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Darunavir (Prezista)

Table of Contents

Darunavir Prezista Summary Drug Summary Key Clinical Trials Resistance Key Drug Interactions Citations Figures

Drug Summary

Darunavir is a potent, later-generation protease inhibitor that must be combined with a pharmacokinetic booster, either cobicistat or ritonavir. Boosted darunavir is an option for initial antiretroviral therapy, but now it is used more often as a common component of salvage regimens for treatment-experienced individuals. Darunavir has a unique resistance pathway and retains activity following the development of drug resistance with most other protease inhibitors, with a notable exception that virologic failure on fosamprenavir can result in cross resistance with darunavir. In addition, darunavir has a high barrier to resistance, and when patients taking darunavir develop virologic failure, darunavir-associated resistance mutations usually are not present. For treatment-naïve patients, ritonavir-boosted darunavir is dosed once daily; for treatment-experienced patients, the dosing of darunavir is determined by whether or not darunavir-associated mutations are present. If they are absent, ritonavir-boosted darunavir can be dosed once daily, but if darunavir-associated mutations are present, the dosing should be twice daily. The fixed-dose combination of darunavir-cobicistat should only be used when once daily darunavir dosing is appropriate. The primary disadvantages of darunavir include moderate gastrointestinal side effects, potential for drug interactions, and possible adverse reactions in individuals with history of severe sulfa allergy (darunavir contains a sulfonamide moiety).

Key Clinical Trials

Darunavir has been extensively studied in treatment-naïve and treatment-experienced individuals. In antiretroviral-naïve adults, a comparison of once-daily ritonavir-boosted darunavir with lopinavir-ritonavir (given once or twice-daily), each with tenofovir DF-emtricitabine, showed similar virologic efficacy between the two arms, except for the subset of participants with pre-treatment HIV RNA levels above 100,000 copies/mL, who achieved higher rates of virologic suppression with ritonavir-boosted darunavir [ARTEMIS]. In treatment-naïve individuals, a randomized comparison of once-daily ritonavir-boosted darunavir and once- daily dolutegravir, each with two NRTIs, showed that the darunavir arm was inferior, largely due to more side effects and treatment discontinuations [FLAMINGO]. In a trial of treatment-naïve individuals randomized to

Page 1/5 ritonavir-boosted darunavir, ritonavir-boosted atazanavir, or raltegravir, each with tenofovir DF-emtricitabine, raltegravir achieved the best virologic outcomes, followed by boosted darunavir, and then boosted atazanavir [ARDENT]. Outcome differences in that trial were largely driven by tolerability. The combination tablet darunavir-cobicistat-tenofovir alafenamide-emtricitabine was shown to be an effective option for treatment- naïve individuals AMBER, including for rapid initiation [DIAMOND], and as a switch strategy for certain treatment-experienced persons EMERALD.

In treatment-experienced individuals with multiclass drug resistance, twice-daily ritonavir-boosted darunavir was compared to other boosted protease inhibitors (each given with an optimized background regimen of NRTIs with or without enfuvirtide); boosted darunavir achieved statistically higher rates of virologic response [POWER 1 and 2]. A noncomparative trial that included individuals with virologic failure and multiclass drug resistance found high rates of virologic success with a salvage regimen that included ritonavir-boosted darunavir (given twice daily) plus raltegravir plus etravirine [TRIO]. In treatment-experienced persons with no darunavir-associated mutations but detectable HIV RNA while taking stable antiretroviral therapy, a randomized switch to either once-daily or twice-daily ritonavir-boosted darunavir plus NRTIs resulted in no statistically significant difference in rates of HIV RNA suppression at week 48 [ODIN].

Several studies demonstrated the effiacacy of monotherapy with ritonavir-boosted darunavir as a simplification strategy in patients with previously suppressed HIV RNA levels on a standard three-drug regimen [MONOI and MONET].

Resistance

For a listing of the most common clinically significant mutations associated with darunavir (DRV) resistance, see the PI Resistance Notes on the Stanford University HIV Drug Resistance Database.

Key Drug Interactions

For complete information on darunavir-related drug interactions, see the Drug Interactions section in the Darunavir (Prezista) Prescribing Information.

