800 mg daily, depending on renal function, and was subsequently adjusted according to the results of ribavirin monitoring. The initial and final doses are shown in Table 3. The intended trough ribavirin plasma con-centration was, as in the dialysis study, in the range 1015 µmol/L, based on steady-state levels in a reference group of 10 patients with normal renal function treated for HCV [8]. The duration of therapy was according to genotype, thus patients 3 through to 7 received a total of 24 weeks of combination therapy, whereas patient 1 being infected with HCV genotype 1a received a longer treatment, initially interferon-alfa-2b for 3 months when ribavirin was added to interferon-alfa-2b for another 12 months. Patient 2 terminated interferon therapy due to side effects but conti-nued with ribavirin monotherapy. Erythropoietin (Table 5) and iron, given as oral iron sulfate, 100200 mg daily, or i.v. iron saccarate, 100 mg/week, were given in order to treat ribavirin-induced anemia. Hyperuricaemia was managed with sodiumbicarbonate/probenicide or allopurinol.
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Virological monitoring and general monitoring
HCV genotyping was carried out by means of a modifi-cation of the method of Okamato [11]. Qualitative HCV-RNA-PCR (Amplicor, Roche Diagnostics, Indianapolis, IN) was analysed at 4, 8, 12 and 24 weeks during therapy in patients 3 through to 7, in patient 1 at 48 weeks as well, and in all after cessation of therapy at least at 6 months. Patient 2, not having completed interferon therapy, was not tested further.
General monitoring, initially once monthly, consisted of full blood counts and CRP as well as serum alanine aminotransferase (ALT) and serum urate. Hb, serum ferritin and hypochromic ertythrocytes were followed monthly for anaemia control. Serum albumin, urine albumin/24 h and haematuria were followed during therapy and at follow-up. Renal function was assessed by endogenous creatinine clearance, except for case 5 where only iohexol clearance was available.
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Results |
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The renal outcome was favourable in all cases. In all patients serum albumin normalized and albuminuria decreased substantially to levels <0.5 g/24 h, except for case 7 who currently has an albuminuria of 4.6 g/24 h, as compared with 10 g/24 h prior to therapy. Case 7, who presented with rapidly progressing renal insufficiency, terminated anti-viral therapy 6 months ago and is still HCV-RNA negative and in partial renal remission. The renal damage is most likely irreversible, considering the chronic changes on the renal biopsy. On the other hand, the rapid loss of renal function has been halted.
Haematuria was no longer detectable at follow-up in cases 1, 2, 4, 5 and 7. GFR normalized in patients 1 and 6 and stabilized in the remainder of the cases, except for case 2 who improved from 10 to 38 ml/min in GFR during treatment with ribavirin only. These results are summarized in Table 4.
Patients 3 and 6 with vasculitis rapidly improved, in case 3 the skin lesions improved and the neurological manifestations cleared whereas in case 6 the oral ulcers, which had been present for 2 years disappeared after introduction of anti-viral therapy. In both cases fever subsided and CRP dropped. Other immunomodulatory treatment was discontinued or tapered to a low level, i.e. chloroquine phosphate in case 6 and prednisone 10 mg in case 3. Patient 3, who relapsed virologically, remained in renal remission for 9 months, when a minor vasculitic flare occurred. In both patients cryoglobulinaemia and RF were no longer detectable, in case 3 PR3-ANCA decreased to borderline levels. Case 6 had low levels of MPO antibodies at presentation which disappeared after treatment, and both ANA and anti-DNA remained at low levels, apart from a temporary increase coinciding with an episode of painful swelling of the wrists a few weeks after cessation of therapy. This was treated successfully with a low dose of prednisone, which is now tapered.
The intended ribavirin plasma concentration of 1015 µmol/l was reached within 46 weeks with the exception of case 3, who only tolerated a fairly low dose due to gastrointestinal side effects.
Side effects
All patients had initial flu-like syndrome, myalgia and fatigue attributed to interferon. Patient 6 had fever for 48 h after injection of pegylated interferon throughout therapy. Some patients suffered neutropenia and lowered platelet levels but did not require interferon dose modifications. Infections were scarce, but patient 4 had pneumonia at the end of treatment and patient 6 had a large ulcer on her knee, suggestive of a vasculitic manifestation, which also needed additional treatment with antibiotics.
Some patients had mood disturbances, but none needed antidepressant therapy.
