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Baseline Resistance to NNRTI as a Predictor of Virologic Failure in Treatment-naïve Subjects Receiving Efavirenz-based Regimens in ACTG A5095
Daniel Kuritzkes*1,2, Daniel Kuritzkes*1,2, C Lalama3, H Ribaudo3, M Marcial1, W Meyer4, C Shikuma5, K Klingman6, B Schackman7, E Acosta8, R Gulick7, and the ACTG A5095 Protocol Team
1Brigham and Women's Hosp, Boston, MA, US; 2Harvard Med Sch, Boston, MA, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Quest Diagnostics, Inc, Baltimore, MD, US; 5Univ of Hawaii, Honolulu, US; 6Div of AIDS, NIAID, NIH, Bethesda, MD, US; 7Weill Med Coll of Cornell Univ, New York, NY, US; and 8Univ of Alabama at Birmingham, US
Background: Sentinel surveys
show an increasing prevalence of non-nucleoside reverse transcriptase inhibitors
(NNRTI) -resistance mutations in HIV-1 from newly diagnosed, treatment-naïve
persons. In ACTG 5095, a randomized trial comparing the efficacy of efavirenz (EFV)
+ 2 or 3 NRTI, 20 of the 193 (10%) subjects meeting protocol-defined virologic
failure had observed NNRTI-resistant virus at baseline. Since this subset is a
selected cohort (only those with a poor virologic response) we designed a
case-cohort study to determine the impact of baseline NNRTI resistance on
response to an EFV-based regimen.
Methods: The case-cohort
sample included a random cohort (n = 220)
of the 765 EFV-treated subjects plus the unselected subjects with virologic
failure. Genotyping of HIV-1 protease and RT was performed on stored plasma
samples (TRUGENE version 10). Based on this case-cohort sample, the prevalence
of NNRTI resistance among non-failures was estimated and modified Cox
proportional hazards models estimated the relative risk of virologic failure in
the presence and absence of baseline NNRTI resistance. Intent-to-treat and
as-treated analyses were performed.
Results: Of the 220 subjects
in the randomly sampled cohort, 57 (26%) had virologic failure and 163 (74%) were
non-failures. The 136 subjects with virologic failure not selected in the
random sample were added to the cohort to make up a case-cohort sample of 356
(193 virologic failures, 163 non-failures). Baseline characteristics of
subjects in the sample (median plasma HIV-1 RNA = 4.77 log10 copies/mL;
median CD4 count = 203 cells/mm3) were similar to the remaining
A5095 subjects. Of the 345 subjects in the case-cohort sample with sufficient
follow-up to be at risk of virologic failure, 342 had baseline genotype
results. In the intent-to-treat analysis, 16 (8%) subjects with virologic
failure and 3 (2%) non-failures had baseline NNRTI resistance. Of note, 3 of 3 non-failures
with resistant virus received EFV + 3 NRTI compared to 3 of 16 with virologic
failure. The prevalence of protease inhibitor resistance or possible resistance
was 9% among both non-failures and subjects with virologic failure. Both Cox
analyses of the intent-to-treat and as-treated groups showed a significant
increase in risk of virologic failure for subjects with baseline NNRTI resistance
compared to those without (intent-to-treat: HR 2.27, 95%CI 1.15, 4.49, p = 0.018; as-treated: HR 2.61, 95%CI 1.30, 5.20, p = 0.007).
Conclusions: Baseline NNRTI
resistance more than doubled the risk of virologic failure in EFV-treated
subjects. These results support guidelines recommending resistance testing
before starting ART.
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