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


  1. de Meyer et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 49: 2314-2321, 2005
  2. De Meyer S et al. Resistance profile of darunavir: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses 24(3): 379-388, 2008
  3. Moltó J et al. Darunavir inhibitory quotient predicts the 48-week virological response to darunavir-based salvage therapy in HIV-infected protease inhibitor-experienced patients. Antimicrob Agents Chemother [Epub ahead of print 25 august], 2008
  4. Van Marck H et al. Unravelling the complex resistance pathways of darunavir using bioinformatics resistance determination (BIRD). Sixteenth International HIV Drug Resistance Workshop, Barbados, abstract 128, 2007
  5. Johnson VA et al. Update of the drug resistance mutations in HIV-1: Spring 2008. Top HIV Med 16(1): 62-68, 2008
  6. Delaugerre C et al. Key amprenavir resistance mutations counteract dramatic efficacy of darunavir in highly experienced patients. AIDS 21(9): 1210-1213, 2007
  7. Delaugerre C et al. Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen AIDS 22(14): 1809-1813, 2008
  8. Picchio G et al. Prior utilization or resistance to amprenavir at screening has minimal effect on the 48-week reponse to darunavir/r in the POWER 1, 2, and 3 studies. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 609, 2007
  9. Coakley E et al. Defining the upper and lower phenotypic clinical cut-offs for darunavir/ritonavir by the PhenoSense assay. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 610, 2007
  10. Madruga JV et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 370: 49-58, 2007
  11. Mitsuya Y et al. Prevalence of darunavir resistance-associated mutations: patterns of occurrence and association with past treatment. Clin Infect Dis: 196: 1177-1179, 2007
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.