Low level viremia and HIV-1 drug resistance in patients with virological rebound after suppression with a first line antiretroviral regimen

Transcription

1 Low level viremia and HIV-1 drug resistance in patients with virological rebound after suppression with a first line antiretroviral regimen Manuela Colafigli Catholic University of S. Heart Rome, Italy

2 Background and objective Low level virological rebound (LLVR) may be observed in HIV-infected patients even after virological suppression LLVR may be associated with subsequent virological failures Consequences on the development of drug resistance unclear Objective of this study was to evaluate the association of LLVR with appearance of resistance mutations at VF in patients on a first line antiretroviral regimen

3 Methods Patients with a GRT available after starting a first line regimen based on NNRTI or bpi and achieving at least one VL<50 copies/ml selected (years ) Data regarding viroimmunological tests and treatment history collected first available GRT after virologic suppression chosen as a proxy of VF

4 Statistical analysis Definitions LLVR: VL>50 copies/ml and <1000 copies/ml. (in patients with > 1 LLVR the highest VL was considered) Presence of drug resistance mutations (DRM): any major IAS mutation fall 2011 Analysis Univariate and multivariate logistic regression predictors of presence of DRM

5 Results Patients characteristics (n=222) Variable Age, median (IQR) 40 (34-47) Male gender, n (%) 155 (72) Geographic area, n (%): Northern Italy Central Italy Southern Italy Subtype, n(%): B CRF02_AG F1 C G Other 123 (55.4) 91 (41.4) 7 (3.2) 181 (81.5) 14 (6.3) 11 (5) 4 (1.8) 4 (1.8) 8 (3.6) Year of sampling, median (IQR) 2007 ( ) Baseline VL, median log 10 copies/ml (IQR) 4.87 ( ) Baseline CD4, median cells/µl (IQR) 191 (71-362)

6 Variable LLVR and Drug Resistance Mutations at virologic failure Log 10 VL at LLVR, median (IQR) 2.30 ( ) VL at LLVR, n (%) No LLVR <50 copies/ml 50 to 100 copies/ml 101 to 500 copies/ml 501 to 1000 copies/ml 102 (45.9) 29 (13.1) 76 (34.2) 15 (6.8) Presence of any major IAS-defined DRM, n (%) 85 (38.3) Presence of any NRTI DRM, n (%) 65 (29.3) Presence of any NNRTI DRM, n (%) 50 (22.5) Presence of any major PI DRM, n (%) 24 (10.8)

7 2% 12% Antiretroviral drugs 7% Backbone 35% Third Drug NNRTI PIr 35% 9% 56% 44% 3(F)TC/TDF ABC/3TC AZT/3TC D4T+DDI D4T+3TC Other 15% 7% 1% PIr type 2% 15% 60% LPV ATV DRV IDV APV/TPV SQV 42% NN type EFV NVP 58%

8 Variable Predictors of any major DRM Univariate analysis OR (95% CI) P value Multivariate analysis OR (95% CI) P value Presence vs absence of LLVR* 2.83 ( ) < ( )* <0.001* Calendar year of sequencing, per 1 year more recent VL at LLVR, n (%) No LLVR <50 copies/ml 50 to 100 copies/ml 101 to 500 copies/ml 501 to 1000 copies/ml NRTI backbone: 3(F)TC/TDF ABC/3TC AZT/3TC D4T/DDI D4T/3TC Other 0.92 ( ) ( ) ( ) 2.92 ( ) ( ) ( ) 1.57 ( ) 9.00 ( ) 2.25 ( ) 2.89 ( ) < ( ) 2.92 ( ) 16.9 ( ) 0.32 ( ) 0.92 ( ) 3.56 ( ) 2.13 ( ) 1.62 ( ) < Use of NNRTI-based vs PI-based cart 2.09 ( ) ( ) Atripla vs other 0.91 ( ) Not evaluated Age, male gender, baseline VL and CD4 cell count: not significant at univariate analysis *: substitute for VL at LLVR in an alternative multivariate model

