Hcv infection, peripheral nerve and central nervous system: from diagnosis to treatment

Eular On-line Course on Rheumatic Diseases – module °42a
Clodoveo Ferri, Marco Sebastiani, Patrice Cacoub, David Saadoun
CRYOGLOBULINEMIA
AND SYSTEMIC MANIFESTATIONS OF HEPATITIS C VIRUS
IN-DEPTH-DISCUSSION II
Antiviral therapy in Mixed Cryoglobulinemia Vasculitis
With the discovery of HCV as the etiologic agent for most cases of mixed cryoglobulinemia new opportunities and problems for crafting therapy of HCV MC have emerged. While optimum therapy is still unclear a series of recent studies suggest a role for both antiviral as well as targeted immunosuppressive therapy on autoreactive B cells in the treatment of HCV-MC depending on the activity and severity of the underlying vasculitis and the status of the underlying infection. Peg-Interferon alpha plus Ribavirin.
The treatment of HCV infection (i.e. in the absence of HCV-MC) has progressed dramatically over the past 15 years with the standard of pegylated interferon alpha and ribavirin therapy leading to sustained virologic clearance in nearly 60% of patients. Mazzaro et al have reported 1 on the results of eighteen consecutive HCV-MC patients treated with Peg-IFNα2b (1.0 µg/kg each week subcutaneously) plus ribavirin (1000 mg daily) for 12 months. At the end of treatment HCV-RNA became undetectable in 15 (83%) patients and most patients improved clinically. At the end of follow-up, only eight (44%) patients were still sustained clinical and virological responders and cryoglobulin disappear in 6 (33%) cases. One major weakness of this study was the lower Peg-IFN dosage used in comparison with that usually recommended in HCV We reported the results 2 of a monocentric study with 72 consecutive HCV-MC patients who received treatment with IFNα-2b (n=32) (3 millions IU x 3/week) or Peg-IFNα-2b (n=40) (1.5 µg/kg/week), both combined with oral ribavirin (600 to 1,200 mg/day) for at least 6 months 2. Following antiviral therapy, purpura resolved in 86% of cases, arthralgia in 80%, peripheral neuropathy in 68% and renal involvement in 41%. A significant decrease of proteinuria was observed in sustained virological responders, whereas no significant change in serum creatinine level was seen. Cryoglobulin disappeared in 25 (37.8%) cases. Peg-IFNα plus ribavirin achieved a higher rate of complete clinical (67.5% vs 56.2%), virological (62.5% vs 53.1%) and immunological response (57.5% vs 31.2%) as compared with standard IFNα plus ribavirin, regardless of HCV genotype and viral load 2. Sub-group analysis of the 40 HCV-MC patients treated with Peg-IFNα plus ribavirin showed a complete recovery of skin involvement in 21/24 (87.5%), arthralgia in 18/22 (81.8%), peripheral neuropathy in 20/27 (74%) and nephropathy in 5/10 (50%) cases, respectively. Compared with standard IFN α- 2b/ribavirin, there was a shorter duration of anti-HCV therapy (13.2 vs. 18.3 months), less frequent Eular On-line Course on Rheumatic Diseases – module °42a
Clodoveo Ferri, Marco Sebastiani, Patrice Cacoub, David Saadoun
use of corticosteroids (35 vs. 47%) and a lower rate of death (5 vs. 18.7%) with Peg-IFN α- 2b/ribavirin. In multivariate analysis, an early virologic response (i.e. at month +3) [(odds ratio (OR), 3.53; 95% CI 1.18 to 10.59)] was independently associated with a complete clinical response of MC. A glomerular filtration rate lower than 70 ml/min (OR 0.18; 95% CI 0.05 to 0.67) was negatively associated with a complete clinical response of MC 2. Although, HCV-MC patients with HCV genotype 1 and/or previous failure to therapy displayed a lower clinical response rate, these factors were not independently associated with a poor clinical response in multivariate analysis. Epidemiological features, HCV viral load, transaminases or liver damage did not influence the clinical outcome in this study 2. The reappearance of HCV RNA was observed in 8 (11.1%) patients with a median time after discontinuing therapy of 2 months (range 1-3). Six of them experienced a relapse of MC vasculitis. Eight deaths were noted due to cardiovascular disease (n=3), hepatocarcinoma (n=2), liver failure (n=2), and sepsis (n=1). In 39/70 (56%) patients, side effects included fatigue (47.2%), fever (37.5%), anemia (33.3%), myalgia (25%), neutropenia (20%), depression (15.2%), thrombocytopenia (5%), pruritus (4.1%) and alopecia (2.7%). When compared with IFN α-2b/ribavirin, patients who received Peg- IFN α-2b/ribavirin had a similar rate of adverse events (53.1% vs. 55%, respectively). No therapy interruptions were needed. A dose reduction of antiviral therapy was required for 11 patients. Rituximab plus antiviral therapy
