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

PLoS One. 2015 Jul 15;10(7):e0133028. doi: 10.1371/journal.pone.0133028. eCollection 2015.

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.

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiretroviral Therapy, Highly Active*
  • Antiviral Agents / therapeutic use*
  • Coinfection
  • Drug Administration Schedule
  • Female
  • HIV / drug effects
  • HIV / growth & development
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV Infections / pathology
  • HIV Infections / virology
  • Hepacivirus / drug effects
  • Hepacivirus / growth & development
  • Hepatitis C, Chronic / blood
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / pathology
  • Hepatitis C, Chronic / virology
  • Humans
  • Injections, Intravenous
  • Interferon-alpha / therapeutic use
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / virology
  • Male
  • Middle Aged
  • Oligopeptides / therapeutic use
  • Patient Safety
  • Polyethylene Glycols / therapeutic use
  • Prospective Studies
  • Protease Inhibitors / therapeutic use
  • RNA, Viral / antagonists & inhibitors*
  • RNA, Viral / blood
  • Recombinant Proteins / therapeutic use
  • Ribavirin / therapeutic use
  • Silybin
  • Silymarin / therapeutic use*
  • Treatment Outcome
  • Viral Load / drug effects

Substances

  • Antiviral Agents
  • Interferon-alpha
  • Oligopeptides
  • Protease Inhibitors
  • RNA, Viral
  • Recombinant Proteins
  • Silymarin
  • Polyethylene Glycols
  • Ribavirin
  • Silybin
  • telaprevir
  • peginterferon alfa-2a

Associated data

  • ClinicalTrials.gov/NCT01816490

Grants and funding

This study has been conducted within the framework of the Swiss HIV Cohort Study (SHCS), which is funded by the Swiss National Science Foundation (grant number 33CS30_134277, SHCS project 688). The investigational medicine product was provided by Rottapharm│Madaus. The members of the Swiss HIV Cohort Study are: Aubert V, Barth J, Battegay M, Bernasconi E, Böni J, Bucher HC, Burton-Jeangros C, Calmy A, Cavassini M, Egger M, Elzi L, Fehr J, Fellay J, Furrer H (Chairman of the Clinical and Laboratory Committee), Fux CA, Gorgievski M, Günthard H (President of the SHCS), Haerry D (deputy of "Positive Council"), Hasse B, Hirsch HH, Hösli I, Kahlert C, Kaiser L, Keiser O, Klimkait T, Kouyos R, Kovari H, Ledergerber B, Martinetti G, Martinez de Tejada B, Metzner K, Müller N, Nadal D, Pantaleo G, Rauch A (Chairman of the Scientific Board), Regenass S, Rickenbach M (Head of Data Center), Rudin C (Chairman of the Mother & Child Substudy), Schöni-Affolter F, Schmid P, Schultze D, Schüpbach J, Speck R, Tarr P, Telenti A, Trkola A, Vernazza P, Weber R, Yerly S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.