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Steady Drop in Resistant Virus Rates at Virologic Failure in Italy
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
More than 90% of people in a multicenter Italian study had resistance-linked mutations upon virologic failure in 2001, but that rate slid to 67% in 2007 [1]. Individual mutations conferring resistance to newer antiretrovirals--tenofovir, atazanavir, tipranavir, and darunavir--did appear more frequently in recent years, but their overall prevalence remained minuscule.
Clinicians from three centers in Rome and Reggio Emilia genotyped 3813 viral samples from 2344 people who had tried several regimens from 2001 through 2007, looking for mutations appearing on the IAS-USA list [2]. They defined class resistance as detection of at least one major IAS-USA mutation conferring resistance to a nucleoside (NRTI), nonnucleoside (NNRTI), or protease inhibitor (PI). About 90% of patients studied had subtype B HIV-1.
Overall prevalence of virus with at least one mutation dropped from 90.4% in 2001 to 67.5% in 2007, a highly significant swoon (P < 0.001). Resistance to all three classes dipped from 27.6% in 2001 to 11.7% in 2007 (P < 0.001). Accordingly, resistance rates plunged for each class individually--from 87.0% to 57.7% for NRTIs, from 49.1% to 36.0% for NNRTIs, and from 58.3% to 27.6% for PIs. Median number of resistance mutations at failure also dropped significantly for each class from 2001 through 2007 (P < 0.001):
· NRTIs: from 3 (interquartile range [IQR] 1 to 5) to 1 (IQR 0 to 3)
· NNRTIs: from 2 (IQR 1 to 2) to 1 (IQR 0 to 2)
· PIs: from 1 (IQR 1 to 3) to 0 (IQR 0 to 2)
During the study period overall NNRTI use rose significantly from 59.4% in 2001 to 70.0% in 2007 (P < 0.001), while overall PI prescribing stayed flat. The median percentage of people having their first regimen failure climbed from 5.8% to 15.4% (P < 0.001). Use of only one NRTI, d4T, declined significantly (61.3% to 12.0%, P < 0.001). Detection of the tenofovir-associated K65R mutation rose from only 1% to 3% during the study span, while tenofovir use rocketed from 0% to 47.6% (P < 0.001). The only other NRTI mutation that became more frequent was the thymidine analog (AZT or d4T) mutation K219E. Frequency of the L74V mutation, a product of ddI or abacavir failure, dropped from 11% to 5%
Rates of key NNRTI mutations L100I, K101P, K103N, V106A, Y181C, and G190S all decayed significantly from 2001 through 2007 (P < 0.05), as use of NNRTIs in failing regimens fell from 40.4% to 26.0% (P < 0.001). V106I, a secondary mutation that heightens resistance to efavirenz in K103N or Y188L mutants [3], turned up in 2% of 2001 samples and in 4% of 2007 samples, a nonsignificant increase.
Meanwhile PI use at first genotypic resistance testing climbed significantly from 55.8% in 2001 to 66.7% in 2007, P < 0.001). Rates of three mutations conferring resistance to newer PIs jumped significantly (P < 0.05) during the study period but stayed at relatively low levels:
· I50L (atazanavir): from 0.0% to 1.2%
· L89V (darunavir): from 2.8% to 8.1%
· V82T (tipranavir): from 0.8% to 5.7%
Use of these three PIs also rose significantly in the people studied (P < 0.001).
The investigators attribute the overall tail-off in resistance mutations at failure to use of more potent regimens and greater reliance on genotyping to guide treatment choices.
References
1. Santoro MM, Ceccherini-Silberstein F, Narciso P, et al. Declining of HIV-1 drug resistance in treatment-failing patients: a potential association with more effective antiretroviral regimens. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 2.
2. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2007. Topics HIV Med. 2007;15:119-125.
3. Bacheler L, Jeffrey S, Hanna G, et al. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J Virol. 2001;75:4999-5008
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