9 Variable Predictors of NNRTI resistance Calendar year of sequencing, +1 year more recent VL at LLVR, n (%) No LLVR <50 copies/ml 50 to 100 copies/ml 101 to 500 copies/ml 501 to 1000 copies/ml NRTI backbone: 3(F)TC/TDF ABC/3TC AZT/3TC D4T/DDI D4T/3TC Other Univariate analysis OR (95% CI) P value Multivariate analysis OR (95% CI) P value ( ) ( ) ( ) 2.33 ( ) 6.14 ( ) 0.28 ( ) 1.72 ( ) 3.33 ( ) 1.50 ( ) 5.00 ( ) ( ) 1.40 ( ) 8.60 ( ) 0.31 ( ) 0.65 ( ) 2.23 ( ) 0.62 ( ) 2.74 ( ) Presence of the RT mutation D67N ( ) < ( ) Presence of the RT mutation K70R ( ) < ( ) Presence of the RT mutation M184V ( ) < ( ) <0.001 Presence of the RT mutation K219Q 9.44 ( ) ( ) Exposure to NNRTIs: None NVP EFV 6.58 ( ) 6.95 ( ) <0.001 < ( ) 9.47 ( ) <0.001 <0.001 Age, male gender, baseline VL and CD4 cell count, other major NRTI DRM, presence or absence of LLVR, time to VS, time to LLVR, time to VF: not significant at univariate analysis

10 Variable Predictors of PI resistance Univariate analysis OR (95% CI) P value Multivariate analysis OR (95% CI) P value Calendar year of sequencing, +1 more recent 0.91 ( ) ( ) VL at LLVR, n (%) No LLVR <50 copies/ml 50 to 100 copies/ml 101 to 500 copies/ml 501 to 1000 copies/ml NRTI backbone: 3(F)TC/TDF ABC/3TC AZT/3TC D4T/DDI D4T/3TC Other 1.06 ( ) 1.24 ( ) 1.42 ( ) 0.56 ( ) 1.32 ( ) 2.54 ( ) 1.84 ( ) 1.45 ( ) ( ) 0.75 ( ) 0.65 ( ) 0.95 ( ) 0.80 ( ) 3.79 ( ) 0.75 ( ) 0.68 ( ) Presence of the RT mutation M41L ( ) < ( ) Presence of the RT mutation K65R 5.91 ( ) ( ) Presence of the RT mutation D67N 7.18 ( ) ( ) Presence of the RT mutation M184V 6.75 ( ) < ( ) Presence of the RT mutation T215F ( ) ( ) Presence of the RT mutation T215Y ( ) < ( ) Exposure to ritonavir-boosted IDV 3.46 ( ) ( ) Age, male gender, baseline VL and CD4 cell count, calendar year of sequencing, exposure to other PIr, other major NRTI DRM, presence or absence of LLVR, time to VS, time to LLVR, time to VF: not significant at univariate analysis

11 Conclusions LLVR are associated with an increased risk of resistance at subsequent virological failure, particularly to NNRTI and when NNRTI-based therapies are employed The type of backbone does not influence the risk of resistance after LLVR A closer virological monitoring is required with NNRTI-based regimens in case of LLVR

12 Acknowledgments Università Cattolica del S. Cuore Simona Di Giambenedetto Roberta Gagliardini Roberto Cauda Divisione Universitaria Mal. Infettive, Siena Andrea De Luca Dipartimento di biotecnologie, Università di Siena Maurizio Zazzi Genny Meini Università di Bergamo Franco Maggiolo Clinica Mal. Infettive, Università di Perugia Daniela Francisci Virologia, Università di Torino Valeria Ghisetti Ospedale S. Maria Annunziata, Firenze Massimo Di Pietro Ospedale S. Martino, Genova Antonio Di Biagio Virologia, Università di Modena Monica Pecorari Università di Genova Maurizio Setti Clinica Mal. Infettive, Modena Vanni Borghi Ospedale S. Raffaele, Milano Nicola Gianotti