AREVIR May 2012 Chris Verhofstede, Aids Reference Laboratory, Ghent University, Belgium
Maraviroc initiated in only a limited number of patients for whom tropism testing is requested (25.1% of the R5 predictions) Repeated requests for the same patient can be expected Validity in time of an R5 prediction? Mechanisms responsible for co ‐ receptor switch Presence of X4/DM virus is associated with a faster CD4 decline, faster disease progression, poorer response to ART X4/DM viruses can be transmitted – infection with X4/DM virus is associated with faster progression Added value of baseline tropism testing? Predict the chance for early tropism shift?
244 individuals newly diagnosed with HIV ‐ 1 between 2001 and 2009 in Ghent that had follow ‐ up samples available and remained treatment naive for at least 3 months (maximum 9 years).
Genotypic tropism testing on plasma RNA Prediction using Geno2pheno; FPR of 10% Singleton testing (repeated in triplicate in switching patients)
Results of X4/DM prevalence studies suggest a low prevalence of tropism switch 0.8% ‐ 15.9% X4/DM in recent infections 10% ‐ 18.9% X4/DM in chronic infections 31.4% ‐ 52% X4/DM in late stage disease
2 nd sample 2 nd sample R5 R5 175 (92.6%) 175 (92.6%) 1 st sample R5 1 st sample R5 189 (84.0%) 189 (84.0%) 2 nd sample 2 nd sample 225 225 X4 X4 (92.2%) (92.2%) 14 (7.4%) 14 (7.4%) succesfully succesfully 244 sequences 244 sequences patients patients 2 nd sample 2 nd sample X4 X4 1 st sample X4 1 st sample X4 33 (91.7%) 33 (91.7%) 36 (16.0%) 36 (16.0%) 2 nd sample 2 nd sample R5 R5 Technical Technical 3 (8.3%) 3 (8.3%) failures failures 19 (7.8%) 19 (7.8%)
Patient Date V3 FPR CD4 Viral load Patient 1: infection with X4 strain, super ‐ infection 6/04/2005 C T R P N N N T R R S I G I G P G K T F Y A T G D V I G D I R K A H C 2 6,8 658 61600 with R5 virus 12/08/2005 - - - - - - - - - - - - - - - - - -/Q - - - - - - - - - - - - - - - - - 11,5 466 65300 22/02/2006 - - - - - - - - - - - - - - - - - Q - - - - - - - - - - - - - -/R - Y - 12,5 407 10900 Patient Date V3 FPR CD4 Viral load 29/05/2007 - - - - - - - - - - - - - - - - - Q - - - - - - - - - - - - - X - Y - 17 242 12303 21/11/2008 C T R P G N N T R K S I H L G P G R A W Y T T G E V I G N P R K A H C 1 3,8 609 600 26/01/2009 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3,8 403 507 27/03/2009 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3,8 378 1418 18/06/2009 C T R P N N N T G K S I H L G P G R A F F V T G R I I G N I R Q A H C 3 7,4 711 37863 19/01/2010 - - - - X - - - - - - -/V -/N -/I - - - - -/V X - -/A - - - - - - -/D X - -/Q - - - 12 298 67799 19/10/2009 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 7,4 1080 91209 1/02/2010 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 7,4 764 19768 31/05/2010 - - - - - - - - - - - - - - - - - - - - - - - - - - - - -/D - - -/E - -/Y - 8,1 728 / 27/09/2010 - - - - -/S - - - - - - - - - - - - - - - - -/A - - - - - - D - - -/E - - - 15,4 538 8686 18/04/2011 - - - - - - - - - - - - - - - - - - - - - - - - - - - - D - - E - Y - 57,1 533 12939 Patients 2 and 3
R5/R5 R5/X4 p ‐ value n = 189 175 14 Age (yr) (n = 189) 175 14 Median (IQR) 40 (34 ‐ 46) 41 (31 ‐ 51) 0,788 Gender (n = 189) 175 14 Male 144 (82%) 11 (79%) 0,720 Female 31 (18%) 3 (21%) Race or ethnicity (n = 189) 175 14 Caucasian 145 (84%) 14 (100%) 0,228 Other 27 (16%) 0 (0%) Transmission route (n = 170) 158 12 Homosexual contact 109 (69%) 10 (84%) 0,514 Heterosexual contact 43 (27%) 1 (8%) 0,190 Other 6 (4%) 1 (8%) 0,407 Transmitted drug resistance (n = 189) 175 14 Yes 9 (5%) 0 (0%) 1,000 No 166 (95%) 14 (100%) Virus subtype (n = 189) 175 14 B 128 (75%) 11 (79%) 0,411 non B 43 (25%) 3 (21%) Follow ‐ up period , Mean (IQR), months (n = 189) 35 (19 ‐ 46) 31 (21 ‐ 38) 0,703
R5/R5 R5/X4 p ‐ value n = 189 175 14 CCR5 genotype (n = 184) 170 14 wt/wt 144 (85%) 13 (93%) 0,697 wt/ Δ 32 26 (15%) 1 (7%) Baseline CD4 + T cell count (cells/mm + ) (n = 178) 164 14 Median (IQR) 498 (365 ‐ 653) 491 (339 ‐ 590) 0,457 CD4 <350 36 (22%) 4 (29%) 0,496 CD4 between 350 and 500 47 (29%) 3 (21%) 0,520 CD4 >500 81 (49%) 7 (50%) 0,781 Baseline viral load (log cp/ml) (n = 186) 172 14 Median (IQR) 4,46 (3,95 ‐ 4,96) 4,43 (3,96 ‐ 4,77) 0,867 Therapy initiation (n = 189) 175 14 Yes 137 (78%) 14 (100%) 0,077 No 38 (22%) 0 (0%) Drug free period , Mean (IQR), months (n = 152) 32 (15 ‐ 44) 31 (21 ‐ 38) 0,947 Treatment initiation CD4 + T cell count (cells/mm + ) (n = 178) 164 14 Median (IQR) 360 (274 ‐ 482) 227 (159 ‐ 409) 0,015 Treatment initiation viral load (log cp/ml) (n = 183) 170 13 Median (IQR) 4,55 (3,84 ‐ 4,98) 4,81 (4,24 ‐ 5,07) 0,297 FPR at diagnosis (%) (n = 189) 175 14 Median (IQR) 59 (31 ‐ 81) 27 (15 ‐ 48) 0,001 FPR < 50 73 (42%) 12 (86%) 0,001 FPR > 50 102 (58%) 2 (14%)
Switch after 4y FPR 10% ‐ 25%: 28% FPR 25% ‐ 50%: 9.7% FPR 50% ‐ 75%: 7.1% FPR 75% ‐ 100%: 3.2%
Overall low rate of co ‐ receptor switch in ART ‐ naive individuals (17/225 ) Tropism shift is associated with need to initiate treatment during the study period and with a lower CD4 count at treatment initiation FPR of the baseline sample is highly predictive for R5 to X4/DM switch. Additional study needed to understand the mechanisms behind this No tropism shift in the first 2 years in naive patients with a baseline FPR >50% suggesting that in these patients the tropism result might remain valid for at least 2 years
ARL ARC Dirk Vogelaers, Linos Vandekerckhove Virginie Mortier, Jacqueline Reynaerts Bea Vandergucht, Jolanda Pelgrom Els Demecheleer, Delfien Staelens Filip Van Wanzeele, Steven Callens Marlies Schauvliege, Kenny Dauwe Erica Sermyn, Filip Moerman Leen Vancoillie, Kristen Chalmet Jean Plum
Recommend
More recommend
