Double Filtration Plasmapheresis for Hepatitis C Virus (HCV) Genotype 1 Patients With High Viral Load
Double Filtration Plasmapheresis for Hepatitis C Virus (HCV) Genotype 1 Patients With High Viral Load
Hepatitis C virus (HCV) infection, a leading cause of cirrhosis, hepatocellular carcinoma
 (HCC) and liver transplantation, affects approximately 170 million individuals worldwide. The
 prevention of HCV transmission and early intervention of HCV infection are urgently needed to
 reduce or halt the liver-related morbidity and mortality. Double filtration plasmapheresis
 (DFPP) has been with widespread use in clinical practice for several indications with plasma
 filters optimized for the respective elimination targets with excellent safety. By way of the
 plasma separator, the blood is separated into plasma and cell components. Separated plasma is
 then led into the plasma component separator where the pores of the plasma component
 separator further fractionate the plasma into large and small molecular components. The large
 molecular components, including pathogenic substances, is removed and discarded and the small
 molecular components, including proteins such as albumin and gamma-globulin, are returned to
 the patient and mixed with the cell components. After the initiation of pegylated interferon
 plus ribavirin (Peg-IFN+RBV) therapy, the rapid first phase relates to a significant
 reduction in virus production and the degradation of free virus particles, which is followed
 by a second much slower one reflecting the elimination and clearance of infected cells. In
 HCV patients, high baseline viral load at the initiation of therapy is considered to be a
 negative predictor for systemic vascular resistance (SVR) for HCV genotype 1 patients.
 Reduction of baseline viral load by means of therapeutic double filtration plasmapheresis
 (DFPP) may represent a plausible adjunct for improved antiviral therapy to reduce the virus
 load with the initiation of treatment in synergy with Peg-IFN and RBV combination therapy.
 Recently, several clinical studies in evaluating the therapeutic efficacy and safety of DFPP
 in conjunction with IFN-based therapy were conducted for treatment-naïve genotype 1 high
 viral load CHC patients, and CHC patients who underwent liver transplantation. These studies
 showed that patients with DFPP treatment had more favorable HCV early viral kinetics to those
 without DFPP treatment. Furthermore, all these studies showed excellent safety after DFPP
 treatment. Therefore, the investigators aimed to conduct a large-scaled randomized controlled
 trial to evaluate the overall response of DFPP for HCV genotype 1 patients with high viral
 load.
Hepatitis C virus (HCV) infection, a leading cause of cirrhosis, hepatocellular carcinoma
 (HCC) and liver transplantation, affects approximately 170 million individuals worldwide. The
 prevention of HCV transmission and early intervention of HCV infection are urgently needed to
 reduce or halt the liver-related morbidity and mortality. Currently, combination therapy with
 peginterferon (Peg-IFN) and ribavirin (RBV) has become the standard of care for chronic
 hepatitis C (CHC) patients, with an overall sustained virologic response (SVR) rate of
 54-63%. Treatment with weekly Peg-IFN and weight-based RBV for 48 weeks resulted in a
 significantly higher SVR rate than that for 24 weeks in patients with HCV genotype 1
 infection. While HCV genotype 1 patients who had both rapid virologic response (RVR) and low
 pretreatment viral load could receive short duration of therapy without compromising the
 treatment responses, those who had either high baseline viral load or failed to achieve RVR
 should receive at least 48 weeks of treatment. RVR is considered the most important factor
 for SVR. Furthermore, several studies have repeated shown that high baseline viral load (>
 400,000~800,000 IU/mL) was closely associated with failure to achieve RVR in these patients.
 Therefore, efforts to improve the RVR rate is important to facilitate the overall treatment
 responses.

 Double filtration plasmapheresis (DFPP), a well established method of therapeutic apheresis,
 has been with widespread use in clinical practice for several indications with plasma filters
 optimized for the respective elimination targets. By way of the plasma separator, the blood
 is separated into plasma and cell components. Separated plasma is then led into the plasma
 component separator where the pores of the plasma component separator further fractionate the
 plasma into large and small molecular components. The large molecular components, including
 pathogenic substances, is removed and discarded and the small molecular components, including
 proteins such as albumin and gamma-globulin, are returned to the patient and mixed with the
 cell components.

