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"Ultradeep" Detection of Pretreatment Mutations Has Little Impact on Long-Term PI (Reyataz/r) Response
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Detection of pretreatment mutations that may have compromised certain antiretrovirals tested in a clinical trial had little or no impact on 84- or 144-week confirmed virologic failure, according to retrospective analysis a trial assessing the protease inhibitor (PI) atazanavir [1].
Ultradeep sequencing and other supersensitive assays can detect antiretroviral-resistant virus that represents a tiny minority of a person's viral population, whereas standard genotyping detects only mutations that make up about 20% or more of a viral population. Some research suggests that minority populations of resistant virus can affect virologic outcome if patients begin a first-line regimen compromised by those mutations.
To test the long-term virologic impact of minority mutant populations, ARIES trial investigators retrospectively analyzed viral samples with Ultradeep Sequencing (Roche/454 LifeSciences) to determine how many study participants had virus bearing resistance mutations not detected by standard genotyping, and then to see if these small populations of resistant virus affected long-term virologic outcome [2].
In ARIES 515 antiretroviral-naive people in the United States, Puerto Rico, and Canada began abacavir/lamivudine plus atazanavir/ritonavir for 36 weeks. At that point 419 responders were randomized to maintain or discontinue ritonavir for an additional 48 weeks. Atazanavir alone proved noninferior to atazanavir/ritonavir 48 weeks after randomization. Study participants could remain part of the trial group through week 144.
The new analysis involved 250 randomly selected ARIES participants, all of whom had virus lacking the following mutations on standard genotyping:
-- Reverse transcriptase mutations K65R, L74V, and Y115F
-- Two or more thymidine analog mutations (TAMs): M41L, D67N, K70R, or K219Q/E, plus any mutation at L210 or T215
-- Three or more protease mutations at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, or L90
The new analysis involved 247 of 250 pretreatment samples that had paired Ultradeep and standard population sequencing results. In 34 of these 247 people (14%), Ultradeep Sequencing detected mutations that would have excluded that patient from the study: 33 had one or more protease mutations and 1 had a reverse transcriptase mutation.
Twenty of the 247 people with paired samples met confirmed virologic failure criteria by week 144. But only 5 of these 20 (25%) had Ultradeep evidence of a pretreatment mutation that would have excluded them from the trial.
Twenty-five of 34 people (73.5%) in whom Ultradeep spotted exclusionary mutations had a viral load below 50 copies at study week 30 and were randomized at week 36 to maintain or stop ritonavir. Of these 25 people, 19 of 19 followed through 84 weeks and 15 of 16 followed through 144 weeks maintained a sub-50-copy viral load.
Standard population sequencing detected one or more World Health Organization (WHO)-defined transmitted mutations in 32 of 247 people (13%) with matched Ultradeep and standard samples. In contrast, Ultradeep detected WHO-defined transmitted mutations in 81 of these 247 people (33%). Nonnucleoside mutations accounted for 17 mutations detected by population sequencing and 44 mutations detected by Ultradeep Sequencing.
The ARIES investigators noted that low-level nonnucleoside mutations missed by standard genotyping may have an impact on response in a trial testing a nonnucleoside regimen, because nonnucleosides have a lower resistance threshold than protease inhibitors. In ARIES, though, "use of a boosted protease inhibitor through the first 36 weeks provided a high genetic barrier [to resistance]." As result, the researchers proposed, success of a boosted protease inhibitor regimen may depend more on factors such as adherence than on pretreatment low-level resistance.
References
1. Ross LL, Squires K, Young B, et al. Pre-therapy detection of transmitted low-abundance HIV-1 resistance mutation-containing variants in antiviral-naive subjects and implications for subsequent clinical therapy response. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H2-796.
2. Squires KE, Young B, Dejesus E, et al for the ARIES study team. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients. AIDS. 2010;24:2019-2027.
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