Early data from test-tube studies indicated darunavir (Prezista) is active against HIV with high-level resistance to other protease inhibitors and that resistance may develop more slowly than with other protease inhibitors.1
A sub-analysis of resistance in the 24-week pooled POWER 1,2, and 3 data (using 600mg DRV/100mg RTV dosed twice daily) in treatment-experienced patients showed that darunavir (DRV) has a high genetic barrier to resistance and that a a large number of background DRV mutations are required for resistance to develop.
This study found that the incremental number of DRV resistance-associated mutations (RAMs) was more predictive of treatment outcome than were the IAS-USA PI-associated RAMs.2 The baseline darunavir-fold change in EC50 (drug concentration needed to give half of the maximal response) was a strong indicator of virological response at 24 weeks.
A 48-week study of response in highly treatment-experienced patients also found that the virtual inhibitory quotient (vIQ) was more predictive of response to therapy in highly-treated patients than was DRV trough concentration or RAMS alone. It was further suggested that the target vIQ of darunavir should be 1.5 to successfully suppress viral load.3
The mutations most associated with a reduced response to darunavir in treatment-experienced patients were V32I, I50V, I54M, L76V, and V82F. Other RAMS with a smaller impact were L10F, K20T, L33F, M36L, I47V, F53L, G73S/C, I84V, and L90M.4 Additional mutations to DRV/rtv include I54L, V11I, and L89V.5
Opinion is divided on whether past amprenavir experience actually lessens the efficacy of darunavir. Presence of the I50V or V32I + I47V RAMs, that are amprenavir-specific was determined as the cause of darunavir failure in highly-experienced patients.6 Further analysis of those data led to recommendations to lower the cutoff number of DRV mutations to two, take someone off a failing DRV-containing regimen by 24 weeks, and to consider the use of tipranavir after failure on darunavir.7
However, in the POWER 1, 2, and 3 studies, prior use of amprenavir, fosamprenavir, or lopinavir did not influence response to DRV/r.8 2
One analysis found that the presence of I50V, conferred fourfold genotypic resistance. Because boosted darunavir has such a high barrier to resistance, a decline in clinical efficacy requires at least a 10-fold decreased susceptibility. Complete loss of activity requires about 90-fold decreased susceptibility.9
In 48-week data from the TITAN study (that included PI-naive and PI-experienced patients), a significantly higher number of those on a DRV/r-based regimen achieved viral load below 400 copies/ml than did those on a lopinavir/r-based regimen. In patients overall who experienced virological failure, those on the darunavir/r regimen developed fewer PI- and nucleoside analog-associated mutations.10
One sizable US study reported that a number of mutations that confer resistance to darunavir are extremely uncommon (less than 0.5% prevalent) in treatment-naive patients. Darunavir mutations were most often seen in patients treated with amprenavir or fosamprenavir, as they have a similar structure to darunavir. (Aside from those drugs, DRV seems to have little cross-resistance to the other PI drugs.) The great majority of patients were found to have less than four darunavir mutations, so a good response would be expected in most patients.11