Dig Dis Sci DOI 10.1007/s10620-014-3085-7
CASE REPORT
Membranoproliferative Glomerulonephritis, Type II Cryoglobulinemia and Triple Therapy for Hepatitis C: A Case Series and Review of the Literature Kevin Humphries • Jama M. Darling A. Sidney Barritt IV
•
Received: 6 November 2013 / Accepted: 18 February 2014 Ó Springer Science+Business Media New York 2014
Keywords Hepatitis C Triple therapy Boceprevir Telaprevir Cryoglobulinemia Membranoproliferative glomerulonephritis
Introduction Extra hepatic manifestations of chronic hepatitis C (HCV) include type II cryoglobulinemia. Previous studies suggest pegylated interferon (Peg-INF) plus ribavirin (RBV) is an effective treatment for HCV related type II cryoglobulinemia [1–4]. The current clinic use of triple therapy is in its second year and the landmark phase 3 clinical trials for telaprevir and boceprevir showed substantial improvements in efficacy for the treatment of genotype 1 HCV [5–9]. However, there are minimal data on the safety and efficacy of triple therapy for HCV-related type II cryoglobulinemia. Cryoglobulins are detectable in 40–70 % of patients with HCV [10, 11], and overt vasculitis develops in 5–10 % of patients [12]. Cryoglobulin associated vasculitis can lead to neuropathy, skin ulcers, and most notably renal disease in the form of membranoproliferative glomerulonephritis (MPGN) [12, 13]. Renal disease secondary to type II cryoglobulinemia is associated with increased mortality [14]. Treatment of cryoglobulinemia with the antiviral regimen of Peg-INF plus RBV yields cryoglobulin clearance in half of the patients [3]. Treatment with corticosteroids, rituximab and K. Humphries Department of Medicine, University of North Carolina, Chapel Hill, NC, USA J. M. Darling A. S. Barritt IV (&) Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA e-mail: [email protected]
plasmapheresis are employed in the treatment of HCV associated cryoglobulin vasculitis, though with varying long-term success, as these do not eliminate the underlying viral antigen trigger [15, 16]. Likewise, there is concern that prolonged immunosuppression may lead to accelerated HCV-related liver disease and impairment of viral clearance on anti-HCV therapy [17]. Treatment guidelines for genotype 1 HCV now recommend performing a risk–benefit analysis on the individual patient when considering triple therapy [18]. Unfortunately, there is insufficient clinical data when weighing triple therapy risks and benefits in patients with cryoglobulinemia and associated renal disease, especially the impact of reduced renal function on the new protease inhibitors. The initial phase III trial of boceprevir only included patients with a serum creatinine below the upper limits of normal, while telaprevir was only studied in patients with a creatinine clearance (CrCl) greater than 50 ml/min. This would exclude patients with MPGN which had progressed to CKD stage 3b-5; though patients with subclinical renal disease may have participated in clinical trials. In addition, trials for both drugs excluded patients with conditions requiring longterm corticosteroid use [5, 7]. This would likely exclude patients with vasculitic skin ulcers, as this condition is frequently treated with long-term corticosteroids albeit with variable efficacy [19]. Thus we sought to describe the treatment experience of four patients with overt clinical manifestations of MPGN and/or laboratory proven cryoglobulinemia in a case series at one academic clinical center.
Methods We identified four patients at the University of North Carolina Liver Center who had type II cryoglobulinemia or
123
Dig Dis Sci Table 1 Patient characteristics Characteristics
Patient 1
2
3
4
Age/gender
53 F
23 F
58 M
42 M
IL28B
CC
CT
CC
CT
Vasculitis manifestations
Leg ulcer
MPGN
MPGN, rash
MPGN, neuropathy
Proteinuria
Not detected
2?
2?
2?
