Treatment of Extrahepatic Manifestations of Chronic Hepatitis C Viral Infection A Challenge

REVIEWS Treatment of Extrahepatic Manifestations of Chronic Hepatitis C Viral Infection A Challenge C. TĂNĂSESCU, R. IONESCU Clinic of Internal Medicine, Colentina Hospital, C. Davila University of Medicine, Bucharest, Romania Often, chronic hepatitis C infection is clinically manifested as extra hepatic disease. Therapy of the extra hepatic manifestations (EHM) is always difficult and based on the optimal and individual association of antiviral treatment, immunosuppressant and plasma cleaning techniques. We observed for 4 years 246 patients admitted to Colentina Internal Medicine Clinic, of whom 168 were diagnosed as chronic C hepatitis. 130 of those patients have had at least one EHM. In our experience, the presence of an EHM is significantly correlated with lack of early viral response and sustained viral response, as well. Cryoglobulinemic vasculitis needs to be treated with oral or pulse corticotherapy associated to plasmapheresis. When present, peripheral neuropathy and cryocrit greater than 10% are indicators of need of more than 3 plasmapheresis sessions. Key words: extra hepatic manifestations, cryoglobulinemic vasculitis, plasmapheresis. Chronic hepatitis C virus (HCV) infection, one of the most important cases of chronic liver disease, is a real public health problem worldwide. It is estimated that there are over 200 million people infected with HCV around the world. In the USA alone, HCV infection is causing 10 to 12000 deaths per year [1]. Clinically, HCV infection is very heterogeneous, ranging from accidental discovery in an otherwise asymptomatic patient to discovery while searching the etiology of a chronic liver disease that is already cirrhosis [2]. Between these extremes, extrahepatic manifestations (EHM) of HCV infection are often revealing. The incidence of EHM is highly variable (from 38 to74%, depending on author). [3][4]. There are numerous such manifestations described, but not all cases can be proven to have causality relation with HVC infection [5]. Anyway, the diversity of extrahepatic organs involvement in the HCV infection suggests that this infection is rather a systemic disease than a local one [6][7], and precludes to active searching of this infection in any case of confirmed autoimmune disease [8]. Table I lists the principal extrahepatic manifestations of chronic HCV infection. Treatment of the extrahepatic disease in HCV infection is an ever challenge, mostly because of the diversity of EHM and of the autoimmune involvement in variable individual degree. Mixed cryoglobulinemia Renal manifestations membranoproliferative glomerulonephritis membrane glomerulonephritis Skin involvement flat lichen pruritus porfiria cutanea tarda Rheumatologic manifestations rheumatoid syndrome polymyositis / dermatomyositis Sicca (Sjögren) syndrome Polyarteritis nodosa Giant-cell arteritis AntiphosPholipid syndrome ROM. J. INTERN. MED., 2010, 48, 1, 3 7 Table I Main extra hepatic manifestations of chronic HCV infection Pulmonary involvement Idiopathic pulmonary fibrosis Cardiac manifestations myocarditis dilative cardiomyopathy hypertrophic cardiomyopathy Endocrine involvement thyroid disease type II diabetes mellitus Neurological manifestations peripheral sensory / motor neuropathy Hematological involvement immune thrombocytopenic purpura non-hodgkin lymphoma

