Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: results from the REALIZE trial.
In the Phase 3 REALIZE study, 662 genotype 1 hepatitis C virus (HCV)-infected patients with prior peginterferon/ribavirin treatment failure (including relapsers, partial, and null responders) were randomized to 12 weeks of telaprevir given immediately (T12/PR48) or following 4 weeks of peginterferon/ribavirin (lead-in T12/PR48), or 12 weeks of placebo (PR48), combined with a total of 48 weeks of peginterferon alfa-2a/ribavirin. Sustained virologic response (SVR) rates were 64% (T12/PR48), 66% (lead-in T12/PR48), and 17% (PR48). This analysis aimed to characterize treatment outcomes and viral variants emerging in telaprevir-treated patients not achieving SVR. HCV NS3·4A population sequencing was performed at baseline, during treatment, and follow-up. Telaprevir-resistant variants were classified into lower-level (3- to 25-fold 50% inhibitory concentration [IC(50) ] increase: V36A/M, T54A/S, R155I/K/M/T, and A156S) and higher-level (>25-fold IC(50) increase: V36M+R155K and A156T/V) resistance. Resistant variants were uncommon at baseline. Overall, 18% (52%, 19%, and 1% of prior null and partial responders and relapsers, respectively) of telaprevir-treated patients had on-treatment virologic failure, with no significant difference with or without a lead-in. Virologic failure during the telaprevir-treatment phase was predominantly associated with higher-level resistance; virologic failure during the peginterferon/ribavirin-treatment phase was associated with higher- or lower-level, or wildtype variants, depending on genotype. Relapse occurred in 9% of patients completing assigned treatment and was generally associated with lower-level resistant variants or wildtype. Resistant variants were no longer detectable by study end (median follow-up of 11 months) in 58% of non-SVR patients.


CONCLUSIONS
In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of the use of a lead-in and were consistent with those previously reported. In most patients, resistant variants became undetectable over time.
Janssen Infectious Diseases BVBA, Beerse, Belgium. sdmeyer@its.jnj.com.
Sandra
S
De Meyer
Inge
I
Dierynck
Anne
A
Ghys
Maria
M
Beumont
Bjorn
B
Daems
Ben
B
Van Baelen
James C
JC
Sullivan
Douglas J
DJ
Bartels
Tara L
TL
Kieffer
Stefan
S
Zeuzem
Gaston
G
Picchio
D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D012254:Ribavirin / Q000627:therapeutic use; D017211:Treatment Failure
D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C100416:peginterferon alfa-2a