Fibrosure score fibrosis
F1–F2
NA
F0
F4
Necroinflammation
A0–A1
NA
A1
G3
Treatment for vasculitis
Glucocorticoids plasmapheresis
None
Glucocorticoids, rituxumab, plasmapheresis
Glucocorticoids, rituxumab, plasmapheresis
Age is at the time of triple therapy treatment initiation. All patients were HCV genotype 1. All patients had type II cryglobulinemia (polyclonal IgG with monoclonal RF) F female, M male, MPGN membranoproliferative glomerulonephritis, NA not available
Table 2 Treatment characteristics Treatment characteristics
Patient 1
3a
2
4
DAA
Boceprevir
Telaprevir
Telaprevir
Telaprevir
Previous treatment
No
Yes (Peg-IFN ? RBV)
No
Yes (Peg-IFN ?RBV)
Pre-treatment viral load (IU/ml)
150,596
863,650
3,110,452
60,286
Week 4 HCV RNA (IU/ml)
Detected \ 12
Detected \ 12
ND
ND
Week 8 HCV RNA (IU/ml)
ND
Week 12 HCV RNA (IU/ml)
ND
Detected \ 12
ND
ND
EOT HCV RNA 24 Weeks post-treatment
ND SVR
ND SVR
ND SVR
ND SVR
RBV dose reduced
Yes
Yes
Yes
Yes
PEG-IFN reduced
Yes
No
Yes
Yes
Pre-treatment cryoglobulinemia
Yes
No
Yes
Yes
Post-treatment cryoglobulinemia
No
No
No
Yes
Clinical response
Complete
Partial
No
No
All HCV RNA values were assessed with Abbott real-time HCV PCR (LLOQ 12 IU/ml) Clinical response: Defined by resolution vasculitic ulcers if present, improvement in neuropathy, improvement of renal function and/or resolution of skin rash DAA direct acting antiviral, ND not detected, HCV RNA hepatitis C virus RNA, EOT end of treatment, NA data not available at time of publication a
Qualified for response guided therapy
biopsy proven MPGN and completed triple therapy for hepatitis C. Patient demographic characteristics, HCV genotype, cryoglobulin presence, renal histology and renal function were extracted from the medical record. Glomerular filtration rates (GFR) were estimated with the modification of diet in renal disease study equation using patients’ serum creatinine, age, gender, and race [20]. The Fibrosure (Labcorp, Burlington, USA) score was used to estimate liver fibrosis when available in the medical record. Serum HCV viral load measurements were performed with
123
Abbott Real Time HCV assay (Abbott Laboratories, Abbott Park, USA). The medical record was also reviewed for vasculitis treatments, including systemic corticosteroids, rituximab, and plasmapheresis (Tables 1, 2, 3).
Results The four patients in this series had diverse clinical presentations and treatment courses. Three of the four patients
Dig Dis Sci Table 3 Laboratory monitoring Measure
Patient 1
2
3
4
Hemoglobin (G/DL) Pre-treatment
15.3
15
14.1
12.3
Nadir
9.8
10.6
7.1
9.1
WBC (9109/l) Pre-treatment
3.3
4.6
3.4
11.5
Nadir
1.5
1.9
3.4
2.4
1.7
2.5
5.6
9.7
0.7
0.8
2.6
1.5
ANC (9109/l) Pre-treatment Nadir Platelets (9109/l) Pre-treatment
93
289
314
189
Nadir
46
130
36
52
Received epoetin
No
No
Yes
Yes
Received RBC transfusion
No
No
Yes
No
GFR (ml/min/1.73/m2) Pre-treatment
67
57
51
72
Nadir
65
51
45
63
End of treatment
86
59
52
76
WBC white blood cell count, ANC absolute neutrophil count, GFR glomerular filtration rate
had laboratory proven type II cryoglobulinemia; one patient had MPGN in the absence of detectable cryoglobulins. Three patients were treated with telaprevir; one patient was treated with boceprevir. Liver disease severity ranged from F0 to F2 as measured by Fibrosure and one patient had biopsy-proven cirrhosis. Baseline GFR ranged from 51 to 72 ml/min/1.73 m2. No patient discontinued triple therapy due to futility or intolerance. All patients had non-detectable HCV RNA at the end of treatment. All four patients had sustained virologic response (SVR). Patient 1 A 54-year-old Caucasian female with genotype 1(could not be subtyped) HCV complicated by type-II cryoglobulinemia who was naı¨ve to therapy underwent boceprevir-based triple therapy. She was IL28B genotype CC. Fibrosure scoring indicated portal to bridging fibrosis (F1–F2). Four months prior to initiation of HCV treatment, she was admitted to the hospital for lower extremity vasculitis with ulceration and profound weakness from neuropathy as well as urine sediment showing dysmorphic RBCs and granular casts Protein was not detected on urinalysis. She underwent five plasmapheresis treatments and a prednisone taper. This patient was maintained on low dose prednisone (prednisone dose ranged from 2.5 to 5 mg daily) throughout her triple therapy course. Her pre-treatment GFR was 67 ml/min/
1.73 m2 with a cryoglobulin level of 6 % precipitate. Pretreatment HCV RNA titer was 1.51 9 105 IU/ml. HCV viral load was undetectable at treatment weeks 8 and 24. She completed a 28-week total treatment course according to the response-guided therapy (RGT) algorithm [5]. Serum hemoglobin fell from 15.3 to 9.8 g/dl. Platelet count fell from 93 to 46 9 109/l. White blood cell count (WBC) fell from 3.3 to 1.5 9 109/l. The RBV dosing was decreased from 1,200 mg to 1,000 mg daily secondary to anemia; Peg-IFN was decreased from 180 mcg weekly to 135 mcg weekly secondary to leukopenia. GFR remained stable while on treatment. HCV RNA was undetectable at the end of treatment and at 24 weeks post-treatment, indicating SVR. Her cryoglobulins fell post-treatment and she was tapered off prednisone with a complete clinical and virologic response. Patient 2 A 23-year-old Caucasian female with genotype 1b HCV was a prior partial responder to dual therapy with peg-IFN and RBV. She was IL28B genotype CT and did not have clinical evidence of advanced liver disease. She had a history of biopsy proven MPGN with 2? protein on urinalysis, but did not have cyroglobulins on pre-treatment laboratory testing. She was started on telaprevir-based triple therapy and required a 48-week course of therapy. The patient required RBV dose reduction from 800 mg daily to 600 mg daily secondary to a reduction in hemoglobin from 15 to 10.6 g/dl. Initial PEG-IFN dosing was 135 mcg/week secondary to body mass; no further dose reductions were required. The patient did not receive erythropoietin. GFR was 57 ml/min/1.73 m2 at treatment initiation; GFR nadir was 51 ml/min/1.73 m2 during treatment. Pre-treatment HCV RNA titer was 8.64 9 105 IU/ml. HCV RNA was detectable, though below 12 IU/ml at week 4. HCV RNA was undetectable at treatment weeks 24 and 48. HCV RNA at 24-weeks posttreatment was undetectable indicating SVR. Patient 3 A 59-year-old Caucasian male with genotype 1(could not be subtyped) HCV who was naı¨ve to therapy underwent a 24-week course of response-guided telaprevir-based triple therapy. His IL28B genotype was CC. Fibrosure scoring indicated no fibrosis (F0) and minimal inflammation. Clinical manifestation of his vasculitis included MPGN and skin ulcers. Prior to treatment, 3.8 g of protein were found on 24 h urine collection, along with 2? protein on urinalysis. MPGN was managed with pulse dose corticosteroids (methylprednisolone 500 mg for 2 days) and five plasmapheresis treatments during the triple therapy course. Pre-treatment cryoglobulin levels were 27 % precipitate.