4 C. Tănăsescu, R. Ionescu 2 Knowing the pathogenic role of HCV, it seems logical that, at least in those cases in which this role is certain (e.g. cryoglobulinemia), the therapeutic approach should be antiviral. There are data that show the antiviral treatment as efficacious on EHM, whether it is Interferon [9], Ribavirin (10 13) or their combination [10][14 16]. Nevertheless, the risk of reoccurrence of EHM is still important, despite this therapy. From another point of view, every time the EHM is severe, showing intense autoimmune stimulation, it is logical to take the immunosuppressive approach. But this, in turn, may interfere with antiviral self defense mechanisms of the human body, leading to increase of viral replication and to elevation of aminotransferases [17]. One must not forget also plasmapheresis, which, by mechanically removing cryoglobulins, contributes to the treatment of EHM. On the other hand, when done immediately after antiviral therapy, it may interfere its plasma clearance, thus diminishing its efficacy [18]. There are some papers on other promising therapies of EHM [e.g.: rituximab [19][20]], but these have not entered daily clinical practice yet. COLENTINA INTERNAL MEDICINE DEPARTMENT EXPERIENCE Between January 2004 and December 2008 we followed 246 patients chronically infected with HCV, of which 168 had chronic hepatitis. 130 of these patients had at least one EHM on HCV infection. The mean number of EHM in our patients was 1,861. Figure 1 shows the percent of patients having from 1 to 5 EHMs (Fig. 1). number of patients followed by the percentage of all EHMs): mixed cryoglobulinemia [108; 30.85%] cutaneous manifestations: porfiria cutenea tarda, pruritus [18; 5.14%] hematological manifestations: lymphoma, anemia, leucopenia, thrombocytopenia [14; 4%] diabetes mellitus [42; 12%] arthralgias [38; 10.85%] neuropathies [26; 7.02%] thyroid disease [8; 2.70%] pulmonary fibrosis [2; 0.54%] nephropathy [9; 2.43%] Sjögren syndrome [18; 6.48%] serological abnormalities [67; 20.81%]. THERAPY Antiviral treatment, with pegilated Interferon and Ribavirin, was used on 157 of the 168 chronic hepatitis C patients, irrespective of the presence of extrahepatic manifestations at the start of treatment. The rest had some form of vasculitis ever since the diagnosis of their HCV infection. Actually, in 64 (34.04%) of the 188 EHMs patients, the EHM preceded their HCV infection diagnosis, even though one would expect the opposite. These patients had had variable diagnoses, the most frequent being: toxic mixed polyneuropathy, rheumatoid arthritis, glomerulonephritis. 119 of the 130 patients having at least 1 EHM were treated against the virus. 41 (34.45%) of these patients were considered to be responsive (their viral load after 3 months of therapy was undetectable) (Fig. 2), whereas 22 (57.89%) of those without EHMs responded to antiviral therapy (Fig. 3). Fig. 2. Percent of responders in patients with EHM. Fig. 1. Percent of patients with 1 to 5 EHM. We observed the following extrahepatic manifestations in our patients (in brackets is the Comparing these figures, we find a p-value of 0.038 showing that having at least one EHM is associated with non-responsiveness to antiviral therapy. Moreover, this statistically significant association is also

3 Treatment of chronic hepatitis C viral infection 5 Fig. 3. Percent of responders in patients without EHM. maintained for sustained viral response : 55.54% (12) patients and 19.51% (8) patients with and without EHM, respectively, had undetectable viral loads at 6 months after stopping therapy (p-value = 0.024) (Fig. 4). Fig. 4. Sustained viral response (SVR) in patients without EHM. There were 24 (20.16%) of the 119 treated patients to whom the EMH occurred during the antiviral therapy. Knowing the immune modulating effects of Interferon we assessed its implication in the occurrence of the EHM by checking the viral load of these patients as soon as possible after the EHM appeared. If the viral load was rising, we considered the EHM as result of the HCV and that happened in 15 out of 24 patients. On the contrary, if the viral load was 20% less than the last measurement, as in the rest of 9 out of the 24 patients, we considered the EHM as result of the antiviral treatment. The most frequent EHM encountered as a result of the Interferon therapy were peripheral neuropathy (8 cases) and articular involvement (6 cases), sometimes rheumatoid arthritis-like (4 cases). Besides the antiviral therapy, some of the