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Resistance Measured by Clinical Cutoff Drops Sharply From 1998 to 2007
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
Using Virco-defined clinical cutoffs, a Virco team figured that overall resistance prevalence in viral samples sent for resistance testing slipped from 82% in December 1998 to 66.5% in June 2007 [1]. This massive retrospective analysis found nelfinavir, lamivudine (3TC), and abacavir to be the most often compromised drugs in viral isolates tested in 2005-2007.
Virco investigators rated resistance in 242,003 viral samples that clinicians sent for routine resistance testing. The study excluded viral isolates from people enrolled in clinical trials. Virco calculated fold-change in 50% inhibitory concentration from viral genotype according to the vircoTYPE 4.2.01 system. The researchers defined reduced susceptibility to a drug as a fold-change in susceptibility above that drug's lower clinical cutoff--the point at which virus begins to escape that drug's control.
By that measure, 82% of viruses tested in December 1998 were resistant to one or more drugs, compared with 66.5% of viruses tested in June 2007. That finding is all the more remarkable when one considers that clinicians presumably sent a large majority of these samples to Virco because a regimen had failed. Overall prevalence of resistance to nucleosides fell from just over 70% of tested viruses in December 1998 to about 40% in June 2007. In that time prevalence of resistance to protease inhibitors (PIs) dropped from just over 60% to about 40%. Resistance to nonnucleosides climbed from about 40% of samples in December 1998 to about 52% in June 2000, then fell back to 40% at the last follow-up point.
The percentage of samples resistant to one or more drugs in each of the first three antiretroviral classes dipped from 30.5% in 1998 to 15.7% in 2007. Only tiny proportions of tested isolates had resistance-conferring mutations but no evidence of reduced susceptibility to nucleosides (2%), nonnucleosides (0.1%), or protease inhibitors (PIs) (0.1%).
Prevalence of the K65R tenofovir-induced mutation climbed from 1% at the end of 1998 to almost 8% in 2003-2004 but stayed flat after that. Among PI mutations, I47A and I47V (both lopinavir-related mutations), I50V (fosamprenavir and darunavir), and I50L (atazanavir) have become more common in Virco-tested isolates, but the prevalence of all these mutations remains well below 10%.
In 44,975 viral samples submitted from July 2005 through June 2007 that had reduced susceptibility to at least one antiretroviral, HIV had most often lost susceptibility to nelfinavir (61.7% of viral samples), 3TC (60.4%), and abacavir (57.1%) and least often lost susceptibility to darunavir/ritonavir (3.8%), tipranavir/ritonavir (13.8%), and saquinavir/ritonavir (19.3%). Except for nelfinavir, reduced-susceptibility rates were routinely higher for reverse transcriptase inhibitors than for PIs.
The Virco team saw three factors contributing to the overall drop in "clinically relevant" reduced susceptibility to antiretrovirals--smarter treatment planning by clinicians, stronger antiretroviral regimens, and wider use of pretreatment resistance testing.
Reference
1. Sista P, Wasikowski B, Pattery T, Bacheler L. Nine-year trends in clinically-relevant reduced HIV-1 susceptibility to antiretrovirals. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 41.
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