[20] Impact of baseline protease mutations on virological response to darunavir–ritonavircontaining therapy in protease inhibitor-experienced patients (PREDIZISTA Study)

16th International HIV Drug Resistance Workshop

12-16 June 2007, Barbados

IMPACT OF BASELINE PROTEASE MUTATIONS ON VIROLOGICAL RESPONSE TO DARUNAVIR–RITONAVIRCONTAINING THERAPY IN PROTEASE INHIBITOR-EXPERIENCED PATIENTS (PREDIZISTA STUDY)

Antivir Ther. 2007; 12:S22 (abstract no. 20)

I Pellegrin¹, L Wittkop², D Breilh³, P Merel¹, B Winters⁴, M Bonarek⁵, D Neau⁵, D Bollens⁶, JL Pellegrin⁵, PM Girard⁶, HJA Fleury¹, MC Saux³, R Thiébaut² and L Morand-Joubert⁶
¹Departments of Virology, Bordeaux University Hospital, Bordeaux, France; ²INSERM U875 and U593, Bordeaux University Hospital, Bordeaux, France; ³Internal Medicine and Infectious Diseases, Bordeaux University; Hospital, Bordeaux, France; ⁴Virco BVBA, Mechelen, Belgium; ⁵Pharmacy, Bordeaux University Hospital, Bordeaux, France; ⁶Saint-Antoine Hospital, Paris, France

BACKGROUND: To assess the impact of HIV-1 mutations on virological responses to darunavir/ritonavir (DRV/r)- based regimens in protease inhibitor (PI)-experienced HIV-patients.

METHODS: Heavy antiretroviral-experienced subjects with virological failure (VF) were included in an observational cohort study and received a DRV/r (600mg/100mg twice daily)-based regimen. VF at M3 was defined by HIV–RNA >400 copies/ml. Sequencing of HIV–reversetranscriptase and protease was performed at baseline. Mutations (www.iasusa.org) with a prevalence >10% and a P-value <0.25 (univariate logistic regression) were retained. Among these, different mutations sets were tested with a removing procedure (Cochran-Armitage test). Genotypic and phenotypic score (GSS, cPSS) were calculated, virtual phenotype (Virco^®TYPE,) predicted fold change (vFC) was assessed.

RESULTS: Sixty-seven patients (M/F=53/14, median [Q1–Q3] age=45 [42–53] years) initiated a DRV/r-containing regimen with co-prescribed T20 for 40 of them. Prior antiretroviral exposure was 10 (9–13) years with 15 (8–19) previous lines of treatment including 5 (3–6) previous PI. At baseline, CD4+ and HIV-1-RNA were 129 (37–274)/µl and 4.7 (4–5.3) log₁₀ copies/ml, respectively. Median number of major and minor protease IAS mutations were 4 (4–6) and 9 (7–10) respectively. At M3, 40% of patients were considered as VF. HIV-1–RNA decrease was -2.1 (-2.6 – -1.1) log₁₀ copies/ml, CD4+ increase was 67 (20–128)/µl. Presence of following baseline protease mutations were associated with VF: I13V (P=0.05), V32I (P=0.04), L33F/I/V/L (P=0.03), E35D (P=0.02), M36I/L/V (P=0.06), M46I/L (P=0.2), I47V/A/I (P=0.01), F53L (P=0.09), I62V (P=0.1), V77I/L (P=0.16), L90M (P=0.18) and I93L/M (P=0.2). I50V (prevalence <10%) could not be evaluated. The selection procedure led to the following genotypic score: I13V+V32I+ L33F/I/V/L+E35D+M36I/L/V+I47V/A/I+F53L+I62V. According to <4, 4–5 and >5 mutations cut-offs, VF occurred in 11% (2–30), 48% (30–67) and 100% (63–100) of patients with a decrease in HIV-1-RNA of -2.2 (-3.1 – -1.9), -2.1 (-2.7 – -1), -0.3 (-1–0) log₁₀ copies/ml. Failure was associated with CDC stage (P=0.02), CD4+ nadir (P=0.04), baseline CD4+ (P=0.007), baseline number of major PI-resistance mutations (P=0.02), vFC (P=0.04), and DRV/r score (P=2.10^-4).

CONCLUSIONS: Sixty percent of heavy pretreated patients were considered as success at M3 on DRV/r-based HAART. DRV/r-score (built with this stringent endpoint) should be further investigated in order to define the individual impact of each retained mutation. Furthermore, their potential compensatory effect for associated major mutations, not retained in the present study population, should be elucidated.

2007-06-12
20

Copyright © 2006 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.