123
Dig Dis Sci
RBV was temporarily held secondary to anemia and then dose reduced from 1,000 mg daily to 400 mg daily. Hemoglobin fell from 14.1 to 7.1 g/dl. The patient required packed red blood cell transfusions and erythropoietin support during treatment course. Peg-IFN was reduced from 180 to 135 mcg weekly. GFR declined from 51 to 45 ml/min/1.73 m2 during treatment. At treatment end, cryoglobulins were not detected and GFR was 52 ml/min/ 1.73 m2. However, his renal function continued to decline after treatment. Seven weeks after treatment end, he progressed to end stage renal disease (ESRD), requiring hemodialysis. Pre-treatment HCV RNA titer was 3.11 9 106 IU/ml. HCV RNA was undetectable at weeks 4, 12, and 24. The patient completed a 24-week RGT course. HCV RNA was undetectable 24 weeks post-treatment, indicating SVR. Patient 4 A 42-year-old Caucasian male with genotype 1b underwent 48 weeks of telaprevir-based triple therapy. He was a partial responder to previous pegylated interferon and RBV and had biopsy-confirmed cirrhosis. He had well compensated liver disease. His IL28B genotype was CT. Clinical manifestations of his type II cryoglobulinemic vasculitis included neuropathy and MPGN. His cryoglobulin levels were 2–4 % prior to therapy. Urinalysis prior to treatment revealed 2? protein. His MPGN had been managed with plasmapheresis, steroids, and rituximab approximately 5 months prior to HCV therapy. His CD19/CD20? B cells were \1 % at the initiation of triple therapy and he was maintained on 5 mg of prednisone throughout his treatment course. RBV was reduced from 1,200 mg daily to 600 mg daily secondary to anemia. Hemoglobin fell from 12.3 to 9.1 g/ dl. The patient required erythropoietin support. With blood count recovery, RBV was titrated back up to 1,000 mg daily. Peg-IFN was dose reduced from 180 to 135 mcg secondary to anemia. GFR decreased from 72 to 63 ml/ min/1.73 m2 during treatment. Pre-treatment HCV RNA was 6.03 9 105 IU/ml. HCV RNA was undetectable at weeks 4, 12, 24 and 48. HCV RNA was undetectable 24-weeks post-treatment, indicating SVR. Despite his virologic response, his cryglobulin level was 2 % precipitate post-treatment with ongoing proteinuria and peripheral vasculitis. He was continued on low dose prednisone and periodic Rituximab infusions.
