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Darunavir (Prezista)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Uses
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of darunavir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for darunavir treatment
References
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Drug Labeling (Package Insert)
Darunavir (Prezista)
Class

Protease inhibitor

Background
U.S. Manufacturer

Tibotec

Approval

Darunavir received accelerated approval from the U.S. Food and Drug Administration (FDA) in 2006 for use in combination with ritonavir by adults with HIV strains that are resistant to other protease inhibitors. In 2008, darunavir received traditional FDA approval for use in treatment-experienced adults as well as approval for use in initial therapy in adults.

Initial FDA approval was based on 2 randomized, controlled Phase IIb studies in patients with extensive prior treatment with protease inhibitors, nucleoside analogues, and nonnucleoside reverse transcriptase inhibitors. All patients had HIV-1 with evidence of resistance to protease inhibitors. Patients received darunavir (boosted by ritonavir) or a comparator ritonavir-boosted protease inhibitor selected for each individual with the assistance of resistance testing. Each patient also was given an optimized background regimen that included nucleoside analogues with or without enfuvirtide. At 24 weeks, the darunavir group had higher rates of virologic response (defined as ≥1 log10 decrease in HIV RNA) and viral suppression to <400 copies/mL and to <50 copies/mL than did the comparator group; these differences were statistically significant.(1,2,3)

Formulation and Dosing

Darunavir is available in tablets for adult and pediatric dosing. It is approved for once-daily dosing in treatment-naive adults and those with no mutations associated with resistance to darunavir. It is approved for twice-daily dosing in patients with evidence of resistance to darunavir. In children, it must be given twice daily. It must be taken in combination with ritonavir to achieve effective plasma concentrations.

Dosing of Darunavir + Ritonavir
AdultTreatment naive or patients with no mutations associated with resistance to darunavir*Darunavir 800 mg QD + ritonavir 100 mg QD
Treatment experienced with ≥1 mutation associated with resistance to darunavir*Darunavir 600 mg BID + ritonavir 100 mg BID
PediatricAge <6 years or weight <20 kg Not FDA approved
Age 6 to <18 years
Wt ≥20 kg to <30 kgDarunavir 375 mg BID + ritonavir 50 mg BID
Wt ≥30 kg to <40 kgDarunavir 450 mg BID + ritonavir 60 mg BID
Wt ≥40 kgDarunavir 600 mg BID + ritonavir 100 mg BID (adult dosage)

Key to abbreviations: BID, twice daily; QD, once daily.

*(V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V)

Darunavir must be taken with food.
Darunavir interacts with other medications, including some antiretrovirals; dosage adjustments may be required and certain combinations are contraindicated. For more information about drug interactions, see "Combinations" below and refer to the Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for darunavir with other antiretrovirals.
No dosage adjustment is necessary for patients with renal insufficiency.
Consult product labeling for detailed dosing information.
FDA Pregnancy Category C.
Clinical Uses
Combinations

Darunavir must be coadministered with ritonavir. As with all antiretrovirals, darunavir + ritonavir should be used only in combination regimens.

Darunavir has clinically significant interactions with many medications, including other antiretrovirals. Darunavir both inhibits and is metabolized by the cytochrome P450 enzyme system (CYP3A). Thus, darunavir may increase the concentrations of drugs metabolized by these pathways, and may in turn be affected by other drugs that affect CYP3A. Darunavir may increase the serum concentrations of certain antimicrobials, lipid-lowering agents, calcium channel blockers, antiarrhythmics, erectile dysfunction agents, ergots, and other agents. Darunavir also may reduce the concentrations of certain medications, including paroxetine and sertraline. Similarly, certain drugs or herbal preparations may cause therapeutically significant alterations in darunavir concentrations. For example, rifampin induces darunavir metabolism and decreases darunavir concentrations; rifampin should not be given concomitantly with darunavir. Note that the coadministered ritonavir is a potent inhibitor of CYP3A and CYP2D6, and is an inducer of other hepatic enzyme systems; thus it also interacts with other medications.(4) Information about drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

Darunavir also appears to have significant and complex interactions with certain other antiretroviral medications. For example, coadministration with efavirenz or lopinavir/ritonavir decreases the concentration of darunavir while increasing that of the coadministered antiretroviral. Combination with indinavir increases the concentration of both drugs, and coadministration with saquinavir decreases the concentration of darunavir without affecting that of saquinavir. To date, the clinical significance of these interactions is not clear, and information on dosage adjustment of antiretrovirals in darunavir-containing combinations is not available. It is recommended that darunavir + ritonavir not be used in combination with protease inhibitors other than atazanavir and that it be used cautiously with efavirenz.(4) For additional information, see Dosage Adjustments for ARV-ARV Drug Interactions.

Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate the combination of ritonavir-boosted darunavir, dosed once daily, plus tenofovir/emtricitabine as a "preferred" regimen for initial treatment of HIV infection. They identify ritonavir-boosted darunavir plus abacavir/lamivudine as an "alternative" regimen for initial therapy.

Darunavir has been studied in both initial and salvage therapy. It has not been adequately assessed for use in the treatment of pediatric patients; studies are under way.

In antiretroviral-naive adults, darunavir + ritonavir (given once daily) was compared with lopinavir + ritonavir (given once or twice daily); both treatment groups also were given emtricitabine + tenofovir. At 48 weeks, 84% of darunavir + ritonavir recipients and 78% of lopinavir + ritonavir recipients had HIV RNA <50 copies/mL. In the subgroup of patients with pre treatment HIV RNA >100,000 copies/mL, a greater proportion of those taking darunavir had HIV RNA <50 copies/mL (79% vs 67%, p<0.05).(5)

In patients with advanced HIV disease, extensive prior exposure to at least 3 classes of antiretrovirals, and evidence of resistance to protease inhibitors, 2 Phase IIb studies (described above in "Approval") compared darunavir + ritonavir (given twice daily) with other ritonavir-boosted protease inhibitors, each in combination with a background regimen. In pooled analysis, the group that received darunavir/ritonavir 600/100 mg twice daily had higher rates of virologic response (61% vs 15%) and viral suppression to <50 copies/mL (45% vs 10%) at 48 weeks than the group that received comparator protease inhibitors.(6) These differences were statistically significant (p<0.0001). The inclusion of enfuvirtide in the antiretroviral regimen of those without previous exposure to this drug significantly improved the rates of virologic response in the darunavir groups (HIV RNA <50 copies/mL in 58% vs 44% of patients treated with and without enfuvirtide, respectively).(6) The mean increase in CD4 cell count was higher in the darunavir + ritonavir treatment groups than in the control group (102 cells/µL vs 19 cells/µL; p<0.0001). It is not known whether the superior virologic and CD4 cell count responses seen in the darunavir recipients in these studies will result in improved clinical outcomes.

Another randomized controlled study in patients with extensive treatment experience (and resistance to protease inhibitors and nonnucleoside reverse transcriptase inhibitors) compared the combination of darunavir + ritonavir (given twice daily) and etravirine to darunavir + ritonavir without etravirine; all patients received other background antiretrovirals. At 48 weeks, recipients of darunavir + ritonavir and etravirine had higher rates of viral suppression to <50 copies/mL (61% vs 40%, p <0.0001).(7) These results indicate the importance of including at least 2 active agents, if possible, in the regimens of patients with resistance to antiretrovirals.(8) In subjects with limited treatment experience, a randomized comparison of darunavir + ritonavir (given twice daily) and lopinavir + ritonavir in patients with limited treatment experience showed HIV RNA suppression to <50 copies/mL in 71% of darunavir recipients versus 60% of lopinavir recipients at 48 weeks (p=0.005); CD4 cell increases were similar in both groups.(8)

In treatment-experienced patients with HIV RNA >1,000 copies/mL while on stable ART, a randomized switch to either once-daily or twice-daily darunavir + ritonavir (each given with nucleoside/nucleotide analogs) resulted in no statistically significant difference in rates of HIV RNA suppression at week 48 (72% vs 71%, respectively). Importantly, the study excluded subjects who had any darunavir-associated resistance mutations at baseline.(9)

Factors Affecting Adherence

Symptomatic adverse effects of darunavir include diarrhea, nausea, headache, and rash. Laboratory abnormalities include hyperlipidemia and increases in amylase and hepatic transaminase levels.(1,2,4,6,8) Liver toxicity, including severe hepatitis, has been reported in some patients taking darunavir; the risk of hepatoxicity may be higher for persons with chronic hepatitis B or C or other chronic liver disease. Hepatic transaminase levels should be monitored, particularly in patients with liver disease.

Darunavir contains a sulfonamide moiety and should be used cautiously in patients with sulfonamide allergy.

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with darunavir is initiated.

Darunavir has not been studied thoroughly in patients taking the drug during pregnancy; it is classified as an FDA Pregnancy Category C drug.

Resistance

Resistance to darunavir is associated with the selection of 1 or more of several resistance mutations.

Implications of darunavir resistance for treatment with other antiretrovirals

In vitro studies of darunavir + ritonavir show the emergence of a number of protease mutations; however, the resistance profile of darunavir in human subjects has not been characterized fully. Results from studies of darunavir in antiretroviral-naive patients (now under way) are needed to identify darunavir resistance in initial therapy and to assess its implications for subsequent treatment. In patients with multiple preexisting mutations associated with resistance to protease inhibitors, emergent protease mutations included V11F, I15V, V32I, L33F, I47V, I50V, I54L/M, and L89V.(4,10) In in vitro studies, viral isolates resistant to darunavir also were resistant to all other available protease inhibitors with the exception of tipranavir; some viruses remained susceptible to tipranavir.(4,10) Clinical correlations for these observations are not available.

