18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

VIROLOGIC FAILURE OF REGIMENS CONTAINING TWO NRTIS PLUS EFAVIRENZ IS NOT ASSOCIATED WITH THE SELECTION OF MUTATIONS IN THE CONNECTION OR RNASE H DOMAINS OF REVERSE TRANSCRIPTASE

Antivir Ther 2009; 14 Suppl 1:A34 (abstract no. 32)

J Brehm¹, CW Sheen¹, M Hughes², C Lalama², R Haubrich³, S Riddler¹, N Sluis-Cremer¹ and J Mellors^1
1University of Pittsburgh, Pittsburgh, PA, USA; ²Harvard School of Public Health, Boston, MA, USA; ³University of California San Diego, San Diego, CA, USA

BACKGROUND: Mutations in the connection and RNase H domains of HIV type-1 (HIV-1) reverse transcriptase (RT) can confer resistance to RT inhibitors (RTI), but it is unknown how frequently such mutations occur with virologic failure on currently recommended regimens. We therefore sequenced full-length RT in baseline and failure plasma samples from patients randomized to the two NRTIs plus efavirenz arm of ACTG 5142: a multicentre study of initial therapy for HIV-1 infection.

METHODS: Of the 60 patients with confirmed virologic failure, 53 with pretherapy and virologic failure (with HIV-1 RNA>450 copies/ml) sample pairs were studied. Viral RNA was extracted, converted to cDNA and RT was amplified by nested PCR and sequenced. Polymerase domain mutations were identified using the IAS–USA mutation table. Sequences at failure were compared with paired pretherapy sequences and to subtypes B, C or A/E consensus. McNemar’s test was used to test the significance of differences in mutation frequency.

RESULTS: RTI resistance mutations in the polymerase domain were identified in 23 of 53 (43%) failure samples. Polymerase domain mutations significantly associated with virologic failure were K103N (1.9% pretherapy versus 25% at failure; P=0.0015) and M184V/I (1.9% versus 15%; P=0.023). Mutations in connection/RNase H domains having higher frequency at virologic failure were R358K (7.5% pretherapy versus 11% at failure), A371V (0% versus 1.9%), A376S (1.9% versus 5.7%), T/M377L (13% versus 17%), V467I (17% versus 21%) and S519N (28% versus 32%). None of these differences were statistically significant (P>0.25 for each comparison). G333E or D (13%) and V365I (3.7%) were detected pretherapy, but were not more frequent at failure. E312Q, G335C, N348I, A360I/V and Q509L were never detected.

CONCLUSIONS: Virologic failure of two NRTIs plus efavirenz was associated with the frequent selection of mutations in the polymerase domain, but not in the connection or RNase H domains of RT. Previously reported mutations in the connection and RNase H domains of RT were probably not detected because failure was identified early using a sensitive protocol-specified definition and the treatment regimen contained efavirenz and not nevirapine, which can select N348I.

2009-06-09
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