|
11th Conference on Retroviruses and Opportunistic InfectionsSan Francisco, California - February 8 - 11, 2004 |
 |
Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th:Abstract No. 39
J Mellors
1, S Palmer2, D Nissley2, M Kearney2, E Halvas1, C Bixby1, L Demeter3, S Eshleman4, K Bennett5, S Hart6, F Vaida5, M Wantman5, J Coffin2, and S Hammer for the ACTG 398 Study Group7
1Univ. of Pittsburgh, PA, USA; 2Drug Resistance Prgm., NCI, NIH, DHHS, Frederick, MD, USA; 3Univ. of Rochester, NY, USA; 4Johns Hopkins Univ., Baltimore, MD, USA; 5Harvard Sch. of Publ. Hlth., Boston, MA, USA; 6Frontier Sci. and Technology Res. Fndn., Amherst, NY, USA; and 7Columbia Univ., New York, NY, USA
BACKGROUND: The role of minor (low-frequency) drug-resistant variants in failure of antiretroviral therapy is not defined. In ACTG 398, 212 NNRTI-experienced and 269 NNRTI-naïve patients were randomized to efavirenz (EFV), abacavir, adefovir, and amprenavir plus a second PI or placebo. This allowed us to examine relations between NNRTI experience, NNRTI resistance, virologic response, and emergence of EFV resistance.
METHODS: Baseline genotypes were obtained in 452/481 patients by a standard (ViroSeq v2.0). Minor NNRTI-resistant variants were sought with single genome RT-PCR and sequencing (SGS) and a Ty1/HIV-1 RT yeast system that detects EFV-resistant colonies. Phylogenetic analyses were performed with the neighbor joining method.
RESULTS: Virologic failure was associated with NNRTI experience (p <0.001), baseline NNRTI mutations (p <0.001), and development of EFV resistance (p <0.001). Standard genotype did not identify NNRTI mutations in baseline samples from 48 (22%) NNRTI-experienced patients. Virologic response in this group was no better than in the experienced group with baseline NNRTI mutations (n = 166), suggesting that standard genotype was insensitive for NNRTI-resistant variants. Baseline plasma from a random sample of 11 NNRTI-experienced and 12 NNRTI-naïve patients experiencing virologic failure despite negative standard genotypes for NNRTI mutations were assayed for NNRTI-resistant variants. Such variants were identified by SGS in 6/11 NNRTI-experienced patients with the following frequencies per positive patient: 181C and 190A (5/15 sequences); 181C (3/19); 181C (3/22); 108I (2/35); 103N (1/33); and 103N (1/34). By comparison, NNRTI-resistant variants were found in 2/12 NNRTI-naïve patients: 100I and 225L (1/33 sequences each) and 103N (1/41 sequences). The Ty1/HIV-1 RT assay detected EFV-resistant colonies in 8/10 NNRTI-experienced patients with the following frequencies: 7.2, 3.3, 2.8, 1.7, 1.7, 0.9, 0.8, and 0.6%. In NNRTI-naïve patients, resistant colonies were found in only 2/12 patients with frequencies of 0.6% and 0.4%. Phylogenetic analyses showed clustering of the baseline NNRTI-resistant variants identified by SGS with the genotype at virologic failure in 5/6 NNRTI-experienced patients. In the 2 NNRTI-naïve patients, the 103N variant clustered with the failure genotype but the 100I/225L variants did not.
CONCLUSIONS: Prior NNRTI expsoure can select minor NNRTI-resistant variants that are missed by standard genotyping and can contribute to failure of EFV-based regimens.
040208
39
Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.
