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Therapeutic Methods and Therapies TCIM
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1.
PLoS One ; 10(7): e0133028, 2015.
Article in English | MEDLINE | ID: mdl-26176696

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.


Subject(s)
Antiretroviral Therapy, Highly Active , Antiviral Agents/therapeutic use , HIV Infections/drug therapy , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/drug therapy , RNA, Viral/antagonists & inhibitors , Silymarin/therapeutic use , Adult , Coinfection , Drug Administration Schedule , Female , HIV/drug effects , HIV/growth & development , HIV Infections/blood , HIV Infections/pathology , HIV Infections/virology , Hepacivirus/drug effects , Hepacivirus/growth & development , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/pathology , Hepatitis C, Chronic/virology , Humans , Injections, Intravenous , Interferon-alpha/therapeutic use , Liver Cirrhosis/blood , 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/blood , Recombinant Proteins/therapeutic use , Ribavirin/therapeutic use , Silybin , Treatment Outcome , Viral Load/drug effects
2.
AIDS ; 28(15): 2231-9, 2014 Sep 24.
Article in English | MEDLINE | ID: mdl-25036184

ABSTRACT

OBJECTIVE: The presence of minority nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 variants prior to antiretroviral therapy (ART) has been linked to virologic failure in treatment-naive patients. DESIGN: We performed a large retrospective study to determine the number of treatment failures that could have been prevented by implementing minority drug-resistant HIV-1 variant analyses in ART-naïve patients in whom no NNRTI resistance mutations were detected by routine resistance testing. METHODS: Of 1608 patients in the Swiss HIV Cohort Study, who have initiated first-line ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI before July 2008, 519 patients were eligible by means of HIV-1 subtype, viral load and sample availability. Key NNRTI drug resistance mutations K103N and Y181C were measured by allele-specific PCR in 208 of 519 randomly chosen patients. RESULTS: Minority K103N and Y181C drug resistance mutations were detected in five out of 190 (2.6%) and 10 out of 201 (5%) patients, respectively. Focusing on 183 patients for whom virologic success or failure could be examined, virologic failure occurred in seven out of 183 (3.8%) patients; minority K103N and/or Y181C variants were present prior to ART initiation in only two of those patients. The NNRTI-containing, first-line ART was effective in 10 patients with preexisting minority NNRTI-resistant HIV-1 variant. CONCLUSION: As revealed in settings of case-control studies, minority NNRTI-resistant HIV-1 variants can have an impact on ART. However, the implementation of minority NNRTI-resistant HIV-1 variant analysis in addition to genotypic resistance testing (GRT) cannot be recommended in routine clinical settings. Additional associated risk factors need to be discovered.


Subject(s)
Drug Resistance, Viral , Genotyping Techniques/methods , HIV Infections/virology , HIV Reverse Transcriptase/genetics , HIV-1/enzymology , HIV-1/genetics , Mutation, Missense , Adult , Alleles , Anti-Retroviral Agents/therapeutic use , Female , HIV-1/isolation & purification , Humans , Male , Microbial Sensitivity Tests/methods , Middle Aged , Retrospective Studies , Treatment Outcome
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