Discussion This case series represents the first description of SVR achievement with triple therapy in patients with HCV
123
complicated by type II cryoglobulinemia and/or MPGN. In a prior study of patients with HCV associated cryoglobulinemia treated with triple therapy, 69.6 % of subjects had undetectable HCV RNA at treatment week 24 [21]. This virologic response rate is similar to the phase three trials for boceprevir and telaprevir. However, the above mentioned study did not include follow-up determination of SVR [21]. In our study, all patients were at 24-weeks posttreatment; all demonstrated SVR. Our high SVR rate may be partially due to at least two of the four patients having genotype 1b and three of the four being non-cirrhotic [5–9]. Thus our study adds to a growing body of evidence that triple therapy is an effective antiviral treatment in patients with HCV complicated by type II cryoglobulinemia. Overall, renal function decreased during triple therapy in our patients. In a larger observational study, triple therapy was associated with a decline in GFR in patients with normal renal function at baseline [22]. The authors suggested temporary renal insufficiency may be a class effect of protease inhibitors, especially in patients with risk factors for impaired renal function, namely, older age, hypertension and diabetes [22]. Triple therapy use in patients with MPGN and/or type II cryoglobulinemia is all the more complicated as it involves an immune complexmediated disease. Because interferon upregulates the immune system, it can potentially worsen vasculitis and thus worsen renal function during treatment [23]. For this reason, corticosteroids and plasmapheresis have previously been recommended as induction treatment for severe cryoglobulinemia vasculitis before beginning antiviral therapy [4, 23]. Our treatment experience suggests immunosuppressive agents may be used during triple therapy. In this limited series, three of four patients received corticosteroids prior to and during therapy with one having suppressed B cells from Rituximab at the initiation of HCV treatment; all had undetectable HCV RNA early in the treatment course without subsequent viral breakthrough. Though immunosuppressive agents have been used successfully with PegIFN and RVN alone [24], more treatment experience with immunosuppressive agents and triple therapy is needed to characterize the risk of viral breakthrough. Two of four patients had impaired renal function despite clearance of cryoglobulins. Patient 2, a prior partial responder, did not have cryoglobulins, but had decreased renal function and biopsy proven MPGN at the onset of triple therapy. Ultimately, her renal function was preserved after triple therapy. Patient 3 had SVR and cryoglobulin clearance, but progressive decline in renal function after triple therapy, eventually reaching ESRD. Patient 4 had ongoing MPGN and cryoglobulinemia despite viral clearance. Persistent renal disease after HCV has been described previously and suggests other mechanisms for HCV-
Dig Dis Sci
associated renal disease [25]. Over time, B cells may undergo sequential mutations which render them HCVindependent [26]. All patients in this series required RBV dose reductions secondary to anemia. Anemia is on average more severe with the use of telaprevir and boceprevir compared to PegINF plus RBV alone [27]. Anemia may be even more severe in patients with impaired renal function, as RBV is renally eliminated. Fortunately, in the case of triple therapy, RBV doses can be reduced in the setting of anemia without lessoning rates of SVR [28, 29]. If triple therapy allows for more flexibility in Peg-IFN and RBV dosing, it may be more advantageous in patients with renal disease. That being said, the use of triple therapy may also expose patients with renal disease to more risk in the form of renal function impairment and more severe anemia. Currently, antiviral therapy is the cornerstone of management of hepatitis C cryoglobulinemia [4]. These recommendations are based on the treatment experience with PegIFN plus RBV. As newer antiviral agents and interferon-free treatment regimens emerge, more research will be needed to gauge treatment efficacy in patients with HCV-associated renal disease and cryoglobulinemia. Moving forward, first generation protease inhibitors will likely remain clinically relevant, competing on price point in resource limited areas or as part of interferon free therapies. Our experience with triple therapy in hepatitis C genotype 1 patients with cryoglobulinemia suggests the recommendation for antiviral treatment in hepatitis C cryoglobulinemia can be extrapolated to include triple therapy in genotype 1 patients. Acknowledgments This work was supported, in part, by the National Institutes of Health, 1KL2-RR025746-03 and UL1-RR025747. Conflict of interest
None.
References 1. Cacoub P, Lidove O, Maisonobe T, et al. Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum. 2002;46:3317–3326. 2. Cacoub P, Saadoun D, Limal N, Sene D, Lidove O, Piette J-C. PEGylated interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum. 2005;52:911–915. 3. Saadoun D, Resche-Rigon M, Thibault V, Piette J-C, Cacoub P. Antiviral therapy for hepatitis C virus–associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum. 2006;54:3696–3706. 4. Saadoun D, Delluc A, Piette JC, Cacoub P. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol. 2008;20:23–28. 5. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–1206.
6. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–1217. 7. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364: 2405–2416. 8. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–2428. 9. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014–1024. 10. Donada C, Crucitti A, Donadon V, Tommasi L, Zanette G, Crovatto M, et al. Systemic manifestations and liver disease in patients with chronic hepatitis C and type II or III mixed cryoglobulinaemia. J Viral Hepat. 1998;5:179–185. 11. Nagasaka A, Takahashi T, Sasaki T, Takimoto K, Miyashita K, Nakamura M, et al. Cryoglobulinemia in Japanese patients with chronic hepatitis C virus infection: host genetic and virological study. J Med Virol. 2001;65:52–57. 12. Saadoun D, Landau DA, Calabrese LH, Cacoub PP. Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford). 2007;46:1234–1242. 13. Charles ED, Dustin LB. Hepatitis C virus-induced cryoglobulinemia. Kidney Int. 2009;76:818–824. 14. Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004;33:355–374. 15. Saadoun D, Resche-Rigon M, Sene D, Perard L, Karras A, Cacoub P. Rituximab combined with Peg-interferon-ribavirin in refractory hepatitis C virus-associated cryoglobulinaemia vasculitis. Ann Rheum Dis. 2008;67:1431–1436. 16. Cacoub P, Terrier B, Saadoun D. Hepatitis C virus-induced vasculitis: therapeutic options. Ann Rheum Dis. 2014;73:24–30. 17. Lake JR. The role of immunosuppression in recurrence of hepatitis C. Liver Transpl. 2003;9:S63–S66. 18. Jacobson IM, Pawlotsky J-M, Afdhal NH, Dusheiko GM, Forns X, Jensen DM, et al. A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat. 2012;19:1–26. 19. Pietrogrande M, De Vita S, Zignego AL, Pioltelli P, Sansonno D, Sollima S, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev. 2011;10:444–454. 20. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–254. 21. Saadoun D, Resche Rigon M, Thibault V, Longuet M, Pol S, Blanc F, et al. Peg-IFNa/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis. 2013 Apr 20. 22. Mauss S, Hueppe D, Alshuth U. Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. Hepatology. 2014;59:46–48. 23. Iannuzzella F, Vaglio A, Garini G. Management of hepatitis C virus-related mixed cryoglobulinemia. Am J Med. 2010;123: 400–408. 24. Saadoun D, Resche Rigon M, Sene D, Terrier B, Karras A, Perard L, et al. Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood. 2010;116:326–334; quiz 504–505.
