Kinetics of hepatitis C (HCV) viraemia and quasispecies during treatment of HCV associated cryoglobulinaemia with pulse cyclophosphamide

Abstract

Objective: To investigate the effect of pulse cyclophosphamide treatment on hepatitis C virus (HCV) kinetics and quasispecies in interferon α (IFNα) resistant HCV related cryoglobulinaemic vasculitis. Methods: Reports on two patients with severe manifestations of HCV related cryoglobulinaemia who failed to respond to interferon α are given. Both patients were treated with pulse cyclophosphamide (750-1000 mg/ month for six and 11 months, respectively). HCV RNA was quantified and HCV quasispecies determined in cryoprecipitates and supernatants before and during treatment. Results: Cryocrit and complement activation decreased in both patients with rebound of cryocrit in one case during continuing pulse cyclophosphamide treatment. Vasculitic symptoms improved. Alanine aminotransferase (ALT) levels and HCV viral load (0.2-0.4 log) increased slightly and reached pretreatment levels after cyclophosphamide was stopped. A highly heterogeneous quasispecies was found in the cryoprecipitate and supernatant of one patient, whereas the viral population was homogeneous in the other patient. After six cycles of cyclophosphamide, viral distances decreased non-significantly. However, phylogenetic analysis showed the evolution of distinct viral strains in one patient and replacement of the main viral population by another population in the second patient. Conclusions: Immunosuppressive treatment with pulse cyclophosphamide has a temporary limited effect on HCV associated cryoglobulinaemia and leads to a reversible increase of ALT levels and HCV viral load. Short term immunosuppression does not affect the viral heterogeneity as measured by amino acid and nucleotide distances in the hypervariable region 1 of HCV. A change of quasispecies was observed, but further studies are needed to evaluate if this does affect the outcome of IFNα treatment in such patients.

Rheumatic manifestations of hepatitis C infection

“…Concerns regarding their immediate effect on liver function have not been substantiated from clinical experience [19]. After short courses of immunosuppressive therapy (corticosteroids ± cyclophosphamide), the increase in HCV viremia level is modest and transient [19,25], although no significant change in viral quasispecies (a marker of viral diversity) was found in a recent study [25]. Data for the effect of prolonged immunosuppressive therapy on liver function for patients with vasculitis are not available.…”

Virus Adaptation and Selection Following Challenge of Animals Vaccinated against Classical Swine Fever Virus

“…Adaptation under high selective pressure (such as during antiviral treatment, in the presence of neutralizing antibodies or following vaccination) has the potential to lead to the selection of adaptive escape variants. Examples of this process have been described in vivo and in vitro with the hepatitis C virus (HCV) [12,13,14,15] and in vitro for CSFV [16].…”

KRIOGLOBULINEMIChESKIY VASKULIT

“…Учитывая риск нарастания вире-мии на фоне цитостатиков [56], в последующем при ВГС-ассоциированном КВ рекомендуется начинать этиологи-ческое лечение ИФН α. В лечении тяжелых форм КВ ис-пользуются комбинации экстракорпоральных методов ле-чения (плазмаферез, криоаферез, двойная фильтрация плазмы, аферез с гепаринокриофракционированием) в со-четании с комбинированной пульс-терапией ГК и цито-статиками. Дальнейшие исследования по терапии КВ, ос-ложненного развитием лимфопролиферативных заболева-ний [46,57] с тяжелыми неврологическими проявлениями и поражением почек, моноклональными CD 20 антитела-ми ответят на вопрос о их месте в лечении КВ. Рекоменда-ции по использованию небиологических и биологических лекарственных препаратов у больных с ревматическими проявлениями на фоне хронической вирусной инфекции ВГС и ВГВ, разработанные Американской ассоциацией ревматологов, гепатологов и Европейской ассоциацией ге-патологов, рассмотрены в специальном обзоре [58].…”