Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency

Annette Bruchfeld1, Karin Lindahl2, Lars Ståhle3, Magnus Söderberg4 and Robert Schvarcz2

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



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Hepatitis C virus (HCV) infection is associated with renal manifestations, such as membranoproliferative glomerulonephritis (MPGN) with or without cryoglobulinaemia, membranous glomerulonephritis (MGN) and focal segmental glomerulosclerosis (FSGS). Standard treatment for HCV is interferon and ribavirin, but in renal insufficiency ribavirin has been contraindicated due to fear of side effects.

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 (6–12 months). Ribavirin in plasma was monitored by high-performance liquid chromatography (HPLC) to avoid over-dosing, aiming at a target concentration of 10–15 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 200–800 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



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Hepatitis C virus (HCV) infection has been associated with glomerular disease, the foremost being membrano-proliferative glomerulonephritis (MPGN) with or without mixed cryoglobulinaemia [1,2], but cases of membranous glomerulonephritis (MGN) and focal segmental glomerulosclerosis (FSGS) have also been reported [2,3].

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.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Seven patients were referred to the Division of Infectious Diseases and the Division of Renal Medicine at Huddinge University Hospital, where a diagnosis of chronic hepatitis C and renal disease was made. Four were male and three female, with a median age of 47 years (range 43–70). The diagnosis was based on clinical presentation, HCV-RNA-PCR analysis and HCV genotyping, presence of autoantibodies and cryoglobulins, as well as complement analysis (Tables 1 and 3). The renal disease was confirmed by histology in all cases (Figure 1, Table 2), whereas liver biopsy was performed in four out of seven patients (Table 3). All patients presented with glomerulonephritis (GN) and renal insufficiency with a median glomerular filtration rate (GFR) of 58 ml/min (range 10–65), decreased serum albumin with a median of 22 g/l (range 16–32) and albuminuria with a median of 3 g/24 h (range 0.8–10). Six out of seven patients also had microscopic haematuria (Table 4) and all patients were hypertensive. Serum-alanine transferase (ALT) was slightly elevated in all patients at presentation except in case 7, who had normal levels. Patients 3 and 6 presented with an active vasculitic disease with fever, elevated C-reactive protein (CRP) (58 and 100 mg/l, respectively). In case 3 purpura, pleuritis, cerebral vasculitis with headache and fluctuating speech difficulties and peripheral sensory neuropathy was present whereas case 6 had a long-standing history of oral ulcers and fairly recent skin ulcers. Both tested positive for cryoglobulins and had low or borderline C4, consistent with a diagnosis of cryoglobulinaemic vasculitis. Case 1 also had an elevated CRP of 35 mg/l and low C4, suggestive of immune complex mediated disease but cryoglobulinaemia could not be confirmed.


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Table 1. Background data, clinical manifestations and immunological profile

 

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Table 3. Background data on viral strain, liver biopsy findings and treatment, including final ribavirin dose

 


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Fig. 1. Light microscopical picture from case 1; MPNG with segmental crescent formation. PAS-methenamine-silver stain, original magnification x400.

 

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Table 2. Findings on renal biopsy

 

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Table 4. Viral and renal response to antiviral treatment

 
Patients 3 and 6 had a history of autoimmune disease and the presence of autoantibodies had been detected earlier. Case 3 had a 12-year history of low-grade vasculitis with detectable C-ANCA with PR3 antibodies as well as occasional rheumatoid factor (RF) positivity, whereas case 6 had a history of juvenile rheumatoid arthritis. In both these cases anti-viral therapy for a previously known chronic HCV infection had been discussed but was withheld fearing activation of autoimmune disease. At referral, patient 3 was treated with 30 mg of prednisone due to active vasculitic manifestations and patient 6 was treated with chlorokine phosphate due to skin lesions suggestive of discoid lupus.

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 10–15 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, 100–200 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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Table 5. Adverse events and treatment

 
Ribavirin monitoring
Ribavirin plasma concentration monitoring was determined by HPLC [9]. Trough levels were examined on average three times during the initial 2–3 months of therapy, at which time most patients had reached steady state. Subsequently, ribavirin levels were monitored occasionally or when required, e.g. in connection with infections or unexpected haemoglobin (Hb) reductions.