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Dig Dis Sci 25. Latt N, Alachkar N, Gurakar A. Hepatitis C virus and its renal manifestations: a review and update. Gastroenterol Hepatol (NY). 2012;8:434–445. 26. Landau D-A, Saadoun D, Halfon P, Martinot-Peignoux M, Marcellin P, Fois E, et al. Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis Rheum. 2008;58:604–611. 27. Barritt AS, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology. 2012;142:1314–1323.e1.
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28. Poordad F, Sulkowski M, Reddy R, Di Bisceglie AM, Zeuzem S, Afdhal N, et al. Anemia had no effect on efficacy outcomes in treatment-naı¨ve patients who received telaprevir-based regimen in the advance and illuminate phase 3 studies. Gastroenterology. 2011;140:S898-899. 29. Roberts S, Andreone P, Pol S, et al. Impact of anemia and ribavirin dose reduction on SVR to a telaprevir-based regiment in patients with HCV genotype 1 and prior peginterferon/ribavirin treatment failure in the phase II REALIZE study. Hepatology. 2011;1007A–1008A.
CASE REPORT
Membranoproliferative Glomerulonephritis, Type II Cryoglobulinemia and Triple Therapy for Hepatitis C: A Case Series and Review of the Literature Kevin Humphries • Jama M. Darling A. Sidney Barritt IV
•
Received: 6 November 2013 / Accepted: 18 February 2014 Ó Springer Science+Business Media New York 2014
Keywords Hepatitis C Triple therapy Boceprevir Telaprevir Cryoglobulinemia Membranoproliferative glomerulonephritis
Introduction Extra hepatic manifestations of chronic hepatitis C (HCV) include type II cryoglobulinemia. Previous studies suggest pegylated interferon (Peg-INF) plus ribavirin (RBV) is an effective treatment for HCV related type II cryoglobulinemia [1–4]. The current clinic use of triple therapy is in its second year and the landmark phase 3 clinical trials for telaprevir and boceprevir showed substantial improvements in efficacy for the treatment of genotype 1 HCV [5–9]. However, there are minimal data on the safety and efficacy of triple therapy for HCV-related type II cryoglobulinemia. Cryoglobulins are detectable in 40–70 % of patients with HCV [10, 11], and overt vasculitis develops in 5–10 % of patients [12]. Cryoglobulin associated vasculitis can lead to neuropathy, skin ulcers, and most notably renal disease in the form of membranoproliferative glomerulonephritis (MPGN) [12, 13]. Renal disease secondary to type II cryoglobulinemia is associated with increased mortality [14]. Treatment of cryoglobulinemia with the antiviral regimen of Peg-INF plus RBV yields cryoglobulin clearance in half of the patients [3]. Treatment with corticosteroids, rituximab and K. Humphries Department of Medicine, University of North Carolina, Chapel Hill, NC, USA J. M. Darling A. S. Barritt IV (&) Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA e-mail: [email protected]
plasmapheresis are employed in the treatment of HCV associated cryoglobulin vasculitis, though with varying long-term success, as these do not eliminate the underlying viral antigen trigger [15, 16]. Likewise, there is concern that prolonged immunosuppression may lead to accelerated HCV-related liver disease and impairment of viral clearance on anti-HCV therapy [17]. Treatment guidelines for genotype 1 HCV now recommend performing a risk–benefit analysis on the individual patient when considering triple therapy [18]. Unfortunately, there is insufficient clinical data when weighing triple therapy risks and benefits in patients with cryoglobulinemia and associated renal disease, especially the impact of reduced renal function on the new protease inhibitors. The initial phase III trial of boceprevir only included patients with a serum creatinine below the upper limits of normal, while telaprevir was only studied in patients with a creatinine clearance (CrCl) greater than 50 ml/min. This would exclude patients with MPGN which had progressed to CKD stage 3b-5; though patients with subclinical renal disease may have participated in clinical trials. In addition, trials for both drugs excluded patients with conditions requiring longterm corticosteroid use [5, 7]. This would likely exclude patients with vasculitic skin ulcers, as this condition is frequently treated with long-term corticosteroids albeit with variable efficacy [19]. Thus we sought to describe the treatment experience of four patients with overt clinical manifestations of MPGN and/or laboratory proven cryoglobulinemia in a case series at one academic clinical center.