The major side effect was ribavirin-induced haemolytic anaemia, which necessitated the use of erythropoietin and iron in five out of seven patients, as summarized in Table 5. Ribavirin monitoring was done to minimize over-dosing. In addition, serum ferritin but foremost hypochromic erythrocytes was useful to monitor iron deficiency. Median ferritin (reference range 30350 µg/l) was early during therapy 615 µg/l (range 112833) and later, within months, median ferritin was 704 µg/l (range 4001015) in patients given iron. Case 4 who did not receive iron had a ferritin level of 85 µg/l before therapy and at the end 482 µg/l, which could reflect the degree of haemolytic anaemia in this patient having no sign of infection and by then normalized liver enzymes. On the other hand median hypochromic erythrocytes (reference <2.5%) were initially 11.9% (range 10.120.4) and later median 7.8% range 1.417.1) in patients treated with iron, reflecting a decrease in iron deficiency. By intensified anaemia therapy Hb levels of 105130 g/l were achieved (Table 5). The dose of erythropoietin varied (Table 5), but in general more was given to patients with a low GFR or as in case 6 coinciding with a slow drop in CRP, believed to be caused by vasculitis and her ulcer of the knee. Hyperuricaemia was in the first two cases severe. Case 1 had a maximum of 728 µmol/l (reference 160450 µmol/l), whereas case 2 reached 1270 µmol/l with symptoms from the joints. This caused us to give the following patients prophylactic treatment as shown in Table 5 and uric acid was kept at acceptable levels.
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Discussion |
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As in our previous study on dialysis patients [8], ribavirin plasma concentration was monitored and we aimed at a trough level interval of 1015 mmol/l at steady state, based on a study on 10 HCV-infected patients with normal renal function. The average daily ribavirin dose in the present study was between 200 and 800 mg, the lower dose given to patients with a markedly reduced renal function. The recommended dose for patients with normal renal function is 8001200 mg daily, depending on body weight. We have recently conducted a study [12], which specifically addresses the role of renal function in ribavirin clearence. We found, in contrary to current dose recommendations based on body weight (PegIntron, Summary of Products Characteristics, Schering-Plough), that renal function is a significantly better predictor of ribavirin clearance than body weight alone. Our results in the dialysis patient study [8], as well as those in the current study, emphasizes the importance of renal function for ribavirin dosage. A recent study from Jain et al. [13] describing the use of ribavirin in 72 liver transplant recipients shows a significant correlation between the degree of anaemia and renal function and the authors suggest ribavirin dose modifications based on renal function, which is in accordance with our findings. Based on a population pharmacokinetic analysis [12] we have constructed a formula for initial ribavirin dosing aiming at a steady state concentration taking both GFR and body weight into consideration. Ribavirin has a long half-life, which results in long times to reach steady state. This is even more pronounced in renal insufficiency. For cases like these this could be handled with a loading dose and subsequent ribavirin monitoring, which was used clinically in the cases presented, which explains some of the dose modifications in Table 3. On the other hand, in some cases the dose was increased due to improvement in renal function in order to reach target concentration. A dosing algorithm in an average patient with a range of estimated creatinine clearance (CockcroftGault) is given in Table 6, modified after [12]. For large deviations in body weight and creatinine clearance <20 ml/min additional dosing modifications are likely. In the dialysis study the average daily ribavirin dose was between 170300 mg [8,12]. In the pharmaco-kinetic study [12] we also found a significant interindividual variability in ribavirin clearance making ribavirin monitoring desirable at least in patients with more prominent renal insufficiency or in patients with pronounced side-effects.
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The use of pegylated interferon-alfa-2b in two patients has in our experience been a valuable novelty. Compared with interferon-alfa-2b three times weekly, the injection is given once weekly, which is more convenient for the patient. Many side effects as initial flu-like symptoms, myalgia and fatigue are similar to interferon-alfa-2b and the vasculitis patient had injection-related fever for most of the treatment, but the general impression was that the tolerance was good.