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.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Six out of seven patients became HCV-RNA-PCR negative within 12 weeks of therapy, cases 3 and 6 at 4 weeks, case 7 at 8 weeks and finally cases 1, 4 and 5 at 12 weeks. All patients responded biochemically with normalization of ALT. Four patients 1, 4, 5 and 6, have sustained viral response with a follow-up in the range of 12–32 months. Patient 7 is also HCV-RNA-PCR negative, with a 6-month follow-up. Patient 3 relapsed virologically within 3 months of terminating anti-viral therapy. Patient 2 terminated interferon therapy after 2 weeks due to side effects in spite of a lowered interferon dose, but has remained in renal remission with ribavirin monotherapy for 36 months, supported by low-dose erythropoietin and iron.

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 10–15 µmol/l was reached within 4–6 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 30–350 µg/l) was early during therapy 615 µg/l (range 112–833) and later, within months, median ferritin was 704 µg/l (range 400–1015) 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 10.1–20.4) and later median 7.8% range 1.4–17.1) in patients treated with iron, reflecting a decrease in iron deficiency. By intensified anaemia therapy Hb levels of 105–130 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 160–450 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.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This retrospective study is the first to describe concentration-controlled ribavirin treatment together with interferon therapy in HCV-related glomerular disease in patients with renal insufficiency and shows that ribavirin can be used with reasonable safety, although with a certain reservation for the limited number of patients. This is similar to our previous findings in dialysis patients [8]. In addition, to our knowledge the use of pegylated interferon, which two of the seven patients received, has not been described previously in the literature with regard to renal disease.

As in our previous study on dialysis patients [8], ribavirin plasma concentration was monitored and we aimed at a trough level interval of 10–15 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 800–1200 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 (Cockcroft–Gault) 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 170–300 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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Table 6. Starting doses (mg/day) for ribavirin target concentration adjusted for creatinine clearance in a 70 kg patient

 
The outcome of treatment has been fairly successful in this group of patients, which all had HCV genotype 2 and 3, except for case 1 with genotype 1a. Genotype 1 is more difficult to treat and the duration of anti-viral therapy warranted is 48 weeks [10]. Four out of six patients are in both renal and virological remission, with improved or stable renal function and only low-grade albuminuria. One patient who did not tolerate interferon has been in stable renal remission for over 2 years with ribavirin monotherapy. The only patient who relapsed virologically still maintained renal remission for 9 months. In this case it was not clear if the major clinical problem was HCV- or ANCA-related. However, the anti-viral treatment led to a rapid improvement in the patient’s condition. Interferon has also been used in a small number of cases with Churg-Strauss vasculitic disease with some success [14]. It is therefore possible that the treatment had an additional beneficial influence apart from the anti-viral effect.