Methods We identified four patients at the University of North Carolina Liver Center who had type II cryoglobulinemia or
123
Dig Dis Sci Table 1 Patient characteristics Characteristics
Patient 1
2
3
4
Age/gender
53 F
23 F
58 M
42 M
IL28B
CC
CT
CC
CT
Vasculitis manifestations
Leg ulcer
MPGN
MPGN, rash
MPGN, neuropathy
Proteinuria
Not detected
2?
2?
2?
Fibrosure score fibrosis
F1–F2
NA
F0
F4
Necroinflammation
A0–A1
NA
A1
G3
Treatment for vasculitis
Glucocorticoids plasmapheresis
None
Glucocorticoids, rituxumab, plasmapheresis
Glucocorticoids, rituxumab, plasmapheresis
Age is at the time of triple therapy treatment initiation. All patients were HCV genotype 1. All patients had type II cryglobulinemia (polyclonal IgG with monoclonal RF) F female, M male, MPGN membranoproliferative glomerulonephritis, NA not available
Table 2 Treatment characteristics Treatment characteristics
Patient 1
3a
2
4
DAA
Boceprevir
Telaprevir
Telaprevir
Telaprevir
Previous treatment
No
Yes (Peg-IFN ? RBV)
No
Yes (Peg-IFN ?RBV)
Pre-treatment viral load (IU/ml)
150,596
863,650
3,110,452
60,286
Week 4 HCV RNA (IU/ml)
Detected \ 12
Detected \ 12
ND
ND
Week 8 HCV RNA (IU/ml)
ND
Week 12 HCV RNA (IU/ml)
ND
Detected \ 12
ND
ND
EOT HCV RNA 24 Weeks post-treatment
ND SVR
ND SVR
ND SVR
ND SVR
RBV dose reduced
Yes
Yes
Yes
Yes
PEG-IFN reduced
Yes
No
Yes
Yes
Pre-treatment cryoglobulinemia
Yes
No
Yes
Yes
Post-treatment cryoglobulinemia
No
No
No
Yes
Clinical response
Complete
Partial
No
No
All HCV RNA values were assessed with Abbott real-time HCV PCR (LLOQ 12 IU/ml) Clinical response: Defined by resolution vasculitic ulcers if present, improvement in neuropathy, improvement of renal function and/or resolution of skin rash DAA direct acting antiviral, ND not detected, HCV RNA hepatitis C virus RNA, EOT end of treatment, NA data not available at time of publication a
Qualified for response guided therapy
biopsy proven MPGN and completed triple therapy for hepatitis C. Patient demographic characteristics, HCV genotype, cryoglobulin presence, renal histology and renal function were extracted from the medical record. Glomerular filtration rates (GFR) were estimated with the modification of diet in renal disease study equation using patients’ serum creatinine, age, gender, and race [20]. The Fibrosure (Labcorp, Burlington, USA) score was used to estimate liver fibrosis when available in the medical record. Serum HCV viral load measurements were performed with
123
Abbott Real Time HCV assay (Abbott Laboratories, Abbott Park, USA). The medical record was also reviewed for vasculitis treatments, including systemic corticosteroids, rituximab, and plasmapheresis (Tables 1, 2, 3).
Results The four patients in this series had diverse clinical presentations and treatment courses. Three of the four patients
Dig Dis Sci Table 3 Laboratory monitoring Measure
Patient 1
2
3
4
Hemoglobin (G/DL) Pre-treatment
15.3
15
14.1
12.3
Nadir
9.8
10.6
7.1
9.1
WBC (9109/l) Pre-treatment
3.3
4.6
3.4
11.5
Nadir
1.5
1.9
3.4
2.4
1.7
2.5
5.6
9.7
0.7
0.8
2.6
1.5
ANC (9109/l) Pre-treatment Nadir Platelets (9109/l) Pre-treatment
93
289
314
189
Nadir
46
130
36
52
Received epoetin
No
No
Yes
Yes
Received RBC transfusion
No
No
Yes
No
GFR (ml/min/1.73/m2) Pre-treatment
67
57
51
72
Nadir
65
51
45
63
End of treatment
86
59
52
76
WBC white blood cell count, ANC absolute neutrophil count, GFR glomerular filtration rate
had laboratory proven type II cryoglobulinemia; one patient had MPGN in the absence of detectable cryoglobulins. Three patients were treated with telaprevir; one patient was treated with boceprevir. Liver disease severity ranged from F0 to F2 as measured by Fibrosure and one patient had biopsy-proven cirrhosis. Baseline GFR ranged from 51 to 72 ml/min/1.73 m2. No patient discontinued triple therapy due to futility or intolerance. All patients had non-detectable HCV RNA at the end of treatment. All four patients had sustained virologic response (SVR). Patient 1 A 54-year-old Caucasian female with genotype 1(could not be subtyped) HCV complicated by type-II cryoglobulinemia who was naı¨ve to therapy underwent boceprevir-based triple therapy. She was IL28B genotype CC. Fibrosure scoring indicated portal to bridging fibrosis (F1–F2). Four months prior to initiation of HCV treatment, she was admitted to the hospital for lower extremity vasculitis with ulceration and profound weakness from neuropathy as well as urine sediment showing dysmorphic RBCs and granular casts Protein was not detected on urinalysis. She underwent five plasmapheresis treatments and a prednisone taper. This patient was maintained on low dose prednisone (prednisone dose ranged from 2.5 to 5 mg daily) throughout her triple therapy course. Her pre-treatment GFR was 67 ml/min/