 DFPP has been used in the treatment of many diseases such as neurological diseases, collagen
 diseases, hematological diseases, skin diseases, and renal diseases, and its efficacy and
 safety have been well established. It is noteworthy to mention that DFPP has been indicated
 to treat CHC in Japan since April 2008. In Germany, the safety of DFPP in LDL-apheresis was
 analyzed within a retrospective multicenter investigation including data from 1702 ambulatory
 DFPP-LDL-apheresis treatments of 52 patients (REMUKAST Study). Ninety-eight percent of the
 treatments bear no serious adverse events while only 2% of slight hypotensive episodes were
 observed. In a recent investigation, efficacy and safety of DFPP was compared with the HELP
 (Heparin-induced Extracorporeal LDL-Cholesterol Precipitation) system in a cross-over design.
 No serious adverse events occurred in this study including 44 treatments.

 During chronic infection, the level of serum HCV RNA is in a steady state with only minor
 fluctuations in untreated patients. A dynamic equilibrium, involving hepatocytes and plasma
 components, exists between new viral production and viral destruction during chronic HCV
 infection. After the initiation of Peg-IFN plus RBV therapy, the viral decline can be divided
 into two major phases. Over the first 24 - 48 h the initial dose of PEG-IFN/RBV leads to a
 first decline of HCV RNA which ranges from 0.5-2.0 log levels. This rapid first phase relates
 to a significant reduction in virus production and the degradation of free virus particles,
 which is followed by a second much slower one reflecting the elimination and clearance of
 infected cells.

 As described above, a high baseline viral load (HCV-RNA > 800,000 IU/mL) at the initiation of
 therapy is considered to be a negative predictor for SVR for HCV genotype 1 patients.
 Reduction of baseline viral load by means of therapeutic DFPP may represent a plausible
 adjunct for improved antiviral therapy to reduce the virus load with the initiation of
 treatment in synergy with Peg-IFN and RBV combination therapy. Therefore the rationale for
 the effect of DFPP is that the reduced amount of virus during the initiation phase supports
 the therapeutic efficacy of Peg-IFN and RBV combination therapy by preventing liver
 reinfection by circulating HCV.

 Recently, several small-scaled clinical studies in evaluating the therapeutic efficacy and
 safety of DFPP in conjunction with IFN-based therapy were conducted for treatment-naïve
 genotyp1 high viral load CHC patients, and CHC patients who underwent liver transplantation.
 These studies showed that patients with DFPP treatment had more favorable HCV early viral
 kinetics to those without DFPP treatment. The large-scaled non-randomized clinical study
 totally evaluating 104 CHC patients showed that the addition of DFPP had a higher SVR rate to
 those without DFPP treatment in HCV genotype 1 patients with baseline viral load > 100,000
 IU/mL (70.8% versus 50.0%), probably due to eliminating a substantial part of viral particles
 from the dynamic equilibrium of the liver and plasma compartments. Furthermore, all these
 studies showed excellent safety after DFPP treatment. However, these studies were limited by
 the small case numbers and non-randomized assignment, making the role of DFPP in improving
 the efficacy of difficult-to-treat HCV patients still debated. Therefore, the investigators
 aimed to conduct a large-scaled randomized controlled trial to evaluate the overall response
 of DFPP for HCV genotype 1 patients with high viral load.
Inclusion Criteria:

 -  Treatment naïve

 -  Age 18 and older

 -  Anti-HCV (Abbott HCV EIA 2.0, Abbott Diagnostic, Chicago, IL) positive > 6 months

 -  Detectable serum quantitative HCV-RNA (Cobas Taqman v2.0, Roche Diagnostics) with HCV
 RNA > 800,000 IU/mL

 -  HCV genotype 1 (Inno-LiPA, Innogenetics)

 -  A liver biopsy consistent with the diagnosis of chronic hepatitis C

 Exclusion Criteria:

 -  Anemia (hemoglobin < 13 gram per deciliter for men and < 12 gram per deciliter for
 women)

 -  Neutropenia (neutrophil count <1,500 per cubic milliliter)

 -  Thrombocytopenia (platelet <90,000 per cubic milliliter)

 -  Co-infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)

 -  Chronic alcohol abuse (daily consumption > 20 gram per day)

 -  Decompensated liver disease (Child-Pugh class B or C)

 -  Serum creatinine level more than 1.5 times the upper limit of normal

 -  Autoimmune liver disease

 -  Neoplastic disease

 -  An organ transplant

 -  Immunosuppressive therapy

 -  Poorly controlled autoimmune diseases, pulmonary diseases, cardiac diseases,
 psychiatric diseases, neurological diseases, diabetes mellitus

 -  Evidence of drug abuse

 -  Unwilling to have contraception