Interpretation of Genotypic HIV-1 Resistance to Darunavir and Virological Response: Validation of Available Systems and of a New Score

Abstract

Background

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

Zaccarelli

, Tozzi

, Lorenzini

Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS 2005; 19: 1081–1089.

Di Giambenedetto

, Colafigli

, Pinnetti

Genotypic resistance profile and clinical progression of treatment-experienced HIV type 1-infected patients with virological failure. AIDS Res Hum Retroviruses 2008; 24: 149–154.

Maggiolo

, Ripamonti

, Airoldi

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 Trials 2007; 8: 9–18.

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.

Clumeck

, Pozniak

, Raff

, European Aids Clinical Society (EACS) Executive Committee. Guidelines for the clinical management and treatment of HIV-infected adults in Europe. Version 5.3. (Accessed 01 April 2011.) Available from http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf.

BHIVA Treatment Guidelines Writing Group. British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med 2008; 9: 563–608.

HIV/AIDS Italian Expert Panel. Linee guida Italiane sull'utilizio degli antiretrovirali nelle persone con infezione da HIV. (Updated 15 July 2010. Accessed 12 April 2011.) Available from http://www.salute.gov.it/imgs/C_17_pubblicazioni_1301_allegato.pdf.

Kovalevsky

A.Y.

, Liu

, Leshchenko

Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114. J Mol Biol 2006; 363: 161–173.

Kovalevsky

A.Y.

, Tie

, Liu

Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem 2006; 49: 1379–1387.

10.

De Meyer

, Azijn

, Surleraux

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 2005; 49: 2314–2321.

11.

Sayer

J.M.

, Liu

, Ishima

, Weber

I.T.

, Louis

J.M.

Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease. J Biol Chem 2008; 283: 13459–13470.

12.

Koh

, Matsumi

, Das

Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem 2007; 282: 28709–28720.

13.

Clotet

, Bellos

, Molina

J.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. Lancet 2007; 369: 1169–1178.

14.

Madruga

J.V.

, Berger

, McMurchie

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. Lancet 2007; 370: 49–58.

15.

Ortiz

, Dejesus

, Khanlou

Efficacy and safety of once-daily DRV/RTV versus lopinavir/RTV in treatment-naive HIV-1-infected patients at week 48. AIDS 2008; 22: 1389–1397.

16.

Mills

A.M.

, Nelson

, Jayaweera

Once-daily DRV/RTV vs lopinavir/RTV in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS 2009; 23: 1679–1688.

17.

Johnson

V.A.

, Brun-Vézinet

, Clotet

Update of the drug resistance mutations in HIV-1: December 2008. Top HIV Med 2008; 16: 138–145.

18.

De Meyer

, Vangeneugden

, van Baelen

Resistance profile of DRV: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses 2008; 24: 379–388.

19.

Pellegrin

, Wittkop

, Joubert

L.M.

Virological response to DRV/RTV-based regimens in antiretroviral-experienced patients (PREDIZISTA study). Antivir Ther 2008; 13: 271–279.

20.

Descamps

, Lambert-Niclot

, Marcelin

A.G.

Mutations associated with virological response to DRV/RTV in HIV-1-infected protease inhibitor-experienced patients. J Antimicrob Chemother 2009; 63: 585–592.

21.

Delaugerre

, Pavie

, Palmer

Pattern and impact of emerging resistance mutations in treatment experienced patients failing DRV-containing regimen. AIDS 2008; 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.

Picchio

, De Meyer

, de Béthune

M.P.

Response to ‘key amprenavir resistance mutations counteract dramatic efficacy of DRV in highly experienced patients'. AIDS 2008; 22: 165–167.

25.

Guidelines from the Agence Nationale pour la Rechèrche sur le Sida. (Accessed 30 May 2010.) Available from www.hivfrenchresistance.org/2008/Algo-2008.pdf.

26.

De Luca

, Cingolani

, Di Giambenedetto

Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance. J Infect Dis 2003; 187: 1934–1943.

27.

De Luca

, Di Giambenedetto

, Marando

Improved interpretation and clinical validation of substitutions in HIV-1 protease predicting the virological response to DRV/RTV. Antivir Ther 2008; 13 Suppl. 3: A104.

28.

Zaccarelli

, Lorenzini

, Ceccherini-Silberstein

Historical resistance profile help to predict salvage failure. Antivir Ther 2009; 14: 285–291.