1.73 m2 with a cryoglobulin level of 6 % precipitate. Pretreatment HCV RNA titer was 1.51 9 105 IU/ml. HCV viral load was undetectable at treatment weeks 8 and 24. She completed a 28-week total treatment course according to the response-guided therapy (RGT) algorithm [5]. Serum hemoglobin fell from 15.3 to 9.8 g/dl. Platelet count fell from 93 to 46 9 109/l. White blood cell count (WBC) fell from 3.3 to 1.5 9 109/l. The RBV dosing was decreased from 1,200 mg to 1,000 mg daily secondary to anemia; Peg-IFN was decreased from 180 mcg weekly to 135 mcg weekly secondary to leukopenia. GFR remained stable while on treatment. HCV RNA was undetectable at the end of treatment and at 24 weeks post-treatment, indicating SVR. Her cryoglobulins fell post-treatment and she was tapered off prednisone with a complete clinical and virologic response. Patient 2 A 23-year-old Caucasian female with genotype 1b HCV was a prior partial responder to dual therapy with peg-IFN and RBV. She was IL28B genotype CT and did not have clinical evidence of advanced liver disease. She had a history of biopsy proven MPGN with 2? protein on urinalysis, but did not have cyroglobulins on pre-treatment laboratory testing. She was started on telaprevir-based triple therapy and required a 48-week course of therapy. The patient required RBV dose reduction from 800 mg daily to 600 mg daily secondary to a reduction in hemoglobin from 15 to 10.6 g/dl. Initial PEG-IFN dosing was 135 mcg/week secondary to body mass; no further dose reductions were required. The patient did not receive erythropoietin. GFR was 57 ml/min/1.73 m2 at treatment initiation; GFR nadir was 51 ml/min/1.73 m2 during treatment. Pre-treatment HCV RNA titer was 8.64 9 105 IU/ml. HCV RNA was detectable, though below 12 IU/ml at week 4. HCV RNA was undetectable at treatment weeks 24 and 48. HCV RNA at 24-weeks posttreatment was undetectable indicating SVR. Patient 3 A 59-year-old Caucasian male with genotype 1(could not be subtyped) HCV who was naı¨ve to therapy underwent a 24-week course of response-guided telaprevir-based triple therapy. His IL28B genotype was CC. Fibrosure scoring indicated no fibrosis (F0) and minimal inflammation. Clinical manifestation of his vasculitis included MPGN and skin ulcers. Prior to treatment, 3.8 g of protein were found on 24 h urine collection, along with 2? protein on urinalysis. MPGN was managed with pulse dose corticosteroids (methylprednisolone 500 mg for 2 days) and five plasmapheresis treatments during the triple therapy course. Pre-treatment cryoglobulin levels were 27 % precipitate.
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RBV was temporarily held secondary to anemia and then dose reduced from 1,000 mg daily to 400 mg daily. Hemoglobin fell from 14.1 to 7.1 g/dl. The patient required packed red blood cell transfusions and erythropoietin support during treatment course. Peg-IFN was reduced from 180 to 135 mcg weekly. GFR declined from 51 to 45 ml/min/1.73 m2 during treatment. At treatment end, cryoglobulins were not detected and GFR was 52 ml/min/ 1.73 m2. However, his renal function continued to decline after treatment. Seven weeks after treatment end, he progressed to end stage renal disease (ESRD), requiring hemodialysis. Pre-treatment HCV RNA titer was 3.11 9 106 IU/ml. HCV RNA was undetectable at weeks 4, 12, and 24. The patient completed a 24-week RGT course. HCV RNA was undetectable 24 weeks post-treatment, indicating SVR. Patient 4 A 42-year-old Caucasian male with genotype 1b underwent 48 weeks of telaprevir-based triple therapy. He was a partial responder to previous pegylated interferon and RBV and had biopsy-confirmed cirrhosis. He had well compensated liver disease. His IL28B genotype was CT. Clinical manifestations of his type II cryoglobulinemic vasculitis included neuropathy and MPGN. His cryoglobulin levels were 2–4 % prior to therapy. Urinalysis prior to treatment revealed 2? protein. His MPGN had been managed with plasmapheresis, steroids, and rituximab approximately 5 months prior to HCV therapy. His CD19/CD20? B cells were \1 % at the initiation of triple therapy and he was maintained on 5 mg of prednisone throughout his treatment course. RBV was reduced from 1,200 mg daily to 600 mg daily secondary to anemia. Hemoglobin fell from 12.3 to 9.1 g/ dl. The patient required erythropoietin support. With blood count recovery, RBV was titrated back up to 1,000 mg daily. Peg-IFN was dose reduced from 180 to 135 mcg secondary to anemia. GFR decreased from 72 to 63 ml/ min/1.73 m2 during treatment. Pre-treatment HCV RNA was 6.03 9 105 IU/ml. HCV RNA was undetectable at weeks 4, 12, 24 and 48. HCV RNA was undetectable 24-weeks post-treatment, indicating SVR. Despite his virologic response, his cryglobulin level was 2 % precipitate post-treatment with ongoing proteinuria and peripheral vasculitis. He was continued on low dose prednisone and periodic Rituximab infusions.