Ribavirin-induced anaemia was, as in the dialysis study, a problem. However, with erythropoeitin and iron, Hb was maintained at normal or near normal levels avoiding blood transfusions. Erythropoeitin doses varied between 4000 and 12 000 IU/week, except for one case, where up to 20 000 IU/week was given. The higher need in this patient, in spite of a good renal function, was believed to be related to an ongoing inflammation with elevated CRP causing erythropoeitin resistance. The use of iron is somewhat controversial with regard to hepatitis C and anti-viral therapy. Many HCV-infected patients have elevated ferritin levels and show positive iron staining on liver biopsy. Some studies have seen an additional effect on viral clearance with iron reduction by phlebotomy [15] whereas others have not been able to confirm this finding [16]. There is no data on the effect of iron reduction in combination therapy. Elevated ferritin levels can reflect inflammation, liver disease and iron overload [17] and can be found in ribavirin treatment secondary to the haemolytic anaemia [8]. With the shortcomings of ferritin as a marker of iron stores in this specific situation we therefore monitored the percentage of hypochromic erythrocytes [18] in most patients, as an additional marker for iron deficiency, in order to avoid iron overload, which can be detrimental in liver disease. Some patients already had elevated ferritin levels likely to be caused by liver disease and inflammation and the introduction of low-dose iron increased ferritin levels slightly. Hypochromic erythrocytes however decreased coinciding with an increase in haemoglobin, suggesting that a relative iron deficiency can be present in spite of elevated ferritin levels. It is possible that the use of erythropoietin and low-dose iron, which in our experience is necessary in most cases to enable the use of ribavirin in renal insufficiency, is more important for viral clearance than a possible profibrotic effect of iron during the 612 months of anti-viral therapy. Although the number of cases in the present study is small, the clinical response overall was good and the use of iron did not seem to affect the response rate.
Erythropoeitin was used in five out of seven patients. The patients with lower renal function are obviously at a higher risk of developing ribavirin-induced anaemia and should be treated pre-emptively at the beginning of therapy in order to avoid significant anaemia. In patients with near-normal function it is probably feasible to wait and see, as in cases 4 and 5, where the nadir Hb low was tolerable for the patients.
Therapeutic drug monitoring is not an established standard in ribavirin treatment. We believe, however, that monitoring is necessary in patients with renal insufficiency, in order to avoid unwanted side effects. An optimal target concentration for ribavirin is not yet established, but in recent studies higher ribavirin concentrations in HCV-infected patients with normal renal function resulted in a higher rate of sustained viral response [19,20]. It is reasonable to assume that this would also be the case in patients with renal insufficiency.
Ribavirin-induced hyperuricaemia was treated as described in the results section and Table 5. Hyperuricaemia is probably caused by excessive uric acid production due to the rapid cell turnover secondary to the haemolytic anaemia. In patients with normal renal function this might be less of a clinical problem, although a case report dealing with ribavirin induced uric acid nephrolithiasis was recently published [21]. One patient had high, symptomatic levels of uric acid but is well controlled with allopurinol at the moment. The outcome in this patient (case 2) is also interesting due to the positive response and maintained renal remission for several years with ribavirin only. The liver disease in this case is stable clinically but has not been subject to a renewed liver biopsy.
Finally, one should be aware that the use of interferon can induce or worsen pre-existing autoimmune disease, which has been described in several case reports [22,23]. In one of our patients the time between the end of anti-viral treatment and a vasculitic flare was 9 months, making interferon unlikely to have had a negative influence. In fact interferon, as previously discussed, might have been helpful in the short term but also in the long term one might speculate that treating and suppressing a chronic infection might lessen the strains on the immune system with regard to autoimmune disease. In case 6, the patient developed arthritis after concluding anti-viral therapy with rising ANA and anti-DNA antibodies. This has been described in the literature as post-interferon lupus syndrome [22]. In most cases the symptoms disappear without any additional therapy, but as in case 6, might require corticosteroid therapy. However, autoanti-bodies of different types, including ANA, RF and ANCA have been described in patients naïve to HCV-treatment [24]. It is likely that this in part reflects an activation of the autoimmune system secondary to the HCV infection rather than an established autoimmune disease. Whether autoimmune flares or complications are less common when combining interferon and ribavirin compared with interferon monotherapy is not well investigated. Still the use of anti-viral therapy should be used with some caution and especially patients with pre-existing autoimmune conditions should be treated and monitored carefully keeping potential complications in mind.
To conclude, in our experience it is reasonably safe to use interferon and ribavirin in HCV-related vasculitis and GN irrespective of renal function. However, the use of ribavirin in renal insufficiency should be used with caution and ribavirin plasma monitoring as well as surveillance of side effects is recommended. The implementation of the results in the present study could contribute to improving current treatment options for HCV-related renal disease with or without renal insufficiency and form a foundation for controlled clinical studies in the field.
Conflict of interest statement. A.B., L.S. and R.S. are conducting research sponsored by Schering-Plough Company.
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References |
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