Citations

1. 1.Sekar V, Tomaka F, Lefebvre E, De Pauw M, Vangeneugden T, van den Brink W, Hoetelmans R. Pharmacokinetic interactions between darunavir/ritonavir and opioid maintenance therapy using methadone or buprenorphine/naloxone. J Clin Pharmacol. 2011;51:271-8. [PubMed Abstract] -

Page 2/5 2. 2.Sekar VJ, Lefebvre E, Guzman SS, Felicione E, De Pauw M, Vangeneugden T, Hoetelmans RM. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Antivir Ther. 2008;13:563-9. [PubMed Abstract] -

3. 4.Madruga JV, Berger D, McMurchie M, 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. 2007;370:49-58. [PubMed Abstract] -

4. 5.Rockwood N, Mandalia S, Bower M, Gazzard B, Nelson M. Ritonavir-boosted atazanavir exposure is associated with an increased rate of renal stones compared with efavirenz, ritonavir-boosted lopinavir and ritonavir-boosted darunavir. AIDS. 2011;25:1671-3. [PubMed Abstract] -

5. 7.Chéret A, Nembot G, Mélard A, et al. Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open- label, phase 3 trial. Lancet Infect Dis. 2015;15:387-96. [PubMed Abstract] -

6. 12.Valantin MA, Lambert-Niclot S, Flandre P, et al. Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study. J Antimicrob Chemother. 2012;67:691-5. [PubMed Abstract] -

7. 13.Lambert-Niclot S, Flandre P, Valantin MA, et al. Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy. J Antimicrob Chemother. 2012;67:1470-4. [PubMed Abstract] -

8. 14.Arribas JR, Clumeck N, Nelson M, Hill A, van Delft Y, Moecklinghoff C. The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load [PubMed Abstract] -

9. 15.Arribas J, Pulido F, Hill A, Delft Yv, Moecklinghoff C. Predictors of long-term HIV RNA suppression on darunavir/ritonavir monotherapy in the MONET trial. Int J STD AIDS. 2013;24:679-81. [PubMed Abstract] -

10. 16.Pulido F, Arribas JR, Hill A, Van Delft Y, Moecklinghoff C. Analysis of drug resistance during HIV RNA viraemia in the MONET trial of darunavir/ritonavir monotherapy. Antivir Ther. 2011;16:59-65. [PubMed Abstract] -

11. 17.Pinnetti C, Lorenzini P, Cozzi-Lepri A, et al. Randomized trial of DRV/r or LPV/r QD monotherapy vs maintaining a PI/r-based antiretroviral regimen in persons with suppressed HIV replication. J Int AIDS Soc. 2014;17:19809. [PubMed Abstract] -

12. 19.Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22:1389-97. [PubMed Abstract] -

13. 23.Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naïve HIV-1-positive individuals: 96 week results from FLAMINGO. J Int AIDS Soc. 2014;17:19490. [PubMed Abstract] -

Page 3/5 14. 32.Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2013;14:49-59. [PubMed Abstract] -

15. 53.Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383:2222-31. [PubMed Abstract] -

16. 58.Brown TT, Moser C, Currier JS, et al. Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir. J Infect Dis. 2015;212:1241-9. [PubMed Abstract] -

17. 65.Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. 2014;384:1942-51. [PubMed Abstract] -

18. 71.Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-71. [PubMed Abstract] -

19. 72.Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. 2010;24:2365-74. [PubMed Abstract] -

20. 87.Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone. J Acquir Immune Defic Syndr. 2013;63:355-61. [PubMed Abstract] -

21. 98.Girard PM, Campbell TB, Grinsztejn B, et al. Pooled week 96 results of the phase III DUET-1 and DUET-2 trials of etravirine: further analysis of adverse events and laboratory abnormalities of special interest. HIV Med. 2012;13:427-35. [PubMed Abstract] -

22. 121.Gruber VA, Rainey PM, Moody DE, et al. Interactions between buprenorphine and the protease inhibitors darunavir-ritonavir and fosamprenavir-ritonavir. Clin Infect Dis. 2012;54:414-23. [PubMed Abstract] -

23. 136.Pulido F, Ribera E, Lagarde M, et al. Dual Therapy With Darunavir and Ritonavir Plus Lamivudine vs Triple Therapy With Darunavir and Ritonavir Plus Tenofovir Disoproxil Fumarate and Emtricitabine or Abacavir and Lamivudine for Maintenance of Human Immunodeficiency Virus Type 1 Viral Suppression: Randomized, Open-Label, Noninferiority DUAL-GESIDA 8014-RIS-EST45 Trial. Clin Infect Dis. 2017;65:2112-8. [PubMed Abstract] -

24. 137.Stek A, Best BM, Wang J, et al. Pharmacokinetics of Once Versus Twice Daily Darunavir in Pregnant HIV-Infected Women. J Acquir Immune Defic Syndr. 2015;70:33-41.

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Figures

Figure 1. darunavir-prezista_800mg-tablet

The most up to date version of this content may be obtained from: https://www.hiv.uw.edu/page/treatment/drugs/darunavir

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