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 6–12 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.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Johnson RJ, Willson R, Yamabe H et al. Renal manifestations of hepatitis C virus infection. Kidney Int 1994; 46: 1255–1263[ISI][Medline]
  2. Dagestani L, Pomeroy C. Renal manifestations of hepatitis C infection. Am J Med 1999; 106: 347–354[CrossRef][ISI][Medline]
  3. Stehman-Breen C, Alpers CE, Fleet WP, Johnson RJ. Focal segmental glomerulosclerosis among patients infected with hepatitis C virus. Nephron 1999; 81: 37–40[CrossRef][ISI][Medline]
  4. Misiani R, Bellavita P, Fenili D et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994; 330: 751–756[Abstract/Free Full Text]
  5. Al-Wakeel J, Mitwalli A, Tarif N et al. Role of alpha-interferon in the treatment of primary glomerulonephritis. Am J Kidney Dis 1999; 33: 1142–1146[ISI][Medline]
  6. Zuckerman E, Keren D, Slobidin G et al. Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglob-ulinemia with ribavirin and interferon-alpha. J Reumatol 2000; 27: 2065–2067
  7. Garini G, Allegri L, Carnevali L, Catellani W, Manganelli P, Buzio C. Interferon-alfa. i. Combination with ribavirin as initial treatment for hepatitis C-virus associated cryoglobulinemic membranoproliferative glomerulonephritis. Am J Kidney Dis 2000; 38: 1–5[ISI]
  8. Bruchfeld A, Ståhle L, Andersson J, Schvarcz R. Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection—a pilot study. J Viral Hepat 2001; 8: 287–292[CrossRef][ISI][Medline]
  9. Svensson J-O, Bruchfeld A, Schvarcz R, Ståhle L. Determination of ribavirin in serum using highly selective solid-phase extraction and high performance liquid chromatog-raphy. Ther Drug Monit 2000; 22: 555–565[CrossRef][ISI][Medline]
  10. Chander G, Sulkowski MS, Jenckes MW et al. Treatment of chronic hepatitis C: a systematic review. Hepatology 2002; 36: 135–144[CrossRef][ISI][Medline]
  11. Okamato H, Tokita H, Sakamoto M, Horikita M, Kojina M, Izuka H. Chracterization of the genomic sequence of type V (or 3a) hepatitis C virus isolates and PCR primers for specific detection. J Gen Virol 1993; 74: 2385–2390[Abstract]
  12. Bruchfeld A, Lindahl K, Schvarcz R, Ståhle L. Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis. Ther Drug Monit 2002; 24: 701–708[CrossRef][ISI][Medline]
  13. Jain AB, Eghtesad B, Venkataramanan R et al. Ribavirin dose modification based on renal function is necessary to reduce hemolysis in liver transplant patients with hepatitis C virus infection. Liver Transplant 2002; 8: 1007–1013[CrossRef][ISI][Medline]
  14. Tatsis E, Schnabel A, Gross WL. Interferon-alpha treatment of four patients with the Churg-Strauss syndrome. Ann Intern Med 1998; 129: 370–374[Abstract/Free Full Text]
  15. Fargion S, Fracanzani AL, Rossini A et al. Iron reduction and sustained response to interferon-alpha therapy in patients with chronic hepatitis C: results of an Italian multicenter randomized study. Am J Gastroenterol 2002; 97: 1204–1210[CrossRef][ISI][Medline]
  16. Sievert W, Pianko S, Warner S et al. Hepatic iron overload does not prevent a sustained virological response to interferon-alpha therapy: a long term follow-up study in hepatitis C-infected patients with beta thalassemia major. Am J Gastroenterol 2002; 97: 788–790[CrossRef][ISI][Medline]
  17. Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an index of iron stores. N Engl J Med 1974; 290: 1213–1216[ISI][Medline]
  18. Tessitore N, Solero GP, Lippi G et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant 2001; 16: 1416–1423[Abstract/Free Full Text]
  19. Jen J.F, Glue P, Gupta S, Zambas D, Hajian G. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000; 22: 555–565[CrossRef][ISI][Medline]
  20. Larrat S, Stanke-Labesque F, Plages A, Zarski JP, Bessard G, Souvignet C. Ribavirin quantification in combination treatment of chronic hepatitis C. Antimicrob Agents Chemother 2003; 47: 124–129[Abstract/Free Full Text]
  21. Fontana R. Uric acid nephrolithiasis associated with interferon and ribavirin treatment of hepatitis C. Digest Dis Sci 2001; 46: 920–924[CrossRef][ISI][Medline]
  22. Pouthier D, Theissen F, Humbel RL. Lupus syndrome, hypothyroidism and bullous skin lesions after interferon alfa therapy for hepatitis C in a haemodialysis patient. Nephrol Dial Transplant 2002; 17: 174[Free Full Text]
  23. Garcia-Porrua C, Gonzales-Gay MA, Fernandez-Lamelo F, Paz-Carreira JM, Lavilla E, Gonzales-Lopez MA. Simultaneous development of SLE-like syndrome and autoimmune thyroiditis following alpha-interferon treatment. Clin Exp Rheumatol 1998; 16: 107–108[ISI][Medline]
  24. Clifford BD, Donahue D, Smith L, Cable E, Luttig B, Manns M, Bonkovsky HL. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995; 21: 613–619[ISI][Medline]
Received for publication: 11.10.02
Accepted in revised form: 28. 2.03





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PubMed Citation
Articles by Bruchfeld, A.
Articles by Schvarcz, R.