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  International HIV and Hepatitis Drug Resistance Workshop
June 8-12, 2010,
Dubrovnik Croatia
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Only Two Major PI Mutations (But No Resistance)
in Darunavir Monotherapy Trial

  International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
Only 2 of 48 successfully genotyped people in the MONET darunavir/ritonavir monotherapy trial had a major IAS-USA protease mutation during viral blips -- 1 patient in the monotherapy arm and 1 in the triple-therapy arm [1]. In neither case did the mutant virus show phenotypic evidence of resistance to darunavir, the newest protease inhibitor (PI). The study also found no hints that minor PI mutations evolved in either study arm after repeated sampling.
MONET randomized 256 people on suppressive therapy and with no history of virologic failure to once-daily darunavir/ritonavir monotherapy or to once-daily darunavir/ritonavir with two nucleosides [2]. At week 48 three statistical analysis showed equivalent virologic suppression rates in the two study arms.
The resistance analysis involved 70 people--39 on monotherapy and 31 on triple therapy--who had a viral load above 50 copies during MONET's first 96 weeks. Federico Pulido and colleagues successfully genotyped 48 of these people, 27 on monotherapy and 21 on triple therapy. Only 2 people--1 in each arm--had a detectable major PI mutation during their viral blips.
One person taking darunavir/ritonavir monotherapy, who had no available genotype before the trial, had the darunavir-related mutation L33F during a blip to 63 copies. One person taking triple therapy had the M184V lamivudine/emtricitabine mutation and the PI mutations V82I and L90M before the trial began. After a blip to 73 copies, M184V and L90M re-emerged, along with the PI mutations I54V and V82T.
In both cases the virus remained sensitive to darunavir and the viral load slipped back below 50 copies and remained there through 96 weeks with no change in antiretrovirals.
Fourteen people taking monotherapy had two or more sequential genotypes during sustained bouts of viremia above 50 copies. Genotyping disclosed a median of three minor IAS-USA PI mutations in these people (range 0 to 5). The type and number of minor PI mutations did not change over time in 10 of these 14 people. In 3 people the number of minor PI mutations dropped, and in 1 person the array of minor PI mutations changed.
One minor mutation, L93L/M, proved more common with monotherapy than with triple therapy. Otherwise the two arms did not differ in minor PI mutations. The minor PI mutations detected in MONET are commonly seen in the Stanford database of antiretroviral-naive people, a result suggesting that darunavir/ritonavir was not driving evolution of these mutations.
Together, the results suggest that suppressive darunavir/ritonavir monotherapy does not pose a resistance risk in people who have responded well to antiretroviral therapy and have no record of virologic failure.

1. Pulido F, Arribas J, Hill A, Moecklinghoff C. Evolution of minor IAS-USA PI mutations after repeated genotyping in the MONET trial of darunavir/ritonavir, with or without nucleoside analogues. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 109.
2. Arribas JR, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010;24:223-230.