A. De Luca

A. Di Biagio

B. Bruzzone

F. Adorni

G. Colao

G. Penco

G. Punzi

L. Monno

M. Di Pietro

M. Zazzi on behalf of the ARCA Collaborative Group

P. Meraviglia

P. Vitiello

R. Maserati

S. Rusconi

V. Micheli

English

AIR Universita degli studi di Milano

Determinants of virological response to raltegravir (RAL)-containing regimens and prevalence of RAL-resistance associated mutations at failure in ARCAS. Rusconi (1), P. Vitiello (1), F. Adorni (2), B. Bruzzone (3), A. De Luca (4), V. Micheli (5),  P. Meraviglia (6),  R. Maserati (7),  M. Di Pietro (8),  G. Colao (9),  G. Penco (10), A. Di Biagio (11),  G. Punzi (12),  L. Monno (13) and M. Zazzi (14) on behalf of the ARCA Collaborative Group  (1) Sezione di Malattie Infettive e Immunopatologia, Dipartimento di Scienze Cliniche “Luigi Sacco”, Universita’ degli Studi di Milano, Italy; (2) ITB-CNR, Segrate (MI), Italy; (3) Laboratorio di Igiene Ospedale S. Martino, Genova, Italy; (4) Istituto di Clinica Malattie Infettive, Universita’ Cattolica del Sacro Cuore, Roma, Italy; (5) Laboratorio Microbiologia, Ospedale L. Sacco, Milano, Italy; (6) Seconda Divisione Malattie Infettive, Ospedale L. Sacco, Milano, Italy; (7) Ambulatorio Clinica Malattie Infettive, Fondazione Policlinico S. Matteo, Pavia, Italy; (8) Malattie Infettive, Ospedale SM Annunziata, Antella (FI), Italy; (9) Laboratorio Virologia, Ospedale Careggi, Firenze, Italy; (10) Malattie Infettive, Ospedali Galliera, Genova, Italy; (11) Clinica Malattie Infettive, Ospedale S. Martino, Universita’ degli Studi di Genova, Italy; (12) Laboratorio Virologia, Policlinico, Bari, Italy; (13) Clinica Malattie Infettive, Universita’ degli Studi di Bari, Italy; (14)  University of Siena, Italy.Background: Raltegravir (RAL) is the only so far licensed HIV integrase inhibitor. The determinants of virological response to RAL-containing regimens and the prevalence of integrase mutations associated to RAL failure in different HIV cohorts warrant investigation.Material & Methods: From the Italian database ARCA (www.hivarca.net), we selected  390 RAL-containing regimens from 318 subjects up to December, 2009. These 3-class experienced subjects were failing their current treatment and had complete treatment history available. Selection criteria included availability of HIV-RNA >50 cp/mL, CD4 count and HIV genotype, within 3 months prior to RAL initiation. The GSS and weighted-GSS of the RAL-containing regimen were obtained according to the ARCA built-in algorithm AntiRetroScan. Predictors of 24-week response were analyzed by binomial logistic regression analysis. Different genotypic sensitivity scores (GSS) and weighted-GSS cut-offs were evaluated for sensitivity, specificity, PPV, NPV and AUC in a ROC curve analysis.Results: Seventy-six subjects met the inclusion criteria. The median (min-max) antiretroviral (ARV) exposure at the time of RAL initiation was 11.7 (1.1-19.7) years. Virological response at week 24 was achieved in 71.8%. Statistical analysis revealed an increased virological response rate for CD4 and nadir CD4 with borderline significance (p=.057 and .082, respectively), whereas baseline HIV-RNA did not predict virological response. Each extra unit of GSS (p=.021, OR 6.92 [1.33-35.95]) and weighted-GSS (p=.016, OR 4.87 [1.34-17.69]) was associated with a higher probability of response. When stratifying for different cut-offs (<1 as reference, 1-1.49, >1.5), a significant increase in the virological response appeared for GSS 1-1.49 (OR 6.29 [1.02-38.65]), GSS >1.5 (OR 11.43 [1.15-113.11]) and weighted-GSS >1.5 (OR 5.67 [1.07-30.08]). GSS cut-off ≥1 showed sensitivity=75%, specificity=72.7%, PPV=87.5%, NPV=53.3% and the widest AUC (p=.022) versus other cut-offs, whereas weighted-GSS cut-off ≥1.5 had lower sensitivity and specificity, PPV=85.0%, NPV=42.1% and the widest although not statistically significant AUC (p=.108). The median number of mutation in the protease (PRO) at virological failure was inferior than at baseline: 10.5 (3-21) versus 12 (3-18), whereas there was not such a difference in reverse transcriptase (RT). Notably, week-24 non-responders had a higher number of mutations compared to responders, both in PRO (13 [4-21] versus 7.5 [3-13]) and RT (7.5 [0-16] versus 5.5 [0-13]). Integrase (IN) genotype was available in 12 RAL-failing subjects. Six of these did not show any mutation or just natural polymorphisms. Conversely, resistance mutations associated to RAL failure were detected in the other six subjects (three with N155H, three with G140S plus Q148H). Conclusions: In this cohort analysis, unresponsiveness to RAL-containing regimens among subjects with a 3-class experience was relatively low. The activity of the background regimen was a major predictor of response as shown by GSS and weighted-GSS. Although few IN genotypes were available at failure, notably half of these cases were without IN resistance mutations suggesting adherence issues. 

Determinants of virological response to raltegravir (RAL)-containing regimens and prevalence of RAL-resistance associated mutations at failure in ARCA

https://air.unimi.it/bitstream/2434/146059/2/RALSorrento2010_Abs_final.doc

Determinants of virological response to raltegravir (RAL)-containing regimens and prevalence of RAL-resistance associated mutations at failure in ARCA

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