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A Lead-In with Silibinin Prior to Triple-Therapy Translates into Favorable Treatment Outcomes in Difficult-To-Treat HIV/Hepatitis C Coinfected Patients.

AbstractBACKGROUND:
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.
METHODOLOGY:
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.
CONCLUSION:
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.
TRIAL REGISTRATION:
ClinicalTrials.gov NCT01816490.
AuthorsDominique L Braun, Andri Rauch, Manel Aouri, Nina Durisch, Nadia Eberhard, Alexia Anagnostopoulos, Bruno Ledergerber, Beat Müllhaupt, Karin J Metzner, Laurent Decosterd, Jürg Böni, Rainer Weber, Jan Fehr, Swiss HIV Cohort Study
JournalPloS one (PLoS One) Vol. 10 Issue 7 Pg. e0133028 ( 2015) ISSN: 1932-6203 [Electronic] United States
PMID26176696 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Interferon-alpha
  • Oligopeptides
  • Protease Inhibitors
  • RNA, Viral
  • Recombinant Proteins
  • Silymarin
  • Polyethylene Glycols
  • Ribavirin
  • Silybin
  • telaprevir
  • peginterferon alfa-2a
Topics
  • Adult
  • Antiretroviral Therapy, Highly Active
  • Antiviral Agents (therapeutic use)
  • Coinfection
  • Drug Administration Schedule
  • Female
  • HIV (drug effects, growth & development)
  • HIV Infections (blood, drug therapy, pathology, virology)
  • Hepacivirus (drug effects, growth & development)
  • Hepatitis C, Chronic (blood, drug therapy, pathology, virology)
  • Humans
  • Injections, Intravenous
  • Interferon-alpha (therapeutic use)
  • Liver Cirrhosis (blood, drug therapy, pathology, virology)
  • Male
  • Middle Aged
  • Oligopeptides (therapeutic use)
  • Patient Safety
  • Polyethylene Glycols (therapeutic use)
  • Prospective Studies
  • Protease Inhibitors (therapeutic use)
  • RNA, Viral (antagonists & inhibitors, blood)
  • Recombinant Proteins (therapeutic use)
  • Ribavirin (therapeutic use)
  • Silybin
  • Silymarin (therapeutic use)
  • Treatment Outcome
  • Viral Load (drug effects)

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