Implications of resistance to other antiretrovirals for darunavir treatment

Although no single mutation has been found to confer high-level resistance to darunavir, resistance mutations selected by other protease inhibitors can contribute to darunavir resistance. A number of protease mutations, including V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, and L89V, are associated with decreased virologic response to darunavir, particularly in ≥2 of these are present. In addition, the total number of primary protease mutations (as defined by the International AIDS Society-USA [IAS-USA]) is associated with diminished response to darunavir. If 7 or more protease resistance mutations are present at baseline, the probability of darunavir + ritonavir treatment failure increases significantly.(4,10,11)

Phenotypic analysis has demonstrated that virologic response to darunavir + ritonavir is most likely if the baseline darunavir fold change in the half maximal inhibitory concentration (IC50) value (compared with reference darunavir susceptibility) is less than 10.(4,6,10,11,12) In several analyses, the phenotypic fold change to darunavir has been the best predictor of virologic response to darunavir-containing regimens. The phenotypic clinical cutoff has not been defined.

Regimens containing darunavir + ritonavir and another active agent (eg, an entry inhibitor, an integrase inhibitor, or a second-generation NNRTI) may be effective as subsequent regimens in individuals without prior exposure to these agents and, in patients with extensive ARV resistance, they appear to be more effective than regimens containing darunavir + ritonavir without an additional active agent. Genotypic or phenotypic testing may be useful in predicting the likelihood of response to darunavir following failure of regimens containing other antiretrovirals.

References
1.   Katlama C, Esposito R, Gatell JM, Goffard JC, Grinsztejn B, Pozniak A, Rockstroh J, Stoehr A, Vetter N, Yeni P, Parys W, Vangeneugden T; the POWER 1 study group. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS. 2007 Feb 19;21(4):395-402.
2.   Haubrich R, Berger D, Chiliade P, Colson A, Conant M, Gallant J, Wilkin T, Nadler J, Pierone G, Saag M, van Baelen B, Lefebvre E; POWER 2 Study Group. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS. 2007 Mar 30;21(6):F11-8.
3.  Katlama C, Berger D, Bellos N, et al. Efficacy of TMC114/r in 3-class experienced patients with limited treatment options: 24-week planned interim analysis of 2 96-week multinational dose-finding trials. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston. Abstract 164LB.
4.  Darunavir [package insert]. East Bridgewater, NJ: Tibotec Therapeutics: 2010; update forthcoming.
5.  DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir vs lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at Week 48: ARTEMIS. Program and abstracts of the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2007; Chicago, Illinois. Abstract H-718b.
6.   Clotet B, Bellos N, Molina JM, Cooper D, Goffard JC, Lazzarin A, Wohrmann A, Katlama C, Wilkin T, Haubrich R, Cohen C, Farthing C, Jayaweera D, Markowitz M, Ruane P, Spinosa-Guzman S, Lefebvre E; POWER 1 and 2 study groups. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007 Apr 7;369(9568):1169-78.
7.  Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, Schechter M, Peeters M, Picchio G, Vingerhoets J, Woodfall B, De Smedt G; DUET-1, DUET-2 study groups.
8.   Madruga JV, Berger D, McMurchie M, Suter F, Banhegyi D, Ruxrungtham K, Norris D, Lefebvre E, de Bethune MP, Tomaka F, De Pauw M, Vangeneugden T, Spinosa-Guzman S; TITAN study group. 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.
9.  Cahn P, Fourie J, Grinsztejn B, et al. Efficacy and safety at 48 weeks of once-daily vs twice-daily DRV/r in treatment-experienced HIV-1+ patients with no DRV resistance associated mutations: the ODIN Trial. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, California. Abstract 57.
10.  De Meyer S, A Hill, De Baere I, et al. Effect of Baseline Susceptibility and On-treatment Mutations on TMC114 and Control PI Efficacy: Preliminary Analysis of Data from PI-experienced Patients from POWER 1 and POWER 2. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-9, 2006; Denver. Abstract 157.
11.  De Meyer S, Vangeneugden T, Lefebvre E, van Marck H, Azijn H, De Baere I, van Baelen B, de Béthune MP. Response to TMC114 is Based on Genotypic/Phenotypic Resistance: POWER 1/2/3 pooled analysis. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 12-16 November 2006. Poster 196.
12.  Pozniak A, Saag M, Bellos N, et al. Efficacy of TMC114/r in treatment-experienced HIV patients: factors influencing outcome in the pooled 24-week analysis of POWER 1, 2 and 3. In: Program and abstracts of the 12th Annual Conference of the British HIV Association; March 29-April 1, 2006; Brighton, United Kingdom. Abstract P3.