title: A Lead-In with Silibinin Prior to Triple-Therapy Translates into Favorable Treatment Outcomes in Difficult-To-Treat HIV/Hepatitis C Coinfected Patients.
abstract: BACKGROUND
  The efficacy of first-generation protease inhibitor based triple-therapy against hepatitis C virus (HCV) infection is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and non-response to previous peginterferon-ribavirin. These patients have a low chance of achieving a sustained virologic response (SVR) using first generation triple-therapy, with a success rate of only 20%. We investigated the efficacy and safety of lead-in therapy with intravenous silibinin followed by triple-therapy in this difficult-to-treat patient group.
  
  
  METHODS
  Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented previous treatment failure on peginterferon-ribavirin. The intervention was a lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days, followed by triple-therapy (peginterferon-ribavirin and telaprevir) for 12 weeks, and peginterferon-ribavirin alone for 36 weeks. Outcome measurements were HCV-RNA after silibinin lead-in and during triple-therapy, SVR data at week 12, and safety and tolerability of silibinin.
  
  
  RESULTS
  We examined sixteen HIV/HCV-coinfected patients with previous peginterferon-ribavirin failure, of whom 14 had a fibrosis grade METAVIR ≥F3. All were on successful antiretroviral therapy. Median (IQR) HCV-RNA decline after silibinin therapy was 2.65 (2.1-2.8) log10 copies/mL. Fifteen of sixteen patients (94%) had undetectable HCV RNA at weeks 4 and 12, eleven patients (69%) showed end-of-treatment response (i.e., undetectable HCV-RNA at week 48), and ten patients (63%) reached SVR at week 12 (SVR 12). Six of the sixteen patients (37%) did not reach SVR 12: One patient had rapid virologic response (RVR) (i.e., undetectable HCV-RNA at week 4) but stopped treatment at week 8 due to major depression. Five patients had RVR, but experienced viral breakthroughs at week 21, 22, 25, or 32, or a relapse at week 52. The HIV RNA remained below the limit of detection in all patients during the complete treatment period. No serious adverse events and no significant drug-drug interactions were associated with silibinin.
  
  
  CONCLUSIONS
  A lead-in with silibinin before triple-therapy was safe and highly effective in difficult-to-treat HIV/HCV coinfected patients, with a pronounced HCV-RNA decline during the lead-in phase, which translates into 63% SVR. An add-on of intravenous silibinin to standard of care HCV treatment is worth further exploration in selected difficult-to-treat patients.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01816490.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Dominique L
authors.initials: DL
authors.lastname: Braun
authors.affiliation: Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Manel
authors.initials: M
authors.lastname: Aouri
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Nina
authors.initials: N
authors.lastname: Durisch
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Nadia
authors.initials: N
authors.lastname: Eberhard
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Alexia
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
authors.affiliation: Clinic for Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Metzner
authors.affiliation: Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Decosterd
authors.affiliation: Swiss National Center for Retroviruses, Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Böni
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Weber
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Fehr
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents / Q000627:therapeutic use*; D060085:Coinfection; D004334:Drug Administration Schedule; D005260:Female; D006678:HIV / Q000187:drug effects / Q000254:growth & development; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D016174:Hepacivirus / Q000187:drug effects / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006801:Humans; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use; D061214:Patient Safety; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000627:therapeutic use; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011480:Protease Inhibitors; D012367:RNA, Viral; D011994:Recombinant Proteins; D012838:Silymarin; D011092:Polyethylene Glycols; D012254:Ribavirin; D000077385:Silybin; C486464:telaprevir; C100416:peginterferon alfa-2a