patients presenting EHM also received EHM-specific therapies, most often corticosteroids. Seventy four (68.52%) of the 108 cryoglobulinemic patients received 0.5 mg/kg Prednison or equivalents. In 12 cases of articular involvement there were also used 0.25 to 0.5 mg/kg Prednison or equivalents. Even though there is no consensus regarding therapy of cryoglobulinemic vasculitis associated to HCV infection, bearing in mind that its presence signifies intense autoimmune stimulation, the therapeutic approach of all the cryoglobulinemic patients consisted initially of corticotherapy in variable doses between 0.5 and 1 mg/kg Prednison, or pulse-therapy with Metil-prednisolon 250 to 1000 mg/d for 3 to 5 days, according to its severity. (All patients having VAS2003 score over 12, hypocomplementemia, ESR over 50mm/h received pulse-therapy). Part of the patients [5], concomitantly also received antiviral therapy, because they were already on that treatment at the time of the occurrence of the EHM. All patients having their cryocrit greater than 5% have had a number of plasmapheresis sessions between 2 and 6. There was a significant correlation between the necessity of more than 3 plasmapheresis sessions and cryocrit over 10% (p=0.032) and peripheral neurological involvement (p=0.028). So, these two variables are criteria for the necessity of more than 3 plasmapheresis sessions. Unfortunately, we have never had the chance to treat cryoglobulinemic vasculitis with Rituximab. The efficacy of these therapies on the vasculitis process was good (9 patients with Vasculitis Disease Index [VDI]=0), poor (3 patients with VDI 0) or absent (4 deaths). The 4 deaths were caused by cerebral vasculitis (1 case), severe infection (2 cases) and hepatic failure (1 case). Due to the variability of the time elapsed between admission and beginning of treatment (whether medication or plasmapheresis) and of the used doses, we could not significantly conclude with regard to the usefulness of the 3 therapies. We consider that this situation is the result of the lack of consensus regarding the therapeutic approach of cryoglobulinemic vasculitis. CONCLUSIONS In our study, the presence of EHM of chronic HCV infection correlates with non-responsiveness on antiviral therapy (p=0.038). Similarly, the absence of EHM correlates with getting sustained viral response (p=0.024). Therapy of the EHM is antiviral treatment. When cryoglobulinemia is present, even without secondary vasculitis, the majority of patients (68.52) also receive corticotherapy medium dose. The extent of the vasculitic process can be estimated using VAS2003 and VDI, severe

6 C. Tănăsescu, R. Ionescu 4 vasculitis being associated with infection duration longer than 3 years (p=0.030), renal impairment (p=0.036), hypocomplementemia (p=0.044) and viral load less than 800000IU/ml (p=0.041). When cryoglobulinemic vasculitis is characterized by ESR greater than 50 mm/h, hypocomplementemia and VAS2003 score greater than 12, patients must receive pulse-therapy corticotherapy. One must not underestimate the usefulness of plasmapheresis, the necessity of more than 2 sessions being correlated to the presence of peripheral neuropathy (p=0.032) and to a pre-therapeutic cryocrit over 10% (p=0.028). Adesea, manifestările clinice ale infecţiei cronice cu virusul hepatitic C (VHC) sunt reprezentate de afectarea extrahepatică. Terapia manifestărilor extrahepatice (MEH) este întotdeauna dificilă şi se bazează pe asocierea cât mai judicioasă, şi adaptată individual, dintre tratamentul antiviral, imunosupresie şi tehnici de epurare plasmatică. În Clinica Medicală Colentina au fost urmăriţi, de-a lungul a 4 ani, 246 pacienţi cu infecţie cronică VHC, dintre care 168 aveau hepatită cronică şi dintre aceştia 130 prezentând cel puţin o manifestare extrahepatică. În experienţa clinicii noastre, prezenţa unei MEH se corelează semnificativ statistic cu lipsa răspunsului viral precoce şi a celui susţinut. Vasculita