Resistance

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 that data let 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][9]

One analysis found that the presence of I50V, conferred fourfold genotypic resistance. Because boosted darunavir has such as 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.^[10]

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/mm 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.^[11] 

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 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.^[12]