Efficacy of All-Oral Anti-Viral Therapy for Symptomatic Hepatitis C Virus Infection-Related Cryoglobulinemia
Condition: Hepatitis C; Cryoglobulinemia
MeSH terms: Hepatitis A; Hepatitis C; Virus Diseases; Hepatitis; Cryoglobulinemia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      10 patients with chronic genotype 1 HCV infection and mixed cryoglobulinemia will be treated
      with Ledipasvir/Sofosbuvir 90mg/400 mg FDC once daily for 12 weeks (naïve subjects or
      non-cirrhotic treatment experienced subjects) or 24 weeks (treatment experienced subjects
      with cirrhosis).

      The researchers anticipate that approximately 20% of subjects may have cirrhosis.
    

Detailed description: 
      The treatment of extrahepatic disease manifestations of HCV has largely paralleled that of
      hepatic disease. Interferon was reported to have efficacy for MC even before linkage of the
      syndrome to HCV in 1989, and successful combination therapy with ribavirin was found to
      eliminate virus and lead to the resolution of immunologic abnormalities associated with
      extrahepatic disease. In addition, ~75% of HCV-associated indolent asymptomatic
      lymphoproliferative diseases remit with successful antiviral therapy. However, in many
      instances, MC (notably cutaneous vasculitis) will relapse with recurrence of virus, and may
      occasionally persist even after clearance. In particular, side effects of Interferon alpha,
      including the uncovering of frank autoimmune disease, theoretically may mitigate response of
      extrahepatic disease to treatment. Peg-interferon increased the response rate of MC, and
      decreased the duration of treatment, but side effects remained problematic.

      An alternative approach to the treatment of MC has been the use of immunomodulatory agents.
      In particular, B-cell expansion in peripheral blood and in lymphoid follicles in the liver
      prevalent amongst HCV-infected persons provided a rationale for the use of depletion as a
      therapeutic strategy. Rituximab (anti-CD20) monotherapy has been used mostly for treatment
      failures/intolerance or in the setting NHL, and has yielded response rates in the setting of
      involvement of skin (73%); MPGN (70%); joint (53%); and nerve (36%). However, this monoclonal
      antibody (MAb) has the potential to form immune-complexes with mixed cryoglobulin RF and
      cause clinical vasculitis in patients with high cryocrits, and may raise the HCV RNA level in
      rare patients, causing cytotoxicity. Following Rituximab with Peg-IFN plus ribavirin achieved
      greater than a 60% complete response (CR) in patients resistant to combination treatment
      alone. Other approaches include the use of Aldesleukin, an inducer of regulatory T-cell
      activity, MAbs targeted to specific B-cell subsets or costimulatory signal molecules (e.g.
      BAFF) or agents inhibiting the interaction of HCV core antigen with C1q in cryoprecipitates
      via the receptor for the globular domain of C1q (gC1qR).

      The development of low molecular weight inhibitors of the non-structural proteins (NSPs)
      elaborated by HCV, in particular 5A, 5B nucleoside and non-nucleoside polymerase inhibitors,
      and inhibitors of 3/4A serine proteases; to selectively inhibit HCV replication has raised
      the prospect of "all-oral" treatment for both hepatic and extrahepatic manifestations of
      disease. However, the use of first generation direct-acting antiviral agents (Telaprevir® and
      Boceprevir® linear NS3/4A protease inhibitors) was limited by frequent escape mutants,
      efficacy restricted to genotype-1, need to retain protocols including PegIFN and ribavirin,
      potential for significant drug interactions, and serious side effects. In a trial of
      combination therapy including Telaprevir® for 13 patients with MC, all had significant AEs,
      including asthenia (92%), anemia (84%), neutropenia and bacterial infection (54%). Approval
      of an uridine nucleoside analogue that selectively inhibits HCV NS5B RNA-dependent RNA
      polymerase (Sofosbuvir) by the FDA late 2013 has led to proof-of-concept trials in which
      combination all-oral therapy has proven effective for both genotype 1 and other genotypes,
      with a number of other regimens under development. In particular, the combination of
      Sobosbuvir (SOF) and Ledipasvir (LDV) has been reported to have almost universal efficacy in
      a 12 week regimen for genotype 1, and the combination of SOF and Ribavirin (RBV) for
      genotypes 2-6 in a 24 week regimen. However, persistence of cryoglobulinemia even after viral
      clearance with the newer regimens has also raised the question of whether longer treatment
      regimens may be appropriate in the setting of significant extrahepatic disease. Thus, the
      timing is right to initiate a trial of all-oral treatment to rigorously evaluate the effect
      on extrahepatic disease, and to re-establish the efficacy of antiviral therapy in halting the
      direct and indirect role of HCV in driving autoimmune disease and lymphoproliferation. Using
      an interferon-sparing regimen to treat patients with HCV-related cryoglobulinemia will help
      answer the question as to whether immunomodulating therapy plays a role at all in eradicating
      cryoglobulins long-term, and whether antiviral therapy alone is adequate. If the latter,
      appreciable morbidity and mortality may be saved in avoiding treating these potentially sick,
      often cirrhotic patients, with immunomodulatory therapies.
    

Intervention name(s): Harvoni; Epclusa
Intervention type(s): Drug; Drug
Intervention description(s): 12 weeks for naïve subjects or non-cirrhotic treatment experienced subjects; or 24 weeks for treatment experienced subjects with cirrhosis; once daily for 12 weeks (naïve subjects, non-cirrhotic treatment experienced or treatment experienced subjects with compensated cirrhosis) for genotype 1-6 subjects.
Other intervention name(s): Ledipasvir/Sofosbuvir; LDV/SOF FDC; Sofosbuvir/Velpatasvir
Intervention MeSH terms: Sofosbuvir; Ledipasvir, sofosbuvir drug combination; Sofosbuvir-velpatasvir drug combination; Ledipasvir; Velpatasvir
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatitis C; Cryoglobulinemia