crioglobulinemică necesită utilizarea corticoterapiei sistemice, oral sau în puls, asociată cu plasmafereza. Prezenţa polineuropatiei periferice şi valoarea criocritului mai mare de 10% se corelează cu necesitatea a mai mult de 3 şedinţe de plasmafereză. Corresponding author: Dr. R. Ionescu Internal Medicine Clinic, Colentina Clinical Hospital, Ward II 19 21, Şos. Ştefan cel Mare Blvd, sector 2 Bucharest, Romania E-mail: tane67@gmail.com REFERENCES 1. National Digestive Diseases Information Clearinghouse. Chronic Hepatitis C: Current Disease Management. NIH Publication 07-4230, November 2006. 2. SEEFF L.B., BUSKCEL-BALES Z., WRIGHT A.L. et al., Long-term mortality after transfusion-associated non-a, non-b hepatitis. N. Engl. J. Med., 1992; 327: 1906 1911. 3. CACOUB P., POYNARD T., GHILLANI P. et al., Extrahepatic manifestations in patients with chronic hepatitis C. MULTIVIRC Group. Arthritis Rheum. 1999; 42:2204 2212. 4. CACOUB P., RENOU C., ROSENTHAL E. et al., Extrahepatic manifestations associated with hepatitis C virus infection: a prospective multicenter study of 321 patients. The GERMIVIC (Groupe d Étude et de Recherche en Médicine Interne et Maladies Infectieuses sur le Virus de l hépatite C). Medicine (Baltimore) 2000; 79: 47 56. 5. PESSOA M.G., FOX R.K., WRIGHT T., Extrahepatic manifestations of hepatitis C. In: Schiff E.R., Sorrel M.F., Madrey W.C. (Eds). Diseases of the liver. Lippincott, Williams and Wilkins, 2003: 906. 6. FERRI C., MONTI M., LA CIVITA L. et al., Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood, 1993; 82:3701 4. 7. ZIGNEGO A.L., FERRI C., GIANNINI C., LA CIVITA L., CARRECCIA G., LONGOMBARDO G. et al., Hepatitis C virus infection in mixed cryoglobulinemia and B-cell non-hodgkin s lymphoma: evidence for a pathogenic role. Arch. Virol. 1997; 142:545 55. 8. TANASESCU C., Manifestari extrahepatice in hepatitele cronice virale. In: Grigorescu M. (Ed.). Tratat de hepatologie, Editura Medicală Naţională, 2004: 478. 9. CRESTA P., MUSSET L., CACOUB P. et al., Response to Interferon treatment and disappearance of cryoglobulinemia in patients infected by hepatitis C virus. 10. DURAND J.M., CACOUB P., LUNEL-FABIANI F. et al., Ribavirin in hepatitis C related cryoglobulinemia. J. Rheumatol., 1998; 25:1115 7. 11. HEAGY W., CRUMPACKER C., LOPEZ P.A., Inhibition of immune functions by antiviral drugs. J. Clin. Invest., 1991; 87:1916 24.

5 Treatment of chronic hepatitis C viral infection 7 12. FRIED M.W., SHIFFMAN M.L., REDDY K.R. et al., Peg interferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med., 2002; 347:975 982. 13. MANNS M.P., MCHUTCHISON J.G., GORDON S.C. et al., Peg interferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet, 2001; 358:958 965. 14. CACOUB P., LIDOVE O., MAISONOBE T. et al., Interferon-alfa and ribavirin treatment in patients with hepatitis C virusrelated systemic vasculitis. Arthritis Rheum 2002; 46:3317 26. 15. MAZZARA C., ZORAT F., COMAR C. et al., Interferon plus ribavirin in patients with hepatitis C virus positive mixed cryoglobulinemia resistant to interferon. J. Rheumatol., 2003; 30:1775 81. 16. JACCARD A., LOUSTAUD V., TURLURE P., Ribavirin and immune thrombocytopenic purpura. Lancet, 1998; 351:1660 1. 17. THIEL J., PETERS T., MAS MARQUES A. et al., Kinetics of hepatitis C (HCV) viraemia and quasispecies during treatment of HCV associated cryoglobulinemia with pulse cyclophosphamide. Ann. Rheum. Dis., 2002; 61: 838 841. 18. HAUSFATER P., CACOUB P., ASSOGBA U. et al., Plasma exchange and interferon-alpha pharmacokinetics in patients with hepatitis C virus-associated systemic vasculitis. Nephron. 2002; 91: 627 630. 19. SANSONNO D., DE RE V., LAULETTA G. et al., Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-cd20. Blood, 2003; 101: 3881 3826. 20. ZAJA F., DE VITA S., MAZZARO C. et al., Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood, 2003; 101: 3827 3834. Received February 20, 2010

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