There is not yet consensus on interpretation of genotypic HIV-1 resistance to darunavir (DRV). We validated existing rules and a newly derived score.
Methods
Protease inhibitor (PI)-failing patients starting a DRV/ritonavir-based regimen, with available baseline resistance genotypes, were extracted from three Italian databases. Virological response (VR) was analysed between 4 and 32 follow-up weeks, defined as a drop from baseline HIV RNA of ≥2 log10 or a value <50 copies/ml if the last measurement had been obtained at ≤12 weeks and as HIV RNA<50 copies/ml if it had been obtained at >12 weeks of follow-up. DRV/ritonavir resistance was interpreted by seven algorithms. A new weighted score (DRV-2009) was derived and validated, analysing associations of protease mutations with VR.
Results
A total of 217 patients were analysed, with a mean (±sd) follow-up time of 17 (±9) weeks. At baseline, median HIV RNA was 4.26 log10 copies/ml (IQR 3.11-5.03); VR was achieved in 135/217 (62%) patients. Adjusting for use of a new drug class, number of previous PIs experienced, CD4+ T-cell count and HIV RNA, only the Rega DRV/ritonavir interpretation was significantly associated with VR (per increase in susceptibility category, OR 1.94, 95% CI 1.32–2.86; P<0.001). The DRV-2009 score V11I+L33F+R41K+I47V+2*I-50V+2*I54M+K55R+D60E+L74P+L76V+N88D+2*L89V– L10I/V–I13V–G16E–G48V–F53I/L–I62V–I66F–V77I (<0 indicating susceptibility, 0–1 intermediate resistance and ≥2 resistance) correlated with VR in the derivation set (n=132, R=0.395; P<0.001). In the validation set (n=85), after adjusting for mutual interpretation and new use of enfuvirtide, DRV-2009 (P=0.017) and Rega (P=0.013) were both independently associated with VR.
Conclusions
In contrast to the other algorithms, both the DRV-2009 score and Rega interpretation showed a robust predictive capacity of VR to DRV/ritonavir-con-taining regimens.
References
1.
ZaccarelliM., TozziV., LorenziniP.Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS2005; 19: 1081–1089.
2.
Di GiambenedettoS., ColafigliM., PinnettiC.Genotypic resistance profile and clinical progression of treatment-experienced HIV type 1-infected patients with virological failure. AIDS Res Hum Retroviruses2008; 24: 149–154.
3.
MaggioloF., RipamontiD., AiroldiM.Resistance costs and future drug options of antiretroviral therapies: analysis of the role of NRTIs, NNRTIs, and PIs in a large clinical cohort. HIV Clin Trials2007; 8: 9–18.
4.
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. (Updated 10 January 2011. Accessed 01 April 2011.) Available from http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
BHIVA Treatment Guidelines Writing Group.British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med2008; 9: 563–608.
KovalevskyA.Y., LiuF., LeshchenkoS.Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114. J Mol Biol2006; 363: 161–173.
9.
KovalevskyA.Y., TieY., LiuF.Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem2006; 49: 1379–1387.
10.
De MeyerS., AzijnH., SurlerauxD.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 Chemother2005; 49: 2314–2321.
11.
SayerJ.M., LiuF., IshimaR., WeberI.T., LouisJ.M.Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease. J Biol Chem2008; 283: 13459–13470.
12.
KohY., MatsumiS., DasD.Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem2007; 282: 28709–28720.
13.
ClotetB., BellosN., MolinaJ.M.Efficacy and safety of DRV-RTV 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. Lancet2007; 369: 1169–1178.
14.
MadrugaJ.V., BergerD., McMurchieM.Efficacy and safety of DRV-RTV compared with that of lopinavir–RTV at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet2007; 370: 49–58.
15.
OrtizR., DejesusE., KhanlouH.Efficacy and safety of once-daily DRV/RTV versus lopinavir/RTV in treatment-naive HIV-1-infected patients at week 48. AIDS2008; 22: 1389–1397.
16.
MillsA.M., NelsonM., JayaweeraD.Once-daily DRV/RTV vs lopinavir/RTV in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS2009; 23: 1679–1688.
17.
JohnsonV.A., Brun-VézinetF., ClotetB.Update of the drug resistance mutations in HIV-1: December 2008. Top HIV Med2008; 16: 138–145.
18.
De MeyerS., VangeneugdenT., van BaelenB.Resistance profile of DRV: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses2008; 24: 379–388.
19.
PellegrinI., WittkopL., JoubertL.M.Virological response to DRV/RTV-based regimens in antiretroviral-experienced patients (PREDIZISTA study). Antivir Ther2008; 13: 271–279.
20.
DescampsD., Lambert-NiclotS., MarcelinA.G.Mutations associated with virological response to DRV/RTV in HIV-1-infected protease inhibitor-experienced patients. J Antimicrob Chemother2009; 63: 585–592.
21.
DelaugerreC., PavieJ., PalmerP.Pattern and impact of emerging resistance mutations in treatment experienced patients failing DRV-containing regimen. AIDS2008; 22: 1809–1813.
22.
Stanford University HIV Drug Resistance Database. (Accessed 30 May 2010.) Available from http://hivdb.stanford.edu.
23.
Laboratory for Clinical and Evolutionary Virology, Rega Institute for Medical Research, Katholieke Universiteit Leuven. Rega algorithms. (Accessed 30 May 2010.) Available from http://www.rega.kuleuven.be/cev/index.php?id=30.
24.
PicchioG., De MeyerS., de BéthuneM.P.Response to ‘key amprenavir resistance mutations counteract dramatic efficacy of DRV in highly experienced patients'. AIDS2008; 22: 165–167.
De LucaA., CingolaniA., Di GiambenedettoS.Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance. J Infect Dis2003; 187: 1934–1943.
27.
De LucaA., Di GiambenedettoS., MarandoF.Improved interpretation and clinical validation of substitutions in HIV-1 protease predicting the virological response to DRV/RTV. Antivir Ther2008; 13 Suppl. 3: A104.
28.
ZaccarelliM., LorenziniP., Ceccherini-SilbersteinF.Historical resistance profile help to predict salvage failure. Antivir Ther2009; 14: 285–291.