Discussion This case series represents the first description of SVR achievement with triple therapy in patients with HCV
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complicated by type II cryoglobulinemia and/or MPGN. In a prior study of patients with HCV associated cryoglobulinemia treated with triple therapy, 69.6 % of subjects had undetectable HCV RNA at treatment week 24 [21]. This virologic response rate is similar to the phase three trials for boceprevir and telaprevir. However, the above mentioned study did not include follow-up determination of SVR [21]. In our study, all patients were at 24-weeks posttreatment; all demonstrated SVR. Our high SVR rate may be partially due to at least two of the four patients having genotype 1b and three of the four being non-cirrhotic [5–9]. Thus our study adds to a growing body of evidence that triple therapy is an effective antiviral treatment in patients with HCV complicated by type II cryoglobulinemia. Overall, renal function decreased during triple therapy in our patients. In a larger observational study, triple therapy was associated with a decline in GFR in patients with normal renal function at baseline [22]. The authors suggested temporary renal insufficiency may be a class effect of protease inhibitors, especially in patients with risk factors for impaired renal function, namely, older age, hypertension and diabetes [22]. Triple therapy use in patients with MPGN and/or type II cryoglobulinemia is all the more complicated as it involves an immune complexmediated disease. Because interferon upregulates the immune system, it can potentially worsen vasculitis and thus worsen renal function during treatment [23]. For this reason, corticosteroids and plasmapheresis have previously been recommended as induction treatment for severe cryoglobulinemia vasculitis before beginning antiviral therapy [4, 23]. Our treatment experience suggests immunosuppressive agents may be used during triple therapy. In this limited series, three of four patients received corticosteroids prior to and during therapy with one having suppressed B cells from Rituximab at the initiation of HCV treatment; all had undetectable HCV RNA early in the treatment course without subsequent viral breakthrough. Though immunosuppressive agents have been used successfully with PegIFN and RVN alone [24], more treatment experience with immunosuppressive agents and triple therapy is needed to characterize the risk of viral breakthrough. Two of four patients had impaired renal function despite clearance of cryoglobulins. Patient 2, a prior partial responder, did not have cryoglobulins, but had decreased renal function and biopsy proven MPGN at the onset of triple therapy. Ultimately, her renal function was preserved after triple therapy. Patient 3 had SVR and cryoglobulin clearance, but progressive decline in renal function after triple therapy, eventually reaching ESRD. Patient 4 had ongoing MPGN and cryoglobulinemia despite viral clearance. Persistent renal disease after HCV has been described previously and suggests other mechanisms for HCV-
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associated renal disease [25]. Over time, B cells may undergo sequential mutations which render them HCVindependent [26]. All patients in this series required RBV dose reductions secondary to anemia. Anemia is on average more severe with the use of telaprevir and boceprevir compared to PegINF plus RBV alone [27]. Anemia may be even more severe in patients with impaired renal function, as RBV is renally eliminated. Fortunately, in the case of triple therapy, RBV doses can be reduced in the setting of anemia without lessoning rates of SVR [28, 29]. If triple therapy allows for more flexibility in Peg-IFN and RBV dosing, it may be more advantageous in patients with renal disease. That being said, the use of triple therapy may also expose patients with renal disease to more risk in the form of renal function impairment and more severe anemia. Currently, antiviral therapy is the cornerstone of management of hepatitis C cryoglobulinemia [4]. These recommendations are based on the treatment experience with PegIFN plus RBV. As newer antiviral agents and interferon-free treatment regimens emerge, more research will be needed to gauge treatment efficacy in patients with HCV-associated renal disease and cryoglobulinemia. Moving forward, first generation protease inhibitors will likely remain clinically relevant, competing on price point in resource limited areas or as part of interferon free therapies. Our experience with triple therapy in hepatitis C genotype 1 patients with cryoglobulinemia suggests the recommendation for antiviral treatment in hepatitis C cryoglobulinemia can be extrapolated to include triple therapy in genotype 1 patients. Acknowledgments This work was supported, in part, by the National Institutes of Health, 1KL2-RR025746-03 and UL1-RR025747. Conflict of interest
None.
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