 |
|
|
| |
Short-Term Raltegravir Monotherapy Does Not Predispose Patients to Develop RAL Resistance During Subsequent Combination Therapy: Analysis of Samples From Protocol 004
|
| |
| |
Download the PDF here
Reported by Jules Levin
CROI 2010 Feb 16-19 SF
Michael D. Miller, Richard J.O. Barnard, Marc Witmer, Jing Zhao, Bach-Yen Nguyen, Hedy Teppler, and Daria Hazuda for the Protocol 004 Team
Merck & Co., Inc., West Point PA
ABSTRACT
Background. Raltegravir (RAL) is an HIV-1 Integrase Strand Transfer Inhibitor approved for treatment of HIV-1 infection. Protocol 004 was a Phase 2, multi-center, double-blind, 2-part randomized placebo-controlled dose-ranging study of RAL in treatment-naïve HIV-1 infected patients. Part 1 of this study enrolled 35 patients who received RAL monotherapy (at one of 4 doses) or placebo for 10 days. All Part 1 participants were eligible to enroll in Part 2, in which patients received tenofovir plus lamivudine in combination with RAL at their respective Part 1 dose or efavirenz (for patients who received placebo in Part 1). A total of 29 Part 1 participants (25 from RAL arms, 4 from placebo arm) were treated in Part 2. The goals of the current analysis were 1) to assess efficacy and durability of RAL combination therapy for patients who received RAL monotherapy, and 2) to use a sensitive 454 deep sequencing method to determine whether any minority RAL resistance mutations emerged during RAL monotherapy.
Methods. Virologic failure was defined as either non-response (viral load [VL] never reached <400 copies/ml) or virologic relapse (relapse defined as 2 consecutive VL > 400/ml after initially achieving VL<400/ml, or a >1 log10 increase in VL above the VL nadir. Deep sequencing of the integrase gene was performed by 454 Life Sciences using archived Part 1 plasma samples. When possible, for each patient, deep sequencing was attempted for 3 time points: Part 1 baseline (pre-therapy), an on-therapy sample with VL> 400/ml, and Part 2 baseline (or 14d after the end of monotherapy).
Results. Minority variants with RAL resistance mutations were observed infrequently by deep (454) sequencing in all Part 1 samples. Only one of 25 patients who received RAL monotherapy in Part 1 experienced virologic relapse during 96 weeks of RAL/TDF/3TC treatment in Part 2. At the time of failure, this patient’s virus had no detectable genotypic resistance to RAL and no phenotypic or genotypic resistance to TDF or 3TC. Of the five patients who discontinued treatment prior to 96 weeks, 4 patients had VL<50/ml at the time of discontinuation (weeks 64 to 81) and 1 patient discontinued after 2 weeks of therapy.
Conclusions. Using 454 deep sequencing methods, mutations associated with RAL resistance were rarely detected in patients receiving RAL monotherapy and these minority variants did not result in virologic failure during subsequent combination therapy with TDF and 3TC.
INTRODUCTION
Protocol 004 is an ongoing Phase 2, multi-center, double-blind, 2-part randomized placebo-controlled dose-ranging study of RAL in treatment-naïve HIV-1 infected patients with total 240 week duration. Safety and efficacy results through week 144 have been published or presented (Part 1: Markowitz, et al., 2006, J Acquir Immune Defic Syndr; 43:509; Part 2: Markowitz, et al., 2007, J Acquir Immune Defic Syndr 46:125; Markowitz, et al., 2009, J Acquir Immune Defic Syndr 52:350; Gotuzzo et al, 2009, IAS abstract MOPEB030). Week 192 results are presented at this meeting (Gotuzzo, et al, abstract #K-127).
The overall study design is shown in Figure 1. Part 1 of this study enrolled 35 patients who received RAL monotherapy (at one of 4 doses) or placebo for 10 days. All Part 1 participants were eligible to enroll in Part 2, in which patients received tenofovir plus lamivudine in combination with RAL at their respective Part 1 dose or efavirenz (for patients who received placebo in Part 1).
The goals of the present analysis were 1) to assess efficacy and durability of RAL combination therapy through week 96 specifically for patients who received RAL monotherapy, and 2) to use a sensitive 454 deep sequencing method to determine whether any minority RAL resistance-associated mutations emerged during RAL monotherapy.
RESULTS
|
| |
|
|
|
|
|