Based on the limitations of each therapy (i.e. antiviral and rituximab), and the 30% of MC patients that continue to have active disease while receiving anti-CD20 monoclonal antibody or antiviral therapy, the combination of rituximab with Peg-IFNα-ribavirin appears logical. Saadoun et al reported sixteen consecutive HCV-MC patients treated with rituximab (375mg/m² intravenously weekly for 4 weeks) combined with Peg-IFNα2b (1.5µg/kg/week subcutaneously) plus ribavirin (600-1,200 mg/day orally) for 12 months 3. All patients had severe active disease resistant to previous combination therapy with standard or Peg-IFNα2b plus ribavirin. Fifteen patients (93.7%) showed clinical improvement, 10 of whom (62.5%) were complete responders. Compared with clinical complete responders, the partial or non responders had a 3.6 times longer duration of vasculitis prior to therapy and a lower rate of early virologic We and other 4 extended our experience to thirty eight HCV-MC patients who received a combination of Rituximab (375mg/m²) once a week for one month followed by Peg-interferon (IFN)-α (2a, 180µg or 2b, 1.5µg/kg) weekly plus ribavirin (600-1,200 mg) daily for 48 weeks 5. They were compared to fifty five HCV- MC patients treated by Peg-IFN α/ribavirin with the same modalities. In the whole population of HCV-MC patients (n = 93), a complete clinical response was achieved in 73.1% (68 of 93), cryoglobulin clearance in 52.7% (49 of 93), and a sustained virologic response in 59.1% (55 of 93). Compared with Peg-IFN- alpha/ribavirin, rituximab plus Peg-IFN-alpha/ribavirin-treated patients had a shorter time to clinical remission (5.4 +/- 4 vs 8.4 +/- 4.7 months, P = .004), better renal response rates (80.9% vs 40% of complete response, P = .040), and higher rates of cryoglobulin clearance (68.4% vs 43.6%, P = .001) and Eular On-line Course on Rheumatic Diseases – module °42a
Clodoveo Ferri, Marco Sebastiani, Patrice Cacoub, David Saadoun
clonal VH1-69(+) B-cell suppression (P < .01). Treatment was well tolerated with 11% of discontinuation resulting from antiviral therapy and no worsening of HCV RNA under rituximab. New antiviral agents
Triple therapy with peginterferon, ribavirin, and a specifically targeted antiviral agent such as a protease inhibitor (Boceprevir or Telaprevir) will soon be available to improve sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 and clinical response of vasculitis. In an open-label trial, we are currently evaluating the efficacy of 800 mg of boceprevir or 750 mg of telaprevir (thrice daily), an NS3 protease inhibitor, in combination with peginterferon alfa-2a (180µg) or 2b (1.5 µg/kg) and ribavirin (800 to 1400 mg/day) in 19 HCV-MC patients with genotype 1. Seventeen out of the 19 (89.5%) have cleared the virus and are in clinical remission of the vasculitis. The 2 remaining were considered as virological non responders (i.e. persistent HCV RNA) and partial clinical responders. The tolerance was poor, asthenia and cytopenia were frequent. REFERENCES
Mazzaro C, Zorat F, Caizzi M, et al. Treatment with peg-interferon alfa-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia: a pilot study. J Hepatol. 2005;42:632-638. Saadoun D, Resche-Rigon M, Thibault V, Piette JC, Cacoub P. Antiviral therapy for hepatitis C virus--associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum. Saadoun D, Resche-Rigon M, Sene D, Perard L, Piette JC, Cacoub P. Rituximab combined with Peg-Interferon-Ribavirin in refractory HCV-associated cryoglobulinemia vasculitis. Ann Rheum Dammacco F, Tucci FA, Lauletta G, et al. Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study. Blood. Saadoun D, Resche Rigon M, Sene D, et al. Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood.

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